MX2012003138A

Methods for treating psoriasis.

Abstract

The invention provides methods of treating psoriasis in a subject by administering to a subject an antibody capable of binding to the p40 subunit of IL- 12 and/or IL-23.

MX2012003138A, drawing sheet 1 — Sheet 1 of 352

Term

No projected expiry on record.

54 claims: 24 independent, 30 dependent

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CLAIMS REIVINDICACIONES 1. Un método para tratar la psoriasis en un sujeto que comprende administrar al sujeto una primera cantidad de dosis de one. A method of treating psoriasis in a subject comprising administering to the subject a first quantity of doses of 5 an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, according to a first periodicity, and administering a second quantity of antibody doses, or antigen binding portion thereof, at the same periodicity, thereby treating psoriasis in 5 un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, de acuerdo con una primera periodicidad, y administrar una segunda cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, a la misma periodicidad, para de tal modo tratando la psoriasis en 10 the subject. 10 el sujeto.
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A method of treating psoriasis in a subject comprising administering to the subject the first dose amount of an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL- 23 agree 2. Un método para tratar la psoriasis en un sujeto que comprende administrar al sujeto la primera cantidad de dosis de un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, de acuerdo 15 con una primera periodicidad, y administrar una segunda cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una segunda periodicidad, para de tal modo tratar la psoriasis en el sujeto. fifteen with a first periodicity, and administering a second amount of antibody dose, or antigen-binding portion thereof, according to a second periodicity, thereby treating psoriasis in the subject.
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15 periodicidad de administración del anticuerpo, o porción de unión al antígeno del mismo, es de aproximadamente una vez cada cuatro semanas. fifteen Periodicity of administration of the antibody, or antigen-binding portion thereof, is approximately once every four weeks. 15. El método de la reivindicación 2, en donde la primera periodicidad de administración del anticuerpo, o porción de unión fifteen. The method of claim 2, wherein the first periodicity of administration of the antibody, or binding portion 20 al antígeno del mismo, es de aproximadamente una vez por semana. twenty to its antigen, it is approximately once a week.
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24. The method of claiming duration of the first periodicity is weeks. 24. El método de la reivindicación duración de la primera periodicidad es de semanas.
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25. The method of claiming duration of the first periodicity is weeks. 25. El método de la reivindicación duración de la primera periodicidad es de semanas.
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26. The method of claiming duration of the first periodicity is weekly. 26. El método de la reivindicación duración de la primera periodicidad es de semana.
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27. The method of claiming duration of the second periodicity is weeks. 27. El método de la reivindicación duración de la segunda periodicidad es de semanas.
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28. The method of claiming duration of the second periodicity is weeks. 28. El método de la reivindicación duración de la segunda periodicidad es de semanas.
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29. The method of claiming duration of the second periodicity is weeks. 29. El método de la reivindicación duración de la segunda periodicidad es de semanas.
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30. The method of claiming duration of the second periodicity is weeks. 30. El método de la reivindicación duración de la segunda periodicidad es de semanas.
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31. The method of claiming duration of the second periodicity is 31. El método de la reivindicación duración de la segunda periodicidad es de 1 ó 2, en donde la aproximadamente 4 one or 2, where approximately 4 1 ó 2, en donde la aproximadamente 2 one or 2, where approximately 2 1 ó 2, en donde la aproximadamente 1 one or 2, where approximately 1 1 ó 2, en donde la aproximadamente 60 one or 2, where the approximately 60 1 ó 2, en donde la aproximadamente 44 one or 2, where approximately 44 1 ó 2, en donde la aproximadamente 12 one or 2, where approximately 12 1 ó 2, en donde la aproximadamente 4 one or 2, where approximately 4 1 ó 2, en donde la aproximadamente 2 semanas one or 2, where the approximately 2 weeks 517 517 about 12 weeks. aproximadamente 12 semanas.
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41. The method of any of claims 38-40, wherein the loss of PASI response is the loss of the 41. El método de cualquiera de las reivindicaciones 38-40, en donde la pérdida de respuesta de PASI es la pérdida de la 5 PASI response from a single region of the body. 5 respuesta de PASI de una sola región del cuerpo.
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42. The method of any of claims 38-40, wherein the loss of PASI response is the loss of PASI response from two regions of the body. 42. El método de cualquiera de las reivindicaciones 38-40, en donde la pérdida de respuesta de PASI es la pérdida de respuesta de PASI de dos regiones del cuerpo.
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43. The method of any of claims 38-40, 10 wherein the loss of PASI response is the loss of PASI response from three regions of the body. 43. El método de cualquiera de las reivindicaciones 38-40, 10 en donde la pérdida de respuesta de PASI es la pérdida de respuesta de PASI de tres regiones del cuerpo.
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44. The method of any of claims 38-40, wherein the loss of PASI response is the loss of PASI response from four regions of the body. 44. El método de cualquiera de las reivindicaciones 38-40, en donde la pérdida de respuesta de PASI es la pérdida de respuesta de PASI de cuatro regiones del cuerpo. 15 15
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45. El método de cualquiera de las reivindicaciones 41-44, en donde la región del cuerpo se selecciona del grupo que consiste del torso, extremidades inferiores, extremidades superiores, y cabeza y cuello. Four. Five. The method of any of claims 41-44, wherein the body region is selected from the group consisting of the torso, lower extremities, upper extremities, and head and neck.
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51. The method of any of claims 1-50, wherein the antibody is administered subcutaneously. 51. El método de cualquiera de las reivindicaciones 1-50, en donde el anticuerpo se administra de manera subcutánea.
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52. A method of treating psoriasis in a subject comprising administering to the subject an antibody, or binding portion 52. Un método para tratar la psoriasis en un sujeto que comprende administrar al sujeto un anticuerpo, o porción de unión 10 to the antigen thereof, which is capable of binding to the p40 subunit of IL-12 and / or IL-23, according to a periodicity of about once every 4 weeks, to thereby treat psoriasis in the subject. 10 al antigeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, de acuerdo con una periodicidad de aproximadamente una vez cada 4 semanas, para de tal modo tratar la psoriasis en el sujeto.
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53. A method of treating psoriasis in a subject who 53. Un método para tratar la psoriasis en un sujeto que 15 comprende administrar al sujeto un anticuerpo, o porción de unión al antigeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, de acuerdo con una periodicidad de aproximadamente una vez de cada 12 semanas, para de tal modo tratar la psoriasis en el sujeto. fifteen comprises administering to the subject an antibody, or antigen binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, according to a periodicity of about once every 12 weeks, to thereby treat psoriasis in the subject. 20 20
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5 4. A method of treating psoriasis in a subject comprising administering to the subject:5 4. Un método para tratar la psoriasis en un sujeto que comprende la administración al sujeto de: a) a first dose amount of an antibody, or antigen binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23;and a) una primera cantidad de dosis de un anticuerpo, o porción de unión al antigeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23;y 25 b) a second quantity of dose that is 25 b) una segunda cantidad de dosis que es de 520 about 40-60% of the first amount of antibody dose, or antigen-binding portion thereof, according to a periodicity of about once every 12 weeks, 520 aproximadamente 40-60% de la primera cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una periodicidad de aproximadamente una vez de cada 12 semanas, 5 to thereby treat psoriasis in the subject. 5 para de tal modo tratar la psoriasis en el sujeto.
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55. The method of any of claims 52-54, wherein the subject reaches at least a PGA count of 0 or 55. El método de cualquiera de las reivindicaciones 52-54, en donde el sujeto alcanza por lo menos un conteo de PGA de 0 ó 1. 1.
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56. The method of any of claims 52-54, IO wherein the subject achieves at least one PASI response 56. El método de cualquiera de las reivindicaciones 52-54, IO en donde el sujeto alcanza por lo menos una respuesta de PASI 75. 75.
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57. The method of any of claims 52-54, wherein the subject achieves at least one PASI response. 57. El método de cualquiera de las reivindicaciones 52-54, en donde el sujeto alcanza por lo menos una respuesta de PASI 90. 90. I5 58. El método de cualquiera de las reivindicaciones 52-54, en donde el sujeto alcanza por lo menos una respuesta de PASI I5 58. The method of any of claims 52-54, wherein the subject achieves at least one PASI response 100. 100. maintains PASI 90 response for at least 4 mantiene la respuesta de PASI 90 durante por lo menos 4 521 weeks. 521 semanas. 62. The method of any of claims 52-61, wherein the first dose amount is at least about 200 mg. 62. El método de cualquiera de las reivindicaciones 52-61, en donde la primera cantidad de dosis es de por lo menos aproximadamente 200 mg. 5 63. The method of any of claims 52-61, wherein the second dose amount is at least about 100 mg. 5 63. El método de cualquiera de las reivindicaciones 52-61, en donde la segunda cantidad de dosis es de por lo menos aproximadamente 100 mg. 64. A method of treating psoriasis in a subject comprising administering to the subject:64. Un método para tratar la psoriasis en un sujeto que comprende la administración al sujeto de: 10 a) a first dose amount of an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, according to a first periodicity of about once every 4 weeks;and 10 a) una primera cantidad de dosis de un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, de acuerdo con una primera periodicidad de aproximadamente una vez cada 4 semanas;y b) a second quantity of dose that is b) una segunda cantidad de dosis que es de 15 aproximadamente 40-60% de la primera cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una segunda periodicidad de aproximadamente una vez cada 4 semanas, para de tal modo tratar la psoriasis en el sujeto. fifteen approximately 40-60% of the first antibody dose amount, or antigen-binding portion thereof, according to a second periodicity of approximately once every 4 weeks, to thereby treat psoriasis in the subject. 20 6 5. El método de la reivindicación 64, en donde la primera cantidad de dosis es de por lo menos aproximadamente 200 mg. twenty The method of claim 64, wherein the first dose amount is at least about 200 mg. 66. The method of claim 64, wherein the second dose amount is at least about 100 mg. 66. El método de la reivindicación 64, en donde la segunda cantidad de dosis es de por lo menos aproximadamente 100 mg. 67. The method of claim 64, wherein the 67. El método de la reivindicación 64, en donde la 25 duration of the first periodicity is at least 25 duración de la primera periodicidad es de por lo menos 522 approximately 8 weeks. 522 aproximadamente 8 semanas. approximately 16 weeks. aproximadamente 16 semanas. 10 approximately 44 weeks. 10 aproximadamente 44 semanas. 71. A method of treating psoriasis in a subject comprising administering to the subject: 71. Un método para tratar la psoriasis en un sujeto que comprende la administración al sujeto de: a) a first dose amount of an antibody, or antigen-binding portion thereof, that is capable of binding to the a) una primera cantidad de dosis de un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la I5 p40 subunit of IL-12 and / or IL-23, according to a first periodicity of approximately once every 4 weeks;and I5 subunidad p40 de IL-12 y/o IL-23, de acuerdo con una primera periodicidad de aproximadamente una vez cada 4 semanas;y b) a second dose amount that is approximately 40-60% of the first dose dose of antibody, or antigen-binding portion thereof, according b) una segunda cantidad de dosis que es de aproximadamente 40-60% de la primera cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo 20 con una segunda periodicidad de aproximadamente una vez cada 4 semanas;y twenty with a second periodicity of approximately once every 4 weeks;and c) a second amount of antibody dose, or antigen-binding portion thereof, according to a third periodicity of about once in 12 c) una segunda cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una tercera periodicidad de aproximadamente una vez de cada 12 25 weeks, 25 semanas, 523 to thereby treat psoriasis in the subject. 523 para de tal modo tratar la psoriasis en el sujeto. 72. The method of claim 71, wherein the first dose amount is at least about 200 mg. 72. El método de la reivindicación 71, en donde la primera cantidad de dosis es de por lo menos aproximadamente 200 mg. 73. The method of claim 71, wherein the second dose amount is at least about 100 mg. 73. El método de la reivindicación 71, en donde la segunda 5 cantidad de dosis es de por lo menos aproximadamente 100 mg. about 4 weeks. aproximadamente 4 semanas. approximately 36 weeks. aproximadamente 36 semanas. 78. The method of any of claims 64-77, wherein the subject achieves a PGA count of 0 or 1. 78. El método de cualquiera de las reivindicaciones 64-77, en donde el sujeto alcanza un conteo de PGA de 0 ó 1. 20 7 9. El método de cualquiera de las reivindicaciones 64-77, en donde el sujeto alcanza por lo menos una respuesta de PASI twenty 7 9. The method of any of claims 64-77, wherein the subject achieves at least one PASI response 75. 75. 80. The method of any of claims 64-77, wherein the subject achieves at least one PASI response. 80. El método de cualquiera de las reivindicaciones 64-77, en donde el sujeto alcanza por lo menos una respuesta de PASI 25 90. 25 90. 524 524 81. The method of any of claims 64-77, wherein the subject achieves at least one PASI response. 81. El método de cualquiera de las reivindicaciones 64-77, en donde el sujeto alcanza por lo menos una respuesta de PASI 100. 100. maintains a PASI 90 response for at least 4 weeks. mantiene una respuesta de PASI 90 durante por lo menos 4 semanas. 85. A method of treating psoriasis in a subject population, comprising administering to each subject in the population. 85. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población 15 un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 60% de la población de sujetos alcanzan una respuesta de PASI 75 en aproximadamente la semana 12. fifteen an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 60% of the subject population achieve a PASI 75 response in about week 12. 86. A method of treating psoriasis in a population of 86. Un método para tratar la psoriasis en una población de 20 sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 25% de la población de sujetos alcanzan una respuesta de PASI 90 en aproximadamente la semana 12. twenty subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, wherein at least 25% of the population of subjects reach a PASI 90 response at approximately week 12. 25 8 7. A method of treating psoriasis in a population of 25 8 7. Un método para tratar la psoriasis en una población de 525 subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, wherein at least 10% of subject population achieve a response 525 sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 10% de la población de sujetos alcanzan una respuesta 5 of PASI 100 in approximately week 12. 5 de PASI 100 en aproximadamente la semana 12. 88. The method of any of claims 85-87, comprising administering to each subject in the population: 88. El método de cualquiera de las reivindicaciones 85-87, que comprende la administración a cada sujeto en la población de: a) a first quantity of antibody dose, or antigen-binding portion io thereof, according to a first periodicity of about once every 4 weeks;and a) una primera cantidad de dosis de anticuerpo, o porción io de unión al antígeno del mismo, de acuerdo con una primera periodicidad de aproximadamente una vez cada 4 semanas;y b) administer a second dose amount that is approximately 40-60% of the first dose dose of antibody, or antigen-binding portion thereof, according b) administrar una segunda cantidad de dosis que es de aproximadamente 40-60% de la primera cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo 15 con una segunda periodicidad de aproximadamente una vez cada fifteen with a second periodicity of approximately once every 4 weeks. 4 semanas. 89. The method of any of claims 85-87, comprising administering to each subject in the population: 89. El método de cualquiera de las reivindicaciones 85-87, que comprende la administración a cada sujeto en la población de: 20 a) una primera cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una primera periodicidad de aproximadamente una vez cada 4 semanas;y twenty a) a first amount of antibody dose, or antigen-binding portion thereof, according to a first periodicity of about once every 4 weeks;and b) a second dose amount that is approximately 40-60% of the first dose amount of b) una segunda cantidad de dosis que es de aproximadamente 40-60% de la primera cantidad de dosis de 25 antibody, or antigen-binding portion thereof, according 25 anticuerpo, o porción de unión al antígeno del mismo, de acuerdo 526 with a second periodicity of approximately once every 4 weeks;and 526 con una segunda periodicidad de aproximadamente una vez cada 4 semanas;y c) a second amount of antibody dose, or antigen-binding portion thereof, according to a c) una segunda cantidad de dosis de anticuerpo, o porción de unión ai antígeno del mismo, de acuerdo con una 5 third periodicity of about once every 12 weeks. 5 tercera periodicidad de aproximadamente una vez de cada 12 semanas. 90. The method of any of claims 52-89, wherein the psoriasis is moderate to severe or chronic psoriasis. 90. El método de cualquiera de las reivindicaciones 52-89, en donde la psoriasis es psoriasis moderada a severa o crónica. 91. The method of any of claims 52-89, 10 wherein the psoriasis is plaque psoriasis. 91. El método de cualquiera de las reivindicaciones 52-89, 10 en donde la psoriasis es psoriasis en placas. 92. The method of any of claims 52-89, wherein the antibody is administered subcutaneously. 92. El método de cualquiera de las reivindicaciones 52-89, en donde el anticuerpo se administra de manera subcutánea. 93. The method of any of claims 52-89, wherein the antibody is a human antibody. 93. El método de cualquiera de las reivindicaciones 52-89, en donde el anticuerpo es un anticuerpo humano. 15 94. El método de cualquiera de las reivindicaciones 52-87, en donde el anticuerpo es ABT-874. fifteen 94. The method of any of claims 52-87, wherein the antibody is ABT-874. 95. The method of any of the preceding claims, wherein the subject or subject population achieves at least one PASI 75 response in approximately the 95. El método de cualquiera de las reivindicaciones anteriores, en donde el sujeto o población de sujetos alcanza por lo menos una respuesta de PASI 75 en aproximadamente la 20 semana 24. twenty week 24. 96. The method of any of the preceding claims, wherein the subject or subject population achieves at least one PASI 75 response at approximately week 52. 96. El método de cualquiera de las reivindicaciones anteriores, en donde el sujeto o población de sujetos alcanza por lo menos una respuesta de PASI 75 en aproximadamente la semana 52. 25 9 7. The method of any one of the claims 25 9 7. El método de cualquiera de las reivindicaciones 527 above, where the subject or population of subjects reaches at least a PGA count of 0 or 1 in approximately week 24. 527 anteriores, en donde el sujeto o población de sujetos alcanza por lo menos un conteo de PGA de 0 ó 1 en aproximadamente la semana 24. 98. The method of any of the claims 98. El método de cualquiera de las reivindicaciones 5 above, where the subject or subject population reaches at least a PGA count of 0 or 1 in approximately week 52. 5 anteriores, en donde el sujeto o población de sujetos alcanza por lo menos un conteo de PGA de 0 ó 1 en aproximadamente la semana 52. 99. A method of treating psoriasis in a subject population, comprising administering to each subject in the io population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 41% of the subject population achieve at least a PASI 75 response in approximately week 24. 99. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población io un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 41% de la población de sujetos alcanzan por lo menos una respuesta de PASI 75 en aproximadamente la semana 24. 100. A method of treating psoriasis in a population of 100. Un método para tratar la psoriasis en una población de 15 sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 35% de la población de sujetos alcanzan por lo menos un conteo de PGA de 0 ó 1 en aproximadamente la semana 24. fifteen subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, wherein at least 35% of the subject population achieve at least a PGA count of 0 or 1 at approximately week 24. 20 101. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 25% de la población de sujetos alcanzan por lo menos twenty 101. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 25% of the population of subjects reach at least 25 a PASI 75 response in approximately week 52. 25 una respuesta de PASI 75 en aproximadamente la semana 52. 528 528 102. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where by 102. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 5 at least 21% of the subject population achieve at least a PGA count of 0 or 1 in approximately week 52. 5 lo menos 21% de la población de sujetos alcanzan por lo menos un conteo de PGA de 0 ó 1 en aproximadamente la semana 52. 103. The method of any of the preceding claims, wherein the subject or subject population achieves an improvement of a count of the dermatological quality of life index io (DLQI) or average count of the dermatological quality of life index (DLQI) of at least minus about -9. 103. El método de cualquiera de las reivindicaciones anteriores, en donde el sujeto o población de sujetos alcanza una mejora de un conteo del índice de calidad de vida dermatológico io (DLQI) o conteo promedio del índice de calidad de vida dermatológico (DLQI) de por lo menos aproximadamente -9. 104. The method of any of the preceding claims, wherein the subject or subject population achieves an improvement of a count of the short form 36 of synopsis of 104. El método de cualquiera de las reivindicaciones anteriores, en donde el sujeto o población de sujetos alcanza una mejora de un conteo de la forma corta 36 de sinopsis de 15 componente físico de estudio de salud (PCS) o conteo promedio de la forma corta 36 de sinopsis de componente físico de estudio de salud (PCS) de por lo menos aproximadamente 2. fifteen physical component of health study (PCS) or average count of the short form 36 of physical component of health study (PCS) synopsis of at least approximately 2. 105. The method of any of the preceding claims, wherein the subject or population of subjects achieves a 105. El método de cualquiera de las reivindicaciones anteriores, en donde el sujeto o población de sujetos alcanza una 20 mejora de un conteo de la forma corta 36 de sinopsis de componente mental de estudio de salud (MCS) o conteo promedio de la forma corta 36 de sinopsis de componente mental de estudio de salud (MCS) de por lo menos aproximadamente 4. twenty improvement of a short form 36 count of health study mental component (MCS) synopsis or average count of 36 short form of health study mental component (MCS) synopsis of at least approximately 4. 106. The method of any of the claims 106. El método de cualquiera de las reivindicaciones 25 previous, where the subject or population of subjects reaches a 25 anteriores, en donde el sujeto o población de sujetos alcanza una 529 improvement of a visual analog scale count or visual analog scale mean count for psoriasis-related pain (VAS-Ps) of at least about -25. 529 mejora de un conteo de escala análoga visual o conteo de promedio de escala análoga visual para el dolor relacionada con la psoriasis (VAS-Ps) de por lo menos aproximadamente -25. 107. The method of any of the claims 107. El método de cualquiera de las reivindicaciones 5 above, where the subject or subject population achieves an improvement of a visual analog scale count for pain related to psoriatic arthritis (VAS-PsA) or average visual analog scale count for pain related to psoriatic arthritis (VAS -PSA) of at least approximately 5 anteriores, en donde el sujeto o población de sujetos alcanza una mejora de un conteo de escala análoga visual para el dolor relacionado con la artritis psoriásica (VAS-PsA) o conteo promedio de escala análoga visual para el dolor relacionado con la artritis psoriásica (VAS-PsA) de por lo menos aproximadamente 10 -32. 10 -32. 108. A method of treating psoriasis in a population of subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL- 23, where the 108. Un método para tratar la psoriasis en una población de sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde la I5 población de sujetos alcanza una velocidad de respuesta de ia mínima diferencia clínicamente importante (MCID) para el dolor relacionado con la psoriasis (VAS-Ps) de por lo menos aproximadamente 60%. The subject population achieves a minimally clinically important difference (MCID) response speed for psoriasis-related pain (VAS-Ps) of at least approximately 60%. 109. A method of treating psoriasis in a population of 109. Un método para tratar la psoriasis en una población de 20 sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde la población de sujetos alcanza una velocidad de respuesta de la mínima diferencia clínicamente importante (MCID) para el índice twenty subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where the population of subjects reaches a response rate of the least clinically important difference (MCID) for the index 25 quality of life (DLQI) of at least 25 de calidad de vida dermatológico (DLQI) de por lo menos 530 about 70% in about week 12. 530 aproximadamente 70% en aproximadamente la semana 12. 110. A method of treating psoriasis in a population of subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, which is 110. Un método para tratar la psoriasis en una población de sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es 5 capable of binding to the p40 subunit of IL-12 and / or IL-23, where the population of subjects achieves a response speed of the least clinically important difference (MCID) for the dermatological quality of life index (DLQI) of at least about 81% in about week 52. 5 capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde la población de sujetos alcanza una velocidad de respuesta de la mínima diferencia clínicamente importante (MCID) para el índice de calidad de vida dermatológico (DLQI) de por lo menos aproximadamente 81% en aproximadamente la semana 52. 10 111. A method of treating psoriasis in a population of subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where the population of subjects reaches a response speed of 10 111. Un método para tratar la psoriasis en una población de sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde la población de sujetos alcanza una velocidad de respuesta de la 15 mínima diferencia clínicamente importante (MCID) para el deterioro de actividad total (TAI) de por lo menos aproximadamente 45% en aproximadamente la semana 12. fifteen Minimum Clinically Important Difference (MCID) for Total Activity Impairment (TAI) of at least approximately 45% at approximately week 12. 112. A method of treating psoriasis in a subject population comprising administering to each subject in the population. 112. Un método para tratar la psoriasis en una población de sujetos que comprende administrar a cada sujeto en la población 20 un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde la población de sujetos alcanza una velocidad de respuesta de la mínima diferencia clínicamente importante (MCID) para el deterioro de actividad total (TAI) de por lo menos twenty an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where the subject population achieves a response speed of the least clinically important difference ( MCID) for total activity impairment (TAI) of at least 25 about 57% in about week 52. 25 aproximadamente 57% en aproximadamente la semana 52. 531 531 113. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where by 113. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antigeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 5 at least 65% of the population of subjects achieve at least a PGA 0/1 response at approximately week 12, where each subject was treated with a biologic prior to administration of the antibody. 5 lo menos 65% de la población de sujetos alcanzan por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 12, en donde cada sujeto se trató con un biológico antes de la administración del anticuerpo. 114. A method of treating psoriasis in a population of io subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 74% of the subject population reaches at least one PASI 75 response in approximately week 12, in 114. Un método para tratar la psoriasis en una población de io sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antigeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 74% de la población de sujetos alcanza por lo menos una respuesta de PASI 75 en aproximadamente la semana 12, en 15 donde cada sujeto se trató con un biológico antes de la administración del anticuerpo. fifteen where each subject was treated with a biological before the administration of the antibody. 115. A method of treating psoriasis in a subject population, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, which is 115. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antigeno del mismo, que es 20 capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 78% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 12, en donde ninguno de los sujetos se trató con un biológico antes de la administración del anticuerpo. twenty capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 78% of the subject population achieves at least a PGA 0/1 response at approximately week 12, where none of the subjects was treated with a biological before administration of the antibody. 25 116. A method of treating psoriasis in a population of 25 116. Un método para tratar la psoriasis en una población de 532 subjects, which comprises administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 82% of the subject population reaches at least 532 sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 82% de la población de sujetos alcanza por lo menos 5 a PASI 75 response at approximately week 12, where none of the subjects were treated with a biologic prior to administration of the antibody. 5 una respuesta de PASI 75 en aproximadamente la semana 12, en donde ninguno de los sujetos se trató con un biológico antes de la administración del anticuerpo. 117. A method of treating psoriasis in a subject population, comprising administering to each subject in the io population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 78% of the subject population reaches at least a PGA 0/1 response at approximately week 52, where each subject was treated with a biologic prior to 117. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población io un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 78% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 52, en donde cada sujeto se trató con un biológico antes de la 15 administración del anticuerpo. fifteen administration of the antibody. 118. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where by 118. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 20 lo menos 79% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 52, en donde ninguno de los sujetos se trató con un biológico antes de la administración del anticuerpo. twenty at least 79% of the subject population achieves at least a PGA 0/1 response at approximately week 52, where none of the subjects were treated with a biologic prior to administration of the antibody. 119. A method of treating psoriasis in a population of 119. Un método para tratar la psoriasis en una población de 25 subjects, which comprises administering to each subject in the population 25 sujetos, que comprende administrar a cada sujeto en la población 533 an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 71% of the subject population achieves at least one response PGA 0/1 in approximately week 12, 533 un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 71% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 12, en 5 where each subject has a previous history of psoriatic arthritis. 5 donde cada sujeto tiene un historial anterior de artritis psoriásica. 120. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where by 120. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 10 at least 78% of the subject population reaches at least a PASI 75 response in approximately week 12, where each subject has a prior history of psoriatic arthritis. 10 lo menos 78% de la población de sujetos alcanza por lo menos una respuesta de PASI 75 en aproximadamente la semana 12, en donde cada sujeto tiene un historial anterior de artritis psoriásica. 121. A method of treating psoriasis in a subject population, comprising administering to each subject in the population. 121. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población 15 un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 77% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 12, en donde ninguno de los sujetos tiene un historial anterior de artritis fifteen an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 77% of the subject population achieves at least one response PGA 0/1 at approximately week 12, where none of the subjects has a prior history of arthritis 20 psoriásica. twenty psoriatic. 122. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where by 122. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 25 at least 81% of the subject population reaches at least 25 lo menos 81% de la población de sujetos alcanza por lo menos 534 a PASI 75 response at approximately week 12, where none of the subjects has a prior history of psoriatic arthritis. 534 una respuesta de PASI 75 en aproximadamente la semana 12, en donde ninguno de los sujetos tiene un historial anterior de artritis psoriásica. 123. A method of treating psoriasis in a population of 123. Un método para tratar la psoriasis en una población de 5 subjects, which comprises administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 77% of the subject population achieves at least a PGA 0/1 response at approximately week 52, in 5 sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 77% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 52, en 10 where each subject has a previous history of psoriatic arthritis. 10 donde cada sujeto tiene un historial anterior de artritis psoriásica. 124. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where by 124. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 15 lo menos 79% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 52, en donde ninguno de los sujetos tienen un historial anterior de artritis psoriásica. fifteen at least 79% of the subject population achieves at least a PGA 0/1 response at approximately week 52, where none of the subjects have a prior history of psoriatic arthritis. 125. A method of decreasing the risk that a subject 125. Un método para disminuir el riesgo de que un sujeto 20 tratado con un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL23, desarrolle un acontecimiento cardiovascular adverso importante, que comprende: twenty treated with an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL23, develops a major adverse cardiovascular event, comprising: (a) seleccionar un sujeto que tiene menos de 2 factores de (a) select a subject who has less than 2 factors of 25 risk selected from the group consisting of (i) an index of 25 riesgo seleccionados del grupo que consiste de (i) un índice de 535 body mass over 30, (i¡) a history of diabetes mellitus, (iii) blood pressure greater than 140/90, (iv) a history of myocardial infarction, (v) a history of angina requiring hospitalization, ( vi) a history of coronary artery disease 535 masa corporal de mayor de 30, (i¡) un historial de diabetes mellitus, (iii) presión arterial mayor de 140/90, (iv) un historial de infarto de miocardio, (v) un historial de angina que requiere hospitalización, (vi) un historial de enfermedad arterial coronaria 5 requiring revascularization, (vii) a history of peripheral artery disease, (viii) a history of congestive heart failure requiring hospitalization, (ix) a history of stroke or transient ischemic attack;and (b) administering the antibody, or antigen-binding portion thereof, to the selected subject, thereby decreasing the risk of the subject developing significant adverse cardiovascular events. 5 que requiere revascularización, (vii) un historial de enfermedad de arteria periférica, (viii) un historial de falla cardíaca congestiva que requiere hospitalización, (ix) un historial de accidente cerebrovascular o ataque isquémico transitorio;y (b) administrar el anticuerpo, o porción de unión al lo antígeno del mismo al sujeto seleccionado, para de tal modo disminuir el riesgo de que el sujeto desarrolle acontecimientos cardiovasculares adversos importantes. 126. The method of claim 125, wherein the 126. El método de la reivindicación 125, en donde el 15 anticuerpo es ABT-874. fifteen Antibody is ABT-874. 127. The method of claim 125 or 126, wherein the subject has 1 risk factor. 127. El método de la reivindicación 125 ó 126, en donde el sujeto tiene 1 factor de riesgo. 128. The method of claim 125 or 126, wherein the subject has 0 risk factors. 128. El método de la reivindicación 125 ó 126, en donde el sujeto tiene 0 factores de riesgo. 20 1 29. El método de cualquiera de las reivindicaciones anteriores, en donde el MACE es infarto de miocardio. twenty 1 29. The method of any of the preceding claims, wherein the MACE is myocardial infarction. 130. The method of any of claims 125128, wherein the MACE is stroke. 130. El método de cualquiera de las reivindicaciones 125128, en donde el MACE es accidente cerebrovascular. 131. The method of any one of the preceding claims 25, wherein the antibody, or antigen-binding portion 131. El método de cualquiera de las reivindicaciones 25 anteriores, en donde el anticuerpo, o porción de unión al antígeno 536 thereof, it is administered in a first dose amount of at least about 100 mg to about 200 mg. 536 del mismo, se administra en una primera cantidad de dosis de por lo menos aproximadamente 100 mg a aproximadamente 200 mg. 132. The method of any of the preceding claims, wherein the antibody, or antigen-binding portion 132. El método de cualquiera de las reivindicaciones anteriores, en donde el anticuerpo, o porción de unión al antígeno 5 thereof, it is administered in a second dose amount of at least about 100 mg to about 200 mg. 5 del mismo, se administra en una segunda cantidad de dosis de por lo menos aproximadamente 100 mg a aproximadamente 200 mg. 133. The method of claim 132, wherein the risk factors are reassessed before 133. El método de la reivindicación 132, en donde los factores de riesgo se evalúan nuevamente antes de la 10 administration of the second amount of dose to the subject. 10 administración de la segunda cantidad de dosis al sujeto. 134. The method of any of claims 52-54 and 64-77, wherein the subject achieves at least a 50% reduction in the PASI count. 134. El método de cualquiera de las reivindicaciones 52-54 y 64-77, en donde el sujeto alcanza por lo menos una reducción de 50% del conteo de PASI. 135. The method of any of claims 52-54 135. El método de cualquiera de las reivindicaciones 52-54 15 y 64-77, en donde el sujeto alcanza por lo menos una reducción de 80% del conteo de PASI. fifteen and 64-77, where the subject achieves at least an 80% reduction in the PASI count. 136. A method of treating psoriasis in a subject population, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, which is 136. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es 20 capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 69% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 12, en donde cada sujeto tuvo un PASI de línea base mayor de 20 antes de la administración del anticuerpo. twenty capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 69% of the subject population achieves at least a PGA 0/1 response at approximately week 12, where each Subject had a baseline PASI greater than 20 prior to administration of the antibody. 25 1 37. A method of treating psoriasis in a population of 25 1 37. Un método para tratar la psoriasis en una población de 537 subjects, which comprises administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 79% of the subject population reaches at least 537 sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 79% de la población de sujetos alcanza por lo menos 5 a PGA 0/1 response at approximately week 12, where each subject had a baseline PASI of Less than or equal to 20 prior to administration of the antibody. 5 una respuesta de PGA 0/1 en aproximadamente la semana 12, en donde cada sujeto tuvo un PASI de línea base Inferior o Igual a 20 antes de la administración del anticuerpo. 138. A method of treating psoriasis in a subject population, comprising administering to each subject in the population. 138. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población 10 an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 79% of the subject population achieves at least one response of PASI 75 in approximately week 12, where each subject had a baseline PASI greater than 20 before 10 un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 79% de la población de sujetos alcanza por lo menos una respuesta de PASI 75 en aproximadamente la semana 12, en donde cada sujeto tuvo un PASI de línea base mayor de 20 antes 15 de la administración del anticuerpo. fifteen of the administration of the antibody. 139. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where by 139. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 20 lo menos 81% de la población de sujetos alcanza por lo menos una respuesta de PASI 75 en aproximadamente la semana 12, en donde cada sujeto tuvo un PASI de línea base inferior o igual a 20 antes de la administración del anticuerpo. twenty at least 81% of the subject population reaches at least a PASI 75 response in approximately week 12, where each subject had a baseline PASI of less than or equal to 20 prior to administration of the antibody. 140. A method of treating psoriasis in a population of 140. Un método para tratar la psoriasis en una población de 25 subjects, which comprises administering to each subject in the population 25 sujetos, que comprende administrar a cada sujeto en la población 538 an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 67% of the subject population achieves at least one response PGA 0/1 in approximately week 12, 538 un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 67% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 12, en 5 where each subject had a baseline weight of greater than or equal to 100 kg prior to administration of the antibody. 5 donde cada sujeto tuvo un peso de línea base de mayor o igual a 100 kg antes de la administración del anticuerpo. 141. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, which is 141. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en ia población un anticuerpo, o porción de unión al antígeno del mismo, que es 10 capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 80% of the subject population achieves at least a PGA 0/1 response at approximately week 12, where each subject had a baseline weight of less than 100 kg prior to administration of the antibody. 10 capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 80% de la población de sujetos alcanza por lo menos una respuesta de PGA 0/1 en aproximadamente la semana 12, en donde cada sujeto tuvo un peso de la línea base de menos de 100 kg antes de la administración del anticuerpo. 15 142. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 72% de la población de sujetos alcanza por lo menos fifteen 142. A method of treating psoriasis in a subject population, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 72% of the subject population reaches at least 20 una respuesta de PASI 75 en aproximadamente la semana 12, en donde cada sujeto tuvo un peso de línea base mayor o igual a 100 kg antes de la administración del anticuerpo. twenty a PASI 75 response at approximately week 12, where each subject had a baseline weight of greater than or equal to 100 kg prior to administration of the antibody. 143. A method of treating psoriasis in a subject population, comprising administering to each subject in the population. 143. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población 25 an antibody, or antigen-binding portion thereof, which is 25 un anticuerpo, o porción de unión al antígeno del mismo, que es 539 capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 85% of the subject population achieves at least one PASI 75 response at approximately week 12, where each subject had a baseline weight of less than 100 539 capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 85% de la población de sujetos alcanza por lo menos una respuesta de PASI 75 en aproximadamente la semana 12, en donde cada sujeto tuvo un peso de línea base de menos de 100 5 kg before administration of the antibody. 5 kg antes de la administración del anticuerpo. 144. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where at least 41% of the population of subjects maintains at least a PGA 0/1 response through at least week 52 of treatment. 144. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por io lo menos 41% de la población de sujetos mantiene por lo menos una respuesta de PGA 0/1 a través de por lo menos la semana 52 de tratamiento. 145. A method of treating psoriasis in a subject population, comprising administering to each subject in the population. 145. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población 15 un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 79% de la población de sujetos mantiene por lo menos una respuesta de PGA 0/1 a través de por lo menos la semana 52 de tratamiento. fifteen an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 79% of the subject population maintains at least one response PGA 0/1 through at least week 52 of treatment. 20 146. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 45% de la población de sujetos mantiene por lo menos twenty 146. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 45% of the subject population maintains at least 25 a PASI 75 response through at least week 52 25 una respuesta de PASI 75 a través de por lo menos la semana 52 540 of treatment. 540 de tratamiento. 147. A method of treating psoriasis in a subject population, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, which is 147. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es 5 capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 82% of the subject population maintains at least one PASI 75 response through at least week 52 of treatment . 5 capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 82% de la población de sujetos mantiene por lo menos una respuesta de PASI 75 a través de por lo menos la semana 52 de tratamiento. 148. A method of treating psoriasis in a population of io subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 23% of the subject population maintains at least one PASI 75 response through at least week 52 148. Un método para tratar la psoriasis en una población de io sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 23% de la población de sujetos mantiene por lo menos una respuesta de PASI 75 a través de por lo menos la semana 52 15 de tratamiento. fifteen of treatment. 149. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where by 149. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 20 lo menos 63% de la población de sujetos mantiene por lo menos una respuesta de PASI 75 a través de por lo menos la semana 52 de tratamiento. twenty at least 63% of the subject population maintains at least one PASI 75 response through at least week 52 of treatment. 150. The method of any of claims 144, 146 and 148, comprising administering to each subject in the 150. El método de cualquiera de las reivindicaciones 144, 146 y 148, que comprende la administración a cada sujeto en la 25 population of: 25 población de: 541 541 a) a first amount of antibody dose, or antigen-binding portion thereof, according to a first periodicity of about once every 4 weeks;and a) una primera cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una primera periodicidad de aproximadamente una vez cada 4 semanas;y b) a second dose amount that is approximately 40-60% of the first antibody dose amount, or antigen-binding portion thereof, according to a second periodicity of about once every b) una segunda cantidad de dosis que es de 5 aproximadamente 40-60% de la primera cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una segunda periodicidad de aproximadamente una vez cada 4 weeks. 4 semanas. 151. The method of any of claims 145, io 147 and 149, comprising administering to each subject in the population: 151. El método de cualquiera de las reivindicaciones 145, io 147 y 149, que comprende la administración a cada sujeto en la población de: a) a first amount of antibody dose, or antigen-binding portion thereof, according to a first periodicity of about once every 4 weeks;and a) una primera cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una primera periodicidad de aproximadamente una vez cada 4 semanas;y 15 b) una segunda cantidad de dosis que es de aproximadamente 40-60% de la primera cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una segunda periodicidad de aproximadamente una vez cada 4 semanas;y fifteen b) a second dose amount that is approximately 40-60% of the first antibody dose amount, or antigen-binding portion thereof, according to a second periodicity of about once every 4 weeks;and 20 c) una segunda cantidad de dosis de anticuerpo, o porción de unión al antígeno del mismo, de acuerdo con una tercera periodicidad de aproximadamente una vez cada 12 semanas. twenty c) a second amount of antibody dose, or antigen-binding portion thereof, according to a third periodicity of about once every 12 weeks. 152. The method of any of claims 52-54 152. El método de cualquiera de las reivindicaciones 52-54 25 and 64-67, where the subject achieves a PGA of 0 or 1 in less than 25 y 64-67, en donde el sujeto alcanza un PGA de 0 ó 1 en menos de 542 approximately 171 days. 542 aproximadamente 171 días. 153. The method of claim 152, wherein the patient reaches a PGA of 0 or 1 in approximately 69 days. 153. El método de la reivindicación 152, en donde el paciente alcanza un PGA de 0 ó 1 en aproximadamente 69 días. 154. The method of any of claims 52-54 154. El método de cualquiera de las reivindicaciones 52-54 5 and 64-67, where the patient reaches a PASI 75 response in less than approximately 140 days. 5 y 64-67, en donde el paciente alcanza una respuesta de PASI 75 en menos de aproximadamente 140 días. 155. The method of claim 154, wherein the patient reaches a PASI 75 in approximately 56 days. 155. El método de la reivindicación 154, en donde el paciente alcanza un PASI 75 en aproximadamente 56 días. 156. The method of any of claims 52-54 156. El método de cualquiera de las reivindicaciones 52-54 10 and 64-67, where the subject achieves at least an improvement in 10 y 64-67, en donde el sujeto alcanza por lo menos una mejora del
54
60% del conteo de PASI y mantiene por lo menos una mejora de 60% del conteo de PASI a través de por lo menos la semana 52 de tratamiento. 60% of the PASI count and maintains at least a 60% improvement in the PASI count through at least week 52 of treatment. 157. A method of treating psoriasis in a population of 157. Un método para tratar la psoriasis en una población de 15 sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 10% de la población de sujetos alcanza un conteo de fifteen subjects, which comprises administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, wherein at least 10% of the subject population reaches a count of PGA de 0 en la semana 24 de tratamiento. PGA of 0 at week 24 of treatment. 20 1 58. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 5% de la población de sujetos alcanza por lo menos una twenty 1 58. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 5% of the subject population reaches at least one 25 PASI 50 response in approximately week 2. 25 respuesta de PASI 50 en aproximadamente la semana 2. 543 543 159. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where at least 70% of the population of subjects achieve at least one PASI 50 response and maintain at least one PASI 50 response through at least week 52 of treatment. 159. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 70% de la población de sujetos alcanza por lo menos una respuesta de PASI 50 y mantienen por lo menos una respuesta de PASI 50 a través de por lo menos la semana 52 de tratamiento. 160. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where at least 5% of the subject population reaches at least one PASI 75 response in approximately week 4. 160. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 5% de la población de sujetos alcanza por lo menos una respuesta de PASI 75 en aproximadamente la semana 4. 161. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where at least 40% of the subject population achieves at least one PASI 75 response and maintains at least one PASI 75 response through at least week 52 of treatment. 161. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 40% de la población de sujetos alcanza por lo menos una respuesta de PASI 75 y mantiene por lo menos una respuesta de PASI 75 a través de por lo menos la semana 52 de tratamiento. 162. A method of treating psoriasis in a subject population, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, which is 162. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es 544 capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 10% of the subject population achieves at least one PASI 90 response at approximately week 8. 544 capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 10% de la población de sujetos alcanza por lo menos una respuesta de PASI 90 en aproximadamente la semana 8. 163. A method of treating psoriasis in a population of 163. Un método para tratar la psoriasis en una población de 5 subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, wherein at least 25% of the subject population achieves at least one PASI 90 response and maintains at least one response 5 sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 25% de la población de sujetos alcanza por lo menos una respuesta de PASI 90 y mantiene por lo menos una respuesta 10 of PASI 90 through at least week 52 of treatment. 10 de PASI 90 a través de por lo menos la semana 52 de tratamiento. 164. A method of treating psoriasis in a subject population, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, which is 164. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es 15 capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 5% de la población de sujetos alcanza por lo menos una respuesta de PASI 100 en aproximadamente la semana 8. fifteen capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 5% of the subject population achieves at least one PASI 100 response at approximately week 8. 165. A method of treating psoriasis in a subject population, comprising administering to each subject in the population. 165. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población 20 un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 10% de la población de sujetos alcanza por lo menos una respuesta de PASI 100 y mantiene por lo menos una respuesta de PASI 100 a través de por lo menos la semana 52 de twenty an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 10% of the subject population achieves at least one response of PASI 100 and maintains at least one PASI 100 response through at least week 52 of 25 treatment. 25 tratamiento. 545 545 166. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, where by 166. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 5 at least 5% of the subject population achieves at least a PGA count of 0 or 1 in approximately week 4. 5 lo menos 5% de la población de sujetos alcanza por lo menos un conteo de PGA de 0 ó 1 en aproximadamente la semana 4. 167. A method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 35% of the subject population achieves at least a PGA count of 0 or 1 and maintains at least a PGA count of 0 or 1 throughout at least week 52 of treatment. 167. Un método para tratar la psoriasis en una población de sujetos, que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es io capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 35% de la población de sujetos alcanza por lo menos un conteo de PGA de 0 ó 1 y mantiene por lo menos un conteo de PGA de 0 ó 1 a través de por lo menos la semana 52 de tratamiento. 15 168. El método de cualquiera de las reivindicaciones 52-54 y 64-67, en donde el sujeto alcanza un conteo del índice de severidad de psoriasis de uñas (NAPSI) de aproximadamente 2.1 o menos. fifteen 168. The method of any of claims 52-54 and 64-67, wherein the subject achieves a nail psoriasis severity index score (NAPSI) of approximately 2.1 or less. 169. The method of any of claims 52-54 169. El método de cualquiera de las reivindicaciones 52-54 20 y 64-67, en donde el sujeto alcanza un conteo del índice de severidad de psoriasis de uñas (NAPSI) de aproximadamente 1.2 o menos. twenty and 64-67, where the subject achieves a nail psoriasis severity index score (NAPSI) of approximately 1.2 or less. 170. The method of any of claims 52-54 and 64-67, wherein the subject achieves a count of the index of 170. El método de cualquiera de las reivindicaciones 52-54 y 64-67, en donde el sujeto alcanza un conteo del índice de 25 dermatological quality of life (DLQI) of approximately 0 or 1. 25 calidad de vida dermatológico (DLQI) de aproximadamente 0 ó 1. 546 546 171. The method of any of claims 52-54 and 64-67, wherein the subject achieves a clinically significant reduction in the dermatological quality of life index (DLQI) count. 171. El método de cualquiera de las reivindicaciones 52-54 y 64-67, en donde el sujeto alcanza una reducción clínicamente significativa del conteo de índice de calidad de vida dermatológico (DLQI). 5 172. The method of claim 171, wherein the subject achieves a clinically significant reduction in the DLQI count at approximately week 24. 5 172. El método de la reivindicación 171, en donde el sujeto alcanza una reducción clínicamente significativa del conteo de DLQI en aproximadamente la semana 24. 173. The method of claim 171, wherein the subject achieves a clinically significant reduction in DLQI io count at approximately week 52. 173. El método de la reivindicación 171, en donde el sujeto alcanza una reducción clínicamente significativa del conteo de io DLQI en aproximadamente la semana 52. 174. The method of any of claims 52-54 and 64-67, wherein the subject or subject population achieves an improvement in the dermatological quality of life index (DLQI) count of at least about -7 at week 12. 174. El método de cualquiera de las reivindicaciones 52-54 y 64-67, en donde el sujeto o población de sujetos alcanza una mejora del conteo de índice de calidad de vida dermatológico (DLQI) de por lo menos aproximadamente -7 en la semana 12. 15 175. Un método para tratar la psoriasis en una población de sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 35% de la población de sujetos alcanza un conteo del fifteen 175. A method of treating psoriasis in a population of subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 35% of the subject population reaches a count of 20 índice de calidad de vida dermatológico (DLQI) de 0 ó 1 en aproximadamente la semana 24. twenty dermatological quality of life index (DLQI) of 0 or 1 in approximately week 24. 176. A method of treating psoriasis in a population of subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, which is 176. Un método para tratar la psoriasis en una población de sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es 25 capable of binding to the p40 subunit of IL-12 and / or IL-23, whereby 25 capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 547 At least 18% of the subject population reaches a dermatological quality of life index (DLQI) count of 0 or 1 at approximately week 52. 547 lo menos 18% de la población de sujetos alcanza un conteo del índice de calidad de vida dermatológico (DLQI) de 0 ó 1 en aproximadamente la semana 52. 177. A method of treating psoriasis in a population of 177. Un método para tratar la psoriasis en una población de 5 subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, wherein at least 50% of the subject population achieves a clinically significant reduction in the quality of life index count 5 sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por lo menos 50% de la población de sujetos alcanza una reducción clínicamente significativa del conteo de índice de calidad de vida 10 dermatological (DLQI) at approximately week 24. 10 dermatológico (DLQI) en aproximadamente la semana 24. 178. A method of treating psoriasis in a population of subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL- 23, where 178. Un método para tratar la psoriasis en una población de sujetos que comprende administrar a cada sujeto en la población un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en donde por 15 lo menos 20% de la población de sujetos alcanza una reducción clínicamente significativa del conteo de índice de calidad de vida dermatológico (DLQI) en aproximadamente la semana 52. fifteen at least 20% of the subject population achieves a clinically significant reduction in the dermatological quality of life index (DLQI) count at approximately week 52. 179. The method of any of claims 64-77 and 52-54, wherein the subject reaches a minimum Diff to 179. El método de cualquiera de las reivindicaciones 52-54 y 64-77, en donde el sujeto alcanza una mínima diferencia 20 clínicamente importante (MCID) en cualquiera de uno o más resultado de calidad de vida relacionada con la salud seleccionados del grupo que consiste de índice de calidad de vida dermatológico (DLQI), deterioro de actividad total (TAI), dolor relacionado con Ps (VAS-Ps), dolor relacionado con artritis twenty clinically important (MCID) in any one or more health related quality of life outcome selected from the group consisting of dermatological quality of life index (DLQI), total activity impairment (TAI), Ps related pain (VAS -Ps), arthritis-related pain 25 psoriatic (VAS-PsA), short form count 36 of synopsis of 25 psoriásica (VAS-PsA), conteo de forma corta 36 de sinopsis de 548 mental component of health study (MCS) and short form count 36 of synopsis of physical component of health study (PCS). 548 componente mental de estudio de salud (MCS) y conteo de forma corta 36 de sinopsis de componente físico de estudio de salud (PCS). 180. The method of any of the claims 180. El método de cualquiera de las reivindicaciones 5 above, where the method comprises the administration to the subject or to each subject in the population of:5 anteriores, en donde el método comprende la administración al sujeto o a cada sujeto en la población de: a) a first quantity of antibody doses, or antigen binding portion thereof, according to a first periodicity of about once every 4 weeks;and io b) a second dose amount that is approximately 40-60% of the first antibody dose amount, or antigen binding portion thereof, according to a second periodicity of about once every a) una primera cantidad de dosis de anticuerpo, o porción de unión ai antigeno del mismo, de acuerdo con una primera periodicidad de aproximadamente una vez cada 4 semanas;y io b) una segunda cantidad de dosis que es de aproximadamente 40-60% de la primera cantidad de dosis de anticuerpo, o porción de unión al antigeno del mismo, de acuerdo con una segunda periodicidad de aproximadamente una vez cada 4 weeks. 4 semanas. 15 181. El método de cualquiera de las reivindicaciones anteriores, en donde el método comprende la administración al sujeto o a cada sujeto en la población de: fifteen 181. The method of any of the preceding claims, wherein the method comprises administering to the subject or to each subject in the population: a) approximately 200 mg ABT-874 once every four weeks for two doses;and a) aproximadamente 200 mg de ABT-874 una vez cada cuatro semanas para dos dosis;y 20 b) aproximadamente 100 mg de ABT-874 cada cuatro semanas después de lo anterior. twenty b) approximately 100 mg ABT-874 every four weeks thereafter. 182. The method method of any of the preceding claims, wherein the method comprises administering to the subject or to each subject in the population of: 182. El método de método de cualquiera de las reivindicaciones anteriores, en donde el método comprende la administración al sujeto o a cada sujeto en la población de: 25 a) approximately 200 mg ABT-874 in the weeks 25 a) aproximadamente 200 mg de ABT-874 en las semanas 549 549 O and 4;and O y 4;y b) approximately 100 mg ABT-874 at week 8 and every 4 weeks thereafter. b) aproximadamente 100 mg de ABT-874 en la semana 8 y cada 4 semanas después de lo anterior. 183. A method of treating psoriasis in a subject who 183. Un método para tratar la psoriasis en un sujeto que 5 includes the administration to the subject of: 5 comprende la administración al sujeto de: a) about 200 of an antibody, or antigen-binding portion thereof, that is capable of binding the IL-12 and / or IL-23 p40 subunit, once every four weeks for two doses;and io b) approximately 100 mg of antibody, or antigen-binding portion thereof, every four weeks thereafter, to thereby treat psoriasis in the subject. a) aproximadamente 200 de un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, una vez cada cuatro semanas para dos dosis;y io b) aproximadamente 100 mg de anticuerpo, o porción de unión al antígeno del mismo, cada cuatro semanas después de lo anterior, para de tal modo tratar la psoriasis en el sujeto. 184. A method of treating psoriasis in a subject comprising administering to the subject: 184. Un método para tratar la psoriasis en un sujeto que comprende la administración al sujeto de: 15 a) aproximadamente 200 mg de un anticuerpo, o porción de unión al antígeno del mismo, que es capaz de unir a la subunidad p40 de IL-12 y/o IL-23, en las semanas 0 y 4;y fifteen a) approximately 200 mg of an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, at weeks 0 and 4;and b) approximately 100 mg of antibody, or antigen-binding portion thereof, at week 8 and every 4 weeks b) aproximadamente 100 mg de anticuerpo, o porción de unión al antígeno del mismo, en la semana 8 y cada 4 semanas 20 después de lo anterior, para de tal modo tratar la psoriasis en el sujeto. twenty after the above, to thereby treat psoriasis in the subject. 185. The method of claim 183 or 184, wherein the antibody is ABT-874. 185. El método de la reivindicación 183 ó 184, en donde el anticuerpo es ABT-874. 186. A method of treating psoriasis in a subject who 186. Un método para tratar la psoriasis en un sujeto que 25 includes the administration to the subject of: 25 comprende la administración al sujeto de: 550 550 a) approximately 200 ABT-874 once every four weeks for two doses;and a) aproximadamente 200 de ABT-874 una vez cada cuatro semanas para dos dosis;y b) approximately 100 mg ABT-874 every four weeks after the above, b) aproximadamente 100 mg de ABT-874 cada cuatro semanas después de lo anterior, 5 to thereby treat psoriasis in the subject. 5 para de tal modo tratar la psoriasis en el sujeto. 187. A method of treating psoriasis in a subject comprising administering to the subject: 187. Un método para tratar la psoriasis en un sujeto que comprende la administración al sujeto de: a) approximately 200 mg ABT-874 in the weeks a) aproximadamente 200 mg de ABT-874 en las semanas 0 and 4;and io b) approximately 100 mg ABT-874 at week 8 and every 4 weeks thereafter, to thereby treat psoriasis in the subject. 0 y 4;y io b) aproximadamente 100 mg de ABT-874 en la semana 8 y cada 4 semanas después de lo anterior, para de tal modo tratar la psoriasis en el sujeto. 551 551

Independent claims24

3,715 paragraphs in 335 sections, as filed

(54) Title: METHODS TO TREAT PSORIASIS. (54) Title: METHODS FOR TREATING PSORIASIS.

(57) Summary

The invention provides methods of treating psoriasis in a subject by administering to an subject an antibody capable of binding to the p40 subunit of IL-12 and / or IL-23.

(57) Abstract

The invention provides methods of treating psoriasis in a subject by administering to a subject an antibody capable of binding to the p40 subunit of IL-12 and / or IL-23.

METHODS TO TREAT PSORIASIS

Cross Reference to Related Applications

This request claims priority to the Request

North American Series No. 61 / 242,288 titled Methods of Treating Psoriasis, filed September 14, 2009,

North American Application Series No. 61 / 245,967 titled Methods of Treating Psoriasis, filed on September 25, 2009, North American Application Series No. 61/297623, titled Methods of Treating Psoriasis, filed January 22, 2010, and North American Application Series No. 61 / 360,299, entitled Methods of Treating Psoriasis, filed on June 30, 2010, the full content of each of which is expressly incorporated herein by reference.

Background of the Invention

Psoriasis is an inflammatory disease mediated by T cells that is considered to be one of the most common autoimmune diseases, affecting approximately 2% to 3% of adults, although the overall prevalence varies widely (Stern

RS, et al., J Investig Dermatol Symp Proc 2004, 9:

136-39; Davidson A and Diamond Β. N Engl J Med 2001, 345: 340-50; Langley RGB, et al., Ann Pheum Dis 2005, 64 (Suppl II): ¡118-23). Psoriasis has a major impact on quality of life (de Korte J, et al., J Investig

Dermatol Symp Proc 2004, 9: 140-7; Krueger G, et al.,

Arch Dermatol 2001, 137: 280-4; Finlay AY and Coles EC, Br J Dermatol 1995, 132: 236-44) and is associated with a number of psychological and psychosocial problems (Kimball AB, et al., Am J Clin Dermatol 2005, 6: 383-92; Russo PA, et al., Australes J Dermatol 2004, 45: 155-9). Many traditional psoriasis therapies have toxic adverse effects; therefore, its long-term use is limited (Lebwohl M. and Ali S., J Am Acad Dermatol 2001, 45: 487-98; Lebwohl M. and Ali S., J Am Acad Dermatol 2001, 45: 649-61). Furthermore, many psoriasis patients are not satisfied with traditional therapies (Stern RS, et al., J Investig Dermatol Symp Proc 2004, 9: 136-39; Finlay AY and Ortonne JP, J Cutan Med Surg 2004, 8: 310-20 ); Thus, there is a clear need for therapies that are safer and easier to use and that can be prescribed on a long-term basis.

Interleukin-12 (IL-12) and related cytosine IL-23 are members of the IL-12 superfamily of cytosines that share a common p40 subunit (Anderson EJR, et al., Springer Semin Immunopathol 2006, 27: 425-42) . Both cytosines contribute to the development of helper cell immune response type 1T (Th 1) in psoriasis, but each has a unique role (Rosmarin D and Strober BE, J Drugs Dermatol 2005, 4: 318-25 ; Hong K, et al., J Immunol 1999, 162: 7480-91; Yawalkar N, et al., J Invest Dermatol 1998, 1 1 1: 1053-57). IL-12 primarily stimulates differentiation of Th1 cells and subsequent secretion of interferon-gamma, while IL-23 preferably stimulates differentiation of untreated T cells into effector helper T cells (Th17) that secrete IL- 17, a proinflammatory mediator (Rosmarin D and Strober BE, J Drugs Dermatol 2005, 4: 318-25; Harrington Le, et al., Nature Immunol 2005, 6: 1123-32; Park H, et al. Nature Immunol 2005, 6: 1132-41). Overexpression of IL-12 p40 and IL-23 p40 messenger RNA in psoriatic skin lesions suggests that inhibition of IL-12 and IL-23 with a neutralizing antibody to the IL-12/23 p40 subunit protein may offer an effective therapeutic process for the treatment of psoriasis (Yawalkar N, et al., J Invest Dermatol 1998, 1 11: 1053-57; Lee E, et al., J

Exp Med 2004, 199: 125-30; Shaker OG, et al., Clin Biochem 2006, 39: 119-25; Piskin G, et al., J Immunol 2006, 176: 1908-15). Such therapeutic processes for the treatment of psoriasis are clearly needed in the art. Brief Description of the Invention

The present invention provides methods and compositions for treating psoriasis, eg, chronic psoriasis, using an antibody, or antigen-binding portion thereof, that binds human IL-12 and / or human IL-23.

In one aspect, the invention provides methods of treating psoriasis in a subject comprising administering to the subject a first dose amount of an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL- 12 and / or IL-23, according to one periodicity, and administering a second amount of the antibody, or antigen-binding portion thereof, at the same periodicity, thereby treating psoriasis in the subject.

In another aspect, the invention provides methods of treating psoriasis in a subject comprising administering to the subject a first quantity of doses of an antibody, or antigen-binding portion io thereof, that is capable of binding to the p40 subunit of IL -12 and / or IL-23, according to a first periodicity, and administering a second dose amount of the antibody, or antigen-binding portion thereof, according to a second periodicity, thereby treating psoriasis in the subject.

In various embodiments, the first dose amount of the antibody, or antigen-binding portion thereof, is therefore

<td></td><td colspan="5">minus about 100 mg to about 200 mg, is at least about 100 mg, or is at least</td>

<td> 20</td><td>approximately</td><td>200 mg. In</td><td>other modalities,</td><td colspan="2">the first</td>

<td></td><td>amount of dose</td><td>of the antibody,</td><td>or joint portion</td><td colspan="2">to antigen</td>

<td></td><td>of it is</td><td colspan="2">about 100 mg,</td><td> 110</td><td>mg,</td>

<td></td><td>approximately</td><td>120 mg,</td><td>approximately</td><td> 130</td><td>mg,</td>

<td></td><td>approximately</td><td>140 mg,</td><td>approximately</td><td> 150</td><td>mg,</td>

<td> 25</td><td>approximately</td><td>160 mg,</td><td>approximately</td><td> 170</td><td>mg,</td>

about 180 mg, about 190 mg, about 200 mg.

The second dose amount of the antibody, or antigen-binding portion thereof, may be the same as the first dose amount of the antibody, or antigen-binding portion thereof, or different than the first dose amount of the antibody, or antigen-binding portion thereof. In various embodiments, the second dose amount of the antibody, or antigen-binding portion thereof, is at least about 100 mg to about 200 mg, is at least about 200 mg, or is at least about 100 mg. In another embodiment, the second dose amount of the antibody, or antigen-binding portion thereof, is approximately 40-60% of the first amount of

I5 dose of the antibody, or antigen binding portion thereof, or approximately 190-210% of the first dose amount of the antibody, or antigen binding portion thereof. In other embodiments, the first dose amount of the antibody, or antigen-binding portion thereof, is approximately 100 mg, 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, about 180 mg, about 190 mg, 200 mg.

The first and second periodicities of administration of the antibody, or antigen-binding portion thereof, may be approximately once per week, approximately once every two weeks, approximately once every four weeks. In one embodiment, the second periodicity of administration of the antibody, or antigen-binding portion thereof, is approximately once every 30-200 days.

The duration of the first periodicity can be approximately 12 weeks, approximately 8 weeks, approximately 4 weeks, approximately 2 weeks, or approximately 1 week. The duration of the first periodicity can be at least about 12 weeks, at least about 8 weeks, at least about 4 weeks, at least about 2 weeks, or at least about 1 week.

The duration of the second periodicity can be approximately 60 weeks, approximately 44 weeks, approximately 12 weeks, approximately 4 weeks, approximately 2 weeks, or approximately 1 week. The duration of the second periodicity can be at least about 60 weeks, at least about 44 weeks, at least about 12 weeks, at least about 4 weeks, at least about 2 weeks, or at least about 1 week .

In one embodiment, the second number of doses is

Ί administered to the subject over a flare of psoriasis. In another embodiment, the second amount of dose is administered to the subject prior to a psoriasis flare.

Psoriasis flare can be indicated by loss of a Psoriasis Area and Severity Index (PASI) response 90, by loss of a Psoriasis Area and Severity Index (PASI) response 75, by loss of response of the Psoriasis Area and Severity Index (PASI) 50, or due to the loss of a Global Assessment classification of the

Clear or minimal Medical (PGA).

Loss of a PASI response can be loss of PASI response from a single body region, loss of PASI response from two body regions, loss of PASI response from three body regions, or loss of PASI response from four regions of the body.

The body region can be torso, lower extremities, upper extremities, or head and neck.

In another aspect, the invention provides a method of treating psoriasis in a subject comprising administering to the subject an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL -23, according to a periodicity of about once every 4 weeks, thereby treating psoriasis in the subject.

In yet another aspect, the invention provides a method of treating psoriasis in a subject comprising administering to the subject an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, according to a periodicity of about once every 12 weeks, thereby treating psoriasis in the subject.

In a related aspect, the invention provides a method of treating psoriasis in a subject comprising administering to the subject; a) a first dose amount of an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23; and b) a second dose amount that is approximately 40-60% of the first dose dose of the antibody, or antigen-binding portion thereof, according to a periodicity of about once every 12 weeks, thereby treats psoriasis on the subject.

I5 In one modality, the subject achieves at least a PGA count of 0 or 1. In one modality, the subject achieves at least one PASI 75 response. In one modality, the subject achieves at least one PASI response. 90. In one modality, the subject achieves at least one PASI response

one 00. In one modality, the subject maintains the PGA count of or 1 during treatment. In one modality, the subject maintains the PASI 75 response during treatment. In one modality, the subject maintains the PASI 90 response during treatment.

In one embodiment, the first dose amount is at least about 200.

In one embodiment, the second dose amount is at least about 100.

In another aspect, the invention provides a method of treating psoriasis in a subject comprising administering to the subject: a) a first dose amount of an antibody, or antigen-binding portion thereof, that is capable of binding to the IL-12 and / or IL-23 p40 subunit, according to a first periodicity of about once every 4 weeks; and b) io administering a second dose amount that is approximately 40-60% of the first dose dose of the antibody, or antigen-binding portion thereof, according to a second periodicity of about once every week, thereby Psoriasis in the subject is treated.

In one embodiment, the first dose amount is at least about 200.

In one embodiment, the second dose amount is at least about 100.

In one embodiment, the duration of the first periodicity is 20 for at least about 8 weeks.

In one embodiment, the duration of the second periodicity is at least about 4 weeks, at least about 16 weeks, or at least about weeks.

In another aspect, the invention provides a method of treating psoriasis in a subject comprising administering to the subject: a) a first dose amount of an antibody, or antigen-binding portion thereof, that is capable of binding to the subunit IL-12 and / or IL-23 p40, according to a first periodicity of about once every 4 weeks; and b) a second dose amount that is approximately 40-60% of the first dose dose of the antibody, or antigen binding portion thereof, according to a second periodicity of about once every 4 weeks; and c) the second dose amount of the antibody, or antigen binding portion thereof, according to a third periodicity of about once every 12 weeks, thereby treating psoriasis in the subject.

In one embodiment, the first amount of dose is so

I5 minus about 200.

In one embodiment, the second dose amount is at least about 100.

In one embodiment, the duration of the first periodicity is at least approximately 8 weeks.

In one embodiment, the duration of the second periodicity is at least approximately 4 weeks.

In one embodiment, the duration of the third periodicity is at least about 12 weeks or at least about 36 weeks.

In one embodiment, the subject achieves a PGA count of 0 or 1, eg, at approximately week 12. In one embodiment, the subject achieves at least one PASI 75 response, eg, at approximately week 12. In one embodiment, the subject reaches at least one PASI 90 response, eg, at approximately week 12. In one embodiment, the subject achieves at least one PASI 100 response, eg, at approximately week 12.

In one modality, the subject maintains the PGA count of 0 or 1 throughout the duration of the treatment. In one modality, the subject maintains the PASI 75 response throughout the duration of treatment. In one modality, the subject maintains the PASI 90 response throughout the duration of treatment.

In another aspect, the invention provides a method of treating psoriasis in a population of subjects, comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 60% of the subject population reach a PASI 75 response at approximately week 12.

In yet another aspect, the invention provides a method of treating psoriasis in a population of subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 25% of the subject population achieve a PASI 90 response at approximately week 12.

In yet another aspect, the invention provides a method of treating psoriasis in a subject population comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 10% of the subject population reach a PASI 100 response at approximately week 12.

In one embodiment, the method comprises administering to each subject in the population: a) a first dose amount of the antibody, or antigen-binding portion thereof, according to a first periodicity of about once every 4 weeks; and b) administering a second dose amount that is approximately 40-60% of the first dose dose of the antibody, or antigen-binding portion thereof, according to a second periodicity of about once every week.

In one embodiment, the method comprises administering to each subject in the population: a) a first dose amount of the antibody, or antigen-binding portion thereof, according to a first periodicity of about once every 4 weeks; and b) a second dose amount that is approximately 40-60% of the first dose dose of the antibody, or antigen-binding portion thereof, according to a second periodicity of about once every week; and c) the second dose amount of the antibody, or antigen-binding portion thereof, according to a third periodicity of about once every 12 weeks.

In one embodiment, the antibody is administered subcutaneously.

In one embodiment, the antibody is a human antibody. In a preferred embodiment, the antibody is ABT-874.

In one embodiment, the subject or subject population reaches at least one PASI 75 response in approximately week 24 or at least one PASI 75 response in approximately week 52. In another embodiment, the subject or subject population achieves at least a PGA count of 0 or 1 in approximately week 24 or at least a PGA count of 0 or 1 in approximately week 52.

IL-12 and / or IL-23, where at least 41% of the subject population reaches at least one PASI 75 response in approximately week 24.

In yet another aspect, the invention is directed to a method of treating psoriasis in a population of subjects, by administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit IL-12 and / or IL-23, where at least 35% of the subject population reaches at least a PGA count of 0 or 1 at approximately week 24.

In a further aspect, the invention is directed to a method of treating psoriasis in a population of subjects, by administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 25% of the population of subjects reaches at least a PASI 75 response in approximately week 52.

In another aspect, the invention is directed to a method of treating psoriasis in a population of subjects by administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where at least 21% of the subject population achieves at least a PGA count of 0 or 1 at approximately week 52.

In certain modalities of the preceding aspects, the subject or population of subjects achieves (i) an improvement in a count of the Dermatological Quality of Life Index (DLQI) or count of the average Dermatological Quality of Life Index (DLQI) of at least about -9; (ii) an improvement in a Short Form 36 compilation count of the Physical Component of

Health Study (PCS) or Component Collection count

Average Physical (PCS) of at least about 2; (iii) an improvement in a count of the Short Form 36 of Collection of the Mental Component of Health Study (MCS) or count of the Short Form 36 of Collection of the Mental Component of

Average Health Study (PCS) of at least approximately 4; (iv) an improvement in a visual analogue scale count or average visual analogue scale count for psoriasis-related pain (VAS-Ps) of at least approximately -25; (v) an improvement in a visual analog scale count for psoriatic arthritis related pain (VAS-PsA) or average visual analog scale count for psoriatic arthritis related pain (VAS-PsA) of at least about -32 ; and / or (vi) a minimum clinically important difference response rate (MCID) for psoriasis-related pain (VAS-Ps) of at least approximately 60%.

In several aspects, the invention is directed to a method of treating psoriasis in a population of subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit IL-12 and / or IL-23, where the population of subjects reaches (i) a response speed of the least clinically important difference (MCID) for the Dermatological Quality of Life Index (DLQI) of at least approximately 70% in approximately week 12; (ii) a response rate of the least clinically important difference (MCID) for the Dermatological Quality of Life Index (DLQI) of at least approximately 81% at approximately week 52; (iii) a minimal clinically important difference (MCID) response rate for Total Activity Impairment (TAI) of at least about 45% at about week 12; and / or (iv) a Minimal Clinically Important Difference (MCID) response rate for Impaired Total Activity (TAI) of at least approximately 57% at approximately week 52. In one embodiment, the antibody, or antigen-binding portion thereof, is administered once every four weeks. In another embodiment, the antibody, or antigen-binding portion thereof, is administered once every 12 weeks.

In further aspects, the invention is directed to a method of treating psoriasis in a population of subjects, by administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where (i) at least 65% of the subject population achieves at least a PGA 0/1 response at approximately week 12, where each subject was treated with a biological before administration of the antibody; (ii) at least 74% of the subject population reaches at least a PASI 75 response in approximately week 12, where each subject was treated with a biologic prior to administration of the antibody; (¡II) at least 78% of the subject population reaches at least a PGA 0/1 response at approximately week 12, where none of the subjects were treated with a biologic prior to administration of the antibody; (¡V) at least 82% of the subject population reaches at least a PASI 75 response in approximately week 12, where none of the subjects was treated with a biologic prior to administration of the antibody; (v) at least 78% of the io subject population reaches at least a PGA 0/1 response at approximately week 52, where each subject was treated with a biologic prior to administration of the antibody; (vi) at least 79% of the subject population achieves at least a PGA 0/1 response in approximately the week

52, where none of the subjects was treated with a biological before administration of the antibody; (vii) at least 71% of the subject population reaches at least a PGA 0/1 response at approximately week 12, where each subject has a prior history of psoriatic arthritis; (viii) at least

7 8% of the subject population reaches at least a PASI 75 response in approximately week 12, where each subject has a prior history of psoriatic arthritis; (¡X) at least 77% of the subject population achieves at least a PGA 0/1 response in approximately the week

12, where none of the subjects have a previous history of psoriatic arthritis; (x) at least 81% of the subject population reaches at least a PASI 75 response in approximately week 12, where none of the subjects have a prior history of psoriatic arthritis; (xi) at least

77% of the subject population achieves at least a PGA 0/1 response at approximately week 52, where each subject has a prior history of psoriatic arthritis; and / or (xii) at least 79% of the subject population achieves at least a PGA 0/1 response at approximately io week 52, where none of the subjects have a prior history of psoriatic arthritis.

In yet another aspect, the invention is directed to methods of decreasing the risk that a subject treated with an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL- 23, will develop a Major Adverse Cardiovascular Event (MACE). Methods include (a) selecting a subject who has less than 2 risk factors selected from the group consisting of (i) a body mass index (BMI) greater than 30, (ii) a history of diabetes mellitus, (iii) blood pressure greater than 140/90, (iv) a history of myocardial infarction, (v) a history of angina requiring hospitalization, (vi) a history of coronary artery disease requiring revascularization, (vii) a history of disease of peripheral arteries, (viii) a history of congestive heart failure requiring hospitalization, (ix) a history of stroke or transient ischemic attack; and (b) administering the antibody, or antigen-binding portion thereof, to the selected subject; thereby decreasing the risk that the subject will develop a Cardiovascular Event

Adverse Important. In a particular embodiment, the antibody is ABT-874 or ustekinumab.

In certain modalities, the subject has 0 or 1 risk factor. In certain modalities, MACE is myocardial infarction and / or cerebrovascular accident.

In other embodiments, the antibody, or antigen-binding portion thereof, is administered to the selected subject in a first quantity of doses of at least about 100 mg to about 200 mg. In a further embodiment, the antibody, or antigen-binding portion thereof, is administered to the selected subject in a second quantity of doses of at least about 100 mg to about 200 mg. In certain modalities, the risk factors are reevaluated before the administration of the second quantity of doses to the selected subject.

In certain embodiments of the various aspects of the invention, the subject achieves at least a 50% reduction in PASI count. In one aspect the subject achieves at least a 50% reduction in PASI count in approximately week 4.

In other embodiments of the various aspects of the invention, the subject achieves at least an 80% reduction in PASI count. In one aspect the subject achieves at least an 80% reduction in PASI count in approximately week 1 2.

In further aspects, the invention is directed to a method of treating psoriasis in a population of subjects, which comprises administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the subunit IL-12 and / or IL-23 p40, wherein: (i) at least 69% of the subject population reaches at least a PGA 0/1 response at approximately week 12, where each subject has a baseline PASI of greater than 20 prior to administration of the antibody; (ii) at least 79% of the subject population reaches at least a PGA 0/1 response in approximately week 12, where each subject has a baseline PASI of less than or equal to 20 before administration of the antibody; (iii) at least 79% of the subject population reaches at least a PASI 75 response in approximately week 12, where each subject has a baseline PASI of greater than 20 prior to administration of the antibody; (iv) at least 81% of the subject population reaches at least a PASI 75 response in approximately week 12, where each subject has a baseline PASI of less than or equal to 20 before administration of the antibody; (v) at least 67% of the subject population achieves at least a PGA 0/1 response in approximately week 12, where each subject has a baseline weight of greater than or equal to 100 kilograms prior to administration of the antibody; (vi) at least 80% of the subject population reaches at least a PGA 0/1 response in approximately week 12, where each subject has a baseline weight of less than 100 kilograms prior to administration of the antibody; (vile) at least 72% of the subject population reaches at least a PASI io 75 response in approximately week 12, where each subject has a baseline weight greater than or equal to 100 kilograms prior to antibody administration; and / or (viii) at least 85% of the subject population reaches at least a PASI 75 response in approximately week 12, where each subject has a baseline weight of less than 100 kilograms prior to administration of the antibody.

In still further aspects, the invention is directed to a method of treating psoriasis in a population of subjects comprising administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the subunit IL-12 and / or IL-23 p40, where: (i) at least 41% of the subject population maintains at least a 0/1 PGA response through at least week 52 of treatment ; (i¡) at least 79% of the subject population maintains at least one response

PGA 0/1 through at least week 52 of treatment; (iii) at least 45% of the subject population maintains at least one PASI 75 response through at least week 52 of treatment; (iv) at least 82% of the subject population maintains at least one PASI 75 response through at least week 52 of treatment; (v) at least 23% of the subject population maintains at least one PASI 75 response through at least week 52 of treatment; and / or (vi) at least 63% of the subject population io maintains at least one PASI 75 response through at least week 52 of treatment.

In certain embodiments of the various aspects of the invention, the method of treating psoriasis comprises administering to each subject in a population: a) a first dose amount of the antibody, or antigen-binding portion thereof, according to a first periodicity of about once every 4 weeks; and b) administering a second dose amount that is approximately 40-60% of the first dose amount of the antibody, or antigen-binding portion thereof, according to a second periodicity of about once every 4 weeks.

In other embodiments of the various aspects of the invention, the method of treating psoriasis comprises administering to each subject in a population: a) a first dose amount of the antibody, or antigen-binding portion thereof, according to a first periodicity of about once every 4 weeks; and b) a second dose amount that is approximately 40-60% of the first dose dose of the antibody, or antigen binding portion thereof, according to a second periodicity of about once every 4 weeks; and c) the second dose amount of the antibody, or antigen binding portion thereof, according to a third periodicity of about once every 12 weeks.

io In certain embodiments of the various aspects of the invention, a treated subject suffering from psoriasis achieves a PGA of 0 or 1 of less than about 171 days. In some modalities, a treated subject suffering from psoriasis achieves a PGA of 0 or 1 of less than about 30, 40, 50, 60, 70,

80, 85, 90, 95, 100, 105, 1 10, 115, 120, 125, 130, 135, 140, 145,

150, 155, 160, 165, 166, 167, 168, 169 or 170 days. In certain modalities, a patient reaches a PGA of 0 or 1 for approximately 69 days.

In related embodiments of the various aspects of the invention, the patient achieves a PASI 75 response in less than about 140 days. In some modalities, a treated subject suffering from psoriasis achieves a PASI 75 of less than about 30, 40, 50, 60, 70, 80, 85, 90, 95,

100, 105, 1 10, 1 15, 120, 125, 130, 135, 136, 137, 138 or 139 days.

In certain modalities, the patient reaches a PASI 75 for approximately 56 days.

In still other embodiments of the various aspects of the invention, the subject achieves at least a 60% improvement in PASI count and maintains at least a 60% improvement in PASI count, for example, through at least less the week of treatment.

