Compounds and methods for therapy and diagnosis of lung cancer

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COMPOUNDS AND METHODS FOR THERAPY AND DIAGNOSIS OF LUNG CANCER

TECHNICAL FIELD

The present invention relates generally to therapy and diagnosis of cancer, such as lung cancer. The invention is more specifically related to polypeptides comprising at least a portion of a lung tumor protein, and to polynucleotides encoding such polypeptides. Such polypeptides and polynucleotides may be used in vaccines and pharmaceutical compositions for prevention and treatment of lung cancer, and for the diagnosis and monitoring of such cancers.

BACKGROUND OF THE INVENTION

Lung cancer is the primary cause of cancer death among both men and women in the U.S., with an estimated 172,000 new cases being reported in 1994. The five-year survival rate among all lung cancer patients, regardless of the stage of disease at diagnosis, is only 13%. This contrasts with a five-year survival rate of 46% among cases detected while the disease is still localized. However, only 16% of lung cancers are discovered before the disease has spread.

Early detection is difficult since clinical symptoms are often not seen until the disease has reached an advanced stage. Currently, diagnosis is aided by the use of chest x-rays, analysis of the type of cells contained in sputum and fiberoptic examination of the bronchial passages. Treatment regimens are determined by the type and stage of the cancer, and include surgery, radiation therapy and/or chemotherapy. In spite of considerable research into therapies for the disease, lung cancer remains difficult to treat.

Accordingly, there remains a need in the art for improved vaccines, treatment methods and diagnostic techniques for lung cancer.

SUMMARY OF THE INVENTION

Briefly stated, the present invention provides compositions and methods for the diagnosis and therapy of cancer, such as lung cancer. In one aspect, the present

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WO 00/61612 PCT/US00/08896 invention provides polypeptides comprising at least a portion of a lung tumor protein, or a variant thereof. Certain portions and other variants are immunogenic, such that the ability of the variant to react with antigen-specific antisera is not substantially diminished. Within certain embodiments, the polypeptide comprises a sequence that is encoded by a polynucleotide sequence selected from the group consisting of: (a) sequences recited in any one of SEQ ID NO: 1-3, 6-8, 10-13, 15-27, 29, 30, 32, 34-49, 51, 52, 54, 55, 57-59, 61-69, 71, 73, 74, 77, 78, 80-82, 84, 86-96, 107-109, 111, 113, 125, 127, 128, 129, 131-133, 142, 144, 148-151, 153, 154, 157, 158, 160, 167, 168, 171, 179, 182, 184-186, 188-191, 193, 194, 198-207, 209, 210, 213, 214, 217, 220-224,

253-337, 345, 347 and 349; (b) variants of a sequence recited in any one of SEQ ID

NO: 1-3, 6-8, 10-13, 15-27, 29, 30, 32, 34-49, 51, 52, 54, 55, 57-59, 61-69, 71, 73, 74, 77, 78, 80-82, 84, 86-96, 107-109, 111, 113, 125, 127, 128, 129, 131-133, 142, 144, 148-151, 153, 154, 157, 158, 160, 167, 168, 171, 179, 182, 184-186, 188-191, 193, 194, 198-207, 209, 210, 213, 214, 217, 220-224, 253-337, 345, 347 and 349; and (c) complements of a sequence of (a) or (b). In specific embodiments, the polypeptides of the present invention comprise at least a portion of a tumor protein that includes an amino acid sequence selected from the group consisting of sequences recited in any one of SEQ ID NO: 152, 155,156, 165,166, 169,170, 172, 174, 176, 226-252,338-344 and 346, and variants thereof.

The present invention further provides polynucleotides that encode a polypeptide as described above, or a portion thereof (such as a portion encoding at least 15 amino acid residues of a lung tumor protein), expression vectors comprising such polynucleotides and host cells transformed or transfected with such expression vectors.

Within other aspects, the present invention provides pharmaceutical compositions comprising a polypeptide or polynucleotide as described above and a physiologically acceptable carrier.

Within a related aspect of the present invention, vaccines for prophylactic or therapeutic use are provided. Such vaccines comprise a polypeptide or polynucleotide as described above and an immunostimulant.

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The present invention further provides pharmaceutical compositions that comprise: (a) an antibody or antigen-binding fragment thereof that specifically binds to a lung tumor protein; and (b) a physiologically acceptable carrier.

Within further aspects, the present invention provides pharmaceutical compositions comprising: (a) an antigen presenting cell that expresses a polypeptide as described above and (b) a pharmaceutically acceptable carrier or excipient. Antigen presenting cells include dendritic cells, macrophages, monocytes, fibroblasts and B cells.

Within related aspects, vaccines are provided that comprise: (a) an antigen presenting cell that expresses a polypeptide as described above, and (b) an immunostimulant.

The present invention further provides, in other aspects, fusion proteins that comprise at least one polypeptide as described above, as well as polynucleotides encoding such fusion proteins.

Within related aspects, pharmaceutical compositions comprising a fusion protein, or a polynucleotide encoding a fusion protein, in combination with a physiologically acceptable carrier are provided.

Vaccines are further provided, within other aspects, that comprise a fusion protein, or a polynucleotide encoding a fusion protein, in combination with an immunostimulant.

Within further aspects, the present invention provides methods for inhibiting the development of a cancer in a patient, comprising administering to a patient a pharmaceutical composition or vaccine as recited above.

The present invention further provides, within other aspects, methods for removing tumor cells from a biological sample, comprising contacting a biological sample with T cells that specifically react with a lung tumor protein, wherein the step of contacting is performed under conditions and for a time sufficient to permit the removal of cells expressing the protein from the sample.

Within related aspects, methods are provided for inhibiting the development of a cancer in a patient, comprising administering to a patient a biological sample treated as described above.

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Methods are further provided, within other aspects, for stimulating and/or expanding T cells specific for a lung tumor protein, comprising contacting T cells with one or more of: (i) a polypeptide as described above; (ii) a polynucleotide encoding such a polypeptide; and/or (iii) an antigen presenting cell that expresses such a polypeptide; under conditions and for a time sufficient to permit the stimulation and/or expansion of T cells. Determined T cell populations comprising T cells prepared as described above are also provided.

Within further aspects, the present invention provides methods for inhibiting the development of a cancer in a patient, comprising administering to a patient an effective amount of a T cell population as described above.

The present invention further provides methods for inhibiting the development of a cancer in a patient, comprising the steps of: (a) incubating CD4⁺and/or CD8⁺ T cells determined from a patient with one or more of: (i) a polypeptide comprising at least an immunogenic portion of a lung tumor protein; (ii) a polynucleotide encoding such a polypeptide; and (iii) an antigen-presenting cell that expressed such a polypeptide; and (b) administering to the patient an effective amount of the proliferated T cells, and thereby inhibiting the development of a cancer in the patient. Proliferated cells may, but need not, be cloned prior to administration to the patient.

Within further aspects, the present invention provides methods for determining the presence or absence of a cancer in a patient, comprising: (a) contacting a biological sample obtained from a patient with a binding agent that binds to a polypeptide as recited above; (b) detecting in the sample an amount of polypeptide that binds to the binding agent; and (c) comparing the amount of polypeptide with a predetermined cut-off value, and therefrom determining the