In another aspect, the invention is directed to a method of treating psoriasis in a population of subjects, which comprises administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the subunit IL-12 and / or IL-23 p40, wherein; (i) at least 10% of the subject population achieves a PGA count of 0 at week 24 of treatment; (ii) at least 5% of the subject population reaches at least a PASI 50 response in approximately week 2; (iii) at least 70% of the subject population achieves at least one PASI 50 response and maintains at least one PASI 50 response through at least week 52 of treatment; (iv) at least 5% of the subject population achieves at least one response

PASI 75 in approximately week 4; (v) at least 40% of the subject population achieves at least one PASI 75 response and maintains at least one PASI 75 response through at least week 52 of treatment; (vi) at least 10% of the subject population reaches at least a PASI 90 response in approximately week 8; (vii) at least 25% of the subject population achieves at least one PASI 90 response and maintains at least one PASI 90 response through at least week 52 of treatment; (viii) at least 5% of the subject population reaches at least a PASI 100 response in approximately week 8; (ix) at least 10% of the subject population achieves at least one PASI 100 response and maintains at least one PASI 100 response through at least week 52 of treatment; (x) at least

5% of the subject population reaches at least one count of

PGA of 0 or 1 at approximately week 4; and / or (xi) at least 35% of the subject population achieves at least a PGA count of 0 or 1 and maintains at least a PGA count of 0 or 1 throughout at least week 52 of treatment.

In certain embodiments of the various aspects of the invention, the subject achieves a Nail Psoriasis Severity Index (NAPSI) count of approximately 2.1 or less. In certain modalities, the subject achieves a count of the index of

Nail Psoriasis Severity (NAPSI) of approximately 2.1 or less at approximately week 24. In related modalities of the various aspects of the invention, the subject achieves a Nail Psoriasis Severity Index (NAPSI) count of approximately 1.2 or less. In certain modalities, the subject achieves a Nail Psoriasis Severity Index (NAPSI) count of approximately 1.2 or less at approximately week 52.

In other embodiments of the various aspects of the invention, the subject achieves a count of the Quality of

Dermatological Life (DLQI) of approximately 0 or 1. In certain modalities, the subject achieves a count of the Dermatological Quality of Life Index (DLQI) of approximately 0 or 1 in approximately week 24 or in approximately week

52.

In certain modalities, the subject achieves a clinically significant reduction in the count of the Dermatological Quality of Life Index (DLQI). A clinically significant reduction in the Dermatologic Quality of Life Index (DLQI) count may, for example, be a decrease of more than 5 points in the DLQI count. In one modality, the subject achieves a clinically significant reduction in DLQI count at approximately week 24. In one modality, the subject achieves a clinically significant reduction in DLQI count in approximately one week

52.

In certain modalities, the subject or subject population achieves an improvement in the Dermatological Quality of Life Index (DLQI) count of at least approximately -7, for example, at week 12.

In a further aspect, the invention is directed to a method of treating psoriasis in a population of subjects, which comprises administering to each subject in the population an antibody, or antigen-binding portion thereof, which is capable of binding to the p40 subunit of IL-12 and / or IL-23, where: (i) at least 35% of the population of subjects reaches a count of the Dermatological Quality of Life Index (DLQI) of 0 or 1 in approximately the week 24; (ii) at least 18% of the population of subjects reaches a count of the Dermatological Quality of Life Index (DLQI) of 0 or 1 in approximately week 52; (Ii) at least 50% of the subject population achieves a clinically significant reduction in the Dermatological Quality of Life Index (DLQI) count at approximately week 24; and / or (iv) at least 20% of the subject population achieves a clinically significant reduction in count of the Dermatological Quality of Life Index (DLQI) at approximately week 52.

In various modalities of the various aspects of the invention, the subject achieves a minimum clinically important difference (MCID) in one or more health-related qualities of life outcomes selected from the group consisting of the Dermatological Quality of Life Index (DLQI ), Impaired Total Activity (TAI), pain related to Ps (VAS-Ps), pain related to psoriatic arthritis (VAS-PsA), Count of Short Form 36 of Synopsis of the Mental Component of Health Study (MCS) and count of Short Form 36 of

Synopsis of the Physical Component of the Health Study (PCS). In various modalities, the subject achieves a minimal clinically important difference (MCID) in two, three, four, five or six of the Dermatological Quality of Life Index (DLQI), Impairment of

Total Activity (TAI), pain related to Ps (VAS-Ps), pain related to psoriatic arthritis (VAS-PsA), count of Short Form 36 of Synopsis of the Mental Component of Health Study (MCS) or count of Short Form 36 Synopsis of the Physical Component of the Health Study (PCS).

In related modalities, the subject population reaches a clinically important minimum difference response speed (MCID) for one or more of the health-related qualities selected from the group consisting of the Dermatological Quality of Life Index (DLQI), Impairment of

Total Activity (TAI), pain related to Ps (VAS-Ps), pain related to psoriatic arthritis (VAS-PsA), count of the Short Form 36 of Synopsis of the Mental Component of Health Study (MCS) and count of the Form Section 36 of Synopsis of the Physical Component of the Health Study (PCS). In various modalities, the subject population achieves a clinically important least difference response speed (MCID) for two, three, four, five, or six of the Dermatological Quality of Life Index (DLQI), Total Activity Impairment (TAI), Ps-related pain (VAS-Ps), psoriatic arthritis-related pain (VAS-PsA), Count of Short Form 36 of Synopsis of the Mental Component of Health Study (MCS) or count of Short Form 36 of Synopsis of the Physical Component of Health Study (PCS).

In one embodiment of all the foregoing aspects of the invention, the method comprises administering to the subject or to each subject in the population; a) a first dose amount of the antibody, or antigen-binding portion thereof, according to a first periodicity of about once every 4 weeks; and b) administering a second dose amount that is approximately 40-60% of the first dose dose of the antibody, or antigen-binding portion thereof, according to a second periodicity of about once every week.

In another embodiment of all of the foregoing aspects of the invention, the method comprises administering to the subject or to each subject in the population: a) approximately 200 mg ABT-874 once every four weeks for two doses; and b) approximately 100 mg ABT-874 every four weeks thereafter.

In yet another embodiment of all the foregoing aspects of the invention, the method comprises administering to the subject or to each subject in the population: a) approximately 200 mg ABT-874 at weeks 0 and 4; and b) approximately 100 mg of ABT-874 at week 8 and every 4 weeks thereafter. In one embodiment, the antibody is ABT-874 (ie Briakinumab ™).

In a further aspect, the invention provides a method of treating psoriasis in a subject comprising administering to the subject: a) approximately 200 mg of an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit IL-12 and / or IL-23, once every four weeks for two doses; and b) about 100 mg of the antibody, or antigen-binding portion thereof, every four weeks thereafter, thereby treating psoriasis in the subject. In one embodiment, the antibody is ABT-874. In one embodiment, the psoriasis is plaque psoriasis, eg, chronic plaque psoriasis, such as moderate to severe chronic plaque psoriasis.

In still a further aspect, the invention provides a method of treating psoriasis in a subject comprising administering to the subject: a) approximately 200 mg of an antibody, or antigen-binding portion thereof, that is capable of binding to the subunit IL-12 and / or IL-23 p40, at weeks 0 and 4; and b) about 100 mg of the antibody, or antigen-binding portion thereof, at week 8 and every 4 weeks thereafter, thereby treating psoriasis in the subject. In one embodiment, the antibody is ABT-874. In one embodiment, the psoriasis is plaque psoriasis, eg, chronic plaque psoriasis, such as moderate to severe chronic plaque psoriasis.

In still a further aspect, the invention provides a method of treating psoriasis in a subject which, which comprises administering to the subject: a) approximately 200 mg ABT-874 once every four weeks for two doses; and b) approximately 100 mg ABT-874 every four weeks thereafter, thereby treating psoriasis in the subject.

In one embodiment, the antibody is ABT-874. In one embodiment, the psoriasis is plaque psoriasis, eg, chronic plaque psoriasis, such as moderate to severe chronic plaque psoriasis.

In still a further aspect, the invention provides the method of treating psoriasis in a subject, which comprises administering to the subject: a) approximately 200 mg ABT-874 at weeks 0 and 4; and b) approximately 100 mg ABT-874 at week 8 and every 4 weeks thereafter, thereby treating psoriasis in the subject. In one embodiment, the antibody is ABT-874. In one embodiment, the psoriasis is plaque psoriasis, eg, chronic plaque psoriasis, such as moderate to severe chronic plaque psoriasis.

In one embodiment, psoriasis is chronic psoriasis. In one embodiment, the psoriasis is plaque psoriasis, eg, chronic plaque psoriasis. In another embodiment, the psoriasis is chronic psoriasis, eg, chronic plaque psoriasis. In yet another embodiment, the psoriasis is moderate to severe psoriasis, for example, moderate to severe plaque psoriasis, moderate to severe chronic psoriasis, or moderate to severe chronic plaque psoriasis. In one embodiment, the subject has had a clinical diagnosis of psoriasis for at least 6 months. In another embodiment, the subject has had stable plaque psoriasis for at least 2 months.

In one embodiment, the antibody is administered via subcutaneous injection.

In one embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention is capable of binding to an epitope of the p40 subunit of IL-12 and / or IL23.

In another embodiment, the antibody, or antigen-binding portion thereof, is capable of binding to the epitope of the p40 subunit when the p40 subunit is bound to the p35 subunit of IL-12. In yet another embodiment, the antibody, or antigen-binding portion thereof, is capable of binding to the epitope of the p40 subunit when the p40 subunit is bound to a p19 subunit, i.e., the p19 subunit of IL-23. In one embodiment, the antibody, or antigen-binding portion thereof, is capable of binding the p40 subunit epitope when the p40 subunit is bound to the p35 subunit of IL-12 and when the p40 subunit is bound to a subunit p19.

In one embodiment, the antibody, or antigen-binding portion thereof, binds to an epitope of the IL12 p40 subunit to which an antibody selected from the group consists of the Y61 and J695 junctions.

In another embodiment, the antibody is further capable of binding to a first heterodimer and is also capable of binding to a second heterodimer, where the first heterodimer comprises the p40 subunit of 11-12 and the p35 subunit of 11-12, and in where the second heterodimer comprises the p40 subunit of IL-12 and a p19 subunit, i.e. the p19 subunit of IL-23.

In a further embodiment, the antibody neutralizes the activity of the first heterodimer. In another embodiment, the antibody neutralizes the activity of the second heterodimer. In yet another embodiment, the antibody neutralizes the activity of the first heterodimer and the second heterodimer.

In a further embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with a Cl5or 1 x 109 M or less, or that inhibits the production of human IFNy with an IC50 1 x 1O '10 M or less.

In one embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention, cleaves the p40 subunit of IL-12 with a Kd 1 x 1O '10 M or less or a dissociated constant of 1 x 1 O '3 s'1 or less, as determined by surface plasmon resonance.

In one embodiment, the isolated antibody, or antigen-binding portion thereof, used in the methods of the invention is a chimeric antibody, a humanized antibody, or a human antibody.

In another embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention has a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 25 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26;

In a further embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention has a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 27 and a light chain CDR2 that comprises the amino acid sequence of the

SEQ ID NO: 28.

In one embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention has a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 29 and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 30.

In another embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention is capable of binding to an interleukin comprising a p40 subunit. In one embodiment, the interleukin comprises a p40 subunit and a p35 subunit, for example, the interleukin is IL-12. In another embodiment, the interleukin comprises a p40 subunit and a p19 subunit, for example, the Interleukin is IL-23. In yet another embodiment, the antibody, or antigen-binding portion thereof, neutralizes the activity of the interleukin.

In one embodiment, the antibody, or antigen-binding portion thereof, binds to an epitope of the p40 subunit.

In one embodiment, the antibody, or antigen-binding portion thereof, is administered to a subject in a pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise an additional agent, such as a therapeutic agent, for example, budenoside, epidermal growth factor, corticosteroids, cyclosporine, suIfasalazine, aminosalicylates, 6mercaptopurine, azathioprine, metronidazole, lipoxygenase inhibitors, mesalamine, olsalazine, antioxidants, thromboxane inhibitors, IL-1 receptor antagonists, monoclonal anti-IL-Ιβ antibodies, monoclonal anti-IL-6 antibodies, growth factors, elastase inhibitors, pyridinyl-imidazole compounds, antibodies or agonists of TNF, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF, antibodies to CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or its ligands, methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids, prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, IRAK, NIK, IKK, p38, MAP kinase inhibitors, enzymatic inhibitors of IL-Ιβ converters, enzymatic inhibitors of TNFa, T-cell signaling inhibitors, metalloproteinase inhibitors, suIfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble soluble cytosine receptors, p55 TNF receptor, soluble p75 TNF receptor, sIL-IRI, SIL-1RII, SIL-6R, anti-inflammatory cytosines, IL-4, IL-10, IL-11, IL-13 and TGFp.

In another embodiment, the therapeutic agent in the pharmaceutical composition administered to the subject may be selected from the group consisting of anti-TNF antibodies and antibody fragments thereof, TNFR-Ig constructs, TACE inhibitors, PDE4 inhibitors, corticosteroids, budenoside , dexamethasone, sulfasalazine, 5-aminosalicylic acid, olsalazine, enzyme inhibitors that convert IL-Ιβ, IL-1 ra, inhibitors of tyrosine kinase, 6-mercaptopurines and IL-11.

In another embodiment, the therapeutic agent can be selected from the group consisting of corticosteroids, prednisolone, methylprednisolone, azathioprine, cyclophosphamide, cyclosporine, methotrexate, 4-aminopyridine, tizanidine, interferon20 31a, interferon-βΐ b, copolymer 1, hyperbaric oxygen, immunoglobulin , clabribine, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAPII, GM-CSF, FGF antibodies or agonists , PDGF, antibodies to CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or its ligands, methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, buprofen, corticosteroids, prednisolone, phosphodiesterase inhibitors, adenosine agonists, anti complement, adrenergic agents, IRAK, NIK, IKK, p38 or MAP kinase inhibitors, IL-Ιβ converting enzyme inhibitors, TACE inhibitors, T cell signaling inhibitors, kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptop or kidneys, angiotensin-converting enzyme inhibitors, soluble cytosine receptors, soluble p55 TNF receptor, soluble p75 TNF receptor, sIL-IRI, slL-1RII, slL-6R, SIL-13R, ant¡-P7s, p-selectin glycoprotein ligand, anti-inflammatory cytosines, IL-4, IL10, IL-13 and TGFp.

In one embodiment, the antibody, or antigen binding portion thereof, used in the methods of the invention binds human IL-12 and / or human IL-23 and dissociates from human IL-12 and / or human IL-23 respectively with a Kd 1 x 10 '1° M or less and a dissociated constant of 1 x 10 '3 s'1 or less, as determined by surface plasmon resonance. In one embodiment, the antibody, or antigen-binding portion thereof, cleaves from human IL-12 and / or human IL-23 with a dissociated constant of S1 1 x 10-4 or less. In another embodiment, the antibody, or antigen-binding portion thereof, cleaves human IL-12 and / or human IL-23 with a dissociated constant of 1 x 10-5s-1 or less.

In another embodiment, the antibody, or antigen-binding portion thereof, binds human IL-12 and human IL-23 and dissociates from human IL-12 and / or human IL-23, respectively, with a dissociated constant of 1 χ 10 '2 s'1 or less, as determined by surface plasmon resonance. In yet another embodiment, the antibody, or antigen-binding portion thereof, cleaves from human IL-12 and / or human IL-23 with a dissociated constant of 1 χ 10 '3 s'1 or less. In yet another embodiment, the antibody, or antigen-binding portion thereof, cleaves human IL-12 and / or human IL-23 with a dissociated constant of 1 χ 10 '4 s'1 or less. In another embodiment, the antibody, or antigen-binding portion thereof, cleaves from human IL-12 and / or human IL-23 with a dissociated constant of 1 x 10 '5s'1 or less.

In yet another embodiment, the antibody, or antigen-binding portion thereof, binds human IL-12 and human IL-23 and dissociates from human IL-12 and / or human IL-23, respectively, with a Kd 1.34 χ 10 '1° M or less. In yet another embodiment, the antibody, or antigen-binding portion thereof, binds human IL-12 and human IL-23 and dissociates from human IL-12 and / or human IL-23, respectively, with a Kd from 9.74 χ 10 '11 M or less. In one embodiment, the antibody, or antigen-binding portion thereof, is a recombinant antibody, or antigen-binding portion thereof.

In one embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention is a neutralizing antibody, eg, neutralizes the activity of human IL-12 and / or human IL-23. In one embodiment, the neutralizing antibody, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 1 O '9 M or less. In another embodiment, the neutralizing antibody, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 of 1 x 10 '1° M or less. In yet another embodiment, the neutralizing antibody to, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 of 1 x 10 '11 M or less. In yet another embodiment, the neutralizing antibody, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro phytohemagglutinin blast proliferation assay (PHA assay) with an IC50 of 1 x 10 '7 M or less. In yet another embodiment, the neutralizing antibody, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 of 1 x 10 '8 M or less. In one embodiment, the neutralizing antibody, or antigen-binding portion thereof, inhibits the production of human IFNy with an IC50 of 1 x 10 '1θ M or less. In yet another embodiment, the neutralizing antibody, or antigen-binding portion thereof, inhibits the production of human IFNy with an IC50 1 x 10 '11 M or less. In a still further embodiment, the neutralizing antibody, or antigen-binding portion thereof, inhibits the production of human IFNy with an IC50 5x10 '12 M or less.

In one embodiment, the antibody, or an antigen-binding portion thereof, used in the methods of the invention

a) Inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '9 M or less;

<td></td><td>b)</td><td>has a heavy chain CDR3 comprising</td><td>the</td>

<td> 10</td><td>sequence</td><td>amino acid of SEQ ID NO: 25; and</td><td></td>

<td></td><td>c)</td><td>has a light chain CDR3 comprising</td><td>the</td>

<td></td><td>sequence</td><td colspan="2">amino acid of SEQ ID NO: 26. In a</td>

modality, the antibody further has a heavy chain CDR2 comprising the amino acid sequence of SEQ ID

NO: 27; and a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 28. In yet another embodiment, the antibody, op antigen binding option thereof, also has a heavy chain CDR1 comprising the amino acid sequence from SEQ ID NO: 29; and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 30. In yet another embodiment, the antibody, or antigen-binding portion thereof, further inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '1° M or less. In yet another embodiment, the antibody, or antigen-binding portion thereof, further inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 1 O '11 M or less.

In one embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31, and a variable chain region light comprising the amino acid sequence of SEQ ID NO: 32.

In one embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention comprises a heavy chain constant region selected from the group consisting of constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE. In one embodiment, the heavy chain constant region of the antibody is IgG1. In another embodiment, the antibody is a Fab fragment, F (ab ') 2 fragment, or a single chain Fv fragment.

In one embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention cleaves human IL-12 and / or human IL-23 with a Kd 1 x 10 '1° M or less and binds to an epitope on the p40 subunit of human IL-12 and / or human IL-23.

In one embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention is a human antibody, or antigen-binding portion thereof, which

a) Dissociate from human IL-12 with a dissociated constant of 1 x 10 '3 s'1 or less, as determined by surface plasmon resonance;

b) has a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and

c) has a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26.

In another embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention cleaves human IL-12 with a dissociated constant of 1 x 10 '4 s 1 or less. In a further embodiment, the human antibody, or antigen-binding portion thereof, cleaves human IL-12 with a dissociated constant of 1 x 105 s1 or less.

In one embodiment, the antibody, or antigen binding portion thereof, used in the methods of the invention is a human antibody, or antigen binding portion thereof, that binds human IL-12 and comprises:

a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 26; and a heavy chain CDR3 domain comprising the amino acid sequence of SEO ID NO: 25.

In one embodiment, the antibody, or antigen-binding portion thereof, has a light chain variable region (LCVR) that has a CDR3 domain that comprises the amino acid sequence of SEQ ID NO: 26, and has a variable region heavy chain (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 25. In another embodiment, the antibody, or antigen-binding portion thereof, comprises an LCVR which further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 28 and an HCVR which further comprises a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27. In yet another embodiment, LCVR further has the CDR1 domain comprising the amino acid sequence of SEQ ID NO: 30 and HCVR has a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 29.

In one embodiment, the antibody, or antigen-binding portion thereof, binds human IL-12 and human IL-23 and is the J695 antibody (also referred to as ABT-874), or an antigen-binding portion thereof.

In one embodiment, the antibody, or antigen-binding portion thereof, binds human IL-12 and human IL-23 and dissociates human IL-12 and / or human IL-23 with a Kd 1.34 x

10'1° M or less, and neutralizes human IL-12 and human IL-23.

In one embodiment, the antibody, or antigen-binding portion thereof, cleaves human IL-12 and / or human IL-23 with a Kd 9.74 x 10 '11 M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with a

Cl so of 1 χ 10 '7 M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with a Cl so of 1 χ 1Ο 'θ M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with a Cl so of 1 χ 10 '9 M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with a

1 x 10 'cl so1° M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with a Cl so of 1 χ 10 '11 M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits the production of

Human IFNy with an IC50 1 x 10 '1° M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits the production of human IFNy with an IC50 1 x 10 '11 M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits the production of human IFNy with an IC50 5 χ 10 '12 M or less.

In one embodiment, the antibody, or antigen-binding portion thereof, used in the methods of the invention inhibits IL-12 and IL-23 binding to its receptor in an IL-12 or IL-23 receptor binding assay. (RBA), respectively, with a

CI50 1 χ 10 '9 M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits IL-12 and IL-23 that bind to its receptor in an IL-12 or IL23 receptor binding assay (RBA), respectively, with an IC50 1 x 1O '10 M or less. In one embodiment, the antibody, or antigen-binding portion thereof, inhibits IL-12 and IL-23 that bind to its receptor in an IL-12 or IL-23 receptor binding assay (RBA), respectively, with a CI50 1 x 10 '11 M or less.

Brief Description of Drawings

Figure 1 shows the patient's disposition of the test. (The term "eow" refers to the dosage every two weeks).

Figure 2 shows the percentage of patients with at least 75% improvement in the area index and severity of psoriasis (PASI 75) during the 12-week portion of the test. By week 8, except for 200 mg χ 1 group, the percentage of patients having a PASI 75 response was statistically significantly higher (p <0.001) in each ABT-874 treatment group for each comparison with placebo based in an analysis of variation of observed data for the intention-to-treat population. (The term "eow" refers to every two weeks of dosing.)

Figure 3 shows the improvement in average percentage in the count of area index and severity of psoriasis (PASI) of the baseline. Data show that * p <0.001 for each ABT-874 treatment group compared to placebo at all time points (except eow 100 mg at week 1, p = 0.023) based on analysis of data variation observed for the intention-to-treat population. (The term "eow" refers to the dosage every two weeks).

Figures 4A-C show the percentage of patients who maintained a response of PASI 50, PASI 75 and PASI 90, respectively, in week 24 of the test, that is, in 12 weeks after the suspension of the administration of the antibody.

Figure 4D shows the percentage of patients who maintain a PASI 75 response over time during the test period at week 24.

Figure 5A shows the average percentage improvement from baseline in PASI counts from week 4 to week 1 2.

Figure 5B shows the average percentage improvement from baseline in PASI counts from week 4 to week 12 of subsequent repeated treatment.

Figure 6A shows the time concentration curve of serum for IV dosage of ABT-874.

Figure 6B shows the serum concentration time curve for SC dosing of ABT-874.

Figure 7A shows the percentage of patients who again achieved a PASI 75 response after repeated treatment.

Figure 7B shows the average time to achieve a PASI 75 response across all ABT-874 dosing groups during repeat treatment.

Figure 7C shows the average time of loss of a 5 PASI 75 response after the first 12 weeks of treatment.

Figure 7D shows the percentage of patients achieving a PGA count of 0 or 1 after repeated treatment.

Figures 8A-8B show the alignments of the heavy chain variable region amino acid sequence of a series of human antibodies that bind human IL-12 compared to the Cos-3 / JH3 and Dpl18 Lv1042 germline sequences. Kabat numbering is used to identify amino acid positions. For the wild type Joe 9, the complete sequence is shown. For the other antibodies, only these amino acid positions are shown that differ from the wild type Joe 9.

Figures 8C-8D show the light chain variable region amino acid sequence alignments of a series of human antibodies binding human IL-12. Kabat numbering is used to identify amino acid positions. For the wild type Joe 9, the complete sequence is shown. For the other antibodies, only these amino acid positions differing from the wild type Joe 9 are shown.

Figures 9A-9E show the CDR positions in the Y61 antibody heavy chain that were mutated by site-directed mutagenesis and the respective amino acid substitutions at each position. The graphs to the right of the figures show the dissociations for the substituted antibodies (black bars) with respect to the unmutated Y61 (open bar).

Figures 9F-9H show the CDR positions in the Y61 antibody light chain, which were mutated by site-directed mutagenesis and the respective amino acid substitutions at each position. The graphs to the right of the figures show the dissociates for the substituted antibodies (black bars) with respect to unmutated Y61 (open bar).

Figure 10 shows the average PASI count over the repeated treatment time. The mean PASI (SD) counts at repeat treatment for all 58 patients who received repeat treatment after loss of PASI 50 response during the observation / repeat treatment phase. N values represent the number of patients receiving repeat treatment. EOW = every two weeks; PASI = Psoriasis Area and Severity index.

Figure 11 shows the PASI 75 loss time during the observation / repeat treatment phase. The time of loss of response during the observation / repeated treatment phase is plotted; This loss is followed by the main achievement of a PASI 75 response in the first 12 weeks of the endpoint. Loss of response was calculated from the time of the last dose received during the first 12 weeks of the study. N values represent the number of patients who lose response. EOW = every two weeks; PASI = Psoriasis Area and Severity index.

Figure 12 shows the time to reach PASI 75 during the observation / repeat treatment phase. Among patients who achieved a PASI 75 response after repeated ABT-874 treatment during the observation / repeat treatment phase, the time to achieve response is represented for each ABT874 treatment group. The values of N represent the number of patients who achieved the response. EOW = every two weeks; PASI = Psoriasis Area and Severity index.

Figure 13 shows the percentage of patients who achieved PASI 75 and PASI 90 at week 12.

Figures 14A-14D show the percentage of patients who achieved PASI 75 and PASI 90 at week 12 in four specific body regions: (A) head and neck; (B) upper extremities; (C) torso; and (D) lower extremities.

<td>The</td><td>Figure</td><td> 15</td><td>shows</td><td>the</td><td>percentage of</td><td>patients</td><td>than</td>

<td colspan="2">reached PASI</td><td>75 and</td><td>PASI 90</td><td>in</td><td>week 12.</td><td></td><td></td>

<td>The</td><td>Figure</td><td> 16</td><td>shows</td><td>the</td><td>percentage of</td><td>patients</td><td>than</td>

they reached PASI 75 at week 12 by baseline body weight.

Figure 17 shows the percentage of patients who achieved PASI 75 at week 12 in patients with and without a history of psoriatic arthritis.

Figure 18 shows the percentage of patients who achieved the PASI 75 response at week 12 in patients with severe or very severe baseline physician global assessment.

Figure 19 shows the percentage of patients who achieved the PASI 75 response at week 12 of baseline PASI.

Figure 20 shows the VERO study design from Example 12.

Figure 21 shows the target disposition through the VERO study of Example 12.

Figure 22 shows the PGA response of “Non-existent” or minimal ”at week 12 of the VERO study.

Figure 23 shows the PASI response rates at week 12 of the VERO study.

Figure 24 shows the maintenance of PGA 0/1 response rates from week 12 to week 52, analyzed using the non-responsive imputation from the VERO study.

Figure 25 shows the percentages of patients who maintain the PASI 75 and 90 responses at week 52, analyzed using the non-responsive imputation from the VERO study.

Figure 26 shows the timing of major adverse cardiac events relative to study drug dosage from the VERO study.

Figure 27 shows the study design of Example 13.

Figure 28 shows the percentage of patients who achieved PGA 0/1 (“Non-existent” or “Minimum) at week 12 *. PGA = Global Physician Assessment; non-responsive imputation; P <0.001, ABT-874 against placebo and ABT-874 against etanercept.

Figure 29 shows the percentage of patients who achieved a PASI 75 response at week 12 *. PASI = Psoriasis Area and Severity index; 'unanswered imputation; P <0.001, ABT-874 against placebo and ABT-874 against etanercept.

Figure 30 shows the percentage of patients who achieved a PASI 90 response at week 12 *. PASI = Psoriasis Area and Severity index; 'unanswered imputation; P <0.001, ABT-874 against placebo and ABT-874 against etanercept.

Figure 31 shows the percentage of patients who achieved a PASI 100 response at week 12 *. PASI = Psoriasis Area and Severity index; 'unanswered imputation; P <0.001, ABT-874 against placebo and ABT-874 against etanercept.

Figure 32 shows the study design in Example 14.

Figure 33 shows the percentage of patients who achieved a PGA 0/1 (“Nonexistent” or “Minimum) in the week.

12. * P <0.001, ABT-874 versus placebo, τ0.00 <0.001, ABT-874 against ETN, NRI.

Figure 34 shows the percentage of patients achieving a PASI 75 response at week 12. * F <0.001, ABT-874 versus placebo, tP <0.001, ABT-874 against ETN, NRI.

IO Figure 35 shows the PASI 90 response speed at week 12. * P <0.001, ABT-874 vs. placebo, T P <0.001, ABT-874 against ETN, NRI.

Figure 36 shows the PASI 100 response speed at week 12. * P <0.001, ABT-874 versus placebo,

I5 ψ0.00 <0.001, ABT-874 against ETN, NRI.

Figure 37 depicts the results of certain Phase III clinical studies demonstrating the efficacy of ABT-874 in moderate to severe psoriasis, as described in Example 23.

Figure 38 depicts the provisional efficacy results and specifically, PASI 75 in time after treatment with ABT-874, as described in Example 23.

Figure 39 depicts the provisional efficacy results and specifically, PASI 100 in time after treatment with ABT-874, as described in Example 23.

Figure 40 depicts the frequency of MACE after administration with ABT-874, as described in Example 23.

Figure 41 shows the study design as described in Example 24. A = 2: 1 random assignment; B * = all patients who have a “nonexistent” or “minimal” overall physician evaluation count at week 12 were stratified by treatment received during the induction phase and again randomized to 2: 2: one.

Figure 42 shows the study flow and patient disposition as described in Example 24. 'Lack of efficacy was defined as a' mild 'or higher PGA count. ThetLack of efficacy was defined as a “moderate” or higher PGA count.

Figure 43 shows the physician's overall evaluation counts of “nonexistent” or “minimal” per treatment group during the induction phase as described in Example 24. Intention-to-treat analysis: patients with lack of evaluation counts global were considered non-responders. p <0.001 at week 12, based on the center-adjusted Cochran-Chimney-Haenszel test; p = 0.186 for week 1, and p <0.001 for weeks 4 to 12 based on the jicuadrado test.

Figure 44 shows the average improvement in area index and psoriasis severity counts for the treatment group during the induction phase as described in Example 24.

The intention-to-treat: loss of area index and severity of psoriasis analysis was imputed with the previous observation, excluding baseline, carried out. p <0.001 for all ANCOVA-based time points with treatment as a factor and baseline value as covariate.

Figure 45 shows the maintenance of the doctor's global evaluation counts of “nonexistent or“ minimum ”until week 52 (A), and the proportions reached by the PASI 75 (B) responses, and the PASI 100 (C) responses. ) Until the week

52, as described in Example 24. 'One patient in the ABT-874 group every 4 weeks was randomized again but did not receive any study drug in the maintenance phase. ^ Represents all patients who received ABT-874 in the Induction Phase, have a physician overall assessment count of "non-existent" or "minimal" at week 12, and was randomized again in the

Maintenance phase. The intention analysis to treat:

Patients with a lack of overall physician evaluation counts were considered non-responders (A). Intention to treat analysis: patients with a lack of PASI counts were considered non-responders (B and C). P-values based on the quicuadrado test.

Figure 46 shows the study design and dosing regimens as described in Example 25. toIn the week

24, patients who achieved £ 75 SBP and a PGA of 0 or 1 maintained their current MTX dosage weekly until week 51. The dosage was adjusted only for laboratory abnormalities. Patients in any treatment group who did not achieve PASI & 75 or a PGA of 0 or 1 or who lost response (defined as PASI <50 and PGA £ 3) after week 24 continued the test and were eligible to enroll in a study. Briakinumab ™ Open Label Extension Kit. MTX, methotrexate; PASI, activity index and Severity of Psoriasis; PGA, Global Physician Assessment.

Figure 47 shows the disposition of the patient as described in Example 25. MTX, methotrexate.

Figure 48 shows the Psoriasis Activity and Severity Index (PASI) responses up to week 52 as described in Example 25. The percentages of patients achieving PASI 75 (A), PASI 50 (B), PASI 90 ( C), and PASI 100 (D) were significantly higher in the Briakinumab ™ group than the methotrexate (MTX) group at week 8 (or earlier) and at all time points through week 52. * p <0001 against

MTX.

Non-responsive imputation was used to handle the missing data.

Figure 49 shows the average percentage improvements in Psoriasis Activity counts and Severity Index (PASI) from the baseline as described in Example 25. At each visit, the average percentage improvement from the baseline was significantly greater in the Briakinumab ™ group than the methotrexate (MTX) group (p <0 001 at all time points). The last observation carried out was used to handle the missing data.

Figure 50 shows the percentages of patients achieving a Global Physician Assessment (PGA) of 0 or 1 (“nonexistent” or “minimal”) up to week 52 as described in Example 25. * p <0001 against methotrexate ( MTX).

Figure 51 shows the baseline changes in the Dermatologic Quality of Life Index (DLQI) count per visit as described in Example 25. Patients in the Briakinumab ™ group have statistically significantly greater decreases from the baseline. in DLQI counts compared to the MTX group at all determined time points. * p <0 001 against methotrexate (MTX).

Detailed description of the invention

In order to more easily understand the present invention, certain terms are first defined.

The term "activity enhancing amino acid residue" 20 includes an amino acid residue that enhances the activity of the antibody. It should be understood that the activity enhancing amino acid residue may substitute an amino acid residue at a contact, hypermutation or preferred selective mutagenesis position and, in addition, more than one activity enhancing amino acid residue may be present within one or more CDRs . An activity enhancing amino acid residue includes, an amino acid residue that improves the binding specificity / affinity of an antibody, for example the anti-human IL-12 antibody that binds human IL-12. The activity enhancing amino acid residue is also desired to include an amino acid residue that enhances the neutralizing potency of an antibody, eg, the human IL-12 antibody which inhibits human IL-12.

The term "antibody" includes an immunoglobulin molecule comprised of four polypeptide chains, two heavy (H) chains, and two light (L) chains interconnected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2, and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into hypervariability regions, called complementarity determining regions (CDRs), interspersed with regions that are more conserved, called the framework regions. Each VH and

VL is made up of three CDRs and four FRs, arranged from amino58 terminal to carboxy-terminal in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In one embodiment, the antibody used in the compositions and methods of the invention is the antibody described in North American Patent No. 6,914,128, incorporated by reference herein. In another embodiment, the antibody used in the compositions and methods of the invention is the ABT-874 antibody (also designated J695; Abbott Laboratories).

The term "antigen binding portion" of an antibody (or "antibody portion") includes fragments of an antibody that retain the ability to specifically bind an antigen (eg, hLL-12). It has been shown that the antigen binding function of an antibody can be performed by the fragments of a full length antibody. Examples for joining fragments within the term "antigen binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a fragment F (ab ')2, a bivalent fragment comprising two Fabs fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the single arm VL and VH domains of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341: 544-546), consisting of a VH domain; and (vi) an isolated complementary determining region. Furthermore, although the two Fv fragment domains, VL and VH, are encoded for separate genes, they can be linked, using recombinant methods, by a synthetic linker that allows them to be made as a single protein chain in which the VL and VH combine to form monovalent molecules (known as single chain Fv (scFv); see eg Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Nati. Acad. Sel . USA 85: 5879-5883). Such single chain antibodies are also desired to be understood within the term "antigen binding portion" of an antibody. Other forms of single chain antibodies, such as diabodies are also understood. Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, using a linker that is too short allowing it to combine between the two domains on the same chain, thereby forcing the domains to combine with complementary domains from another chain and create two antigen binding sites (see for example, Holliger, P., et al. (1993) Proc. Nati. Acad. Sci. USA 90: 6444-6448; Poljak, RJ, et al. (1994) Structure 2: 1121-1123). Still further, an antibody or antigen-binding portion thereof may be part of larger immunoadhesion molecules, formed by covalent or non-covalent association of the antibody or antibody portion with one or more other proteins or peptides.

Examples of such immunoadhesion molecules include the use of the central streptavidin region to make a tetrameric scFv molecule (Kiprlyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6: 93-101) and the use of a cysteine residue , a C-terminal pollhistldin tag and label peptide for making bi-and bilated scFv molecules (Kipriyanoy, SM, et al. (1994) Mol. Immunol. 31: 1047-1058). Antibody portions, such as Fab and F (ab ') fragments2They can be prepared from complete io antibodies using conventional techniques, such as digestion of papain or pepsin, respectively, from complete antibodies. Furthermore, the antibodies, antibody portions, and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein. Preferred antigen binding portions are whole domains or pairs of full domains.

The term "retromutation" refers to a process in which some or all of the somatically mutated amino acids of a human antibody are replaced with the corresponding germline residues of a homologous germline antibody sequence. The heavy and light chain sequences of the human antibody of the invention are separately aligned with the germline sequences in the VBASE database to identify the sequences with the highest homology. Differences in the human antibody of the invention are returned to the germline sequence by mutating the defined nucleotide positions encoding such a different amino acid. The role of each identified amino acid as well as the candidate for retromutation should be investigated for a direct or indirect role in antigen binding, and any amino acids found after mutation to affect any desirable characteristics of the human antibody should not be included in the final human antibody. ; As an example, the activity enhancing amino acids identified by the selective mutagenesis process will not undergo retromutation. To minimize the number of amino acids, these amino acid positions found because they are different from the closest germline sequence but identical to the corresponding amino acid in a second germline sequence consist of retromutation, they can remain, provided that the second germline sequence is identical and collinear to the sequence of the human antibody of the invention at least 10, preferably 12 amino acids, on both sides of the amino acid in question. Retromutation can occur at any stage of antibody optimization; preferably, retromutation occurs directly before or after the selective mutagenesis process. Preferably, retromutation occurs directly prior to the selective mutagenesis process.

The phrase "human interleukin 12" (abbreviated herein as hLL-12, or IL-12), as used herein, includes a human cytosine that is primarily secreted by macrophages and dendritic cells. The term includes a heterodimeric protein comprising a 35 kD subunit (p35) and a 40 kD subunit (p40) that are both linked together with a disulfide bridge. The heterodimeric protein is referred to as a "p70 subunit. The structure of human IL-12 is further described in, for example, Kobayashi, et al. (1989) J. Exp Med. 170: 827-845; Seder, et al. (1993) Proc. Nati.

Acad. Sci. 90: 10188-10192; Ling, et al. (1995) J. Exp Med. 154: 116-127; Podlaski, et al. (1992) Arch. Biochem. Biophys. 294: 230-237. The term human IL-12 is intended to include recombinant human IL-12 (rhlL-12), which can be prepared by standard recombinant expression methods.

The terms "Kabat numbering", "Kabat definitions" and "Kabat labeling" are used interchangeably herein. These terms, which are recognized in the art, refer to a numbering system of amino acid residues that are more variable (i.e. hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or a antigen-binding portion thereof (Kabat et al. (1971) Ann. NY Acad, Sci. 190: 382-391 and, Kabat, EA, et al. (1991)

Sequences of Proteins of Immunological Interest, fifth edition,

US Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.

io Kabat numbering is used herein to indicate the positions of amino acid modifications made in the antibodies of the invention. For example, Y61 anti-IL-12 antibody can be mutated from serine (S) to glutamic acid (E) at position 31 of heavy chain CDR1 (H31S- »E), or glycine (G) can be mutated to tyrosine (Y) at position 94 of the light chain CDR3 (L94G- »Y).

The term "human antibody" includes antibodies that have variable and constant regions that correspond to human germline immunoglobulin sequences as described by Kabat et al. (See Kabat, et al. (1991) Sequences of Proteins of Immunological Interest, fifth edition, US Department of Health and Human Services, NIH Publication No. 91-3242). Human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (eg, mutations introduced by site-specific or site-specific random mutagenesis in vitro or, for example, in CDRs and in particularly the CDR3. Mutations are preferably introduced using, Λ the "selective mutagenesis process" described herein. The human antibody can have at least one position substituted by an amino acid residue, eg, an activity enhancing amino acid residue which is not encoded by the human germline immunoglobulin sequence.

The human antibody can have up to twenty positions substituted by amino acid residues that are not part of the human germline immunoglobulin sequence. In other modalities, up to ten, up to five, up to three or up to two positions are replaced. In a preferred embodiment, these replacements are within the CDR regions as described in detail below. However, the term "human antibody", as used herein, is not intended to include antibodies in which the CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto sequences of human structure.

The phrase "recombinant human antibody" includes human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (further described in Section II, below), antibodies isolated from a combinatorial, recombinant, human antibody library (further described in Section III, below), antibodies isolated from an animal (eg, a mouse) that is transgenic to human immunoglobulin genes (see eg, Taylor, LD, et al. (1992) Nucí. Acids Res. 20: 6287-6295) or prepared, expressed antibodies , created or isolated by any other means involving the splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences (see Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human

Services, NIH Publication No. 91-3242). In certain embodiments, however, such recombinant human antibodies undergo in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions. of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, it cannot naturally exist within the germline repertoire of human antibody in vivo. In certain embodiments, however, such recombinant antibodies are the result of the process of selective mutagenesis or retromutation, or both.

An "isolated antibody" includes an antibody that is substantially free of other antibodies that have different antigenic specificities (eg, an isolated antibody that specifically binds hlL-12 is substantially free of antibodies that specifically bind antigens except for hlL-12). An isolated antibody that specifically binds hlLio 12 can bind IL-12 molecules from other species (discussed in further detail below). Furthermore, an isolated antibody can be substantially free of other cellular material and / or chemicals.

A "neutralizing antibody" (or an "antibody that neutralizes hlL-12 activity") includes an antibody whose binding to hlL-12 results in inhibition of the biological activity of hlL-12. This inhibition of hlL-12 biological activity can be determined by measuring one or more indicators of hlL-12 biological activity, such as inhibition of human phytohemagglutinin blast proliferation in a phytohemagglutinin (PHA) proliferation assay, or inhibition of receptor binding in a human IL-12 receptor binding assay (see Example 3-Interferon-Gamma Induction Assay North American Patent No. 6,914,128). These indicators of biological activity of hlL-12 can be determined by one or more of several standard in vitro or in vivo assays known in the art (see Example 3 of North American Patent No. 6,914,128).

The term "activity" includes activities such as the binding specificity / affinity of an antibody for an antigen, eg, an anti-hLL-12 antibody that binds to an IL-12 antigen and / or the neutralizing potency of an antibody eg an anti-hLL-12 antibody whose binding to hlL-12 inhibits the biological activity of hlL-12, for example, inhibition of PHA blast proliferation or inhibition of receptor binding in a human IL-12 receptor binding assay (see Example 3 of North American Patent No. 6,914,128).

The phrase "surface plasmon resonance includes an optical phenomenon that allows the analysis of biospecific interactions in real time by detecting alterations in protein concentrations within a biosensor matrix, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ). For additional descriptions, see Example 5 of North American Patent No. 6,914, .128. and Jónsson, U., et al. (1993) Ann. Biol. Clin. 51: 19-26; Jónsson, U., et al. (1991) Biotechniques 11: 620-627; Johnsson, B., et al. (1995) J. Mol. Recognit. 8: 125-131; and Johnson, B., et al. (1991) Anal. Biochem. 198: 268-277.

The term "KORff ”, as used herein, is desired to refer to the dissociated constant for dissociation of an antibody from the antibody / antigen complex.

The term "Kd", As used herein, is desired to refer to the dissociation constant of a particular antibody-antigen interaction.

The phrase "nucleic acid molecule" includes molecules of

DNA and RNA molecules. A nucleic acid molecule can be single-stranded or double-stranded, but is preferably double-stranded DNA.

The phrase "isolated nucleic acid molecule", as used herein in reference to nucleic acids encoding antibodies or antibody portions (eg, VH, VL, CDR3) that bind hlL-12 including "isolated antibodies", includes a nucleic acid molecule in which the nucleotide sequences encoding the antibody or antibody portion are free from other nucleotide sequences encoding antibodies or antibody portions that bind antigens except hlL-12, the other sequences of which can naturally flanking nucleic acid in human genomic DNA. Thus, for example, an isolated nucleic acid of the invention encoding a VH region of an anti-IL12 antibody does not contain any other sequences encoding other VH regions that bind antigens except for IL-12. The phrase "isolated nucleic acid molecule" is also intended to include sequences encoding bivalent, bispecific antibodies, such as diabodies in which regions of

VH and VL do not contain any of the other sequences except for the diabody sequences.

The term "vector" includes a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double catenary DNA loop in which additional DNA segments can be ligated. Another type of vector is a viral vector, where additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (eg, bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).

Other vectors (eg, non-episomal mammalian vectors) can be integrated into the genome of a host cell for introduction into the host cell, and thereby replicate along with the host genome. Furthermore, certain vectors are capable of directing the expression of at least two other residues to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors"). Generally, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can alternatively be used as the plasmid which is the most generally used form of the vector. However, the invention is desired to include such other forms of expression vectors, such as viral vectors (eg, replication-defective retroviruses, adenoviruses, and adeno-associated viruses), which serve as equivalent functions.

The phrase "recombinant host cell" (or simply "host cell") includes a cell into which a recombinant expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular target cell but to the progeny of such a cell. Because certain modifications may occur in successive generations due to mutation or environmental influences, such progeny may, in fact, not be identical to the stem cell, but is still included within the scope of the term "host cell" as used in the present.

The term "modifier", as used herein, is intended to refer to change one or more amino acids in the antibodies or antigen-binding portions thereof. Change can occur by adding, substituting, or deleting an amino acid at one or more positions. The change can occur using known techniques, such as PCR mutagenesis.

The phrase "contact position" includes an amino acid position in the CDR1, CDR2 or CDR3 of the heavy chain variable region or the light chain variable region of an antibody which is occupied by an amino acid that comes into contact with the antigen in one of the twenty-six known antibody-antigen structures. If a CDR amino acid is in any of the 26 known solved structures of the antibody-antigen complexes in contact with the antigen, then this amino acid can be considered to occupy a contact position. Contact positions are more likely to be occupied by an amino acid that contacts the antigen than non-contact positions. Preferably a contact position is a CDR position that contains an amino acid that contacts the antigen in more than 3 of the 26 structures (> 11.5%). More preferably a contact position is a CDR position that contains an amino acid that contacts the antigen in more than 8 of the 25 structures (> 32%).

The term "hypermutation position" includes an amino acid residue that occupies the position in the CDR1, CDR2 or CDR3 region of the heavy chain variable region or the light chain variable region of an antibody that is considered to have a high frequency or probability for somatic hypermutation during in vivo affinity maturation of the antibody. "High frequency or probability for somatic hypermutation" includes frequencies or probabilities of a 5 to about 40% chance that the residue will undergo somatic hypermutation during in vivo affinity maturation of the antibody. It should be understood that all ranges within this stated range are also desired to be part of this invention, eg, 5 to about 30%, eg, 5 to about 15%, eg, 15 to about 30%.

The term "preferred selective mutagenesis position" includes an amino acid residue that occupies a position in the CDR1, CDR2 or CDR3 region of the heavy chain variable region or the light chain variable region that can be considered to be a contact and a position of hypermutation.

The phrase "selective mutagenesis process" includes a method of enhancing the activity of an antibody by selecting and individually transforming the CDR amino acids for at least one preferred selective mutagenesis, hypermutation, and / or contact position. A "selectively transformed" human antibody is an antibody that contains a mutation at a selected position that uses a selective mutagenesis process. In another embodiment, the selective mutagenesis process is desired to provide a method of selected individual amino acid residues preferably mutated in the heavy chain variable region CDR1, CDR2 or CDR3 (hereinafter H1, H2, and H3, respectively), or CDR1, CDR2, or CDR3 of the light chain variable region (hereinafter designated L1, L2, and L3, respectively) of an antibody. Amino acid residues can be selected from selective mutagenesis positions

ΊΊ preferred, contact positions, or hypermutation positions. Individual amino acids are selected based on their position in the light or heavy chain variable region. It should be understood that a hypermutation position may also be a contact position. In one embodiment, the selective mutagenesis process is a "targeted process". The language "directed process" is desired to include a method of selected individual amino acid residues preferably mutated into CDR1, CDR2 or CDR3 of the heavy chain variable region or CDR1, CDR2 or ODR3 of the light chain variable region of a antibody in a targeted manner, eg, a "Group Driven Process or" CDR Driven Process ". In the "Group Driven Process", the individual amino acid residues in particular the groups that target selective mutations including groups I (including L3 and H3), II (including H2 and L1) and III (including L2 and H1), the groups that are listed in order of preference for addressing. In the "CDR Driven Process", individual amino acid residues in particular CDRs are targeted for selective mutations in the order of preference by targeting as follows: H3, L3, H2, L1, H1 and L2. The selected amino acid residue is mutated, for example, to at least two other amino acid residues, and the effect of the mutation on the activity of the antibody is determined. Activity is measured as a change in the binding specificity / affinity of the antibody, and / or neutralizing potency of the antibody. It should be understood that the selective mutagenesis process can be used for optimization of any antibody derived from any source including phage display, transgenic animals with germline genes of human IgG, human antibodies isolated from human B cells. Preferably, the selective mutagenesis process is used in antibodies that cannot be optimized and also uses phage display technology. It should be understood that antibodies from any source including phage display, transgenic animals with germline genes of human IgG, human antibodies isolated from human B cells can be back-mutated before or after the selective mutagenesis process.

The term "activity enhancing amino acid residue" includes an amino acid residue that enhances the activity of the antibody. It should be understood that the activity enhancing amino acid residue may substitute an amino acid residue at a preferred selective mutagenesis position, contact position, or a hypermutation position, and, in addition, more than one activity enhancing amino acid residue may be present within of one or more CDRs. An activity enhancing amino acid residue includes, an amino acid residue that improves the binding specificity / affinity of an antibody, for example the anti-human IL-12 antibody that binds human IL-12.

The activity enhancing amino acid residue is also desired to include an amino acid residue that enhances the neutralizing potency of an antibody, eg, the human IL-12 antibody that inhibits human IL-12.

The term "Cmax"Refers to the maximum concentration or maximum serum or plasma of an agent observed in a subject after administration.

The term "Tmax”Refers to the time in which Cmax occurred.

The term "bioavailability" or "F%" refers to a fraction or percentage of a dose which is absorbed and enters the systemic circulation after administration of a given dosage form. The agent dose can be administered through any route, and preferably via intravenous or subcutaneous injection.

The term "combination" as in the phrase "a first agent in combination with a second agent" includes the co-administration of a first agent and a second agent, which for example can be dissolved or intermixed in the same pharmaceutically acceptable carrier, or the administration of a first agent, followed by the second agent, or the administration of the second agent, followed by the first agent. The present invention, therefore, includes combination therapeutic treatment methods and combination pharmaceutical compositions.

The term "concomitant" as in the phrase "concomitant therapeutic treatment" includes administering one agent in the presence of a second agent. A concomitant therapeutic treatment method includes methods in which the first, second, third, or additional agents are co-administered. A concomitant therapeutic treatment method also includes methods in which the first or additional agents are administered in the presence of a second or additional agents, where the second or additional agents, for example, may have been previously administered. A concomitant therapeutic treatment method can be performed in stages by different performers. For example, a performer may administer a first agent to a subject and a second agent may administer a second agent to the subject, and the administration steps may be performed at the same time, or nearly the same time, or at distant times, provided the first agent (and additional agents) are after administration in the presence of the second agent (and additional agents). The performer and the subject can be the same entity (eg human).

The term "combination therapy", as used herein, refers to the administration of two or more therapeutic substances, for example, an anti-IL-12 antibody, anti-IL-23, and another drug. The other drugs can be administered concomitantly with, before, or after administration of an anti-IL-12 antibody, anti-IL-23.

The term "dosage", as used herein, refers to the administration of a substance (eg, an anti-IL-12 antibody, anti-IL-23) to achieve a therapeutic objective (eg, treatment of psoriasis).

As used herein, the term "5-dose amount" refers to the amount, eg, milligrams (mg), of the substance which is administered to the subject. In one embodiment, the dose amount is a fixed dose, for example, it is not dependent on the weight of the subject to which the substance is administered. In another embodiment, the dose amount is not a fixed dose, for example, it is dependent on the weight of the subject to which the substance is administered. Exemplary dose amounts, eg, fixed dose amounts, for use in the methods of

<td></td><td>the invention</td><td colspan="2">include,</td><td>approximately</td><td> 100</td><td>mg,</td>

<td></td><td>approximately</td><td> 110</td><td>mg,</td><td>approximately</td><td> 120</td><td>mg,</td>

<td> 15</td><td>approximately</td><td> 130</td><td>mg,</td><td>approximately</td><td> 140</td><td>mg,</td>

<td></td><td>approximately</td><td> 150</td><td>mg,</td><td>approximately</td><td> 160</td><td>mg,</td>

<td></td><td>approximately</td><td colspan="2">170 mg,</td><td>approximately</td><td>180 mg</td><td>, or</td>

<td></td><td>approximately</td><td> 190</td><td>mg,</td><td>approximately</td><td> 200</td><td>mg,</td>

<td></td><td>approximately</td><td> 210</td><td>mg,</td><td>approximately</td><td> 220</td><td>mg,</td>

<td> 20</td><td>approximately</td><td> 230</td><td>mg,</td><td>approximately</td><td> 240</td><td>mg,</td>

<td></td><td>approximately</td><td> 250</td><td>mg,</td><td>approximately</td><td> 260</td><td>mg,</td>

<td></td><td>approximately</td><td> 270</td><td>mg,</td><td>approximately</td><td> 280</td><td>mg,</td>

<td></td><td>approximately</td><td>290 mg,</td><td colspan="2">or about 300</td><td>mg. In</td><td>yet</td>

In another embodiment, the dose amount is about 100 to about 300 mg. In still another embodiment, the dosage amount is about 100 to about 200 mg. Interval intermediates at the intervals cited above are also contemplated by the invention. For example, ranges that have any one of these values as the upper or lower limits are also desired to be part of the invention, for example, about 110 mg to about 170 mg, about 150 mg to about 220 mg, etc.

As used herein, the term "periodicity" as it relates to the administration of a substance (eg, an antibody that binds p40 to the IL-12 and / or IL-23 subunit) refers to a recurring cycle (regular) to administer the substance to a subject. In one embodiment, the recurring cycle of administration of the substance to the subject achieves a therapeutic goal. The periodicity of administration of the substance can be approximately once a week, once every two weeks, approximately once every three weeks, approximately once every 4 weeks, approximately once every 5 weeks, approximately once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, about once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, about once every 16 weeks, about once every 17 weeks, about once every 18 weeks, about once every 19 weeks, about once every 20 weeks, about once every 21 weeks, about once every 22 weeks, about once every 23 weeks, about once every 24 weeks, about once every 5-10 days, about once every 10-20 days, about once every 10-50 days, about once every 10-100 days, about once every 10-200 days, about once every 25-35 days, about once every 20-50 days, about once every 20-100 days, about once every 20-200 days, about once every 30-50 days, about once every 30-90 days, about once every 30-100 days, about once every 30-200 days, about once every 50-150 days, about once every 50-200 days, about once every 60-180 days, or about once every 80-100 days. The periodicity intermediary at the times mentioned above are also contemplated by the invention. The interval intermediary at the intervals cited above are also contemplated by the invention. For example, ranges having any of these values as the upper or lower limits are also desired to be part of the invention, for example, about 110 days to about 170 days, about 160 days to about 220 days, etc.

As used herein, the phrase "periodicity of about once every 4 weeks" as it relates to the administration of a substance (eg, an antibody that binds p40 to the IL-12 and IL-23 subunit), refers to a recurring (regular) cycle to administer the substance to a subject of about once every 4 weeks, about once every 28 days, or about once every month. In one embodiment, the recurring cycle of administering the substance to the subject achieves or maintains a therapeutic goal (eg, treating psoriasis), or alone or in conjunction with other recurring cycles (eg, if a first periodicity, then in conjunction with a second and / or third periodicity, if a second periodicity, then together with a first and / or third periodicity; and if a third periodicity, then together with a first and second periodicity) to administer the substance. Preferably the substance is administered once every 22-34 days, every 24-32 days, even more preferably every 26-30 days (eg every 26, 27, 28, 29 or 30 days), and more preferably every 28 days.

As used herein, the phrase "periodicity of about once every 12 weeks" as it relates to the administration of a substance (eg, an antibody that binds p40 to the IL-12 and IL-23 subunit), refers to a recurring (regular) cycle of administering the substance to a subject of approximately once every 12 weeks, approximately once every 84 days, or approximately once every 3 months. In one embodiment, the recurring cycle of administering the substance to the subject achieves or maintains a therapeutic goal (eg, treating psoriasis), or alone or in conjunction with other recurring cycles (eg, if a first periodicity, then in conjunction with a second and / or third periodicity, if a second periodicity, then together with a first and / or third periodicity; and if a third periodicity, then together with a first and second periodicity) of administering the substance.

Preferably the substance is administered once every 78-90 days, every 80-88 days, even more preferably every 82-86 days (eg, every 82, 83, 84, 85 or 86 days), and more preferably every 84 days.

The "duration of a periodicity" refers to a time over which the recurring cycle of administration occurs.

For example, a duration of the periodicity of administration of a substance may be approximately 12 weeks during which the periodicity of administration is approximately once every week. For example, a periodicity duration may be approximately 6 weeks during which the administration periodicity is approximately once every 4 weeks, for example, the substance is administered at week zero and at week four.

The periodicity duration can be approximately 1

<td>week,</td><td>approximately</td><td> 2</td><td>weeks, approximately</td><td> 3</td>

<td>weeks,</td><td>approximately</td><td> 4</td><td>weeks, approximately</td><td> 5</td>

<td>weeks,</td><td>approximately</td><td> 6</td><td>weeks, approximately</td><td> 7</td>

<td>weeks,</td><td>approximately</td><td> 8</td><td>weeks, approximately</td><td> 9</td>

<td>weeks,</td><td>approximately</td><td> 10</td><td>weeks, approximately</td><td> 11</td>

<td>weeks,</td><td>approximately</td><td> 12</td><td>weeks, approximately</td><td> 15</td>

<td>weeks,</td><td>approximately</td><td> 20</td><td>weeks, approximately</td><td> 25</td>

<td>weeks,</td><td>approximately</td><td> 30</td><td>weeks, approximately</td><td> 35</td>

<td>weeks,</td><td>approximately</td><td> 40</td><td>weeks, approximately</td><td> 45</td>

<td>weeks,</td><td>approximately</td><td> 50</td><td>weeks, approximately</td><td> 52</td>

<td>weeks,</td><td>approximately</td><td> 55</td><td>weeks, approximately</td><td> 60</td>

<td>weeks,</td><td>approximately</td><td> 70</td><td>weeks, approximately</td><td> 80</td>

<td>weeks,</td><td>approximately !</td><td colspan="3">90 weeks, or about 100</td>

<td>weeks,</td><td>or longer.</td><td>In</td><td>a modality, the duration</td><td>of</td>

Periodicity is for a length of time necessary or required to achieve a therapeutic objective, for example, treatment, maintenance of treatment, etc. for example, they maintain a count of PASI 50, PASI 75, PASI 90, PASI 100, or PGA of count 0 or 1. The durations of a periodicity broker at the times mentioned above are also contemplated by the invention.

The periodicity duration can be approximately 4

<td>weeks,</td><td>approximately</td><td> 8</td><td>weeks,</td><td>approximately</td><td> 12</td>

<td>weeks,</td><td>approximately</td><td> 16</td><td>weeks,</td><td>approximately</td><td> 20</td>

<td>weeks,</td><td>approximately</td><td> 24</td><td>weeks,</td><td>approximately</td><td> 28</td>

<td>weeks,</td><td>approximately</td><td> 32</td><td>weeks,</td><td>approximately</td><td> 36</td>

<td>weeks,</td><td>approximately</td><td> 40</td><td>weeks,</td><td>approximately</td><td> 44</td>

<td>weeks,</td><td>approximately</td><td> 48</td><td>weeks,</td><td>approximately</td><td> 52</td>

weeks, or longer. The periodicity duration can be at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, so minus about 28 weeks, at least about 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, or at least about 52 weeks.

Furthermore, the periodicity duration can be at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 15 weeks, at least about 20 weeks, at least about 25 weeks, at least about 30 weeks, at least about 35 weeks, at least about 40 weeks, for at least about 45 weeks, at least about 50 weeks, at least about 55 weeks, at least about 60 weeks, at least about 70 weeks, at least about 80 weeks, at least about 90 weeks, or at least about

100 weeks.

The term "treated," "treat," or "treatment" includes the reduction or relief of at least one symptom associated with or caused by the condition, disorder, or disease to be treated. For example, treatment may be to reduce one or more symptoms of a disorder or to end eradication of a disorder. "Treatment or" treat "(eg, treating psoriasis) means achieving or maintaining a therapeutic goal. "Treatment" or "treat" can mean maintaining a response to a previous treatment (eg, a previous response achieved after the administration of a first quantity of doses according to a first periodicity; or achieved after the administration of a first quantity of doses according to a first periodicity and a second quantity of doses according to a second periodicity; or reached after the administration of a first quantity of doses according to a first periodicity and a first or second quantity of doses according to a second periodicity, and a first, second, or third quantity of doses according to a third periodicity . "Treating" or "treating psoriasis can mean achieving or maintaining a PGA count of 0/1 or a response count of PASI 50, PASI 75, PASI 90, or PASI 100 for a period of time during or after the treatment (for example, at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 52, 54, 56, 58, or 60 weeks or longer). "Treating" or "treating" psoriasis can also mean achieving or maintaining a Quality of Life result

Related to Health (HRQOL). HRQOL results include Dermatologic Quality of Life Index (DLQI), visual analog scales for Ps-related pain (VAS-Ps) and psoriatic arthritis-related pain (VAS-PsA), Short Form 36 counts from the Mental Study Study component. Health (MCS) and Physical (PCS), and Total Activity Deterioration (TAI) counts. "Treating" or "treating" psoriasis may also mean achieving or maintaining a Clinically Important Minor Difference (MCID) for any of the HRQOL results provided herein, eg, any one or combination of DLQI, VAS25 Ps, VAS-PsA, MCS, PCS and TAI. "Treating" or "treating" psoriasis can also mean achieving or maintaining a clinically important least difference response rate (MCID) for any of the HRQOL results provided herein, eg, any one or combination of DLQI ,

VAS-Ps, VAS-PsA, MCS, PCS and TAI. "Treatment of or" treating "psoriasis may also mean achieving or maintaining a clinically significant reduction in any of the HRQOL results provided herein, eg, any one or combination of DLQI, VAS-Ps, VAS-PsA, MCS, PCS and TAI.

"Treating" or "treating" psoriasis can also mean achieving or maintaining a Nail Psoriasis Severity Index (NAPSI) count for a period of time during or after treatment (for example, at least 2, 4 , 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50,

52, 54, 56, 58 or 60 weeks or longer). "Treating or" treating "psoriasis can also mean achieving or maintaining any of the results provided herein in a certain percentage of a population of subjects (eg, at least about 10%, 15%, 20%, 25 %, 30%, 35%, 40%, 45%, 50%,

55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% of a population of subjects).

The term "kit as used herein" refers to a filled product comprising the components with which they administer the anti-IL-12, anti-IL-23 antibody of the invention for the treatment of an IL-12 related disorder . The kit preferably comprises a box or container containing the kit components. The box or container is fixed with a label or a protocol approved by the Ministry of Health and Consumption. The box or container contains the components of the invention that are preferably contained within plastic, polyethylene, polypropylene, ethylene, or propylene containers. The containers can be tubes or bottles with a lid. The kit may also include instructions for administering an anti-IL-12, anti-IL-23 antibody.

Various aspects of the invention are described in further detail in the following subdivisions.

I. Human Antibodies Binding to the p40 Subunit of Human IL-12 / Human IL-23

This invention provides methods and compositions for using human antibodies, or antigen-binding portions thereof, that bind human IL-12 for the treatment of psoriasis. The invention also includes methods and compositions for using an antibody that binds IL-12 and IL-23. Preferably, the human antibodies used in the invention are recombinant, neutralizing anti-human hLL-12 / IL-23 antibodies.

In one embodiment, the antibody used in the invention is the ABT-874 antibody (see North American Patent No. 6,914,128). ABT-874 is a fully human antibody against interleukin 12 (IL-12) and IL-23. Linked with great affinity to the p40 subunit common to IL-12 and IL-23, validated targets in the treatment of psoriasis (Ps).

Antibodies binding to the human IL-12 / IL-23 p40 subunit can be selected, for example, by analyzing one or more V cDNA libraries.L and VH human with hLL-12, for example by phage display techniques as described in Example 1 of the

North American Patent No. 6,914,128. Library analysis of

V cDNAL and VH Human initially identified a series of anti-IL-12 antibodies of which an antibody, referred to herein as "Joe 9" (or "Joe 9 wild type"), was further selected for development. Joe 9 is a relatively low affinity human IL-12 antibody (eg, a KORff of about 0.1 sec 1), is still useful to specifically bind and detect hLL-12. The affinity of the Joe 9 antibody was improved by driving the mutagenesis of heavy and light chain CDRs, producing a panel of light and heavy chain variable regions that were "mixed and matched" and further mutated, leading to numerous anti-hlL-antibodies. Additional 12 with increased affinity for hLL-12 (see Example 1, Figure 2 of North American Patent No. 6,914,128 (see Table 2 of Appendix A attached thereto)) and the sequence alignments of Figures 1A-D of North American Patent No.

6.9 1 4,128 (see Figure 8A-D herein).

Of these antibodies, the human anti-hLL-12 antibody referred to herein as Y61 demonstrated a significant improvement in binding affinity (eg, a KORapproximately 2 x 10 'ft4 sec1). The Y61 anti-hlL-12 antibody was selected for further affinity maturation by individually mutating specific amino acid residues within the heavy and light chain CDRs. Y61 amino acid residues were selected for site specific mutation (selective mutagenesis process) based on the amino acid residue occupying a preferred selective mutagenesis position, contact position and / or hypermutation. A summary of the substitutions at the selected positions on the heavy and light chain CDRs is shown in Figures 2A-2H of North American Patent No. 6,914,128 (Figures 9A-H herein). A preferred recombinant io neutralizing antibody of the invention, designated herein as J695 (also designated ABT-874 (Abbott Laboratories), resulting from a Gly to Tyr substitution at position 50 of the Y61 light chain CDR2s, and a substitution Gly to Tyr at the Y61 light chain CDR3 position.

Amino acid sequence alignments of the heavy and light chain variable regions of a panel of anti-IL-12 antibodies used in the invention, in the lineage of wild type Joe 9 to J695, are shown in Figures 1A-1D North American Patent No. 6,914,128 (Figures 8A-D herein). These sequence alignments allowed for the identification of consensus sequences for preferred heavy and light chain variable regions of antibodies of the invention that bind hlL-12, as well as consensus sequences for CDR3, CDR2, and CDR1, in the lineage of Joe 9 to J695. Furthermore, the analysis of mutagenesis of

Y61 briefly presented in Figures 2A-2H of the Patent

North American No. 6,914,128 (Figures 9A-H herein) allowed the identification of consensus sequences for the hlL-12 binding heavy and light chain variable regions, as well as consensus sequences for the binding CDR3, CDR2, and CDR1 hlL-12 in the Y61 to J695 lineage comprising sequences with Y61 modifications that still retain good hlL-12 binding characteristics. The preferred CDR, VH and VL sequences of the invention (including consensus sequences) as identified by the sequence identifiers in the Linked Sequence Listing, are compiled below.

<td>SEC ID NOT:</td><td>CHAIN OF ANTIBODY</td><td>REGION</td><td>SEQUENCE</td>

<td> 1</td><td>Joe 9 to J695 consensus</td><td>CDR H3</td><td>(H / S) -GS- (H / Y) -D- (N / T / Y)</td>

<td> 2</td><td>Joe 9 to J695 consensus</td><td>CDR L3</td><td>Q- (S / T) -Y- (D / E) - (S / R / K) - (S / G / Y) - (L / F / T / S) - (R / S / T / W / H) - (G / P) - (S / T / Y / L) - (R / S / M / T / L) - (V / l / T / M / L)</td>

<td> 3</td><td>Joe 9 to J695 consensus</td><td>CDR H2</td><td>FlRYDGSNKYY- adsvkg</td>

<td> 4</td><td>Joe 9 to J695 consensus</td><td>CDR L2</td><td>(G / Y) -N- (D / S) - (Q / N) -RP- S</td>

<td>SEC ID NOT:</td><td>CHAIN OF ANTIBODY</td><td>REGION</td><td>SEQUENCE</td>

<td> 5</td><td>Joe 9 to J695 consensus</td><td>CDR H1</td><td>FTFS- (S / E) -YGMH</td>

<td> 6</td><td>Joe 9 to J695 consensus</td><td>CDR L1</td><td>(S / T) -G- (G / S) - (R / S) -SN- l- (G / V) - (S / A) - (N / G / Y) - (T / D) -V- (K / H)</td>

<td> 7</td><td>Joe 9 to J695 consensus</td><td>VH</td><td>(VH sequence complete; see list of sequences)</td>

<td> 8</td><td>Joe 9 to J695 consensus</td><td>VL</td><td>(VL sequence complete; see list of sequences)</td>

<td> 9</td><td>Y61 to J695 from consensus</td><td>CDR H3</td><td>H- (G / V / C / H) - (S / T) - (H / T / V / R / I) - (D / S) - (N / K / A / T / S / F / W / H)</td>

<td> 10</td><td>Y61 to J695 from consensus</td><td>CDR L3</td><td>QSY- (D / S) - (Xaa) - (G / D / Q / L / F / R / H / N / Y) -TH- PALL</td>

<td> 1 1</td><td>Consensus Y61 to J695</td><td>CDR H2</td><td>lT7TZYj'-T- (K / A) -Y- D / S / E / A) - (G / Rl-S- (Xaa) - K- (Y / E) -YADSVKG</td>

<td> 12</td><td>Y61 to J695 from consensus</td><td>CDR L2</td><td>(G / Y / S / T / N / Q) -NDQR- $</td>

<td> 13</td><td>Y61 to J695 from consensus</td><td>CDR H1</td><td>FTF- (Xaa) - (Xaa) - (Y / H) - (G / M / A / N / S) -MH</td>

<td> 14</td><td>Y61 to J695 consensus</td><td>CDR L1</td><td>SGGRSNlG- (S / C / R / N / D / T) - (N / M / I) - (T / Y / D / H / K / P) -VK</td>

<td> 15</td><td>Y61 to J695 consensus</td><td>VH</td><td>(VH sequence complete; see list of sequences)</td>

<td>SEC ID NOT:</td><td>CHAIN OF ANTIBODY</td><td>REGION</td><td>SEQUENCE</td>

<td> 16</td><td>Y61 to J695 from consensus</td><td>VL</td><td>(VL sequence complete; see list of sequences)</td>

<td> 17</td><td>Y61</td><td>CDR H3</td><td>HGSHDN</td>

<td> 18</td><td>Y61</td><td>CDR L3</td><td>QSYDRGTHPALL</td>

<td> 19</td><td>Y61</td><td>CDR H2</td><td>FlRYDGSNKYY- ADSVKG</td>

<td> 20</td><td>Y61</td><td>CDR L2</td><td>GNDQRPS</td>

<td> 21</td><td>Y61</td><td>CDR H1</td><td>FTFSSYGMH</td>

<td> 22</td><td>Y61</td><td>CDR L1</td><td>SGGRSNlGSNTVK</td>

<td> 23</td><td>Y61</td><td>VH</td><td>(VH sequence complete; see list of sequences)</td>

<td> 24</td><td>Y61</td><td>VL</td><td>(VL sequence complete; see list of sequences)</td>

<td> 25</td><td>J695</td><td>CDR H3</td><td>HGSHDN</td>

<td> 26</td><td>J695</td><td>CDR L3</td><td>QSYDRYTHPALL</td>

<td> 27</td><td>J695</td><td>CDR H2</td><td>FlRYDGSNKYY- ADSVKG</td>

<td> 28</td><td>J695</td><td>CDR L2</td><td>YNDQRPS</td>

<td> 29</td><td>J695</td><td>CDR H1</td><td>FTFSSYGMH</td>

<td> 30</td><td>J695</td><td>CDR L1</td><td>SGSRSNlGSNTVK</td>

<td> 31</td><td>J695</td><td>VH</td><td>(VH sequence complete; see list of sequences)</td>

<td> 32</td><td>J695</td><td>VL</td><td>(VL sequence complete; see sequence listing)</td>

Antibodies produced from affinity maturation of wild type Joe 9 were functionally characterized by surface plasmon resonance analysis to determine constant Kd and Koff. A series of antibodies was produced that has a constant Koff within the range of about 0.1 s'1 to about 1 x 10 '5 s'1, and more preferably a KOff of approximately 1 x 10 '4 s'1 at 1 x 10 '5 s'1 or less. Antibodies were also characterized in vitro so that their ability to inhibit the proliferation of the phytohemagglutinin io (PHA) blast, as described in Example 3 of North American Patent No. 6,914,128. A series of antibodies was produced that have an IC50 value in the range of about 1x10 '6 M to about 1x10 '11 M, more preferably approximately 1χ10 '1θ M at 1x10 '11 M o

I5 minor.

Accordingly, in one aspect, the invention provides methods and compositions for using an isolated human antibody, or antigen-binding portion thereof, that binds human IL12 and dissociates from human IL-12 with a constant of constant Koff of 0.1 s'1 or less, as determined by surface plasmon resonance, or that inhibits phytohemagglutinin blast proliferation in an in vitro phytohemagglutinin blast proliferation assay (PHA analysis) with an IC50 1 x 10 '6 M or less. In preferred embodiments, the antibody

Isolated human IL-12, or an antigen-binding portion thereof, dissociates from human IL-12 with a constant of constant Koff 1 x 10-2 s'1 or less, or inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '7 M or less. In more preferred embodiments, the antibody of

Isolated human IL-12, or an antigen-binding portion thereof, dissociates from human IL-12 with a constant of constant KOR1 x 10 'ff3 s'1 or less, or inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '8 M or less. In more preferred embodiments, the antibody of

Isolated human IL-12, or an antigen-binding portion thereof, dissociates from human IL-12 with a constant of constant KOR1 x 10 'ff4 s'1 or less, or inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '9 M or less. In more preferred embodiments, the antibody of

Isolated human IL-12, or an antigen-binding portion thereof, dissociates from human IL-12 with a constant of constant KOR1 x 10 'ff5 s'1 or less, or inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with a Cl5or 1 x 10 '1° M or less. In still more preferred embodiments, the isolated human IL-12 antibody, or an antigen-binding portion thereof, cleaves from human IL-12 with a constant of constant Kof1 x 10 f5 s1 or less, or inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 of 1 x 10 '11 M or less.

The dissociation rate constant (Koff) an IL-12 antibody can be determined by surface plasmon resonance (see Example 5 of North American Patent No. 6,914,128). Generally, surface plasmon resonance analysis measures the real-time binding interactions between ligand (recombinant human IL-12 immobilized on a biosensor matrix) and analyte (antibodies in solution) by surface plasmon resonance (SPR) using the BIAcore system (Pharmacia Biosensor, Piscataway, NJ). Surface plasmon analysis can also be performed by immobilizing the analyte (antibodies in a biosensor matrix) and presenting the ligand (recombinant IL-12 in solution). The neutralizing activity of IL-12 antibodies, or antigen-binding portions thereof, can be determined using one or more of several suitable in vitro assays (see Example 3 of North American Patent No. 6,914,128).

It is well known in the art that antibody heavy and light chain CDRs play an important role in the binding specificity / affinity of an antibody for an antigen. Accordingly, the invention encompasses human antibodies that have Joe 9 heavy and light chain CDRs, as well as other antibodies that have CDRs that have been modified to improve the binding specificity / affinity of the antibody. As demonstrated in Example 1 of North American Patent No. 6,914,128, from a series of modifications to light and heavy chain CDRs results in affinity maturation of human anti-hLL-12 antibodies. Alignments of the heavy and light chain variable region amino acid sequence of a series of human antibodies ranging from wild type Joe 9 to human IL-12 binding J695 are shown in Figures 1A-1D of North American Patent No. 6,914,128 (Figures 8A-D herein). Consensus sequence motifs for antibody CDRs can be determined from sequence alignment. For example, a consensus motif for VH CDR3 from lineage Joe 9 to J695 comprises the amino acid sequence: (H / S) -GS- (H / Y) -D- (N / T / Y) (SEQ ID NO:

1), which comprises amino acids from position 95 to 102 of the consensus HCVR shown in SEQ ID NO: 7. A consensus motif for VL CDR3 comprises the amino acid sequence: Q- (S / T) -Y- (D / E) - (S / R / K) - (S / G / Y) - (L / F / T / S) 15 (R / S / T / W / H) - (G / P) - (S / T / A / L) - (R / S / M / T / LV / I / T / M / L) (SEQ ID NO:

2), comprising amino acids from position 89 to 97 of the consensus LCVR shown in SEQ ID NO: 8.

Accordingly, in another aspect, the invention provides methods and compositions comprising an isolated human antibody, or an antigen-binding portion thereof, having the following characteristics:

a) Inhibit phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 1 O '6 M or less;

b) has a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 1; and

c) has a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 2.

In a preferred embodiment, the antibody further comprises a VH CDR2 comprising the amino acid sequence: FlRYDGSNKYYADSVKG (SEQ ID NO: 3) (comprising amino acids from position 50 to 65 of the consensus HCVR comprising the amino acid sequence of the SEQ ID NO: 7) and further comprises a VL CDR2 comprising the amino acid sequence: (G / Y) -N- (D / S) - (Q / N) -RPS (SEQ ID

NO: 4) (comprising amino acids from position 50 to 56 of the consensus LCVR comprising the amino acid sequence of SEQ ID NO: 8).

In another preferred embodiment, the antibody further comprises a VH CDR1 comprising the amino acid sequence: FTFS- (S / E) -YGMH (SEQ ID NO: 5) (comprising amino acids from position 27 to 35 of the consensus HCVR comprising the amino acid sequence of SEQ ID NO: 7) and further comprises a VL CDR1 comprising the amino acid sequence: (S / T) -G- (G / S) - (R / S) -SN- | - (G / V) 20 (S / A) - (N / G / Y) - (T / D) -V- (K / H) (SEQ ID NO: 6) (comprising amino acids from position 24 to 34 of the consensus LCVR comprising the amino acid sequence of SEQ ID NO: 8).

In yet another preferred embodiment, the antibody used in the invention comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 7 and an LCVR comprising the amino acid sequence of SEQ ID NO: 8.

Additional consensus motifs can be determined based on the mutational analysis performed on Y61 leading to the J695 antibody (summarized in Figures 2A-2H of the Patent

North American No. 6,914,128; Calculate 9A-H here). As shown by the graphs shown in Figures 2A-2H of North American Patent No. 6,914,128 (Figures 9A-H herein), certain residues of the Y61 heavy and light chain CDRs were favorable to replacement without significant io impair the binding properties of hlL-12 of the antibody. For example, individual substitutions at position 30 in CDR H1 with twelve different amino acid residues did not significantly reduce the constant Koff of the antibody, indicating that this position is favorable for substitution with a variety of different amino acid residues. Thus, based on the consensus motifs of the mutational analysis (ie, positions within Y61 that were favorable to substitution by other amino acid residues) were determined. The consensus motifs for heavy and light chain CDR3s are shown in SEQ ID NOs: 9 and 10, respectively, the consensus motifs for heavy and light chain CDR2s are shown in SEQ ID NOs: 11 and 12, respectively, and the consensus motifs for heavy and light chain CDR1s are shown in SEQ ID NOs: 13 and 14, respectively. The reasons for consensus for the regions of

ID NOs: 15 and 16,

VH and VL are shown in SEQs respectively.

Accordingly, in one aspect, the invention includes an isolated human antibody, or an antigen-binding portion 5 thereof, having the following characteristics:

a) Inhibit phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 χ 10 '9 M or less;

b) has a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and io c) has a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

In a preferred embodiment, the antibody further comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 11 and further comprises a VL CDR2 comprising the amino acid sequence of SEQ ID

NO: 12.

In another preferred embodiment, the antibody further comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 13 and further comprising a VL CDR1 comprising the amino acid sequence of SEQ ID

NO: 14.

In yet another preferred embodiment, the antibody used in the invention comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 15 and an LCVR comprising the amino acid sequence of SEQ ID NO: 16.

100

A preferred antibody used in the invention, Y61 of human anti-hlL-12 antibody, can be produced by affinity maturation of wild type Joe 9 by CDR3 PCR mutagenesis (as described in Example

one North American Patent No. 6,914,128). Y61 has an improved specificity / binding affinity determined by surface plasmon resonance and by in vitro neutralization assay. The Y61 heavy and light chain CDR3s are shown in SEQ ID NOs: 17 and 18, respectively, the

Y61 heavy and light chain CDR2s are shown in SEQ ID NOs: 19 and 20, respectively, and Y61 heavy and light chain CDR1s are shown in SEQ ID NOs: 21 and 22, respectively. Y61 VH has the amino acid sequence of SEQ ID NO: 23 and Y61 VL has the amino acid sequence of SEQ ID NO: 24 (these sequences are also shown in Figures 1A-1D of North American Patent No. 6,914,128 (Figures 8A-D herein) aligned with Joe9).

Accordingly, in another aspect, the use of the features of the invention of an isolated human antibody, or an antigen-binding portion thereof, which

a) Inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '9 M or less;

b) has a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and

c) has a light chain CDR3 comprising the

101 amino acid sequence of SEQ ID NO: 18.

In a preferred embodiment, the isolated human antibody, or an antigen-binding portion thereof, used in the methods and compositions of the invention has a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 19 and a Light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 20.

In another preferred embodiment, the isolated human antibody, or an antigen-binding portion thereof, used in the methods and compositions of the invention, has a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 21 and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 22.

In yet another preferred embodiment, the isolated human antibody, or an antigen-binding portion thereof, used in the methods and compositions of the invention comprising the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable region comprising the amino acid sequence of the

SEQ ID NO: 24.

In certain embodiments, the full length antibody comprises a heavy chain constant region, such as constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA, and IgE, and any allotypic variants thereof as described in Kabat (Kabat , EA, et al. (1991) Sequences of

102

Proteins of Immunologícal Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242). Preferably, the antibody heavy chain constant region is a lgG1 heavy chain constant region. Alternatively, the antibody portion may be a Fab fragment, an F (ab 'fragment2) or a single-chain Fv fragment.

Modifications of individual Y61 residues led to the production of a panel of antibodies shown in Figures 2A-2H of North American Patent No. 6,914,128 (Figures 9A-H herein). The binding specificity / affinity of each antibody was determined by surface plasmon resonance and / or by in vitro neutralization assay.

Accordingly, in another aspect, the invention offers an isolated human antibody, or an antigen-binding portion thereof, which

a) Inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '9 M or less;

b) has a heavy chain CDR3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 404-SEQ ID NO: 469; and

c) has a light chain CDR3 comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 534-SEQ ID NO: 579.

In the preferred embodiment, the isolated human antibody, or

103 an antigen-binding portion thereof, used in the methods and compositions of the invention has a heavy chain CDR2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 335-SEQ

ID NO: 403; and a light chain CDR2 comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 506-SEQ ID NO: 533.

In another preferred embodiment, the isolated human antibody, or an antigen-binding portion thereof, has a heavy chain CDR1 comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 288-SEQ ID NO: 334 ; and a light chain CDR1 comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 470-SEQ ID NO: 505.

In yet another preferred embodiment, the isolated human antibody, or an antigen-binding portion thereof, comprising the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

In certain embodiments, the full-length antibody comprising a heavy chain constant region such as lgG1, lGG2, lgG3, lgG4, IgM, IgA and IgE constant regions and any allotypic variants thereof as described in

Kabat (Kabat, EA, et al. (1991) Sequences of

104

Proteins of Immunological Interest, Fifth Edition, US. Department of Health and Human Services, NIH Publication No. 91-3242). Preferably, the antibody heavy chain constant region is a lgG1 heavy chain constant region. Alternatively, the antibody portion may be a Fab fragment, an F (ab 'fragment2) or a single-chain Fv fragment.

A particularly preferred recombinant neutralizing antibody, J695, that can be used in the invention was produced io by site-directed mutagenesis of contact amino acids residues and hypermutation of antibody Y61 (see Example 2 of North American Patent No. 6,914,128 and Section III then). J695 differs from Y61 by a Gly to Tyr substitution at Y61 at position 50 of the light chain CDR2 and by a Gly to Tyr substitution at position 94 of the light chain CDR3. J695 heavy and light chain CDR3s are shown in SEQ ID NOs: 25 and 26, respectively, J695 heavy and light chain CDR2s are shown in SEO ID NOs: 27 and 28, respectively, and CDR1s of J695 heavy and light chain are shown in SEQ ID NOs: 29 and 30, respectively. The VH of J695 has the amino acid sequence of SEQ ID NO: 31 and the VL of J695 has the amino acid sequence of SEQ ID NO: 32 (these sequences are also shown in Figures 1A-1D of the Patent

North American No. 6,914,128 (Figures 8A-D herein),

105 aligned with Joe9).

Accordingly, in another aspect, the invention offers an isolated human antibody, or an antigen-binding portion thereof, which

a) Inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '9 M or less;

b) has a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 25; and

c) has a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26.

In the preferred embodiment, the isolated human antibody, or an antigen-binding portion thereof, used in the invention has a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and a light chain CDR2 which comprises the amino acid sequence of the

SEQ ID NO: 28.

In another preferred embodiment, the isolated human antibody, or an antigen-binding portion thereof, used in the invention has a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 29, and a light chain CDR1 which comprises the amino acid sequence of the

SEQ ID NO: 30.

In yet another preferred embodiment, the isolated human antibody, or an antigen-binding portion thereof, used in the invention has a heavy chain variable region that

106 it comprises the amino acid sequence of SEQ ID NO: 31, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 32.

In certain embodiments, the full length antibody comprises a heavy chain constant region, such as the constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA, and IgE and any allotypic variants therein as described in Kabat Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of

Health and Human Services, NIH Publication No. 91-3242). Preferably, the antibody heavy chain constant region is a lgG1 heavy chain constant region. Alternatively, the antibody portion may be a Fab fragment, a fragment of F (ab '2) or a single-chain Fv fragment.

Additional mutations in the preferred consensus sequences for CDR3, CDR2, and CDR1 of antibodies in the Joe 9 to J695 lineage, or the Y61 to J695 lineage, can be made to provide additional anti-IL-12 antibodies of the invention.

Such modification methods can be performed using standard molecular biology techniques, such as by PCR mutagenesis, single directed contact, or hypermutation amino acid residues in light chain and / or heavy chain CDRs, followed by kinetic and functional analysis of the antibodies. modified as described herein (for

107 example, neutralization analysis described in Example 3 of North American Patent No. 6,914,128, and by BIAcore analysis, as described in Example 5 of North American Patent No. 6,914,128).

Accordingly, in another aspect the invention offers the use of an isolated human antibody, or an antigen-binding portion thereof, which

a) Inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '6 M or less;

io b) comprises a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 3 and a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, or a mutant thereof having one or more amino acid substitutions at a preferred selective mutagenesis position or a hypermutation position, wherein the mutant has a constant kORff not more than ten times greater than the antibody comprising a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 3, and a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5; and

c) comprises a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 2, a CDR2 of

108 light chain comprising the amino acid sequence of SEQ ID NO: 4, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 6, or a mutant thereof having one or more amino acid substitutions in a preferred selective mutagenesis position or a hypermutation position, where the mutant has a constant kof, not more than ten times greater than the antibody comprising a

Light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 2, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 4, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 6.

In another aspect the use of features of the invention of an isolated human antibody, or an antigen-binding portion thereof, which

a) Inhibits the proliferation of phytohemagglutinin blast in an in vitro PHA assay with a Cl5or 1 x 10 '9 M or less;

b) comprises a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO; 9, one

Heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO; 11 and a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 13, or a mutant thereof having one or more amino acid substitutions at a preferred selective mutagenesis position, contact position or a position of hypermutation, where

109 the mutant has a constant kORff not more than ten times greater than the antibody comprising a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 13;

and

c) comprises a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 14, or a mutant thereof having one or more amino acid substitutions at a preferred selective mutagenesis position, contact position, or a hypermutation position, wherein the mutant has a constant koff not more than ten times greater than the antibody comprising a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR2 comprising the amino acid sequence of

SEQ ID NO: 12, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 14.

One of skill in the art will also appreciate that additional mutations to the CDR regions of an antibody, for example in Y61 or J695, can be made to provide additional anti-IL-12 antibodies of the invention. Such methods

110 Modifications can be performed using standard molecular biology techniques, as described above. The functional and kinetic analysis of the modified antibodies can be performed as described in Example 3 of the Patent

North American No. 6,914,128 and Example 5 of North American Patent No. 6,914,128, respectively. Modifications of individual Y61 residues leading to the identification of J695 are shown in Figures 2A-2H of North American Patent No. 6,914,128 (Figures 9A-H herein) and are described in Example 2 of North American Patent No. .6,914,128

Accordingly, in another aspect the use of features of the invention of an isolated human antibody, or an antigen-binding portion thereof, which

a) Inhibits the proliferation of phytohemagglutinin blast in an in vitro PHA assay with a Cl5or 1 x 10 '9 M or less;

b) comprises a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 19 and a heavy chain CDR1 comprising the sequence amino acid of SEQ ID NO: 21, or a mutant thereof having one or more amino acid substitutions at a preferred selective mutagenesis position or a hypermutation position, wherein the mutant has a constant koff not more than ten times greater than the antibody

111 comprising a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a heavy chain CDR1 comprising the sequence amino acid of SEQ ID NO: 21; and

c) comprises a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 18, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a light chain CDR1 comprising the io amino acid sequence of SEQ ID NO: 22, or a mutant thereof having one or more amino acid substitutions at a preferred selective mutagenesis position or a hypermutation position, wherein the mutant has a constant kof { not more than ten times greater than the antibody comprising a

Light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 18, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 22.

In another aspect the use of features of the invention of an isolated human antibody, or an antigen-binding portion thereof, which

a) Inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC50 1 x 10 '9 M or less;

b) comprises a heavy chain CDR3 that

112 it comprises the amino acid sequence of SEQ ID NO: 25, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 27 and a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 29 , or a mutant thereof having one or more amino acid substitutions at a preferred selective mutagenesis position or a hypermutation position, wherein the mutant has a constant kORff not more than ten times greater than the antibody comprising a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 25, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 27 , and a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 29; and

c) comprises a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 30, or a mutant thereof having one or more amino acid substitutions at a preferred selective mutagenesis position or a hypermutation position, wherein the mutant has a constant koff not more than ten times greater than the antibody comprising a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and

113 a light chain CDR1 comprising the amino acid sequence of SEQ ID NO; 30.

In yet another embodiment, the invention provides the use of isolated human antibodies, or antigen-binding portions thereof, that neutralize the activity of human IL-12, and at least one additional primate IL-12 selected from the group consisting of of baboon IL-12, marmoset IL-12, chimpanzee IL-12, cynomolgo IL-12 and macaque IL-12 from India, but they do not neutralize the activity of mouse IL-12.

IIο II Selection of Recombinant Human Antibodies

Recombinant human antibodies that can be used in the invention can be isolated by assaying a recombinant combinatorial antibody library, preferably a scFv phage display library, prepared using human VL and VH cDNAs prepared from the mRNA derived from human lymphocytes. Methods for identifying antibodies that can be used in methods and compositions of the invention are described in North American Patent No. 6,914,128, incorporated by reference herein. Methodologies for preparing and analyzing such libraries are known in the art. In addition to commercially available kits for generating phage display libraries (eg Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and Stratagene SurfZAP ™ Phage Display Kit, Catalog No. 240612) , examples

114 Particularly favorable methods and reagents for use in generating and analyzing antibody display libraries can be found in, for example, Kang et al. PCT Publication No. WO 92/18619; Winter et al. PCT Publication No. WO 92/20791; Breitling et al. PCT Publication No. WO 93/01288; McCafferty et al. PCT Publication No. WO 92/01047; Garrard et al. PCT Publication No. WO 92/09690; Fuchs et al. (1991) Bio / Technology 9: 13701372; Hay et al. (1992) Hum Antibod Hybridomas 3.:8185; Huse et al. (1989) Science 246: 1275-1281; McCafferty et al., Nature (1990) 348: 552-554: Griffiths et al. (1993) EMBO J 12: 725-734; Hawkins et al. (1992) J Mol Biol 226: 889-896; Clackson et al. (1991) Nature 352: 624-628: Gram et al. (1992) PNAS 89: 3576-3580; Garrad et al. (1991) Bio / Technology 9: 1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 1 9: 4133-4137; and Barbas et al. (1991) PNAS 88: 7978-7982.

The antibody libraries used in this method are preferably scFv libraries prepared from human VL and VH cDNAs. The scFv antibody libraries are preferably analyzed using recombinant human IL-12 as the antigen to select for human heavy and light chain sequences that have binding activity to IL-12. To select for specific antibodies to the IL115 p35 subunit or the p70 heterodimer, assays were performed in the presence of the excess free p40 subunit. Subunit preferences can be determined, for example, by Friguet micro-titration, as described in Example 1 of North American Patent No. 6,914,128.

Once the initial human VL and VH segments are selected, "mix-and-match" experiments, in which different pairs of the selected VL and VH segments are analyzed for IL-12 binding, are performed to select combinations of preferred VL / VH pairs (see Example 1 of North American Patent No. 6,914,128). Additionally, to further enhance affinity and / or lower the dissociated constant for hlL-12 binding, the VL and VH segments of the preferred VL / VH pairs can be randomly mutated, preferably within the CDR3 region of VH and / or VL, in a process analogous to the in vivo somatic mutation process responsible for the affinity maturation of antibodies during a natural immune response. This in vitro affinity maturation can be achieved by amplifying VH and VL regions using PCR primers complementary to VH CDR3 or VL CDR3, respectively, whose primers have been "boosted" with a random mix of the four nucleotide bases in certain positions such that the resulting PCR products encode VH and VL segments in which random mutations are

116 have introduced into the CDR3 regions of VH and / or VL. These randomly mutated VH and VL segments can be reselected and reanalyzed to bind to hlL-12, and sequences exhibiting high affinity and low dissociated constant for IL-12 binding can be selected. Table 2 of Appendix A of North American Patent No. 6,914,128 (see Table 2 of Appendix A attached thereto) shows antibodies that exhibit altered binding specificity / affinity produced as a result of affinity maturation in vitro.

After selection, isolation and testing of a recombinant immunoglobulin display library for an anti-hLL-12 antibody of the invention, nucleic acid encoding the selected antibody can be recovered from phage particles (eg, genome of phage) and subcloned into other expression vectors by standard recombinant DNA techniques. If desired, the nucleic acid can be further manipulated to create other forms of the antibody of the invention (eg, linked to nucleic acid encoding additional immunoglobulin domains, such as additional constant regions). To express an isolated recombinant human antibody by analyzing a combinatorial library, the DNA encoding the antibody was cloned into a recombinant expression vector and introduced into mammalian host cells, as further described in detail in

Section IV below.

117

Methods for selecting human IL-12 binding antibodies by phage display technology, and affinity maturation of selected antibodies by random or site directed mutagenesis of CDR regions are described in further detail in Patent Example 1

North American No. 6,914,128.

As described in Example 1 of the Patent

North American No. 6,914,128, analyze cDNA libraries from

Human VL and VH identified a series of anti-IL-12 antibodies, 10 of which the Joe 9 antibody was selected for further development. A comparison of the Joe 9 heavy chain variable region with the heavy chain germline sequences selected from the VBASE database reveals that

Joe 9 was similar to the COS-3 germline sequence. COS-3 15 belongs to family VH3 of germline sequences.

Family VK3 It is part of the germline repertoire of human VH that is grouped into seven families, VH1-VH7, based on nucleotide sequence homology (Tomlinson et al. (1992) J. Mol. Biol., 227, 77Q-7Q8 and Cook et al. (1995) Immunology Today, 16, 237-242). Family VH3 It contains the largest number of members and makes the largest contribution to the germline repertoire. For any V germline antibody sequenceH3 given human, the amino acid sequence identity within the V familyH3 integer is high (see for example Tomlinson and

118 collaborators (1992) J. Mol. Biol., 227, 776-798 and Cook et al. (1995) Immunology Today, 16, 237-242). The range of amino acid sequence identity between any of two family germline VH sequences

Vh3 it ranges from 69-98 residues to approximately 100 VH residues, (ie 69-98% amino acid sequence homology between any two germline VH sequences). For most pairs of germline sequences, there are at least 80 or more identical amino acid residues (ie, at least 80% amino acid sequence homology). The high degree of homology of the amino acid sequence among members of the V familyH3 gives rise to certain amino acid residues that are present at key sites in the CDR and framework regions of the

VH. These amino acid residues confer structural characteristics on the CDRs.

Studies of antibody structures have shown that CDR conformations can be grouped into families of canonical CDR structures based on key amino acid residues that occupy certain positions in the CDR and framework regions. Therefore, there are similar local CDR conformations in different antibodies that have canonical structures with identical key amino acid residues (Chothia et al. (1987) J. Mol. Biol., 196, 901-917 and Chothia et al. (1989) Nature, 342, 877-883). Inside to the family

119

Vh3 there is a preservation of the identity of the amino acid residue at key sites for the canonical structures of CDR1 and CDR2 (Chothia et al. (1992) J. Mol. Biol., 227, 799-817).

The germline VH gene of COS-3 is a member of the V familyH3 and it is a variant of the germline 3-30 VH allele (DP-49). COS-3 differs from Joe9's VH amino acid sequences in only 5 positions. The high degree of amino acid sequence homology between VH and COS-3 of

Joe9, and between VH of Joe9 and other members of the V familyH3 it also confers a high degree of structural homology to CDR (Chothia et al. (1992) J. Mol. Biol., 227, 799-817; Chothia et al. (1987) J. Mol. Biol., 196, 901-917 and Chothia et al. (1989) Nature, 342, 877-883).

The expert will appreciate that based on the high canonical structural and amino acid sequence similarity to Joe 9, other members of the V familyH3 They may also be used to generate antibodies that bind human IL-12. This can be done, for example, by selecting an appropriate VL by chain transposition techniques (Winter et al. (1994) Annual Rev. Immunol., 12, 433-55), or by grafting CDRs from a rodent or other human antibody including Antibody CDRs of this invention on a V family scaffoldH3.

The human lambda V germline repertoire is grouped into 10 families based on sequence homology of

120 nucleotide (Williams et al. (1996) J. Mol. Biol., 264, 220-232). A comparison of the Joe 9 light chain variable region with the light chain germline sequences selected from the VBASE database revealed that

Joe 9 was similar to the DPL8 lambda germline. Joe9's VL differs from the DPL8 sequence in only four framework positions, and is highly homologous to the framework sequences of the other family members νλone. Based on the high homology of the canonical amino acid and structural sequence similar to Joe 9, other family members 1XV can also be used to generate antibodies that bind human IL-12. This can be done, for example, by selecting an appropriate VH by chain transposition techniques (Winter et al. Supra), or by grafting CDRs from a rodent or other human antibody including CDRs from antibodies of this invention onto a family framework. νλ1.

The methods of the invention are desired to include recombinant antibodies that bind to hLL-12, which comprises a heavy chain variable region derived from a member of the V family.H3 of germline sequences, and a light chain variable region derived from a member of the ν familyλone of germline sequences. Furthermore, the skilled person will appreciate that any member of the V-family heavy chain sequenceH3 can be combined with any member of the V-family light chain sequencex1.

121

Those skilled in the art will also appreciate that DNA sequence polymorphisms that lead to changes in the germline amino acid sequences may exist within a population (eg, the human population). Such genetic polymorphism in germline sequences may exist between individuals within a population due to natural allelic variation. Such natural allelic variations can typically result in 1-5% variations in the nucleotide sequence of a gene. Any and all such nucleotide variations and amino acid polymorphisms resulting in germline sequences that are the result of natural allelic variation are desired to be within the scope of the invention.

Accordingly, in one aspect, the invention offers an isolated human antibody, or an antigen-binding portion thereof, having the following characteristics:

a) that binds human IL-12 and dissociates from human IL-12 with a dissociated constant of 0.1 s'1 or less, as determined by surface plasmon resonance, or that inhibits phytohemagglutinin blast proliferation in an in vitro phytohemagglutinin blast proliferation assay (PHA assay) with an IC50 1 x 10 '6 M or less.

b) has a heavy chain variable region comprising of an amino acid sequence selected from a germline family member VH3, where the region

122 heavy chain variable has a mutation at a contact or hypermutation position with an activity enhancing amino acid residue.

c) has a light chain variable region comprising of an amino acid sequence selected from a germline family member of VX1, wherein the light chain variable region has a mutation at a preferred selective mutagenesis position, contact or hypermutation position with an activity enhancing amino acid residue.

In a preferred embodiment, the isolated human antibody, or antigen binding, has a mutation in heavy chain CDR3s. In another preferred embodiment, the isolated human antibody, or antigen binding, has a mutation in the light chain CDR3. In another preferred embodiment, the isolated human antibody, or antigen binding, has a mutation in the heavy chain CDR2. In another preferred embodiment, the isolated human antibody, or antigen binding, has a mutation in the light chain CDR2. In another preferred embodiment, the isolated human antibody, or antigen binding, has a mutation in heavy chain CDR1. In another preferred embodiment, the isolated human antibody, or antigen binding, has a mutation in the light chain CDR1.

One of ordinary skill in the art will appreciate that based on the high amino acid sequence similarity between members of the V germline familyH3, or between members of the germline family νλone light chain, which

123 Mutations to germline sequences can provide additional antibodies that bind human IL-12. Table 1 of North American Patent No. 6,914,128 (see Table 1 of Appendix A attached thereto) shows the germline sequences of members of the V family.H3 and demonstrates significant sequence homology within family members. They also show in Table 1 of the Patent

North American No. 6,914,128 (see Table 1 of Appendix A, thereto) are the germline sequences for the io family members νλone. The heavy and light chain sequences of

Joe 9 are provided as a comparison. Mutations to germline sequences of VH3 or family members VXone they can be done, for example, at the same amino acid positions as those made in the antibodies of the invention (for example mutations in Joe 9). Modifications can be made using standard molecular biology techniques, for example by PCR mutagenesis, targeting individual amino acid residues in the germline sequences, followed by kinetic and functional analysis of the modified antibodies as described herein (for example, neutralization analysis described in Example 3 of North American Patent No. 6,914,128, and by BIAcore analysis, as described in Example 5 of North American Patent No. 6,914,128).

Therefore, in one aspect, the use of features

124 of the invention of an isolated human antibody, or an antigen-binding portion thereof, having the following characteristics:

a) has a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 595-667, wherein the heavy chain variable region has a mutation at a position of selective mutagenesis, contact or preferred hypermutation position with an activity enhancing amino acid residue. io b) has a light chain variable region comprising of an amino acid sequence selected from the group consisting of SEQ ID NOs: 669-675, wherein the light chain variable region has a mutation at a position of selective mutagenesis, preferred contact or hypermutation position with an activity enhancing amino acid residue.

One of ordinary skill in the art will appreciate that based on the high similarity of the amino acid sequence between

Joe 9 and the COS-3, 20 heavy chain germline sequence and between Joe 9 and the DPL8 lambda germline sequence, that other mutations to the CDR regions of these germline sequences may provide additional antibodies that bind to human IL-12. Such modification methods can be performed using standard molecular biology techniques as described above.

125

Accordingly, in one aspect, the use of features of the invention of an isolated human antibody, or an antigen-binding portion thereof, having the following features:

a) that binds human IL-12 and dissociates from human IL-12 with a dissociated constant of 0.1 s1 or less, as determined by surface plasmon resonance, or that inhibits phytohemagglutinin blast proliferation in an in vitro phytohemagglutinin blast proliferation assay (

PHA) with an IC50 1 x 10θ M or less.

b) has a heavy chain variable region comprising the germline amino acid sequence COS-3, wherein the heavy chain variable region has a mutation at a preferred selective mutagenesis position, contact or hypermutation position with a residue of activity enhancing amino acid.

c) has a light chain variable region comprising the DPL8 germline amino acid sequence, wherein the light chain variable region has a mutation at a preferred selective mutagenesis position, contact or hypermutation position with an enhancer amino acid residue of activity.

Due to certain amino acid residues that occupy key sites in the CDR and framework regions in the light and heavy chain variable region, the structural characteristics are

126 confer in these regions. In particular, the CDR2 and CDR1 regions undergo canonical structural classifications. Since there is a high level of amino acid sequence homology between family members, these canonical features are present between family members. The expert will appreciate that modifications in amino acid residues conferred by these canonical structures would produce additional antibodies that bind IL-12. Modifications can be made using standard or molecular biology techniques as described above.

Accordingly, in another aspect, the use of features of the invention of an isolated human antibody, or an antigen-binding portion thereof, having the following features:

PHA) with an IC50 1 χ 10 '6 M or less.

b) has a heavy chain variable region comprising of an amino acid sequence selected from a germline family member VH3, wherein the heavy chain variable region comprises a CDR2 that is structurally similar to CDR2s of other family members of

127 germ line VH3, and a CDR1 that is structurally similar to CDR1s of other members of the V germline familyH3, and wherein the heavy chain variable region has a mutation at a preferred selective mutagenesis position, contact or hypermutation position with an activity enhancing amino acid residue;

c) has a light chain variable region comprising of an amino acid sequence selected from a member of the germline family Vx1, wherein the light chain variable region comprises a CDR2 that is structurally similar to CDR2s of other germline family members νλ1, and a CDR1 that is structurally similar to

CDR1s of other germline V family membersx1, and wherein the light chain variable region has a mutation at a preferred selective mutagenesis position, contact or hypermutation position with an activity enhancing amino acid residue.

The recombinant human antibodies used in the invention have variable and constant regions that are homologous to human germline immunoglobulin sequences selected from the VBASE database. Mutations to recombinant human antibodies (eg, by random mutagenesis or PCR mutagenesis) give rise to amino acids that are not encoded by human germline immunoglobulin sequences. Also, the

128 Recombinant antibody libraries derived from human donors will contain antibody sequences that differ from their corresponding germline sequences due to the normal process of somatic mutation that occurs during development of the B cell. It should be noted that if the "germline" sequences obtained by PCR amplification encode the amino acid differences in the framework regions of the true germline configuration (ie, differences in the amplified sequence from the germline sequence true), it may be desirable to change these amino acid differences back to true germline sequences (i.e. "Retromutation" of framework residues to the germline configuration). Thus, the present invention may optionally include a retromutation step. To do this, the germline encoded heavy and light chain amino acid sequences (as found in the VBASE database as an example) are first compared to the mutated immunoglobulin heavy and light chain scaffold amino acid sequences. to identify amino acid residues in the mutated immunoglobulin scaffold sequence that differs from the closest germline sequences. Then, the appropriate nucleotides of the mutated immunoglobulin sequence are transformed again to correspond to the germline sequence, using the

129 genetic code to determine what nucleotide changes need to be made. Mutagenesis of the mutated immunoglobulin scaffold sequence is performed by standard methods, such as PCR-mediated mutagenesis (in which Mutated nucleotides are incorporated into PCR primers such that the PCR product contains the mutations) or site-directed mutagenesis. site. The role of each amino acid identified as a candidate for retromutation will be investigated for a direct or indirect role in antigen binding, and any amino acids found after mutation to affect any desirable characteristics of the human antibody should not be included in the final human antibody; As an example, the activity enhancing amino acids identified by the selective mutagenesis process will not undergo retromutation. Assays to determine the characteristics of the antibody resulting from mutagenesis may include ELISA, competitive ELISA, in vitro and in vivo neutralization assay and / or (see eg Example 3 of North American Patent No. 6,914,128) immunohistochemistry with tissue sections from various sources (including human, primate and / or other species).

To minimize the number of amino acids subjected to retromutation these amino acid positions found to be different from the closest germline sequence but identical to the corresponding amino acid in a second germline sequence may remain, provided

130 that the second germline sequence is identical and collinear to the sequence of the human antibody of the invention at least 10, preferably 12 amino acids, on both sides of the amino acid in question. This would ensure that any peptide epitope presented to the immune system by the professional antigen presenting cells in a subject treated with the human antibody of the invention will not be foreign but identical to the same antigen, that is, the immunoglobulin encoded by the second line sequence. germinal. Retromutation can occur at any stage of antibody optimization; preferably, retromutation occurs directly before or after the selective mutagenesis process. More preferably, retromutation occurs directly prior to the selective mutagenesis process.

III. Modifications to Selective Mutagenesis Positions, contact v / o Preferred Hypermutation Positions

Typically, selection of antibodies with improved affinities can be performed using phage display methods, as described in section II above and in the Patent

North American No. 6,914,128, incorporated by reference herein. This can be accomplished by random mutation combinations of CDR residues and generating large libraries containing antibodies of different sequences. However, for these selection methods to work, the antibody-antigen reaction must tend to equilibrium to

131 allow, at a certain time, the preferential binding of high affinity antibodies to the antigen. The selection conditions that will allow the equilibrium to be established cannot be determined (probably due to additional non-specific interactions between the antigen and phage particle) when phage display methods were used to improve the affinity of anti-IL-12 antibodies. selected, upon reaching a certain level of affinity reached (i.e., that of the Y61 antibody). Therefore, antibodies with even higher affinities cannot be selected by phage display methods. Thus, at least certain antibodies or antigens, phage display methods are limiting their ability to select for antibodies with highly improved binding specificity / affinity. Accordingly, a method called the Selective Mutagenesis Process that does not require maturation of phage expression of antibodies, was established to overcome this limitation and is provided by the invention. Although this Selective Mutagenesis Process was developed to overcome limitations using the phage display system, it should be noted that this method can also be used with the phage display system. Furthermore, the selective mutagenesis process can be used to enhance the activity of any antibody.

To improve activity (for example, affinity or activity

132 neutralizing) of an antibody, one would ideally like to mutate every CDR position in the heavy and light chains to any other possible amino acid residue. However, since there are, on average, 70 CDR positions within an antibody, such a process will be time consuming and labor intensive. Accordingly, the method of the invention allows an improvement in the activity of the antibody by mutating only certain selected residues within the heavy and / or light chain CDRs. Furthermore, the method of the invention allows improvement in antibody activity without affecting other desirable properties of the antibody.

The determination of which amino acid residues of a variable region of the antibody are in contact with an antigen cannot be exactly predicted based on primary sequence or their positions within the variable region. However, sequence alignments of antibodies with different specificities driven by Kabat et al. Have identified CDRs as local regions within variable regions that differ significantly between antibodies (Kabat et al. (1971) Ann. NY Acad, Sci. 190: 382-393 Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242). Structural studies have shown that the antigen-binding surface is formed by residues of

133 amino acids present in CDRs. Other amino acid residues outside of CDR are also known to play structural roles or to be directly involved in antigen binding. Therefore, for each pair of antigen5 antibody, the amino acid residues inside and outside the CDRs may be important.

Sequence alignment studies by Tomlison et al. Identified a number of positions on heavy and light chain CDR1 and CDR2, and on a portion of the kappa chain CDR3 that are frequent sites of somatic mutation. (Tomlison et al. (1996) J. Mol. Biol. 256: 813-817). In particular, positions H31, H31B, H33, H33B, H52B, H56, H58, L30, L31, L31A, L50, L53, L91, L92, L93, and L94 were identified as frequent sites for somatic mutation. However, this analysis excludes important heavy chain CDR3 regions, and light chain CDR3 sections that are known to be at the center of an antibody binding site, and potentially provide important interactions with an antigen. Furthermore, Tomlison et al. Proposes that somatic diversity alone does not necessarily predict a role of a specific amino acid in antigen binding, and suggests conserved amino acid residues that contact the antigen, and different amino acid residues that do not contact with the antigen. This conclusion is further supported by mutational studies in the

134 role of somatic mutations for antibody affinity (Sharon, (1990), PNAS, 87: 4814-7). Nineteen somatic mutations in a high affinity anti-p-azophenylarsonate antibody were simultaneously replaced by their corresponding germline residues, generating a germline version of the anti-Ars antibody that has a loss of two hundred fold activity. The full affinity of the anti-Ars antibody can be recovered by restoring only three of the nineteen somatic mutations, demonstrating that io many somatic mutations can be allowed not to contribute to antigen binding activity.

The result can be explained in part by the diversity nature of the antibody itself. Immature B cells can initially produce low affinity antibodies that recognize a number of self or non-self antigens. Furthermore, antibodies can undergo affinity maturation sequence variations that can cause self-reactivity. Hypermutation of such low affinity antibodies can serve to suppress autoreactivity ("negative selection") and increase affinity for the foreign antigen. Therefore, analysis of primary and structural data from a large number of antibodies does not provide a method to predict (1) the role of somatic hyper-mutation sites in the affinity maturation process versus the process to decrease affinity towards

135 unwanted antigens, or (2) how a given amino acid contributes to the properties of a specific antigen-antibody pair.

Other attempts to direct the role of specific amino acid residues in antigen recognition were made by analyzing a number of crystal structures of antigen-antibody complexes (MacCallum et al. (1996) J. Mol. Biol. 262: 732-745). The potential role of localized positions inside and outside the CDRs was indicated. The positions in the CDRs involved in the antigen that binds more than 10 of the 26 structures analyzed include H31, H33, H50, H52, H53, H54, H56, H58, H95, H96, H97, H98 and H100 in the heavy chain and L30A , L32, L91, L92, L93, L94, L96 on the light chain. However, the authors noted that prediction of antigen contacts using these and other structural data may over and under predict contact positions, leading to speculation that a different strategy may have to be applied to different antigens.

Pini et al. Describe multiple random selection residues in antibody CDR sequences in a large phage display library to rapidly increase antibody affinity (Pini et al. (1998) J. Biol Chem. 273: 21769-21776). However, the high affinity antibodies discussed by Pini et al. Have mutations at a total of eight positions, and a reductive analysis of which changes are absolutely required for

136 Improved antibody affinity becoming impractical due to the large number of possible combinations to be tested for the smallest number of required amino acids.

Furthermore, multiple random selection residues may not necessarily preserve other desired properties of the antibody. Desirable properties or characteristics of an antibody are recognized in the art and include, for example, preservation of non-cross reactivity, for example, with other proteins or human tissues, and preservation of antibody sequences that are close to improvement in immunoglobulin sequences of human germ line of neutralizing power. Other desirable properties or characteristics include ability to preserve species cross-reactivity, ability to preserve epitope specificity, and ability to preserve high expression levels of protein in mammalian cells. Desirable properties or characteristics can be observed or measured using art-recognized techniques including but not limited to ELISA, competitive ELISA, in vitro and in vivo neutralization assays (see for example Example 3 of North American Patent No. 6,914,128), immunohistochemistry with tissue sections from different sources including human, primate, or other sources as needed may be, and studies for expression in mammalian cells using transient expression or stable expression.

137

Furthermore, the Pini et al. Method may introduce more changes than the minimum number currently required to improve affinity and may lead to antibodies that trigger the formation of anti-human antibody (HAMA) in human subjects.

Furthermore, as discussed elsewhere, phage display as shown here, or another related method that includes ribosome display, may not work properly achieving certain affinities between the antibody and antigen and the conditions required to achieve equilibrium. they can be established within a reasonable time frame due to additional interactions including interactions with other phage or ribosome components and the antigen.

The person skilled in the art can gather interesting scientific information about the origin of antibody diversity from the teachings of the references discussed above. The present invention, however, provides a method of increasing the antibody affinity of a specific antigen-antibody pair while preserving other relevant or desirable characteristics of the antibody. This is especially important when considering the desirability of imparting a multiplicity of different characteristics on a specific antibody that includes antigen binding.

If the starting antibody has desirable properties or characteristics that need to be preserved, a process of

138 Selective mutagenesis may be the best strategy to preserve these desirable characteristics while enhancing the activity of the antibody. For example, in Y61 mutagenesis, the objective was to increase the affinity for hlL-12, and to enhance the neutralizing potency of the antibody while preserving desired properties. The desired properties of Y61 include (1) preservation of non-cross reactivity with other human proteins or tissues, (2) preservation of fine epitope specificity, i.e. recognizing a p40 epitope preferably in the context of the p70 (p40 / p35) heterodimer, thereby preventing binding interference from free soluble p40; and (3) generation of an antibody with heavy and light chain amino acid sequences that are as close as possible to their respective germline immunoglobulin sequences.

In one embodiment, the method of the invention provides a selective mutagenesis process as a strategy to preserve the desirable properties or characteristics of the antibody while improving the affinity and / or neutralizing potency. The term "selective mutagenesis process" as defined above and includes a method of individually mutated selected amino acid residues. The amino acid residues to be mutated can first be selected from preferred selective mutagenesis positions, after contact positions, and after positions of

139 hypermutation. The individual selected position can be mutated to at least two other amino acid residues and the effect of the mutation of both on the desired properties of the antibody, and improvement in antibody activity is determined.

The Selective Mutagenesis Process comprises the stages of:

select candidate positions in order 1); preferred selective mutagenesis positions 2) contact positions; 3) hypermutation positions and classifying the io positions based on position location within the heavy and light chain variable regions of an antibody (CDR3 preferred over CDR2 preferred over CDR1);

individually mutated candidate preferred selective mutagenesis positions, hypermutation 15 and / or contact positions in order to classify all other possible amino acid residues and analyze the effect of individual mutations on antibody activity to determine amino acid residues activity enhancers;

if necessary, making step-by-step combinations of the individual activity enhancing amino acid residues and analyzing the effect of the various combinations on the activity of the antibodies; selecting mutated antibodies with activity enhancing amino acid residues and aligning the mutant antibodies based on the location and identity of the amino acid substitutions with respect to their potential

140 immunogenetic. The highest ranking is given to mutant antibodies that comprise an amino acid sequence that is almost identical to a variable region sequence that is described in a germline database, or has an amino acid sequence that is comparable to other human antibodies. . A lower classification is given to mutant antibodies that contain an amino acid substitution that is rarely found in germline sequences or the sequences of other human antibodies. The lowest ranking is given to mutant antibodies that contain an amino acid substitution that is rarely found in germline sequences or the sequences of other human antibodies. As indicated above, mutant antibodies comprising at least one activity enhancing amino acid residue located in CDR3 are preferred over CDR2 which is preferred over CDR1. CDRs of heavy chain variable regions are preferred over those of the light chain variable region.

Mutant antibodies can also be studied for improvement in activity, for example when compared to their corresponding parental antibody. The improvement in activity of the mutant antibody can be determined for example, by neutralization assay, or binding specificity / affinity by surface plasmon resonance analysis (see Example 3 of North American Patent No. 6,914,128).

Preferably, the improvement in activity can be at least 2141 times greater than the parental antibody. The improvement in activity can be at least “χΓ a“ x2 times greater than the parental antibody where "xi" and "x2”Are integers between and including 2 to 20, including intervals within the state range, for example 2-15, for example 5-10.

Mutant antibodies with the activity-enhancing amino acid residue can also be studied to determine if at least one other desirable property has been preserved after the mutation. For example, with anti-hlL-12 antibodies tested for, (1) preservation of non-cross reactivity with other human proteins or tissues, (2) preservation of epitope recognition, i.e. recognizing a p40 epitope preferably in the context of the p70 heterodimer (p40 / p35), thereby preventing binding interference from free soluble p40; and (3) generation of antibodies with heavy and light chain amino acid sequences that are as close as possible to their respective germline immunoglobulin sequences, and the determination of which will be least likely to produce a human immune response based on the number of germline sequence differences. The same observations can be made on an antibody that has more than one of the activity enhancing amino acid residues, for example at least two or at least three activity enhancing amino acid residues, to determine whether property retention has occurred. or

142 desirable feature.

An example of the use of a "selective mutagenesis process" in Y61 mutagenesis is described below.

Individual mutations H31S- »E, L50—> Y, or L94G-» Y each enhanced neutralization activity of the antibody. However, when the combination clones were tested, the activity of the combined clone H31S- »E + L50-» Y + L94G-> Y was not better than L50- »Y + L94G-> Y (J695). Thus, the change from the germline amino acid residue Ser to Glu at the position

31 CDR1 was unnecessary for the enhanced activity of J695 on Y61. The selective mutagenesis process therefore identified the minimum number of changes that contributed to the final activity, thereby reducing the immunogenetic potential of the final antibody and preserving other desired properties of the antibody.

Isolated DNA encoding VH and VL produced by the selected mutagenesis process can be converted to full-length antibody chain genes, to genes in the Fabs fragment for a scFV gene, as described in section IV. For expression of VH and VL regions produced by the selected mutagenesis process, expression vectors encoding the heavy and light chain can be transfected into a variety of host cells as described in detail in section IV. Preferred host cells include host cells

143 prokaryotic, eg, E coli, or eukaryotic host cells, eg, yeast cells, eg, S. cerevisae. Most of the preferred eukaryotic host cells are mammalian host cells, described in detail in section IV.

The selective mutagenesis process provides a method of producing antibodies with enhanced activities without prior affinity maturation of the antibody by other means. The selective mutagenesis process provides a method of producing antibodies with improved affinities that have undergone retromutations. The selective mutagenesis process also provides a method to enhance the activity of matured affinity antibodies.

The skilled artisan will recognize that the selective mutagenesis process can be used in standard antibody manipulation techniques known in the art. Examples include, but are not limited to, CDR-grafted antibodies, chimeric antibodies, scFV fragments, Fabs fragments of full-length antibodies, and human antibodies from other sources, eg, transgenic mice.

Rapid large-scale mutational analysis of antibodies includes in vitro transcription and translation using ribosome hexibition technology (see, eg, Hanes et al., (1997) Proc. Nati. Acad. Sci. 94: 4937-4942; Dalí Acqua and collaborators, (1998) Curr. Opin. Struc. Biol. 8: 443-450; He and

144 collaborators, (1997) Nucleic Acid Res. 25: 5132-5134), and

North American Patents Nos. 5,643,768 and 5,658,754 issued by Kawasakl. The selective mutagenesis process also provides a method of producing antibodies with enhanced activities that can be screened using ribosome expression techniques.

In the methods of the invention, the antibodies or antigen-binding portions thereof are further modified by altering Individual positions in the HCVR CDRs and / or

IO LCVR. Although these modifications can be made in phage-expressed antibodies, the method is advantageous in that it can be done in antibodies that are expressed in other types of host systems, such as bacterial, yeast, or mammalian cell expression systems. The positions

Individuals within the CDRs selected for modification are based on the positions that are a contact and / or hypermutation position.

Preferred contact positions and hypermutation positions as defined herein are shown in Table

3 of North American Patent No. 6,914,128 (see Appendix A of North American Patent No. 6,914,128 and Figure 3 of Appendix A attached thereto) and its modification according to the method of the invention is described in detail in Example 2 of the Patent North American No. 6,914,128. Preferred contact positions are selected from the group consisting of

145

<td>L53,</td><td>L55,</td><td>L91,</td><td>L92,</td><td>L93</td><td colspan="2">, L94 and</td><td>L96.</td><td>The</td><td>positions of</td>

Preferred hypermutation are selected from the group consisting of H30, H31, H31B, H32, H52, H56, H58, L30, L31, L32, L53, and L93. The most preferred amino acid residues (designated as "preferred selective mutagenesis positions) are contact and hypermutation positions and are selected from the group consisting of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94. Particularly preferred contact positions are selected from the group consisting of L50 and L94.

Preferred activity enhancing amino acid residues substitute for localized amino acid residues at the positions selected from the group consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95,

H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94, and L96. The most preferred activity enhancing amino acid residues replace amino acid residues located at positions H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94. Particularly, preferred activity enhancing amino acid residues replace localized amino acid residues at positions selected from the group consisting of L50 and L94.

146

In general, the method of the invention involves selecting a particular preferred selective mutagenesis position, contact position and / or hypermutation within a heavy or light chain CDR of a mother antibody of interest, or antigen-binding portion thereof. , randomly mutagenizing this individual position (eg, by genetic means using a mutagenic oligonucleotide to generate a "mini-library" of modified antibodies), or mutating a position to specific desired amino acids, to identify activity-enhancing amino acid residues that express, and purify the modified antibodies (eg, in a non-phage display host system) by measuring the activity of the modified antibodies to the antigen (for example, measuring constants kORff by BIAcore analysis), repeating these steps for other CDR positions, as necessary, and combining individual mutations shown for enhanced activity and testing whether the combinations generate an antibody with even higher activity (eg, affinity or neutralizing potency) of the mother antibody, or antigen-binding portion thereof.

Accordingly, in one embodiment, the invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, comprising:

a) providing a mother antibody or binding portion

147 to its antigen;

b) select in order a 1) preferred selective mutagenesis position, 2) contact position, or 3) hypermutation position within a complementary determining region (CDR) for mutation, thereby identifying a selected preferred selective mutagenesis position , contact position or hypermutation;

c) individually mutating the selected preferred selective mutagenesis position, contact position or hypermutation to at least two other amino acid residues thereby creating a panel of mutated antibodies, or antigen binding portions thereof;

d) evaluating the activity of the panel of mutated antibodies, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof;

e) optionally, repeating steps a) to d) for at least one other preferred selective mutagenesis position, contact position or hypermutation;

f) combining, in the parent antibody, or antigen-binding portion thereof, individual mutations shown to have enhanced activity, to form combination antibodies, or antigen-binding portions thereof; and

g) evaluating the activity of the combination antibodies, or antigen-binding portions thereof, with

148 relative to the mother antibody or antigen-binding portion thereof; until an antibody, or antigen-binding portion thereof, with improved activity, relative to the parent antibody, or antigen-binding portion thereof, is obtained.

Preferably, the selected antibody or antibodies have enhanced activity without loss or with retention of at least one desirable characteristic or property of the parent antibody as described above. The desirable characteristic or property can be measured or observed by the expert using techniques recognized in the art.

Preferred contact positions are selected from the group consisting of H30, H31, H31B, H32, H33, H35, H50,

H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H1O1, L30,

L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96. Preferred hypermutation positions are selected from the group consisting of H30, H31, H31B, H32, H52, H56, H58, L30, L31, L32, L53, and L93. The most preferred selective mutagenesis positions are selected from the group consisting of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92,

L93 and L94. Particularly preferred contact positions are selected from the group consisting of L50 and L94.

In another embodiment, the invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, comprising:

a) providing a mother antibody or binding portion

149 to its antigen;

b) selecting a preferred selective mutagenesis position, contact position or hypermutation within a complementary determining region (CDR) for mutation;

c) individually mutating the selected preferred selective mutagenesis position, contact position or hypermutation to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen binding portions thereof;

d) evaluating the activity of the panel of mutated antibodies, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof, thereby identifying an activity-enhancing amino acid residue;

e) optionally, repeating steps a) to d) for at least one other preferred selective mutagenesis position, contact position or hypermutation;

f) combining, in the parent antibody, or antigen-binding portion thereof, two individually active enhancing amino acid residues shown to have enhanced activity, to form combination antibodies, or antigen-binding portions thereof; and

g) evaluating the activity of the combination antibodies, or antigen-binding portions thereof, with two activity-enhancing amino acid residues, with

150 relative to the mother antibody or antigen-binding portion thereof;

until an antibody, or antigen binding portion thereof, with improved activity, relative to the parent antibody, or antigen binding portion thereof, is obtained.

Preferred contact positions are selected from the group consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96. Preferred hypermutation positions are selected from the group consisting of H30, H31, H31B, H32, H52, H56, H58, L30, L31, L32, L53, and L93. The most preferred selective mutagenesis positions are selected from the group consisting of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92,

L93 and L94. Particularly preferred contact positions are selected from the group consisting of L50 and L94.

In another embodiment, the invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, comprising:

a) providing a mother antibody or antigen binding portion thereof;

b) selecting a preferred selective mutagenesis position, contact position or hypermutation within a complementary determining region (CDR) for mutation;

c) individually mutate the position of mutagenesis

151 selected preferred selected, contact position or hypermutation to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen binding portions thereof;

e) optionally, repeating steps a) to d) for at least one other preferred selective mutagenesis position, contact position or hypermutation;

f) combining, in the parent antibody, or antigen-binding portion thereof, three individually active enhancing amino acid residues shown to have enhanced activity, to form the combining antibodies, or antigen-binding portions thereof; and

until an antibody, or antigen-binding portion thereof, with enhanced activity, relative to the parent antibody, or antigen-binding portion thereof, is obtained.

152

Preferably the activity enhancing amino acid residue replaces localized amino acid residues at the positions selected from the group consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95 ,

H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55,

L91, L92, L93, L94 and L96.

Following mutagenesis of individual selected positions, mutated clones can be sequenced to identify which amino acid residues have been introduced at the selected position in each clone. A small number of clones (for example, approximately 24) can be selected for sequencing, which statistically must produce 10-15 unique antibodies, while a larger number of clones (for example, greater than 60) can be sequenced to ensure that the antibodies with Every possible substitution at the selected position is identified.

In one embodiment, the contact and / or hypermutation positions within the CDR3 regions of the heavy and / or light chains are first selected for mutagenesis.

However, for antibodies that have already been affinity matured in vitro by random mutagenesis of the CDR3 regions via selection for phage display, it may be preferable to first select the contact and / or hypermutation positions within CDR1 or CDR2 of the heavy chain and / or light.

153

In a more preferred embodiment, preferred selective mutagenesis positions within the CDR3 regions of the heavy and / or light chains are first selected for mutagenesis. However, for antibodies that have already been affinity matured in vitro by random mutagenesis of CDR3 regions via phage display selection, it may be preferable to first select preferred selective mutagenesis positions within CDR1 or CDR2 of the heavy chain and / or or light.

In a further preferred embodiment, optimization of an antibody selected by the selective mutagenesis process is done sequentially as follows: Preferred selective mutagenesis positions selected from the group consisting of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31,

L32, L50, L91, L92, L93, L94 are mutated by at least 2 other amino acids each (preferably 5-14 other amino acids) first and the resulting antibodies are characterized for increased affinity, neutralizing potency (and also possibly at least one other property or retained property discussed elsewhere). If a single-position mutation of preferred selective mutagenesis does not increase the affinity or neutralizing potency in all or sufficiently, and even the combination of multiple activity-enhancing amino acids that replace amino acids at preferred selective mutagenesis positions does not give rise to an antibody of

154 In combination with the target activity (including affinity and / or neutralizing potency), additional amino acid residues will be selected for selective mutagenesis from the group consisting of H35, H50, H53, H54, H95, H96, H97, H98,

L30A and L96 are mutated to at least 2 other amino acids each (preferably 5-14 other amino acids) and the resulting antibodies are characterized for increased affinity, neutralizing potency (and possibly also at least one other trait or retained property discussed in another part).

If a single amino acid residue mutation selected from the group consisting of H35, H50, H53, H54, H95, H96, H97, H98, L30A and L96 do not increase activity by including (affinity and / or neutralizing potency) in all or not enough and even if the combination of multiple activity enhancing amino acids that replace amino acids at these positions does not result in a combination antibody that complies with the directed activity (including affinity and / or target neutralizing potency), additional amino acid residues will be selected for selective mutagenesis from the group consisting of H33B, H52B, L31A and will mutate to at least 2 other amino acids each (preferably 5-14 other amino acids) and the resulting antibodies are characterized for increased affinity, neutralizing potency (and also possibly at least one other trait or conserved retained property discussed elsewhere).

155

It should be understood that the sequential selective mutagenesis process can terminate at any of the steps described above as soon as an antibody with the desired activity (including affinity and neutralizing potency) has been identified. If the mutagenesis of the previously selected positions has identified activity enhancing amino acid residues but the combination antibody still does not meet the stated targets for activity (including affinity and neutralizing potency) and / or if the identified activity enhancing amino acids also affect other desired characteristics and are therefore unacceptable, the remaining CDR residues may undergo mutagenesis (see Section IV).

The method of the invention can be used to enhance the activity of an antibody, or antigen-binding portion thereof, to achieve a predetermined target activity (eg, a predetermined affinity and / or neutralizing potency, and / or a desired property or characteristic ).

Accordingly, the invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, to achieve a predetermined target activity, comprising:

a) providing a mother antibody an antigen binding portion thereof;

b) selecting a preferred selective mutagenesis position selected from the group consisting of H30, H31,

156

Η31Β, Η32, Η33, Η52, Η56, Η58, L30, L31, L32, L50, L91, L92, L93, L94.

c) individually mutating the selected preferred selective mutagenesis position to at least two other amino acid residues to thereby create a first panel of mutated antibodies, or antigen-binding portions thereof;

d) evaluating the activity of the first panel of mutated antibodies, or the antigen binding portions thereof determined whether the single-position mutation of selective mutagenesis produces an antibody or antigen binding portion thereof with the predetermined target activity or a partial objective activity;

e) combining in a stepwise manner, in the parent antibody, or antigen-binding portion thereof, individual mutations shown to have improved activity, to form combination antibodies, or antigen-binding portions thereof;

f) evaluating the activity of the combination antibodies, or antigen-binding portions thereof, determining whether the combination antibodies, or antigen-binding portions thereof have the predetermined target activity or a partial target activity;

g) if steps d) or f) do not give rise to a portion of

157 binding to the antibody or antigen thereof having the predetermined target activity, or an antibody with only partial activity, the additional amino acid residues selected from the group consisting of H35, H50, H53, H54,

H95, H96, H97, H98, L30A, and L96 are mutated to at least two other amino acid residues thereby to create a second panel of mutated antibodies or antigen-binding portions thereof;

h) evaluating the activity of the second panel of mutated antibodies or antigen-binding portions thereof, to determine whether the single amino acid residue mutation selected from the group consisting of H35, H50, H53, H54, H95, H96, H97 , H98, L30A and L96 result from an antibody or antigen binding portion thereof, having the predetermined target activity or a partial activity;

i) combining in a stepwise manner into the mother antibody, or antigen-binding portion thereof, individual mutations from step g) shown to have improved activity, to form combination antibodies, or antigen-binding portions of the themselves;

j) evaluating the activity of the combination antibodies or antigen-binding portions thereof, to determine whether the combination antibodies, or antigen-binding portions thereof have the predetermined target activity or a partial target activity;

158

k) if steps h) or j) do not result in an antibody or antigen binding portion thereof having the predetermined target activity, or result in an antibody with only partial activity, additional amino acid residues selected from the group which it consists of H33B, H52B and L31A are mutated to at least two other amino acid residues thereby to create a third panel of mutated antibodies or antigen-binding portions thereof;

l) evaluating the activity of the third panel of mutated io antibodies or antigen-binding portions thereof, to determine whether a single amino acid residue mutation selected from the group consisting of H33B, H52B and L31A resulted in a binding portion to the antibody or antigen thereof, having the predetermined target activity or a partial activity;

m) combining in a stepwise manner into the parent antibody, or antigen-binding portion thereof, the individual mutation from step k) shown to have improved activity, to form combination antibodies, or antigen-binding portions, thereof;

n) evaluating the activity of the combination antibodies or antigen-binding portions thereof, to determine whether the combination antibodies, or antigen-binding portions thereof have the predetermined target activity thereby to produce a portion of union to

159 antibody or antigen thereof with a predetermined target activity.

A number of methods of mutagenesis can be used, including PCR assembly, Kunkel-directed oligonucleotide mutagenesis (dut-ung-), and thiophosphate (Amersham Sculptor kit).

A wide variety of host expression systems can be used to express mutated antibodies, including bacterial, yeast, baculoviral, and mammalian expression systems (as well as phage display systems). An example of a suitable bacterial expression vector is pUC119 (Sfi). Other antibody expression systems are known in the art and / or described later in Section V.

Modified antibodies, or antigen-binding portions thereof, produced by the method of the invention can be identified without reliance on phage display methods for selection. Accordingly, the method of the invention is particularly advantageous for enhancing the activity of a recombinant mother antibody or antigen-binding portion thereof, which was obtained by selection in a phage display system but whose activity cannot be further enhanced by mutagenesis. in phage display system.

Accordingly, in another embodiment, the invention provides a method of improving the affinity of an antibody,

160 or antigen-binding portion thereof, comprising:

a) providing a recombinant mother antibody or antigen-binding portion thereof; which was obtained by selection in a phage display system but whose activity cannot be further enhanced by mutagenesis in the phage display system;

b) selecting a preferred selective mutagenesis position, contact position or hypermutation within a complementary determinant line (CDR) for mutation,

<td> 10</td><td colspan="2">thereby identifying a selected hypermutation;</td><td>position</td><td>of</td><td>contact or</td>

<td></td><td>c)</td><td>individually mutate the</td><td>position</td><td>of</td><td>mutagenesis</td>

<td></td><td>selective</td><td>selected preferred,</td><td>position</td><td>of</td><td>contact or</td>

hypermutation to at least two other amino acid residues 15 thereby to create a panel of mutated antibodies, or antigen-binding portions thereof, and express the panel in a non-phage display system;

d) evaluating the activity of the panel of mutated antibodies, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof;

e) optionally repeating steps b) to d) for at least one other selective mutagenesis position, contact position or preferred hypermutation;

f) combining, in the parent antibody, or antigen-binding portion thereof, individual mutations shown to

161 have enhanced activity, to form combination antibodies, or antigen-binding portions thereof; and

g) evaluating the activity of the combination antibodies, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof;

until an antibody, or antigen-binding portion thereof, with enhanced activity, relative to the parent antibody, or antigen-binding portion thereof, is obtained.

With available methods it is not possible or extremely time consuming to derive an antibody with increased binding affinity and neutralizing potency while retaining other properties or characteristics of the antibodies as discussed above. The method of this invention, however, can

162 easily identify such antibodies. The antibodies subjected to the method of this invention can come from any source.

Therefore, in another embodiment, the invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, comprising:

a) providing a recombinant mother antibody or antigen-binding portion thereof;

b) selecting a preferred selective mutagenesis position, contact position or hypermutation within a complementary determining region (CDR) for mutation, thereby identifying a selected preferred selective mutagenesis position, contact position or hypermutation;

c) individually mutating the selected preferred selective mutagenesis position, contact position, or hypermutation to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen binding portions thereof, and express the panel in an appropriate expression system;

e) evaluating the panel of mutated antibodies, or portions

163 antigen binding thereof, relative to the parent antibody or antigen binding portion thereof to at least one other property or characteristics, wherein the property or characteristic is one that needs to be preserved in the antibody;

until an antibody, or antigen-binding portion thereof, with improved activity and at least one conserved property or characteristic, relative to the parent antibody, or antigen-binding portion thereof, is obtained.

In a preferred embodiment, the contact positions are selected from the group consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98,

H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96 and the other feature is selected from 1) preservation of

I5 non-cross reactivity with other human proteins or tissues, 2) preservation of epitope recognition, i.e. recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free, soluble and / or p40 binding interference 3) to produce an antibody with an immunoglobulin sequence close to the germ line.

164 preservation of epitope recognition, i.e. recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents binding interference from free, soluble p40 and / or 3) to produce an antibody with an immunoglobulin sequence close to that of germ line.

In a more preferred embodiment, the residues for selective mutagenesis are selected from the preferred selective mutagenesis positions from the group consisting of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, io L92, L93, L94 and the other characteristic is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2) preservation of epitope recognition, that is, recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free, soluble p40 binding interference and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

In a more preferred embodiment, the contact positions are selected from the group consisting of L50 and L94 and the other feature is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2) preservation of epitope recognition, is say recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents binding interference from free, soluble p40 and / or 3) to produce an antibody with a sequence of

165 Immunoglobulin close to the germ line.

If therefore, the affinity of an antibody for a specific antigen is improved, but where the phage display method (or related system includes ribosome display) is no longer applicable, and other desirable properties or characteristics should be maintained, the method of the invention can be used. Accordingly, in another embodiment, the invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, which comprises:

a) providing a recombinant mother antibody or antigen-binding portion thereof; which was obtained by selection in phage display system but whose activity cannot be further enhanced by mutagenesis in the phage display system;

b) selecting a preferred selective mutagenesis position, contact position or hypermutation within a complementary determining region (CDR) for mutation, thereby identifying a selected preferred mutagenesis position, contact position or selected hypermutation;

166 in a non-phage display system;

d) evaluating the activity of the mutated antibody panel, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof such that it identifies an activity-enhancing amino acid residue;

c) evaluating the panel of mutated antibodies, or antigen-binding portions thereof, relative to the mother antibody or antigen-binding portion thereof, at least one other property or characteristic, where the property or characteristic is one that needs maintained, until an antibody, or antigen-binding portion thereof, with enhanced activity and at least one trait or conserved trait, relative to the parent antibody, or antigen binding portion thereof, is obtained.

f) optionally, repeating steps a) to e) for at least one other preferred selective mutagenesis position, contact position or hypermutation;

g) combining, in the mother antibody, or antigen-binding portion 20 thereof, at least two individual activity enhancing amino acid residues shown to have enhanced activity and at least one conserved property or characteristic, to form combination antibodies , or antigen-binding portions thereof; and

h) evaluating the activity of the antibodies of

167 combination, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof;

until an antibody, or antigen-binding portion thereof, with enhanced activity and at least one other property or characteristic conserved, relative to the parent antibody, or antigen-binding portion thereof, is obtained.

In a preferred embodiment, the contact positions are selected from the group consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98,

H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96 and the other characteristic is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2 ) preservation of epitope recognition, i.e. recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free p40 binding interference, soluble and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

168 p70 p40 / p35 heterodimer that prevents binding interference from free, soluble p40 and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

In a more preferred embodiment, the residues for selective mutagenesis are selected from the preferred selective mutagenesis positions from the group consisting of H30,

H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94 and the other characteristic is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2) preservation of epitope recognition, i.e. recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free p40 Binding Interference, soluble and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

In a more preferred embodiment, the contact positions are selected from the group consisting of L50 and L94 and the other characteristic is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2) preservation of epitope recognition, is say recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free p40 binding interference, soluble and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

In another embodiment, the invention provides a method for

169 enhance the activity of an antibody, or antigen binding portion thereof, comprising:

b) selecting a preferred selective mutagenesis position, contact position or hypermutation within a complementary determining region (CDR) for mutation,

<td>such</td><td>mode by identifying a</td><td>position</td><td>of</td><td>contact or</td>

<td colspan="2">selected hypermutation;</td><td></td><td></td><td></td>

<td>c)</td><td>individually mutate the</td><td>position</td><td>of</td><td>mutagenesis</td>

<td>selective</td><td>selected preferred,</td><td>position</td><td>of</td><td>contact or</td>

hypermutation to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen binding portions thereof, and express the panel in a non-phage display system;

d) evaluating the activity of the mutated antibody panel, or antigen binding portions thereof, relative to the parent antibody or antigen binding portion thereof such that it identifies an activity enhancing amino acid residue;

e) evaluating the panel of mutated antibodies, or antigen binding portions thereof, relative to the parent antibody

170 or antigen-binding portion thereof at least one other property or characteristic, wherein the property or characteristic is one that needs to be maintained, until an antibody, or antigen-binding portion thereof, with enhanced activity and therefore least one trait or conserved trait, relative to the parent antibody, or antigen-binding portion thereof, is obtained.

In a preferred embodiment, the contact positions are selected from the group consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96 and the other characteristic is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2) preservation of epitope recognition, that is, recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free, soluble p40 binding interference and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

171 p70 p40 / p35 heterodimer that prevents binding interference from free, soluble p40 and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

In a more preferred embodiment, the residues for selective mutagenesis are selected from the preferred selective mutagenesis positions from the group consisting of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94 and the other characteristic is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2) preservation of epitope recognition, that is, recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free, soluble p40 binding interference and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

In another embodiment, the invention provides a method for

172 enhance the activity of an antibody, or antigen-binding portion thereof, comprising:

c) individually mutating the selected preferred selective mutagenesis positions, contact position or hypermutation to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen-binding portions thereof, and express the panel in a non-phage display system;

e) evaluating the panel of mutated antibodies, or antigen-binding portions thereof, relative to the parent antibody

173 or antigen-binding portion thereof at least one other property or characteristic, wherein the property or characteristic is one that needs to be maintained, until an antibody, or antigen-binding portion thereof, with enhanced activity and therefore less a conserved characteristic, relative to the parent antibody, or antigen-binding portion thereof, is obtained.

f) optionally, repeating steps a) to e) for at least one other preferred selective mutagenesis position, contact position or hypermutation;

g) combining, in the parent antibody, or antigen-binding portion thereof, at least two individual activity enhancing amino acid residues shown to have enhanced activity and at least one conserved property or characteristic, to form combination antibodies, or antigen binding portions thereof; and

h) evaluating the activity of the combination antibodies, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof;

In a preferred embodiment, the contact positions are

174 select from the group consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98,

H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96 and the other characteristic is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2) preservation of epitope recognition, i.e. recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free p40 binding interference, soluble and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

In another preferred embodiment, the hypermutation positions are selected from the group consisting of H30, H31, H31B, H32, H52, H56, H58, L30, L31, L32, L53 and L93 and the other characteristic is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2) preservation of epitope recognition, i.e. recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free p40 binding interference, soluble and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

175 preservation of non-cross reactivity with other human proteins or tissues, 2) preservation of epitope recognition, i.e. recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free, soluble and / or p40 binding interference or 3) to produce an antibody with an immunoglobulin sequence close to the germ line.

In a more preferred embodiment, the contact positions are selected from the group consisting of L50 and L94 and the other characteristic is selected from 1) preservation of non-cross reactivity with other proteins or human tissues, 2) preservation of epitope recognition, is say recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents free p4Ó binding interference, soluble and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline.

IV. Modifications of other CDR residues

Finally, all CDR residues in a given antibody pair identified by any means to be required as activity enhancing amino acid residues and / or required directly or indirectly to bind the antigen and / or to retain other desirable properties or characteristics of the antibody. Such CDR residues are referred to as "preferred selective mutagenesis positions". It should be noted that in specific circumstances that

176 Preferred selective mutagenesis can also be identified by other means including antibody and antigen co-crystallization and molecular modeling.

If preferred attempts to identify activity enhancing amino acids 5 that target the preferred selective mutagenesis positions, contact positions, or hypermutation described above have been exhausted, or if further improvements are required, the remaining CDR residues may be modified as described later. It should be understood that the antibody may already be modified at any one or more contact or hypermutation positions according to the

<td>modalities</td><td>discussed before</td><td>but</td><td>may require improvement</td>

<td>additional.</td><td>Therefore, in</td><td>other</td><td>modality, invention</td>

<td>provides</td><td>a method to</td><td colspan="2">improve the activity of a</td>

<td>antibody,</td><td>or joint portion</td><td>to the</td><td>antigen thereof, which</td>

<td>understands:</td><td></td><td></td><td></td>

<td colspan="3">a) provide an antibody</td><td>mother or union portion</td>

to its antigen;

b) selecting an amino acid residue within a complementarity determining region (CDR) for mutation with the exception of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95 , H96, H97, H98, H101, L30, L31,

L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96;

c) individually mutate the position selected by, for example, at least two other amino acid residues of such

177 mode for creating a transformed antibody or a panel of mutated antibodies, or antigen-binding portions thereof;

d) evaluating the activity of the transformed antibody or the panel of mutated antibodies, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof such that it identifies an activity-enhancing amino acid residue ;

e) evaluating the transformed antibody or mutated antibody panel, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof, for changes in at least one other property or characteristic until a antibody, or antigen-binding portion thereof, with enhanced activity, relative to the parent antibody, or antigen-binding portion thereof.

Preferably, the other property or characteristic is selected from 1) preservation of non-cross reactivity with other human proteins or tissues, 2) preservation of epitope recognition, i.e. recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents interference from binding of free, soluble p40 and / or 3) to produce an antibody with an Immunoglobulin sequence close to the germline

IF mutagenesis of a single residue is not sufficient, other residues may be included; therefore, in another modality, the

178 Invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, comprising:

a) providing a mother antibody or antigen-binding portion thereof;

c) individually mutating the selected position to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen-binding portions thereof;

e) repeating steps b) to d) for at least one other CDR position that is not the position selected below b) or one position in H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31,

L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96;

f) combining, into the parent antibody, or binding portion

179 to the antigen thereof, at least two individual activity enhancing amino acid residues shown to have enhanced activity, to form combination antibodies, or antigen-binding portions thereof; and

g) evaluating the activity of the combination antibodies, or antigen-binding portions thereof, with two activity-enhancing amino acid residues, relative to the parent antibody or antigen-binding portion thereof until an antibody, or binding portion to the antigen thereof, with improved activity, relative to the mother antibody, or antigen-binding portion thereof, is obtained.

If the preferred attempts to identify activity enhancing amino acids that target the contact or ohmpermutation positions described above are exhausted, or if further improvements are required, and the antibody in question cannot be further optimized by mutagenesis and expression methods in phage (or related ribosome display) the remaining CDR residues can be modified as described below. It is to be understood that the antibody may already be modified at any one or more preferred selective mutagenesis position, contact positions, or permutation in accordance with the modalities discussed above but may require further improvement.

Therefore, in another embodiment, the invention provides a method of enhancing the activity of an antibody, or portion of

180 antigen binding thereof, comprising:

b) selecting a choice of an amino acid residue within a complementarity determining region (CDR) for mutation with the exception of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58 , H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and;

c) individually mutating the selected contact or hypermutation position to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen-binding portions thereof, and express the panel in a display system non-phage;

d) evaluating the activity of the panel of mutated antibodies, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof,

<td>so that</td><td>identifies</td><td>a</td><td>residue</td><td>of</td><td>enhancer amino acid</td><td>of</td>

<td>exercise;</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>and)</td><td>evaluating</td><td>the</td><td>panel</td><td>of</td><td>mutated antibodies,</td><td> 0</td>

<td>servings</td><td>of Union</td><td>to the</td><td>antigen</td><td>of the</td><td>same in relation</td><td>to the</td>

mother antibody or antigen-binding portion thereof, for changes in at least one other property or characteristic,

181 until an antibody, or antigen-binding portion thereof, with enhanced activity, relative to the parent antibody, or antigen-binding portion thereof, is obtained.

If a single mutagenesis is not sufficient to increase the affinity of the antibody, other residues may be included in the mutagenesis. Therefore, in another embodiment, the invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, comprising;

a) providing a mother antibody or antigen-binding portion thereof which was obtained by selection in a phage display system but whose activity cannot be further enhanced by mutagenesis in the phage display system;

182

L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96;

c) individually mutating the selected position to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen-binding portions thereof and expression in a non-phage display system;

e) repeating steps b) to d) for at least one other position that is not the position selected below b) or a position in H30, H31, H31B, H32, H33, H35, H50, H52, H52A,

H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32,

L34, L50, L52, L53, L55, L91, L92, L93, L94;

g) combining, in the parent antibody, or antigen-binding portion thereof, at least two individually active enhancing amino acid residues shown to have enhanced activity, to form combination antibodies, or antigen-binding portions thereof ; and

h) evaluating the activity and other property or characteristic of the combination antibodies, or antigen-binding portions thereof, with two activity-enhancing amino acid residues, relative to the parent antibody or

183 antigen binding portion thereof;

until an antibody, or antigen-binding portion thereof, with enhanced activity, relative to the parent antibody, or antigen-binding portion thereof, is obtained.

IO that prevents free, soluble p40 binding interference and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline

Preferred attempts to identify activity enhancing amino acids that focus on the preferred selective mutagenesis positions, contact positions, or hypermutation described may be exhausted, or further improvements may be required, and it is important to retain other properties or characteristics of the antibody.

Therefore, in another embodiment, the invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, without affecting other characteristics, comprising:

a) providing a mother antibody or antigen-binding portion thereof;

b) selecting an amino acid residue within a

184 Complementarity determining region (CDR) for mutation with the exception of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96;

c) individually mutating the selected position to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen-binding portions thereof;

e) evaluating the panel of mutated antibodies, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof, for changes in at least one other property or characteristic until an antibody, or portion Antigen binding thereof, with improved activity and retained the other property or characteristic, relative to the parent antibody, or antigen binding portion thereof, is obtained.

185 preferably in the context of the p70 p40 / p35 heterodimer that prevents free, soluble p40 binding interference and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline

If single residue mutagenesis is not sufficient, other residues may be included; therefore, in another embodiment, the invention provides a method of enhancing the activity of an antibody, or antigen-binding portion thereof, comprising:

a) providing a mother antibody or antigen-binding portion thereof;

b) selecting an amino acid residue within a complementarity determining region (CDR) for mutation with the exception of H30, H31, H31B, H32, H33, H35, H50, H52,

H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94, and L96;

c) individually mutating the selected position to at least two other amino acid residues thereby to create a panel of mutated antibodies, or antigen-binding portions thereof;

186

e) evaluating the panel of mutated antibodies or antigen binding portions thereof, relative to the parent antibody or antigen portion thereof, for changes in at least one other characteristic or property;

e) repeating steps b) to e) for at least one other CDR position that is not the position selected below b) or one position in H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53 , H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96;

f) combining, in the parent antibody, or antigen-binding portion thereof, at least two individual activity enhancing amino acid residues shown to have enhanced activity and not affect at least one other property or characteristic, to form the combination antibodies, or antigen-binding portions thereof; and

g) evaluating the activity and retention of at least one other property or characteristic of combination antibodies, or antigen-binding portions thereof, with two activity-enhancing amino acid residues, relative to the parent antibody or binding portion to the antigen thereof until an antibody, or antigen-binding portion thereof, with enhanced activity and at least one other property or characteristic conserved, relative to the parent antibody, or antigen binding portion thereof, is obtained.

Mutagenesis of Selective Mutagenesis Position

187 Preferred, contact residues and hypermutation may not have sufficiently increased the affinity of the antibody, and mutagenesis and phage display method (or related ribosome display method) may no longer be useful and at least one other characteristic or property of the Antibody must be preserved.

Therefore, in another embodiment the invention provides a method of improving the affinity of an antibody or an antigen-binding portion thereof, comprising:

a) providing a mother antibody or antigen-binding portion thereof that was obtained by selection in a phage display system but whose activity cannot be further enhanced by mutagenesis in the phage display system;

d) evaluating the activity of the panel of mutated antibodies,

188 or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof such that it identifies an activity-enhancing amino acid residue;

e) evaluating the panel of mutated antibodies, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof, for changes in at least one other property or characteristic until an antibody, or portion antigen binding thereof, with improved activity, relative to the parent antibody, or antigen binding portion thereof, is obtained.

Preferably, the other characteristic or property is selected from 1) preservation of non-cross reactivity with other human proteins or tissues, 2) preservation of epitope recognition, i.e. recognition of the p40 epitope preferably in the context of the p70 p40 / p35 heterodimer that prevents interference from binding of free, soluble p40 and / or 3) to produce an antibody with an immunoglobulin sequence close to the germline

a) providing a mother antibody or binding portion

189 the antigen thereof which was obtained by selection in a phage display system but whose activity cannot be further enhanced by mutagenesis in the phage display system;

d) evaluating the activity and retention of at least one other property or characteristic of the mutated antibody panel, or antigen-binding portions thereof, relative to the parent antibody or antigen-binding portion thereof, thereby identifying a activity enhancing amino acid residue;

e) repeating steps b) to d) for at least one other CDR position that is not the position selected below b) or one position in H30, H31, H31B, H32, H33, H35, H50, H52,

H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31,

L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96;

190

f) combining, in the mother antibody, or antigen-binding portion thereof, at least two individual activity enhancing amino acid residues shown to have enhanced activity and not to affect at least one other property or characteristic, so as not to forming combination antibodies, or antigen-binding portions thereof; and

g) evaluating the activity and retention of at least one property or characteristic of the combination antibodies, or antigen-binding portions thereof with two residues of the activity-enhancing amino acids, relative to the parent antibody or antigen-binding portion thereof until an antibody, or antigen-binding portion thereof, with enhanced activity and at least one other characteristic or conserved property, relative to the parent antibody, or antigen binding portion thereof, is obtained.

V, Antibody Expression

An antibody, or an antibody portion of the invention can be prepared by recombinant expression of heavy and light chains of immunoglobulin genes in a host cell. To express an antibody recombinantly, a host cell is transfected with one or more DNA fragments that support recombinant expression vectors by encoding the immunoglobulin light and heavy chains of the antibody such that the light or heavy chains are expressed in the host cell. and,

191 preferably secreted in the medium in which the host cells are cultured, from which medium the antibodies can be recovered.

Standard recombinant DNA methodologies are used to obtain antibody light and heavy chain genes and incorporate these genes into recombinant expression vectors and introduce the vectors into host cells, as described in Sambrook, Fritsch and Maniatis (eds), Molecular Cloning; A Laboratory Manual, Second Edition, Coid Spring io Harbor, NY, (1989), Ausubel, FM et al. (eds.) Current

Protocols in Molecular Biology, Greene Publishing Associates, (1989) and in North American Patent No. 4,816,397 by Boss et al.

To obtain a DNA fragment encoding the Joe 9 heavy chain variable region by weight or an antibody related to Joe 9 by weight, antibodies specific for human IL12 were monitored from human libraries and mutated, as described in section II . Once the DNA fragments encoding the Joe 9 by weight and VH and VL segments related to Joe 9 by weight are obtained, the mutagenesis of these sequences is carried out by standard methods, such as site-directed mutagenesis of PCR (PCR mediated mutagenesis in which the mutated nucleotides are incorporated into the PCR primers such that the PCR product contains mutations) or other methods of mutagenesis

192 directed to the site. Human IL-12 antibodies showing a level of activity and binding specificity / affinity, for example J695, where they have subsequently been manipulated by recombinant DNA techniques, for example to convert at least two other region residues variable to full-length antibody chain genes, Fab fragment genes, or a scFv gene. In these manipulations, a DNA fragment encoding VL or VH is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker. The term "operably linked", as used in this context, means that two fragments are joined so that the amino acid sequences encoded by two fragments are left in frame.

Isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operably linking the DNA encoding VH to another DNA molecule encoding heavy chain constant regions (CH1, CH2, and CH3). Human heavy chain constant region gene sequences are known in the art (see for example Kabat, EA et al (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, North American Department of Human Health Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The region

193 heavy chain constant can be a constant region of IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD and any allotypic variant thereof as described in Kabat (Kabat, EA et al (1991) Sequences of Proteins of Immunological Interest,

Fifth Edition, North American Department of Human Health Services, NIH Publicatlon No. 91-3242), but more preferably as a constant region lgG1 or lgG4. For a Fab fragment heavy chain gene, the DNA encoding a VH can be operably linked to another molecule of

DNA encoding only the heavy chain constant CH1 strand.

Isolated DNA encoding the VL region can be converted into a light chain gene (as well as a Fab light chain gene) by operatively linking the DNA encoding the VL encoding DNA to another DNA molecule encoding the constant region light chain, CL. Human light chain constant region gene sequences are known in the art (see for example Kabat, EA et al (1991) Sequences of Proteins of Immunological Interest, Fifth Edition,

North American Department of Human Health Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The light chain constant region may be a kappa or lambda constant region, but more preferably it is a lambda constant region.

194

To create a scFv gene, DNA fragments encoding a VH or VL are operably linked to another fragment encoding a flexible linker, for example encoding the amino acid sequence (Gly4-Ser), such that the VH and VL sequences can be expressed as a contiguous single chain protein, with VL and VH regions linked by the flexible linker (see for example Bird et al., (1988) Science 242; 423-426 ; Houston et al., (1988) Proc. Nati. Acad. Sci USA 85: 5879-5883; McCafferty et al., Nature (1990) 348: 552-554).

To express the antibodies or antibody portions of the invention, the DNAs encoding full or partial length heavy and light chains, obtained as described above, are inserted into the expression vectors such that the genes are operatively linked to transcriptional and translational control sequences. In this context, the term "operably linked" is intended to mean that an antibody gene is ligated into a vector so that the transcriptional and translational control sequences have their intended function of regulating the transcription and translation of the antibody gene. The expression vector and the expression control sequences are selected to be compatible with the expression host cell used. The antibody light chain gene and the antibody heavy chain gene can be inserted into the separate vector or more typically both genes are inserted into the same vector of

195 expression. Antibody genes are inserted into the expression vector by standard methods (eg, ligation of complementary restriction sites in the antibody and vector gene fragment or blunt end ligand if no restriction sites exist). Before insertion of J695 J695-related heavy or light chain sequence, the expression vector may contain antibody constant region sequence. For example, a scope to convert J695 or J695-related VH and VL sequences to full-length antibody genes and light chain constant regions, respectively, such that the VH segment is operably linked to (a) segment (s) within the vector and segment VL is operatively linked to segment CL within the vector. Additionally or alternatively, the recombinant expression vector may encode a signal peptide that facilitates secretion of the antibody chain from a host cell. The antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame at the amino terminus of the antibody chain gene. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (ie a signal peptide from a non-immunoglobulin protein).

In addition to at least two other antibody chain residues, the recombinant expression vectors of the invention contain regulatory sequences that control the

196 expression of at least two other antibody chain residues in a host cell. The term "regulatory sequence" is intended to include promoters, enhancers, and other expression control elements (eg, polyadenylation signals) that control the transcription or translation of at least two other antibody chain residues. These regulatory sequences are described, for example, in Gúeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). It can be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences, may depend on these factors such as the choice of the host cell to transform, the level of expression of the desired protein, etc. Preferred regulatory sequences for mammalian host cell expression include viral elements that target high levels of protein expression in mammalian cells, such as promoters and / or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter / enhancer), Simian virus 40 (SV40) (as the promoter / enhancer of

SV40), adenoviruses (eg, the major late adenovirus promoter (AdMLP)) and chick. For another description of viral regulatory elements and sequences thereof, see, for example, North American Patent No. 5,168,062 by Stinski, North American Patent No. 4,510,245 by Bell et al., And

North American Patent No. 4,968,615 by Schaffner et al., The

197

North American Patent No. 5,464,758 by Bujard et al., And North American Patent No. 5,654,168 by Bujard et al.

In addition to at least two other antibody chain residues and regulatory sequences, the recombinant expression vectors of the invention may contain additional sequences, such as sequences that regulate vector replication in host cells (eg, origin of replication) and selectable marker genes. The selectable marker gene facilitates the selection of host cells into which the vector has been introduced (see for example, US Patent Nos. 4,399,216; 4,634,665 and 5,179,017, all by Axel et al.). For example, the selectable marker gene typically offers resistance to drugs, such as

G418, hydromycin or methotrexate, in a host cell into which the vector has been introduced. Preferred selectable marker genes include dihydrofolate reductase (DHFR) gene (for use in dhfr 'host cells with methotrexate selection / amplification) and the neogen (for G418 selection).

For light and heavy chain expression, the expression vector (s) encoding the light and heavy chains is (are) transfected into a host cell by standard techniques. The various forms of the term "transfection are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into

198 a prokaryotic or eukaryotic host cell, eg, electroporation, calcium-phosphate precipitation, DEAE-dextran transfection, and the like. Although it is theoretically possible to express the antibodies of the invention either in prokaryotic or eukaryotic host cells, the expression of antibodies in eukaryotic cells and more preferably mammalian host cells, is most preferred because eukaryotic cells and in particular mammalian cells, they are more preferred than prokaryotic cells to assemble and secrete an appropriately folded active immunoglobulin antibody. Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary cells (CHO cells) (including dhfr-CHO cells, described in Urlaub and

Chasin, (1980) Proc. Nati. Acad. Sci. USA 77: 4216-4220, used with a DHFR selectable marker, for example as described in RJ Kaufman and PA Sharp (1982) Mol. Biol. 159: 601-621), NSO myeloma cells, COS cells, and SP2 cells. When the recombinant expression vectors encoding at least two other antibody residues are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow expression of the antibody in the host cells, or , more preferably, the secretion of the antibody in the culture medium in which the

199 host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.

Host cells can also be used to produce intact antibody portions, such as Fab fragments or scFv molecules. Variations of the aforementioned procedure will be understood to be within the scope of the present invention. For example, it may be desirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antibody of this invention. Recombinant DNA technology can also be used to remove some or all of the DNA encoding either the light chain or the heavy chain (but not both) from an antibody of this invention. Recombinant DNA technology can also be used to remove some or all of the DNA that encodes either light chains or heavy chains that do not need to bind to hlL-12. The express molecules of these truncated DNA molecules are also contained by the antibodies of the invention. Furthermore, bifunctional antibodies can be produced, in which one light chain and one heavy chain are an antibody of the invention and another light and heavy chain are specific for an antigen other than hLL-12 by crosslinking an antibody of the invention with a second antibody by standard chemical crosslinking methods.

200

In a preferred system for recombinant expression of an antibody, or antigen-binding portion, of the invention, a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr'CHO cells. by calcium phosphate mediated transfection. Within the recombinant expression vector, at least two other antibody heavy and light chain residues are each operably linked to regulatory enhancer / promoter elements (eg derived from

SV40, CMV, adenoviruses, and the like, such as an enhancer

CMV / AdMLP promoter regulatory element or an enhanced SV40 / AdMLP promoter regulatory element) to have high levels of gene transcription. The recombinant expression vector also contains a DHFR gene, which allows selection of CHO cells that have been transfected with the vector using methotrexate selection / amplification. Selected transformed host cells are cultured to allow expression of antibody heavy and light chains and intact antibody is recovered from the culture medium. Standard molecular biological techniques are used to prepare the recombinant expression vector, transfect host cells, select transformers, culture host cells, and recover antibody from the culture medium. The antibodies or antigen-binding portions thereof of the invention can be

201 expressing in a mammal (eg mouse) that it is transgenic for human immunoglobulin genes (see eg Taylor, LD, et al., (1992) Nucí, Acids Res. 20: 62876295). Plant cells can also be modified to create transgenic plants expressing the antibody or antigen-binding portion thereof, of the invention.

In view of the foregoing, another aspect of the invention pertains to nucleic acid, vector, and host cell compositions that can be used for recombinant expression of the antibodies and antibody portions of the invention. Preferably, the invention features isolated nucleic acids encoding CDRs of J695, J695 heavy and / or heavy chain full variable region. Accordingly, in one embodiment, the invention features an isolated nucleic acid encoding an antibody heavy chain variable region encoding the J695 heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 25. Preferably, the acid Nucleic encoding the antibody heavy chain variable region subsequently encodes a J695 heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 27. More preferably, the nucleic acid encoding the antibody heavy chain variable region subsequently encodes a J695 heavy chain CR1 comprising the amino acid sequence of SEQ ID NO: 29. Even more preferably, the isolated nucleic acid encodes a region

202 Antibody heavy chain variable comprising the amino acid sequence of SEQ ID NO: 31 (the entire VH region of J695).

In other embodiments, the invention features an isolated nucleic acid encoding an antibody light chain variable region encoding J695 light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 26. Preferably, the nucleic acid encoding the Antibody light chain variable region encodes a J695 light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 28. More preferably, the nucleic acid encoding the antibody light chain variable region subsequently encodes a J695 light chain CDR1 comprising an amino acid sequence SEQ ID NO: 30. Even more preferably, the isolated nucleic acid encodes a variable region of Antibody light chain comprising an amino acid sequence of SEQ ID NO: 32 (complete VL region of J695).

The invention also provides recombinant expression vectors encoding both an antibody heavy chain and an antibody light chain. For example, in one embodiment, the invention provides a recombinant expression vector that encodes:

203

a) an antibody heavy chain having a variable region comprising the amino acid sequence SEQ IC NO: 31; and

b) an antibody light chain having a variable region 5 comprising the amino acid sequence SEQ IC NO:

32.

The invention also provides host cells into which one or more of the recombinant expression vectors of the invention have been introduced. Preferably, the host io cell is a mammalian host cell, more preferably the host cell is a CHO cell, an NSO cell, or a COS cell. Still later the invention provides a method for synthesizing a recombinant human antibody of the invention by culturing a host cell of the invention in an appropriate culture medium until a recombinant human antibody of the invention is synthesized. The method may subsequently comprise the recombinant human antibody from the culture medium.

SAW. Pharmaceutical compositions and pharmaceutical administration

Antibodies and antibody portions of the invention can be incorporated into appropriate pharmaceutical compositions for administration to a subject. Commonly, the pharmaceutical composition comprises an antibody or antibody portion of the invention and a pharmaceutically carrier

204 acceptable. As used herein, "the pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of the following, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, or the like, as well as combinations thereof. In many cases it is preferable to include isotonic agents, for example sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers can subsequently comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which improve the shelf life or effectiveness of the antibody or antibody portion.

Antibodies and antibody portions of the invention can be incorporated into a pharmaceutical composition suitable for parenteral administration. Preferably, the antibody or antibody portions will be prepared as an injectable solution containing 0.1-250 mg of antibody. The injectable solution can be made up of liquid or lyophilized dosage in a flint or vial, ampoule or prefilled syringe. The buffer can be Lhistidine (1-50 mM), optimally 5-10 mM, with a pH of 5.0 a

205

7.0 (optimally a pH of 6.0). Other suitable buffers include, but are not limited to sodium succinate, sodium citrate, sodium phosphate, or potassium phosphate. Sodium chloride can be used to modify the toxicity of the solution at a concentration of 0-300mM (optimally 150mM for a liquid dosage form). Cryoprotectants can be included for a lyophilized dosage form, mainly sucrose 0-10% / optimally 0.5-1.0%). Other suitable cryoprotectants include trehalose and lactose. The bulking agents can be included in a lyophilized dosage form, mainly with 1-10% mannitol (optimally 24%). Stabilizers can be used in both liquid and lyophilized dosage forms, primarily with 1-50 mM L-Methionine (optimally 5-10 mM). Other suitable bulking agents include glycine, arginine, may be included as 00.05% polysorbate 80 (optimally 0.005-0.01%). Additional surfactants include but are not limited to polysorbate 20 and BRIJ surfactants.

In one embodiment, the invention provides a formulation comprising the antibody in combination with a polyol, a surfactant, a stabilizer, and a buffer system with a pH of about 5 to 5. In one embodiment, said formulation is free or metallic. In a preferred embodiment, the formulation comprises the antibody and mannitol, histidine, methionine, polysorbate 80, hydrochloric acid, and water.

206

In one embodiment, an aqueous formulation is prepared by comprising the antibody in a pH buffer solution. The buffer of this invention has a pH range of from about 4 to about 8, preferably from about 4.5 to about 7.5, more preferably from about 5.5 to about 6.5, and more preferably has a pH of from about 6.0 to about 6.2. In a particularly preferred embodiment, the buffer has a pH of about 6. The intermediate ranges of the aforementioned pH are also part of this invention. For example, ranges of values using a combination of any of the aforementioned values such as upper and / or lower limits to be included. Examples of buffers that will control pH within the range include acetate (eg, sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate, phosphate, and other organic acid buffers. In a preferred embodiment of the invention, the formulation contains a buffer system comprising histidine. In a preferred embodiment of the invention, the formulation contains a buffer system comprising histidine. In a preferred embodiment of the invention, the buffer is histidine, for example L-histidine. In preferred embodiments, the formulation of the invention comprises a buffer system comprising approximately 1-100 mM histidine, preferably

207 approximately 5-50 mM and more preferably 10 mM histidine. One of skill in the art will recognize that sodium chloride can be used to modify the toxicity of the solution, for example at a concentration of 1-300mM and optimally 150mM for a liquid dosage form.

A polyol, which acts as a toner and can stabilize the antibody, is also included in the formulation. The polyol is added to the formulation in an amount that can vary relative to the isotonicity of the formulation.

The aqueous formulation is preferably isotonic. The amount of polyol added can also vary with respect to the molecular weight of the polyol. For example, a minor amount of a monosaccharide (eg mannitol) can be added, compared to a disaccharide (such as trehalose). In one embodiment of the invention, the polyol that is used in the formulation as a tonicity agent is mannitol. In a preferred embodiment, the composition comprises about 10 to about 100 mg / ml or about 20 to about 80, about 20 to about

7 0, about 30 to about 60, about 30 to about 50 mg / ml mannitol, for example, about 10, about 20, about 30, about 40, about 60, about 70, about 80, about 90, and about 100 mg / ml of mannitol. In a modality

208 Preferred, the formulation comprises about 40 mg / ml mannitol (corresponding to about 4% mannitol). IN a preferred embodiment, the composition comprises between about 1% to about 10% mannitol, more preferably between about 2% to about 6% mannitol, and more preferably about 4% mannitol. In another embodiment of the invention, the sorbitol polyol is included in the formulation.

A stabilizer or antioxidant is also added to the antibody formulation. A stabilizer can be used in both liquid and lyophilized dosage forms. The formulations of the invention preferably comprise the stabilizer methionine, for example L-Methionine. Other stabilizers useful in formulations of the invention are known to those of skill in the art and include, but are not limited to glycine and arginine. Cryoprotectants can be included in a lyophilized dosage form, primarily sucrose (eg sucrose at 1-10%, and optimally sucrose at 0.5-1.0%). Other suitable cryoprotectants include trehalose and lactose.

A detergent or surfactant is also added to the antibody formulation. Exemplary detergents include nonionic detergents such as polysorbates (eg polysorbate 20, 80, etc.) or poloxamers (eg poloxamer

209

188). The amount of detergent added is calculated to reduce the aggregation of the formulated antibody and / or minimize particle formation in the formulation and / or reduce adsorption.

In a preferred embodiment of the invention, the formulation includes a surfactant that is polysorbate. In another preferred embodiment of the invention, the formulation contains the detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) sorbitanmonooleate (see Fiedler,

Lexikon der Hifsstoffe, Edtio Cantor Verlag Aulendorf, 4th edition, 1996). In a preferred embodiment, the formulation contains between 0.001 to about 0.1% polysorbate 80, or between about 0.005 and 0.05% polysorbate 80, for example about 0.001, about 0.005, about 0.01, about 0.05, or about 0.1 polysorbate 80. In A preferred embodiment of about 0.01% polysorbate 80 is found in the formulation of the invention.

In a preferred embodiment of the invention, the formulation is a 1.0 ml solution in a container containing the ingredients shown in Table 1. In another embodiment, the formulation is a 0.8 ml solution in a container.

Table 1: A 1.0 mi Solution1Formulation of J695 for injection

210

<td>Name of ingredient</td><td>Quantity</td><td>Function</td>

<td>Antibody (J695)2)</td><td>50.0 or 100.0 mg</td><td>Active substance</td>

<td>Excipients:</td><td></td><td></td>

<td>Mannitol</td><td>40 mg</td><td>Tonicity agent</td>

<td>Polysorbate 80</td><td>0.10 mg</td><td>Dete rgente / Surfa otante</td>

<td>Histidine</td><td>1.55 mg</td><td>Shock absorber</td>

<td>Methionine</td><td>1.49 mg</td><td>Stabilizer</td>

<td>Injectable water</td><td>For 1 mi</td><td>Solvent</td>

<td>Hydrochloric acid</td><td>cbp</td><td>PH adjustment to 6.0</td>

1) Density of solution: 1.0398 g / ml 2) Concentrate is used

In one embodiment, the formulation is a formulation described in US Patent Application No.

12 / 625,057, which is published as US 2010/0172862 A1, the content of which is incorporated by reference only.

In one embodiment, the formulation contains the agents identified above (i.e., antibody, polyol, surfactant, stabilizer, and buffer) and is essentially free of one or more preservatives, such as benzyl alcohol, phenol, m-cresol, chlorobutanol, and benzethonium Cl . In another embodiment, a preservative can be included in the formulation, particularly where the formulation is a multiple dose formulation. One or more pharmaceutically acceptable carriers, excipients, or stabilizers such as those described in Remington's Pharmaceutical Sciences, issue 16,

Osol, A. Ed. (1980) can be included in the formulation since

211 they do not adversely affect the desired characteristics of the formulation. Acceptable vehicles, excipients, or stabilizers are non-toxic to the containers at the doses and concentrations used and include; additional buffering agents; cosolvents; antioxidants such as ascorbic acid, chelating agents such as EDTA; metal complexes (eg Zn-protein complexes); biodegradable polymers such as polyesters; and / or salt-forming counterions such as sodium.

In one embodiment, the formulations of the invention have improved properties compared to formulations known in the art. For example, the formulations of the invention have improved shelf life and / or stability compared to art-recognized formulations. In one embodiment, the formulations of the invention have a shelf life of at least 18 months, for example in the liquid or solid state. In another embodiment, the formulations of the invention have a shelf life of at least 24 months, for example in the liquid or solid state. In a preferred embodiment, the formulations of the invention have a shelf life of at least 24 months at a temperature of 2-8 ° C. In a preferred embodiment, the formulations of the invention have a shelf life of at least months or at least 24 months at a temperature of between about -20 and -80 ° C. In another embodiment, the formulations of the invention maintain a stability that

212 At least 5 freeze / thaw cycles of the formulation follow. In a preferred aspect, the formulations of the invention comprise, for example an antibody, comprising at least a portion of the lambda light chain, for example J695, wherein the formulation has improved resistance to fragmentation of the lambda light chain, for example separation reduced lambda light chain, as compared to art recognized formulations.

In one embodiment, the formulations of the invention are substantially metal-free. In one embodiment, the formulations of the invention are substantially free of a metal selected from the group consisting of Fe2 +, Fe3 +, Ca2 + and

Cu1 +. In one embodiment, the formulations of the invention comprise an amount of metal that is low enough to reduce or prevent separation of the lambda chain in the presence of histidine, for example the metal is present in a concentration of less than about 5,060 ppb, less about 1,060 ppb, less than about 560 ppb, less than about 350 ppb, less than about 310 ppb, less than about 310, less than about 300 ppb, less than about 250 ppb, less than about 200 ppb, less than about 160 ppb, less than about 150 ppb, less than about 140 ppb, less than about

one 30 ppb, less than about 120 ppb, less than

213 about 110 ppb, less than about 100 ppb, less than about 90 ppb, less than about 80 ppb, less than about 70 ppb, less than about 60 ppb, less than about 50 ppb, less than about 40 ppb, less than about 30 ppb, less than about 20 ppb, less than about 10 ppb, less than about 1 ppb. In one embodiment, the metal is present in a concentration of less than about 160 ppb. In one embodiment, the metal is present in a concentration of less than about

110 ppb. In one embodiment, the metal is present at a concentration of less than about 70 ppb, for example a concentration of about 60 ppb. Maximum concentrations intermediate to the aforementioned concentrations, for example less than about 65 ppb, are also part of this invention. Subsequently, ranges of values using a combination of any of the aforementioned values as upper and / or lower limits, for example concentrations between about 50 ppb and about 70 ppb, should also be included.

In one embodiment, the formulations of the invention are substantially metal free by subjecting at least one method to remove the metal, such as filtration, buffer exchange, chromatography, or resin exchange. Useful procedures to remove metal from

214 Formulations of the invention are known to those skilled in the art and are described in the application. In one embodiment, the formulations of the invention comprise a metal chelator, for example such that the molecule is not separated into a hinge-like region or is separated within the hinge-like region at a level that is less than the level of separation. observed in the absence of the metal chelator. In the inventive formulations, the metal chelator may be, for example, a siderophore, callxarenes, an amyl polycarboxylic acid, a hydroxyaminocarboxylic acid, a glycine substituted by N, a 2 (2-amino-2-oxoethyl) aminoethanesulfonic acid ( BES), a bidentate, trldentate or hexadentate iron chelator, a copper chelator, and derivatives, analogs and combinations thereof. Metal chelants useful in formulations of the invention are known to those skilled in the art, and are described below below.

Particularly useful siderophores in formulations of the invention include, but are not limited to aerobactin, agrobactin, azotobactin, bacilobactin, N- (5-C3-L (5am i nopentyl) h id roxicarbamoyl) -propinoam ido) penti 1) -3 (5- (Nhydroxyacetamido) -pentyl) (carbamoyl) -propionhydroxamic (deferoxamine, desferrioxamine, or DFO or DEF), desferrioticin, enterobactin, erythrobactin, ferricrome, ferrioxamine B, ferrioxamine E, fluviabactin, mourarin, C, fusarin, C vibriobacti na, vulnibactin,

215 yersiniabactin, ornibactin and derivatives, analogs and combinations thereof.

Aminopolycarboxylic acids useful in formulations of the invention include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), nitriloacetic acid (NTA), trans-diaminocyclohexane tetraacidic acid (DCTA). Pentacetic acid diethylenetriamine (DTPA), N-2-acetamido-2iminodiacetic acid (ADA), aspartic acid, bis (aminoethyl) glycol ether Ν, Ν, Ν ', Ν'-tetracetic (EGTA), glutamic acid, and N acid, N'-bis- (2-hydroxybenzyl) ethylenediamine-N, N'diacetic (HBED), and derivatives, analogs, and combinations thereof.

Hydroxyaminocarboxylic acids useful in the formulations of the invention include, but are not limited to acid

N-hydroxyethylaminodiacetic (HIMDA), N, N'-bishid rox ieti Ig I icin (bicin) and N- (trishidroxymethylmethyl) glycine (tricine) and derivatives, analogs and combinations thereof. N-substituted glycins, eg, glycylglycine, as well as derivatives, analogs, or combinations thereof, are also useful as metal chelants in formulations of the invention. The 2- (2-amino-2-oxoethyl) aminoethanesulfonic acid metal chelator (BES) and derivatives, analogs and combinations thereof can be used.

Particular calixarenes useful in the formulations of the invention include, but are not limited to, an oligomer

216 macrocyclic or cyclic based on the hydroxyalkylation product of a phenol or an aldehyde and derivatives, analogs and combinations thereof. Particular copper chelators useful in the invention include triethylenetetramine (trientine), tetraethylenepentamine, D-penicillamine, ethylenediamine, bispyridine, phenanthroline, batophenanthroline, neocuproine, batocuproine sulfonate, cuprizona, cos, cis-1,3,5-triaminocyclohexane (T) , tachpyr and derivatives, analogs and combinations thereof.

Additional metal chelators that can be used in formulations of the invention include a hydroxypyridine derivative, a hydrazone derivative, and a hydroxyphenyl derivative or a nicotinyl derivative, such as 1,2-dimethyl-3-hydroxypyridine-4-one (Deferiprone , DFP or Ferriprox); 2-deox¡-2 (N-carbam oil metí I - [N '-2' metí I-3 '- hydroxy pyridin a-4'-o na]) - Dglucopyranosyl (Feralex-G), hydrazone pyridoxal isonicotinyl (PIH ); 4,5-dihydro-2- (2,4-dihydroxyphenyl) -4-methylthiazol-4-carboxylic acid (GT56-252), 4- [3,5-b is (2-h id roxi fe n il) acid - [1,2,4] triazol-1yl] benzoic (ICL-670); N, N'-bis (ohydroxybenzyl) ethylenediamine-N, N'-diacetic acid (HBED), 5-chloro-7-iodo-quinoline-8-ol (clioquinol) and derivatives, analogs and combinations thereof.

It can be recognized that combinations of two or more of the above metal chelators can be used in combination in the formulations of the invention. For example,

217 In a particular embodiment of the invention, the formulation comprises a combination of DTPA and DEF. In another embodiment, the formulation comprises a combination of EDTA, EGTA and

DEF.

The amount of antibody present in the formulation is determined, for example, taking into account the desired dose volumes and route (s) of administration. In one embodiment of the invention, the concentration of the antibody in the formulation is between about 0.1 to about 250 mg of antibody per ml of liquid formulation. In one embodiment of the invention, the concentration of antibody in the formulation is between about 1 to about 200 mg of antibody per ml of liquid formulation. In various embodiments, the concentration of antibody in the formulation is between about 30 to about 140 mg per ml, between about 40 to about 120 mg / ml, between about 50 to about 110 mg / ml or between about 60 to about 100 mg / ml. ml. The formulation is especially suitable for large doses of antibody of more than 15 mg / ml. In various embodiments, the concentration of antibody in the formulation is approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 mg / ml. In a preferred embodiment, the concentration of the antibody is 50 mg / ml. In another preferred embodiment, the

218 Antibody concentration is 100 mg / ml. In a preferred embodiment, the antibody concentration is at least about 100 mg / ml, at least about 110 mg / ml, or at least about 120 mg / ml.

In various embodiments of the invention, the concentration of the antibody in the formulation is approximately 0.1-250 mg / ml, approximately 0.5-220 mg / ml, approximately 1-210 mg / ml, approximately 5-200 mg / ml, approximately 10 -195 mg / ml, approximately 15-190 mg / ml, approximately 20-185 mg / ml, approximately 25-180 mg / ml, approximately 30-175 mg / ml, approximately 35-170 mg / ml, approximately 40-165 mg / ml, approximately 45-160 mg / ml, approximately 50-155 mg / ml, approximately 55-1850 mg / ml, approximately 60 145 mg / ml, approximately 70-135 mg / ml, approximately 7515 130 mg / ml, approximately 80-125 mg / ml, approximately 85 120 mg / ml, approximately 90-115 mg / ml , approximately 95110 mg / ml, or approximately 100 mg / ml. The intermediate ranges at the aforementioned concentrations, for example, about 31-174 mg / ml, are also considered part of the invention. For example, ranges of values using a combination of any previously quoted value as upper and / or lower limits are included.

In one, the formulation provides an effective dose of 40mg, 50mg, 80mg, 100mg, or 200mg per injection of the active ingredient, the antibody. In another modality, the

219 Formulation provides an effective dose ranging from approximately 0.1 to 250 mg of antibody. If desired, the effective daily dose of the pharmaceutical formulation can be administered in two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In one embodiment of the invention, the dose of the antibody in the formulation is between about 1 to about 200 mg. In one embodiment, the dose of antibody in the io formulation is between about 30 to about 140 mg, between

<td>approximately</td><td> 40</td><td>and approximately</td><td>120 mg,</td><td>between</td>

<td>approximately</td><td> 50</td><td>and approximately</td><td>110 mg,</td><td>between</td>

<td>approximately</td><td> 60</td><td>and approximately</td><td>100 mg, or</td><td>between</td>

<td>approximately</td><td> 70</td><td>and approximately</td><td>90 mg. In</td><td>a</td>

In this embodiment, the pharmaceutical composition includes the antibody in a dose of from about 100 to about 200 mg. In a later embodiment, the composition includes the antibody in about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or

250 mg / ml.

The intermediate ranges at the aforementioned doses, for example at about 2-139 mg, are also considered part of this invention. For example, ranges of values using a combination of values using a combination

220 Any of the values cited as upper and / or lower limits must also be included.

The compositions of this invention can be in a variety of forms. This includes liquid, semi-solid, and solid dosage forms (eg, injectable solutions and infusions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends on the route of administration and therapeutic application. Typical preferred compositions are in the form of injectable solutions or infusions, such as compositions similar to those used for passive immunization of humans with other antibodies. The preferred route of administration is parenteral (eg intravenous, subcutaneous, intraperitoneal, intramuscular). In a preferred embodiment, the antibody or antigen-binding fragment thereof is administered by subcutaneous injection.

Therapeutic compositions typically must be sterile and stable under manufacturing and storage conditions. The composition can be formulated as a solution, microemulsion, dispersion, liposome or other suitable ordered structure of high drug concentrations. Sterile injectable solutions can be prepared by incorporating the active compound (i.e. antibody or portion of antibody) in the required amount of an appropriate solvent or combination of ingredients listed above,

221 as required, followed by sterile filtering. Generally, dispersions are prepared by incorporating the active ingredient into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile, lyophilized powders for the preparation of sterile injectable solutions, the preferred methods of vacuum drying and spray drying preparation resulting in an active ingredient powder plus any additional desired ingredients of a previously filtered sterile solution of the same. The fluidity of a solution itself can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, for example monostearate salts and gelatin.

The antibodies or antibody portions of the present invention can be administered by a variety of methods known in the art, although for many other therapeutic applications the preferred route / modality of administration is subcutaneous injection, intravenous injection, or infusion. As can be appreciated by one skilled in the art, the route / modality of administration will vary depending on the desired results. In some embodiments, the active ingredient can be prepared with a vehicle that will protect the compound from

222 rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as vinyl ethylene acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of these formulations are patented or generally known to those skilled in the art. See for example Sustained and Controlled Release Drug Delivery

Systems, JR Robinson, ed. Marcel Dekker, Inc. New York, 1928.

In some embodiments, an antibody or antibody portion of the invention can be administered orally, for example, with an inert diluent or an assimilable edible vehicle. The compound (and other ingredients, if desired) can be included in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subjects' diet. For oral therapeutic administration, the compounds can be incorporated with excipients and used in the form of ingestible tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. To administer a compound of the invention by another parenteral route of administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent this inactivation.

223

Supplemental active compounds can also be incorporated into the compositions. In some embodiments, an antibody or antibody portion of the invention is co-formulated with and / or co-administered with one or more additional therapeutic agents that are useful in treating disorders in which IL-12 activity is detrimental. For example, an anti-hLL-12 antibody or antibody portion of the invention may be co-formulated and / or co-administered with one or more antibodies that bind other targets (eg, antibodies

IO that bind other cytosines or that bind cell surface molecules.) Subsequently, one or more antibodies of the invention can be used in combination with one or more therapeutic agents below. These combination therapies can be advantageously using lower doses of administered therapeutic agents, avoiding possible toxicities or complications related to various mono therapies. It will be appreciated by a skilled practitioner that when the antibodies of the invention are used as part of a combination therapy, a lower dose of antibody may be desirable than when the antibody is only administered to a subject (eg a synergistic therapeutic effect may be achieved through the use of combination therapy, which, in turn, allows the use of a lower dose of the antibody to achieve the desired therapeutic effect.

224

Interleukin 12 plays a critical role in pathology related to a variety of diseases involving the immune and inflammatory elements. These diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lime arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus. Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin-dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, sclerodermal dermatitis

I0 atopic dermatitis, graft-versus-host disease, organ transplant rejection, organ transplant-related immune or water disease, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, Graves disease, nephrotic syndrome, chronic fatigue syndrome , Wegener's granulomatosis, Henoch-Schoenlein purpura, microscopic kidney vasculitis, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, septicemia syndrome, cachexia, diseases infections, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, cerebrovascular infarction, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, heart attack myocardium, Addison's disease, sporadic polyglandular deficiency type I and polyglandular type II, syndrome

225

Schimdt, adult respiratory distress syndrome (acute), alopecia areata, seronegative arthritis, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitis arthropathy, synovitis in clothing, chlamydia, Yersinia and Salmonella related arthropathy, spondyloarthropathy, atheromatous disease / arteriosclerosis, atopic allergy, autoimmune blistering disease, pemphigus vulgaris, pemphigus foliaceus, pemphigus, linear IgA disease, autoimmune hemolytic anemia, Coombs Positive Hemolytic Anemia, Acquired Pernicious Anemia, Juvenile Pernicious Anemia, Myalgic Encephalitis / Royal Free Disease, Chronic Mucocutaneous Candidiasis, Giant Cell Arteritis, Primary Sclerosing Hepatitis, Acquired Autoimmune Hepatitis Syndrome, Immunodeficiency Related Diseases acquired, Hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, pulmonary fibrosis, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease related to mixed connective tissue disease, interstitial lung disease related to systemic sclerosis, interstitial lung disease related to rheumatoid arthritis, interstitial lung disease related

226 with systemic lupus erythematosus, dermatomyositis / polyomyositis-related lung disease, Sjógren's disease-related lung disease, ankylosing spondylitis-related lung disease, diffuse vasculitic lung disease, hemosiderosis-related lung disease, drug-induced interstitial lung disease, fibrosis due to radiation, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type 1 autoimmune hepatitis (classical or lupoid autoimmune hepatitis), type 2 autoimmune hepatitis (anti-LKM antibody hepatitis), mediated autoimmune hypoglycemia, insulin resistance type B with acanthosis nigricans, hypoparathyroidism, acute immune disease related to organ transplantation, Chronic organ transplant-related immune disease, osteoarthritis, primary sclerosing cholangitis, idiopathic leukopenia, autoimmune neutropenia, NOS kidney disease, glomerulonephritis, microscopic kidney vasculitis, Lyme disease, lupus erythematosus discoidus, idiopathic male infertility or sperm, autoimmunity multiple sclerosis (all subtypes), insulin dependent diabetes mellitus, sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis,

227

Still, systemic sclerosis, Takayasu's disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, autoimmune hypothyroidism with goiter (Hashimoto's disease), autoimmune atrophic hypothyroidism, phacocenic uveitis, Human antibodies, and antibody portions of the invention can be used to treat autoimmune diseases, particularly those related to inflammation, including rheumatoid spondylitis, allergy, autoimmune diabetes, autoimmune uveitis.

Preferably, the antibodies of the invention or antigen-binding portions thereof, are used to treat rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin-dependent diabetes mellitus, and psoriasis, as described in detail in section VI.

A human antibody, or antibody portion of the invention can be administered with one or more additional therapeutic agents useful in the treatment of autoimmune and inflammatory diseases.

The antibodies of the invention, or antigen binding portions that can be used alone or in combination to treat these diseases. It should be understood that the IL-12 antibodies of the invention or the antigen binding portion thereof which can be used alone or in combination with an additional agent, for example a therapeutic agent, the agent

228 additional being selected by a person skilled in the art for its intended purpose. For example, the additional agent may be an art-recognized therapeutic agent useful for treating the disease or condition being treated by the antibody or beneficial attribute to the therapeutic composition, for example an agent that effects the viscosity of the composition.

Subsequently it should be understood that the combinations to be included within the invention are those combinations useful for their intended purpose. The agents set forth below are illustrative for their purposes and are not intended to limit. The combinations that are part of this invention can be antibodies of the present invention and at least one additional agent selected from the list below. The combination may also include more than one additional agent, for example two or three additional agents if the combination is such that the composition formed can perform its intended function. Subsequently, the additional agents described herein used in combination with an IL-2 antibody, are not limited to the disorder that is attributed to treatment.

Preferred combinations are nonsteroidal anti-inflammatory drugs also referred to as NSAIDS which include drugs like Ibuprofen. Other preferred combinations are corticosteroids including prednisolone; the well-known side effects of steroid use can be

229 reduced or even eliminated by decreasing the required spheroid dose when treating patients in combination with anti-IL-12 antibodies of this invention. Non-limiting examples of therapeutic agents for rheumatoid arthritis with which an antibody, an antibody portion of the invention may be combined including the following; cytosine suppressive anti-inflammatory drugs (CSAIDs); antibodies or antagonists of other human cytosines or growth factors, for example TNF (including Adalimumab / HUMIRA), LT, IL-1, IL-2, IL-6, IL-7,

IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF. The antibodies of the invention, or antigen-binding portions thereof, can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, or their ligands including CD154 (gp39 or CD40L).

Preferred combinations of therapeutic agents can interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists such as chimeric, humanized, or human TNF antibodies, D2E7, (North American Application 08 / 599,226 filed February 9, 1996), cA2 (Remicade ™), CDP 571, anti-TNF antibody fragments (eg CDP870), and soluble p55 or p75 TNF receptors, derivatives thereof, (p75TNFR1gG (Enbrel ™) or p55TNFR1gG (Lenercept), the soluble IL-13 receptor (slL-13), and also TNFa that converts the

230 enzyme inhibitors (TACE); similarly IL-1 inhibitors (eg, lnterleukin-1 converting enzyme inhibitors, such as Vx740, orlL-1RA etc.) can be effective for the same reason. Other preferred combinations include Interleukin 11, anti-P7s glycoprotein ligand and pselectin. Still another preferred combination are the key players in the autoimmune response that can act in parallel, dependent on, or in conjunction with IL-12 function; especially preferred are IL-18 antagonists including IL-18 antibodies or soluble IL-18 receptors, or IL-18 binding proteins. IL-12 and IL-18 have been shown to overlap but different functions and a combination of antagonists to both may be the most effective. Still other preferred combinations include antagonists of the CD80 (B7.1) or CD86 (B7.2) co-stimulatory pathway including antibodies, soluble receptors or antagonistic ligands.

Anti-IL12 antibodies or antigen binding portions can also be combined with agents, such as methotrexate, 6-MP, azathioprine sulfasalazine, mesalazine, chloroquine olsalazine / hydroxychloroquine, penicillamine, au rotiomalate (intramuscular and oral), azathioprine, Colchicine, cost reduction (inhaled and local injection, oral), beta2 adrenergic agonists (salbutamol, terbutaline, salmeteral), xanthines, (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, opratropium and ocitropium, cyclosporine, FK506, rapamycin,

231 mycophenolate mofetil, leflunomide, NSAIDs, for example ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, antithrombolytics, adenosine inhibitor agonists, complement agents, adrenergic agents, agents that interfere with signaling by proinflammatory cytosines such as TNFa or 1 (eg IRAK, NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzyme inhibitors (eg Vx740), anti-P7s, p-selectin glycoprotein ligand (PSGL), TNFa converting enzyme inhibitors (TACE), T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytosine receptors and derivatives thereof (eg soluble p55 or p75 TNF receptors) and derivatives of p75TNFRIgG (Enbrel ™) and p55TNFRIgG (Lenercept), slL-1 Rl, slL-1 Rll, sll_-6R, soluble receptor IL-1 3 (slL-13) anti-inflammatory cytosines (eg IL-4, IL-10, IL-11, IL-13 and TGF3). Preferred combinations include methotrexate or leflunomide and in cases of moderate or rheumatoid arthritis, cyclosporine.

Non-limiting examples of therapeutic agent agents for inflammatory bowel disease with which an anti-IL-12 antibody, or antibody portion, can be combined include the following; growth factor

232 epidermal; corticosteroids; cyclosporine, sulfasalazine; aminosalicylates; 6-mercaptopu quarrel; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxan inhibitors; receptor antagonists

IL-1, monoclonal anti-IL-Ιβ antibodies; anti-IL-6 monoclonal antibody; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies or antagonists of other human cytosines or growth factors, for example TNF (including Adalimumab / HUMIRA),

LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GMCSF, FGF and PDGF. The antibodies of the invention, or antigen-binding portions thereof, can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or other ligands. The antibodies of the invention, or antigen binding portions, can also be combined with agents, such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs; for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antitrimbolitic agents, complement inhibitors, adrenergic agents, agents that interfere with signaling by proinflammatory cytosines such as TNFa or IL-1 (for example IRAK, NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzyme inhibitors (eg Vx740), anti-P7s,

233 p-selectin glycoprotein ligand (PSGL), TNFa converting enzyme inhibitors, T cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-me rcaptopuin, angiotensin converting enzyme inhibitors, receptors soluble cytosine and derivatives thereof (eg soluble TNF p55 or p75 receptors, SIL-1RI, SIL-1RII, SLL-6R, soluble IL-13 receptor (slL-13)) and anti-inflammatory cytosines (eg IL-4, IL-10, IL-11, IL-13 t TGFp).

io Preferred examples of therapeutic agents for Crohn's disease in which an antibody or antigen-binding portion can be combined including the following; TNF antagonists, eg anti-TNF antibodies, D2E7 (Adalimumab / HUMIRA), cA2 (Remicade ™), CDP571, anti-TNF antibody fragments (eg CDP870), TNFRIg, INFR-lg constructs (p75TNFRIgG (Enbrel ™) and p55TNFRIgG (Lenercept)), anti-P7s, p-selectin glycoprotein ligand (PSGL), soluble IL-13 receptor (slL-13), and PDE4 inhibitors. The antibodies of the invention, or antigen-binding portions thereof, can be combined with corticosteroids, eg, budenoside and dexamethasone. Antibodies can also be combined with agents such as sulfasalazine, 5-aminosalicylic acid and olsalazine and agents that interfere with synthesis or action of proinflammatory cytosines such as IL-1, for example IL-Ιβ converting enzyme inhibitors (for

2. 3. 4 example Vx740) and IL-1ra. The antibodies or antigen-binding portion thereof can also be used with T-cell signaling inhibitors, for example, tyrosine kinase 6-mercaptopurine inhibitors. Antibodies or antigen-binding portions thereof can be combined with IL-11.

Non-limiting examples of therapeutic agents for multiple sclerosis with which an antibody, or antibody portion, can be combined including the following; corticosteroids, prednisolone; petylprednisolone; azathioprine;

cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-βΐ a (Avonex; Biogen); interferon-βΐ b (Betaseron; Chiron / Berlex); Copolymer 1 (Cop-1; Copaxone; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; clabribine; antibodies or antagonists of other human cytosines or growth factors, eg TNF, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP -II, GM-CSF, FGF and PDGF. Antibodies of the invention, or antigen-binding portions thereof, can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD90 or its ligands. Antibodies of the invention or antigen-binding portions thereof can be combined with agents, such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, eg ibuprofen, corticosteroids

235 such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombolytic agents, complement inhibitors, adrenergic agents, agents that interfere with proinflammatory cytosine signaling such as TNFa or

IL-1 (eg IRAK, NIK, IKK, p38 or MAP kinase inhibitors), IL-Ιβ converting enzyme inhibitors (eg Vx740), anti-P7s, p-selectin glycoprotein ligand (PSGL), TACE inhibitors, inhibitors of T cell signaling such as kinase inhibitors, metalloproteinase inhibitors, io sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin enzyme inhibitors, soluble cytosine receptors and derivatives thereof (eg soluble p55 or p75 TNF receptors, sIL-IRI, slL-1RII, SIL-6R, soluble IL-13 receptor (slL-13)) and anti-inflammatory cytosines (for example IL-4, IL-10,

IL-13 and TGFp).

Preferred examples of therapeutic agents for multiple sclerosis in which the antibody or binding portion of

<td></td><td>antigen of</td><td>the same</td><td>they can</td><td>combine</td><td>to include</td>

<td></td><td>interferon-β,</td><td>for example,</td><td>ΙΡΝβΙθ</td><td>and iFNpib;</td><td>copaxone,</td>

<td> 20</td><td colspan="2">corticosteroids, inhibitors</td><td>from IL-1</td><td>inhibitors</td><td>of TNF and</td>

<td></td><td>antibodies to</td><td>ligand CD40 and</td><td>CD80.</td><td></td><td></td>

An antibody, antibody portion, can be used in combination with other agents to treat skin conditions. For example, an antibody, antibody portion, or other IL-12 inhibitor of the invention is combined with PUVA therapy.

236

PUVA is a combination of psoralen (P) and long-wave ultraviolet radiation (UVA) that is used to treat many different skin conditions. The antibodies, antibody portions, or other IL-12 inhibitors of the invention can also be combined with pimecrolimus. In another embodiment, the antibodies of the invention are used to treat psoriasis, where the antibodies are administered in combination with tacrolimus. In a later embodiment, tacrolimus and IL-12 inhibitors are administered in combination with methotrexate and / or cyclosporine. In yet another embodiment, the IL-12 inhibitor of the invention is administered with excimer laser treatment to treat psoriasis.

The pharmaceutical compositions of the invention may include a "therapeutically effective amount" or a "prophylactically effective amount" of an antibody or antibody portion of the invention. A "therapeutically effective amount" refers to an effective amount, in dosages and for periods of time necessary, to obtain the desired therapeutic result. A therapeutically effective amount of the antibody or antibody portion can vary according to factors such as disease status, age, gender, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also the amount in which any toxic or deleterious effects of the antibody or

237 Antibody portion is compensated for beneficial effects therapeutically. A "prophylactically effective amount" refers to an effective amount, in dosages and for periods of time necessary, to achieve the desired prophylactic result. Commonly, since a prophylactic dose is used in subjects before or at an early stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount.

Dose regimens can be adjusted to provide the optimal desired response (eg, a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased by the demands of the therapeutic situation.

It is especially advantageous to formulate parenteral compositions in dosage unit forms of administration and dosage uniformity. The unit dosage form as used herein refers to physically described units suitable as unit doses for mammalian subjects to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are directed by and directly dependent on (a) the unique characteristics of the

238 active compound and the particular therapeutic or prophylactic effect to be obtained and (b) the inherent limitations in the technique of composing such an active compound for the treatment of sensitivity in individuals.

Treatment of psoriasis can be accomplished by administering a unit dose amount (or greater than a sub-dose resulting in the dose amount) of a substance according to a simple periodicity.

In one embodiment, a method of treating psoriasis in a subject comprises administering to an subject an antibody, or an antigen-binding portion thereof, which is capable of binding the p40 subunit of IL-12 and / or IL-23, according to a periodicity of about once every 4 weeks, and therefore treating psoriasis in the subject.

In another embodiment, a method of treating psoriasis in a subject comprises administering to an subject an antibody or antigen-binding portion thereof, which is capable of binding to the p40 subunit of IL-12 and / or IL-23, of according to a periodicity of about once every 12 weeks, and therefore treating psoriasis in the subject.

Therefore, a simple periodicity can be used in a simple treatment regimen. Alternatively, multiple periodicities can be used in a single treatment regimen. For example, a first quantity of doses can be administered according to a first periodicity.

239 and then the first dose amount or a second dose amount can be administered according to a second periodicity. Subsequently, the first dose quantity or second dose quantity administered according to a second periodicity may optionally be followed by a first, second or third dose quantity administered according to a third periodicity.

In one embodiment, an antibody, or antigen-binding portion thereof, which is capable of binding to the p40 subunit of IL-12 and / or IL-23 is administered to a subject as a first dose amount according to one periodicity and is subsequently administered to the subject as a second quantity of doses in the same periodicity.

In another embodiment, an antibody or antigen-binding portion thereof, which is capable of binding to the p40 subunit of IL-12 and / or IL-23 is administered to a subject in a first quantity of doses according to a periodicity and is subsequently administered to the subject as a second quantity of dose according to a second periodicity.

In one embodiment, an antibody, an antigen-binding portion thereof, which is capable of binding to the p40 subunit of IL-12 and / or IL-23 is administered to a subject in a first quantity of doses according to one periodicity and is subsequently administered as a second dose amount according to a second periodicity and is subsequently

240 administered to the subject as a first, second, or third dose amount according to a third periodicity.

The first dose amount of the antibody, or antigen-binding portion thereof, can be at least about 100 mg to about 200 mg, is at least about 100 mg, or is at least 200 mg. The first dose amount of the antibody, or antigen-binding portion thereof, may be approximately 100 mg,

<td>approximately</td><td> 110</td><td>mg,</td><td>approximately</td><td> 120</td><td>mg,</td>

<td>approximately</td><td> 130</td><td>mg,</td><td>approximately</td><td> 140</td><td>mg,</td>

<td>approximately</td><td> 150</td><td>mg,</td><td>approximately</td><td> 160</td><td>mg,</td>

<td>approximately</td><td> 170</td><td>mg,</td><td>approximately</td><td> 180</td><td>mg,</td>

about 190 mg, or about 200 mg. In one embodiment, the first dose amount is approximately 180-220 mg, 185-215 mg, 190-210 mg, 0 195-205 mg. In one embodiment, the first dose amount is 200 mg. In one embodiment, the first dose amount is approximately 80-120 mg, 85-115 mg, 90-110 mg, or 95-105 mg. In one embodiment, the first dose amount is 100 mg. It should be noted that intermediate doses at the above specified doses are also included, for example 105 mg, 127 mg, etc.

The second dose amount of the antibody, or antigen binding portion, may be similar to the first dose amount of the antibody, or antigen binding portion thereof, or different from the first dose amount of the antibody, or portion

241 binding to the antigen thereof. The second dose amount of the antibody, or antigen-binding portion thereof, can be at least about 100 mg to about 200 mg, is at least 200 mg, or is at least about

100 mg. Alternatively, the second dose amount of the antibody, or antigen-binding portion thereof, is approximately 40-60% (eg 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60%), for example about 50% of the first dose amount of the antibody or antigen-binding portion thereof, or about 190- 210% (for example, 190, 191, 192, 193,

194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210%), for example about 200% of the first dose amount of the antibody or antigen-binding portion thereof. The second dose amount of the antibody or antigen-binding portion may be about 100 mg, about 110, about 120 mg,

<td></td><td>approximately</td><td> 130</td><td>mg,</td><td>approximately</td><td> 140</td><td>mg,</td>

<td></td><td>approximately</td><td> 150</td><td>mg,</td><td>approximately</td><td> 160</td><td>mg,</td>

<td> 20</td><td>approximately</td><td> 170</td><td>mg,</td><td>approximately</td><td> 180</td><td>mg,</td>

<td></td><td>approximately</td><td>190 mg</td><td colspan="2">or about 200</td><td>mg. In</td><td>a</td>

modality, the second dose amount is about 80-120mg, 85-115mg, 90-110mg or 05-195mg. In one embodiment the second amount of 100 mg dose. In another embodiment, the second amount of dose is approximately

242

180-220 mg, 185-215 mg, 190-210 mg, 195-205 mg. In one embodiment, the second dose amount is 200 mg. It should be noted that intermediate doses to the aforementioned doses are also included, for example 105 mg, 127 mg, etc.

The first and second periodicity of administration of the antibody, or antigen-binding portion thereof, may be once a week, about once every two weeks, about once every four weeks. The second periodicity of administration of the antibody or antigen-binding portion thereof may be approximately once every 20-300 days.

The duration of the first periodicity may be about 15 weeks, about 8 weeks, about 4 weeks, about 2 weeks, or about 1 week.

The duration of the second periodicity may be about 20 weeks, about 44 weeks, about 12 weeks, about 4 weeks, about 2 weeks, or about 1 week.

The duration of a third periodicity may, for example, be approximately 4 weeks, approximately 12

243 weeks, about 24 weeks, about 36 weeks, about 48 weeks, or about 60 weeks.

Accordingly, in one aspect, a method of treating psoriasis in a subject comprises administering to a subject a first dose amount of an antibody, or an antigen-binding portion thereof, which is capable of binding to the p40 subunit. IL-12 and / or IL-23; and a second amount of the io dose which is about 40-60% of the first dose amount of the antibody or antigen-binding portion thereof, according to a periodicity of about once every 12 weeks, thus treating the psoriasis in the subject.

In another aspect, a method of treating psoriasis in a subject comprises administering to the subject a first quantity of an antibody, or antigen-binding portion thereof, which is capable of binding to the p40 subunit of IL-12 and / or IL-23, according to a first periodicity of approximately once every 4 weeks; and administering a second dose amount that is approximately 40-60% of the first dose dose of the antibody or antigen-binding portion thereof, according to a second periodicity of about once every 4 weeks, thereby treating psoriasis in the subject.

244

In another aspect, a method of treating psoriasis in a subject comprises administering to the subject a first dose amount of an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, according to a first periodicity of approximately once every 4 weeks; and a second dose amount that is approximately 40-60% of the first antibody dose amount, or antigen-binding portion thereof, according to a second periodicity of about once every

4 weeks; and the second dose amount of the antibody, or antigen-binding portion thereof, according to a third periodicity approximately once every 12 weeks, thereby treating psoriasis in the subject.

In one embodiment, the second dose amount is administered to the subject in an exacerbation of psoriasis. In another embodiment, the second dose amount is administered to the subject prior to an exacerbation of psoriasis.

The exacerbation of psoriasis can be monitored by determining the Psoriasis Area and Severity Index (PASI,

FOR ITS ACRONYMS IN ENGLISH), for example, PASI 100 response, PASI 90 response, PASI 75 response, PASI 50 response, PASI response from a single body region, two body regions, three body regions, or four regions of the body, for example, torso, lower extremities, upper extremities, or head and neck. Alternatively, the

245 Psoriasis exacerbation can be monitored by determining the degree of the Global Physician Assessment (PGA).

In one embodiment, the subject achieves or maintains a specific response to treatment. In one modality, the subject achieves or maintains at least one PASI 50 response. In one modality, the subject achieves or maintains at least one PASI 75 response. In one modality, the subject achieves or maintains at least one response. PASI 90. In one modality, the subject achieves or maintains at least one PASI 100 response. In one embodiment, the PASI 50, 75, 90, or 100 response is reached by approximately (eg, at least approximately) at week 4, 5, 6, 7, 8, 9, 10,

11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,

28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,

45, 46, 47, 48, 49, 50, 51 or 52 after treatment (eg after initial treatment, eg at week 0). In one embodiment, the PASI 50, 75, 90, or 100 response is held for approximately (eg, at least approximately) 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17,

18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,

35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 weeks, for example, after the administration of a first quantity of doses in a first periodicity, or after the administration of a first or second quantity of doses in a second periodicity, or after the administration of

246 a first or second or third dose quantity according to a third periodicity. In one modality, the PASI 50, 75, 90, or 100 response is maintained, once reached, throughout the duration of treatment.

In one modality, the subject achieves a PGA count of 0 or 1. In one modality, the PGA count of 0 or 1 is reached by approximately (eg, at least approximately) week 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,

20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,

37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 after treatment (eg after initial treatment, for example at week 0 ). In one embodiment, the PGA count of 0 or 1 is maintained for approximately (eg, at least approximately) 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,

31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,

48, 49, 50, 51, 52 weeks, for example after the administration of a first quantity of doses in a first periodicity, or after the administration of a first or second quantity of doses in a second periodicity, or after the administration of a first, second or third dose quantity according to a third periodicity. In one modality, the PGA count of 0 or 1 is maintained, once it is reached, throughout the duration of the treatment.

In one modality, the subject reaches a PGA count of 0,

247 that is, total cleaning. In one embodiment the PGA count of 0 is reached in approximately (for example, at least approximately) week 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,

15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,

32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,

49, 50, 51, or 52 after treatment (for example, after initial treatment, for example at week 0). In one embodiment, the PGA count of 0 is maintained for approximately (for example, at least approximately)

4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,

40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 weeks, for example, after administration of a first quantity of doses in a first periodicity, or after administration

I5 of a first or second dose quantity in a second periodicity, or after the administration of a first, second or third dose quantity according to a third periodicity. In one modality, the PGA count of 0 is maintained, once it is reached, throughout the duration of the treatment.

A method of treating psoriasis in a population of subjects may comprise administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23. , where at least 60% of the population of subjects achieve a response

248 of PASI 75, for example, in about week 12.

A method of treating psoriasis in a population of subjects may comprise administering to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23. , where at least 25% of the population of subjects reach a PASI 90 response, for example, in approximately week 12.

A method of treating psoriasis in a population of subjects may comprise administering to each subject in the population an io antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL- 23, where at least 10% of the population of subjects reach a PASI 100 response, for example, in approximately week 12.

A method of treating psoriasis in a subject or a population of subjects may comprise administering to the subject or to each subject in the population an antibody, or antigen-binding portion thereof, which is capable of binding to the p40 subunit of IL-12. and / or IL-23, wherein the subject or a percentage of the subject population (eg, at least 10%, 15%,

20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,

75%, 80%, 85%, 90%, 95%, 99%, or 100% of a population of subjects) reaches at least one PASI 50 response in approximately week 12, 24, 36, 48, 52, or 60.

A method of treating psoriasis in a subject or a population of subjects may comprise administering to the subject or to

249 each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, wherein the subject or a percentage of the population of subjects ( for example, at least 10%, 15%,

20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,

75%, 80%, 85%, 90%, 95%, 99%, or 100% of a population of subjects) reaches at least one PASI 75 response in approximately week 12, 24, 36, 48, 52, or 60.

A method of treating psoriasis in a subject or a population of subjects may comprise administering to the subject or to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where the subject or a percentage of the subject population (for example, at least 10%, 15%,

20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,

75%, 80%, 85%, 90%, 95%, 99%, or 100% of a population of subjects) reaches at least one PASI 90 response in approximately week 12, 24, 36, 48, 52, or 60.

A method of treating psoriasis in a subject or a population of subjects may comprise administering to the subject or to each subject in the population an antibody, or the antigen-binding portion thereof, which is capable of binding to the p40 subunit of IL-12. and / or IL-23, wherein the subject or a percentage of the subject population (eg, at least 10%, 15%,

2 0%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,

250

75%, 80%, 85%, 90%, 95%, 99%, or 100% of a population of subjects) reaches at least one PASI 100 response in approximately week 12, 24, 36, 48, 52, or 60.

A method of treating psoriasis in a subject or a population of subjects may comprise administering to the subject or to each subject in the population an antibody, or antigen-binding portion thereof, that is capable of binding to the p40 subunit of IL-12 and / or IL-23, where the subject or a percentage of the subject population (for example, at least 10%, 15%,

20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,

75%, 80%, 85%, 90%, 95%, 99%, or 100% of a population of subjects) reaches at least a PGA count of 0 or 1 in approximately week 12, 24, 36, 48 , 52, or 60.

In one aspect, the subject or the population of treated subjects achieved an improvement in a count of the Dermatological Quality of Life Index (DLQI) or average count of the Dermatological Quality of Life Index (DLQI) of per at least about -6.8, -6.9, -7.0, -8.0, 8.5, -9, -10, -10.5, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20 or below. An improvement in DLQI is a reduction in DLQI count, for example, a reduction by at least about 6.8, 6.9, 7.0, 8.0, 8.5, 9, 10, 10.5, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20 or more. The Dermatological Quality of Life Index (DLQI) is a patient-described measurement of the degree to which psoriasis impacts quality of life in relation to health.

251

The DLQI produces a count that has a range of 0 to 30, with a lower count indicating a lower impact.

In certain modalities, the subject achieves a clinically significant reduction in the count of the Quality of

Dermatological Life (DLQI). A clinically significant reduction in the Dermatologic Quality of Life Index (DLQI) count may, for example, be a decrease of no more than 5 points in the DLQI count.

In another aspect, the subject or population of the treated subjects achieves an improvement in a count of the Short Form 36 of the Synopsis of the Physical Component of the Health Study (PCS, FOR ITS ACRONYMS IN ENGLISH) or the average count of the Synopsis of the Physical Component (PCS) of at least about 2, 3, 4, 5, 6, or more. An improvement in PCS is an increase in PC count, for example, an increase of at least about 2, 3, 4, 5, 6, or more.

In another aspect, the subject or population of the treated subjects achieves an improvement in a count of the Short Form 36 of the Synopsis of the Mental Component of the Health Study (MCS,

FOR ITS ACRONYMS IN ENGLISH) or average Mental Component Synopsis (MCS) count of at least approximately 3.5, 4, 4.5, 6, 6.5, 7, or more. An improvement in PC is an increase in the MCS count, for example, an increase of at least about 3.5, 4, 4.5, 6, 6.5, 7, or more.

In another aspect, the subject or population of the subjects

252 Treated achieves improvement in visual analog count or visual analog mean count for psoriasis related pain (VAS-Ps) of at least about -25, -26, 27, -28, -29, -30, -31 , -32, -33, -34, -35, -40, -45, -50, or less.

An improvement in VAS-Ps is a reduction in the VAS-Ps count, for example, a reduction of at least about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40 , 45, 50, or more.

In another aspect, the subject or population of treated subjects achieves an improvement in a visual analogue scale count io for pain related to psoriatic arthritis (VAS-PsA) or an average visual analogue scale count for arthritis related pain psoriatic (VAS-PsA) of at least about -25, -26, -27, -28, -29, -30, -31, -32, -33, -34, 35, -40, -45, - 50 or less. An improvement in VAS-PsA is a reduction in the VAS-Ps count, for example, a reduction of at least about 25, 26, 27, 28, 29, 30, 31, 32, 33,

34, 35, 40, 45, 50, or more.

In another aspect, the population of treated subjects achieves a clinically important least difference response rate (MCID) in any one or more HRQOL results including, for example, DLQI, TAI, VAS-Ps, Vas-PsA, MCS and PCS of at least about 60%, 65%, 70%,

75%, 80%, 85%, 90%.

In another aspect, the population of treated subjects achieves a response rate of minimal clinical difference.

253 Important (MCID) for psoriasis-related pain (VAS-Ps) of at least about 60%, 65%, 70%, 75%, or more, for example, at about week 12 or at about week 52 .

In another aspect, the population of treated subjects achieves a clinically important least difference response rate (MCID) for the Dermatologic Quality of Life Index (DLQI) of at least approximately 70%, 75%, 80% or more in about week 12.

In another aspect, the population of treated subjects reaches a clinically important least difference response rate (MCID) for Impaired Total Activity (TAI) of at least approximately 45%, 50%, 55%, 60%, 70% or more in about week 12.

In another aspect, the population of treated subjects reaches a clinically important least difference response rate (MCID) for Impaired Total Activity (IAT) of at least approximately 50%, 55%, 57%, 60%, 65% or more in about week 52.

In another aspect, efficacy can be determined by

254 Nail Psoriasis Severity Index (NAPSI) counts, ranging from 0 (no psoriatic nail) to 80 (psoriasis on all finger nails). In certain modalities, the subject achieves a Psoriasis Severity Index count of

NAPSI nails about 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or less. In certain modalities, the subject achieves a Nail Psoriasis Severity Index (NAPSI) count of approximately 2.1 or less. In certain modalities, the subject reaches a Nail Psoriasis Severity Index (NAPSI) count of approximately 2.1 or less at approximately week 24. In certain modalities, the subject achieves a Nail Psoriasis Severity Index (NAPSI) count of approximately 1.2 or less. In certain modalities, the subject reaches a Nail Psoriasis Severity Index (NAPSI) count of approximately 1.2 or less at approximately week 52.

In another respect at least 40%, 45%, 50%, 55%, 60%, 65%, or more of the population of treated subjects achieve at least a PGA 0/1 response at approximately week 12, where each subject was treated with a biological before the administration of the antibody.

In another aspect, at least 50%, 55%, 60%, 65%, 70%, 75% of the population of treated subjects achieve at least one PASI 75 response in approximately one week.

12, where each subject was treated with a biological before the

255 administration of the antibody.

In another aspect, at least 60%, 65%, 70%, 75%, 78%, or more of the population of treated subjects achieve at least a PGA 0/1 response in approximately Week

12, where none of the subjects was treated with a biological agent before administration of the antibody.

In another aspect, at least 60%, 65%, 70%, 75%, 80%, 82% or more of the subject population achieve at least a PASI 75 response in approximately week 12, in which none of the subjects was treated with a biologic prior to administration of the antibody.

In another aspect, at least 60%, 65%, 70%, 75%, 78%, or more of the population of treated subjects achieve at least a PGA 0/1 response in approximately the week

52, where each subject was treated with a biological before administration of the antibody.

In another aspect at least 60%, 65%, 70%, 75%, 79%, 80%, 82% or more of the population of treated subjects achieve at least a PGA 0/1 response in approximately the week 52, wherein none of the subjects had a biological prior to administration of the antibody.

In another aspect, at least 50%, 55%, 60%, 65%, 70%, 71%, or more of the population of treated subjects achieve at least a PGA 0/1 response at approximately week 12 , where each subject treated has a history

256 anterior psoriatic arthritis.

In another aspect, at least 60%, 65%, 70%, 75%, 78%, or more of the population of treated subjects achieve at least one PASI 75 response in approximately the week

12, where each treated subject has a previous history of psoriatic arthritis.

In another aspect, at least 60%, 65%, 70%, 75%, 77%, or more of the population of treated subjects achieve at least a PGA 0/1 response in approximately Week

12, where none of the treated subjects have a previous history of psoriatic arthritis.

In another aspect, at least 60%, 65%, 70%, 75%, 81%, or more of the population of treated subjects achieve at least one PASI 75 response in approximately one week.

12, where none of the treated subjects have a previous history of psoriatic arthritis.

In another aspect, at least 60%, 65%, 70%, 75%, 77%, or more of the population of treated subjects achieve at least a PGA 0/1 response in approximately the week

52, where each treated subject has a previous history of psoriatic arthritis.

In another aspect, at least 60%, 65%, 70%, 75%, 79%, or more of the population of treated subjects achieve at least a PGA 0/1 response in approximately the week

52, where none of the treated subjects has a history

257 anterior psoriatic arthritis.

In another aspect, at least 50%, 55%, 60%, 65%, 69%, or more of the subject population achieve at least a PGA 0/1 response at approximately week 12, where each subject had a PASI baseline greater than 20 before administration of the antibody.

In another aspect, at least 60%, 65%, 70%, 75%, 79%, or more of the subject population achieve at least a PGA 0/1 response in approximately week 12, at io where each subject had a PASI baseline less than or equal to 20 before administration of the antibody.

In another aspect, at least 60%, 65%, 70%, 75%, 79%, or more of the subject population achieve at least one PASI 75 response in approximately week 12, where each subject had a PASI baseline greater than 20 before administration of the antibody.

In another respect, at least 60%, 65%, 70%, 75%, 80%, 81%, or more of the subject population achieve at least one PASI 75 response in approximately week 12, where each subject had a PASI baseline less than or equal to 20 before administration of the antibody.

In another aspect, at least 50%, 55%, 60%, 65%, 67%, or more of the subject population achieve at least a PGA 0/1 response at approximately week 12, where each subject had a baseline weight greater than or equal to

258

100 kilograms before administration of the antibody.

In another aspect, at least 60%, 65%, 70%, 75%, 80%, or more of the subject population achieve at least a PGA 0/1 response at approximately week 12, where each subject had a baseline weight of less than 100 kilograms prior to administration of the antibody.

In another aspect, at least 50%, 55%, 60%, 65%, 70%, 72% or more of the subject population achieve at least one PASI 75 response in approximately week 12, where each subject had a baseline weight of greater than or equal to 100 kilograms prior to administration of the antibody.

In another respect, at least 60%, 65%, 70%, 75%, 80%, 85%, or more of the subject population achieve at least one PASI 75 response in approximately week 12, in

I5 where each subject had a baseline weight of less than 100 kilograms prior to administration of the antibody.

It should be noted that dosage values may vary with the type and severity of the condition to be alleviated. It should be further understood that for any specific, particular dosing regimen the subject should be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the compositions, and that the dosing intervals set forth herein are exemplary only and are not intended to limit the scope or practice of the

259 claimed composition.

Vile. Uses of the Invention

The invention provides methods of inhibiting IL-12 activity in a subject suffering from a disorder in which IL-12 activity is harmful.

IL-12 has been implicated in the pathophysiology of a wide variety of disorders (Windhagen et al., (1995) J. Exp. Med. 182: 1985-1996; Monta et al. (1998) Arthritis and Rheumatism. 41: 306-314 ; Bucht et al., (1996)

IO Clin. Exp. Immunol. 103: 347-367; Fais et al., (1994) J. Interferon Res. 14: 235-238; Parronchi et al., (1997) Am. J. Path. 150: 823-832; Monteleone et al., (1997) Gastroenterology. 112: 1 169-1 178, and Berrebi et al., (1998) Am. J. Path 152: 667-672; Parronchi et al. (1997) Am. J. Path. 150: 823-832). The invention provides methods of inhibiting IL-12 activity in a subject suffering from such a disorder, which method comprises administering to the subject an antibody or portion of the antibody of the invention such that IL-12 activity in the subject is inhibited. Preferably IL-12 is human IL-12 and the subject is a human subject. Alternatively, the subject may be a mammal that expresses an IL-12 with which an antibody of the invention cross-reacts. Still further the subject may be a mammal into which hlL-12 has been introduced (eg, by administration of hlL-12 or by expression of an hlL-12 transgene). An antibody

260 The invention can be administered to a human subject for therapeutic purposes (discussed further below). Furthermore, an antibody of the invention can be administered to a non-human mammal that expresses an IL-12 with which the antibody cross-reacts for veterinary purposes or as an animal model of human disease.

With respect to the latter, such animal models can be useful in evaluating the therapeutic efficiency of the antibodies of the invention (eg, testing dosage and time courses of administration).

As used herein, the phrase "a disorder in which IL-12 activity is harmful is intended to include diseases and other disorders where the presence of IL-12 in a subject suffering from the disorder has been shown to be or be suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder. Accordingly, a disorder in which IL-12 activity is harmful is a disorder in which inhibition of IL-12 activity is expected to alleviate the symptoms and / or progression of the disorder. Such disorders can be evidenced, for example, by an increase in the concentration of IL-12 in a biological fluid of a subject suffering from the disorder (for example an increase in the concentration of IL-12 in serum, plasma, slnovial fluid, etc. . from the subject), which can be detected, for example, used with an anti-IL-12 antibody as described

261 previously. There are numerous examples of disorders where IL-12 activity is harmful. In one embodiment, the antibodies or antigen-binding portions thereof can be used in therapy to treat the diseases or disorders described herein. In another embodiment, the antibodies or antigen-binding portions can be used for the manufacture of a medicine to treat the diseases or disorders described herein. The use of the antibodies and the antibody portions of the invention in the treatment of some specific non-limiting disorders is discussed further below:

A. Rheumatoid arthritis

Interleukin-12 has been implicated in playing a role in inflammatory diseases such as rheumatoid arthritis. The inducible message for IL-12p40 has been detected in the synovium of patients with rheumatoid arthritis and IL-12 has been shown to be present in the synovial fluids of patients with rheumatoid arthritis (see for example Morita et al. (1998) Arthritis and Rheumatism 41 306 -314). IL-12 positive cells have been found to be present in the lining layer of rheumatoid arthritis synovium. The human antibodies and antibody portions of the invention can be used to treat, for example, rheumatoid arthritis, juvenile rheumatoid arthritis, Lyme arthritis, rheumatoid spondylitis, osteoarthritis, and gouty arthritis. Normally, the antibody, or

262 Antibody portion, is routinely administered, although for certain disorders, local administration of the antibody or antibody portion may be beneficial. An antibody, or antibody portion, of the invention can also be administered with one or more additional therapeutic agents useful in the treatment of autoimmune diseases.

In the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis, treating mice with an anti-IL-12 mAb (mouse anti-mouse IL-12 monoclonal antibody,

C17.15) before arthritis profoundly suppresses the onset, and reduces the incidence and severity of the disease. Treatment with anti-IL-12 mAb just after the onset of arthritis reduced the severity, but subsequent treatment of the mice with anti-IL-12 mAb after the onset of disease had minimal effect on disease severity. .

B. Crohn's disease

Interleukin-12 also plays a role in inflammatory bowel disease, Crohn's disease. Increased IFN-γ and IL-12 expression occurs in the intestinal mucosa of patients with Crohn's disease (see Fais et al., (1994) J. Inferieron Res. 14: 235-238; Parronchi et al., 1997 ) Amer. J. Pathol. 1 50: 823-832; Monteleone et al., (1997) Gastroenterology 112: 11691178; Berrebi et al., (1998) Amer. J. Pathol. 152: 66725 6 7 2). Anti-IL-12 antibodies have been shown to suppress the

263 disease in mouse models of colitis, eg, TNBS-induced colitis IL-2 mice, and recently in IL-10 deficient mice. Accordingly, the antibodies, and antibody portions, of the invention can be used in the treatment of inflammatory bowel diseases.

C. Multiple Sclerosis lnterleukin-12 has been implicated as an essential mediator of multiple sclerosis. Expression of the inducible message from IL-12 p40 or from IL-12 itself can be demonstrated in lesions of patients with multiple sclerosis (Windhagen et al., (1995) J. Exp. Med. 182: 1985-1996, DrUlovic et al., (1997) J. Neurol. Sci. 147: 145-150). Chronic progressive patients with multiple sclerosis have high levels of IL-12 circulation. Investigations with T cells and antigen-presenting cells (APCs) from patients with multiple sclerosis revealed a series of self-perpetuating immune interactions as the basis of progressive multiple sclerosis leading to a Th1-type immune response. Increased IFN-γ secretion from T cells led to increased production of IL-12 by APCs, which perpetuated the cycle of chronic immune activation and Th1-like disease (Balashov et al., (1997) Proc Nati. Acad. Sci. 94: 599-603). The role of IL-12 in multiple sclerosis has been investigated using mouse and rat models with allergic encephalomyelitis

264 experimental (EAE) of multiple sclerosis. In an EAE model of or

Recurrent-remitting multiple sclerosis in mice, pretreatment with anti-IL-12 mAb delayed paralysis and reduced clinical score. Treatment with anti-IL-12 mAb at the peak of paralysis or during the subsequent remission period reduced the clinical score. Accordingly, the antibodies or antigen-binding portions thereof of the invention may serve to alleviate the symptoms associated with multiple sclerosis in humans.

D Insulin Dependent Diabetes Mellitus

Interleukin-12 has been implicated as an important mediator of insulin-dependent diabetes mellitus (IDDM). IDDM was induced in NOD mice by administration of IL-12 and anti-IL-12 antibodies were protected in an adoptive IDDM transfer model. Patients with early-onset IDDM frequently experience a so-called honeymoon period, during which some residual function of the islet cell is maintained. These residual islet cells produce insulin and regulate blood glucose levels better than administered insulin. Treating these early-onset patients with an anti-IL-12 antibody can prevent further destruction of islet cells, thereby maintaining an endogenous source of insulin.

E. Psoriasis

Interleukin-12 (IL-12) and related IL-23 cytosine are

265 have been implicated as essential mediators in psoriasis. Psoriasis involves acute and chronic skin lesions that are associated with a TH1-type cytosine expression profile (Hamid et al. (1996) J. Allergy Clin. Immunol. 1: 225-231; Turka et al. (1995) Mol. Med . 1: 690-699). IL-12 and IL-23 contribute to the development of the helper T-cell type 1T (Th1) immune response in psoriasis. Furthermore, the messenger RNA of IL-12 p40 and IL-23 p40 is over-expressed in psoriatic skin lesions. Accordingly, the antibodies or antigen-binding portions io of the invention may serve to alleviate chronic skin disorders such as psoriasis.

In one embodiment, the invention provides a method of treating psoriasis. Treatment for psoriasis frequently includes topical corticosteroids, vitamin D analogues, and topical or oral retinoids, or combinations thereof. In one embodiment, an IL-12 and / or IL-23 antibody is administered in combination with or the presence of one of these common treatments. Additional therapeutic agents that can be combined with IL-12 and IL-23 antibody for the treatment of psoriasis are described in detail below.

The diagnosis of psoriasis is generally based on the appearance of the skin. Additionally, a skin biopsy, or scraping and culture of skin plaques, may be necessary to rule out other skin disorders. An x-ray can be used to check for persistence and presence of

266 psoriatic arthritis joint pain.

Improvements in psoriasis in a subject can be monitored by the subject's Psoriasis Area and Severity Index (PASI) count. The method for determining PASI has been described in

Fredriksson and Pettersson (1978) Dermatológica 157: 238 and Marks et al. (1989) Arch Mermatol 125: 235. Briefly, the index is based on the evaluation of four anatomical sites, including the head, upper extremities, torso, and lower extremities, erythema, induration, and scaling io using a 5-point scale (0 = no symptoms; 1 = slight ; 2 = moderate; 3 = marked; 4 = very marked). Based on the degree of injury at a given anatomical site, a numerical value is assigned to the affected area (0 = 0; 1 = <10%; 2 = 10-29%; 3 = 3049%; 4 = 50-69%; 5 = 70-89%; 6 = 90-100%). The PASI count is then calculated, where the possible range of the PASI count is 0.0 to 72.0 with the highest count representing complete erythroderma of the most severe grade.

In one embodiment of the invention, an IL-12 and / or IL-23 antibody is used for the treatment of psoriasis, including plaque psoriasis, eg, chronic plaque psoriasis, moderate plaque psoriasis, and severe psoriasis in plaques, gouty psoriasis, reverse psoriasis, pustular psoriasis, pemphigus vulgaris, erythrodermic psoriasis, psoriasis associated with inflammatory bowel disease (IBD), and psoriasis associated with rheumatoid arthritis (RA). In another embodiment, the IL267 and / or IL-23 antibody, such as J695 / ABT-874, is used to treat subjects who have psoriasis in combination with PsA. In one embodiment of the invention, the IL-12 and / or IL-23 antibody is used for the treatment of nail psoriasis.

In one aspect, the invention provides methods of treating psoriasis in difficult-to-treat subjects by administering antibodies, and the antigen-binding portions thereof, of the invention, eg, ABT-874. Difficult subjects to treat may include, for example, subjects who have been biologically or previously administered psoriasis treatment, subjects who have had a history of psoriatic arthritis, subjects who have psoriasis and weigh more than 100 kg, and subjects who have a PASI baseline greater than 20. Accordingly, in one aspect, the invention provides methods of treating subjects that have been biologically administered previously by the treatment of psoriasis by administering antibodies, and antigen-binding portions thereof, of the invention, eg, ABT-874. Specifically, the methods involve selecting subjects who have received prior biological treatment and administering antibodies of the invention. As established in Example 19, the data demonstrate the efficacy of ABT-874 in treating psoriasis in this subgroup of subjects. In another aspect, the invention provides methods of treating subjects who have had a history of psoriatic arthritis by administering antibodies, and the antigen-binding portions

268 thereof, of the invention, eg ABT-874. Specifically, the methods involve selecting subjects who have had a history of psoriatic arthritis and administration of antibodies of the invention. In another aspect, the invention provides methods of treating subjects weighing more than 100 kg by administering antibodies, and antigen binding portions thereof, of the invention, eg, ABT-874. Specifically, the methods involve selecting subjects weighing more than 100 kg and administering antibodies of the invention. In still or another aspect, the invention provides methods of treating subjects who had a PASI baseline greater than 20 by administering antibodies, and antigen-binding portions thereof, of the invention, eg, ABT-874. Specifically, the methods involve selecting subjects who have a PASI baseline of greater than 20 before administration of the antibody and administration of antibodies of the invention.

The specific types of psoriasis included in the treatment methods of the invention are described in detail below:

to. Chronic plaque psoriasis

Chronic plaque psoriasis (also referred to as psoriasis vulgaris) is the most common form of psoriasis. Chronic plaque psoriasis is characterized by elevated redness of the plaques of the skin, ranging from a penny size to a larger one. In chronic psoriasis in

269 plates, the plates can be single or multiple, they can vary in size from a few millimeters to several centimeters. The plates are generally red with a scaly surface, and reflect light when gently scratched, creating a silver effect.

Injuries (which are often symmetrical) of chronic plaque psoriasis occur over the entire body, but with a predilection for extensor surfaces, including the knees, elbows, lumbar regions, scalp, and nails. Occasionally chronic plaque psoriasis can occur on the penis, vulva, and joints, but progression is generally absent. The diagnosis of patients with chronic plaque psoriasis is generally based on the clinical characteristics described above. In particular, the distribution, color, and silver flaking of the common lesion in chronic plaque psoriasis are characteristic of chronic plaque psoriasis.

b. Gouty psoriasis

Gouty psoriasis refers to a form of psoriasis with characteristic squamous plaques formed by drops of water. The sharpness of gouty psoriasis generally follows a

Infection, most notably a Strep throat infection. The diagnosis of gouty psoriasis is generally based on the appearance of the skin, and the fact that there is often a recent history of throat involvement.

c. Reverse psoriasis

Reverse psoriasis is a form of psoriasis in which the

270 Patient has smooth, usually moist areas of skin that are red and inflamed, which is different from peeling associated with plaque psoriasis. Reverse psoriasis is also referred to as intertiginous psoriasis or flexural psoriasis. Reverse psoriasis occurs mainly in the armpits, groin, under the breasts, and in other skin folds around the genitals and buttocks, and as a result of the presenting locations, rubbing and sweating can irritate the affected areas.

d. Pustular psoriasis

Pustular psoriasis, also referred to as palmar plantar psoriasis, is a form of psoriasis that causes pus-filled blisters that vary in size and location, but frequently occur on the hands and feet. The blisters can be localized, or spread over large areas of the body. Pustular psoriasis can be delicate and painful, it can cause fever.

and. Other psoriasis disorders

Other examples of psoriatic disorders that can be treated with the IL-12 and / or IL-23 antibody include erythrodermic psoriasis, vulgaris, psoriasis associated with IBD, and psoriasis associated with arthritis, including rheumatoid arthritis.

The present invention is further illustrated by the following examples which are not to be construed as limiting in any way. The content of all references

271 cited, including literature references, issued patents, and published patent applications, as cited throughout this application, is expressly incorporated herein by reference. It should be further understood that the content of all tables annexed hereto (see Appendix A annexed hereto and Appendix A to North American Patent No. 6,914,128) as well as the entire content of North American Patent No. 6,914,128 is incorporated herein by reference.

Table 1 Amino Acid Sequences of the VH3 Germ Line Family

Kabat numbering (Joe9 VH included for comparison

CT

SecCT sec. id aei VH NO Linea '- i SS SSS-G SS Yes SSS 5 Í-ÍTÍ íí i <tp> 29 EVQL V ESGGGLVQPGGS LRLSCAAS G FT t S PP-30 E.VQLVESGGGL VQPGGSLRLS CAAS G FT FS BC15-7 EVQL V ES '' GGGLV QPGCSLRL SCA ASGF TFS VRD26 EV0LLESGGeLVQPG.GSLRL8¿AASGFTFS E VQL VE SGG6LVQPG RS LRLSCAASS FT FD IVQLVrsGGSVVGG VGG VGG VGG VGG VGG LVG 3LRÍSC-AASG-FTFS tV <31iVCSGGGLVGfGG, SI, Kl.SCíkASGFTFS BV Ótv ÉS G GGlíV k PGGS ¿R t SCÁAS.Ó FT FS EV.tfSVaÍ8jGe.e¿VS'pe «8ÍRÍS € AÁeGTT.TS ÉVeL« BSG «BLVXPGGSLRLS, CÁASGrT.FS Ε V QL VE $ GGGL V RPGGSLALSé AASG FT FS

608

LSG4

LSG6

TST

609

610

611

-617 c »» - gl s'ssiü

DHYHD

DHTMS.

DHTMS

DHYMS

DYAMH

DYGMS

DYTMH

DYYMS

GSAMH

HABMS

NAWMS

NABHS

HABMS

HAHHN

NAWMS

HHYMS

NHYTS

NSDMN

HSDMH

HYDMH

SHJMS

SYAMH

SYAMS

SYAMH

SYÁMH

SYAMH

SYAMS

SYAMH

S YAMH

SYAMH

SYAMM

SYAMH

S YAMH

SYAMH

SY AMH

SYAMH

SYDMH

SYEMH

COR H2 tu su s S txs í eses s Ε εésí RTRHKANSYTTBYAASVKG tlRHXAHSYTTEYAASVKG LIRHKRHSYTTBYAASVKG lrh.xahsytteyaasGYGYGYGGHYGYGS. , S.SSSS YTHYADSVKG RIRSKAHS YA T AY Á A SV X «RI RSRT.DGGTTLYAAPVXG RIESKTOGGTTDYAAPVXG RI ksxtOGGTTCYTlAPGGT TK Y AAPV KG RI XS ETGGT TK Y AAPV KG RI XS. .SGOSGYTMYADSVRG YS. .SeHSGYTHXADSVKG GV, .SWNGSRTHYADSVKG GV..SHHGSRTHYVDSVKR GVÍ. «SHHGSRTH YADSVKG

Ah .GTAG.OTYYPGSVKG VI, Y. , SGGS TY YADS VK.G AI. . . GTGGGT..YY-AjOSVXG AI i. .GTGGGTYYADSVKG AI. .SCSGGSTYYADSVKG

AI. .SSNG6STYYADSVKG Al. .SSBGGSTYYAOSVKG AI. .SSHGGSTYYAHSVKG AI. . SGSGGSTYYGOSVKG VI. .SYOGSHKYYTDSVkG vi. .SYDGSMXYYADSVKG VI. .S and »GSHKY YA DS VKG VI. .SYDGSHKYYAOSVKG

VISY DG S Ν KYYA DS V KG VI. . SiYbGSBXYYADS V.XG VL..SYOGSSXYYADSVKG VI ... SYOGSHKYYADSVXG

SAW-:. . SY OG S Ν XYYA DS VK; G AI ... ssgggstyyadsvkg 'AJ. . SSNGGSTYYADSVKG Vj. .is YOGSHKYYAOSVKG vi .. s.ydgshxyyAd & vxg VI. .SYDGSHKYYAOSVKG AI. .GTAG.OTYYPGSVKG

V! · <. SS SGS TIYY ADS V-KG s sxs ss jí ss ass SÁE.SS ?. Síes sssis ϊ se ss RFTISRDDSKHSLYLGMHSLKTEDTÁVYYCAR RLTISREDSKHTLYL.QMSSLXTEDLAVYYCAR RLTISREbSKBTMYLQMSHLKTBOLAVYYCAR RLT IS RED SK Η TLY LOM SS LK Γ EX DLA R FTIS RDHAKBS LYLOMHSLRAEOTA LYHCAR RFTISRDHSKKSLYLQMH'SLRTEDTALY.YCAK R FT IS RDH AKHSLYL OH B 8 LR A BOTA VYYCARRF TIS ROS A KHSL YL OMB S LRAB OT A VY YC AR R FT ISR DD SK Β S RPBS: K8-TL YLQMBSLX.rEDTAVYYCTT R FT LS RDDS RBT LJL OMB SL KTE DT AV YYC.TT RF IT SRDOSK HTL YL OMH S t KT E DT AVYYCTT RFTISRDDSKKTLYLQMNSLKTEDTAVYYCTT RFT IS RDDSKBT LYtOMNSLKTEDTAVYY CTT RFTISRDDSRBTLY Lomes KT L T E DT AVY YCT RFTISRbNAKBSPYLOMHSLRAEDTAVYYCVK RFTISRDKKKKSLYLQMHSLRAEDTAVYYCVX RF IT-S RD HSR Β TLYL OT «S l RAED T. AVYYCVRR FII S.RDN.S RB SL YLOEB RRRA E DMA VY YC V R. RFI 1.8 RDHSRHFLYQOMH SLRPEDHAVYYC RFTISRBHAjtBSLYLQMSSLRAGOTA VR-VYYCAR RFTISRDNS.KHTLYLOMBSLRAEDTAVYYCAR RFTISROHAKBSLYLQMBSLRAEDMAVYYCAR rftis-romaxhsLylomhslraedmavyycar RFTISRbHSKBTLYL.OMKSLRA¿bTAVYYCAK R DH SX FT í HT SR L YV QMS SLRÁE DT AV YYCVX RRTISRDHSXBTL'YVQKSSLRAEOT.A VYYCVX RFTISRDHSKBTLYLQMGSLRAEDHAVYYCAB RFTrSRDHSXBTLYLOMBSLRAEDTAVYYCAX 'RFTI RF SRDNSXKTLYLQMBSLRAEDTAV.YYCAR -T XS RDH SXB T l YL qmhs L RAE DTA VYY CAR RFTLSRbHSXHTl, YLQkSSLRABOT & .VyY: CAfc RFTISROHSXBTLYLOMBSLRAEOTAVYYCAR R FT I · SR DBS XKTLY Lombs lra E DT & V and YC AR RFT.ISRpHSXBTLYLQHBSARAEDTAVYYCAR RrTiSRbHS'KB.TLÍLOMBSLRAEDTAVYYCAR RFTIS RDH S KHTL YLOMBSLRA EDTAV YYCAR RFTI.SRDBSKBTLYLOMBSLRAEOTAVYkCAR R FT IS RDH S Κ.ΝΓ LY VQH.S SLRA BOOT VYYCVX R FT I'S R DH SX KT ¿YL ÓM HS LR AE DT A VY YC ARR F'A IS R OH SX BTL YL QMS SL RAE OTA VYY CAR RF TISRDMSkNTLY LQMH EL RA BOTA VYY CA fi RFTIS RDH SX NT LYL QMN SL RA E DT Á VY YC ÁK

r.fttsrémAknslylombsirágdtavyycar R FT IS RD Ν AK N SL.YL QMN SL RA E DT * VY YC AR

ESESÍEeSEfíSTE HVRQAPGKGLEBVG BVRQAQGKGLEtVG HVRQAQGKGLELVG WVRQAQGKGLELVG BVRQAPGKGLEBVS BVRQAPGKGLEWVS HVRQAPGKGLBBVS HIROAPGXGLEBVs Η X ROA P GEG L E5 "S v BVRQASSKGÍ.EBVG WVROAPG KG L EBV G WVR0APGRGLEBVG BVR0AP5KGLEHVG bVrqapgkgeewvg

BVRQAPGKGLÉBVG hvroapgkglehvg

W.yRQAPGKGLEWVS

BVRQAP'GKGIíEWVS bvhoApgkgléBvs

HARKAPGKGI.EHVS "VRQAPGKGLEHVS bvroatgkglebvs WVRQAPGKGLEHVS BVRQA pgkgebkvs Β VR OA PGK GL É" Η VROA VS PG XG LΕ Μ Β BVROAPGKGLBYVS VS VR 0 APGX GL É: YVS HVRQAPGKOLEYVS WVRQAPGKGLEBVS svroapgxgléwya Η VR 0 A PG K 'L Ε ΒV A, K VR0 A PG KG L EBV A bvro'ápgkglebva BVROAP.eKSI.BWVA.

bvróapgxgLebva BVHQ'APGKGLEMVA Β VRQA p G KG LE Η VA BV.RÓ.A PG XGL Ε Η VAWVR OA PGX ¿LE YVS BVROAPGKGLBYVS 'WVRQ'A PGX OLE Η VA BVAOAPGKG LEW VA WVRG

EVQLVESGGeLVKPGSSLRLSCAASGFTFS _EVQLVBS GGÁ L VK P GGS LR LSC ÁA SG FT Ρ9

Op-39 E VQIV E SG GGLV Q? GGS LRL S'C PASGF TF S

E VQLV ESC 6GL VQPGG S LR LSC AA SG Γ T FS

BVQ L VÉ SGGGLVOPGGS¿RL SCA ASG FT.FS 'EVQLVESGCGÍ.V (iFGGStRI, SGAASGFTFS

V3-IS

Gp-40

613 dp «59

Ái-16p

620 ^21

ΣΣΓ

-62T

624

625

626

628

629

630

631

SF

653

W

635

SF

63T

638

9p. T VQ ti VE SG GGLV E P6GSLRLSCA AS 6 FT FS 13 •• ¿VÍÜÍ # BseGetVÓ »eeÍE¿4SíéAM'GFf-rS EVQLVETGGGLIQPGGS1RLSCAASGFTV8 E VQL V 0S6G GLV 8 PGG S LRLSCASS GVSGS: EVQl.i.SSGGGI.VÓPGGsí-Rl'SCAÁs'GrT.FS fin EVQLVES GGGL VQ PG GS i RL S CS AS G FT FS

-Pl EyQLVBsGCGLVÓ'PGGSLRLSeSABC FT-FS v3 ~ 64 EVOS V ES GGGL'VQ PG G SLRL SCAAS GFT Γ S SVQLLESGGGLVqPGGSLKLSCAASGFTFS OV QL VES GGG VV OP c R8 LRL SC A ASGFTV

837

QVQLVESGGGVVQPGRSLRLSCAASGFTFS _QVQLVESeeeVyOPeB.SEaÍSCAA $ G.PTFS

B48 OVO LVÉ 3 GCGV VOP GB SARISCAASG PTfS

QVQLVESGGGVVQPGRSLRLSCAASGFTFS

QV QLVESG GG VVQ PG RS L AL SCAASGF TF S

QVQLVESGGGVVQPGRSLRLSCAASGFTFS

QVQLVESGGGVVqPGRSLRLSCAASGFTFS

VQL VESG GGL VOPGG SLRL SCS ASG FT FS

0VQL VESGGGL V QpGG.SL RLSCS ASGFT FS

Ó v QIÍV SSOGGV v QF GRSLRLSCA ASGFT FS

OVQLV 6 S «GGV VQPG R SL RL SCAASGFTFS

QV QL VE SG GC VV QPG RS LR LS CAAS G FTFS

B VQ 1V ES G GG LVQPGG8LRL SC AA SC FT.FS

QLVQLVESOG GL VQPGGSLR LSC AÁS G FT FS

843

BS3 as 4

CO3-8.

dp-46

F2M

F3

S7 hy3005 ~ ·

P2 dp-48 dp-58

OR

CM

639

Table 1 (cont.) Line Family Amino Acid Sequences

Germinal VH3

Numbering according to Kabat

ÍJoe9 VH including Dara as arachlon

SEC. ID ΝΟ:

Germline

COR B1

COR 82

ΤΪΓ

641

642 ~ ΗΤ

645;

βΤΓ ~ Ζ7τ ~

W

B1 ___ QVQLVESGGGVVQPGRSLRI.S.CAASGFTFS. B13 _QV QL VE SG GGVV QPGRSLRISCAASGFTFS JjVQLVRSGG.eVVQPGRSLRLSCAASGf TES _20V0Í.VE8GGGVVOPGRSLRLSCAASGFIFS '29' QVOLVESGCGVVQPGRSLRLS'CAASGrTFS B29E QVQLVESGGGVVGPGRSLRLSCAASGETrs B2SW QVQLVESGGSVVQPGRSLRLSCAÁSGFTFS B30__QVQLVESGGGOTQPGRSLRLSCAASGFTFS

R26

ΠΊ

Γ (Ν

Tsó

W

Τ5Γ “ÉT

Τ5Γ

SSF

S5F

ΤδΤ

659

660 πτ

S8F

663

SST

665

SSZ

B32M QVQtVESGCGVVOPGRSLRLSCAASGFTFS eoá-3 QVQLVESGGGVVOPGGSLRLSCXASGFTrs ¿ep-4S_QVQLVESGGGVVQPGRSLRLSCAASGFTFS _VVGQGSVGVSGGVVSQGGGVVSQGGS

PSE ÓVQL.VESGGGVVQPGRSLRLSCAASGFTF.8 V3-30 '. <> VW. «« - 8,8CGYVG> p,C8Í'M.RLgCXAjÍfi.riMiS V3-33 QVQLVESGGGVVQPGRBLRLSCAASGrTFS flp-51 EVQLVESGGGLVOPGGSLRLSCAASGETFS Φ-77 EVQLVESGGGLVKPGGSLRLSCAASGETFS HHG4 «VOL VÍSG GG L VK P GG S LRL3 VESGGGLVRPGGSLRLSCAASGETFS v3- <8 EVQLVESGGGLVOPGnSI.RLSf-AASr.rTFS DP-S2. EDQLVES GGG L VQP GGSL RP SCAA SG FA FS CO »-6 EVQLVE S GGG LV QP GG S LRL S CAASG FTES dp-53 kTQLVBSG66LT0P6GSLRL3CAASGyT.PS_GVGSGVGGVLGVGSGVGGVGGVGVGGVGVGVGVGVGVGGGVGGGVGGS U SVQ1 VE S GG G ¿VQ p OS S LRLS CAASG FT FS aprSO

P6 jota VB 0VQLVQ8GCCWOPCRBLRL3 CAASGPTE 3

SYGMH

SYSMH

SYVLH

SYHHH

SYMMH

SYHMS

SYMMH

SYHMS

SYGMH

Ϊ'ϊ S33 * S GIS SGS 5 MVRQAPGKGLEHVA MVRQAPGKGLEHVA MVRQAPGKGLEHVA MVRQAPGKGLEHVA MVRQAPGKGLEMVA MVRQAPGKGLEHVA MVRQAPGKGLEHVA HVRQAPGKGLEMVA MVRQAPGKGLEHVA Η V ROAPG KGLEΜVA MVRQAPGKGLEHVA mvrq'apgkglemva MVRQAPGKGLEHVA hvkqApgkglehva HVRQAPGKGLEMVA HVRQAPGKGLEMVA MVRQAPGKGLEMVS MVRQAPGKGLEMVS MVRQAPGKGLEMVS MVRQAPGKGLEMVS MVRQAPGKGLEMVS WVRRAPGKGPEWVS MVRQAPGKGLVMVS MVRQAPGKGLVMVS ΜVROAPGKGIBMVA MVRQAPGKGLVMVS Η VRQAP GR OLB Μ VA WVRQAPGKGLIHVA íyeíSSgsssgsjsscgís VI. .SYDGSMKYYA-DSVKG vi., SYDGSSRYYADSVKG VI. . SYDGSNKYYADSVKG VI. i sydgshkYyabevkg vY; ..sYdgsrkyy & osvkG VI .. SYDGSHKYYADSVKG VI..SYDGSHKYYADS.VKG VI., MYD6SΜKYYADSVKG VI..SYDGSHKYYADSVKG El, .RYDGSHKYYXDSVKG VI. . SYDGSHKYYÁDSVKG VI. . MY DG S Η KY YA DS V KG VI..HYDGSHKYYADSVKG vi .. syd'gsnryyxosvkG VI, .sYDGSHKYYADSVKG VI. . HYDGSHK.YY-AbS AKC YI..SSSSSTIYYADSVKG

51 .. 55555YIYYADSVKC

51 ... .5555YIYYÁBSVRG

51 .. 55555YIYYADSVKG YI..SSSSSTIYYADSVKG AIG ... TGGDTYYADSVMG RI..HSDGSSTSYADSVKG RI,, HSDGSSTSYADS VRG 'ΗΓ. . KQDGSBKYYVDSVKG RI. .HSDGSSTSYADSMKG MI, .KODGSBKYYVBSVKe FI..RYDOSMKYYADSVKG

RFTISRDHSKKTLYLQMHSLRLRARLCITVRE

RFTISRDHskHTLYtQMHSLKAÉD'TAVTYCAR

RETI S RDHSRHTLYLQMH S LRABDTAVYYC AR

RFTXSRDBSKHTLYLQMHSLRABDTAVYYCAR

RFTISRDMSKHTLY¿QKH3LRÁJBDTAVYYCAR

RETISRDNSKHRLYLQMHSLRAEDTAVYYCAR

RFTISRDNSKHTLYLOHHSLRABDTAVYYCAR

RFTISRDNSXHTLYLQHHSIRAEDTAVYYCAR rftisróHskhtlylqmkslrAegtavyycar

RETTSRDHSKHTLYLQMHSLRABDTAVYYCAK rftisrdhskhtlylqmhslraedtavYYcAk

R FTIS RD HS KH TL Y LQMM SL RABOTAVYYCA R

RFTISRDBSkHT.LYLQMHSLRÁBDtKVYYCAK

R ET IS RDHS KH TL Y LQMH S tRAED TAVRKretisrdnskhtlylqmhslrabdtavyycar

RETXSReNSTHTt.rLQHSSX.RAB »TAVYYcXR RFT.ISRDHAkHSLYLQMHSlRDEDTAVYYCAR: RFTISMDHAkHSLYLQMHSÍRAEDTÁVYYCAR RFTISROBAKHSLYLQMHSLRAEDTAVYYCAR RFTISROBAXHSLYLQMHSIRABDTAVYYCAR & FTÍ.SRI> H '<ÍÍ ¥ ÉYBOá'as £ IXb' tAtÍYCAR 'retisrpnAkkslylqmhsliaedmavyycar RFTXSRDBAKHTLYLQMNSLRAEDtAVYYCAR RFTISRDNAKHTLYLQMHSLRAEDTAVYYCAR RFTISRDHAKHSLYLQHBSLRAEDTAVYYCAR QFTISRDBAKHTL YLQMHSLRAEDMAVYYCTR RETISRCNAKHSLYLQHHSLRAEDTAVYYCAR RPTI3RDNSKHTLXLQMK8LRA1DTAVIYCTT or

CN m

CN

Table 1 (cont.) Line Family Amino Acid Sequences

Germinal VH3

Numbering according to Kabat í ÍJoe 9 VL including Dara comoaración

CDR you

CDR; I¡2

V ........ CDR ,,

274

SEC. ID 'NO:

gen

You ~ 57Γ

PHEW

ΤΤΓ

TtF íd le i · li

1 «vi» --------. SStátSSÍ'SStfSS 'ϊΧΧϊΧί.ΧϊϊΧΧΒ-ίϊ .SSSSSSSSStDÍSÍ! SSSSXSS. SXS8SSS2SÍ5SSSSSSÍSX3SÍS: X5S5SSS .SXSSSiSÍS iDPSS. QSTOTORBSyStoFCQkVriSC SGSSSHIGNBY.VS "YOQiPGTAPKtLIY DHHKRPS δΙΡ £ 30ίεβ51? 8βΤ5ΑΤ1βίΤ6ί.βΤ0ΒΕΑΒνΚ GTHDSSlSA PPM · QSVLTQP? SV3AAP6QKVTÍSC SGSSSDMGHYA.VS HYQOEPGT ^ Kilij 'BHHKR.PS GÍPDRPSCSKSGTSAT1C1TGÍHPEDEADVYC tiAKPTSPSA SPL2 QSVX.TQPPSASGTPGQRVTISG SGSSSKIGSÍiT. VK HYQQLPGlÁPKI, iiy SHNQRPS GVPDRFSGSKSGTSASLAISGWSEDEADYYC AAWDDSmG DPL3 QSVLTGPPSASSTPGORVT1SC SGSSSHIGSHY.VY KYQQLPGTAPKLLIY RHHQRPS SVPD & FS6SKSGTSAS1AXSGX.RSÉDIABYÍC AAHDPSLSG DPU OSVITOPPSVSEAPRORVTISC SGSSSNIGHH.AVH WYQQEPGKAPKEEIY YDDtlPS GVSORFSGSKSGTSASLAISGIQSEDEADYYC AAHDDSiNG PPt.9 ¿Ο871ΤΟΡ:Ρ3ν8ΰΑΡΰάκνΤΧ5ΰ TGSSSNIGAGYVVH KYQQLPGTXPKHÍIY GHSHRPS GVPDQFSGSKSGTSASLAITGDQSEDEADYYC KAWDHSEHA DPL8 QSVVTQPPSVSGAPGQRVTISC TGSSSHÍGAGYDVH KYQOLPGTXPKLLIY GNSHRPS GVPDRFSGSKSGTSASLAITGLQAEDEADYYCGSYDSSISG JO "VD grV2TQPP8V3g2PgQRVTISC SGGRSHieSHT. VK WYQCEPGÍAPKLLIY CBDQRPS CVPDRFSGSKSGTSABLAIICyOAXOAADXYC ΟΒΧΒΜΑΑβ 'Williams, JMB, 1996, 264, 220-232 a

OR

ΓΊ

U-) fN

<td></td><td></td><td></td><td colspan="2">Table 2</td><td></td><td></td><td></td><td></td>

<td>Clone</td><td>H3SEC ID NO:</td><td>H3</td><td>L3 SEC ID NO .:</td><td>L3.</td><td>koff</td><td>RB IC50 (M) Assay.</td><td>PHA IC50 (M) test.</td><td>IFN gamma IC50 (M)</td>

<td>Joé9: wt</td><td> 77'</td><td>sgsydy</td><td> 110</td><td>QSYDSSLRGSRV</td><td>l.OOE-Ot</td><td>1.50E-06</td><td>liJOOE-O.6</td><td></td>

<td>Joe9 weight</td><td> 77</td><td>SGSYDY</td><td> 110</td><td>QSYDSSLRGSRV</td><td></td><td> •</td><td>5.00Er07</td><td></td>

<td>70-l</td><td> 78</td><td>.HGSHDN</td><td> 110</td><td>Joe9 wt</td><td>1.34 e-2</td><td></td><td>2.00E-07</td><td></td>

<td>70-1 IgGl</td><td> 78</td><td>HGSHDN</td><td> 110</td><td>Joe9 wt</td><td></td><td></td><td>2.00E-07:</td><td></td>

<td> 70-2</td><td> 79</td><td>HGSYDY</td><td>1Í0</td><td>Joe9 wt</td><td> 3.308-02</td><td></td><td>3-5.0E-7</td><td></td>

<td> 70-7</td><td> .80</td><td>RRRSNY</td><td>mess.</td><td>Joe9 wt</td><td> 1.292-01</td><td></td><td>3-5.0E-7</td><td></td>

<td> . 70-13</td><td> 81</td><td>SGSIDY</td><td>mess:</td><td>Joe9 wt</td><td>'7.20E-02</td><td></td><td>3-5.0E-7. *</td><td></td>

<td> 78-34</td><td> 77</td><td>wt</td><td> 111 .</td><td>QSYDRGFTGSRV</td><td>1.6.4 er 2</td><td>2.00E-07</td><td>6. OOE-07</td><td></td>

<td> > 78-25</td><td> 77</td><td>wt</td><td> 112</td><td>QSYDSSLRGSRV</td><td> 5.008-02</td><td></td><td></td><td></td>

<td> : 78-28</td><td> 77</td><td>wt</td><td> 11-2: '</td><td>QSYDSSLRGSRV</td><td>4.66E-02 '</td><td></td><td></td><td></td>

<td> 78-35</td><td> 77</td><td>wt</td><td> 113</td><td>QSYDSSLTGSRV</td><td>4.99Ε-Ό2, ·</td><td>'4.00E-07</td><td></td><td></td>

<td> 79-1</td><td> 77</td><td>wt</td><td> 114</td><td>. QSYDSSLRGSRV</td><td></td><td>2.OOE-07</td><td>6.00E-07</td><td> *</td>

<td> 136-9</td><td> 8.2</td><td>HGSHDD</td><td> 115</td><td>QTYDISESGSRV</td><td> 3,208-03</td><td></td><td></td><td></td>

<td> 136-10</td><td> 62</td><td>HGSHDD</td><td> 116</td><td>QSYDRGFTGSRV</td><td>1.40E-03</td><td> 2>008-09.</td><td></td><td></td>

<td> 136-14</td><td> 83</td><td>HGSHDN</td><td> 117</td><td>QTYPRGFTGSRV</td><td>i.lOE-03</td><td>3.00E-10</td><td> 1.008-07'</td><td></td>

<td> 136-15</td><td> 83</td><td>HGSHDN</td><td> 1,18</td><td>QTYDKGFTGSSV</td><td>7.4 e-4.</td><td> 1.008-10</td><td>2.00E-09</td><td></td>

<td>qerminal line</td><td> 83</td><td>HGSHDN</td><td>lie</td><td>QTYDXGFTGSSV</td><td>4.60E-04</td><td></td><td>6.00E-09</td><td> •</td>

<td> 136-16</td><td> 83</td><td>HGSHDN,</td><td> 119 .</td><td>QSYDRRFTGSRV</td><td>6.1.0E-04</td><td>3.00E-10</td><td>5.00E-09</td><td></td>

<td> 136-17</td><td> 83</td><td>HGSHDN</td><td> 120</td><td>'QSYDWNFTGSRV</td><td>2.90E-05</td><td>2.00E-09</td><td>7.00E-09</td><td></td>

<td> 136-18</td><td> 83</td><td>HGSHDN</td><td> 121</td><td>QSYDRGFTGSRV</td><td> 1.102-03;</td><td> .8,008-10</td><td></td><td></td>

<td> 136-21</td><td> 83</td><td>HGSHDN</td><td> .122.</td><td>QSYDNGFTGSRV</td><td>4.20B-04;</td><td>2.00E-09</td><td></td><td></td>

<td> 136-24</td><td> 83</td><td>HGSHDN. '. ·</td><td> 123</td><td>QSYDNAVTASKV</td><td> 8.908-04</td><td>1.0OE-09</td><td></td><td></td>

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<td colspan="9">Table 2</td>

<td>Clone</td><td>: SEC3 SEC ID NO:</td><td>Ή3</td><td>L3 SEQ ID NO:</td><td> 13</td><td>4 koff ..</td><td>RB IC50 <M test)</td><td>PHA 'IC50 (M) test</td><td>IFN gamma (IC50 (M)</td>

<td>136-15Μ1</td><td> 85</td><td>ΆΚ ..........</td><td> 124</td><td>QSYDRGFTGSRV</td><td></td><td>4.00E-10</td><td></td><td></td>

<td> 149-5</td><td> 87</td><td>.. .... ... T .....</td><td> 125</td><td>QSYDSSLWGTRV</td><td>1.02x10-3</td><td>1.2X10-10</td><td>3.00E-09 '</td><td></td>

<td> 149-12</td><td> 84</td><td>• to ".··-"" . · - i · -.</td><td></td><td></td><td>3.73x10-3</td><td colspan="2">neutralizing</td><td></td>

<td></td><td> 92</td><td>XI HGSHBÜ</td><td> 124</td><td>flSYDRGFTCSSZ</td><td></td><td></td><td></td><td></td>

ΓΊ

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277

<td colspan="9">Table 2</td>

<td>Clone</td><td>H3SEC IQ ΜΠ</td><td>H3</td><td>L3 SEQ ID NO:</td><td>L3</td><td>koff</td><td>RB IC50 (M) test</td><td>PHA IC50 (M) test</td><td>IFN gamma IC50 (M)</td>

<td> •</td><td> 92</td><td>II BeSMOH</td><td> 124 '</td><td>QSTORGPTGSRX</td><td></td><td></td><td></td><td></td>

<td> 103-14 & 9</td><td> 100</td><td>KT HGSHDN</td><td> 132</td><td>QSYDRGFTGSMV</td><td>6.7 e-, 4 ,.</td><td>4.00E-11</td><td>1.20E-09</td><td></td>

<td>103-8 i 2</td><td> 100</td><td>KT HGSHDN</td><td> 133</td><td>QTYDKGFTGSSV</td><td>'5.3 e-4'</td><td></td><td>1.50E-09</td><td></td>

<td> 103-4</td><td> 101</td><td>TT HGSHDN</td><td> ' 134</td><td>QSYDRGíTGARV</td><td>1.6 e-4</td><td>8.60E-11</td><td>9.00Ε-1Ό</td><td></td>

<td> 103-152</td><td> 101</td><td>TT HGSHDN</td><td> 135</td><td>QSYERGíTGARV</td><td></td><td>8.60E-11</td><td></td><td></td>

<td></td><td> 102</td><td>H SGSYBX</td><td> 136.</td><td></td><td></td><td></td><td></td><td></td>

<td> 170-4</td><td> 102</td><td> , >*;. .</td><td> 140</td><td>.... ..already.·..</td><td>8.11E-04</td><td></td><td></td><td></td>

<td> 170-36</td><td> 83</td><td>HGSHDN</td><td> 152</td><td>QSYDRDSTGSRVF</td><td>4.00E-04</td><td>2.00Ε-1Ό</td><td></td><td></td>

<td> 170-25</td><td> 106</td><td>RGSQDT</td><td> 153</td><td>QSYDSSLRGSRVF</td><td>5.00E-04</td><td>5. OOE ^ II</td><td></td><td></td>

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278

<td></td><td></td><td></td><td colspan="2">Table 2</td><td></td><td></td><td></td><td></td>

<td>Clone</td><td>H3 SEC ID NO:</td><td>. Ή3</td><td>L3 SEQ ID NO:</td><td>L3</td><td>koff</td><td>RB IC50 (M) Assay. .</td><td>PHA IC50 (M) test ....</td><td>IFN gamma IC50 (M)</td>

<td></td><td> 106</td><td>SGSYDY</td><td> 136</td><td>QSYÜKGFJgSRgF</td><td></td><td></td><td></td><td></td>

<td>73-B1</td><td> 107.....</td><td>SGSYDY</td><td> 154</td><td></td><td>3.25E-03</td><td>> lE-8</td><td>4</td><td></td>

<td>73-B2</td><td>, io7;</td><td>SGSYDY</td><td> 155'</td><td>H.SES ........</td><td>2.07S-03.</td><td></td><td></td><td></td>

<td>73-B6</td><td> 107</td><td>; SGSYDY</td><td> 156</td><td>H ... NR ----------</td><td>2.51S-03</td><td>> lE-8</td><td></td><td>V -</td>

<td>73-C1</td><td> 107 “</td><td>SSSYDY</td><td> 157</td><td>H ... SR .......</td><td>2.71S-03</td><td>'> lE-8</td><td></td><td></td>

<td>73-C2</td><td> '107</td><td>SGSYDY</td><td> 158</td><td>....I KNOW....... 1</td><td> 3.792-03.</td><td></td><td></td><td></td>

<td>73-C6</td><td> 107</td><td>, SGSYDY '</td><td> 159 ,</td><td>. ... T ..........</td><td>3.96S-03</td><td></td><td></td><td></td>

<td> ' 73-01</td><td>107 I '</td><td>, SGSYDY</td><td> 160</td><td>H ... S ........</td><td>3.99S-03</td><td></td><td></td><td></td>

<td> 73-02</td><td> ; 107</td><td>, SGSYDY</td><td> 161</td><td>, .γ., Τ .-----</td><td>3.56E-03</td><td></td><td></td><td></td>

<td> 73-04</td><td> 107 '</td><td>SSSYDY.</td><td> 162</td><td>HiTK .......</td><td> 5.363-03</td><td></td><td></td><td></td>

<td> 73-05</td><td> 107 '</td><td>SSSYDY</td><td> 163</td><td>HSS</td><td> 3.572^-03,</td><td></td><td></td><td></td>

<td>73-E3</td><td> 107 'T</td><td>... SGSYDY</td><td> 164</td><td>• · - · «SD · · *» · · »·</td><td> 4.982-03</td><td></td><td></td><td></td>

<td>73-E6</td><td> 107 ’</td><td>SGSYDY</td><td> 165</td><td>H..ES ..</td><td> 4.172-03</td><td></td><td></td><td></td>

<td>73-F3</td><td> 107 '</td><td>SGSYDY</td><td> 166</td><td>. .i.APWS .....</td><td>7.08E-03</td><td></td><td></td><td></td>

<td>73-F5</td><td> 107 '</td><td>SSSYDY</td><td> 167</td><td>... DSD .... K ..</td><td>3.74S-03</td><td></td><td></td><td></td>

<td>73-G2</td><td> . 107' '</td><td>SGSYDY</td><td> 168 </td><td>HTN.S ........</td><td>3.98S-03</td><td></td><td></td><td></td>

<td>73-G3</td><td> 107</td><td>SGSYDY</td><td> 169 .</td><td>H ... TR .--------</td><td>3.50E-03</td><td></td><td></td><td></td>

<td>73-G4</td><td> 107</td><td>SGSYDY</td><td> 170</td><td>.... MR .......</td><td>6.58B-03</td><td></td><td></td><td></td>

<td>73-G5</td><td> 107 '</td><td>SGSYDY</td><td> .171 ;</td><td>HSSDS ......</td><td>6.01E-03</td><td></td><td></td><td></td>

<td>73-G6</td><td> 107</td><td>SGSYDY</td><td> 172:</td><td>4. .NTD ... · .-. .</td><td>6.30Ε-Ό3</td><td></td><td></td><td></td>

<td>73-H2</td><td> 107 ’</td><td>SGSYDY</td><td> 173</td><td> ♦ ««· ·,* · < ♦ »·</td><td>.5.93E-03</td><td></td><td></td><td></td>

<td>73-F6</td><td> .107 '</td><td>SGSYDY</td><td> 174</td><td>H ... M ........</td><td>5.87E-03</td><td></td><td></td><td></td>

<td>73-B3</td><td> 107</td><td>SGSYDY</td><td> 175</td><td>Η ... N .---------</td><td>6.85E-03</td><td></td><td></td><td></td>

<td>73-C5</td><td> 107 '</td><td>SGSYDY</td><td> 176</td><td>HH .D ........</td><td>4.84Ε-03</td><td></td><td></td><td></td>

<td>73-B7</td><td> 108 .</td><td>HGSQDN</td><td> 177.</td><td>QSYDSSLRGSRV</td><td>2.50E-03</td><td>7.00E-09</td><td></td><td></td>

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<td colspan="9">Table 2 '. .</td>

<td>Clone · :. S . .</td><td>H3 SEC ID NO:</td><td> 83</td><td>L3 SEQ ID NO:</td><td> 13</td><td>. kof f</td><td>RB IC50 (M) Assay. .</td><td>PHA IC50 (M) test</td><td>IFN gamma IC50 (M)</td>

<td>M2 A2</td><td> 83 </td><td>BGSHDN</td><td> 178</td><td>...... IB.</td><td>4.Q0E-02</td><td></td><td></td><td></td>

<td>M2 A4</td><td>S3</td><td>HGSHDN</td><td> 179</td><td>.., .. s ..? -;</td><td>8.49E-03</td><td></td><td></td><td></td>

<td>M2 A5</td><td> 83</td><td>HGSHDN</td><td> 180</td><td>x. s **. *: * * -.</td><td>4.01E-02</td><td></td><td></td><td> '</td>

<td>H2 B1</td><td> 83</td><td>BGSHDN</td><td> ; 181.</td><td>... ..SL .....</td><td>7..97E-03</td><td></td><td></td><td></td>

<td>• M2 B3</td><td> 83 ’ </td><td>HGSHDN</td><td> 182</td><td>.... IM .....</td><td>4.60E-02</td><td></td><td></td><td></td>

<td>M2 84</td><td> 83</td><td>. HGSHDN</td><td> 183</td><td> ... .1.1......</td><td>4.42E-02</td><td></td><td></td><td></td>

<td>H2 B5</td><td> 83</td><td>HGSHDN</td><td> 184</td><td>... ..SV .....</td><td>8.38Ε-03</td><td></td><td></td><td></td>

<td>M2 B6</td><td> . 83 ·</td><td>HGSHDN</td><td> 185</td><td>......THE</td><td>2.81E-02</td><td></td><td></td><td></td>

<td>M2 C2</td><td> 83</td><td>HGSHDN:</td><td> 181</td><td>.... SL .....</td><td>4, B5E-02</td><td></td><td></td><td></td>

<td>M2 C3</td><td> .83</td><td>; HGSHDN:</td><td> 186</td><td> ,,..1.1..,...</td><td>4.52E-02,</td><td></td><td></td><td></td>

<td>M2 C4</td><td> 83</td><td>HGSHDN</td><td> 181</td><td>.... SL .-------</td><td>8.16E-03</td><td></td><td></td><td></td>

<td>M2 C5</td><td> 83 .</td><td>HGSHDN</td><td> 187</td><td>.... TAI ... ·· :.</td><td>4.71E-Q2</td><td></td><td></td><td></td>

<td>H2 DI</td><td> 83</td><td>HGSHDN</td><td> 188</td><td>....GO.......</td><td>3.7IE-O2</td><td></td><td></td><td></td>

<td>M2 D2</td><td> 83</td><td>HGSHDN</td><td> 189</td><td>, ... IRS .. ,, ./.</td><td>3.85E-02</td><td></td><td></td><td></td>

<td>M2D3</td><td> 83</td><td>HGSHDN</td><td> 190</td><td>.... NRL ......</td><td>3.33E-02</td><td></td><td></td><td></td>

<td>M2 D4</td><td> 83</td><td>HGSHDN</td><td> 191</td><td>. . .ETS. ; ·. . . . .</td><td>5.31E-02</td><td></td><td></td><td></td>

<td>M2D5</td><td> 83</td><td>HGSHDN</td><td> 192</td><td>.... SSS ......</td><td>5.18E-02</td><td></td><td></td><td></td>

<td>M2 D6</td><td> 83</td><td>HGSHDN</td><td> 193</td><td>.... S ... A ....</td><td>5.31E-O2</td><td></td><td></td><td></td>

<td>M2 The</td><td> 83</td><td>HGSHDN</td><td> 194</td><td>., T. .K ... s, ..</td><td>.5.32E-O2</td><td></td><td></td><td></td>

<td>M2 Έ2</td><td> 83</td><td>, HGSHDN</td><td> 195</td><td>.... N ........</td><td>4.77E-02</td><td></td><td></td><td></td>

<td>M2 E6</td><td> 83</td><td>HGSHDN</td><td> 196</td><td></td><td>9.77E-03</td><td></td><td></td><td></td>

<td>M2 F1</td><td> 83/</td><td>.HGSHDN</td><td> ' 197</td><td>.... SDV, ...,.</td><td>6.16E-02</td><td></td><td></td><td></td>

<td>»2 K5</td><td> 83</td><td>HGSHDN</td><td> 198</td><td>....TO.........</td><td>9.90E-03</td><td></td><td></td><td></td>

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280

<td colspan="9">Table 2</td>

<td>Clone</td><td>H3 SEC ID NO:</td><td>ΗΪ</td><td>L3 SEQ ID NO:</td><td>, L3</td><td>koff</td><td>RB IC50 (M) test</td><td>PHA IC50 (M) test. „.</td><td>IFN gamma IC50 (M)</td>

<td></td><td></td><td></td><td> 124</td><td>OSYDRGETG8RV</td><td></td><td></td><td></td><td></td>

<td>TO 5</td><td> 83</td><td>HGSHDN</td><td> 199</td><td>....... THPSML</td><td>1.12E-O3</td><td></td><td></td><td></td>

<td>A12</td><td> 83</td><td>HGSHDN</td><td> 200</td><td>...... TTPRPM</td><td>1.43E-03</td><td></td><td></td><td></td>

<td> A4</td><td> 83</td><td>HGSHDN</td><td> 201</td><td>,. ., · ... RNPALT</td><td>X. 478-03</td><td></td><td></td><td></td>

<td>A6</td><td> 83</td><td>HGSHDN</td><td> 202</td><td>THPWLR</td><td>1.87E-03</td><td></td><td></td><td></td>

<td>A10</td><td> 83. '</td><td>HGSHDN</td><td> 203</td><td>...... NSPATV</td><td>X. 8.78-03:</td><td></td><td></td><td></td>

<td>All</td><td> 83</td><td>HGSHDN</td><td> 204</td><td>. ...... TFPSPQ</td><td> 2.078-03</td><td></td><td></td><td></td>

<td>C2</td><td> .83 .</td><td>HGSHDN</td><td> 205</td><td>.... ..LNPSAT</td><td> ?.238-03.</td><td></td><td></td><td></td>

<td>A8</td><td> 83</td><td>.HGSHDN</td><td> 206</td><td>...... KSNKML</td><td>2.37E-03</td><td></td><td></td><td></td>

<td>B8</td><td> 83</td><td>HGSHDN</td><td> 207</td><td>....... HTAHLY</td><td> 2.408-03</td><td></td><td></td><td></td>

<td>C6</td><td> 83</td><td>HGSHDN</td><td> 208</td><td>....... QTPSIT</td><td> 2 .:428-.03.,</td><td></td><td></td><td></td>

<td>A3</td><td> 83</td><td>HGSBDN</td><td> 209</td><td>....... YPRNIL</td><td>2.51E-03</td><td></td><td></td><td></td>

<td>Sil</td><td> 83 -</td><td>HGSHDN</td><td> 210</td><td>...... ITPGLA</td><td>2.95E-03</td><td></td><td></td><td></td>

<td>H.H</td><td> 83</td><td>HGSBDN</td><td> 211</td><td>...... QPHAVL</td><td>3.04E-03</td><td></td><td></td><td></td>

<td>CIO</td><td> 83</td><td>HGSHDN</td><td> 212:</td><td>.. ...... NSPIPT</td><td>3.10E-03</td><td></td><td></td><td></td>

<td>C4</td><td> 83.</td><td>HGSHDN</td><td> 213</td><td>...... TPNNSF</td><td> 3,232-03</td><td></td><td></td><td></td>

<td>C3.</td><td> 83;</td><td>HGSHDN</td><td> 214</td><td>.... S.VDPGPY</td><td>3 '.. 34B-O3</td><td></td><td></td><td></td>

<td>B2</td><td> 83 '</td><td>HGSHDN</td><td> 215</td><td>RPRHAL</td><td>3.61E-03</td><td></td><td></td><td></td>

<td>A2</td><td> 83 ;</td><td>HGSHDN</td><td> 21«</td><td>...... PYHPIR</td><td>3.80E-03</td><td></td><td></td><td></td>

<td>C5</td><td> . 83</td><td>HGSHDN</td><td> .217</td><td>....... PHTQPT</td><td>3.91E-03</td><td></td><td></td><td> *</td>

<td>A7</td><td> 83- '</td><td>HGSHDN</td><td> 218</td><td>...... HNNFSP</td><td> 3 , :958-03.</td><td></td><td></td><td></td>

<td>C9</td><td> 83;</td><td>HGSHDN</td><td> 219</td><td>. . . ... .PTHLPH</td><td> 3.978-03</td><td></td><td></td><td></td>

<td>B3</td><td> 83</td><td>'HGSHDN</td><td> . 220</td><td>..TPSYPT</td><td>4.12B-03</td><td></td><td></td><td></td>

<td>EC</td><td> 83</td><td>HGSHDN</td><td> 221</td><td>... ..S.TSNLLP</td><td> 9,358-03</td><td></td><td></td><td></td>

<td>B7</td><td> 83 ”</td><td>HGSHDN</td><td> 222</td><td>... f .. .. DSNHDh</td><td>5.45B-O3</td><td></td><td></td><td></td>

<td>To the</td><td> 83 '</td><td>HGSHDN</td><td> 223</td><td>...... LPRLTH</td><td>5.66E- 03</td><td></td><td></td><td></td>

<td>C7</td><td> .83 '</td><td>HGSHDN</td><td> 224.</td><td>...... IPTSYL</td><td>5.83E-03</td><td></td><td></td><td></td>

<td>; ci2</td><td> 83 .</td><td>HGSHDN</td><td> 225</td><td>...... LRVQAP</td><td>5.85E-03</td><td></td><td></td><td></td>

<td>B10</td><td> 83</td><td>HGSHDN</td><td> 226</td><td>...... LSDSPL</td><td>S.048-03</td><td></td><td></td><td></td>

<td>I know</td><td> 83</td><td>HGSHDN</td><td> 227</td><td>.... S.SLRRIL</td><td>7.58E-03</td><td></td><td></td><td></td>

<td>...... A9</td><td> 83</td><td>HGSHDN</td><td> 228</td><td>PARTSP</td><td>7.98E-03</td><td></td><td></td><td></td>

<td>B9</td><td> 83</td><td>HGSHDN</td><td> 229</td><td>..RAAHPQ</td><td>6.6SE-03</td><td></td><td></td><td></td>

O (N ι / Ί

CS v * »o

l / Ί

<td colspan="9">Table 2</td>

<td>Clone</td><td>H3 SEC ID NO:</td><td>H3</td><td>L3 SEQ ID NO:</td><td>L3</td><td>koif</td><td>RB IC50 (M) test</td><td>PHA IC50 (M) test</td><td>IFN gamma IC50 (M)</td>

<td></td><td></td><td></td><td> 124</td><td>QSXDRGPTGSSZ</td><td></td><td></td><td></td><td></td>

<td>177-D7</td><td> . 83</td><td>HGSHDN</td><td> 230</td><td>...... TQPABI</td><td>4.07E ^ -04</td><td></td><td></td><td></td>

<td>177-G6</td><td> 83</td><td>HGSHDN</td><td> 231</td><td>. . . .THPTMI.</td><td>5.50E-04</td><td></td><td></td><td></td>

<td> 177-09</td><td> 83</td><td>HGSHDN</td><td> 232</td><td>...... RIPABT</td><td>6.32E-04</td><td></td><td> *</td><td></td>

<td>177-C6</td><td> 83 '</td><td>HGSHDN</td><td> • .233</td><td>. · ...... THPVPA</td><td>7.94E-04</td><td></td><td></td><td></td>

<td>I77-H5</td><td> 83</td><td>HGSHDN</td><td> 234</td><td>..SBPIPA</td><td>I.32E-03</td><td></td><td></td><td></td>

<td> 177-89</td><td> 83</td><td>HGSHDN</td><td> 235</td><td>,. .THPVPA</td><td>1.58E-03</td><td></td><td></td><td></td>

<td>177-H10</td><td> 83</td><td>HGSHDN</td><td> 236</td><td>., i THPTMY</td><td>3.44E-03</td><td></td><td></td><td></td>

<td>144 — Fl</td><td> 83</td><td>HGSHDN</td><td> 237</td><td>., .... HHYTTF</td><td>5.80E-04</td><td></td><td></td><td></td>

<td>43-E3</td><td> 83</td><td>HGSHDN</td><td> 238</td><td> ... s... SHPAAE</td><td>8.00E-04</td><td></td><td></td><td></td>

<td>43-E9</td><td> 83</td><td>HGSHDN</td><td> 239</td><td>... ... .TIPSIE</td><td>S.OOErO ^</td><td></td><td></td><td> •</td>

<td>43-G2</td><td> 83</td><td>HGSHDN</td><td> 240</td><td>...... SSPAIM</td><td>7.00E-04</td><td></td><td></td><td></td>

<td>. 43-G3</td><td> 83</td><td>HGSHDN</td><td> 241</td><td>... IWPNLN</td><td>9.00E-04</td><td></td><td>s</td><td></td>

<td>31-A6</td><td> 83</td><td>HGSHDN</td><td> 242</td><td>... THPNLN</td><td>5.00E-04</td><td></td><td></td><td></td>

<td>31-B5</td><td> 83</td><td>HGSHDN</td><td> 243</td><td>...... THPSIS</td><td>5.00E-04</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 12.4.</td><td>fiSYDRGFTCSBS</td><td></td><td></td><td></td><td></td>

<td> Y17</td><td> 83</td><td>HGSHDN</td><td> 244</td><td>QSYDRGSAPMIN.</td><td>8.90E-05</td><td>4.50E-10</td><td>> lE-8</td><td></td>

<td>Y19</td><td> 83</td><td>HGSHDN</td><td> 245</td><td>QSYDRGHHPAMS</td><td>2.26E-04 '</td><td>3.00E-11</td><td>> lB-8</td><td></td>

<td>Y38</td><td> 83</td><td>HGSHDN</td><td> 246</td><td>.THPSIT</td><td>5.08E-04</td><td>f'5 '; 50E - 11</td><td>2.60E-09</td><td></td>

<td>Y45</td><td> 83</td><td>HGSHDN</td><td> 247</td><td>------- TDPAIV</td><td>6.17E-04</td><td>4.Ό0Ε-11</td><td>4.30E-09</td><td></td>

<td>Y61</td><td> 83</td><td>HGSHDN</td><td> 248</td><td>...... THPALL.</td><td>2.75 é-4 '</td><td>4E-11</td><td>1.40E-10</td><td></td>

<td>Y61 IgG</td><td> 83</td><td>HGSHDN</td><td> 248</td><td>..... THPALL</td><td>1.50E-04</td><td>1.60E-11</td><td>1.30E-10</td><td></td>

<td>Y61 IgG germline</td><td> 83</td><td>HGSHDN</td><td> 248</td><td>...... THPALL</td><td>1.50E-04</td><td>1.60E-11</td><td>1.30E-10</td><td>l¿60E-10</td>

<td>Y139</td><td> 83</td><td>HGSHDN</td><td> 249</td><td>.... ... SHPALT</td><td>5.92E-04.</td><td>3E-11.</td><td>4.50E-10</td><td></td>

<td>Y139 IgGl</td><td> 83</td><td>HGSHDN</td><td> 24 9</td><td>...... SHPALT</td><td></td><td></td><td>l.OOE-09</td><td></td>

<td>Y174</td><td> 83</td><td>HGSHDN</td><td> 250</td><td>. ... ... TTPAPE.</td><td>7.55E-O4</td><td>6E-11</td><td>2.OOE-09</td><td></td>

<td>Y17 7</td><td> 83</td><td>HGSHDN</td><td> 251</td><td>...... SHPTLI.</td><td>6.6ΪΕ-Ο4</td><td>5E-.11</td><td>1..00E-09</td><td></td>

<td>' TO 5</td><td> 83</td><td>HGSHDN</td><td> 252</td><td>.. ...... THPSML</td><td>4.50E-04</td><td>6.60E-11</td><td></td><td></td>

<td>A12</td><td> 83</td><td>HGSHDN</td><td> 253</td><td>...... TTPRPM</td><td>.5.57E-O4</td><td>2.SOS-10</td><td></td><td></td>

<td>D9.</td><td> 83</td><td>HGSHDN</td><td> 25.4.</td><td>...... RLPAQT</td><td>3.21E-04</td><td>3-5E-09</td><td> »</td><td></td>

<td>G6</td><td> 83</td><td>HGSHDN</td><td> 255</td><td>..... ... THPLTI</td><td>5.08E-04</td><td>1E-10</td><td>1.00E-09</td><td></td>

<td>G6 IgGl</td><td> 83</td><td>HGSHDN</td><td> 255</td><td>.... ... .THPLTI</td><td></td><td></td><td>1.00E-09</td><td></td>

<td>C6</td><td> 83</td><td>HGSHDN</td><td> 256</td><td>QSYDRGQTPSIT</td><td>1.07E-03</td><td>.3.5E-10</td><td>1.00E-08</td><td></td>

<td>Y5S</td><td> 83</td><td>HGSHDN ·</td><td> 257</td><td>QSYDRGTHFQMY</td><td>1.06E-O3</td><td>1.4.0E-TD</td><td>> 1E— 8</td><td></td>

OR

CM

ΜΊ

CM

ΙΖΊ

OR

Table 2

282

<td></td><td></td><td></td><td></td><td>Table 2</td><td></td><td></td><td></td><td></td>

<td>Clone</td><td>H3SEC ID NOl</td><td> 83</td><td>L3 SEQ ID NO:</td><td> 1/3</td><td>kof</td><td>RB IC50 (M) test</td><td>PHA IC50 (M) test.</td><td>IFN gamma IC50 (M)</td>

<td>A4</td><td> 83:</td><td>HGSHDN</td><td> 258</td><td>.QSYDRGRNPALT</td><td>6.30E-04</td><td>2.50E-10</td><td></td><td></td>

<td>A03</td><td> 83</td><td>HGSHDN.</td><td> 259</td><td>QSYDRGTHPLTM</td><td>• 3.04E-04</td><td>3.00E-11</td><td>4.00E-10</td><td></td>

<td>A03 IgGl</td><td> 83</td><td>HGSHDN</td><td> 260</td><td>QSYDRGTHPLTM</td><td>3.04 e-4</td><td>; 2.90E-11</td><td>3.80E-10 '</td><td></td>

<td>germline A03 IgG</td><td> 83</td><td>HGSHDN</td><td> 260</td><td>QSYDRGTHPLTM</td><td>2.50E-04</td><td>3.50E-11</td><td>1.75E-10</td><td></td>

<td>99-B11</td><td> 83</td><td>HGSHDN</td><td> 261</td><td>QSYDSGYTGSRV</td><td>5.40E-03</td><td></td><td></td><td></td>

<td>99-Cll</td><td> 83</td><td>HGSHDN ·</td><td> 262</td><td>qsypsgftgsrv</td><td>5.70E-03</td><td></td><td></td><td></td>

<td>99-H4</td><td> 83 '</td><td>HGSHDN</td><td> 263</td><td>QSYDSRFTGSRV</td><td>4.80E-03</td><td></td><td></td><td></td>

<td>99-E9</td><td> 83 . -7</td><td>HGSHDN</td><td> 262</td><td>QSYDSGFTGSRV</td><td>5.40E-03</td><td></td><td></td><td></td>

<td>99-H7</td><td> 83</td><td>HGSHDN</td><td> '264</td><td>QSYPDGTPASRV</td><td>3.30E-03,</td><td></td><td></td><td></td>

<td>99-H11</td><td> 83</td><td>HGSHDN</td><td> 265</td><td>QSYSTHMPISRV</td><td>4.90E-03</td><td></td><td></td><td></td>

<td>99-F6</td><td> 83 ;</td><td>.HGSHDN</td><td> 266</td><td>, QSYDSGSTGSRV</td><td>4.90E-03</td><td></td><td></td><td></td>

<td>99-F7</td><td> 83 ' '</td><td>HGSHDN</td><td> 267</td><td>QSYPNSYPISRV</td><td>4.80E-03</td><td></td><td></td><td></td>

<td>99-F8</td><td> 83</td><td>HGSHDN</td><td> 268</td><td>QSYIRAPQQV</td><td>3.70E-03;</td><td></td><td></td><td></td>

<td>99-F11</td><td> 83 '</td><td>HGSHDN</td><td> 262.</td><td>QSYDSGFTGSRV:</td><td>5.40E-03</td><td></td><td></td><td></td>

<td> 99-67</td><td> 83</td><td>HGSHDN</td><td> 269</td><td>QSYLKSRAFSRV</td><td>4.80E-03</td><td></td><td></td><td></td>

<td>99-Gll</td><td> 83 </td><td>HGSHDN</td><td> 270</td><td>QSYDSRFTGSRV</td><td>4.30E-03</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 124</td><td>OSYDRSFTGSKV</td><td></td><td></td><td></td><td></td>

<td>L3.3R3M-B1</td><td> 83 ;</td><td>HGSHDN</td><td> 271</td><td>...... FTGSMV</td><td>5.46E + 00</td><td></td><td></td><td></td>

<td>7 L3.3R3M-B3</td><td> 83</td><td>HGSHDN</td><td> 272</td><td>... ·> .FTGSMV</td><td>5.51E + 00</td><td></td><td></td><td></td>

<td>L3.3R3M-C6</td><td> 83 </td><td>HGSHDN</td><td> 273</td><td>...... FTGFDG</td><td>6.17E + 00</td><td></td><td></td><td></td>

<td>L3.3R3M-F9</td><td> 831</td><td>HGSHDN</td><td> 274</td><td>....... TftPALS</td><td>4.99E + OO</td><td></td><td></td><td></td>

<td>........ Í3.3R3M-G8:</td><td> 83</td><td>HGSHDN</td><td> 275</td><td>. · ..... SYPALR</td><td>5.5SE + 00</td><td></td><td></td><td></td>

<td>L3.3R3M-H6</td><td> 83 ?</td><td>. . HGSHDN</td><td> 276</td><td>...... NHPNSN</td><td>5.69E + Q0</td><td></td><td></td><td></td>

<td>L3.3R3M-H10</td><td> 83 '</td><td>HGSHDN</td><td> 277</td><td>...... .TAPSLL</td><td>5.35ΕΉΟΟ</td><td></td><td></td><td></td>

<td>L3.3R3M-A3</td><td> 83</td><td>HGSHDN</td><td> , 278</td><td>. . .... FTGSMV</td><td>) 5.37Ε + 0Ό</td><td></td><td></td><td></td>

<td>L3.3R3M-F8</td><td> 83</td><td>HGSHDN</td><td> 279</td><td>....... TTPRIR</td><td>'4 ..99E + OO</td><td></td><td></td><td></td>

<td>l3.3R3M-G1</td><td> 83</td><td>.HGSHDN</td><td> 280</td><td>FTGSMV</td><td>4.21E + OO</td><td></td><td></td><td></td>

<td>L3.3R3M-G7</td><td> 83</td><td>HGSHDN</td><td> 281</td><td>. ... FTGSMV</td><td>4.24E + OO</td><td></td><td></td><td></td>

<td>L3.3R3M-H11</td><td> 83</td><td>HGSHDN</td><td> 282</td><td>... ..... MIPALT</td><td>3.95E + 00</td><td></td><td></td><td></td>

a one

CN a

CN

<td colspan="9">Table 2</td>

<td>Clone</td><td>H3 SEC ID NO :,</td><td>H3.</td><td>L3 SEQ ID NO:</td><td>L3</td><td>koff</td><td>RB IC50 (M) Assay. .</td><td>PHA IC50 (M) test</td><td>IFN gamma IC50 (M)</td>

<td>Y61-L94N</td><td> 109</td><td>CKT HGSHDN</td><td> 283</td><td>QSY0RNTHPALL</td><td></td><td></td><td>8.00E-11</td><td></td>

<td>Y61-L94F</td><td> 109</td><td>CKT HGSHDN</td><td> 284</td><td>QSYDRFTHPALL</td><td></td><td></td><td>6.00E-11</td><td></td>

<td>Y61-L94Y</td><td> 109</td><td>Smell HGSHDN '</td><td> 285</td><td>QSYDRYTHPALL</td><td></td><td>2.00E-11.</td><td>2.00E-11</td><td></td>

<td>Y61-L94Y IgG</td><td> 109</td><td>CKT HGSHDN</td><td> 285</td><td>QSYDRYTHPALL</td><td>1.27E-04</td><td>6.00E-11</td><td>5 .OOE-ll? ·</td><td>4.OOE-11</td>

<td>Y61-L50Y</td><td> 109</td><td>CKT HGSHDN</td><td> 286</td><td>QSYDRGTHPALL</td><td></td><td>2. 00E-11</td><td></td><td>2.OOE-11</td>

<td>Y61-LS0Y * IgG</td><td>7 109-</td><td>CKT HGSHDN</td><td> 286</td><td>QSYDRGTHPALL</td><td>6.98E-05 '</td><td></td><td>2.OOE-11</td><td>3.00E-11</td>

<td>Y61-L50Y-H31E ** IgG</td><td> 109</td><td>CKT HGSHDN</td><td> 286</td><td>QSYDRGTHPALL</td><td>2.99E-05 '</td><td></td><td>6.00E-11</td><td>2.00E-11</td>

<td>Y61-L50Y-H31E- 1.94Y ** IgG</td><td> 109</td><td>CKT HGSHDN</td><td> 287</td><td>QSYDRYTHPALL</td><td>4.64É-05</td><td></td><td>1.OOE-11</td><td>1; OOE-11</td>

<td>J695 (Y61-L94Y- L50Y IgG *)</td><td>I09</td><td>CKT HGSHDN</td><td> 287</td><td>QSYDRYTHPALL</td><td>5.14E ^ 05 '</td><td>5.00E-11</td><td>1.OOE-11</td><td>5.00E-12</td>

OR

ΓΊ (N

O • η

284

<td colspan="6">Table 3</td>

<td rowspan="2">Kabat number</td><td>CDR H1</td><td colspan="3">CDR H2</td><td>CDR H3</td>

<td>Y61 VH</td><td>FTFS 3 YG Μ H</td><td colspan="3">FIRYDGSNKYYADSVKG</td><td>HGSHDN</td>

<td>Contact positions</td><td>£ £ £ £ X</td><td colspan="3">£ £ £ £ £ £ X</td><td>X. £ £ £ £</td>

<td>Hypermutation positions</td><td>SSK</td><td colspan="3">X £ £</td><td></td>

<td rowspan="2">Kabat number</td><td colspan="2">CDR L1</td><td>CDR L2</td><td colspan="2">; CDR L3</td>

<td>Y61 VL</td><td colspan="2">SGGRSNIGSN Γ VK</td><td>GNDQRPS</td><td colspan="2">QSYDRGT Η P AL L</td>

<td>Hypermutation positions</td><td colspan="2">& & £ X</td><td>£ x £ X</td><td colspan="2">X £ £ £ X</td>

<td>Hypermutation positions i</td><td colspan="2">X £ £</td><td> £</td><td colspan="2"> £</td>

<td colspan="6">x Contact positions and / or hypermutation x Contact positions v / o hiDermutation mutated in Y61</td>

Aa aa

285

Table 4. Neutralization Activity in the Presence of Free IL 12 p40 Excess

<td>SEQ ID NO:</td><td>• Clone</td><td>PHA Test IC50 (M) p70: p40 1: 0</td><td>PHA test IC50 (M) p70: p40 1:20</td><td>PHA IC50 (M) test p70: p40 1:50</td>

286

EXAMPLES

Example 1: Efficiency of the fully human IL-12 / IL-23 Monoclonal Antibody, ABT-874, in the Treatment of

Moderate to Severe Plaque Psoriasis

ABT-874 is a fully human antibody against interleukin-12 (IL-12) and IL-23. It binds with great affinity to the common p40 subunit for both IL-12 and IL-23, both validated targets in the treatment of psoriasis (Ps).

The objective of the following study was to evaluate the efficacy of subcutaneous injections of ABT-874 in the treatment of patients with moderate to severe plaque Ps.

Adult patients with a body surface area of> .10% (BSA) and a Psoriasis Area and Severity Index (PASI) count of> .12 were chosen for this study.

<td>I5</td><td>placebo controlled,</td><td>double-blind</td><td>in the week</td><td> 12</td><td>The</td>

<td></td><td>patients were assigned</td><td>by way of</td><td>random of</td><td> 1</td><td>to 6</td>

<td></td><td>ramifications: 1) 100 mg</td><td>by ABT-874</td><td colspan="2">every two weeks</td><td>(every</td>

two weeks) for 12 weeks; 2) a dose of 200 mg of ABT-874 at week 0; 3) 200 mg of ABT-874 every week for 4 weeks; 4) 200 mg of ABT-874 every two weeks for 12 weeks; 5) 200 mg of ABT-874 every week for 12 weeks; or 6) placebo. The primary end point was a response of> .PASI 75 at week 12. Other efficacy assessments included the Physician's Global Assessment (PGA) and

PASI 50. Patients who met the end point

287 Primary entered a repeat / blind treatment phase at week 36 and were monitored for time to loss of response.

A total of 180 patients participated in the study, 30 in each branch. The characteristics of the baseline were similar between ramifications and indicative of moderate to severe PS (all average values except% of the man): age, 46 years, man 74%; 21 years of duration of Ps; PASI 19; and 25% BSA affected. At week 12, the percentages of patients achieving> PASI 75 were statistically significantly higher for patients in each of the 5 ABT-874 branches versus placebo (93%, 63%, 90%, 93%, 90%, against 3%, respectively, p <0.001, ITT). Furthermore, the percentages of patients achieving> .PASI50 were statistically significantly higher for patients in each of the 5 ABT-874 branches versus placebo (100%, 77%, 97%, 97%, and 100%, vs. 17%, p <0.001). The average percentage decrease (improvement) in PASI at week 12 was 90%, 70%, 92%, 92%, and 90%, respectively, in the ABT-874 branches, and 26% for the placebo. Similarly, the percentages of patients with a PGA of Nonexistent / Minimum were 83%, 50%, 73%, 87%, and 87%, respectively, in the ABT-874 branches, and 3% for placebo.

In conclusion, ABT-874 was considerably more efficient than placebo in treating plaque psoriasis

288 moderate to severe.

Example 2: Safety and Efficacy of the fully human IL12 / -23 Monoclonal Antibody, ABT-874, in the Treatment of

Moderate to Severe Plaque Psoriasis

ABT-874 is a fully human antibody against interleukin 12 (IL-12) and IL-23. It binds with great affinity to the common p40 subunit in IL-12 and IL-23, validated targets in the treatment of psoriasis (PS). The objective of this Phase II study was to investigate the efficacy and safety of subcutaneous injections of ABT-874 in the treatment of PS in moderate to severe plaques.

Adults with Ps affecting> .10% of the body surface area (BSA) and a PASI count> 12 were chosen for this double-blind, placebo-controlled study at week 12.

Patients were randomized from 1 to 6 branches: 1) 100 mg ABT-874 every two weeks (eow) for 12 weeks; 2) a dose of 200 mg of ABT-874 at week 0; 3) 200 mg of ABT-874 every week for 4 weeks; 4) 200 mg of ABT-874 every two weeks for 12 weeks; 5) 200 mg of ABT-874 every week for 12 weeks; or 6) placebo. The primary end point was a ¡> PASI 75 response at week 12. Patients who met the primary endpoint entered a repeat / blind treatment phase at week 36 and were monitored for time to loss of response. All patients were evaluated by

289 security until week 54.

180 patients were enrolled in the study, 30 in each branch. The characteristics of the baseline were similar between ramifications and indicative of moderate to severe PS (all average values except% of the man): age, 46 years, man 74%; 21 years of duration of Ps; PASI = 19; and 25% BSA affected. At week 12, the% of patients with> _PASI 75 were statistically significantly higher in each of the 5 ABT-874 branches versus placebo (93%, 63%, 90%, 93%,

90%, against 3%, respectively, p <0.001, ITT). During the week

12, DB phase, infectious AEs for the ABT-874 groups had an interval of 23 - 43% and for the placebo group it was 23%, with the most common being nasopharyngitis (7-17% for ABT-874; 3 % for placebo). There are no statistically significant differences between the ramifications. No AEs of serious infections were reported, and no deaths occurred.

In conclusion, ABT-874 was significantly more effective than placebo in treating moderate to severe plaque Ps, and appears to have a favorable safety profile.

Example 3: Maintenance of the Response with the Completely Human IL-12 / -23 Monoclonal Antibody, ABT-874, in the

Treatment of Psoriasis in Moderate to Severe Plaques

The efficacy and safety of ABT-874 were evaluated in a 12-week, Phase II, randomized controlled trial and a follow-up phase at week 36. The objective of the following example was

290 To analyze the maintenance of the suspension of the follow-up of the therapy response during the second 12 weeks of this Phase II study of subcutaneous injections of ABT-874 in the treatment of moderate to severe plaque Ps.

Adults with Ps affecting> 10% of body surface area (BSA) and a PASI count> 12 were chosen for this double-blind, placebo-controlled study at week 12. Patients randomized from 1 of 6 branches :

1) 100-mg ABT-874 every two weeks (eow) for 12 weeks;

2) a dose of 200 mg of ABT-874 at week 0;

3) 200 mg of ABT-874 every week for 4 weeks;

4) 200 mg of ABT-874 every two weeks for 12 weeks;

5) 200 mg of ABT-874 every week for 12 weeks; or

6) placebo.

The primary endpoint was a ^ PASI 75 response at week 12. Patients who met the primary endpoint entered a repeated / blind treatment phase at week 36. Treatment with the study drug was continued, and the Patients were monitored for time to loss of response (a decrease in the PASI count, at any time during the week 36 follow-up period, <PASI 50). The maintenance of the PASI response was evaluated through week 24.

A total of 180 patients participated, 30 in each branch. The

291 Baseline characteristics were similar among the ramifications (average values presented except for the% of men): age, 46 years, man 74%; 21 years of duration of Ps; PASI = 19; and 25% BSA affected.

At week 12, the percentages of patients with & PASI 75 were statistically significantly higher in each of the 5 ABT-874 branches against placebo (Table 1). At week 24, the substantial percentages of PASI 75 responses in the ramifications of active treatments had maintained at least one PASI 50 response.

Table 1: Week 24 Efficiency of ABT-874

<td rowspan="2"></td><td rowspan="2">SPASÍ75 in week 12</td><td colspan="2">Maintenance of</td>

<td>the response of Week 24 Week 12</td><td>PSAI: against</td>

<td>100 mg every two weeks for 12 weeks</td><td> 28/30 (93%)*</td><td> 24/28 (86%)</td><td></td>

<td>200 mg each week for 4 weeks</td><td> 27/30 (90%)*</td><td> 23/27 (85%)</td><td></td>

<td>200 mg every two weeks for 12 weeks</td><td> 28/30 (93%)*</td><td> 26/28 (93%)</td><td></td>

292

<td></td><td>^ PASi75 in</td><td>Maintenance of</td>

<td></td><td>week</td><td>PSAI's response:</td>

<td></td><td> 12</td><td>Week 24 against</td>

<td>week during</td><td></td><td></td>

<td>12 weeks</td><td></td><td></td>

<td>Placebo</td><td> 1/30 (3%)</td><td> -</td>

* p <0.001 against placebo, NRI

In conclusion, ABT-874 was significantly more effective than placebo in treating moderate to severe plaque Ps. The substantial percentages of PASI responses

75 they maintained these responses at week 24, after discontinuation of active therapy.

Example 4: Safety and Efficacy of a fully human IL-12 / -23, ABT-874 Monoclonal Antibody in the Treatment of Moderate to Severe Chronic Plaque Psoriasis

The objective of the following example was to demonstrate the efficacy and safety of a dose range of a human monoclonal antibody IL-12/23 (ABT-874) compared to placebo in the treatment of patients with clinically moderate to severe chronic plaque psoriasis. stable.

I. Materials and Methods

293

A. Study design: The following study was a 12-week, double-blind, multi-center, phase II, placebo-controlled, randomized trial conducted at 24 centers in the United States (16 sites) and Canada (8 sites). ABT-874 (Abbott

Laboratories, Abbott Park, IL) is a human monoclonal antibody with complementary engineering determining regions that has high affinity for the IL-12/23 p40 subunit protein. Patients were randomly assigned in a 1: 1: 1: 1: 1: 1 ratio to receive 1 to 6 treatments: ABT-874 200 mg, 1 dose at week 0 (200 mg x 1); ABT-874 100 mg every two weeks (eow) for 12 weeks (100 mg eow); 200 mg ABT-874 weekly for the first 4 weeks (200 mg χ 4); 200 mg ABT-874 every other week for 12 weeks (200 mg eow); 200 mg of

ABT-874 weekly for 12 weeks (200 mg weekly); or placebo. After week 12, all patients who achieved at least a 75% reduction in psoriasis area index and severity response (PASI 75) continued in a blind observation / repeat treatment phase at week 36.

B. Patients: Patients were 18 years of age and had a clinical diagnosis of psoriasis of at least 6 months (determined by interview and confirmation of patient diagnoses through investigator examination), stable plaque psoriasis of at least 2 months before

294 recognition and at baseline visits as determined by subject interview, moderate to severe plaque psoriasis defined by S1O% of body surface area (BSA) involved at initial visit, PASI count £ 12 at initial visit , and an overall physician evaluation (PGA) of at least moderate disease at the baseline visit.

Patients were disqualified if they had previously been exposed to systemic or biological anti-IL-12 therapy; plaque-free psoriasis; inability to continue

Following IO therapies prior to initial visit: topical psoriasis therapies at least 2 weeks before, ultraviolet B light phototherapy at least 2 weeks, puva therapy-UV light phototherapy at least 4 weeks before, systemic therapies at least 4 weeks before, and biological therapies at least 12 weeks before; required absorption of oral or injectable corticosteroids during the study (inhaled corticosteroids were allowed for stable medical conditions); an asthma exacerbation requiring hospitalization 10 years before recognition; an infection or risk factors for severe infection; a history of malignancies except for successfully treated basic cell carcinoma (patients with a history of squamous cell carcinoma were excluded) or cervical carcinoma in situ; or a history of significant immune reaction (eg, serum sickness or anaphylactoid reaction) to an agent that

295 it contains immunoglobulin G (eg, intravenous gamma globulin, a fusion protein, or monoclonal antibody).

Patients were allowed to continue treatment with medicinal shampoos that contained no corticosteroids, (no beta or alpha-hydroxy acids) mild emollients, or Class VI or Vil low-potency topical corticosteroids on their palms, soles, face, inframammary area, and groin area during the course of the study. The application of these topical psoriasis therapies did not occur within 24 hours of the study visit. Vaccination with a live viral agent was not allowed within a period of 1 month before dosing with ABT-874, during the study, or for 1 month after the last dose of study drug was administered.

The occurrence of any of the following clinically significant abnormal laboratory results led to | immediate withdrawal of a patient from the study: aspartate transaminase or alanine transaminase> 5 times the upper limit of normal; total serum bilirubin> 3 times the upper limit of normal; serum creatinine> 3 times the upper limit of normal;

creatine phosphokinase> 5 times the upper limit of normal; hemoglobin <8 g / dl; white blood cell count <2 χ 109/ l; or platelet count <75 χ 109/ l.

C. Efficacy Assessments: The primary efficacy score was the percentage of patients achieving a PASI 75 response at week 12, defined at least

296 as a 75% reduction in the PASI count relative to the baseline count. PASI is a measure of the severity of psoriatic lesions (in terms of erythema, induration, and desquamation) and the degree of BSA involvement. The count of

PASI ranges from 0 (no psoriasis) to 72 (severe disease) (Fredriksson T, Pettersson U. Dermatológica 1978; 157: 238-44). Other measures of efficacy included the percentage of patients who achieved at least PASI 75 at weeks 1, 2, 4, and 8; the percentage of patients who achieved at least PASI 50 or PASI 90 in weeks 1, 2, 4, 8, and 12; and the percentage of patients who achieved a clear or minimal PGA at week 12 and at weeks 1, 2, 4, and 8. The PGA measures disease severity on a 6-point scale, ranging from 0 (no disease, or clear) to 5 (very severe) (Ko HS. Clinical trial design in psoriasis.

Presented at: 49th Meeting of the Advisory Committee

Dermatological and Ophthalmological; March 20, 1998; Bethesda, MD).

D. Safety Assessments: Adverse events, laboratory data, and vital signs were determined through the study. Patients were closely monitored for signs of infection, malignant tumor, and immune reaction. AEs produced by treatment were defined as events that occurred between week 0 and before 45 days after the last available result of the study drug dose or 1 day before the first dose of the study drug.

297 repeat treatment (for patients continuing in the trial at week 36).

E. Statistical Analysis: Sample size was calculated using nQuery Advisor® 4.0 (Statistical Solutions, Saugus,

MA). With the understanding that 15% of patients in the placebo group would achieve a PASI 75 response at week 12, the study designers determined that a sample size of 26 in each dose group would be adequate to detect at least a difference of 45% from a group treated using Fisher's exact test with 90% energy at a significant two-sided level 0.05. The study was designed to involve approximately 180 patients, with 30 patients in each group.

The intention to treat the population included all patients who were randomized at week 0 and received at least 1 Injection of study drug; This population was used for efficacy analyzes. All tests were performed at a = 0.05. Imputation without response was used for all efficacy analyzes; any patient with a lack of PASI or PGA count at any visit was considered unanswered at that visit. To determine the impact of the missing data, sensitivity analyzes of the 12 week data were completed using the last observation carried out by the method. The primary analysis of the PASI response

75 in week 12 it was done using the following order

298 Sequential to adjust multiplicity: 200 mg weekly against placebo, 200 mg every two weeks against placebo, 100 mg 100 every two weeks against placebo, 200 mg χ 4 against placebo, and 200 mg χ 1 against placebo. The difference in treatment between each ABT-874 treatment group and the placebo group for the change of the average percentage in the PASI count was determined using the analysis of variation, with the PASI baseline count and the treatment group. as factors. Safety analyzes were conducted using the safety population, which included all patients who received at least 1 injection of the study drug.

II Results

A. Patients: A total of 180 patients were randomly assigned from 1 to 6 treatment groups (Figure 1). Most patients (76.7% of placebo-treated patients and 98% of all patients in the ABT-874 treatment group) completed the 12th week portion of the study.

Patients were well balanced across treatment groups with respect to demographic characteristics and disease activity (Table 1). The patients were predominantly male (74.4%) and white (92.2%). The average BSA involvement was 25% and the average PASI count was 18.8.

B. Efficacy: The percentage of patients reaching the primary end point of the PASI 75 response in the week.

299 was statistically significantly higher (p <0.001) in all ABT-874 treatment groups (200 mg x 1: 63.3%, 19 of 30; 100 mg every other week: 93.3%, 28 of 30; 200 mg x 4: 90.0%, 27 of 30; 200 mg every two weeks: 93.3%, 28 of 30;

200 mg weekly: 90.0%, 27 of 30) compared to placebo (3.3%, 1 of 30). For the relatively short duration of this trial, the PASI 75 response in all ABT-874 treatment groups was similar except for the 200 mg x 1 treatment group (Figure 2).

A subgroup analysis by characteristics of baseline disease, (history of psoriatic arthritis, BSA count, and PASI) demographics (gender, age, race, and weight), and baseline therapy for psoriasis within 12 months of receiving study treatment (systematic biologic and nonbiologic, topical, and phototherapy) demonstrated that ABT-874 treated patients within several subgroups that consistently achieved high levels of PASI 75 response at week 12.

Almost 100% of the highest ABT-874 dosing groups achieved at least one PASI50 response during the week

12 (200 mg x 1: 76.7%, 23 of 30; 100 mg every other week:

100.0%, 30 out of 30; 200 mg x 4: 96.7%, 29 of 30; 200 mg every two weeks: 96.7%, 29 of 30; 200 mg weekly: 100.0%, 30 out of 30; placebo: 16.7%, 5 out of 30; p <0.001 for each placebo comparison). The percentage of patients achieving at least one PASI 90 response at week 12 was

300 Statistically significantly higher (p <0.001) in all but 1 (200 mg χ 1) of ABT-874 treatment groups compared to placebo, as follows: 200 mg x 1: 16.7%, 5 out of 30; 100 mg every two weeks: 53.3%, 16 of 30; 200 mg x 4:

63.3%, 19 out of 30; 200 mg every two weeks: 76.6%, 23 of 30;

200 mg weekly: 53.3%, 16 of 30; and placebo: 0%, 0 out of 30. In addition, by week 12, significantly more patients (p <0.001) in all ABT-874 treatment groups had achieved a clear or minimal PGA grade compared to io patients in the placebo group, as follows: 200 mg x 1: 50.0%, 15 of 30; 100 mg every two weeks: 83.3%, 25 of 30; 200 mg x 4: 73.3%, 22 of 30; 200 mg every two weeks: 86.7%, 26 of 30; 200 mg weekly: 86.7%, 26 of 30; against placebo:

3.3%, 1 out of 30.

The percentage of patients reaching the primary endpoint of the PASI100 response at week 12 was statistically significantly higher (p <0.001) in the following ABT-874 treatment groups (200 mg every other week: 46.7% , 14 of 30; 200 mg weekly: 36.7%, 11 of

3 0) compared to placebo (0%, 0 out of 30).

ABT-874's response was rapid. The average percentage improvement in baseline PASI counts increased over a certain period for all ABT-874 treatment groups (Figure 3) and was significantly greater for each ABT-874 treatment group compared to

301 Placebo at each point (p <0.001, except for the 100 mg group every two weeks at week 1, p = 0.023).

C. Safety: ABT-874 therapy was generally well tolerated (Table 2). One (0.7%) of patients treated with ABT5 874 discontinued the study due to localized skin discoloration; 2 (6.7%) of the placebo-treated patients discontinued the study, 1 for psoriatic arthropathy and 1 for ovarian cancer. Two (1.1%) of the patients experienced serious adverse effects (AEs); 1 patient treated with placebo was diagnosed with ovarian cancer on day 37, and 1 patient treated with ABT-874 (200 mg x 1) was diagnosed with costochondritis on day 10. No patient experienced myocardial or cerebral infarctions, and there were no deaths.

Patients who received any dose of ABT-874 were significantly more likely (p = 0.033) than patients who received placebo to experience an EA at least possibly related to the study drug (ABT-874: 36.0%, 54 of 150 ; placebo: 10.0%, 3 of 30; table 2); Most of these AEs were related to the injection site (injection site reaction, erythema, itching, or irritation).

Most of the AEs were soft (Soft AEs occurred in

46.0% [69 of 150] of patients treated with ABT-874 and 30.0% [9 of 30] patients treated with placebo). The most common AE was an injection site reaction, which occurred in 16.7% (25 of 150) of patients treated with any dose of ABT-874 (not

302 reported injection site reactions for placebo-treated patients; p = 0.028; table 3). There were no statistically significant differences between incidences of other AEs in ABT-874 treated patients compared to placebo treated patients. The next most frequently reported AEs were nasopharyngitis and upper respiratory tract infection.

Infectious AEs were reported by 32.8% (59 out of 180) of all patients (placebo: 23.3%, 7 out of 30; all ABT-874 treated patients: 34.7%, 52 out of 150). The most common infectious AEs described for any ABT-874 treatment group were nasopharyngitis (12.0%, 18 of 150), upper respiratory tract infection (10.7%, 16 of 150), and bronchitis and viral infection (both 2.7%, 4 of 150). No serious infectious AEs were reported.

Two patients reported malignant tumors during the study. A placebo-treated patient was diagnosed with ovarian cancer, which was on the course of day 129. A patient treated with ABT-874 (200 mg χ 4) was diagnosed with nonmelanoma skin cancer (squamous cell carcinoma) that was removed on day 133. The medical history for this patient included removal of benign skin growth in March 2005.

There was no clinically significant hematology, chemistry (concentrations including blood glucose), or vital changes in the sample compared to placebo.

Κ)

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LZl (a) Table 1: Initial clinical and demographic characteristics

<td colspan="8">Treatment Group</td>

<td>characteristics</td><td>Placebo N = 30</td><td>200 mg x 1 N = 30</td><td>1 00 mg eow N = 30</td><td>200 mg x 4 N = 30</td><td>200 mg eow N = 30</td><td>200 mg weekly N = 30</td><td>Everybody ABT-874 N = 150</td>

<td>Age, years</td><td> 49±14.4</td><td> 52±12.0</td><td> 45±13.8</td><td> 43±13.8</td><td> 44±16.0</td><td> 46±14.0</td><td> 46±14.1</td>

<td>(%) No. of Targets</td><td> 28 (93.3)</td><td> 25(83.3)</td><td> 28(83.3)</td><td> 27(90.0)</td><td> 30(100.0)</td><td> 28(93.3)</td><td> 1 38(92.0)</td>

<td>Weight, kg</td><td> 89±17.6</td><td> 94±21.2</td><td> 94±17.9</td><td> 92±27.8</td><td> 93±24.1</td><td> 95±18.0</td><td> 94±21.9</td>

<td>Duration of psoriasis, years</td><td> 21±12.4</td><td> 20±13.2</td><td> 24±14.6</td><td> 22±14.2</td><td> 18±11.5</td><td> 18±10.9</td><td> 21 ±1 3.0</td>

<td>PASI count</td><td> 16±2.9</td><td> 18±6.7</td><td> 20±6.3</td><td> 20±7.6</td><td> 20±6.2</td><td> 19±6.3</td><td> 19±6.6</td>

<td>% BSA affected</td><td> 21±9.2</td><td> 24±13.6</td><td> 28±15.7</td><td> 24±13.0</td><td> 29±16.8</td><td> 23±12.6</td><td> 26±14.5</td>

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OR

L / 1

<td colspan="8">Treatment Group</td>

<td>characteristics</td><td>Placebo N = 30</td><td>200 mg x 1 N = 30</td><td>100 mg eow N = 30</td><td>200 mg x 4 N = 30</td><td>200 mg eow N = 30</td><td>200 mg weekly N = 30</td><td>Everybody ABT-874 N = 150</td>

<td>Moderate</td><td> 20(66.7)</td><td> 19(63.3)</td><td> 17(56.7)</td><td> 13(43.3)</td><td> 15(50.0)</td><td> 17(56.7)</td><td> 81 (54.0)</td>

<td>Severe</td><td> 9(30.0)</td><td> 11(36.7)</td><td> 12(40.0)</td><td> 14(46.7)</td><td> 13(43.3)</td><td> 11(36.7)</td><td> 61(40.7)</td>

<td>(%) No. History of PsA</td><td> 9(30.0)</td><td> 7(23.3)</td><td> 12(40.0)</td><td> 9(30.0)</td><td> 6(20.0)</td><td> 9(30.0)</td><td> 43(28.7)</td>

<td colspan="8">(%) No. 'Previous treatment of psoriasis</td>

<td>Topical therapy</td><td> 19(63.3)</td><td> 21(70.0)</td><td> 26(86.7)</td><td> 15(50.0)</td><td> 21(70.0)</td><td> 23(76.7)</td><td> 106(70.7)</td>

<td>Phototherapy</td><td> 1(3.3)</td><td> 6(20.0)</td><td> 4(13.3)</td><td> 4(1 3.3)</td><td> 3(10.0)</td><td> 5(16.7)</td><td> 22(14.7)</td>

<td>Non-biological systemic</td><td> 6(20.0)</td><td> 4(13.3)</td><td> 7(23.3)</td><td> 5(16.7)</td><td> 6(20.0)</td><td> 8(26.7)</td><td> 30(20.0)</td>

<td>Biological systemic</td><td> 3(10.0)</td><td> 3(10.0)</td><td> 7(23.3)</td><td> 6(20.0)</td><td> 4(13.3)</td><td> 7(23.3)</td><td> 27(18.0)</td>

Values are average ± SD unless otherwise noted. 'Within 12 months prior to study treatment BSA = body surface area; eow = every two weeks; PASI = severity index and psoriasis area; PGA = global assessment of the doctor; PsA = psoriatic arthritis (b) Table 2: Conclusion of adverse events produced by clinical treatment hU

Un to

Or a

A

<td colspan="8">Treatment Group</td>

<td>Event</td><td>Placebo N = 30</td><td>200 mg x 1 N = 30</td><td>1 00 mg eow N = 30</td><td>200 mg x 4 N = 30</td><td>200 mg eow N = 30</td><td>200 mg weekly N = 30</td><td>Everybody ABT-874 N = 150</td>

<td>Any AE so less possibly related to him drug*</td><td> 3(10.0)</td><td> 9(30.0)</td><td> 12(40.0)</td><td> 14(46.7)</td><td> 11(36.7)</td><td> 8(26.7)</td><td> 54(36.0)</td>

<td>Any severe AE</td><td> 3(10.0)</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 2(1.3)</td>

<td>Any AET I laughed</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

<td>Any AE that leads to suspension study drug</td><td> 2(6.7)</td><td> 1 (3.3)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

KJ

OR

LZi

<td colspan="8">Treatment Group</td>

<td>Event</td><td>Placebo N = 30</td><td>200 mg x 1 N = 30</td><td>100 mg eow N = 30</td><td>200 mg x 4 N = 30</td><td>200 mg eow N = 30</td><td>200 mg weekly N = 30</td><td>Everybody ABT- 874 N = 150</td>

<td>Any AE at least possibly related with the drug * and be</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td>Any infectious AE</td><td> 7(23.3)</td><td> 7(23.3)</td><td> 9(30.0)</td><td> 13(43.3)</td><td> 13(43.3)</td><td> 10(33.3)</td><td> 52(34.7)</td>

<td>Any infectious AE I laughed</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td>Any malignant neoplasm</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

<td>Deaths</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

* As valued by the researcher. Serious adverse events included the following: any event that resulted in death; any event that was in danger of death; any event that resulted in admission to a hospital for any period of time; any event that occurred while the patient was hospitalized and resulted in a prolonged hospital stay; any event that resulted in a significant or persistent disability / incapacity; or any major medical event that required surgical or medical intervention to prevent serious consequences. EA = adverse event; eow = every two weeks.

Κ)

THE

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OR

THE

Table 3: Adverse events-produced by treatment with an incidence> in any treatment by frequency descent of patients treated without doses of

ABT-874

<td colspan="8">Treatment Group</td>

<td>Event</td><td>Placebo N = 30</td><td>200 mg x 1 N = 30</td><td>100 mg eow N = 30</td><td>200 mg x 4 N = 30</td><td>200 mg eow N = 30</td><td>200 mg weekly N = 30</td><td>Everybody ABT-874 N = 150</td>

<td>Site reaction injection</td><td> 0</td><td> 2(6.7)</td><td> 7(23.3)</td><td> 5(16.7)</td><td> 7(23.3)</td><td> 4(13.3)</td><td> 25(16.7)</td>

<td>Nasopharyngitis</td><td> 1(3.3)</td><td> 4(13.3)</td><td> 4(13.3)</td><td> 3(10.0)</td><td> 2.(6.7)</td><td> 5(16.7)</td><td> 18(12.0)</td>

<td>Tract infection upper respiratory</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 4(13.3)</td><td> 3(10.0)</td><td> 5(16.7)</td><td> 2(6.7)</td><td> 16(10.7)</td>

<td>Headache</td><td> 2(6.7)</td><td> 5(16.7)</td><td> 0</td><td> 1(3.3)</td><td> 3(10.0)</td><td> 2(6.7)</td><td> 11(7.3)</td>

<td>Itching at injection site</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 7(4.7)</td>

<td>Erythema at injection site</td><td> 0</td><td> 0</td><td> 0</td><td> 4(1 3.3)</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 7(4.7)</td>

<td>On site irritation injection</td><td> 0</td><td> 1(3.3)</td><td> 3(10.0)</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 6(4.0)</td>

Ν) <_Λ

Lzi

LZi

<td colspan="8">Treatment Group</td>

<td>Fatigue</td><td> 0</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 5(3.3)</td>

<td>Extremity pain</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 4(2.7)</td>

<td>Arthralgia</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 4(2.7)</td>

<td>Viral infection</td><td> 0</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 4(2.7)</td>

<td>Bronchitis</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 0</td><td> 4(2.7)</td>

<td>Nausea</td><td> 1(3.3)</td><td> 0</td><td> 3(10.0)</td><td> 0</td><td> 0</td><td> 0</td><td> 3.(2.0)</td>

<td>External otitis</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 2(1.3)</td>

<td>Threw up</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Urinary tract infection</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Herpes simplex</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 2(1-3)</td>

<td>Extremity injury</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Pruritus</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

308 * As determined by the investigator

309

III. conclusion

The phase II multicenter, double-blind, placebo-controlled, randomized trial described in this example statistically and clinically demonstrated significant efficacy of ABT-874 in the treatment of moderate to severe chronic plaque psoriasis. Except for ABT-874 treatment group 200 mg χ 1, 90% or more of patients in all ABT-874 treatment groups achieved PASI 75 or higher by week 12, compared to 3.3% of patients treated with placebo. Even in the group that received only 1 dose of the study drug (200 mg x 1), a majority (63.3%) of patients had reached at least PASI 75 by week 12.

Furthermore, almost 100% of patients treated with ABT-874 achieved a PASI 50 or higher, which is considered an improvement.

Clinically significant I5 (Carlin CS, Feldman SR, Krueger JG, Menter A, Krueger GG. J Am Acad Dermatol 2004; 50: 859-66) by week 12. Results for other secondary endpoints such as PASI 90 and PGA clear or minimal, they were consistent with and supported the primary efficacy analysis.

ABT-874's response was rapid. Statistically significant separation between ABT-874 and placebo treated patients occurred from week 1 for improvement of average percentage in PASI counts. The improvement was sustained for the duration of the week 12 trial, including patients in the ABT-874 200 mg χ dosing groups

310

X 4.

ABT-874 was well tolerated, and most AEs were smooth. Although patients treated with ABT-874 were significantly more likely to experience an EA at least possibly related to the study drug, most of these ESAs were related to the injection site (reaction, erythema, pruritus, or irritation in the injection site). There was no apparent association between an increasing dose of ABT874 and an increasing incidence of AEs. Notably, there were no myocardial or cerebral infarcts.

The related immunological events are of particular interest to patients receiving anti-IL-12/23 antibodies. The most frequently reported infectious AEs

I5 were nasopharyngitis, upper respiratory tract infection, bronchitis, and viral infection. There were no infectious AEs to be reported for the duration of this trial. Of the 2 malignant tumors diagnosed during the study, ovarian cancer was diagnosed in a placebo-treated patient, and nonmelanoma skin cancer was diagnosed in an ABT874-treated patient who had a history of benign skin growth.

In conclusion, ABT-874 demonstrated a statistically and clinically significant benefit for the treatment of patients with moderate to severe chronic plaque psoriasis, and was well tolerated.

311

Example 5: Maintenance of the Response with the Completely Human IL-12 / -23 Monoclonal Antibody, ABT-874, in the

Treatment of Moderate to Severe Plaque Psoriasis

The efficacy and safety of ABT-874 were evaluated in a 5 randomized controlled trial, phase II, week 12, and a follow-up phase, at week 36. The objective of the following example was to analyze the maintenance of the response after the suspension of therapy during the second 12 weeks of this Phase II study of subcutaneous injections of ABT-874 io in the treatment of moderate to severe plaque Ps.

Adults with Ps affecting 10% body surface area (BSA) and a 12 PASI count were chosen for this placebo-controlled, double-blind, week 12 study. Patients were randomized from 1 of 6 branches :

1) 100 mg ABT-874 every two weeks (eow) for 12 weeks;

2) a dose of 200 mg of ABT-874 at week 0;

3) 200 mg of ABT-874 every week for 4 weeks;

4) 200 mg of ABT-874 every two weeks for 12 weeks;

5) 200 mg ABT-874 every two weeks for 12 weeks; or

6) placebo.

The primary end point was the response of ¿PASI 75 in the week

312

12. Patients who met the primary endpoint entered a repeat / clergy treatment phase at week 36. Treatment with the study drug was continued, and patients were monitored for PASI count multiple times during the follow-up period. week 36, Including the responses of PASI 50, PASI 75 and PASI 90. The maintenance of the PASI response was evaluated through week 24.

A total of 180 patients participated, 30 in each branch. The initial characteristics were similar among the ramifications (average values presented except for the% of the man): age, 46 years, man 74%; 21 years of duration of Ps; PASI = 19; and 25% BSA affected.

At week 12, the percentages of patients with sPASI 75 were statistically significantly higher in each of the 5 ABT-874 branches against placebo (Table 4). At week 24, the substantial percentages of PASI 75 responses in the ramifications of active treatments had maintained at least a PASI count of & PASI 50. Furthermore, the substantial percentages of PASI 75 responses in the ramifications of active treatments had also maintained at least one PASI count of sPASI 75, as well as a PASI count of sPASI 90 (Table 4 and Figures 4A-C). The percentage of patients who maintain a PASI 75 response over a certain period during the 24th week period is depicted in Figure 4D.

Table 4: Efficacy of ABT-874 at week 24

THE

<td></td><td>> PASI75 in the week 12</td><td>Maintenance of answer of > PASI 50 week 24 against week 12</td><td>Maintenance of answer of > PASI75 week 24 against week 12</td><td>Maintenance of answer of > PASI190 week 24 against week 1 2</td>

<td>100 mg every two weeks for 12 weeks</td><td> 93%*</td><td> 71%</td><td> 60%</td><td> 33%</td>

<td>200 mg every week for 4 weeks</td><td> 90%*</td><td> 82%</td><td> 60%</td><td> 23%</td>

<td>200 mg every two weeks for 12 weeks</td><td> 93% *</td><td> 89%</td><td> 73%</td><td> 53%</td>

<td>200 mg every week for 12 weeks</td><td> 90%*</td><td> 85%</td><td> 83%</td><td> 57%</td>

<td>Placebo</td><td> 3%</td><td> -</td><td> 7%</td><td> 7%</td>

p <0.001 against placebo, NRI.

314

In conclusion, ABT-874 was considerably more efficient than placebo in treating moderate to severe plaque Ps. Substantial percentages of PASI 75 responses maintained a response of sPASI 50, & PASI 75, and sPASI 90 at week 24, after discontinuation of active therapy.

Example 6: Maintenance of the Response with the Completely Human IL-12 / -23 Monoclonal Antibody, ABT-874 in the

Treatment of Moderate to Severe Plaque Psoriasis io The efficacy and safety of ABT-874 was evaluated in a randomized phase II, week 48 controlled trial that included an initial treatment phase at week 12 and a repeated treatment phase at week 36 of the patients who responded to the initial treatment. The efficacy and maintenance results of the initial response results at week 12 are described in the aforementioned examples. The objective of the following example was to examine the response of repeat treatment during the follow-up / repeat treatment phase at week 36 in patients who lost their initial responses from this phase II study of subcutaneous injections of ABT-874 in the treatment of Ps in moderate to severe plaques. The further objective of the following example was to examine the safety of subcutaneous injections of ABT-874 in the treatment of moderate to severe plaque Ps in 48 weeks.

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A

CM

At baseline, demographic and clinical characteristics were similar across treatment groups (summarized in Table 5 below).

Table 5: Baseline of Demographic and Clinical Characteristics

<td colspan="8">Treatment Group</td>

<td></td><td>Placebo</td><td>200 mg x 1</td><td>100 mg eow</td><td>200 mg x 4</td><td>200 mg eow</td><td>200 mg weekly</td><td>Everybody ABT-</td>

<td>characteristics</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>874 N = 150</td>

<td>Age, years</td><td> 49(14.4)</td><td> 52(12.0)</td><td> 45(13.8)</td><td> 43(13.8)</td><td> 44(16.0)</td><td> 46(14.0)</td><td> 46(14.1)</td>

<td>Race (%) No. of Whites</td><td> 28(93)</td><td> 25(83)</td><td> 28(93)</td><td> 27(90)</td><td> 30(100)</td><td> 28(93)</td><td> 138(92)</td>

<td>Weight, kg</td><td> 89(17.6)</td><td> 94(21.2)</td><td> 94(17.9)</td><td> 92(27.8)</td><td> 93(24.1)</td><td> 95(18.0)</td><td> 94(21.9)</td>

<td>Duration of psoriasis, years</td><td> 21(12.4)</td><td> 20(13.2)</td><td> 24(14.6)</td><td> 22(14.2)</td><td> 18(11.5)</td><td> 18(10.9)</td><td> 21 (13.0)</td>

<td colspan="8">PASI count</td>

LA or

THE

Κ)

OR

<td colspan="8">Treatment Group</td>

<td>characteristics</td><td>Placebo N = 30</td><td>200 mg x 1 N = 30</td><td>100 mg eow N = 30</td><td>200 mg x 4 N = 30</td><td>200 mg eow N = 30</td><td>200 mg weekly N = 30</td><td>Everybody ABT-874 N = 150</td>

<td>Average (SD)</td><td> 16(2.9)</td><td> 18(6.7)</td><td> 20(6.3)</td><td> 20(7.6)</td><td> 20(6.2)</td><td> 19(6.3)</td><td> 19(6.6)</td>

<td>Medium, IQ</td><td> 16.1,3.8</td><td> 15.0,7.5</td><td> 18.7,7.4</td><td> 17.0,10.21</td><td> 18.0,10.0</td><td> 16.8,5.8</td><td> 17.3,8.0</td>

<td>% BSA affected</td><td></td><td></td><td></td><td></td><td></td><td>r</td><td></td>

<td>Average (SD)</td><td> 21(9.2)</td><td> 24(13.6)</td><td> 28(15.7)</td><td> 24(13.0)</td><td> 29(16.8)</td><td> 23(12.6)</td><td> 26(14.5)</td>

<td>Medium, IQ</td><td> 17.5,13.0</td><td> 17.5,16.0</td><td> 22.5,19.5</td><td> 20.3,1 7.0</td><td> 22.0,24.5</td><td> 19.5,17.0</td><td> 20.0,21 .0</td>

<td>Moderate</td><td> 20(67)</td><td> 19(63)</td><td> 17(57)</td><td> 13(43)</td><td> 15(50)</td><td> 17(57)</td><td> 81(54)</td>

<td>Severe</td><td> 9(30)</td><td> 11(37)</td><td> 12(40)</td><td> 14(47)</td><td> 13(43)</td><td> 11(37)</td><td> 61(41)</td>

<td>(%) No. History from PsA</td><td> 9(30)</td><td> 7(23)</td><td> 12(40)</td><td> 9(30)</td><td> 6(20)</td><td> 9(30)</td><td> 43(29)</td>

<td colspan="8">(%) No. 'Previous treatment of psoriasis</td>

<td>Topical therapy</td><td> 19(63)</td><td> 21(70)</td><td> 26(87)</td><td> 15(50)</td><td> 21(70)</td><td> 23(77)</td><td> 106(71)</td>

OR

THE

OR

THE tQ

THE

<td colspan="8">Treatment Group</td>

<td>Phototherapy</td><td> 1(3)</td><td> 6(20)</td><td> 4(13)</td><td> 4(13)</td><td> 3(10)</td><td> 5(17)</td><td> 22(16)</td>

<td>Non-biological systemic</td><td> 6(20)</td><td> 4(13)</td><td> 7(23)</td><td> 5(17)</td><td> 6(20)</td><td> 8(27)</td><td> 30(20)</td>

<td>Biological systemic</td><td> 3(10)</td><td> 3(10)</td><td> 7(23)</td><td> 6(20)</td><td> 4(13)</td><td> 7(23)</td><td> 27(18)</td>

BSA, body surface area; PsA, psoriatic arthritis.

'Values are averages of (SD) unless otherwise reported.

'Data are presented for only 3 out of 5 possible categories and therefore do not add up to more than 30 for each group * Within 12 months before study treatment.

318

Adults with psoriasis affecting £ 10% of the body surface area and a count of £ 12 from the Severity and Psioriasis Area Index (PASI) were randomly selected from 1 to 6 ramifications: 1) a dose of 200 mg ABT- 874 at week 0;

2) 100 mg ABT-874 every two weeks (eow) for 12 weeks;

3) 200 mg of ABT-874 weekly for 4 weeks; 4) 200 mg of ABT-874 eow for 12 weeks; 5) 200 mg ABT-874 weekly for 12 weeks; or 6) placebo. The primary end point was the response of a £ PASI 75 at week 12. Patients who met the primary end point entered a repeat treatment phase at week 36. Treatment with the study drug was continued, and patients who lost response (s PASI 50) during weeks 12-36 received repeated treatment with the same assigned dosage regimen during the initial period of week 12. Treatment repeated lasted for 12 weeks. Regardless of arrangement, all patients were monitored for the duration of the study, or until discontinuation.

Of the 180 patients initially enrolled, 130 (1 placebo) entered the repeat treatment phase and 58 (all of ABT-874) were re-treated. The percentages of patients who achieved £ PASI 75 at week 12 and then again at 12 weeks after repeated treatment were as follows for each group: one dose of 200 mg, 63% vs. 55%; 100 mg eow, 93% vs. 94%; 200mg weekly 4wks, 90% vs. 69%; 200 mg eow,

319

93% vs. 75%; and 200 mg weekly, 90% vs. 83%, respectively. Of the total of 58 patients who were portrayed, 76% reached sPASI 75 in 12 weeks after repeated treatment.

The mojoramlento in the PASI counts in a certain period for the portrayed patients is represented in figures 5A-B. Specifically, Figure 5A shows the improvement of the average percentage from the baseline in the PASI count from week 4 to week 12 in the PASI responses, and Figure 5B shows the improvement of the average percentage of the baseline in the PASI responses. PASI counts from week 4 to week 12 after repeated treatment in the PASI 75 responses.

The percentages of patients who achieved £ PASI 50 at 12 weeks after repeated treatment were as follows for each group: one dose of 200 mg, 82%; 100 mg eow, 100%; 200 mg weekly 4 weeks, 77%; 200 mg eow, 83%; and 200 mg weekly, 100%. Of the total of 58 patients who were portrayed, 88% reached sPASI 50 at 12 weeks after repeated treatment.

The percentages of patients who achieved a PGA of “Non-existent” or at least 12 weeks after repeated treatment was as follows for each group: a dose of 200 mg, 36%; 100 mg eow, 75%; 200 mg weekly 4 weeks, 62%; 200 mg eow, 67%; and 200 mg weekly, 83%. Of the total of 58 patients who were portrayed, 64% achieved a PGA

320 of “nonexistent” or minimum in at 12 weeks after repeated treatment.

Adverse events (AEs) occurred S5% in at least 1 treatment group in descending order through week 48 were: nasopharyngitis, injection site reaction, upper respiratory tract infection, headache, hypertension, and arthralgia. A description of the adverse events produced by treatment through week 48 are shown in Table 6 below. A description of the adverse events produced by the treatment with an incidence of ¿5% in any treatment group is shown in Table 7 below.

Table 6: Description of Adverse Events

Produced by Treatment through Week 48 *

Lzi

OR

LZi bü

THE

N)

OR

<td colspan="8">Treatment Group</td>

<td>Event</td><td>Placebo N = 30 (%) n</td><td>200 mg x 1 N = 30 (%) n</td><td>100 mg eow N = 30 (%) n</td><td>200 mg x 4 N = 30 (%) n</td><td>200 mg eow N = 30 (%) n</td><td>200 mg weekly N = 30 (%) n</td><td>Everybody ABT-874 N = 150 (%) n</td>

<td>Any AE so less possibly related to him drug*</td><td> 4(13.3)</td><td> 9(30.0)</td><td> 16(53.3)</td><td> 16(53.3)</td><td> 13(43.3)</td><td> 10(33.3)</td><td> 64(42.7)</td>

<td>Any severe AE</td><td> 4(13.3)</td><td> 1(3.3)</td><td> 0</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 5(3.3)</td>

<td>Any serious AE</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 0</td><td> 4(2.7)</td>

<td>Any AE that leads to suspension of study drug</td><td> 2(6.7)</td><td> 1 (3.3)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

Κ)

Lzi

LZi

<td colspan="8">Treatment Group</td>

<td>Event</td><td>Placebo N = 30 (%) n</td><td>200 mg x 1 N = 30 (%) n</td><td>1 00 mg eow N = 30 (%) n</td><td>200 mg x 4 N = 30 (%) n</td><td>200 mg eow N = 30 (%) n</td><td>200 mg weekly N = 30 (%) n</td><td>Everybody ABT- 874 N = 150 (%) n</td>

<td>Any AE at least possibly drug related and serious *</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 1(0.7)</td>

<td>Any infectious AE</td><td> 7(23.3)</td><td> 10(33.3)</td><td> 12(40.0)</td><td> 14(46.7)</td><td> 16(53.3)</td><td> 10(33.3)</td><td> 62(41.3)</td>

<td>Any serious infectious AE</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 1(0.7)</td>

<td>Any AE from malignant tumor</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

<td>Any lymphoma</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td>Any skin cancer does not melanoma</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

<td>Any AE related to reaction at the site of the injection</td><td> 0</td><td> 4(13.3)</td><td> 11(36.7)</td><td> 12(40.0)</td><td> 11(36.7)</td><td> 6(20.0)</td><td> 44(29.3)</td>

<td>Deaths</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

322

THE

OR

THE

Ν>

OR * Placebo data are for the first 12 weeks of the study only; all data from week 12 previously reported7 As valued by the researcher

AE, adverse event

Table 7: Adverse Events Produced by Treatment with an Incidence of 5% or more in any Treatment Group through Week 48 *

<td colspan="8">Treatment Group</td>

<td>Event</td><td>Placebo N = 30 (%) n</td><td>200 mg x 1 N = 30 (%) n</td><td>1 00 mg eow N = 30 (%) n</td><td>200 mg x 4 N = 30 (%) n</td><td>200 mg eow N = 30 (%) n</td><td>200 mg weekly N = 30 (%) n</td><td>Everybody ABT- 874 N = 150 (%) n</td>

<td>Site reaction injection</td><td> 0</td><td> 2(6.7)</td><td> 7(23.3)</td><td> 5(16.7)</td><td> 7(23.3)</td><td> 4(13.3)</td><td> 25(16.7)</td>

<td>Nasopharyngitis</td><td> 1(33)</td><td> 4(13.3)</td><td> 4(13.3)</td><td> 3(10.0)</td><td> 2-(6.7)</td><td> 5(16.7)</td><td> 18(12.0)</td>

<td>Tract infection upper respiratory</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 4(13.3)</td><td> 3(10.0)</td><td> 5(16.7)</td><td> 2(6.7)</td><td> 16(10.7)</td>

<td>Headache</td><td> 2(6.7)</td><td> 5(16.7)</td><td> 0</td><td> 1(3.3)</td><td> 3(10.0)</td><td> 2(6.7)</td><td> 11(7.3)</td>

LU

M

L * J

Uzi

UZl

<td colspan="8">Treatment Group</td>

<td></td><td>Placebo</td><td>200 mg x 1</td><td>100 mg eow</td><td>200 mg x 4</td><td>200 mg eow</td><td>200 mg weekly</td><td>Everybody ABT-874</td>

<td>Event</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 150</td>

<td>Erythema at injection site</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 14(13.3)</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 8(5.3)</td>

<td>Itching at injection site</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 7(4.7)</td>

<td>Irritation at injection site</td><td> 0</td><td> 1(3.3)</td><td> 3(10.0)</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 6(4.0)</td>

<td>Arthralgia</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 5(3.3)</td>

<td>1 viral infection</td><td> 0</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 5(3.3)</td>

<td>Gastrointestinal viral</td><td> 0</td><td> 1(3-3)</td><td> 0</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 5.(3.3)</td>

<td>Fatigue</td><td> 0</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 5(3.3)</td>

<td>Hypertriglyceridaemia</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 5(3.3)</td>

<td>Extremity pain</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 4(2.7)</td>

<td>Bronchitis</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 0</td><td> 4(2.7)</td>

<td>Pharyngo-laryngeal pain</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 3(2.0)</td>

324

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OR

THE

<td colspan="8">Treatment Group</td>

<td>Blood triglycerides increased</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 0</td><td> 3(2.0)</td>

<td>Urinary tract infection</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 0</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 0</td><td> 3(2.0)</td>

<td>Insomnia</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 0</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 0</td><td> 3.(2.0)</td>

<td>Nausea</td><td> 2(6.7)</td><td> 0</td><td> 3(10.0)</td><td> 0</td><td> 0</td><td> 0</td><td> 3(2.0)</td>

<td>Stomach flu</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 2(1-3)</td>

<td>Rhinorrhea</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 2(1-3)</td>

<td>External otitis</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 2(1.3)</td>

<td>Threw up</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Hypercholesterolemia</td><td> 0</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Increased blood pressure</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 2(1-3)</td>

325

Κ)

THE

<td colspan="8">Treatment Group</td>

<td>Procedural pain</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Extremity injury</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Pruritus</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 1(0.7)</td>

<td>Psoriatic arthropathy</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

LU

K) σ \ * The placebo data are only for the first 12 weeks of the study; all data from week 12 were previously reported.

The above data shows that ABT-874 was highly efficient in treating moderate to severe psoriasis. Upon loss of response and repeated treatment, a majority of patients were able to re-achieve a PASI 75 response. Furthermore, ABT-874 appears to have a favorable long-term safety profile.

327

Example 7: Pharmacokinetics of a Fully Human IL-12/23 Monoclonal Antibody, ABT-874, in Healthy Volunteers

Normal

The tolerability, safety, and pharmacokinetics (PK) of a dose interval of ABT-874 were evaluated in a randomized study with a double-blind, placebo-controlled dose interval. The objective of the following example was to investigate the pharmacokinetics of intravenous (IV) and subcutaneous (SC) injections of ABT-874 in healthy volunteers.

The main inclusion criteria were: (i) healthy male volunteers between 18 and 45 years of age; (ii) no clinically relevant abnormalities in any of the investigations of the research analysis (physical examination, vital signs, electrocardiogram, biochemistry, hematology, urinalysis, serology);

and (iii) normal chest radiographs within a 12-month period before entering the study. The main exclusion criteria were: (i) smoking more than 10 cigarettes per day; (ii) drink more than 30 g of alcohol per day; (iii) positive urine drug control; (iv) chronic infections, especially by intracellular bacterial pathogens such as Mycobacterium tuberculosis; and (v) major infections requiring hospitalization or intravenous antibiotics in an interval of 2 previous years.

Young (18-45 years old), healthy male volunteers received 2 equal doses (1 intravenous and 1 SC administered 8 weeks apart) of 0.1, 0.3, 1.0, or 5.0 mg / kg ABT-874 in one design

328 of two crossed periods (2x2 Latin square). Blood samples for the determination of ABT-874 concentrations were collected before the first dose (0) and at 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72, 120, 168, 336, 504 and 672 hours after dosing. ABT-874 serum concentrations were measured by an enzyme-linked immunosorbent assay.

ABT-874 serum concentrations were tabulated individually, described by statistical characteristics (including geometric mean and geometric standard deviation) and displayed as individual as well as geometric mean concentration, mean, against time curves for intravenous and SC treatment and each treatment group. The following PK parameters were estimated using non-compartmental methods:

• Cmax maximum serum concentration (qg / ml) • Tmax time to reach Cmax (hour) • AUC area below the serum concentration time curve (pg x hr / ml)

4½ period (hour) • CL separation (ml / hr) (for IV administration) • Vz volume of distribution (mi) (for intravenous administration) • CL / F evident CL (ml / hr) (for SC administration ) • V / F Vz evident (mi) (for SC administration)

A total of 64 patients were randomized; 12

329 they received ABT-874 and 4 received placebo for each dose group. ABT-874 appeared to follow bi-exponential kinetics following IV administration, incorporating the terminal phase approximately 7 days after administration. The mean ± SD terminal periods for IV doses 0.1-, 0.3-, 1.0-, and 3.0 were 81.2 ± 55.6, 147 ± 73.2, 208 ± 79.2, and 196 ± 55.4 hours, respectively. The mean ± SD terminal periods for SC doses were 0.1-, 0.3-, 1.0-, and 3.0 mg SC doses were 221 ± 103, 161 ± 92.6, 210 ± 90.9, and 208 ± 79.2 hours, respectively, io The average terminal period for IV administration ranged from 81.2 ± 55.6 hours to 208 ± 79.2 hours. The average terminal period for SC administration ranged from 161 ± 92.6 hours to 221 ± 103 hours. The total average terminal period was 8-9 days.

The pharmacokinetics of ABT-874 (maximum concentration of the drug [Cmax] or area under the curve [AUC]) increased proportionally to the dose after both IV and SC administrations. The serum concentration time curve for IV and SC dosing is shown in Figures 6A and 6B, respectively. The volume of distribution ranged from about 8-101 after IV administration to 24-67 I after SC administration. After SC administration, the time to reach Cmax it was approximately 3-4 days. Bioavailability after SC administration ranged from 42% to 62% for the evaluated doses. Parameters

330 Pharmacokinetics following IV or SC administration at each dose, including Cmax (the maximum serum concentration in pg / m), AUC (area below the serum concentration time curve in pgxhr / ml), tmax (time to reach Cmax in hours), t1/2 (period in hours), CL (separation in ml / hr) and Vz (volume of distribution (mi)), are shown in Table 8 below.

LA or

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THE

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OR

Table 8: PK Parameters (Average ± SD) in Healthy Human Volunteers after the

ABT-874 Administration IV or SC

<td>Cohort</td><td>Route</td><td>Cmax (qg / ml)</td><td>tmax (hr)</td><td>AUCo-oo (qg x hr / ml)</td><td>tl / 2 (hr)</td><td>CL * (ml / hr)</td><td>VzF(me)</td>

'For SC CL / F administration tFor SC V / F administration

332

The above data shows that ABT-874 administered IV and SC at a dose between 0.1 and 5.0 mg / kg was well tolerated by young healthy male individuals. The pharmacokinetic properties of ABT-874, with its 8-9 day period, are as would be expected for an IgG- antibody.

Example 8: Maintenance of Repeated Treatment Response with the Completely Human IL-12 / -23 Monoclonal Antibody, ABT-874, in the Treatment of

Moderate to Severe Plaque Psoriasis io The efficacy and safety of ABT-874 was evaluated in the randomized controlled phase II, week 48 trial, which included an initial treatment phase at week 12 and a repeated treatment phase at week 36. of patients responding to initial treatment. Efficacy results at week 12 and initial response maintenance results are described in Examples 1-5 above. The objective of the following example was to examine the response of repeat treatment during the repeat / follow-up phase of week 36 in patients who lost their initial responses from this phase II study of subcutaneous injections of ABT-874 in the treatment of Ps in moderate to severe plaques. The additional objective of the following example was to examine the safety of subcutaneous injections of ABT-874 in the treatment of moderate to severe plaque Ps over 48 weeks.

The main inclusion criteria for the trial

333 They were: (i) adults with a clinical diagnosis of psoriasis for at least 6 months and stable plaque psoriasis for at least 2 months before the investigation; and (ii) moderate to severe plaque psoriasis (£ 10% involvement of body surface area, £ 12 Psoriasis Area and Severity Index [PASI] count and Global Physician Assessment [PGA] of at least disease moderate) at initial visit.

A first exclusion criterion for the trial was prior exposure to antl-IL-12 systemic or biological therapy. A second exclusion criterion was the inability to continue the following therapies before the baseline visit: topical psoriasis therapies £ 2 weeks before; ultraviolet light (UV) -B phototherapy £ 2 weeks before; psoralen-UV light phototherapy £ 4 weeks before; sstémlcas therapies £ 4 weeks before; and biological therapies £ 12 weeks before.

At baseline, demographic and clinical characteristics were similar across treatment groups (concluded in Table 5 of Example 6, above).

Adults with psoriasis affecting £ 10% of body surface area 20 and a count of Psoriasis Area and Severity Index (PASI) of £ 12 were randomly assigned to 1 to 6 branches: 1) a dose of 200 mg ABT -874 at week 0; 2) 100 mg ABT-874 every two weeks (eow) for 12 weeks; 3) 200 mg of ABT-874 weekly for 4 weeks; 4) 200 mg of ABT-874 eow for 12

334 weeks; 5) 200 mg ABT-874 weekly for 12 weeks; or 6) placebo. The primary end point was a response to PASI 75 at week 12. Patients who met the primary end point entered a repeat treatment phase at week 36. Treatment with the study drug was continued, and patients who lost response (^ PASI 50) during weeks 12-36 received repeated treatment with the same assigned dosage regimen during the initial period of week 12. Treatment repeated was for 12 io weeks. Regardless of arrangement, all patients were monitored for the entire duration of the study, or until discontinuation.

Outcome measurements included the following; (i) percentage of patients achieving PASI 75; (i) time

Average I5 to achieve PASI 75 response after repeated treatment; (iii) average time to lose the percentage of PASI 75 response (iii) percentage of patients with a PGA count of Nonexistent or Minimum after repeated treatment.

Statistical analysis was performed as follows. Intention to treat (ITT) analysis was performed by the randomized treatment group. For PASI scores obtained after repeated treatment with ABT-874, scores were assigned according to study visits according to the number of days after the first dose of repeated treatment. The

335 proportion of patients achieving the PASI response (yes / no) presented according to the visit of the derived study. All statistical tests were two-sided with a significance value of 0.05

Of the 180 patients initially enrolled (30 patients per treatment group), 130 (1 placebo) entered the repeat treatment phase and 58 (all ABT-874) were portrayed. The percentages of patients who achieved sPASI 75 at week 12 and then again at week 12 after repeated treatment were as follows for each group: a dose of 200 mg, 63% vs. 55%; 100 mg eow, 93% vs. 94%;

200 mg weekly 4 wks, 90% vs. 69%; 200 mg eow, 93% vs. 75%; and 200 mg weekly, 90% vs. 83%, respectively. Out of the total of 58 patients who were portrayed, 76% reached £ PASI 75 in 12 weeks after repeated treatment. A majority of patients were able to achieve a PASI 75 response again (Figure 7A).

The average time (in days) to reach PASI 75 during the repeated treatment phase across all ABT-874 dosing groups is depicted in Figure 7B. The average time to reach 2PASI 75 during repeated treatment was as follows for each group: one 200 mg dose, between 60 and 65 days; 100 mg eow, between 55 and 60 days; 200 mg weekly 4 wks, between 55 and 60 days; 200 mg eow, between 25 and 35 days; and 200 mg weekly, between 55 and 60 days, respectively.

336

The average time (in days) to lose PASI 75 after the initial 12 weeks of treatment is depicted in Figure 7C. The average time to lose PASI 75 after initial 12 weeks of treatment was as follows for each group: one 200 mg dose, between 55 and 60 days; 100 mg eow, between 110 and 120 days; 200 mg weekly 4 wks, between 110 and 120 days; 200 mg eow, between 160 and 180 days; and 200 mg weekly, between 180 and 190 days, respectively.

The percentages of patients achieving a PGA of "nonexistent" or minimal (eg, PGA of 0 or 1) within 12 weeks after repeated treatment is depicted in Figure 7D. The percentages of patients achieving a PGA of 0 or 1 during repeated treatment were as follows for each group: a dose of 200 mg, between 35% and 40%; 100 mg eow, between 70% and 80%; 200 mg weekly 4 wks, between 60% and 65%; 200 mg eow, between 60% and 70%; and 200 mg weekly, between 80% and 90%, respectively. Of the total patients who were portrayed, between 60 and 65% achieved a PGA of 0 or 1 after repeated treatment.

Adverse events (AEs) occurring £ 5% in at least 1 treatment group in descending order through week 48 were: nasopharyngitis, injection site reaction, upper respiratory tract infection, headache, hypertension , and arthralgia. A description of the adverse events produced by treatment through

337 from week 48 is shown in Table 6 of Example 6, above. A description of adverse events produced by treatment with an incidence of £ 5% in any treatment group is shown in Table 7 of Example 6, above.

Example 9: Efficacy and Safety of a Fully Human Interlucine 12/23 Monoclonal Antibody for the Treatment of Chronic Plaque Psoriasis: Observation / Retreatment

Week 36 and Open Label Extension Phases Week

I5 60

I. Materials and Methods

A. Study Design

The following was a phase 2, multicenter study consisting of 3 phases: a double-blind, placebo-controlled phase, week 12; a repeated treatment / observation phase week 36; and an open label extension phase, week 60.

Data from the initial week 12 phase of the current study are described above in Examples 1, 2, 4, and 7. Data from the 36 week repeat treatment / observation phase of the current study are described above in

338 Examples 3, 5, 6, and 8. Study methods for the above studies are briefly evaluated in this example with an emphasis on the repeat treatment / observation phase at week 36 and the extension, open label phase at week 60.

one. Treatment Phases During Week 12 Start and Repeated Treatment / Observation

Patients were randomly assigned to 1 to 6 groups as well: a dose of 200 mg ABT-874 at week 0 (200 mg χ 1); ABT-874 100 mg every other week for 12 weeks (100 mg EOW); 200 mg ABT-874 200 weekly for 4 weeks (200 mg χ 4); 200 mg ABT-874 EOW for 12 weeks (200 mg EOW); ABT-874 200 mg weekly for 12 weeks (200 mg weekly); or placebo. Responding patients (i.e., patients achieving a PASI 75 response at week 12 entered the single-blind repeat / observation phase at week 36 in which they were only chosen for repeat ABT treatment. -874 if they lost response; those with no response within 12 weeks were monitored, but were not selected for repeat treatment. During the observation / repeat treatment phase at week 36, patients who lost the PASI 50 response compared to baseline were chosen for 12 weeks of repeated ABT-874 treatment if loss of response occurred after week 12 and up to week 36. Patients portrayed

339 they received the same assigned ABT-874 regimen during the double-blind phase of week 12, except for placebo-assigned patients who received 200 mg of ABT-874 every other week (EOW). Regardless of which branch of the study entered, all patients were monitored until week 54 or until the study was discontinued.

2. Treatment During the Label Extension Phase

Open

Patients who achieved at least one io PASI 75 response at week 12 of Initial treatment and who actively participated in the repeated observation / treatment phase were allowed to enter the open-label extension phase. During this phase of the study, patients who lost the PASI 50 response compared to baseline were portrayed with either 200 mg ABT-874.x 1 dose or x 2 doses (1 dose / wk for 2 weeks) based on your dosing regimen during the initial phase of week 12 of the study. Patients who received 200 mg of ABT-874x 1 dose Included those who were randomly assigned to receive 200 mg χ 1, 100 mg EOW or 200 mg χ 4. Patients who received ABT-874 χ 2 doses Included those who were initially randomized to receive 200 mg EOW, weekly, or placebo. Patients who experienced subsequent loss of PASI 50 response that occurred in less than 12 weeks of previous repeat treatment

340 they were again portrayed with the same dosage regimen (1 or 2 doses of ABT-874); repeat treatment could be repeated until week 56 of the open-label extension phase.

3. Participants

The essential criteria for inclusion were: 18 years of age; clinical diagnosis of psoriasis for ¿6 months; stable plaque psoriasis for 2: 2 months before investigation and at baseline; moderate to severe plaque psoriasis (ie psoriasis in 10% of body surface area at baseline); a ¿12 PASI count at baseline; and a moderate or higher PGA count at baseline.

Essential exclusion criteria included the following: prior anti-IL-12 therapy; diagnosis of non-plaque psoriasis; inability to continue various treatments for psoriasis within predefined time frames, including topical therapies, ultraviolet light phototherapy, and systemic therapies; select risk factors or comorbid disease; and abnormal laboratory values.

Four. Efficacy and Safety Assessments

The primary outcome of the PASI 75 response study at week 12 relative to baseline was described above in Example 3-8. Adverse events, vital signs, and laboratory parameters were monitored throughout all phases of the study. The end points

341 Secondary schools examined during the observation / repeat treatment phase of week 36, and evaluated in the current analysis, include the proportion of patients portrayed who achieved PASI scores of 50, 75, and 90 after 12 weeks of repeated treatment; the average time to loss of PASI 75 response; average time to recover the PASI 75 response among portrayed patients; PGA counts; and security. Secondary endpoints assessed during the open-label extension phase at week 60, and evaluated in the current analysis, include the proportion of patients who achieved PASI 50, 75, and 90 counts 12 weeks after repeated treatment; PGA counts; and security. A further assessment of the week 12 data examined the impact of baseline covariates (eg, weight, PASI or PGA count, history of psoriatic arthritis, or previous therapy) on subsequent PASI 75 achievement and is presented in the present.

PASI counts ranged from 0 = no psoriasis to 72 = severe disease and were calculated as previously described. Disease severity was measured using PGA counts, which ranged from 0 = clear to 5 = very severe as previously described.

5. Statistical analysis

Efficacy analyzes were conducted using the intention-to-treat population (N = 180), which included all

342 patients who were randomized at week 0 and received at least 1 injection of study drug during the double-blind, first week 12 phase of the study. Efficacy analyzes were conducted by the period of observation / repeated treatment in patients who were randomly assigned to ABT-874 at week 0 and who achieved a response of ¿PASI 75 at week 12, n = 130. For the open label extension phase, only data for patients who continued in this phase were analyzed. The efficacy variables in the observation / repeat treatment period and the open-label repeat treatment period were concluded. Patients with a lack of PASI or PGA counts were counted as unanswered. Categorical variables were concluded using the patient count and percentage. Continuous variables were concluded using descriptive statistics (n, average, and standard derivation). Safety analyzes were conducted using the safety population, which included all patients who received at least 1 injection of the study drug.

II. Results

A. Demographic Data of the Patient

Demographic data for these patients was previously described in Examples 3-8 and is concluded below. In the ramifications of ABT-874 treatment, patients, on average, were similar in terms of age.

343 (average, 46 years), were predominantly male (75%) and mainly white (92%), and with an average of 94 kg in weight. The average duration of psoriasis was 21 years, with the average PASI counts of 19. The patients who received ABT-874 were divided between moderate (54%) and severe (41%) psoriasis, as determined by counts of PGA, with an average of 25.6% of its affected body surface area. Previous therapies consisted of topical therapy (71%), followed by non-biological (20%) or systemic biological (18%) or phototherapy (15%).

B. Base Covariates in Responses

At the 12-week assessment, a majority of all ABT-874-treated patients achieved a PASI 75 count regardless of differences in baseline clinical and demographic covariate characteristics (eg, weight, PASI or PGA count, history of psoriatic arthritis, or previous therapy, Table 9).

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Table 9. Week-Twelve PASI 75 Responses Staged by Base Covariates (Double-blind Period; Intention to Treat Set) PASI 75 Response, (%) n / N

<td>Covariate, (%) n</td><td>Placebo</td><td>200 mg x1</td><td>1 00 mg EOW</td><td>200 mg x4</td><td>200 mg EOW</td><td>200 mg Weekly</td><td>All ABT- 874</td>

<td>Weight, kg S100 > 100</td><td> 0/23(0) 1/7(14.3)</td><td> 11/18(61.1) 8/1 2(66.7)</td><td> 1 8/18(100) 10/12(83.3)</td><td> 18/20(90.0) 9/10(90.0)</td><td> 19/20(95.0) 9/10(90.0)</td><td> 20/21 (95.2) 7/9(77.8)</td><td> 86/97(88.7) 43/53 (81.1)</td>

<td>Count PGA severe / very severe</td><td> 1/9(1 1.1)</td><td> 8/1 1(72.7)</td><td> 12/13(92.3)</td><td> 15/17(88.2)</td><td> 1 3/1 5 (88.2)</td><td> 1 1/13(84.6)</td><td> 59/69(85.5)</td>

<td>History arthritis psoriatic Yes No</td><td> 0/9(0) 1/21(4.8)</td><td> 6/7(85.7) 13/23(564.4)</td><td> 1 1/12(91.7) 17/18(94.4)</td><td> 8/9(88.9) 19/21(90.5)</td><td> 5/6(83.3) 23/24(95.8)</td><td> 6/9(66.7) 21/21(100)</td><td> 36/43(83.7) 93/1 07(86.9)</td>

<td>Sex Man Woman</td><td> 1/22(4.5) 0/8 (0)</td><td> 1 5/23(65.2) 4/7(57.1)</td><td> 21/22(95.5) 7/8(87.5)</td><td> 19/21(90.5) 8/9 (88.9)</td><td> 22/23(95.7) 6/7 (85.7)</td><td> 20/23(87.0) 7/7(100)</td><td> 97/1 12(86.6) 32/38(84.3)</td>

Κ) ύ / ι

<td colspan="8">ABT-874 Treatment Group</td>

<td>Covariate, (%) n</td><td>Placebo</td><td>200 mg x1</td><td>1 00 mg EOW</td><td>200 mg x4</td><td>200 mg EOW</td><td>200 mg Weekly</td><td>All ABT- 874</td>

<td colspan="8">Biological systematic treatment in a period of 12 months</td>

<td colspan="8">Systematic non-biological treatment over a 12-month period</td>

<td colspan="8">Topical treatment over a 12-month period</td>

<td colspan="8">Phototherapy over a period of 12 months</td>

BSA = body surface area; EOW = every two weeks; PSAI = Psoriasis Area and Severity index; PGA = Global Physician Assessment

346

C. Observation / Retreatment Phase (36 Weeks)

Patients who responded with a PASI count at the end of the initial study at week 12 were chosen for repeat treatment during the observation / repeat treatment phase at week 36 (n = 130); no response (n = 40) were monitored, but were not chosen for repeat treatment.

Of the 130 patients who were chosen to enter a repeat treatment phase at week 12, 72 patients maintained a response, while 58 patients lost their PASI 50 response and were portrayed with ABT-874 in the subsequent 12 weeks. The average PASI count for the 58 patients portrayed at the time of repeated treatment was 13.85, with an interval of 13.2 to 14.9 across the treatment groups (Figure 10). In patients who lost their PASI 75 response during the observation / repeat treatment phase (n = 120/130), the average time to lose response (calculated from the last dose received during the initial 12 weeks of the study) It has an interval from 57 to 184 days (figure 11). Among patients portrayed, the percentage of patients who achieved PASI 75 counts within 12 weeks after restarting ABT-874 therapy was 54.5% for the 200 mg x 1 treatment group, 93.8% for EOW 100 mg, 69.2% for 200 mg x 4, 75.0% for 200 mg EOW, and 83.3% for 200 mg weekly.

PASI 50 response in 12 weeks after

347 restart of therapy from 76.9% to 100%; The PASI 90 response ranges from 9.1% to 83.3% (Table 10). The single-dose treatment group (ABT-874 200 mg x 1) generally have the lowest proportion of patients achieving a given level of response. Patients who achieved a PASI 75 response during 12 weeks of repeated treatment showed average times to achieve a response that ranges from 30 to 62 days (Figure 12).

Table 10. PASI Responses after 12 Weeks of

Repeated Treatment

<td>Group of Treatment by ABT-874</td><td>PASI 50, n (%)</td><td>PASI 75, n (%)</td><td>PASI 90, N (%)</td>

<td>200 mg weekly (n = 6)</td><td> 6(100)</td><td> 5(83.3)</td><td> 5(83.3)</td>

EOW = every two weeks; PASI = Psoriasis Area and Severity index

Most of the withdrawn patients in each treatment group achieved a PGA count of “nonexistent” or minimal

348 after 12 weeks of repeated treatment (100 mg EOW, 75.0%; 200 mg x4, 61.5%; 200 mg EOW, 66.7%; 200 mg weekly, 83.3%), except for the ABT-874 group 200 χ 1 mg ( 200 mg χ 1, 36.4%). The average time to achieve a PGA count of "nonexistent" or minimal after starting repeat treatment that ranged from 45 to 85 days (200 mg χ 1.85 d; 100 mg EOW, 58 d; 200 mg χ 4 , 58 d; 200 mg EOW, 57 d; 200 mg weekly, 45 d).

Among patients who received ABT-874 during the first 48 weeks of the study (initial observation / repeat treatment phases at week 12 and week 36), there were no deaths and 4 patients with serious adverse events; 1 patient discontinued ABT-874 treatment due to an adverse event (Table 11). Among all patients who received ABT-874, injection site reactions, nasopharyngitis, and upper respiratory tract infections were the only adverse events that occurred with an incidence of> 10% (Table 12).

THE tQ -

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THE

Table 11. Synopsis of Emergent AEs Treatment among all Patients during week 48

<td colspan="8">ABT-874 Treatment Group</td>

<td>Adverse event, n (%)</td><td>Placebo' (n = 30)</td><td>200 mg x1 (n = 30)</td><td>100 mg EOW (n = 30)</td><td>200 mg x4 (n = 30)</td><td>200 mg EOW (n = 30)</td><td>200 mg Week Imente (n = 30)</td><td>Everybody ABT-874 (n = 150)</td>

<td>Any AE at least possibly related to the drug</td><td> 4(13.3)</td><td> 9(30.0)</td><td> 16(53.3)</td><td> 16(53.3)</td><td> 13(43.3)</td><td> 10(33.3)</td><td> 64(42.7)</td>

<td>Any severe AE</td><td> 4(13.3)</td><td> 1(3.3)</td><td> 0</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 5(3.3)</td>

<td>Any AE that leads to DC of study drug</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

<td>Any AE at least possibly related to the drug and serious</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 1(0.7)</td>

<td>Any Infectious AE</td><td> 7(23.3)</td><td> 10(33.3)</td><td> 12(40.0)</td><td> 14(46.7)</td><td> 16(53.3)</td><td> 10(33.3)</td><td> 62(41.3)</td>

<td>Any AE Infectious to be</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 1(0-7)</td>

<td>Any malicious AE</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

<td>Any skin cancer does not melanoma</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(0.7)</td>

<td>Death</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

LU

LA or

THE

Ν)

THE

Ν)

OR

AE = adverse event; DC = suspension; EOW every two weeks.

The data of the toPlacebo are for the first 12 weeks of the study only; all study data at week 12 was previously reported. (Kimball 2008)

The bParticipants who experienced more than 1 serious adverse event counted only once in the total serious adverse event. A total of 4 patients reported 8 AE being: one patient in the 200 mg EOW group reported abscess rupture, diverticular perforation, sepsis, and peritonitis; one patient in the 200 mg EOW group reported facial injury; one patient in the 200 mg x 4 group reported injury; one patient in the 200 mg x 1 group reported costochondritis; one patient receiving placebo reported LU ovarian cancer

Table 12. Emergent Treatment of AEs with an Incidence> 2% in the entire Group of the

ABT-874 treatment during Week 48

<td colspan="8">ABT-874 Treatment Group</td>

<td>Event adverse, n (%)</td><td>Placebo* (n = 30)</td><td>200 mg x1 (n = 30)</td><td>100 mg EOW (n = 30)</td><td>200 mg x4 (n = 30)</td><td>200 mg EOW (n = 30)</td><td>200 mg Weekly (n = 30)</td><td>Everybody ABT- 874 (n = 150)</td>

<td>Reaction at the site of injection</td><td> 0</td><td> 2(6.7)</td><td> 7(23.3)</td><td> 8(26.7)</td><td> 8(26.7)</td><td> 4(13.3)</td><td> 29(19.3)</td>

The

OR

THE

Κ)

L / ι

<td colspan="8">ABT-874 Treatment Group</td>

<td>Adverse event, n (%)</td><td>Placebo3(n = 30)</td><td>200 mg x1 (n = 30)</td><td>100 mg EOW (n = 30)</td><td>200 mg x4 (n = 30)</td><td>200 mg EOW (n = 30)</td><td>200 mg Weekly (n = 30)</td><td>Everybody ABT-874 (n = 150)</td>

<td>Nasopharyngitis</td><td> 1(3.3)</td><td> 5(16.7)</td><td> 6(20.0)</td><td> 3(10.0)</td><td> 4(13.3)</td><td> 5(16.7)</td><td> 23(15.3)</td>

<td>Tract infection upper respiratory</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 5(16.7)</td><td> 3(10.0)</td><td> 5(16.7)</td><td> 2(6.7)</td><td> 17(11.13)</td>

<td>Headache</td><td> 2(6.7)</td><td> 5(16.7)</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 3(10.0)</td><td> 2(6.7)</td><td> 12(8.0)</td>

<td>Erythema in place of injection</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 4(13.3)</td><td> 3(6.7)</td><td> 1(3.3)</td><td> 8(5.3)</td>

<td>Itching in place of injection</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 7(4.7)</td>

<td>On site irritation infection</td><td> 0</td><td> 1(3.3)</td><td> 3(10.0)</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 6(4.0)</td>

<td>Arthralgia</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 5(3.3)</td>

<td>Viral infection</td><td> 0</td><td></td><td> 0</td><td> 2(7.7)</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 5(3.3)</td>

<td>Viral gastroenteritis</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 5(3.3)</td>

<td>Fatigue</td><td> 0</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 1(3-3)</td><td> 5(3.3)</td>

<td>Hypertriglyceridaemia</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 5(3.3)</td>

<td>Extremity pain</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 4(2.7)</td>

<td>Bronchitis</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 0</td><td> 4(2.7)</td>

LZ »<_ / i

<td colspan="8">ABT-874 Treatment Group</td>

<td>Event adverse, n (%)</td><td>Placebo3(n = 30)</td><td>200 mg x1 (n = 30)</td><td>100 mg EOW (n = 30)</td><td>200 mg x4 (n = 30)</td><td>200 mg EOW (n = 30)</td><td>200 mg Weekly (n = 30)</td><td>Everybody ABT- 874 (n = 150)</td>

<td>Pharyngolaryngeal pain I</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 3(2.0)</td>

<td>Influenza</td><td> 1(3.3)</td><td> 0</td><td> 1(3.3)</td><td> 0</td><td> 2(6.7)</td><td> 0</td><td> 3(2.0)</td>

<td>TGs in blood increased</td><td> 1(3.3)</td><td> 0</td><td> 0</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 0</td><td> 3(2.0)</td>

<td>Tract infection urinary</td><td> 2(6.7)</td><td> 1(3.3)</td><td> 0</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 0</td><td> 3(2.0)</td>

<td>Insomnia</td><td> 1(3.3)</td><td> 2(6.7)</td><td> 0</td><td> 1(3.3)</td><td> 1(3.3)</td><td> 0</td><td> 3.(2.0)</td>

<td>Nausea</td><td> 2(6.7)</td><td> 0</td><td> 3(10.0)</td><td> 0</td><td> 0</td><td> 0</td><td> 3(2.0)</td>

AE = adverse event, BP = blood pressure, EOW = every two weeks; TGs = triglycerides The data of thetoPlacebo are for the first 12 weeks of the study only; all study data at week 12 previously reported (Kimball 2008)

353

D. Open Label Extension Phase (60 Weeks)

Patients who achieved a PASI 75 at week 12 and actively participated in the study (i.e., chosen for repeat treatment) during the observation / repeat treatment phase at week 36 were allowed to enter the label extension phase. open (n = 105). There were no appreciable changes in total demographic characteristics in the open label phase, although there was a statistically significant difference between the groups of 200 mg x 1 dose of ABT-874 in the distribution of subjects in each age category (P = 0.010).

After week 48, patients received repeat treatment on loss of response of (<PASI 50) with 200 mg ABT-874 * 1 or * 2 based on their initial randomized dosing group. Of the 105 subjects who entered the open-label extension phase at week 48, 96 (n = 52 and n = 44 for the 200 mg x 1 and x 2 dose groups of ABT874, respectively) were retracted at least once . Patients were portrayed up to 5 times, with the majority of withdrawn patients being portrayed being portrayed 3 times. Nine patients were not portrayed with ABT-874 in the open-label extension phase because they never lost the PASI 50 response, but were monitored until the end of the study.

With each cycle of repeated treatment, the proportion of

354 Patients who achieved PASI 50, 75, and 90 responses generally decreased, and response rates after repeated treatment were lower than those considered after initial treatment (Table 13). However, the proportion of patients achieving a PASI 50 response was similar in the ABT-874 200 200 mg x 2 dose group for the first 3 repeated treatments, and the overall PASI 75 response rates were similar for the first and second repeated treatments. Most of all the patients portrayed achieved a PASI 50 response with the first 3 repeated treatments.

Table 13. PASI responses 13 Weeks after

ABT-874 Retreatment in Phase3 Extension

Open Label

<td>Answer of</td><td>200 mg x</td><td>200 mg x</td><td> 874</td>

<td>First</td><td></td><td></td><td></td>

<td>Treatment</td><td></td><td></td><td></td>

<td>Second</td><td>N = 42</td><td>N = 36</td><td>N = 48</td>

<td>Treatment</td><td></td><td></td><td></td>

355

<td>Answer of</td><td>200 mg x</td><td>200 mg x</td><td> 874</td>

<td>Third Treatment</td><td>N = 31</td><td>N = 20</td><td>N = 51</td>

PGA counts were also declined with each cycle of repeated open-label treatment and were lower than those observed during the initial phase of the study. During the first cycle of repeated treatment, 30.6% of patients receiving 200 mg x 1 dose of ABT-874 and 41.5% of patients receiving 200 mg x 2 dose of ABT-874 achieved a "nonexistent" PGA count at “Minimum” in 12 weeks after repeated treatment. The proportion of patients achieving PGA counts of “Nonexistent or minimal declined shortly after the second cycle of open label repeat treatment 25 (200 mg * 1, 23.7%; 200 mg x 2, 39.4% after

356 12 weeks) but was substantially lower following the third repeated treatment (200 mg * 1, 4.8%; 200 mg x 2, 7.1% after 12 weeks). Sixteen patients (16.7%) in the open-label extension phase experienced an emerging treatment adverse event (occurring on or after each dose of open-label ABT-874 up to 45 days after the stop date of each dose) considered possibly in relation to the study drug (Table 14). While no deaths or serious infections were reported during the io open label extension phase, 3 patients experienced serious adverse events. The only adverse events that occurred with a prevalence of> 5%, but less than 10%, during the open-label extension phase were nasopharyngitis, upper respiratory tract infection, injection site reactions, and hypertension (Table 14 ).

Table 14. Synopsis of AEs Produced by Treatment

During the Phase8 Open Label Extension

<td colspan="4">ABT-874 Treatment Group</td>

<td>Adverse event, (%) n</td><td>200 mg x 1 (n = 52)</td><td>200 mg x 2 (n = 44)</td><td>Everybody ABT-874 (n = 96)</td>

<td>Any AE at least possibly related with the drug</td><td> 11(21.2)</td><td> 5(11.4)</td><td> 16(16.7)</td>

<td>Any severe AE</td><td> 2(3.8)</td><td> 1(2.3)</td><td> 3(3.1)</td>

357

<td colspan="4">ABT-874 Treatment Group</td>

<td>Adverse event, (%) n</td><td>200 mg x one (n = 52)</td><td>200 mg x 2 (n = 44)</td><td>Everybody ABT-874 (n = 96)</td>

<td>Any severe AE</td><td> 2(3.8)</td><td> 1(2.3)</td><td> 3(3.1)</td>

<td>Any serious AE</td><td> 3(5.8)</td><td> 0</td><td> 3.(3.1)</td>

<td>Any AE leading to CD study drug</td><td> 2(3.8)</td><td> 0</td><td> 2(2.1)</td>

<td>Any AE at least possibly related and serious</td><td> 15(28.8)</td><td> 12(29.5)</td><td> 28(29.2)</td>

<td>Any serious infectious AE</td><td> 0</td><td> 0</td><td> 0</td>

<td>Any skin cancer does not melanoma or malignant</td><td> 0</td><td> 0</td><td> 0</td>

<td>Death</td><td> 0</td><td> 0</td><td> 0</td>

<td>Emergent AE treatment with a of treatment</td><td>incidence</td><td colspan="2">> 5% in any group</td>

<td>Nasopharyngitis</td><td> 5(9.6)</td><td> 3(6.8)</td><td> 8(8.3)</td>

<td>Respiratory tract infection higher</td><td> 4(7.7)</td><td> 4(9.1)</td><td> 8(8.3)</td>

<td>Injection site reaction</td><td> 5 (9.6)</td><td> 1(2-3)</td><td> 6(6.3)</td>

<td>Hypertension</td><td> 2(3.8)</td><td> 3(6.8)</td><td> 5(5.2)</td>

<td>Headache</td><td> 1(1.9)</td><td> 3(6.8)</td><td> 4(4,2)</td>

<td>Influenza</td><td> 0</td><td> 3(6.8)</td><td> 3(3.1)</td>

358

ΑΕ = adverse event; DC = suspensiontoAdverse events are reported by patients who received ABT-874 during the open-label extension phase;

96 of 105 patients who entered this phase received repeated treatment.

bPatients who experienced more than 1 serious adverse event were counted only once in the total serious adverse event. In the 2000 mg x 1 group, one patient experienced 10 chest discomfort, chest pain, and dlspnea, one patient experienced obesity, and one patient experienced meningioma.

III. conclusion

The preliminary safety and efficacy profile of ABT-874 in patients who were portrayed for moderate to severe chronic plaque psoriasis was determined. Current study data shows that anti-IL-12/23 therapy holds significant promise for the treatment and repeat treatment of patients with moderate to severe plaque psoriasis.

Among all the patients who received any therapy 20 ABT-874, a great majority of patients reached the response of

PASI 75 after 12 weeks of treatment, regardless of baseline weight, PGA and PASI counts, history of psoriatic arthritis, or previous psoriasis treatment.

After achieving a PASI 75 response after 25 12 weeks of treatment in the initial double-blind period and

359 discontinuation of treatment in the observation / repeated treatment period, many patients were able to maintain a PASI 75 response for a certain time without repeated treatment. The average time to loss of response was longer in patients receiving higher doses of ABT-874, with the average time to lose the PASI 75 response with an interval of up to 184 days in the weekly dosing branch.

Of particular importance, the time required to regain PASI 75 sensitivity among ABT-874-recruited patients was relatively short, ranging from 30 to 62 days. This is the probably related dose, based on how long you had to relapse. In the initial phase of the study at week 12, a PASI 75 response was achieved by most patients in each ABT-874 treatment group after 8 to 12 weeks, with an average of 57 to 85 days. Results from the open-label exposure phase show decreased response for subsequent roundings of repeat treatment

ABT-874. Possible explanations for this reduced response include the abbreviated dosing regimen used during open-label extension (ABT-874 200 mg x 1 or 2), as well as the amount of drug received and corresponding pharmacokinetic factors such as the concentration of

ABT-874.

360

In conclusion, these data show that ABT-874 is an effective and safe treatment option for the treatment and repeated treatment of moderate to severe chronic plaque psoriasis.

Example 10: Efficacy of Treatment with ABT-874, an Iterl ucina-1 2/23 Monoclonal Antibody, Through the Body Regions of Patients with Moderate to Severe Psoriasis

I. Materials and Methods io A. Study Design

The following was a double-blind, placebo-controlled, multi-center, randomized study at week twelve. One hundred and eighty patients with psoriasis affecting ¿10% of the body surface area and a count ¿12 of the Area index and

Psoriasis Severity (PASI) were randomized: one dose of 200 mg of ABT-874 at week 0, 100 mg of ABT874 every two weeks (eow) for 12 weeks, 200 mg of ABT-874 weekly for 4 weeks , 200 mg ABT-874 eow for 12 weeks, 200 mg ABT-874 weekly for

12 weeks, or placebo. The primary end point was the PASI 75 response by week 12. Individual PASI counts in the four body regions used for the evaluation of

PASI were also determined.

B. Main Criteria for Inclusion and Exclusion

The main inclusion criteria for the study were:

361

Adult patients with moderate to severe chronic plaque psoriasis for at least 6 months;

Stable for at least 2 months;

10% BSA;

PASI ¿12; and

Moderate or Severe Global Physician Assessment (PGA)

The main exclusion criteria for the study were:

Previous exposure to any systemic anti-IL-12 therapy, 10 including ABT-874;

Diagnosis of erythrodermic psoriasis, postular psoriasis, medication-exacerbated or medication-induced psoriasis, or newly-started gouty psoriasis;

Diagnosis of other active skin diseases or 15 skin infections that could interfere with the evaluation of psoriasis;

Inability to continue previous medication;

Topics and phototherapy for 2 weeks;

Non-biological systemic therapies for 4 weeks; and 20 Biological for 12 weeks

C. Efficacy Measurements

The following measures of efficacy were used in the present study:

The percentage of patients in each group reaching the 25 response of ¿PASI 75 and ¿PASI 90 at week 12; and

362

The percentage of patients in each group achieving the response of £ PASI 75 and £ PASI 90 at week 12 in specific regions:

Head and neck;

Superior limbs;

Torso; and

Lower extremities

D. Security Measurements

Laboratory results, vital signs, and 10 adverse events (AEs) were used to determine the safety of the treatment.

E. Statistical Methods

The following statistical methods were used to determine the efficacy of the treatment:

Comparison of the proportion of subjects achieving sPASI at week 12 between the ABT-874 dose group and the placebo group using the Fisher exact test, with a 95% double-sided confidence interval for the difference in proportion;

The patients for whom the data were missing were assumed to have no responses (imputation without response); and P <0.05 indicated statistical significance

II.Results

A. Baseline demographics

Baseline clinical and demographic characteristics were similar across treatment groups. See table 15.

LZi

C / Ί

Table 15. Disease Characteristics and Demographic Baseline

<td colspan="9">Treatment Group</td>

<td>Parameter</td><td>Placebo N = 30</td><td>1 dose 200 mg N = 30</td><td>1 00 mg eow N = 30</td><td>4 doses 200 mg N = 30</td><td>200 mg Eow N = 30</td><td>200 mg ew N = 30</td><td>Everybody ABT-874 N = 150</td><td>Total</td>

<td colspan="9">Age (years)</td>

<td>Average</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>(interval)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="3">Average 49.5 (18- 52.5 (24.69)</td><td> 45.0(18-</td><td> 43.0(20-</td><td> 39.0(25-</td><td> 47.0(19-76)</td><td> 46.0(18-79)</td><td> 47.0(18-80)</td>

<td>Woman</td><td colspan="2"> 8(26.7) 7(23.3)</td><td> 8(26.7)</td><td> 9(30.0)</td><td> 7(23.3)</td><td> 7(23.3)</td><td> 38(25.3)</td><td> 46(25.6)</td>

<td colspan="9">Weight (kg)</td>

<td>Average ±</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Κ)

THE

Ν) - -

O LA o

THE

<td colspan="10">Treatment Group</td>

<td>Parameter</td><td>Placebo N = 30</td><td>1 dose 200 mg N = 30</td><td>1 00 mg eow N = 30</td><td>4 doses 200 mg N = 30</td><td>200 mg eow N = 30</td><td colspan="2">200 mg ew N = 30</td><td>Everybody ABT-874 N = 150</td><td>T otal</td>

<td>(interval) Average</td><td> (43.0- 140.0)</td><td>(61.ΟΙ 45.0)</td><td>(60.ΟΙ 25. 0)</td><td> (54.0- 169.0)</td><td> (62.0- 161.0)</td><td colspan="2"> (68.0-1 53.0)</td><td> (54.0(169.0)</td><td> (43.0- 169.0)</td>

<td>History of psoriasis in family, (%) n</td><td> 9(30.0)</td><td> 17(56.7)</td><td> 21(70.0)</td><td> 23(76.7)</td><td> 15(50.0)</td><td colspan="2"> 12(40.0)</td><td> 88(58.7)</td><td> 97(53.9)</td>

<td colspan="2">Psoriasis Duration</td><td colspan="3">Chronicle on Plate (years)</td><td></td><td></td><td></td><td></td><td></td>

<td>Average ± SD</td><td> 21,43±12.40</td><td> 1 9.78±13.18</td><td> 23.95±14.60</td><td> 22.09±14.24</td><td colspan="2"> 18.5±11.52</td><td> 17.93±10.89</td><td> 20.45±12.99</td><td> 20.61±12.87</td>

<td>(interval) average</td><td> 20.55(1.0- 48.1)</td><td> 17.55(1.6- 43.0)</td><td> 22.05(3.2- 59.1)</td><td> 21.0(1.3- 53.0)</td><td colspan="2"> 18.09(0.8- 55.1 )</td><td> 15.68(41.1- 47.1)</td><td> 19.11(0.8- 59.1)</td><td> 19.58(0.8- 59.1)</td>

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OR\

Κ)

THE

<td colspan="9">Treatment Group</td>

<td>Parameter</td><td>Placebo N = 30</td><td>1 dose 200 mg N = 30</td><td>100 mg eow N = 30</td><td>4 doses 200 mg N = 30</td><td>200 mg eow N = 30</td><td>200 mg ew N = 30</td><td>Everybody ABT-874 N = 150</td><td>T otal</td>

<td>Average</td><td> 15.83±2.86</td><td> 17.96±6.72</td><td> 19.93±6.29</td><td> 19.94±7.57</td><td> 19.86±6.20</td><td> 18.96±6.33</td><td> 1 9.33±6.60</td><td> 18. 75±6.27</td>

<td>(interval)</td><td> 16.10(10.2-</td><td> 14.95(12.1-</td><td> 18.65(12.4-</td><td> 16.95(12.3-</td><td> 18.0(1 1.9-</td><td> 16.75(12.2-</td><td> 17.25(11.9-</td><td> 16.85(10.2-</td>

<td>average</td><td> 22.6)</td><td> 35.4)</td><td> 34.4)</td><td> 41 .4)</td><td> 33.4)</td><td> 37.2)</td><td> 4 1.4)</td><td> 41-4)</td>

<td>Average</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>(interval)</td><td> 17.5(11.0-</td><td> 1 7.5(10.0-</td><td> 22.5( 11.0-</td><td> 20.3(10.0-</td><td> 22.0(11.0-</td><td> 19.5(10.0-</td><td> 20.0(1 0.0-</td><td> 20.0(10.0-</td>

<td>Average</td><td> 45.0)</td><td> 57.5)</td><td> 74.0)</td><td> 59.0)</td><td> 82.0)</td><td> 53.0)</td><td> 82.0)</td><td> 82.0)</td>

<td>Minimum</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

KJ

Μ »

Κ3

OR

LZ »

Treatment Group

<td>Moderate</td><td> 20(66.7)</td><td> 19(63.3)</td><td> 17(56.7)</td><td> 13(43.3)</td><td colspan="2"> 15(50.0)</td><td> 17(56.7)</td><td> 81(54.0)</td><td> 10(56.1)</td>

<td>Severe</td><td> 9(30.0)</td><td> 1 1(36.7)</td><td> 12(40.0)</td><td> 14(46.7)</td><td colspan="2"> 13(43.3)</td><td> 1 1(36.7)</td><td> 61(40.7)</td><td> 70(38.9)</td>

<td>Very severe</td><td> 0</td><td> 0</td><td> 1(3.3)</td><td> 3(10.0)</td><td colspan="2"> 2(2.7)</td><td> 2(6.7)</td><td> 8(5.3)</td><td> 8(4.4)</td>

<td>Record Arthritis Psoriatic, (%) n</td><td> 9(30.0)</td><td> 7(23.3)</td><td> 12(40.0)</td><td> 9(30.0)</td><td colspan="2"> 6(20.0)</td><td> 9(30.0)</td><td> 43(28.7)</td><td> 52(28.9)</td>

<td colspan="10">Duration of Psoriatic Arthritis (artos)</td>

<td colspan="3">Average 10.69 * 11.70 13.51 * 10.67</td><td> 1 1.25*12.00</td><td> 13.0*12.60</td><td colspan="2"> 8.6*8.31</td><td> 14.18*11.78</td><td> 12.23*1 1.06</td><td> 11.96*11.07</td>

± SD hJ

LM

K)

OR

LM

<td colspan="10">Treatment Group</td>

<td>(interval) average</td><td> 5.82(0.1- 30.0)</td><td> 16.05(2.2- 31.0)</td><td> 8.03(1.1- 45.1)</td><td> 10.91(0.1- 37.2)</td><td colspan="2"> 4.3 3 (2.6±22.9)</td><td> 1 1.1(0.2- 36.0)</td><td> 8.13(0. 1 - 45. 1 )</td><td> 7.02(0.1 - 45.1)</td>

<td>Inflammation, Sensitivity, 0 Joints stiff, (%) n</td><td> 8(26.7)</td><td> 1 1(36.7)</td><td> 10(33.3)</td><td> 10(33.3)</td><td colspan="2"> 9(30.0)</td><td> 15(50.0)</td><td> 55(36.7)</td><td> 63(35.0)</td>

Section 1.02 eow; biweekly

367

Ew: every week

368

B. Efficacy

A large majority of patients treated with any dose of ABT-874 achieved £ PASI 75 or £ PASI 90 at week 12 compared to placebo (Figure 13).

In specific regions of the body, a large percentage of patients treated with ABT-874 reached £ PASI 75 and £ PASI 90 at week 12 compared to placebo (Figures 14A-14D).

The percentage of patients achieving £ PASI75 and £ PASI90 at Week 12 was higher for all dosing groups with ABT-874 combined against the placebo group (86.0% vs. 3.3% and 57% vs. 0.0% respectively. Dosing groups with ABT-874 combined, a higher percentage achieved improvements of £ 75 and £ 90 in PASI counts as compared to placebo patients for all body regions examined: head and neck (PASI 75, (3.3 % against

13.3%; PASI 90, 72.0% vs. 13.3%), upper extremities (PASI 75,

81.3% against 3.3%; PASI 90, 57.3% vs. 3.3%), torso (PASI 75, 82.0% vs. 3.3%; PASI 90, 68.0% vs. 3.3%), lower extremities (PASI 75, 78.0% vs. 3.3%; PASI 90, 48.0% vs. 0.0 %).

C. Security

A synopsis of the percentage number of subjects with adverse events produced by the treatment was presented in Table 16. Most of the reported AEs were mild or moderate in severity. The percentage of patients who experienced serious AES was low. Most frequently reported treatment-related adverse events that occurred in £ 5% of the patients listed in Table 17.

LM

Table 16. Synopsis of the adverse events produced by the treatment.

ABT-874

<td></td><td>200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

n (%)

Any adverse event (AE) Any AE at least possibly drug related3

Any severe AE

Any serious AE

Any AE leading to suspension of study drug

Any AE at least possibly drug related3

Any infectious AE

LJ

You

SO t-Λ

OR

Any serious infectious AE

Any malicious AE

Any AE lymphoma

Any AE from skin cancer other than melanoma (NMSC)

Any condition AE (except NMSC and lymphoma)

Any condition AE (including lymphomas, except NMSC)

Any AE related to the site of (_Λ

ABT-874

<td></td><td>200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

n (%)

THE

OR

THE bJ

L / ι bO

OR

ABT-874

<td></td><td>200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

<td colspan="8">injection</td>

<td>Deaths0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

eow = every two weeks; ew = every week

to. As or determined by the Investigator.

b. P value = 0.045 against placebo.

c. P value = 0.002 against placebo.

d. Includes deaths not caused by treatment.

Note: Treatment event defined as any adverse event with a start date on or after the first double-blind dose and up to 45 days after the last double-blind dose. An event with unknown severity is considered severe. Fisher exact test P values to compare six treatment groups.

LA or

THE

Κ)

The

Κ)

OR

Table 17. Adverse events produced by treatment that occur in> 5% of patients.

ABT-874

<td></td><td colspan="2">200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td></td><td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

<td>MedDRA Preferred Term</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30 n (%)</td><td>N = 30</td><td>N = 30</td><td>N = 150</td>

<td>Injection site reaction</td><td> 0</td><td> 2 (6.7)</td><td> 7 (23.3)</td><td> 5(16.7)</td><td> 7 (23.3)</td><td> 4(13.3)</td><td> 25(16.7)3</td>

<td>Nasopharyngitis Respiratory tract infection</td><td> 1 (3.3)</td><td> 5 (16.7)</td><td> 6 (20.0)</td><td> 3(10.0)</td><td> 3(10.0)</td><td> 5(16.7)</td><td> 22 (14.7)</td>

<td>higher</td><td> 2 (6.7)</td><td> 2 (6.7)</td><td> 4(13.3)</td><td> 3(10.0)</td><td> 5(16.7)</td><td> 2(6.7)</td><td> 16(10.7)</td>

<td>Headache</td><td> 2 (6.7)</td><td> 5 (16.7)</td><td> 0</td><td> 1 (3-3)</td><td> 3(10.0)</td><td> 2 (6.7)</td><td> 11 (7.3)</td>

<td>Injection site itching</td><td> 0</td><td> 0</td><td> 1 (3.3)</td><td> 2 (6.7)</td><td> 2 (6.7)</td><td> 2(6.7)</td><td> 7 (4.7)</td>

<td>Injection site erythema</td><td> 0</td><td> 0</td><td> 0</td><td> 4(13.3)</td><td> 2 (6.7)</td><td> 1 (3.3)</td><td> 7 (4.7)b</td>

<td>Injection site irritation</td><td> 0</td><td> 1 (3.3)</td><td> 3(10.0)</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 6 (4.0)</td>

LA or

LA to

OR

ABT-874

<td></td><td colspan="2">200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td></td><td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

<td>MedDRA Preferred Term</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30 n (%)</td><td>N = 30</td><td>N = 30</td><td>N = 150</td>

<td>Fatigue</td><td> 0</td><td> 2 (6.7)</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 1 (3.3)</td><td> 5 (3.3)</td>

<td>Arthralgia</td><td> 1 (3.3)</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 4 (2.7)</td>

<td>Vira infection!</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 1 (3.3)</td><td> 1 (3.3)</td><td> 4 (2.7)</td>

<td>Bronchitis</td><td> 0</td><td> 1 (3.3)</td><td> 0</td><td> 1 (3.3)</td><td> 2 (6.7)</td><td> 0</td><td> 4 (2.7)</td>

<td>Hypertriglyceridaemia</td><td> 0</td><td> 1 (3.3)</td><td> 1 (3.3)</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 4 (2.7)</td>

<td>Influenza</td><td> 1 (3.3)</td><td> 0</td><td> 1 (3.3)</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 3 (2.0)</td>

<td>Nausea</td><td> 2 (6.7)</td><td> 0</td><td> 3(10.0))</td><td> 0</td><td> 0</td><td> 0</td><td> 3 (2.0)c</td>

<td>Cysts</td><td> 0</td><td> 1 (3.3)</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 3 (2.0)</td>

<td>Stomach flu</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 2(1.3)</td>

373 bJ

LZl bJ

OR

LZ »

ABT-874

<td></td><td colspan="2">200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td></td><td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

<td>MedDRA Preferred Term</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30 n (%)</td><td>N = 30</td><td>N = 30</td><td>N = 150</td>

<td>External otitis</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 2(1-3)</td>

<td>Threw up</td><td> 1 (3.3)</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 2(1-3)</td>

<td>Hypercholesterolemia</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Urinary tract infection</td><td> 2 (6.7)</td><td> 1 (3.3)</td><td> 0</td><td> 1 (3.3)</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Increased blood pressure</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Limb injury</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2(1-3)</td>

<td>Pruritus</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (3.3)</td><td> 1 (07)</td>

<td>Psoriatic arthropathy</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

374 eow = every two weeks; ew = every week

KJ t-Λ

NJ

OR

to. P value = 0.028

b. P value = 0.052

c. P value = 0.053

Note: Event caused by treatment defined as any adverse event with a start date on or after the first double-blind dose and up to 45 days after the last double-blind dose. An event with unknown severity is considered severe. Fisher exact test P values to compare six treatment groups.

t-Λ

376

III. conclusion

In this study, treatment with ABT-874 led to clinically significant improvements in the four regions of the body that comprise the PASI count, which include traditionally resistant areas such as the head and neck and lower extremities, in patients with moderate to severe psoriasis • Regional as well as total benefits were demonstrated with all doses of ABT-874 compared to placebo • The results of this study support the utility of IL-12/23 as an objective therapeutic in the chronic plaque psoriasis.

Example 11: Effect of baseline characteristics on the efficacy of ABT-874 for the treatment of moderate to severe psoriasis

I. methods

A. Study design

The following was a 12-week, randomized, 20 double-blind, placebo-controlled, multicenter study. One hundred and eighty adult patients with psoriasis affecting £ 10% of body surface area and a psoriasis area and severity index (PASI) count of £ 12 were randomly assigned to a 200 mg dose of ABT-874 at week 0.100 mg ABT-874 every two weeks (eow) for 12 weeks, 200 mg ABT377

874 every week for 4 weeks, ABT-874 200 mg eow for 12 weeks, ABT-874 200 mg every week for 12 weeks, or placebo. The effects of the following baseline characteristics on response speeds of

PASI 75 for 12 weeks: weight, PsA history, PASI count, previous psoriasis treatments and PGA count (severe / very severe). The PGA count was a retrospective analysis. Results are presented for all combined ABT-874 dosage groups after 12 weeks of treatment.

B. Main inclusion and exclusion criteria

The main inclusion criteria for the study were:

Adult patients with moderate to severe chronic plaque psoriasis for at least 6 months;

Stable for at least 2 months;

£ 10% BSA;

£ 12 from PASI; and

Moderate or Severe Overall Physician Assessment (PGA) The main exclusion criteria for the study were:

Previous exposure to any systemic anti-IL-12 therapy, including ABT-874;

Diagnosis of erythrodermic psoriasis, pustular psoriasis, medication-induced or medication-exacerbated psoriasis, or newly developed gouty psoriasis;

Diagnosis of other active diseases or infections of the

378 skin that could interfere with the evaluation of psoriasis;

Inability to continue previous medication;

Topics and phototherapy for 2 weeks;

Systemic non-biological therapies for 4 weeks; and 5 Biological for 12 weeks

C. Measurements of efficacy

The following measures of efficacy were used in the present study:

The percentage of patients in each group achieving a response of £ PASI 75 and £ PASI 90 at week 12; and

Efficacy analysis subgroups (baseline):

Weight (^ 100 kg or> 100 kg)

Psoriatic arthritis (PsA) history

Previous psoriasis treatments

PGA count

D. Security measures

Laboratory results, vital samples, and adverse events (EAs) were used to determine the safety of the treatment.

E. Statistical methods

The following statistical methods were used to determine the efficacy of the treatment:

Comparison of the proportion of subjects achieving ^ PASI 75 at week 12 between the dose group of

ABT-874 and the placebo group using the exact test of

379

Fisher, with a 95% bilateral confidence interval for the difference in the proportion;

The patients for whom the data were absent were assumed to be non-responders (imputation of no 5 responders); and

P <0.05 indicated statistical significance

II. Results

A. Demographics of the baseline

Demographic and clinical baseline characteristics were similar across treatment groups. See table 18.

Κ)

THE

Ν>

OR

THE

Table 18. Demographic and Baseline Disease Characteristics

Treatment Group

<td></td><td colspan="2">200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td colspan="2">Everybody</td>

<td></td><td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td><td>Total</td>

<td>Parameter</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 150</td><td>N = 180</td>

<td>Age (years)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Average ± SD</td><td> 49.2 114.36</td><td> 51.51</td><td> 44.51</td><td> 43.41</td><td> 43.51</td><td> 46.3 1</td><td> 45.91</td><td> 46.4114.15</td>

<td>Medium (interval)</td><td> 49.5</td><td> 12.00</td><td> 13.76</td><td> 13.77</td><td> 15.95</td><td> 14.00</td><td> 14.09</td><td> 47.0</td>

<td>Female</td><td> 8 (26.7)</td><td> 7 (23.3)</td><td> 8 (26.7)</td><td> 9 (30.0)</td><td> 7 (23.3)</td><td> 7 (23.3)</td><td> 38 (25.3)</td><td> 46 (25.6)</td>

Weight (kg)

LJ

OR

Average ± SD

89.3117.57 93.512121 93.9± 17.88 92.1 ±27.85 93.4124.06 94.6118.03 93.5121.85 92.8 1 21.21

AC

OR

AC

K)

OR

Treatment Group

<td></td><td colspan="2">200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td colspan="2">Everybody</td>

<td></td><td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td><td>Total</td>

<td>Parameter</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 150</td><td>N = 180</td>

<td>Means, medium</td><td> 90.0</td><td> 89.5</td><td> 91.1</td><td> 89.0</td><td> 89.0</td><td> 932</td><td> 90.0</td><td> 90.0</td>

<td>(interval)</td><td> (43.0-140.0)</td><td> (61.0-145.0)</td><td> (60.0-125.0)</td><td> (54.0-169.0)</td><td> (620-161.0)</td><td> (68.0-153.0)</td><td> (54.0-169.0)</td><td> (43.0-169.0)</td>

<td colspan="9">Weight group, n (%)</td>

<td colspan="9">Family history of psoriasis</td>

<td colspan="9">Duration of psoriasis plaque chronic (years) Average ± SD</td>

<td>Medium (interval)</td><td> 21.43 ±</td><td> 19.78 ±</td><td>23.95 i</td><td> 22.09 ±</td><td> 18.5 ±</td><td> 17.93 ±</td><td> 20.45 ±</td><td> 20.61 ± 12.87</td>

LA or

THE

Κ)

THE

Κ)

OR

Treatment Group

<td></td><td colspan="2">200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td colspan="2">Everybody</td>

<td></td><td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td><td>Total</td>

<td>Parameter</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 150</td><td>N = 180</td>

<td>Average ± SD</td><td> 15.83 ±2.86</td><td> 17.96 ±</td><td> 19.93 ±</td><td> 19.94 ±</td><td> 19.86 ±</td><td> 18.96 ±</td><td> 19.33 ±</td><td> 18.75 ±6.27</td>

<td>Medium (interval)</td><td> 16.10 (10.2-</td><td> 6.72</td><td> 6.29</td><td> 7.57</td><td> 6.20</td><td> 6.33</td><td> 6.60</td><td> 16.85 (10.2-</td>

BSA (%)

LZi

OR

L / l tO

NJ

OR

Treatment Group

<td></td><td colspan="2">200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td colspan="2">Everybody</td>

<td></td><td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td><td>Total</td>

<td>Parameter</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 150</td><td>N = 180</td>

<td>Average ± SD</td><td> 20.88 ±9.18</td><td> 24.06 ±</td><td> 27.88 ±</td><td> 24.15 ±</td><td> 29.06 ±</td><td> 22.92 ±</td><td> 25.61 ±</td><td> 24.83 ± 13.81</td>

<td>Medium (interval)</td><td> 17.5(11.0-</td><td> 13.58</td><td> 15.68</td><td> 13.05</td><td> 16.84</td><td> 12.61</td><td> 14.45</td><td> 20.0 (10.0-</td>

<td>Minimum</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td>Moderate</td><td> 20 (66.7)</td><td> 19(63.3)</td><td> 17(56.7)</td><td> 13(43.3)</td><td> 15(50.0)</td><td> 17(56.7)</td><td> 81(54.0)</td><td> 101(56.1)</td>

<td>Severe</td><td> 9 (30.0)</td><td> 11(36.7)</td><td> 12(40.0)</td><td> 14(46.7)</td><td> 13(43.3)</td><td> 11(36.7)</td><td> 61(40.7)</td><td> 70(38.9)</td>

LZi or

Lz »bJ

OR

Treatment Group

<td></td><td colspan="2">200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td colspan="2">Everybody</td>

<td></td><td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td><td>Total</td>

<td>Parameter</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 30</td><td>N = 150</td><td>N = 180</td>

<td>Very severe</td><td> 0</td><td> 0</td><td> 1 (3.3)</td><td> 3(10.0)</td><td> 2(6.7)</td><td> 2(6.7)</td><td> 8(5.3)</td><td> 8(4.4)</td>

<td>History of psoriatic arthritis, n (%) Duration of psoriatic arthritis (years)</td><td> 9 (30.0)</td><td> 7(23.3)</td><td> 12(40.0)</td><td> 9(30.0)</td><td> 6(20.0)</td><td> 9(30.0)</td><td> 43(28.7)</td><td> 52(28.9)</td>

<td>Average ± SD</td><td> 10.69± 11.70</td><td> 13.51 ±10.67</td><td> 112511200</td><td> 13011260</td><td> 861831</td><td> 14.18111.78</td><td> 1223111.06</td><td> 11.96111.07</td>

<td>Medium (interval)</td><td> 5.82(0.1-30.0)</td><td> 1605(2231.0)</td><td> 8.03(1.1-45.1)</td><td> 10.91(0.1-372)</td><td> 4.33(261229)</td><td colspan="2"> 11.1(02-36.0) 813(0.1-45.1)</td><td> 7.02(0.1-45.1)</td>

<td>Swollen joints,</td><td> 8 (26.7)</td><td> 11 (36.7)</td><td> 10(33.3)</td><td> 10(33.3)</td><td> 9 (30.0)</td><td> 15(50.0)</td><td> 55 (36.7)</td><td> 63 (35.0)</td>

soft, or stiff, n (%) eow: every two weeks

384 ew: every week

385

B. Efficacy

A higher percentage of patients treated with any dose of ABT-874 who achieved £ PASI 75 or £ PASI 90 at week 12 were compared to placebo (Figure 15).

The effect of baseline characteristics on efficacy was examined. The similar percentages of patients in two weight categories (100 kg or> 100 kg) treated with any dose of ABT874 who achieved a PASI 75 at week 12 (Figure 16). Particularly, at week 12, the percentage of patients who achieved PASI 75 in the groups of 100 kg or> 100 kg was 88.7% against 81.1% respectively. Similar percentages of patients with or without a history of PsA reached PASI 75 at week 12 (Figure 17). In particular, the PASI 75 responses for patients with and without previous PsA were 83.7% against

86.9% respectively. A majority of patients (85.5%) with severe or very severe baseline PGA count achieved PASI 75 at week 12 (Figure 18). Similar percentages of patients in two PASI baseline categories (¿20 or> 20) reached PASI 75 at week 12 (Figure 19). For patients with counts of

PASI baseline of 20 or> 20, 87.0% vs. 84.0% achieved PASI 75 responses at week 12, respectively. Finally, previous psoriasis treatments such as systemic or biological agents, topical agents, or phototherapy did not appear to affect PASI 75 response rates, and thus had minimal effect on the efficacy of ABT-874 (Table 19).

386

Table 19. PASI 75 response at week 12 for previous psoriasis treatment.

<td colspan="2"></td><td colspan="2">Systemic</td><td colspan="2">Biological</td><td colspan="2">Topical</td><td colspan="2">Phototherapy</td>

<td>ABT-874</td><td>% which reached</td><td> 90%</td><td> 85%</td><td> 85.2</td><td> 86.2</td><td> 88.7</td><td> 79.5</td><td> 90.9</td><td> 85.2</td>

<td>Placebo</td><td>% which reached</td><td> 0.0%</td><td> 4.2%</td><td> 0.0%</td><td> 3.7%</td><td> 0.0%</td><td> 9.1%</td><td> 0.0%</td><td> 3.4%</td>

C. Security

A synopsis of the number and percentage of subjects with adverse events produced by the treatment is presented in Table 20. The majority of AEs described were of mild or moderate severity. The percentage of patients who experienced serious AEs was low. The most frequently reported adverse events from treatment that occur in 5% of patients are listed in Table 21.

OR

LM or

LM bJ

LM

Table 20. Synopsis of the adverse events produced by the treatment.

ABT-874

<td></td><td>200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

<td>Any adverse event (AE)</td><td> 18 (60.0)</td><td> 18(60.0)</td><td> 24 (80.0)</td><td> 22 (73.3)</td><td> 23 (76.7)</td><td> 21 (70.0)</td><td> 108 (72.0)</td>

<td>Any AE at least possibly drug related3</td><td> 4(13.3)</td><td> 9 (30.0)</td><td> 14 (46.7)</td><td> 14(46.7)</td><td> 12 (40.0)</td><td> 9 (30.0)</td><td> 58 (38.7)b</td>

<td>Any severe AE</td><td> 4(13.3)</td><td> 1 (3.3)</td><td> 0</td><td> 0</td><td> 1 (3.3)</td><td> 1 (3.3)</td><td> 3 (2.0)</td>

<td>Any serious AE</td><td> 1 (3.3)</td><td> 1 (3.3)</td><td> 0</td><td> 0</td><td> 1 (3.3)</td><td> 0</td><td> 2(1.3)</td>

<td>Any AE that leads to suspension of the drug</td><td> 2(6.7)</td><td> 1 (3-3)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (0.7)</td>

<td>Any serious AE at least possibly</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (3.3)</td><td> 0</td><td> 1 (0-7)</td>

Κ)

LZi

Κ>

Or related to the drug3

Any infectious AE

Any serious infectious AE

Any malicious AE

Any AE from lymphomas

Any AE from skin cancer other than melanoma (NMSC)

Any condition AE (except NMSC and lymphomas)

Any AE of condition (including lymphomas,

LZi or

ABT-874

<td>Placebo N = 30</td><td>200 mg 1 dose N = 30</td><td>100 mg eow N = 30</td><td>200 mg 4 Dose N = 30</td><td>200 mg eow N = 30</td><td>200 mg ew N = 30</td><td>Everybody ABT-874 N = 150</td>

THE

OR

THE

Κ)

THE

ABT-874

<td></td><td>200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

n (%) except NMSC)

Any AE related to injection site reaction Any fatal AE Deaths0

4(13.3)

9(30.0) 10(33.3) 10(33.3) 6(20.0) 39 (26.0)c

389 eow = every two weeks; ew = every week

to. As or determined by the Investigator.

b. P value = 0.045 against placebo.

c. P value = 0.002 against placebo.

d. Includes deaths not caused by treatment.

L / ι

OR

THE

OR

THE

Table 21. Adverse events caused by treatment that occur in> 5% of patients.

ABT-874

<td></td><td>200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

<td colspan="3">MedDRA Preferred Term</td><td colspan="5">n (%)</td>

<td>Injection site reaction</td><td> 0</td><td> 2 (6.7)</td><td> 7 (23.3)</td><td> 5(16.7)</td><td> 7 (23.3)</td><td> 4(13.3)</td><td> 25(16.7)3</td>

<td>Nasopharyngitis</td><td> 1 (3-3)</td><td> 5 (16.7)</td><td> 6 (20.0)</td><td> 3 (10.0)</td><td> 3 (10.0)</td><td> 5 (16.7)</td><td> 22 (14.7)</td>

<td>Upper respiratory tract infection</td><td> 2 (6.7)</td><td> 2 (6.7)</td><td> 4 (13.3)</td><td> 3(10.0)</td><td> 5 (16.7)</td><td> 2 (6.7)</td><td> 16(10.7)</td>

<td>Headache</td><td> 2 (6.7)</td><td> 5 (16.7)</td><td> 0</td><td> 1 (3.3)</td><td> 3 (10.0)</td><td> 2 (6.7)</td><td> 11 (7.3)</td>

LJ

OR

Injection site itching Injection site erythema Injection site irritation Fatigue (3.3) 2 (6.7) (3.3) 2 (6.7)

4(13.3) (10.0) 2 (6.7) (6.7) (6.7) 2 (6.7) (6.7) 7 (4.7) (3.3) 7 (4.7)b

6 (4.0) (3.3) 5 (3.3)

The

OR

The bu

QA hJ

OR

ABT-874

<td></td><td>200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

<td>MedDRA Preferred Term</td><td colspan="7">n (%)</td>

<td>Arthralgia</td><td> 1 (3.3)</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 4 (2.7)</td>

<td>Viral infection</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 1 (3.3)</td><td> 1 (3.3)</td><td> 4 (2.7)</td>

<td>Bronchitis</td><td> 0</td><td> 1 (3.3)</td><td> 0</td><td> 1 (3.3)</td><td> 2 (6.7)</td><td> 0</td><td> 4 (2.7)</td>

<td>Hypertriglyceridaemia</td><td> 0</td><td> 1 (3.3)</td><td> 1 (3.3)</td><td> 2(6.7)</td><td> 0</td><td> 0</td><td> 4 (2.7)</td>

<td>Influenza</td><td> 1 (3.3)</td><td> 0</td><td> 1 (33)</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 3 (2.0)</td>

<td>Nausea</td><td> 2 (6.7)</td><td> 0</td><td> 3 (10.0)</td><td> 0</td><td> 0</td><td> 0</td><td> 3 (2.0)c</td>

<td>Cysts</td><td> 0</td><td> 1 (3.3)</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 3 (2.0)</td>

<td>Stomach flu</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 2(1-3)</td>

LM

OR

LM

Κ)

OR

ABT-874

<td></td><td>200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

<td>MedDRA Preferred Term</td><td colspan="7">n (%)</td>

<td>External otitis</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 2(1.3)</td>

<td>Threw up</td><td> 1 (3.3)</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 2(1-3)</td>

<td>Hypercholesterolemia</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 2(1-3)</td>

<td>Urinary tract infection</td><td> 2 (6.7)</td><td> 1 (3.3)</td><td> 0</td><td> 1 (3-3)</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Increased blood pressure</td><td> 0</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 2(1-3)</td>

<td>Limb injury</td><td> 0</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2(1.3)</td>

<td>Pruritus</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (3.3)</td><td> 1 (07)</td>

<td>Psoriatic arthropathy</td><td> 2 (6.7)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

eow = every two weeks; ew = every week

392

to.

P value = 0.028

Ν)

LA hJ - -

O LA O

THE

ABT-874

<td></td><td>200 mg</td><td>100 mg</td><td>200 mg</td><td>200 mg</td><td>200 mg</td><td>Everybody</td>

<td>Placebo</td><td>1 dose</td><td>eow</td><td>4 Dose</td><td>eow</td><td>ew</td><td>ABT-874</td>

MedDRA Preferred Term n (%)

b. P value = 0.052

c. P value = 0.053

Note: Event produced by the treatment defined as any event

Adverse LJ with an ice date on or after the first double-blind dose and up to 45 days ω after the last double-blind dose. An event with unknown severity is considered severe. Fisher exact test P values to compare six treatment groups.

394

III. conclusion

In this study, a majority of patients with moderate to severe psoriasis treated with ABT-874 achieved a PASI 75 response at week 12. The percentage of patients who achieved PASI 75 at week 12 was similar, regardless of the characteristics of baseline, including weight, physician's overall assessment, PASI counts, history of psoriatic arthritis, or previous psoriasis treatments. Example 12: Efficacy and safety results from a randomized, controlled phase III io trial comparing two ABT-874 dosing regimens with placebo in patients with moderate to severe psoriasis: Vero Study

I. METHODS

Design · Phase III clinical trial, 52 weeks, double-blind, placebo-controlled, multicenter with two phases: Induction and maintenance (figure 20) (NCT00570986) • Induction phase:

Patients were randomly assigned as

2nd 2: 1 and received 1 of 2 treatments:

ABT-874, 200 mg in weeks 0 and 4, followed by 100 mg in week 8

Placebo • Maintenance phase:

- Patients who achieved an evaluation count

395 Physicians overall of "non-existent" or "minimal" (PGA 0/1) at week 12 of the induction phase were randomized as 2: 2: 1 (stratified by treatment received in the induction phase) for 1 of 3 treatment arms:

- ABT-874, 100 mg every 4 weeks (q 4 wk)

ABT-874, 100 mg every 12 weeks (q 12 wk)

Placebo q 4 wk Efficacy and safety measures • Efficacy was measured using a 6-point Global Physician Assessment (PGA) scale and psoriasis area and severity index at weeks 0, 1, 4, and 8 of the induction phase, and every month during the maintenance phase (weeks 12 to 52) • Patients were evaluated for adverse events throughout the study, and up to 45 days after the last dose of study medication

Patients • Essential inclusion criteria:

Adult patients with chronic plaque psoriasis for at least 6 months (and stable for at least 2 months) before baseline

Moderate to severe psoriasis defined by the following at baseline:

Body surface area affected (BSA) of £ 10%

PGA at least “moderate” (defined as £ 3)

396

PASI £ 12 • Essential exclusion criteria;

Previous exposure to anti-interleukin therapy 12, including ABT-874

- Other forms of psoriasis (other than plaque psoriasis)

Treatment with any of the following:

Treatment with topics (i.e., corticosteroids, vitamin D analogues, or retinoids) or UVB phototherapy within 2 weeks of baseline

PUVA phototherapy or systemic treatments for psoriasis within 4 weeks from baseline • Biological treatments within 12 weeks from baseline

Statistical methods • The proportions of patients who achieved the following 3 primary endpoints were compared between treatment groups:

PGA 0/1 at week 12

2θ - 75% improvement from baseline in PASI (PASI 75) at week 12

PGA 0/1 maintenance at week 52 • Efficacy analyzes were conducted in the intention-to-treat population, and missing values were addressed using non-responsive imputation (NRI)

397 • All statistical tests were two-way. The primary analysis at week 12 was conducted using the Cochran-Mantel-Haenszel test. * In all other cases, one-way ANOVA and the chi-square test / Fisher's exact test were used for continuous and discrete variables, respectively .

• The level of statistical significance was set at P <.05 • Adjusted for grouped centers, where the smallest center was grouped with the next smallest center to reach at least 100 patients per grouped center.

RESULTS

Efficacy • 1465 patients enrolled in the Vero study (figure

21)

Induction phase:

ABT-874, N = 981 • Placebo, N = 484

Maintenance phase: (for patients receiving ABT-874 during induction)

ABT-874 q4 wk, N = 298

ABT-874 q12 wk, N = 298

Placebo, N = 149 • Baseline demographics and clinical characteristics were similar between treatment groups (Table 22) (-Λ ο

LZ »

Κ)

Κ) ο

Table 22. Baseline Demographic Data and Clinical Characteristics.

<td></td><td>I phase</td><td>induction</td><td colspan="3">Maintenance phase</td><td></td>

<td>characteristics</td><td>ABT-874</td><td>Placebo</td><td>ABT-874 q4</td><td>ABT-874 q12</td><td>Placebo</td><td>T otal</td>

<td>baseline</td><td>(N = 981)</td><td>(N = 484)</td><td>(N = 298)to</td><td>(N = 298)</td><td>(N = 149)</td><td>(N = 1465)</td>

<td>Average age,</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>yearsb</td><td> 45.7113.2</td><td> 45.1±13.5</td><td> 44.6113.3</td><td> 45.5112.6</td><td> 45.0113.4</td><td> 45.5113.3</td>

<td>Gender (f / m), n</td><td> 315/666</td><td> 141/343</td><td> 92/206</td><td> 97/201</td><td> 49/100</td><td> 456/1009</td>

<td>Caucasian, n (%)</td><td> 888 (90.5)</td><td> 432 (89.3)</td><td> 275 (92.3)</td><td> 278 (93.3)</td><td> 127 (85.2)</td><td> 1320 (90.1)</td>

<td>Weight, kg °</td><td> 93.8123.6</td><td> 93.1±23.0</td><td> 91.3121.3</td><td> 93.7123.4</td><td> 89.3124.6</td><td> 93.5123.4</td>

<td>Count</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>PASIb</td><td> 19.117.5</td><td> 19.317.3</td><td> 18.416.5</td><td> 18.316.2</td><td> 18.918.2</td><td> 19.217.4</td>

AC or

AC

Κ)

AC

Ν) or

<td></td><td colspan="2">Induction phase</td><td colspan="3">Maintenance phase</td><td></td>

<td>characteristics</td><td>ABT-874</td><td>Placebo</td><td>ABT-874 q4</td><td>ABT-874 q12</td><td>Placebo</td><td>T otal</td>

<td>baseline</td><td>(N = 981)</td><td>(N = 484)</td><td>(N = 298)to</td><td>(N = 298)</td><td>(N = 149)</td><td>(N = 1465)</td>

<td>Duration of</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>psoriasis, yearsb</td><td> 18.9±12.3</td><td> 19.2±1 1.9</td><td> 19.1 ±12.1</td><td> 1 8.5±1 2.1</td><td> 18.9±12.4</td><td> 19.0±12.2</td>

<td>Moderate</td><td> 514 (52.4)</td><td> 242 (50.0)</td><td> 170 (57.0)</td><td> 164 (55.0)</td><td> 85 (57.0)</td><td> 756 (51.6)</td>

<td>Severe</td><td> 408 (41 .6)</td><td> 218 (45.0)</td><td> 113 (37.9)</td><td> 124 (41.6)</td><td> 53 (35.6)</td><td> 626 (42.7)</td>

<td>Very severe</td><td> 59 (6.0)</td><td> 24 (5.0)</td><td> 15 (5.0)</td><td> 10 (3.4)</td><td> 11 (7.4)</td><td> 83 (5.7)</td>

<td>Record previous doctor, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Hyperlipidemia</td><td> 145 (14.8)</td><td> 57 (11.8)</td><td> 34 (11.4)</td><td> 51 (17.1)</td><td> 24 (16.1)</td><td> 202 (13.8)</td>

399

LA or

The tO

THE

Κ)

OR

<td></td><td colspan="2">Induction phase</td><td>Phase d</td><td colspan="2">b maintenance</td><td></td>

<td>characteristics</td><td>ABT-874</td><td>Placebo</td><td>ABT-874 q4</td><td>ABT-874 q12</td><td>Placebo</td><td>Total</td>

<td>baseline</td><td>(N = 981)</td><td>(N = 484)</td><td>(N = 298)to</td><td>(N = 298)</td><td>(N = 149)</td><td>(N = 1465)</td>

q4 = every 4 weeks; q12 = every 12 weeks; BSA = Body surface area affected; PASI = index of area and severity of psoriasis; PGA = Global Physician Rating; CVD = Cardiovascular disease; DM = Diabetes Mellitus.

toOne patient in the ABT-874 q4 group was randomized but did not receive any study drug in the maintenance phase.

bAverage value ± SD.

401 • Significantly higher percentages of patients treated with ABT-874 versus placebo reaching PGA 0/1 and PASI 75 endpoints at week 12 (P <.001, NRI for each analysis) (Figures 22 and 23) · Continuous dosing with ABT-874 in subjects who achieved a PGA 0/1 response at week 12 resulted in better maintenance of a PGA 0/1 response in week 52 compared to treatment discontinuation (figure 24) io · ABT-874 dosing every 4 weeks resulted in better maintenance of PASI 75 and PASI 90 responses than dosing every 12 weeks (figure 25 )

Safety · The most common adverse events reported among patients randomly assigned to ABT-874 in the induction phase and in receiving any ABT-874 for 52 weeks were: nasopharyngitis, headache, and respiratory tract infection superiors (table 23)

2nd · 16 patients in the ABT-874 q4 wk treatment group experienced back pain compared to the 6 patients in the q12 wk group, and 3 patients in the placebo group, suggesting a possible dose response relationship for this event. The reason for any potential association is unknown.

LA or

THE

Κ)

THE bJ

OR

Table 23. Adverse events produced by treatment that occur in> 5% of patients

<td></td><td colspan="2">Induction phase</td><td colspan="3">Maintenance phase</td><td></td>

<td></td><td></td><td></td><td></td><td>ABT-874</td><td></td><td>Everybody</td>

<td></td><td>ABT-874</td><td>Placebo</td><td>ABT-874 q4</td><td>q12</td><td>Placebo</td><td>ABT-874</td>

<td>Nasopharyngitis</td><td> 63 (6.4)</td><td> 20 (4.1)</td><td> 39 (13.1)</td><td> 35 (1 1.7)</td><td> 9 (6.0)</td><td> 106 (10.6)</td>

<td>Infection</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>tract</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>respiratory</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>higher</td><td> 49 (5.0)</td><td> 20 (5.0)</td><td> 48 (16.2)</td><td> 24 (8.1)</td><td> 8 (5.4)</td><td> 104 (10.4)</td>

402

THE

OR

THE

IQ

THE

K)

OR

<td></td><td>I phase</td><td>induction</td><td colspan="3">Maintenance phase</td><td></td>

<td></td><td></td><td></td><td></td><td>ABT-874</td><td></td><td>Everybody</td>

<td></td><td>ABT-874</td><td>Placebo</td><td>ABT-874 q4</td><td>q12</td><td>Placebo</td><td>ABT-874</td>

toAll patients were randomly assigned to ABT-874 in the induction phase and randomly assigned to ABT-874 in the maintenance phase.

403

404 • Serious adverse events occurred in 20 patients (2.0%) treated with ABT-874 and 6 patients (1.2%) treated with placebos during the induction phase (Table 24) • Of the serious adverse events, 5 patients (0.5%) in the ABT-874 group and 1 patient (0.2%) in the placebo group involved an infection event (Table 24) • During the placebo-controlled induction phase, 6 disease events were reported in the ABT874 group, while none were reported in the placebo group • Of the malignant events observed in patients treated with ABT-874, the majority were squamous cell or basic cell skin carcinomas (Table 24) • A total of 7 cardiac adverse events Significant (MACE), defined as myocardial infarction, stroke, or cardiovascular death, occurred in patients who received ABT874. There were no MACE events observed in the patients receiving the placebo.

THE

OR

THE

Ν)

The bu

OR

Table 24. Synthesis of the adverse events produced by the treatment and adverse events of interest.

<td></td><td colspan="2">Induction phase</td><td colspan="3">Maintenance phase</td>

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>ABT-874 q4 (N = 297)</td><td>ABT-874 q12 (N = 298)</td><td>Placebo (N = 149)</td>

<td>Any AE leading up to the suspension of the drug study</td><td> 1 7 (1.7)</td><td> 4 (0.8)</td><td> 3 (1-0)</td><td> 6 (2.0)</td><td> 1 (0.7)</td>

<td>Any AE I laughed</td><td> 20 (2.0)</td><td> 6 (12)</td><td> 4 (1.3)</td><td> 9 ( 3.0)</td><td> 2 (1.3)</td>

<td>Deaths</td><td> 1to</td><td> 0</td><td> 0</td><td> 0b</td><td> 0</td>

THE

OR

THE

<td></td><td colspan="2">Induction phase</td><td>Fast</td><td colspan="2">maintenance</td>

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>ABT-874 q4 (N = 297)</td><td>ABT-874 q12 (N = 298)</td><td>Placebo (N = 149)</td>

<td>AEs of interest special:</td><td></td><td></td><td></td><td></td><td></td>

<td>Any infection</td><td> 219 (22.3)</td><td> 96 (19.8)</td><td> 132 (44.4)</td><td> 107 ( 35.9)</td><td> 41 ( 27.5)</td>

<td>1 nffects serious</td><td> 5 (0.5)</td><td> 1 (0.2)</td><td> 0</td><td> 2 (0.7)</td><td> 1 (0.7)</td>

<td>Affections</td><td> 6 (0.6)</td><td> 0</td><td> 3 (1-0)</td><td> 5 (1-7)</td><td> 0</td>

<td>Other</td><td> 2 (0.2)c</td><td>na</td><td> 1 (0.3)d</td><td> 1 (0.3)and</td><td>na</td>

<td>Cardiovascular</td><td> 5 (0.5)’</td><td> 0</td><td> 1 (0.3)9</td><td> 1 (0.3)h</td><td> 0</td>

AE = Adverse event; SCC = Squamous cell carcinoma; BCC

Carcinoma of o

LA or

THE

THE basic cell; na = not applicable.

toOne patient experienced cardiac arrest resulting in death (an event also listed in the AEs of special interest, cardiovascular).

bA death event occurred> 45 days after study suspension in a patient who had a cardiovascular event listed in the AEs of Special Interest. cOne patient diagnosed with lung cancer in the study on day 43, and 1 with nasopharyngeal cancer in the study on day 15.

dA patient diagnosed with colon cancer on day 285 of the study.

andA patient diagnosed with angina cancer on day 266 of the study.

FOne patient had cardiac arrest, 3 had myocardial infarction, and 1 had a stroke.

9One patient had an event of acute coronary syndrome.

hOne patient had a myocardial infarction.

•0

408 • Five of 7 MACE events occurred in the first 2 months of study treatment (Figure 26) • All MACE events occurred in patients who had underlying risk factors for coronary heart disease (CHD)2

CONCLUSIONS • ABT-874 induced rapid responses and significantly higher efficacy in patients with moderate to severe psoriasis compared to placebo • ABT-874 every 4 weeks dosing resulted in better response maintenance than each 12 weeks • A higher incidence of adverse events of infection and condition was observed in patients treated with ABT-874 versus patients treated with placebo. In view of ABT-874's immunomodulatory mechanism, these results are not unexpected and do not support the need for monitoring and surveillance for these events.

• A numerical imbalance was observed for MACE events, with 7 cases reported in the ABT-874 group compared with no events in the placebo group. While cardiovascular events are not unexpected in the psoriasis patient population, further evaluation will determine whether an increase in the number of

409 MACE events is a reproducible phenomenon in patients treated with ABT-874.

Example 13. Efficacy and safety results from a phase III, randomized, controlled study comparing the safety and efficacy of ABT-874 with etanercept (ETN) and placebo in patients with moderate to severe chronic plaque psoriasis

OBJECTIVE

The primary objective of study M10-315 was to compare, in a phase III trial, the efficacy and safety of ABT-874 with io etanercept and placebo in subjects with moderate to severe chronic plaque psoriasis for 12 weeks

METHODS

Main inclusion criteria • Men and women of £ 18 with a clinical diagnosis 15 of chronic plaque psoriasis for at least 6 months • Stable plated Ps for at least 2 months before analysis and visits at baseline (week 0 ) • Affected Body Surface Area (BSA) of £ 10% • Global Physician Assessment (PGA) of at least 20 moderate (£ 3) and PASI count of £ 12 at baseline visit (week 0)

Main exclusion criteria • Previous exposure to systemic antl-IL12 / 23p40 therapy, including ABT-874 · Previous exposure to ETN or known hypersensitivity

410 a ETN • Inability to continue topical therapies, phototherapies, or systemic therapies

Study design (Figure 27) · 12-week, double-blind, double simulation, multicenter, randomized study • Patients were randomly assigned to 1 of 3 following treatment branches (2: 2: 1); "A" indicates the second dose of the week when the doses were administered twice weekly;

• 200 mg of ABT-874 SC in weeks 0 and 4 followed by 100 mg of ABT-874 SC in week 8 • 50 mg of ETN SC twice weekly with 3-4 days of separation in weeks 0, 0a, 1, 1a, 2, 2a, 3, 3a, 4,

4th, 5th, 5th, 6th, 6th, 7th, 7th, 8th, 8th, 9th, 10th, 10th, 11th, and 11th

Placebo SC at week 0 and 4 followed by placebo SC at week 8 to match ABT-874 dosage, or placebo SC twice weekly 3-4 days apart at weeks 0, 0a, 1, 1a, 2 , 2a, 3, 3a, 4, 4a, 5, 5a, 6, 6a, 7,

7a, 8, 8a, 9, 9a, 10, 10a, 11, and 11a to equalize the dosage of

ETN

Efficacy measurements • Proportion of patients achieving a PGA count of “nonexistent” or “minimal” (0/1) at week 12

Proportion of patients achieving a response

411 from PASI 75/90/100 at week 12

Safety measurements • Adverse events and serious adverse events were determined through the study

Statistical methods • Efficacy analyzes were conducted in the intention-to-treat (ITT) population; unresponsive imputation was used to handle missing data • Cochran-Mantel-Haenszel 10 tests stratified by pooled center were used to compare the proportion of patients in each treatment group who achieved PGA 0/1 or PASI 75 in week 12 in the primary analysis • A chi-square test, or Fisher's exact test 15 as appropriate, was used to compare the proportions of patients in each treatment group who achieved the

PASI 90 or 100 in week 12 • All statistical tests were bilateral with the importance level of 0.05

2θ · Safety analyzes were conducted in the safety population; safety variables were briefly presented by treatment group

RESULTS

350 patients enrolled and analyzed

ABT-874, N = 139

412

Etanercept, N = 139 * Placebo, N = 72 • Baseline demographics and clinical characteristics were similar across treatment groups (Table 25)

Table 25. Demographic data of baseline and clinical characteristics.

<td></td><td>Placebo (N = 72)</td><td>Etanercept (N = 139)</td><td>ABT-874 (N = 139)</td><td>Total (N = 350)</td>

<td>Age (years)3</td><td> 45.0 (13.6)</td><td> 45.2 (14.8)</td><td> 44.9(12.9)</td><td> 45.1 (13.8)</td>

<td>Caucasian, n (%)</td><td> 67 (93.1)</td><td> 127 (91.4)</td><td> 122 (87.8)</td><td> 316(90.3)</td>

<td>Psoriasis duration3</td><td> 15.5(11.7)</td><td> 15.2(12.1)</td><td> 16.3(12.0)</td><td> 15.7(11.9)</td>

<td>Body weight (kg)to</td><td> 92.9 (25.2)</td><td> 96.9 (24.9)</td><td> 96.1 (24.5)</td><td> 95.8 (24.8)</td>

<td>PGA, n (%) Moderate</td><td> 34 (47.2)</td><td> 69 (49.6)</td><td> 63 (45.3)</td><td> 166 (47.4)</td>

<td>Severe</td><td> 35 (48.6)</td><td> 63 (45.3)</td><td> 67 (48.2)</td><td> 165 (47.1)</td>

<td>Very severe</td><td> 3 (4.2)</td><td> 7 (5.0)</td><td> 9 (6.5)</td><td> 19 (5.4)</td>

<td>PASI count3</td><td> 18.3(6.4)</td><td> 18.5(6.0)</td><td> 19.4 (7.9)</td><td> 18.8(6.9)</td>

<td>Previous medical history, n (%) Any CVD</td><td> 26 (36.1)</td><td> 56 (40.3)</td><td> 52 (37.4)</td><td> 134 (38.3)</td>

<td>Hyperlipidemia</td><td> 6 (8.3)</td><td> 8 (5.8)</td><td> 15(10.8)</td><td> 29 (8.3)</td>

413

<td></td><td>Placebo (N = 72)</td><td>Etanercept (N = 139)</td><td>ABT-874 (N = 139)</td><td>Total (N = 350)</td>

<td>Mellitus diabetes</td><td> 7 (9.7)</td><td> 13(9.4)</td><td> 9 (6.5)</td><td> 29 (8.3)</td>

Efficacy • A statistically significant higher percentage of patients in the ABT-874 treatment group (72.7%) achieved a PGA of 0/1 at week 12 compared to patients who received either placebo (4.2%) or etanercept (29.5 %), P <0.001 (Figure 28) • A significantly higher statistical percentage of patients in the ABT-874 treatment group (80.6%) achieved a PASI 75 response at week 12 compared to patients receiving placebo (6.9% ) or etanercept (39.6%) [P <0.001] [figure 29]

At week 12, PASI 90 and PASI 100 responses were achieved by a statistically significantly higher percentage of patients in the ABT-874 treatment group (55.4% and 28.8%, respectively) relative to patients receiving placebo (4.2% and 0, respectively) or etanercept (13.7% and 5.8%, respectively) [Figures 30 and 31] Safety • A higher percentage of patients in the ABT-874 and etanercept treatment groups experienced

414 adverse events compared to patients in the placebo treatment group, respectively (50.4%, 49.6%, and 44.4%, respectively) [Table 26] • Treatment discontinuation was low in the etanercept and ABT-874 treatment groups with 2.9% (4/139) of suspension in each group (Table 26) • Serious adverse events were reported in (2.8%) patients who received the placebo (coronary artery disease, psoriasis), one (0.7%) patients who received etanercept (breast cancer), and 2 (1.4%) patients who received ABT-874 (colon cancer, seizure) (table 26) • No deaths occurred during the study (table 26)

Table 26. Synopsis of adverse events produced by the treatment

<td></td><td>Group</td><td>of treatment,</td><td>n (%)</td>

<td></td><td>Placebo</td><td>Etanercept</td><td>ABT-874</td>

<td>Any AE severe</td><td> 2 (2.8)</td><td> 1 (0-7)</td><td> 2 (1.4)</td>

<td>Any AE I laughed</td><td> 2 (2.8)</td><td> 1 (07)</td><td> 2 (1-4)</td>

415

<td></td><td colspan="2">Treatment group,</td><td>n (%)</td>

<td></td><td>Placebo N = 72</td><td>Etanercept N = 139</td><td>ABT-874 N = 139</td>

<td>leading up to the suspension of the drug study</td><td></td><td></td><td></td>

<td>Death</td><td> 0</td><td> 0</td><td> 0</td>

The incidence of adverse events of infection including serious adverse events of infection was comparable between the ABT-874 treatment group and the etanercept treatment group (Table 27) • Eight patients experienced conditions: three in the ABT-874 treatment group (colon, basal cell skin, squamous cell skin), four in the etanercept treatment group (2 basal cell skin, 1 squamous cell skin, breast) and 1 melanoma in the placebo treatment group (Table 27) • Eight patients reported events related to ischemic heart disease. Seven of these events were increased creatine phosphokinase and one coronary heart disease event in a placebo patient • No adverse cardiac events were reported

416 important, defined as myocardial infarction, stroke, or cardiovascular death, in any of the treatment groups (Table 27)

Table 27. Adverse events of interest produced by the treatment

<td></td><td colspan="3">Treatment group</td>

<td></td><td>Placebo</td><td>Etanercept</td><td>ABT-874</td>

<td>Any infection</td><td> 10(13.9)</td><td> 39 (28.1)</td><td> 34 (24.5)</td>

<td>Any infection would</td><td> 0</td><td> 0</td><td> 0</td>

<td>Any infection opportunist</td><td> 0</td><td> 0</td><td> 0</td>

<td>Any condition</td><td> 1 (1.4)</td><td> 4 (2.9)</td><td> 3 (2.2)</td>

<td>Carcinoma of squamous cell</td><td> 0</td><td> 1 (07)</td><td> 1 (0.7)to</td>

<td>Carcinoma of basic cell</td><td> 0</td><td> 2</td><td> 1 (0.7)</td>

<td>Other</td><td> 1 (1.4)b</td><td> 1 (0.7)c</td><td> 1 (0.7)d</td>

<td>Any reaction from the site of injection</td><td> 3 (4.2)</td><td> 12 (8.6)</td><td> 5 (3.6)</td>

<td>Disorder</td><td> 0</td><td> 0</td><td> 1 (0.7)and</td>

417

<td></td><td colspan="3">Treatment group</td>

<td></td><td>Placebo</td><td>Etanercept</td><td>ABT-874</td>

<td>nervous system</td><td></td><td></td><td></td>

<td colspan="3">toA patient diagnosed with neoplasm d</td><td>e lip stage</td>

malignant unspecified, study day 92 bA patient diagnosed with melanoma on study day 30 cA patient diagnosed with breast cancer in situ on study day 11 0

A patient diagnosed with colon cancer on study day 66 andA patient diagnosed with a seizure on study day 73 Significant adverse cardiac event, defined as myocardial infarction, stroke, or cardiovascular death • The most frequently reported adverse events from the 20 treatment occurring in at least 5% of patients In the ABT874 and etanercept treatment groups were upper respiratory tract infection (7.2% and 11.5%, respectively) and nasopharyngitis (7.2% and 7.9%, respectively) (table 28)

Table 28. Adverse events caused by the

418 treatment occurring in £ 5% of patients in any treatment group

<td></td><td colspan="3">Treatment group</td>

<td></td><td>Placebo</td><td>Etanercept</td><td>ABT-874</td>

<td>Tract infection upper respiratory</td><td> 0</td><td> 16 (11.5)</td><td> 10 (7.2)1</td>

<td>Nasopharyngitis</td><td> 6 (8.3)</td><td> 11 (7.9)</td><td> 10(7.2)</td>

TP = 0.017, ABT-874 versus placebo CONCLUSIONS • ABT-874 was superior to placebo and etanercept as demonstrated by the statistically significant result of the two co-primary end points: PGA 0/1 (P <0.001) and PASI 75 ( P <0.001) at 12 weeks • In this study population, no deaths, no MACE, and a comparatively low incidence of infections and serious conditions were reported across treatment groups

Example 14. Efficacy and safety of ABT-874 against etanercept and placebo in patients with moderate to severe psoriasis: The VERTO study

objective

The aim of the VERTO study was to determine the efficacy, safety, and tolerance of ABT-874 compared to

419 etanercept and placebo for the treatment of moderate to severe chronic plaque psoriasis for 12 weeks.

Methods

Main inclusion criteria • Men and women of £ 18 years of age with a clinical diagnosis of chronic plaque psoriasis for at least 6 months • Ps in stable plaques for at least 2 months before analysis and baseline visits (week 0) • Affected Body Surface Area (BSA) of £ 10% • Global Physician Assessment (PGA) of at least moderate (£ 3) and Psoriasis Area and Severity Index (PASI) count of £ 12 at baseline visit (week 0) Main exclusion criteria • Previous exposure to systemic anti-IL12 / 23p40 therapy, including ABT-874 • Previous exposure to ETN or known ETN sensitivity • Inability to continue topical therapies, phototherapies, or systemic therapies

Study design (Figure 32) • 12-week, double-blind, double simulation, multicenter, randomized study • Patients were randomly assigned to 1 of 3 of the following treatment branches (2: 2: 1); "to"

420 indicates the second dose of the week when the doses were administered twice a week:

• 200 mg of ABT-874 SC in weeks 0 and 4 followed by 100 mg of ABT-874 SC in week 8 · 50 mg of ETN SC twice a week with 3-4 days of separation in weeks 0, 0a, 1, 1a, 2, 2a, 3, 3a, 4, 4a, 5, 5a, 6, 6a, 7, 7a, 8, 8a, 9, 9a, 10, 10a, 11, and 11a

Placebo SC at week 0 and 4 followed by placebo SC at week 8 to match ABT-874 dosage, or placebo SC twice a week 3-4 days apart at weeks 0, 0a, 1, 1a , 2, 2a, 3, 3a, 4, 4a, 5, 5a, 6, 6a, 7, 7a, 8, 8a, 9, 9a, 10, 10a, 11, and 11a to equalize the dosage of

ETN

Efficacy measurements · Proportion of patients achieving a count of

PGA “nonexistent” or “minimal” (0/1) at week 12 • Proportion of patients achieving a PASI 75/90/100 response at week 12

Safety measurements · Adverse events and serious adverse events were determined through the study

Statistical methods • Efficacy analyzes were conducted in the intention-to-treat population; non-responsive imputation was used to handle missing data

421 • Cochran-Mantel-Haenszel tests stratified by pooled center were used to compare the proportion of patients in each treatment group who achieved PGA 0/1 or PASI 75 at week 12 · A chi-square test, or the exact proof of

Fisher as appropriate was used to compare the proportions of patients in each treatment group who achieved PASI 90 or 100 at week 12 • All statistical tests were two-tailed with significance level of 0.05 • Safety analyzes were conducted in the security population; safety variables were briefly presented by the treatment group

Results

A total of 347 patients enrolled in VERTO. Baseline demographic and clinical characteristics were similar across treatment groups (Table 29).

LZi

OR

L / l

Κί

LZ * ís)

OR

Table 29

<td></td><td colspan="3">Treatment group</td><td></td>

<td>characteristics</td><td>Placebo (N = 68)</td><td>ETN (N = 141)</td><td>ABT-874 (N = 138)</td><td>Total (N = 347)</td>

<td>Age (years)3</td><td> 44.0 (13.6)</td><td> 43.1 (12.5)</td><td> 43.6 (14.3)</td><td> 43.4 (13.4)</td>

<td>Caucasian</td><td> 65 (95.6)</td><td> 127 (90.1)</td><td> 126 (91.3)</td><td> 318 (91.6)</td>

<td>Black</td><td> 1 (15)</td><td> 7 (5.0)</td><td> 4 (2.9)</td><td> 12 (3.5)</td>

<td>Asian</td><td> 2 (2.9)</td><td> • 6 (4.3)</td><td> 4 (2.9)</td><td> 12 (3.5)</td>

<td>Other</td><td> 0 (0.0)</td><td> 1 (0.7)</td><td> 1 (0.7)</td><td> 2 (0.6)</td>

<td>Duration of psoriasis3</td><td> 19.1 (13.2)</td><td> 17.0 (12.7)</td><td> 16.1 (12.5)</td><td> 17.03 (12.7)</td>

<td>Body weight (kg)to</td><td> 96.5 (27.2)</td><td> 94.5 (20.4)</td><td> 93.2 (22.9)</td><td> 94.3 (22.8)</td>

422

LA or

THE κ>

THE

Κ)

OR

<td></td><td colspan="3">Treatment group</td><td></td>

<td>characteristics</td><td>Placebo (N = 68)</td><td>ETN (N = 141)</td><td>ABT-874 (N = 138)</td><td>T otal (N = 347)</td>

<td>Moderate</td><td> 42 (61.8)</td><td> 72 (51.1)</td><td> 77 (55.8)</td><td> 191 (55.0)</td>

<td>Severe</td><td> 24 (35.3)</td><td> 60 (42.6)</td><td> 57 (41.3)</td><td> 141 (40.6)</td>

<td>Very severe</td><td> 2 (2.9)</td><td> 9 (6.4)</td><td> 4 (2.9)</td><td> 15 (4.3)</td>

<td>PASI count3</td><td> 18.5 (6.9)</td><td> 19.4 (8.0)</td><td> 18.4 (7.2)</td><td> 18.8 (7.5)</td>

<td>Medical history previous, n (%)</td><td></td><td></td><td></td><td></td>

<td>Hyperlipidemia</td><td> 5 (7.4)</td><td> 11 (7.8)</td><td> 15 (10.9)</td><td> 31 (8.9)</td>

<td>Mellitus diabetes</td><td> 4 (5.9)</td><td> 6 (4.3)</td><td> 6 (4.3)</td><td> 16 (4.6)</td>

toAverage (SD).

bA patient who reported 2 or more diagnoses in the same body system that was only counted once in the total body system.

424

Efficacy • A statistically significant higher percentage of patients in the ABT-874 treatment group (71.0%) achieved a PGA of 0/1 at week 12 compared to patients who received placebo (2.9%) or ETN (39.7 %; figure 33) • A statistically significant higher percentage of patients in the ABT-874 treatment group (81.9%) achieved a PASI 75 response at week 12 compared to patients receiving placebo (7.4%) or ETN (56.0%; figure

IO 34) • At week 12, the PASI 90 and PASI 100 responses were achieved by a statistically significant higher percentage of patients in the ABT-874 treatment group (59.4% and 37.0% respectively) compared to patients who received placebo (1.5% and 0%, respectively) or ETN (23.4% and 7.1%, respectively; figures 35 and 36)

Safety • A slightly higher percentage of patients receiving ETN or ABT-874 experienced adverse events compared to patients receiving placebo; however, the safety profile for the two active treatments was similar (Table 30) • Serious adverse events were reported in (2.9%) patients who received ABT-874 (viral infection, melanoma in situ, anxiety / pain, fracture lumbar vertebral), 1

425 (0.7%) patients who received ETN (skin infection), and 1 (1.5%) placebo patients (hip fracture; table 30) • No deaths occurred during the study (table 30) Table 30. Synopsis of adverse events produced by the treatment

<td></td><td colspan="3">Treatment group, n (%)</td>

<td></td><td>Placebo (N = 68)</td><td>ETN (N = 141)</td><td>ABT-874 (N = 138)</td>

<td>Any AE severe</td><td> 1 (15)</td><td> 3 (2.1)</td><td> 6 (4.3)</td>

<td>Any AE I laughed</td><td> 1 (1.5)</td><td> 1 (0.7)</td><td> 4 (2.9)</td>

<td>Any AE leading up to the suspension of the drug study</td><td> 0</td><td> 4 (2.8)</td><td> 4 (2.9)</td>

<td>Deaths</td><td> 0</td><td> 0</td><td> 0</td>

• The percentage of patients with adverse events of infection including serious adverse events of infection was comparable across the treatment groups (Table 31)

Each condition was reported in the ETN and ABT426 groups.

874; one patient receiving ETN was diagnosed with basic cell carcinoma on day 84 of the study, and one patient treated with ABT-874 was diagnosed with malignant melanoma in situ on day 29 of the study (Table 31) · Three incidences of ischemic heart disease AE were reported in the ETN group; 4 incidences were reported for patients treated with ABT-874 • No major adverse cardiac events, defined as myocardial infarction, stroke, or cardiovascular death, were reported in any of the treatment groups (Table 31)

Table 31. Adverse events produced by the treatment of interest

<td></td><td>Group</td><td colspan="2">of treatment, n (%)</td>

<td></td><td>Placebo (N = 68)</td><td>ETN (N = 141)</td><td>ABT-874 (N = 138)</td>

<td>Any infection</td><td> 13 (19.1)</td><td> 34 (24.1)</td><td> 31 (22.5)</td>

<td>Any serious infection</td><td> 0</td><td> 1 (0.7)to</td><td> 1 (0.7)b</td>

<td>Any infection opportunist</td><td> 0</td><td> 0</td><td> 0</td>

<td>T uberculosis</td><td> 0</td><td> 0</td><td> 0</td>

427

<td></td><td>Group</td><td>of treatment,</td><td>n (%)</td>

<td></td><td>Placebo</td><td>ETN (N = 141)</td><td>ABT-874</td>

<td>condition</td><td></td><td></td><td></td>

<td>Skin cancer</td><td> 0</td><td> 1 (0.7)</td><td> 0</td>

<td>different to</td><td></td><td></td><td></td>

<td>melanoma</td><td></td><td></td><td></td>

skin infection. bViral infection.

cPatient who was diagnosed with basic cell carcinoma on day 84 of the study.

dPatient who was diagnosed with malingo melanoma in situ on day 29 of the study.

• The most common adverse events that occurred in patients receiving ABT-874 or ETN were nasopharyngitis, upper respiratory tract infection, injection site reaction, and headache; the most frequent adverse event reported by placebo patients was upper respiratory tract infection (table 32)

Table 32. Adverse events produced by the treatment that occur in ¿5% of the patients in any treatment group

428

<td></td><td colspan="3">Treatment group, n (%)</td>

<td></td><td>Placebo (N = 68)</td><td>ETN (N = 141)</td><td>ABT-874 (N = 138)</td>

<td>Nasopharyngitis</td><td> 2 (2.9)</td><td> 11 (7.8)</td><td> 10 (7.2)</td>

<td>Infection tract respiratory higher</td><td> 6 (8.8)</td><td> 8 (5.7)</td><td> 9 (6.5)</td>

<td>Reaction site of injection</td><td> 3 (4.4)</td><td> 13 (9.2)</td><td> 8 (5.8)</td>

Conclusions ♦ In patients with moderate to severe psoriasis,

ABT-874 was superior to placebo and etanercept as demonstrated by the statistically significant result of the 2 co-primary end points: PGA 0/1 (P <0.001) and PASI 75 (P <0.001) after 12 weeks of treatment • No deaths or MACE events occurred during this study. Furthermore, no difference across treatment groups was considered for the percentage of patients who experienced serious infections or conditions.

429

Example 15. Efficacy and safety of ABT-874 against methotrexate in patients with moderate to severe psoriasis

Objectives: To compare the efficacy and safety of ABT874 with that of methotrexate for the treatment of moderate to severe psoriasis.

Methods: Phase III, 52-week, double-blind, active controlled study (NCT00679731). Patients were randomized to 1: 1: ABT-874 (200 mg at weeks 0 and 4, followed by 100 mg of ABT-874 every 4 weeks for weeks 8-48) or methotrexate (5-25 mg each week). Non-responders (patients with area index and psoriasis severity (PASI) <75 and global physician evaluation> 0/1 at week 24 or PASI <50 and PGA> 3 after week 24) discontinued the study. The four primary end points were the percentage of patients with: PASI 75 at week 24, PGA 0 or 1 at week 24, PASI 75 at week 52, and PGA 0 or 1 at week 52. Safety assessments were they did through the study. Non-responsive imputation was used to handle the missing data.

Results: 317 patients enrolled in the study; 68.8% of patients treated with ABT-874 completed the study compared to 27.6% of patients treated with methotrexate. At week 24, PASI 75 was achieved by 81.8% of patients treated with ABT-874 versus 39.9% of patients treated with methotrexate (P <0.001) and a PGA of 0 or 1 was achieved

430 by 80.5% of ABT-874 patients versus 34.4% of methotrexate patients (P <0.001). At week 52, 66.2% of ABT-874 patients achieved PASI 75 against 23.9% of methotrexate patients (P <0.001), and 63.0% of ABT-874 patients versus 20.2% of patients with methotrexate. Methotrexate achieved a PGA of 0 or 1 (P <0.001). The numbers of patients with serious adverse events or suspension due to adverse events were similar for both treatment groups.

io Conclusions: At weeks 24 and 52, ABT-874 was superior to methotrexate with respect to the primary endpoints of PASI 75 and PGA 0/1 in patients with moderate to severe psoriasis.

Example 16. Treatment of ABT-874 against etanercept or placebo for moderate to severe psoriasis: Health related quality of life results

Objectives: To determine the effects of treatment with ABT874 against etanercept or placebo on health-related quality of life in patients with psoriasis.

2nd Methods: In this 12-week double-blind comparative study, patients were randomly assigned to treatment with ABT-874 (200 mg at weeks 0 and 4, 100 mg at week 8), etanercept (50 mg twice weekly), or placebo. The HRQOL results included the dermatological quality of life index (DLQI), the visual analog scales for

431 pain related to Ps (VAS-Ps) and related to psoriatic arthritis (VAS-PsA), and 36 short form of mental study (MCS) and physical component (PCS) of health study. The lowest DLQI and VAS counts and the highest counts of

MCS and PCS indicated better results. The last observation method performed in advance was used for the missing values. Treatments were compared using covariance analyzes for mean baseline changes at week 12. Percentages of patients with improvement in or

IO on the least clinically important difference (MCID response) were compared with the chi-square tests.

Results: ABT-874 treatment (N = 138) was associated with significantly greater mean improvements (p <0.05) etanercept (N = 141) or placebo (N = 68) in DLQI (-10.3 vs. -8.1 or

-3.0), VAS-Ps (-29.1 vs. -24.0 or -6.1) and MCS (5.4 vs. 3.2 or

1.0), and against placebo only in PCS (4.6 vs. -0.3) and VASPsA (-23.5 vs. -7.2). Significantly higher MCID response rates were observed with ABT-874 against etanercept or placebo for MCS (43.4 vs. 30.6 or 20.6%) and against placebo only for DLQI (81.5 vs. 38.1%), PCS (45.0 vs. 28.6%), VAS- PsA (69.2 vs. 28.6%), and VAS-Ps (56.6 vs. 25.8%).

Conclusions: ABT-874 demonstrated significantly greater improvements in all health-related quality of life outcome measures versus placebo and

432

DLQI, VAS-Ps and MCS against etanercept. Significantly more patients achieved clinically significant improvement with ABT-874 on all outcome measures against placebo and MCS against etanercept.

Example 17. Effects of ABT-874 against etanercept or placebo on health-related quality of life in patients with moderate to severe psoriasis

Objectives: To determine the effects of ABT-874 against etanercept or placebo on health-related quality of life in patients with psoriasis.

Methods: Patients were randomized to 12-week double-blind treatment with ABT-874 (200 mg at weeks 0 and 4, 100 mg at week 8), etanercept (50 mg twice weekly), or placebo. Assessments included the dermatological quality of life index (DLQI), visual analog scales for psoriasis-related pain (VASPs) and psoriatic arthritis-related pain (VAS-PsA), and the short form 36 of the health study counts from the Synopsis of Mental (MCS) and Physical (PCS) component. The last observation method performed in advance was used for the missing values. Covariation analyzes compared treatments at mean changes at week 12 from baseline. Chi-square tests compared treatments with respect to the percentages of patients with improvement in or on the least clinically important difference (MCID response).

433

Results: ABT-874 treatment (N = 139) had a significantly greater improvement (p <0.05) than placebo (N = 72) for all outcomes (DLQI, 11.1 vs. 3.0; PCS, 4.6 vs. 1.1; MCS, 6.3 against 2.1; VAS-Ps, 36.0 against 7.5; VAS-PsA, 38.6 against 3.2). ABT-874 was associated with significantly greater improvement than etanercept (N = 139) for DLQI (11.1 vs. 9.0), VASPs (36.0 vs. 29.4), and MCS (6.3 vs. 3.9). MCID response rates for VAS-Ps were significantly higher for ABT-874 than etanercept or placebo (73.9% vs. 58.0% vs. 29.6%). MCID response rates for DLQI, MCS, PCS, and VAS-PsA were higher with ABT-874 against etanercept or placebo, but the differences were significant only against placebo (DLQI, 81.8% vs. 32.9%; MCS, 45.6% vs. 30.4%; PCS, 55.9% vs. 34.8%; VAS-PsA, 83.9% vs. 20.0%).

Conclusions: Compared to placebo, ABT-874 was associated with significantly greater average improvements and MCID response in all HRQOL measurements. Compared to etanercept, ABT-874 had a significantly greater improvement in DLQI, VAS-Ps, and MCS and higher MCID response speeds for VAS-Ps.

Example 18. Treatment of psoriasis with ABT-874: Effects on quality of life and productivity at work related to health and deterioration of activity

Objectives: To assess the effects of ABT-874 on quality

434 of life, work productivity related to health and deterioration of activity in patients with psoriasis.

Methods: Patients were randomized to receive Induction Phase ABT-874 (200 mg at weeks 0 and 4, 100 mg at week 8) or placebo. Patients who achieved a physician's global assessment at week 12 of "non-existent / minimal" were randomly reassigned to maintenance phase ABT-874 (100mg every 4 [q4] or 12 weeks [q12]) or placebo until week 52. The HRQOL results included the Dermatological Quality of Life Index (DLQI), visual analog scales for plaque psoriasis-related pain and psoriatic arthritis-related pain, and health study counts of the mental and physical component synopsis . Total activity impairment was determined by WPAI-SHP: PSO Questionnaire. The last observation method performed in advance was used for the missing values. The covarlation analysis compared the baseline average improvements at weeks 12 and 52 between treatments. Chi-square tests compared the

2nd percentages of patients with improvement in or on minimal clinically important difference (MCID response).

Results: ABT-874 treatment (N = 981) had significantly faster response times at week 12 of MCID (p <0.05) than placebo (N = 484) for all outcomes (eg DLQI, 78.1% against 19.4%;

435

TAI, 51.4% vs. 15.3%). After the new randomization, MCID response rates at week 52 were significantly higher for ABT-874 q4 (N = 297) than for q12 (N = 298) in all outcomes except arthritis-related pain. psoriatic. Both ABT-874 groups had significantly higher MCID response rates than placebo (N = 149) for all outcomes (eg, DLQI, 81.1% vs. 71.1% vs. 49.3%; TAI, 56.9% vs. 45.1% vs. 31.0 %). The average improvements in all outcomes were significantly greater for ABT-874 than for placebo at week 12 and for ABT-874 q4 than ABT-874 q12 or placebo at week 52.

Conclusion: ABT-874 treatment for psoriasis versus placebo was associated with significantly greater improvements in HRQOL and reduced TAI in the induction and maintenance phases.

Example 19. Responses to ABT-874 across subgroups of patients with moderate to severe psoriasis

Objectives: To evaluate the efficacy of ABT-874 in the subgroups of patients with moderate to severe psoriasis.

Methods: In a 52-week, double-blind study, patients were randomly assigned to ABT-874 (200 mg, weeks 0 and 4; 100 mg, week 8) or placebo (PWB); then yes

PGA “non-existent / minimal” (PGA 0/1) was reached at week 12, ABT-874 100 mg was again randomly assigned

436 every 4 weeks (q4wk), 100 mg every 12 weeks (q12wk), or q4wk PCB (NCT00570986). The primary endpoints were PGA 0/1 (weeks 12 and 52) and PASI 75 (week 12). NRI analysis of the end points was driven by baseline characteristics. Safety was determined through the study.

Results: 1,465 patients were randomized to the baseline (average PASI: 19.2 ± 7.4; ABT-874, N = 981; PWB, N = 484). Responses at week 12 in patients with / without previous biologics, because ABT-874 (n = 173/808) against PWB (n = 76/408) were, PGA 0/1: 65.9% / 78.2% vs. 1.3% / 4.9%; and 75: 74.6% /82.1% of PASI against 1.3 / 5.1%; responses at week 52 for ABT-874-q4wk (n = 46/252) vs. q12wk (n = 49/249) were, PGA 0/1: 78.3% / 79.4% vs. 34.7% / 43.0%. For patients with / without a history of PsA, responses at week 12 for ABT-874 (n = 290/691) against PWB (n = 150/334) were, PGA 0/1: 71.7% / 77.9% against 0.7% / 6.0%; and 75: 78.6% /81.6% of PASI against 1.3% / 6.0%; Week 52 responses for ABT-874q4wk (n = 86/212) vs. q12wk (n = 79/219) were, PGA 0/1: 77.9% / 79.7% vs. 30.4% / 45.7%. More infections and conditions occurred in patients who received ABT-874 against PWB through week 12 (22.3% vs. 19.8% and 0.6% vs. 0, respectively). Major adverse cardiac events occurred in 7 patients treated with ABT-874 (none had previous biologics; 1 had PsA; baseline

437 PASI average: 15.8 ± 3.2). No MACE occurred in PWB-treated patients.

Conclusions: The high percentages of patients treated with ABT-874 reached PGA 0/1 (weeks 12 and 52) and

PASI 75 (week 12), regardless of the treatment or previous biological history of PsA. More infections, conditions and MACE occurred in patients treated with ABT-874 against PWB, indicating the importance of close monitoring of these events.

io Example 20. Long-term safety of ABT-874 for the treatment of moderate to severe psoriasis - interim analysis of an open-label extension study

Introduction: The interim results of an ongoing open label extension (OLE) study of anti-agent IL-12/23, ABT-874, provide preliminary long-term safety data.

Methods: Patients randomized to ABT-874 in a previous phase 2 or 3 trial of psoriasis are eligible for this 160-week, multicenter OLE.

2o complete or lose the answer in the respective previous study. Patients receive 100 mg of ABT-874 every 4 weeks, starting at baseline OLE. This analysis includes all patients with £ 1 dose of ABT-874 during OLE (safety set). Adverse events from the first dose of ABT-874, either from the OLE or from the previous study, and £ 45 are recorded

438 days after the last dose of study drug. This interim analysis provides the data available as of November 26, 2009.

Results: On the final date, the safety set consisted of 2,298 patients (drug exposure 2904.0 PY, 421.7 ± 186.8 days average in treatment; 68.8% of men; average age, 45.2 ± 13.2 years). 2.7% withdrew due to AEs; 89.1% are still enlisted. The AEs that occur in ¿5% of patients were: URI (13.6%), nasopharyngitis (13.4%), io headache (6.7%), arthralgia (5.8%), and hypertension (5.2%). Infectious AEs occurred in 45.5%; serious infections in

1.0% (more commonly: cellulite, n = 8; pneumonia, n = 5; sepsis, n = 4; and diverticulitis, n = 3); and opportunistic infections in 0.3% (candidiasis, n = 3; oral candidiasis, n = 1; esophageal candidiasis, n = 1; and coccidioidomycosis, n = 1). 1.6% of patients had conditions; 1.2% had NMSCs (BCC, n = 15; SCC, n = 16); 1 melanoma occurred in situ. No lymphoma was observed. 18 major adverse cardiovascular events occurred (7 during the previous study, 11 during OLE; heart attack

2nd myocardium, n = 11; stroke, n = 3; and cardiovascular death, n = 4; 72.2% men; 88.9% ¿45 years old; all had ¿2 CAD risks; average time for OLE events 31.5 weeks).

Conclusions: An interim OLE analysis supports the need to closely monitor infection AEs, NMSC, and

439

MACE in patients receiving ABT-874 for the treatment of moderate to severe psoriasis.

Example 21. A pooled analysis of randomized, placebo-controlled phase III clinical trials of anti-Interleukin 12/23 monoclonal antibody, ABT-874.

Objective: To determine the experience of efficacy and safety in moderate to severe psoriasis through phase III clinical trials of ABT-874.

Methods: Data from 3 randomized placebo-controlled io studies were pooled across 12 weeks. In all studies, patients with moderate to severe psoriasis were randomized to 2: 1 for ABT-874 (200 mg at weeks 0 and 4, followed by 100 mg at week 8) or matching placebo. All 3 trials measured the common primary endpoints of the physician's “nonexistent or“ minimal ”global assessment counts (PGA 0/1), and 75% improvement in the line psoriasis area and severity index (PASI 75) base at week 12 (each was analyzed using non-responsive imputation). Secondary endpoints included PASI

2nd 90/100, and DLQI. Adverse events were pooled during each study and up to 45 days from the last dose of study drug.

Results: Data were pooled for 1,882 patients (ABT-874, N = 1,258 [67.4% male, 90.3% Caucasian, mean [SD] 45.3 [13.3] years old; placebo, N = 624, with

440 similar demographics). The baseline PASI was similar between the groups (19.0 [7.5] and 19.1 [7.2] for ABT-874 and placebo, respectively). 75.1% (945/1258) and 80.8% (1017/1258) of patients treated with ABT-874 achieved a PGA 0/1 and PASI 75, respectively, at week 12, compared to 4.2% (26/624) and 5.1% (32/624) of those who received the placebo (p <0.001 for both end points). The PASI 90 responses at week 12 were 60.7% (763/1258) versus 1.8% (11/624) in the ABT-874 versus placebo groups, respectively: the PASI 100 response was 32.4% (407 / 1258) with ABT-874, and was not achieved in the placebo group (p <0.001 for both endpoints). The baseline DLQI counts were 12.9 [7.0] and 12.8 [6.9] for the ABT-874-treated and placebo-treated patients; at week 12, the average percentage change in DLQI for each group was -79.1 [28.9] versus 1.4 [69.8], respectively. The serious adverse event rates were 2.1% and 1.4% for ABT-874 versus placebo. The incidence rates for infectious and serious infectious AEs were 22.6% and 0.5% for ABT-874, and 19.1% and 0.2% for placebo. NMSCs were observed in 6 patients who received ABT-874; no placebo was observed. 5 patients treated with ABT-874 had significant adverse cardiovascular events; no placebo MACE was observed.

Conclusions: The pooled efficacy results of 3

441 Phase III, placebo-controlled trials in moderate to severe psoriasis demonstrated superior PGA and PASI responses with ABT-874 versus placebo. The highest rates of Infection, NMSC, and MACE occurred with ABT-874 versus placebo, highlighting the need to monitor for these events in a larger population with psoriasis.

Example 22. Pooled safety and efficacy results from two phase III trials comparing Briakinumab ™ with etanercept and placebo for the treatment of moderate to severe psoriasis.

Objectives: To provide an integrated analysis of the efficacy and safety results of two independent trials comparing Briakinumab ™ against etanercept (ETN) and placebo (pbo) for the treatment of moderate to severe psoriasis.

Methods: Efficacy and safety data were pooled from two 12-week, phase III, double simulation, randomized trials (NCT00710580, NCT00691964). Patients were randomly assigned 2: 2: 1 to receive Briakinumab ™ (200 mg at weeks 0 and 4, followed by 100 mg at week 8), ETN (50 mg twice weekly), or the equivalent of pbo. At week 12, the primary efficacy endpoints were the percentage of patients who achieved a PGA count of “nonexistent” or “minimal” (0/1) and the percentage of patients who achieved a PASI 75 response. Secondary endpoints included PASI 90 response rates and

442

PASI 100 at week 12. Adverse events (AE) were determined through the study. Non-responsive imputation (NRI) was used to handle the missing data.

Results: The individual trial results demonstrated the superior efficacy of Briakinumab ™ against ETN and pbo (P <0.001, Briakinumab ™ against ETN or pbo, both primary endpoints for both studies). For this pooled analysis, data from 697 patients were analyzed: Briakinumab ™, N = 277; ETN, N = 280; pbo, N = 140. At week 12, 71.8%, 34.6%, and 3.6% of patients treated with

Briakinumab ™, ETN, and pbo, respectively, achieved a PGA 0/1 (P <0.001, Briakinumab ™ against ETN or pbo). The PASI 75 response rates at week for patients treated with Briakinumab ™, ETN, and pbo were 81.2%, 47.9%, and 7.1%, respectively (P <0.001, Briakinumab ™ vs. ETN or pbo). The response rates of PASI 90 and PASI 100 at week 12 were 57.4% / 18.6% / 2.9% and 32.9% / 6.4% / 0.0% for patients treated with Briakinumab ™ / ETN / pbo, respectively (P <0.001 , Briakinumab ™ against ETN or pbo for both PASI 90 and 100). Serious AE rates were: 2.2% / 0.7% / 2.1% for patients treated with Briakinumab ™ / ETN / pbo. Serious infection rates were: 0.4% / 0.4% / 0% for patients treated with Briakinumab ™ / ETN / pbo. There were no deaths or major adverse cardiovascular events (MACE) in any group of

443 treatment.

Conclusions: Pooled efficacy results from two independent trials demonstrate that Briakinumab ™ was superior to ETN and pbo for the treatment of moderate to severe psoriasis. Serious adverse events were low across all groups and no MACE was observed.

Example 23. Long-term safety and efficacy of ABT-874 for the treatment of moderate to severe psoriasis - interim analysis of an open-label extension study

The safety and efficacy of ABT-874 in the treatment of psoriasis were determined on a provisional basis due to the results obtained on November 26, 2009. Patients were eligible for enrollment after completion or loss of response in one trial. phase II or III anterior psoriasis with ABT-874. The duration of the study was planned for 160 weeks with treatment comprising 100 mg of ABT every week starting at week 0.

Previous phase II or phase III clinical trials include the studies set out in Table 33:

Table 33: Phase II and III studies

444

study

Design

Study N

OLE N

M05-736

M06-890

M10-114

Phase II study, 3 periods, dose oscillation; 12 weeks DB, 36 weeks obs./repeated treatment followed by repeated OL treatment of 60 weeks

Phase III study, of periods; Phase of

12-week induction, 40-week maintenance phase

Phase III study, 12 weeks, DB, placebo and active comparator (ETN)

180

1465

1346

347

308

445

<td>study</td><td>Design</td><td>Study N</td><td>OLEN</td>

<td>M10-315</td><td>Phase III study, 12 weeks, DB, placebo and active comparator (ETN)</td><td> 350</td><td> 314</td>

<td>M10-255</td><td>Phase III study, 52 sawdust, DB, active comparator (MTX)</td><td> 317</td><td> 246</td>

The efficacy of ABT-874 in treating moderate to severe psoriasis was demonstrated in these previous studies, as represented in Figure 37.

The data presented in this example represents a provisional analysis of the results.

Maintaining efficacy: Patients evaluated included those (i) with at least one dose of ABT-874 during the previous phase II or III study and in the current open-label extension (OLE) study and (ii) with the A physician's overall assessment count of “nonexistent” or “minimal” (PGA 0/1) in the prior assessment on or before the first dose of OLE. PGA counts and area index responses and

446 Psoriasis severity (PASI) were determined every 12 weeks during the OLE. (Note that enrolled patients in Study M06-890 must have received at least 1 dose of ABT-874 during the induction phase.)

2298 Patients have received at least 1 dose of ABT874 in the OLE until this interim analysis. Specifically, 251 (10.9%) patients have discontinued OLE and 61 (2.7%) have withdrawn due to adverse events. Finally, 625 patients met the criteria for the maintenance efficacy population (ie, patients who had received the loading dose in the initial study (200-200-100 mg) and had a PGA count of “non-existent” or “Minimum upon entering the OLE study). The demographic and clinical characteristics of the population were as follows:

Table 34: Demographic and clinical characteristics of the population in the baseline of the previous study.

<td></td><td>All Briakinumab ™ (N = 2298)</td>

<td>Caucasian, n (%)</td><td> 2101 (91.4)</td>

<td>Age, years, average (SD)</td><td> 45.2(13.2)</td>

<td>Weight, kg, average (SD)</td><td> 93.1 (23.0)</td>

<td>Psoriasis duration, years, average (SD)</td><td> 18.6(12.3)</td>

<td>PASI * before 1ra dose, average (SD)</td><td> 16.6 (8.8)</td>

447

<td></td><td>All Briakinumab ™ (N = 2298)</td>

<td>BSA * before 1ra dose,%, average (SD)</td><td> 24.8(16.1)</td>

'From baseline before 1ra ABT-874 dose (either in a previous study or OLE).

The results of the provisional maintenance efficacy analysis are represented in Figures 38 and 39. Specifically, Figure 38 represents the percentage of patients who have maintained a PASI 75 over a certain period, while Figure 10 39 represents the percentage of patients who they have maintained the PASI 100 for a certain period. These results suggest that the PASI and PGA response levels as achieved in the previous phase II and III studies were generally maintained on additional treatment with 100 mg every four weeks.

Safety analysis: Patients evaluated included those (i) with at least one dose of ABT-874 in the current Open Label Extension (OLE) study and (ii) with the adverse effects of the first dose of ABT-874 received in previous studies or OLE. Safety was determined through the studies and up to 45 days from the last dose of study drug.

The following table summarizes the occurrences of 25 particular harmful effects:

448

Table 35: Provisional security results

<td></td><td>Briakinumab ™ Patients with events (%) (N = 2298)</td><td>Events (E / 100 PYs) (PYs = 2904)</td>

<td>Most common aes *</td><td></td><td></td>

<td>Tract infections upper respiratory</td><td> 313(13.6)</td><td> 426 (14.7)</td>

<td>Nasopharyngitis</td><td> 309(13.4)</td><td> 456(15,7)</td>

<td>Headache</td><td> 154(6.7)</td><td> 220 (7.6)</td>

<td>Arthralgia</td><td> 133 (5.8)</td><td> 146 (5.0)</td>

<td>Hypertension</td><td> 120 (5.2)</td><td> 126 (4.3)</td>

<td>Any infection</td><td> 1045 (45.5)</td><td> 2002 (68.9)</td>

<td>Any serious infection</td><td> 24(1.0)</td><td> 30 (1.0)</td>

<td>Opportunistic infections</td><td> 6 (0.3)</td><td> 6 (0.2)</td>

<td>Condition</td><td> 37(1.6)</td><td> 42 (1.4)</td>

<td>Lymphoma</td><td> 0</td><td> 0</td>

Accordingly, patients receiving ABT-874 for the treatment of moderate to severe psoriasis should be monitored for certain adverse events, particularly infection, non-melanoma skin cancer (NMSC), and cardiovascular events.

449

MACE analysis: Patients evaluated included those with at least one dose of ABT-874 in previous clinical studies or in the current Open Label Extension (OLE) study (N = 2520; 3010.6 Years of patients). A total of 18 MACE (major adverse cardiovascular events) were identified. 7 MACE were identified in a preliminary randomized controlled clinical trial including 5 during the 12-week initial placebo-controlled treatment period and 2 between week 12 and week 52. In addition 11

MACE were identified in the OLE study.

Of the 18 cases of MACE, 11 were non-fatal myocardial infarction, 3 were non-fatal strokes, and 4 were cardiovascular deaths.

The MACE indices were as represented in Table 36.

Table 36. MACE indices

<td>MACE indices:</td><td>MACE (n)</td><td>Patients in years (PYs)</td><td>MACE / WOPYs</td><td>95% Cl</td>

<td>Placebo control period of 12 weeks</td><td> 5</td><td> 376.7</td><td> 1.33</td><td> (0.43, 3.10)</td>

<td>All treatment periods with Briakinumab ™ *</td><td> 18</td><td> 3010.6</td><td> 0.60</td><td> (0.35, 0.94)</td>

'End: November 26, 2009

The MACE frequency seemed to be equally distributed over

450 a certain period as represented in Table 40. Consequently, no association was observed with the duration of exposure to ABT-874.

Another risk analysis was performed whereby standard cardiovascular risk factors were analyzed by univariate analyzes in patients with at least one dose of ABT874 in a previous phase III or phase II study or in the OLE. Standard cardiovascular risk factors include body mass index (BMI), HDLcholesterol, LDL-cholesterol, triglycerides, systolic / diastolic blood pressure, history of hypertension, history of diabetes, history of cardiovascular disease, current smoking and age.

As established in Table 37, the 18 subjects who experienced MACE had the following risk factors:

Table 37: Percentages of patients with MACE who have cardiovascular risk factors

<td>Cardiovascular risk</td><td>n (%)</td>

<td>Current smoking</td><td> 4 (22.2)</td>

451

<td>Cardiovascular risk</td><td>n (%)</td>

<td>Male gender</td><td> 13(72.2)</td>

<td>M445 years / Fs55 years</td><td> 16 (88.9)</td>

<td>Hypertension</td><td> 12(66.7)</td>

<td>Mellitus diabetes</td><td> 4 (22.2)</td>

Four specific cardiovascular risk factors were identified as predictive for MACE including (1) the history of diabetes; (2) a body mass index of at least 30 or higher; (3) inadequate control of blood pressure (blood pressure of at least 140/90 or higher; and (4) a history of cardiovascular disease defined as at least one of (i) myocardial infarction; (ii) angina that requires hospitalization; (iii) coronary artery disease requiring revascularization; (iv) peripheral arterial disease; (v) congestive heart failure requiring hospitalization; (vi) stroke or (vii) transient ischemic attack.

In conclusion, as established in Table 38, the analysis showed that the MACE index was higher in patients with at least 2 cardiovascular risk factors compared to patients who had only 0 or 1 cardiovascular risk factors.

452

Table 38: MACE risk by the number of risk factors

<td>Number of factors of risk*</td><td>MACE (points)</td><td>N</td><td>Proportion</td><td>MACE (Event)</td><td>PY</td><td>E / 100PY</td>

<td>Total</td><td> 18</td><td> 2520</td><td> 0.71%</td><td> 18</td><td> 3010.6</td><td> 0.60</td>

'Diabetes Hx, CVD Hx, BP uncontrolled (£ 140/90) at baseline, BMI £ 30

The data confirms that, in patients with one or no cardiovascular risk factor, the MACE index can be significantly reduced by administering ABT-874.

Example 24. A randomized, placebo-controlled phase III trial evaluating the efficacy and safety of two dosing regimens of the fully human interleukin12 / 23 monoclonal antibody, Briakinumab ™, for the treatment of moderate to severe psoriasis

Introduction

An earlier phase II study demonstrated that Briakinumab ™, a fully human anti-IL12 / 23 monoclonal antibody, was effective for the treatment of moderate to severe psoriasis (see, for example, Examples 1-11 above) (Kimball AB , et al., Arch Dermatol 2008; 144: 200-7 The current study

453 in addition, it evaluated the efficacy and safety of Briakinumab ™, and compared two dosage regimens of maintenance therapy against placebo. The findings of this study offer expanded perspectives on the risk benefit5 profile for anti-IL-12/23 treatment in moderate to severe psoriasis.

Methods

Study design, ethics, and participants

A 52-week, randomized, double-blind, placebo-controlled trial was conducted in two phases: a 12-week induction phase and a maintenance phase, during which treatment continued through 52 weeks (Figure 41). At baseline, patients were randomized to 2: 1 to receive Briakinumab ™ or placebo. Treatment started at week 0 with a 200 mg subcutaneous dose of Briakinumab ™, followed by 200 mg at week 4, and 100 mg at week 8; or the placebo equivalent at weeks 0, 4, and 8. At week 12, patients who achieved a “nonexistent” or “minimal” global physician evaluation count (PGA) were again randomized to 2: 2: 1 to receive one of three maintenance regimens: 100 mg of Briakinumab ™ every 4 weeks, 100 mg of Briakinumab ™ every 12 weeks, or placebo every 4 weeks.

The study protocol and the informed consent of the patient were approved by an Independent Ethics Committee or a

454

Institutional Review Board at each participating study site, and informed consent was signed by all patients prior to initiating any study-related procedures. Patients were recruited from 116 clinical sites within the United States of America and Canada. Adults 18 years of age and older were eligible to participate if they had moderate to severe plaque-type psoriasis (defined as 10% affected body surface area, PGA count of at least "moderate", and index area and severity of psoriasis (PASI) of 12) for at least six months, and were candidates for systemic therapy or phototherapy.

Women with childbearing potential were required to use at least two methods of contraception throughout the study and for 60 days after the last dose of study drug; excluding women who were pregnant or breastfeeding from participation. Other reasons for exclusion included previous exposure to an IL12 inhibitor, or any active skin condition that interfered with

2nd evaluation of psoriasis. Patients were not enrolled if they had any poorly controlled medical conditions, or liver, kidney, or hematologic disease. Patients with infections, or risk of severe infections, were also excluded from the study. Analysis of tuberculosis (TB) was conducted in all patients prior to enrollment. Those with a result

455 tests derived from the purified £ 5mm induration protein (regardless of previous BCG vaccination), and / or chest X-ray findings suggestive of latent TB, were not enlisted, unless prophylactic treatment according to What is recommended by local guidelines was instituted before starting study treatment. Patients with a history of the condition, other than successfully treated basic cell skin cancer or non-metastatic squamous cell skin cancer, or cervical carcinoma in situ, were not enrolled.

io The use of the following therapies was not allowed during the study, and should have been discontinued within the respective schedules before baseline: topical treatments, including corticosteroids, vitamin D analogues, or retinoids within the 2-week period ( other than low-potency topical corticosteroids on palms, soles, face, inframammary area, or groin): UVB phototherapy within 2 weeks; psoralen and UVA phototherapy in the period of 4 weeks; systemic non-biological therapies in the 4-week period; or biological therapies in the 12 week period. No use of oral or injectable corticosteroids was allowed; however, inhaled corticosteroids could be discontinued for stable medical conditions.

Objectives and results of the study

The study was conducted to evaluate the efficacy and safety of Briakinumab ™ for the treatment of moderate to psoriasis.

456 severe, and to compare two maintenance dosing regimens against placebo. Three primary endpoints were measured: the PGA count of "non-existent" or "minimal" at weeks 12 and 52, and at least a 75% improvement in baseline PASI (sPASI 75) at week 12. Statistical comparisons were aligned in the following order: 1) PGA response speed at week 12 of "nonexistent or" minimal "for Briakinumab ™ versus placebo; followed by 2) comparison of PASI 75 response rates at week 12 between the two treatment groups; and then 3) PGA response speed at week 52 of "non-existent or" minimal "for Briakinumab ™ each 4-week group against placebo; followed by 4) week 52 PGA maintenance rates of "non-existent" or "minimal" for Briakinumab ™ for each 12-week group versus placebo.

Secondary efficacy analyzes compared the proportions of patients achieving PASI 75, and 90% and 100% improvement in baseline PASI (PASI 90 and PASI 100) over a certain period, change in PASI relative to baseline. , and counts of the dermatological quality of life index (DLQI) in a certain period. PASI 100, PASI 90, and the change from the DLQI baseline at week 12 were the classified secondary endpoints; while average PASI counts and PASI response speeds over a certain period were not classified. The efficacy results were compared between each

457 Briakinumab ™ dosing group versus placebo, and between two Briakinumab ™ dosing groups.

A further analysis evaluated the PGA counts of "Nonexistent" or "minimal", and the PASI 75 responses of the following subgroups: with or without the above biological treatment; with or without psoriatic arthritis (PsA); baseline PASI count of> 20 or £ 20; and baseline weight S100 kg or <100 kg. The prevalence of any cardiovascular medical history or underlying cardiovascular risk factor was determined retrospectively by the treatment group. Patients were evaluated for adverse events throughout the study and for 45 days after the last dose of study treatment.

Statistical analysis

A sample size of 1,350 subjects (900 who received Briakinumab ™, and 450 who received placebo) was estimated a priori to provide> 90% ability to demonstrate the superiority of Briakinumab ™ over placebo (with superiority defined as PGA count of "Nonexistent" or "minimal" in 70% vs. 4% of patients treated with Briakinumab ™ versus placebo at week 12, respectively). Sample sizes required in each treatment group after week 12 were determined by assuming that approximately 630 patients were reassigned randomly, and that 40% of patients who received the

458 Placebo maintained a PGA count of "non-existent" or "minimal" until week 52. It was established that the new random allocation would occur at week 12 in a 2: 2: 1 manner, and that 250 patients assigned to each branch of

Briakinumab ™ and 125 assigned to placebo would provide 90% ability to detect an 18% difference in PGA response rates.

A randomization schedule was prepared and maintained by the study sponsor's statistics department, io, and administered via an interactive voice response system. Random assignment at week 0 was performed by the center; and the new random allocation at week 12 was stratified by the treatment assigned at week 0. All study drug doses were provided in a blinded type, and assigned treatment groups were concealed from study investigators and site staff, subjects, and sponsor clinical team responsible for study conduct.

All statistical tests were two-way with the alpha level set at 0.05. The primary secondary variables and

2nd aligned were analyzed in a hierarchical manner, where each successive comparison was made only if statistical significance was observed with the next highest ranking variable. Efficacy analyzes were conducted in the intention-to-treat population, with imputed missing values using non-responsive imputation for categorical variables and

459 Last observation followed for continuous variables. Primary analyzes were conducted using a CochranMantel-Haenszel test, adjusted for the center. The chi-square test was used for pairwise comparisons. Treatment differences for mean change counts were analyzed using ANCOVA, with treatment as a factor and baseline value as a covariate. One subject randomized at week 12 to each 4-week Briakinumab ™ branch did not receive the study drug during the maintenance phase and was therefore not included in the safety analysis.

Results

Induction phase

1465 patients were randomized (Briakinumab ™, n = 981; placebo, n = 484; figure 42). The baseline demographic and clinical characteristics were comparable between the two treatment groups (Figure 39), and similar to those observed in other phase III clinical trials for moderate to severe psoriasis (Reich K, et al.,

2nd Lancet 2005; 366: 1367-74; Menter A, et al., J Am Acad Dermatol 2008; 58: 106-15; Saurat JH, et al., Br J Dermatol 2008; 158: 558-66; Papp KA, et al., Lancet 2008; 371: 1675-84). The percentages of patients with a related cardiovascular medical history, or risk factors for coronary heart disease (CHD) (Executive Summary

460 of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama 2001; 285: 2486-97) were generally similar between the groups (Table 40).

Compared to placebo, the percentage of patients who achieved a PGA count of “nonexistent” or “minimal” at week 12 was significantly higher with Briakinumab ™ (76.0% in the Briakinumab ™ group versus 4.3% in the placebo group, p <0.001; figure 43). PASI 75 responses were observed in 792 (80.7%) patients receiving Briakinumab ™ compared to 22 (4.5%) placebo-treated patients (p <0.001; Table 41). 61.6% of the patients treated with Briakinumab ™ reached a PASI 90, and 32.2% reached

PASI 100. The response was rapid: a 51.7% reduction in PASI was observed with Briakinumab ™ at week 4, and the improvement continued until week 12, when the average reduction in PASI was 85.4% (Figure 44).

A large reduction in the average DLQI count was also observed in patients treated with Briakinumab ™, indicating significant advantages in quality of life in the 12-week period. The average DLQI count for the Briakinumab ™ group decreased from 12.8 (SD 7.02) at baseline to 2.7 (SD 4.12) at week 12, while DLQI counts in the placebo group remained relatively

461 stable during this period (table 41).

A subgroup analysis showed that more than 65% to 70% of patients who received Brlaklnumab ™ achieved a PGA count of "Nonexistent" or "minimal" and a PASI 75 response at week 12, regardless of prior biological treatment, baseline PASI count, history of psoriatic arthritis, or baseline weight (Table 41).

Maintenance phase

After 12 weeks of treatment, 766 io patients had achieved a “nonexistent” or “minimal” PGA and had entered the maintenance phase, a majority of whom were from the Brlaklnumab ™ group (n = 745; figure 42) . For these patients, 596 were randomly reassigned to continue receiving Brlaklnumab ™ at intervals of 4 15 weeks (n = 298) or 12 weeks (n = 298), while 149 patients were assigned to placebo and were thus withdrawn from Briakinumab ™ treatment (withdrawal group). The demographic and clinical characteristics at baseline for these 3 treatment groups were generally similar, and

2nd comparable to those observed in the induction phase treatment groups (Table 42). This Report excludes efficacy results for patients who initially received placebo and were again randomly assigned to the maintenance phase, since the number in this group was very small (n = 21).

462

The percentages of patients who maintained a count of

PGA of "non-existent" or "minimal" up to week 52 were higher for the two Briakinumab ™ treatment groups than for the treatment withdrawal group, and higher in the dosing branch every 4 weeks (Figure 45 [A] ). Of 149 patients in the withdrawal group, 6.0% had a “nonexistent or“ minimal ”PGA count at week 52 compared to 41.6% and 79.2% of 298 patients each in the 12-week treatment groups and every 4 weeks, io respectively (p <0.001). However, it is notable that the high response levels achieved during induction were delayed for a long period in the withdrawal group: at week 24, during the maintenance phase and 12 weeks after treatment withdrawal, 45.6% of the patients had maintained a PGA count of “nonexistent” or minimal ”.

PASI 75 response rates during the maintenance phase were the highest among patients who continued the Briakinumab ™ treatment; 82.6% and 45.6% of patients in the dosing groups every 4 weeks and

2nd every 12 weeks, respectively, against 8.7% in the withdrawal group that maintained this efficacy response at week 52 (Figure 45B). The PASI 100 responses, achieved by a large proportion of patients who had a PGA count of "non-existent" or "minimal" in the new randomization, generally continued to increase with treatment in

463 progress through week 32 and, in the high-dose branching, did not deteriorate for the remainder of the maintenance phase (Figure 45C). 63.4% and 23.5% in the Briakinumab ™ groups every 4 weeks and every 12 weeks, respectively, had a PASI 100 response at week 52, compared to 4.0% of patients withdrawn from treatment (p <0.001). PASI response rates in patients withdrawn from therapy reflected the results of PGA, with a prolonged return to baseline levels of disease.

Security results

The most commonly observed adverse events in patients receiving Briakinumab ™ were nasopharyngitis, headache, upper respiratory tract infection (URI), and back pain (Table 43). While back pain was observed in all treatment groups, it was reported more frequently in patients who received the

Briakinumab ™ every 4 weeks vs. every 12 weeks, or placebo (5.4% vs. 2.0% and 2.0%, respectively; Table 41). Serious adverse events were observed in 3.3% of

2o all patients who received Briakinumab ™ during the induction and / or maintenance phases. SAE rates during the induction phase were similar for Briakinumab ™ versus placebo (2.0% vs. 1.2%, respectively). During maintenance treatment, the SAE index was highest for the dosing branching every 12 weeks in

464 Comparison with 4-week dosing ramification or placebo (3.0% vs. 1.3% and 1.3%, respectively).

The total infection rate in patients exposed to Briakinumab ™ was higher than the infection rate for placebo during the induction phase (39.8% of 998 vs. 19.8% of 484). Infection rates during maintenance treatment were higher than those observed during the placebo-controlled period, and higher in the 4-week dosing group (Table 43). The total number of infections per 100 patient-years of Briakinumab ™ treatment was 100.1 (663 events, and 662.2 patient-years of Briakinumab ™ exposure). Serious infections were relatively rare for all treatment groups, however they were observed more often in patients treated with Briakinumab ™ versus patients treated with placebo during the first 12 weeks (0.5% vs. 0.2%, respectively). Cellulite, which was observed in 0.4% of patients treated with Briakinumab ™, was the most frequently reported serious infection. There were no serious infections observed beyond week 12 in patients who received the dosage every 4 weeks, and low rates were seen in the ramifications of every 12 weeks and withdrawal of treatment (0.7% and 0.7%, respectively). Opportunistic infections were limited to two non-serious events of oral yeast infection (one patient in each branch of

465 induction phase placebo, and branching every 4 weeks of the maintenance phase); and a serious aggravated cytomegalovirus event, located bilaterally in the eyes, in a patient who received placebo during the induction phase. 69 patients started treatment for latent TB (Briakinumab ™, n = 52; placebo, n = 17) before starting the study drug. No event of TB infection was observed during the study.

Comb inando periods placebo - controlled treatment and maintenance, skin cancers other than melanoma were observed in a total of 10 patients treated with briakinumab ™ (six patients with squamous cell carcinoma, and four carcinoma basal cell; Table 43), none were reported in the placebo branch. Four of the squamous cell carcinoma events were diagnosed within the first 12 weeks of treatment.

Major adverse cardiovascular events (MACE), defined as cardiac arrest, myocardial infarction,

2nd stroke, or acute coronary syndrome, was observed in seven patients treated with Briakinumab ™. No MACE was observed in placebo-treated patients.

Five of the seven events occurred during the induction phase, with onset ranging from 21 to 55 days after the start of study treatment. The two events

466 The rest occurred on days 131 and 225, during maintenance treatment. Of the five events observed during the induction phase, one was cardiac arrest resulting in death, which occurred on the 38th day in a 50-year-old male patient with various underlying risk factors for CHD (including body mass index of £ 30 kg / m2, baseline triglyceride level of> 200 mg / dl, and blood glucose of £ 126 mg / dl). The rest of the events also occurred in patients with 3 or more pre-existing risk factors for CHD.

Discussion

This large, randomized, placebo-controlled trial in patients with moderate to severe psoriasis demonstrated robust efficacy responses to a treatment modality that targets the IL-12/23 pathways, further validating previous work that has linked these Cytosines to psoriasis disease process. After 12 weeks of treatment, the primary endpoints of “nonexistent” or “minimal” PGA and PASI 75 were reached by 76% and 81% of patients treated with Briakinumab ™, respectively. Furthermore, an average improvement of 52% in PASI was observed at week 4, suggesting a rapid onset of efficacy. The percentage of patients achieving a continuous PASI 100 response rose to 20 weeks of treatment, and this degree of improvement held remarkably well through 52 weeks. For each end point,

467 the response was better maintained with the 4-week dosing regimen.

The high level of clinical response that was observed in several subgroups of patients is remarkable. Because patients who have been unable to respond to previous biologic therapy and / or who have severe psoriasis are generally more difficult to treat, the fact that the majority of patients who met these criteria in this study achieved a count of PGA of "non-existent" or "minimal" and the PASI 75 response highlights the considerable efficacy benefits seen with Briakinumab ™. Likewise, equally high response levels were considered in the patients who had arthritic involvement, and in those with a higher weight, in addition to highlighting the particularly robust effects of this anti-IL-1 2/23 agent.

Safety findings in this phase III study were generally consistent with preliminary results in a previous dose range study (Kimball AB, et al., Arch Dermatol 2008; 144: 200-7), particularly with regard to infection rates. observed which were

2nd comparable to those reported for ustekinumab, another antiIL-12/23 (Papp KA, et al., Lancet 2008; 371: 1675-84; Leonardi CL, et al., Lancet 2008; 371: 1665-74). In this study, infection rates seemed higher during maintenance treatment; however, this may have been related to a large number of patients.

468 missing at week 12 as a result of not meeting the “nonexistent” or “minimal” PGA efficacy criteria. However, it is important to note that a potential increased risk for infection with immunomodulatory therapy is not unexpected, and monitoring for these events is warranted during treatment with an anti-IL12 / 23 agent.

The rates of serious infection were low, where the most commonly observed event is cellulite. It is significant that no serious opportunistic TB or fungal infection occurred in this large study; only a single case of candidiasis was observed in a patient who received

Briakinumab ™ every 4 weeks during maintenance treatment. Among the most common adverse events reported, there appeared to be a potential dose response relationship for back pain, as the percentage of patients reporting this event was higher for the 4-week dosing group versus the group. of every 12 weeks or placebo, although an explanation for this is unclear.

Seven major adverse cardiovascular events occurred in this study, all in patients who received Briakinumab ™. Recent evidence suggests that patients with psoriasis may be more likely to have significant risk factors for events.

469 disorders (Ludwig RJ, et al., Br J Dermatol 2007; 156: 271-6; Gisondi P, et al., Br J Dermatol 2007; 157: 6873) and may be at higher risk for myocardial infarction (Gelfand JM , et al., Jama 2006; 296: 17355 41). Convincing evidence from a large, potential, population-based study in a representative broad cohort of psoriasis patients, identified from the UK general practice research database, found that younger age and severe disease independently produced the related risk of myocardial infarction times. Cytosines within atherosclerotic lesions have been reported to promote a Th1 response that leads to the production of interferon and, and a cascade of other cytosines (including tumor necrosis factor, IL-1, and IL-6), creating an environment inflammatory that promotes atherosclerosis (Hansson GK. Inflammation, atherosclerosis, and coronary artery see. N Erigí J Med 2005; 352: 1685-95). In view of the role of Th1-related cytosines in psoriasis, current evidence suggests an association between the inflammatory processes involved in psoriasis and those inherent in coronary artery disease. However, there is a lack of data that distinguishes whether other variables potentially associated with psoriasis, such as insufficient management of lifestyle risk factors or stress, may contribute to the risk of heart disease.

470

No significant cardiovascular adverse event was observed among placebo-treated patients in this study. This finding is consistent with studies in psoriasis patients treated with the IL-12 / blocker, ustekinumab. Four of the 252 patients who received ustekinumab in a phase II, placebo-controlled trial experienced cardiac events that required hospitalization, including two myocardial infarctions and one event of heart failure; while no event occurred in the placebo group (Krueger GG, et al., N Engl J Med 2007; 356: 580-92). In a larger, phase III study of ustekinumab, significant adverse cardiovascular events were observed in 4 of 753 ustekinumab-treated patients, while a single event was observed in a placebo-treated patient after he switched to receiving ustekinumab (Leonardi CL, et al., Lancet 2008; 371: 1665-74). In a comparison trial of ustekinumab and etanercept in patients with moderate to severe psoriasis, 3 cardiovascular events

2nd major adverse events were observed with ustekinumab, while none occurred with etanercept (Griffiths CE, et al., N Engl J Med; 362: 1 18-28). Conversely, no major adverse cardiovascular event was observed in a phase II investigation of Briakinumab ™ (Kimball AB, et al., Arch Dermatol 2008; 144: 200-7), or in a second

471 ustekinumab phase III trial (Papp KA, et al., Lancet 2008; 371: 1675-84). Our retrospective analysis of underlying cardiac risk factors revealed a slight imbalance between the groups; however, these marginal differences may not explain the disproportion of observed cardiac events. Because the MACE observed in the current study and those observed in the previous ustekinumab studies have mainly been isolated from patients exposed to anti-IL-1 2/23 treatment, further evidence will be crucial in determining whether treatment with this New therapy, the potential risk posed by psoriasis itself, or a combination of the two, is contributing to its occurrence. In light of the weight of evidence so far, identification of cardiac risk factors before starting anti-IL 12/23 treatment in patients with psoriasis, and close monitoring during therapy, will be important preventive measures.

Briefly, the efficacy resulting from this 52-week, multicenter, randomized, placebo-controlled trial demonstrates that Briakinumab ™ rapidly induces and maintains high efficacy responses in patients with moderate to severe psoriasis, even among those considered to generally have more treatment problems. Complicated, such as prior failure of biological therapy, arthritic involvement, or higher weight. Efficacy responses were optimally maintained with a monthly dosing regimen. The results of

472 safety were primarily consistent with those seen in the Briakinumab ™ phase II trial, however the number of infections, nonmelanoma skin cancers, and MACE further warranted research in a larger patient population, and highlight the need to monitor these events with the use of anti-lL-12/23 agents.

Table 39. Demographic and Clinical Characteristics at Baseline by Induction Phase Treatment Group.

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>Total (N = 1465)</td>

<td>characteristics</td><td></td><td></td><td></td>

<td>demographic</td><td></td><td></td><td></td>

<td>Age (years)</td><td> 45.7 (13.2)</td><td> 45.1 (13.5)</td><td> 45.5 (13.3)</td>

<td>Weight (kg)</td><td> 93.8 (23.6)</td><td> 93.1 (23.0)</td><td> 93.5 (23.4)</td>

<td>Asian</td><td> 44(4.5%)</td><td> 18 (3.7%)</td><td> 62(4.2%)</td>

<td>Black</td><td> 31 (3.2%)</td><td> 15(3.1%)</td><td> 46 (3.1%)</td>

<td>Caucasian</td><td> 888 (90.5%)</td><td> 432(89.3%)</td><td> 1320 (90.1%)</td>

<td>Other</td><td> 18(1.8%)</td><td> 19(3.9%)</td><td> 37(2.5%)</td>

<td>characteristics</td><td></td><td></td><td></td>

<td>clinics</td><td></td><td></td><td></td>

473

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>T otal (N = 1465)</td>

<td>Superficial area bodily affected (%)</td><td> 24.8 (16.3)</td><td> 25.7 (16.9)</td><td> 25.1 (16.5)</td>

<td>area index and severity of psoriasis</td><td> 19.1 (7.5)</td><td> 19.3 (7.3)</td><td> 19.2 (7.4)</td>

<td>index of quality of life dermatological</td><td> 12.8 (7.0)</td><td> 12.7 (6.9)</td><td> 12.8 (7.0)</td>

<td>Duration of psoriasis (years)</td><td> 18.9 (12.3)</td><td> 19.2 (11.9)</td><td> 19.0 (12.2)</td>

<td>Patients with arthritis psoriatic</td><td> 290(29.6%)</td><td> 150(31.0%)</td><td> 440 (30.0%)</td>

<td>Evaluation global doctor</td><td></td><td></td><td></td>

<td>Moderate</td><td> 514(52.4%)</td><td> 242(50.0%)</td><td> 756(51.6%)</td>

<td>Severe</td><td> 408(41.6%)</td><td> 218(45.0%)</td><td> 626(42.7%)</td>

<td>Very severe</td><td> 59(6.0%)</td><td> 24(5.0%)</td><td> 83(5*7%)</td>

Data is average (SD) on (%).

Table 40. Risk factors for the disease

474 Cardiovascular at Baseline by Induction Phase Treatment Group

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>T otal (N = 1465)</td>

<td>Record doctor of disease cardiovascular</td><td></td><td></td><td></td>

<td>Any disease cardiovascular</td><td> 395 (40.3%)</td><td> 178 (36.8%)</td><td> 573 (39.1%)</td>

<td>Angina</td><td> 6 (0.6%)</td><td> 2 (0.4%)</td><td> 8 (0.5%)</td>

<td>Arrhythmia cardiac</td><td> 8 (0.8%)</td><td> 5 (1.0%)</td><td> 13 (0.9%)</td>

<td>Heart failure congestive</td><td> 4 (0.4%)</td><td> 1 (0.2%)</td><td> 5 (0.3%)</td>

<td>Disease arterial coronary</td><td> 16 (1.6%)</td><td> 5 (1.0%)</td><td> 21 (1.4%)</td>

<td>Hypertension</td><td> 302 (30.8%)</td><td> 139 (28.7%)</td><td> 441 (30.1%)</td>

<td>Heart attack myocardium</td><td> 19 (1.9%)</td><td> 6 (1.2%)</td><td> 25 (1.7%)</td>

<td>Syncope</td><td> 2 (0.2%)</td><td> 0</td><td> 2 (0.1%)</td>

<td>Other</td><td> 171 (17.4%)</td><td> 80 (16.5%)</td><td> 251 (17.1%)</td>

475

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>Total (N = 1465)</td>

<td>Factors of risk cardiovascular and syndrome metabolic <ATPIII 2001></td><td></td><td></td><td></td>

<td>Hypertension (blood pressure 140/90 mm / Hg, or taking the drug antihypertensive)</td><td> 426 (43.4%)</td><td> 199 (41.1%)</td><td> 625 (42.7%)</td>

<td>Smoking</td><td> 304 (31.0%)</td><td> 148 (30.6%)</td><td> 452 (30.9%)</td>

<td>Diabetes mellitus</td><td> 98 (10.0%)</td><td> 40 (8.3)</td><td> 138 (9.4%)</td>

<td>Obesity (BMI 30 kg / m2)</td><td> 508 (51.8%)</td><td> 245 (50.6%)</td><td> 753 (51.4%)</td>

<td>Male ¿45 years</td><td> 374 (38.1%)</td><td> 175 (36.2%)</td><td> 549 (37.5%)</td>

<td>Female? 55 years</td><td> 78 (8.0%)</td><td> 40 (8.3%)</td><td> 118 (8.1%)</td>

<td>LDL cholesterol > 100 mg / dl</td><td> 542 (58.1%)</td><td> 253 (55.0%)</td><td> 795 (57.1%)</td>

476

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>Total (N = 1465)</td>

<td>T riglycerides > 200 mg / dl</td><td> 289 (29.6%)</td><td> 132 (27.4%)</td><td> 421 (28.9%)</td>

<td>HDL cholesterol <40 mg / dl</td><td> 294 (30.1%)</td><td> 145 (30.1%)</td><td> 439 (30.1%)</td>

<td>Multiple factors of risk cardiovascular</td><td></td><td></td><td></td>

<td>> 1 factor risk</td><td> 928 (94.6%)</td><td> 456 (94.2%)</td><td> 1384 (94.5%)</td>

<td>> 2 factors of risk</td><td> 804 (82.0%)</td><td> 386 (79.8%)</td><td> 1190 (81 .2%)</td>

<td>> 3 factors of risk</td><td> 600 (61.2%)</td><td> 268 (55.4%)</td><td> 868 (59.2%)</td>

<td>> 4 factors of risk</td><td> 361 (36.8%)</td><td> 166 (34.3%)</td><td> 527 (36.0%)</td>

<td colspan="2">The data is average (SD;</td><td colspan="2">on (%).</td>

Table 41: Total results of the psoriasis area and severity index (PASI) and dermatological quality of life index (DLQI), and clinical response across the subgroups of patients at week 12 for the non-responsive imputation, unless otherwise indicated

477

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>p-value</td><td></td>

<td>DLQto</td><td></td><td></td><td></td><td></td>

<td>Count</td><td> 12.8 (7.02)</td><td> 12.7 (6.93)</td><td></td><td></td>

<td>average</td><td></td><td></td><td></td><td></td>

<td>Count</td><td> 2.69 (4.12)</td><td> 12.2 (7.58)</td><td></td><td></td>

<td>average</td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">Non-existent PGA or</td><td colspan="2">PASI 75</td>

<td></td><td>ABT-874</td><td>Placebo</td><td>ABT-874</td><td>Placebo</td>

<td>Treatment</td><td></td><td></td><td></td><td></td>

<td>previous</td><td></td><td></td><td></td><td></td>

<td>Biological</td><td> 114/173</td><td> 1/76 (1.3%)</td><td> 129/173</td><td> 1/76 (1 .3%)</td>

<td>biological</td><td> (78.2%)</td><td> (4.9%)</td><td> (82.1%)</td><td> (5.1%)</td>

478

<td>Severity of disease</td><td></td><td></td><td></td><td></td>

<td>History of</td><td></td><td></td><td></td><td></td>

<td>arthritis</td><td></td><td></td><td></td><td></td>

<td>psoriatic</td><td></td><td></td><td></td><td></td>

<td>Weight</td><td></td><td></td><td></td><td></td>

Values are n (%), unless otherwise noted. Missing DLQI counts were imputed with the last observation, other than the baseline, made early (ABT-874, n = 954; placebo, n = 468)

479

Table 42. Demographic and clinical characteristics at baseline of the maintenance phase treatment group, for patients randomized to ABT-874 during the induction phase.

<td></td><td>ABT-874 each 4 weeks (N = 298)</td><td>ABT-874 each 12 weeks (N = 298)</td><td>Withdrawal of ABT-874 (placebo) (N = 149)</td>

<td>characteristics demographic</td><td></td><td></td><td></td>

<td>Age (years)</td><td> 44.6 (13.3)</td><td> 45.5 (12.6)</td><td> 45.0 (13.4)</td>

<td>Weight (kg)</td><td> 91.3 (21.3)</td><td> 93.7 (23.4)</td><td> 89.3 (24.6)</td>

<td>Asian</td><td> 13 (4.4%)</td><td> 7 (2.3%)</td><td> 14 (9.4%)</td>

<td>Black</td><td> 7 (2.3%)</td><td> 7 (2.3%)</td><td> 5 (3.4%)</td>

<td>Caucasian</td><td> 275 (92.3%)</td><td> 278 (93.3%)</td><td> 127 (85.2%)</td>

<td>Other</td><td> 3 (1 .0%)</td><td> 6 (2.0%)</td><td> 3 (2.0%)</td>

<td>characteristics clinics</td><td></td><td></td><td></td>

<td>Superficial area bodily affected (%)</td><td> 23.7 (14.8)</td><td> 22.3 (13.5)</td><td> 25.2 (17.1)</td>

<td>area index</td><td> 18.4 (6.5)</td><td> 18.3 (6.2)</td><td> 18.9 (8.2)</td>

480

<td></td><td>ABT-874 each 4 weeks (N = 298)</td><td>ABT-874 each 12 weeks (N = 298)</td><td>Withdrawal of ABT-874 (placebo) (N = 149)</td>

<td>and severity of psoriasis</td><td></td><td></td><td></td>

<td>index of quality of life dermatological</td><td> 12.7 (7.1)</td><td> 12.6 (6.8)</td><td> 11.9 (7.0)</td>

<td>Duration of psoriasis (years)</td><td> 19.1 (12.1)</td><td> 18.5 (12.1)</td><td> 18.9 (12.4)</td>

<td>Patients with arthritis psoriatic</td><td> 86 (28.9%)</td><td> 79 (26.5%)</td><td> 42 (28.2%)</td>

<td>Evaluation global doctor</td><td></td><td></td><td></td>

<td>Moderate</td><td> 170 (57.0%)</td><td> 164 (55.0%)</td><td> 85 (57.0%)</td>

<td>Severe</td><td> 113 (37.9%)</td><td> 124 (41.6%)</td><td> 53 (35.6%)</td>

<td>Very severe</td><td> 15 (5.0%)</td><td> 10 (3.4%)</td><td> 11 (7.4%)</td>

Data is average (SD) on (%).

Κ)

THE

Table 43: Adverse events observed during the induction phase, during the maintenance phase for patients assigned to ABT-874 in the induction phase, and for all patients exposed to baseline ABT-874 at week 52.

<td></td><td colspan="2">Induction phase</td><td colspan="3">Maintenance phase *</td><td></td>

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>ABT-874 q4 (N = 297)</td><td>ABT-874 q12 (N = 298)</td><td>Placebo (N = 149)</td><td>Everybody ABT-874 (N = 998) ”</td>

<td>Plus frequently observed*</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Nasopharyngitis</td><td> 63 (6.4%)</td><td> 20 (4.1%)</td><td> 39 (13.1%)</td><td> 35 (1 1.7%)</td><td> 9 (6.0%)</td><td> 117 (11.7%)</td>

Κ)

THE bJ

OR

THE

<td></td><td colspan="2">Induction phase</td><td colspan="3">Maintenance phase *</td><td></td>

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>ABT-874 q4 (N = 297)</td><td>ABT-874 q12 (N = 298)</td><td>Placebo (N = 149)</td><td>Everybody ABT-874 (N = 998) '</td>

<td>Infection tract respiratory higher</td><td> 49 (5.0%)</td><td> 20 (4.1%)</td><td> 48 (16.2%)</td><td> 24 (8.1%)</td><td> 8 (5.4%)</td><td> 1 1 3 (1 1.3%)</td>

<td>Any AE leading up to the suspension of the drug study</td><td> 17 (1.7%)</td><td> 4 (0.8%)</td><td> 3 (1.0%)</td><td> 6 (2.0%)</td><td> 1 (0.7%)</td><td> 27 (2.7%)</td>

482

AC

OR

THE

CA ts>

OR

<td></td><td colspan="2">Induction phase</td><td colspan="3">Maintenance phase *</td><td></td>

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>ABT-874 q4 (N = 297)</td><td>ABT-874 q12 (N = 298)</td><td>Placebo (N = 149)</td><td>Everybody ABT-874 (N = 998) '</td>

<td>Any AE I laughed</td><td> 20 (2.0%)</td><td> 6 (1.2%)</td><td> 4 (1 .3%)</td><td> 9 ( 3.0%)</td><td> 2 (1 .3%)</td><td> 33 (3.3%)</td>

<td>Deaths</td><td> 1 (0.1 %)§</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (0.1%)</td>

<td>AEs of interest special</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Any Infection</td><td> 219 (22.3%)</td><td> 96 (19.8%)</td><td> 132 (44.4%)</td><td> 107 ( 35.9%)</td><td> 41 ( 27.5%)</td><td> 397 (39.8%)</td>

<td>Any serious infection</td><td> 5 (0.5%)</td><td> 1 (0.2%)</td><td> 0</td><td> 2 (0.7%)</td><td> 1 (0.7%)</td><td> 8 (0.8%)</td>

<td>Appendicitis</td><td> 1 (0.1%)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (0.1%)</td>

<td>Cellulitis</td><td> 1 (0.1%)</td><td> 0</td><td> 0</td><td> 2 (0.7%)</td><td> 1 (0.7%)</td><td> 4 (0.4%)</td>

THE

OR

THE bJ

THE b->

OR

<td></td><td colspan="2">Induction phase</td><td colspan="3">Maintenance phase *</td><td></td>

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>ABT-874 q4 (N = 297)</td><td>ABT-874 q12 (N = 298)</td><td>Placebo (N = 149)</td><td>Everybody ABT-874 (N = 998) '</td>

<td>Infection cytomegalovirus</td><td> 0</td><td> 1 (0.2%)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td>Pneumonia</td><td> 2 (0.2%)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 2 (0.2%)</td>

<td>Pyelonephritis</td><td> 1 (0.1%)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (0.1%)</td>

<td>Septicemia</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (0.3%)</td><td> 0</td><td> 1 (0.1%)</td>

<td>Candidiasis</td><td> 0</td><td> 1 (0.2%)</td><td> 1 (0.3%)</td><td> 0</td><td> 0</td><td> 1 (0.1%)</td>

<td>Cytomegalovirus</td><td> 0</td><td> 1 (0.2%)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td>Any condition</td><td> 6 (0.6%)</td><td> 0</td><td> 3 (1.0%)</td><td> 5 (1.7%)</td><td> 0</td><td> 14(1 .4%)</td>

<td>Carcinoma of</td><td> 4 (0.4%)</td><td> 0</td><td> 0</td><td> 2 (0.7%)</td><td> 0</td><td> 6 (0.6%)</td>

LM

OR

LM b->

LM bJ

OR

<td></td><td colspan="2">Induction phase</td><td colspan="3">Maintenance phase *</td><td></td>

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>ABT-874 q4 (N = 297)</td><td>ABT-874 q12 (N = 298)</td><td>Placebo (N = 149)</td><td>Everybody ABT-874 (N = 998) '</td>

<td>cell flaky</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Carcinoma of basic cell</td><td> 0</td><td> 0</td><td> 2 (0.7%)</td><td> 2 (0.7%)</td><td> 0</td><td> 4 (0.4%)</td>

<td>Other</td><td> 2 (0.2%)11</td><td> 0</td><td> 1 (0.3%)**</td><td> 1 (0.3%)”</td><td> 0</td><td> 4 (0.4%)</td>

<td>Any event cardiac adverse important</td><td> 5 (0.5%)</td><td> 0</td><td> 1 (0.3%)</td><td> 1 (0.3%)</td><td> 0</td><td> 7 (0.7%)</td>

<td>Heart attack</td><td> 1 (0.1%)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (0.1%)</td>

LA or

THE bJ

THE

<td></td><td colspan="2">Induction phase</td><td>Phase of</td><td colspan="2">maintenance*</td><td></td>

<td></td><td>ABT-874 (N = 981)</td><td>Placebo (N = 484)</td><td>ABT-874 q4 (N = 297)</td><td>ABT-874 q12 (N = 298)</td><td>Placebo (N = 149)</td><td>Everybody ABT-874 (N = 998) '</td>

<td>Heart attack myocardium</td><td> 3 (0.3%)</td><td> 0</td><td> 0</td><td> 1 (0.3%)</td><td> 0</td><td> 4 (0.4%)</td>

<td>Accidents cerebrovascular</td><td> 1 (0.1%)</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 1 (0.1%)</td>

<td>Syndrome</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>coronary</td><td> 0</td><td> 0</td><td> 1 (0.3%)</td><td> 0</td><td> 0</td><td> 1 (0.1%)</td>

<td>acute</td><td></td><td></td><td></td><td></td><td></td><td></td>

Data are patient numbers (%) [patients may have £ 1 event

486 Adverse], * Patients who were randomly assigned to ABT-874 during the induction phase. 'All patients who received at least one dose of ABT-874 during the induction or maintenance phase. ^ Adverse events reported at the incidence rate of & 5% in any of the treatment groups shown.§A patient who hJ

LM

KJ

OR

LM

LM experienced cardiac arrest resulting in death (event also listed in AEs of special interest, cardiovascular). NAn event of death occurred> 45 days after study suspension in a patient who had a cardiovascular event listed in the AEs of special interest. '' A patient diagnosed with lung cancer on day 43 of the study, and 1 with nasopharyngeal cancer on day 15 of the study. “A patient diagnosed with colon cancer on day 285 of the study. ^ A patient diagnosed with angina cancer the day

266 of the study.

487

488

Example 25. Efficacy and safety of Briakinumab ™, a fully human interleukin-12/23 monoclonal antibody, against methotrexate in patients with moderate to severe chronic plaque psoriasis: results at week

52 of a phase III, randomized, double-blind trial

Although there is clear evidence that supports the use of biological therapy for the treatment of psoriasis (Schmitt J, et al., Efficacy and tolerability of biologic and non biologic systemic treatments for moderate-to-severe psoriasis:

meta-analysis of randomized controlled triais. Br J Dermatol 2008; 159: 513-26), there is a need to establish the optimal use of biologics, particularly as alternatives to traditional systemic therapies such as methotrexate (MTX). MTX is the most commonly prescribed systemic therapy for psoriasis worldwide (Menter A, et al., Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol 2009; 61: 451-85). Common harmful effects associated with MTX include

2nd nausea, anorexia, stomatitis, and fatigue, and cumulative or idiosyncratic toxicities of concern including hepatotoxicity, myelosuppression, and pulmonary fibrosis (Menter A, et al., Ibid). Although clinical experience with MTX is abundant, large comparative trials of biological therapy against MTX are scarce. Superior efficiency with

489 adalimumab versus MTX was reported in a 16-week, randomized, phase III trial (Saurat JH, et al., Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: 558-66.), And preliminary results from a 26-week trial demonstrated superior efficacy with infliximab against MTX (Reich K, et al., Infliximab is associated with greater improvement in health-related quality of life versus methotrexate for moderate-to-severe plaque10 type psoriasis-the RESTORE 1 trial. Abstract P1187), but data is limited to long-term use of MTX. This example reports the results of the first trial to assess the efficacy and safety of 1 year of MTX treatment compared to Briakinumab ™ in patients with moderate to severe plaque psoriasis.

METHODS

Patients

This phase III, multicenter, randomized, double blind trial was conducted at 43 sites in Europe and Canada. The patients of

2nd £ 18 year old were eligible to participate if they had a clinical diagnosis of psoriasis during months 2: 6; had stable plaque psoriasis for months 2; were candidates for systemic therapy or phototherapy; and had the implication of ¿10% of body surface area, a doctor's global evaluation count of ¿3, and an activity count

490 of psoriasis and severity index (PASI) of £ 12 at baseline.

Patients were ineligible if they had forms of psoriasis other than plaques or had previously received p40 targeting therapy to IL-12 / -23 or MTX. Patients were also ineligible if they had received treatment with biologics or investigational agents within the previous 12 weeks or 5 drug half-lives, conventional systemic treatment of psoriasis or phototherapy in the period of the previous 4 weeks, or topical in the period 2 weeks from baseline study. Patients were excluded if they had severe infections; a history of clinically significant hematologic, kidney, or liver disease; a history of condition (except successfully treated basic cell carcinoma, non-metastatic cutaneous squamous cell carcinoma, or cervical carcinoma in situ); or a history of active tuberculosis or evidence of latent tuberculosis (unless prophylactic treatment was previously received or started prior to study drug administration).

The study protocol was approved by an ethics committee

2nd independent or institutional review board at each study site, and each patient provided written informed consent.

Procedures

At baseline (week 0), patients were randomized to 1: 1 to receive Briakinumab ™ (200 mg

491 subcutaneous at weeks 0 and 4 and 100 mg every 4 weeks from weeks 8 to 48) or oral MTX (5 to 25 mg every week from weeks 0 to 51) plus oral folate (5 mg every week at from weeks 0 to 51) (figure 46). Patients in the MTX group received 5 mg of MTX at week 0, 10 mg at week 1, and 15 mg every week from weeks 2 to 9. At weeks 10 and 16, the MTX dosage was increased to 5 mg (to 20 mg every week at week 10 and 25 mg every week at week 16) for patients who did not achieve PASI £ 75 or a PGA of 0 or 1. To keep the trial blind, patients in the Briakinumab ™ groups also received placebo capsules to match MTX and placebo tablets to match folate, and patients in the MTX group also received subcutaneous placebo injections to match Briakinumab. ™.

Treatment success was defined as achieving PASI £ 75 and a PGA of 0 or 1 at week 24. Patients in the MTX group who achieved treatment success maintained their current weekly dose of MTX for the remainder of the duration. of the study. At any time during the study, the safety advisor may reduce or retain the MTX dose as a result of patient-reported symptoms, physical examination, adverse events, or laboratory abnormalities (£ 1.5 x limit aspartate aminotransferase or alanine aminotransferase higher than normal, count

492 platelets <100,000 / mm3, total white blood cell count of <3,000 / mm3, creatinine of> 2 x the upper limit of normal). Patients in any treatment group who did not achieve treatment success or who lost response (defined as

PASI <50 and PGA £ 3) after week 24 continued the trial and were eligible to enroll in an open-label extension study of Briakinumab ™. The largest decrease in the percentage of patients in the study occurred between weeks 24 and 28, with more patients remaining in the MTX group than in the Briakinumab ™ group who discontinued on their own due to lack of efficacy. The PASI and PGA responses were calculated in a conservative manner by charging the patients who discontinued the trial as non-responders.

The primary efficacy end points were the percentages of patients who achieved PASI 75 at week 24, a PGA of 0 or 1 at week 24, PASI 75 at week 52, and a PGA of 0 or 1 at week 52. PASI is a measure of the severity of psoriasis skin symptoms, with counts ranging from 0 to 72 (Fredriksson and Pettersson, 1978). A PASI greater than 10 is considered to represent the skin symptoms of moderate to severe psoriasis (Pathirana et al., European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol

Venereol 2009; 23 (Suppl 2): 1-70; Smith et al., Brltish

493

Association of Dermatologists' guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 2009; 161: 987-1019). The PGA used was a 6-point ordinal scale with 0 that is equal to “nonexistent”; 1 "minimum"; 2 "mild"; 3 "moderate"; 4 "severe"; and 5 "very severe" (Ko, 1998).

Secondary efficacy variables included the mean time to achieve PASI 75 response rates, PASI 50/75/90/100 response through week 52, the proportion of patients with a PGA of 0 or 1 per visit during

52 weeks, and the average percentage improvement of

Baseline PASI. Efficacy evaluations also included changing the baseline in nail psoriasis severity index (NAPSI) counts, ranging from 0 (no nail psoriasis) to 80 (psoriasis in all 10). nails) (Rich and Scher, 2003). Patients with non-zero baseline NAPSI counts had NAPSI evaluations at subsequent visits, using a single nail as the target (the nail most affected by psoriasis at baseline), with a NAPSI count interval of 0 to 8.

2o An additional secondary efficacy parameter was the dermatological quality of life index (DLQI), a patient-reported measure of the degree to which psoriasis affects health-related quality of life. The DLQI produces a count that ranges from 0 to 30, with a lower count indicating a lower impact (Finlay and Khan, 1994). Assessments included

494 percentages of patients with a DLQI count of 0 or 1 (no effect of psoriasis) (Hongbo et al., Translating the Science of quality of life into practice: What do dermatology life quality Index scores mean? J Invest Dermatol 2005; 125: 659-64), the percentages of patients with a decrease of s5 points (a clinically significant reduction) (Khilji et al., Clinical meaning of change in Dermatology Life Quality Index scores. Br J Dermatol 2002; 147 (Suppl 62): 50), and changing baseline DLQI counts.

Adverse events, laboratory data, and vital signs were determined through the study. Patients were closely monitored for signs of infection, condition, and immune reaction. Adverse events produced by treatment were defined as those occurring on or after the first dose of study drug and up to 45 days after the last dose of study drug.

Statistic analysis

According to the original study plan, approximately 250 patients had to be randomized. Assuming that the PASI 75 response rates at week 24 were 70% in the Briakinumab ™ group and 50% in the MTX group, this sample size would provide 90% of the ability to demonstrate superiority. Briakinumab ™ on MTX (bilateral chi-square test at 5% significance level). However, due to

495 difficulties in obtaining accurate enrollment numbers on time, more than 250 patients enrolled. Given an actual enrollment number of 317 patients, the energy increased from 90% to 95%. This change in energy had little impact due to the large differences in endpoints between the treatment groups observed in the study.

The intention-to-treat population included all patients who were randomized at week 0. The intention-to-treat population was used for efficacy analyzes. For the primary efficacy evaluations, all comparisons were made using a bilateral CochranMantel-Haenszel test adjusted for each country to an alpha level of 0.05. The type I error rate was controlled to 0.05, adhering to the order defined a priori of the statistical hypotheses. Non-responsive imputation was used to handle the missing data. Any patient with a missing PASI or PGA count at one visit was considered a non-responder at that visit. The last advance observation (LOCF) was used as sensitivity analysis.

2Q For categorical variables, the chi-square test or Fisher's exact test (if the predicted cell size was <5) was used to assess the superiority of Briakinumab ™ against MTX. Non-responsive imputation was used to handle the missing data. LOCF was used as sensitivity analysis.

The average times to reach the PASI 75 response and the

496 PGA counts of 0 or 1 were calculated using the Kaplan-Meier method. The difference of the treatment group was tested using the registry classification test. Patients who did not achieve a response on or before week 52 were censored on the last PASI / PGA assessment date.

Differences between treatment groups in changing PASI, DLQI, and other continuous variables were analyzed using covariance analysis with the baseline value and treatment group in the model. LOCF was used to handle the missing data. Analysis as observed was done as sensitivity analysis. To calculate the percentage change in NAPSI count, only patients with NAPSI counts other than zero baseline were included in the analysis. Wilcoxon 2-sample tests were used to compare the treatment difference in change. LOCF was used to handle the missing data. Analysis as observed was done as sensitivity analysis.

Safety analyzes were conducted using the safety population, which included all patients who received

2nd at least 1 injection of study drug.

RESULTS

A total of 317 patients met the inclusion criteria and were randomly assigned to Briakinumab ™ (N = 154) or MTX (N = 163) (Figure 47). Randomized patients were not excluded from the efficacy analysis

497 (population of intention to treat). A total of 106 (68.8%) patients in the Briakinumab ™ group and 45 (27.6%) patients in the MTX group completed the study until Week 52. The reasons for continuing the study are shown in Figure 47.

The demographic, clinical characteristics, and severity of the baseline disease were similar between the treatment groups (Table 44). The average duration of psoriasis was 18.9 years, the average PASI count was 18.1, and the mean body surface area implication was 26.1%. io Approximately 52% of patients had previously received systemic nonbiological treatment (other than

MTX) and 18% had previously received biological therapy.

Significantly more patients in the

Briakinumab ™ MTX group achieved the primary endpoints of the PASI 75 response at week 24 (81.8% vs. 39.9%; p <0.001) and at week 52 (66.2% vs. 23.9%; p <0.001). The mean time to achieve the PASI 75 response was 56 days for the Briakinumab ™ group versus 140 days for the MTX group (p <0.001). The percentage of patients achieving a PASI 75 response was significantly higher in the Briakinumab ™ group at week 4 and at all time points through week 52 (Figure 48A). Similarly, significant differences between treatment groups were evident at the beginning of week 2 for

PASI 50 and in week 8 for PASI 90 and PASI 100; greater

498 Response rates in the Briakinumab ™ group were maintained through week 52 (Figures 3B-3D). The mean percentage improvement in baseline PASI counts increased over a period of time for both treatment groups but was significantly greater in the Briakinumab ™ group at all time points (Figure 49). The PASI 75/90/100 response rates at week 16 for MTX-treated patients were similar to those observed at CHAMPION week. (Saurat JH, Stingl G, Dubertret L, et al .; CHAMPION Study Investigators. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: 558-66).

Significantly more patients in the

Briakinumab ™ that the MTX group achieved the primary PGA endpoints of 0 or 1 at week 24 (80.5% vs. 34.4%; p <0.001) and at week 52 (63.0% vs. 20.2%; p <0.001). Furthermore, the disease relieved as determined by a PGA of 0 was evident in significantly more patients in the group.

2nd of Briakinumab ™ than the MTX group at week 24 (46.1% vs. 9.2%; p <0.001) and at week 52 (45.5% vs. 9.8%; p <0.001). The average time to achieve a PGA of 0 or 1 was 69 days for the Briakinumab ™ group versus 171 days for the MTX group (p <0.001). Significantly higher percentages of patients in the Briakinumab ™ group achieved a

499

PGA of O or 1 at each time point from week 4 to week 52 (Figure 50).

The baseline NAPSI counts were similar between the treatment groups (Table 44). In the group of

With Briakinumab ™, the average NAPSI count for the target nail decreased from 4.8 at baseline to 2.1 at week 24 and 1.2 at week 52. In the MTX group, the average NAPSI count for the target nail decreased from 4.8 at baseline to 3.0 at week 24 and was also 3.0 at week 52. The baseline change in baseline NAPSI count for the target nail was significantly greater in the Briakinumab ™ group than in the MTX group at week 24 and week 52 (p <0.001 for both comparisons).

Significantly more patients in the

Briakinumab ™ that the MTX group had a DLQI count of 0 or 1 at week 24 (70.8% vs. 34.4%; p <0.001) and at week 52 (61.7% vs. 17.8%; p <0.001). Similarly, significantly more patients in the Briakinumab ™ group than in the MTX group achieved a reduction clinically.

2nd significant in the DLQI count (decrease of £ 5 points) in week 24 (66.2% against 47.9%; p <0.001) and in week 52 (56.5% against 18.4%; p <0.001). Patients in the Briakinumab ™ group had significantly greater baseline decreases in DLQI counts compared to the MTX group at all determined time points (figure

500

51). At week 24, the average DLQI count had decreased from 11.0 at baseline to the Briakinumab ™ group, against a decrease from 11.2 at baseline to 4.6 in the MTX group (difference between groups in change from baseline: -3.0; 95% confidence interval [Cl]: -3.9, -2.1; p <0.001). DLQI counts at week 52 (1.5 in the Briakinumab ™ group vs. 4.6 in the MTX group) reflected a similarly greater change from baseline with Briakinumab ™ vs. MTX (-3.1, 95% Cl: -4.0, -2.2; p <0.001).

For all efficacy variables, sensitivity analyzes were performed for missing data that produced similar results.

Adverse event profiles were similar between Briakinumab ™ and MTX (Table 45). The most common adverse events from treatment were nasopharyngitis, headache, diarrhea, arthralgia, and upper respiratory infection. Diarrhea (9.7% vs. 3.7%, p = 0.04) and injection site related adverse events (8.4% vs. 1.8%; p = 0.009) were more frequent in

2nd the Briakinumab ™ group than in the MTX group.

Of the 317 randomized patients, 22 patients discontinued the study due to 1 or more adverse events. Twelve (7.8%) patients in the Briakinumab ™ group discontinued; adverse events for 5 patients were serious (gastrointestinal hypomotility and infection

501 for legionella, breast cancer, breast neoplasm, prostate cancer, and herpes zoster). Ten (6.1%) patients in the MTX group discontinued; Adverse events for 5 patients were serious (increased liver enzyme and hepatitis, sacroiliitis, diverticulitis, erythrodermic psoriasis, angioedema, and urticaria).

Fourteen (9.1%) patients in the Briakinumab ™ group and 10 (6.1%) patients in the MTX group reported serious adverse events caused by treatment. Seven io patients experienced serious infections, including 4 patients in the Briakinumab ™ group (1 case of Legionella infection with candidemia, and septic shock, 1 case of osteomyelitis, 1 case of herpes zoster, and 1 case of tonsillitis) and 3 patients in the MTX group (2 cases of diverticulitis and 1 case of hepatitis). The incidence rates of serious infectious adverse events were 4.1 and 2.7 per 100 patient-years in the Briakinumab ™ and MTX groups, respectively.

Fourteen patients in each treatment group had evidence derived from positive purified protein at baseline; however, no patients had active tuberculosis in the investigation or tuberculosis-related adverse events reported during the study. Three patients in the Briakinumab ™ group experienced conditions (1 patient had breast cancer, 1 patient had breast neoplasm, and 1 patient had prostate cancer). A death was reported (rupture

502 esophageal in a patient in the MTX group).

There were no reports of major cardiovascular events such as sudden cardiac death, myocardial infarction, or stroke. Six patients in the Briakinumab ™ group and 4 patients in the MTX group had adverse events of ischemic heart disease (2 patients in the Briakinumab ™ group experienced angina pectoris and the rest of the patients experienced increased creatinine phosphokinase), none of which was serious.

DISCUSSION

In this 52-week, phase III, multicenter, randomized, double-blind study, Briakinumab ™ was superior to MTX in reducing the signs and symptoms of moderate to severe plaque psoriasis, improving nail psoriasis, and favorably influencing the quality of life related to the health reported by the patient. Briakinumab ™ treatment produced a rapid clinical response that was sustained through 52 weeks when compared to MTX. No clinically important safety concerns were identified in the study.

The present study is the first comparison assay to evaluate the efficacy and safety of MTX against an IL-12 / -23 p40 neutralizing antibody. Compared to MTX,

Briakinumab ™ demonstrated faster onset of action and

503 superior efficacy through week 52, with a generally similar safety profile. In the Briakinumab ™ group, a PASI 75 response was achieved by 81.8% of patients at week 24 and by 66.2% of patients at week 52. It is difficult to compare 1-year clinical response maintenance with Briakinumab ™ in this trial against ustekinumab in previous trials because the current Briakinumab ™ study was a direct analysis of intention to treat, whereas the ustekinumab trials included increased (Papp KA, et al., Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675-84) and various stages of selection of responding patients (Leonardi CL, et al., Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized , double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371: 1665-74).

This first year study of MTX provides in-depth knowledge of maintaining MTX response. After week 24, there was a relatively sharp decrease in the percentage of patients treated with MTX with a PASI 75 response (39.9% at week 24 compared to 30.7% at week 28) and a further decrease

504 small in the percentage of patients with a PGA of 0 or 1 (34.4% at week 24 compared to 28.8% at week 28). It should be noted that at week 24, patients who did not achieve PASI £ 75 and a PGA of 0 or 1 discontinued the study per protocol. Previous MTX comparison trials have been short-lived. In a 16-week study of MTX versus cyclosporine, no difference in clinical responses was observed between groups (Heydendael VM, et al., Methotrexate versus cyclosporlne in moderate-toI0 severe chronic plaque psoriasis. N Engl J Med 2003; 349; 658-65). The most recent trials have shown better efficacy with biological therapy against MTX. In a 16-week trial of MTX against adalimumab, significantly more patients treated with adalimumab achieved the PASI 75 response at week 16 (80% vs. 36%; p <0.001) (Saurat JH, et al., Efficacy and safety results. from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: 558-66). On the other hand, similar to the results of the

In the second study, the clinical response occurred more rapidly with biological therapy than with MTX. Preliminary results from a 26-week trial of MTX against infliximab showed that significantly more infliximab-treated patients achieved PASI 75 at week 26 (77% vs. 31%;

p <0.001) (Reich K, et al., Infliximab is associated with

505 greater ¡mprovement ¡n health-related quality of life versus methotrexate for moderate-to-severe plaque-type psoriasis — the RESTORE 1 trial. Abstract P1187). Furthermore, the greatest improvement in baseline DLQI counts at week 26 was evident with nfllxlmab than with MTX (-11.3 vs. -9.1; p <0.004) (Reich K, et al., Infllxlmab's associated with greater! mprovement in health-related quality of life versus methotrexate for moderate-severe plaque-type psorlasls-the RESTORE 1 trial. Abstract P1187).

Regarding the long-term safety of MTX, the previous 16-week trials reported liver-related adverse events leading to suspension in 12 (28%) of 43 patients receiving 15 mg each week (Heydendael VM, et al. , Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003; 349; 658-65) and in 4 (4%) of 110 patients who received an initial MTX dosage of 7.5 mg each week that was increased as necessary and tolerated to 25 mg each week (Saurat JH, et al., Efflcacy and safety results from the randomlzed controlled comparatlve study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: 558-66). In the present study of 52 weeks of MTX treatment (5 mg to 25 mg each week, per titration schedule), 16 patients (10%) in the MTX group experienced adverse events

506 related to the liver, but only 2 patients (1%) discontinued the study. These results suggest that starting MTX with a low dosage on top that is titrated as directed and tolerated may be a safe strategy for long-term use of MTX.

Regarding the safety of Briakinumab ™, 52 weeks of treatment was associated with a low incidence of serious adverse events. The incidence of serious infectious adverse events was 4.1 events per 100 patient-years with Briakinumab ™ and 2.7 events per 100 patient-years with MTX. Previous studies have reported an index of 1.3 serious infectious events per 100 patient-years with adalimumab or infliximab (Menter A, et al., Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol 2008; 58: 106-15; Burmester GR, et al., Adalimumab safety and mortallty rates from global clinical triais of six immune-mediated inflammatory diseases. Ann

Rheum Dis 2009; 68: 1863-69). In the present study of

Briakinumab ™, no serious cardiovascular event (eg myocardial infarction, stroke) was reported, contrary to the low frequencies of such events in another Briakinumab ™ trial (reference

M06-890) and in the ustekinumab trials (Krueger GG, and

507 collaborators, A human interleukin-12/23 monoclonal antlbody for the treatment of psoriasis. Λ / Engl J Med 2007; 356: 580-92; Leonardi CL, et al., Efficacy and safety of ustekiriumab, a human ¡nterleuk¡n-12/23 monoclonal antibody, ¡n patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1 ). Lancet 2008; 371: 1665-74; Papp KA, et al., Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675-84).

CONCLUSIONS

In this comparative trial of Briakinumab ™ against MTX in patients with moderate to severe plaque psoriasis, the

Briakinumab ™ demonstrated superior efficacy compared to MTX at all primary and secondary endpoints, including patient-reported measures of clinical response and health-related quality of life with 52 weeks of treatment. Consistent with superior efficacy and a safety profile with no clinically significant results compared to MTX, these results demonstrate a favorable benefit-risk ratio for Briakinumab ™ versus MTX as a therapeutic option for the treatment of psoriasis. Table 44. Demographic and clinical characteristics of the baseline.

508

<td></td><td>Characteristic</td><td>Briakinumab ™</td><td>MTX</td>

<td></td><td>Age (years), average (SD)</td><td>(N = 154) 45.0 (13.1)</td><td>(N = 163) 43.1 (12.9)</td>

<td> 5</td><td>Caucasian</td><td> 149 (96.8)</td><td> 158 (96.9)</td>

<td></td><td>Weight (kg), average (SD)</td><td> 85.1 (17.5)</td><td> 82.0(18.6)</td>

<td></td><td>Psoriasis duration (years), average</td><td> 18.6(11.9)</td><td> 19.1 (11.3)</td>

<td></td><td>(SD) BSA affected by psoriasis (%),</td><td> 26.1 (16.7)</td><td> 26· 1 (16.3)</td>

<td> 10</td><td>average (SD) Psoriatic arthritis history</td><td> 25(16.2)</td><td> 28 (17.2)</td>

<td></td><td>PASI count, average (SD)</td><td> 18.4 (6.7)</td><td> 17-8 (6.1)</td>

<td></td><td>NAPSI count, * average (SD)</td><td> 27.7(16.4)</td><td> 27-9(19.1)</td>

<td></td><td>NAPSI nail count</td><td> 4.8 (2.0)</td><td> 4.8(2.1)</td>

<td> 15</td><td>objective, * average (SD) PGA "Non-existent," Minimum ", or" Mild "</td><td> 0</td><td> 0</td>

<td></td><td>"Moderate</td><td> 75 (48.7)</td><td> 87 (53.4)</td>

<td></td><td>"Severe</td><td> 65 (42.2)</td><td> 72 (44.2)</td>

<td> 20</td><td>"Very severe"</td><td> 14(9.1)</td><td> 4 (2.5)</td>

<td></td><td>DLQI count,1 average (SD)</td><td> 11.1 (6.6)</td><td> 11.3(7.5)</td>

<td></td><td>Previous psoriasis treatment Topical therapy</td><td> 141 (91.6)</td><td> 148 (90.8)</td>

<td></td><td>Phototherapy</td><td> 100 (64.9)</td><td> 105 (64.4)</td>

<td> 25</td><td>Systemic non-biological treatment</td><td> 77 (50.0)</td><td> 89 (54.6)</td>

509

<td>Characteristic</td><td>Briakinumab ™</td><td>MTX</td>

<td>Systemic biological treatment</td><td> 24(15.6)</td><td> 34 (20.9)</td>

<td>Etanercept</td><td> 14(9.1)</td><td> 12 (7.4)</td>

<td>Infliximab</td><td> 9 (5.8)</td><td> 11 (6.7)</td>

<td>Adalimumab</td><td> 5 (3.2)</td><td> 7 (4.3)</td>

<td>Alefacept</td><td> 2(1-3)</td><td> 2(1-2)</td>

<td>Efalizumab</td><td> 6 (3.9)</td><td> 3(1.8)</td>

<td>Other</td><td> 3(1.9)</td><td> 7 (4.3)</td>

Values are n (%) unless otherwise noted.

* N = 115 (Briakinumab ™), N = 108 (MTX).

+ N = 154 (Briakinumab ™), N = 162 (MTX).

BSA, body surface area; DLQI, dermatological quality of life index; MTX, methotrexate; NAPSI, nail psoriasis severity index; PASI, psoriasis area and severity index; PGA, Global Physician Assessment.

Table 45. Adverse events of the treatment group

<td>Event*</td><td>Briakinumab ™</td><td>MTX</td>

<td>Any adverse event</td><td> 131 (85.1)</td><td> 145 (89.0)</td>

<td>Serious adverse events</td><td> 14(9.1)</td><td> 10(6.1)</td>

<td>Adverse events leading to</td><td> 12 (7.8)</td><td> 10 (6.1)</td>

<td>the suspension</td><td></td><td></td>

<td>Common adverse events1</td><td></td><td></td>

<td>Nasopharyngitis</td><td> 44 (28.6)</td><td> 45 (27.6)</td>

510

<td>Event*</td><td>Briakinumab ™</td><td>MTX</td>

<td>Headache</td><td> 18(11.7)</td><td> 22 (13.5)</td>

<td>Diarrhea</td><td> 15 (9.7)*</td><td> 6 (3.7)</td>

<td>Arthralgia</td><td> 12(7.8)</td><td> 11 (6.7)</td>

<td>Respiratory tract infection</td><td> 11 (7.1)</td><td> 12(7.4)</td>

<td>higher</td><td></td><td></td>

<td>Fatigue</td><td> 10(6.5)</td><td> 10(6.1)</td>

<td>Stomach flu</td><td> 10 (6.5)</td><td> 11 (6.7)</td>

<td>Cough</td><td> 9 (5.8)</td><td> 12(7.4)</td>

<td>Nausea</td><td> 9 (5.8)</td><td> 19(11.7)</td>

<td>Influenza</td><td> 8 (5.2)</td><td> 9 (5.5)</td>

<td>Rhinitis</td><td> 8 (5.2)</td><td> 6 (3.7)</td>

<td>Adverse events of interest</td><td></td><td></td>

<td>special</td><td></td><td></td>

<td>Infections</td><td> 89 (57.8)</td><td> 102 (62.6)</td>

<td>Serious infections</td><td> 4 (2.6)</td><td> 3(1-8)</td>

<td>Opportunistic infections</td><td> 1 (0.6)</td><td> 0</td>

<td>Affections</td><td> 3(1-9)</td><td> 0</td>

<td>Cardiovascular events§</td><td> 0</td><td> 0</td>

<td>Ischemic heart disease</td><td> 6 (3.9)</td><td> 4 (2.5)</td>

<td>Deaths11</td><td> 0</td><td> 1 (0.6)</td>

511

Values are n (%).

• Occurred on or after the first dose of study drug and up to 45 days after the last dose of study drug.

'•' Occurred in £ 5% of patients in any treatment group.

* p = 0 04 against the MTX group.

§Any serious adverse event of sudden cardiac death, myocardial infarction, or stroke.

11 Includes deaths not caused by treatment.

MTX, methotrexate.

EQUIVALENTS

Those skilled in the art will recognize, or can make the determination by using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be understood by the following claims.

512

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53 members in 17 offices

This recordMember, by publication datePriority claim7 more offices are in the list below

Priority claims5

Priority claims
Document	Office	Kind	Date
24228809	United States of America	P	2009-09-14
24596709	United States of America	P	2009-09-25
29762310	United States of America	P	2010-01-22
36029910	United States of America	P	2010-06-30
2010048771	United States of America	W	2010-09-14

Members53

Family members, oldest first
Document	Office	Kind
AU2009225797A1	Australia	A1	2009-09-24
CA2717569A1	Canada	A1	2009-09-24
WO2009117289A2	World Intellectual Property Organization (WIPO)	A2	2009-09-24
TW200948379A	Taiwan Province of China	A	2009-12-01
US2010028363A1	United States of America	A1	2010-02-04
WO2009117289A3	World Intellectual Property Organization (WIPO)	A3	2010-04-22
MX2010010265A	Mexico	A	2010-09-30
KR20100126515A	Republic of Korea	A	2010-12-01
IL208069A0	Israel	A0	2010-12-30
IL208069D0	Israel	D0	2010-12-30
EP2274333A2	European Patent Office (EPO)	A2	2011-01-19
CA2773556A1	Canada	A1	2011-03-17
WO2011032148A1	World Intellectual Property Organization (WIPO)	A1	2011-03-17
CN102037011A	China	A	2011-04-27
JP2011515404A	Japan	A	2011-05-19
EP2274333A4	European Patent Office (EPO)	A4	2011-06-15
TW201127400A	Taiwan Province of China	A	2011-08-16
US2011206680A1	United States of America	A1	2011-08-25
AU2010291927A1	Australia	A1	2012-04-12
RU2010142309A	Russian Federation	A	2012-04-27
US8178092B2	United States of America	B2	2012-05-15
SG179135A1	Singapore	A1	2012-05-30
IL218633A0	Israel	A0	2012-05-31
MX2012003138AThis record	Mexico	A	2012-07-04
WO2012097288A1	World Intellectual Property Organization (WIPO)	A1	2012-07-19
EP2477654A1	European Patent Office (EPO)	A1	2012-07-25
CN102630168A	China	A	2012-08-08
US2012219562A1	United States of America	A1	2012-08-30
US2012225080A1	United States of America	A1	2012-09-06
KR20120112384A	Republic of Korea	A	2012-10-11
EP2477654A4	European Patent Office (EPO)	A4	2013-01-23
JP2013504598A	Japan	A	2013-02-07
NZ587765A	New Zealand	A	2013-02-22
TW201309329A	Taiwan Province of China	A	2013-03-01
SG188909A1	Singapore	A1	2013-04-30
US8557239B2	United States of America	B2	2013-10-15
RU2012114854A	Russian Federation	A	2013-10-27
RU2497545C2	Russian Federation	C2	2013-11-10
US2014079714A1	United States of America	A1	2014-03-20
NZ602511A	New Zealand	A	2014-03-28
US2014093516A1	United States of America	A1	2014-04-03
KR20140048229A	Republic of Korea	A	2014-04-23
NZ598722A	New Zealand	A	2014-05-30
TWI461210B	Taiwan Province of China	B	2014-11-21
EP2810954A2	European Patent Office (EPO)	A2	2014-12-10
RU2013132928A	Russian Federation	A	2015-01-27
US8945545B2	United States of America	B2	2015-02-03
EP2810954A3	European Patent Office (EPO)	A3	2015-03-18
TW201513883A	Taiwan Province of China	A	2015-04-16
IN1965DEN2012A	India	A	2015-08-21
HK1203516A	Hong Kong, China	A	2015-10-30
HK1203516A1	Hong Kong, China	A1	2015-10-30
BRPI0908715A2	Brazil	A2	2016-05-03

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	Event	Code
2014-09-15	Transfer or rightsGB	GB
2014-09-15	Change of proprietorshipPD	PD
2014-07-10	Grant or registrationFG	FG
2013-08-09	Transfer or rightsGB	GB
2013-08-09	Transfer or rightsGB	GB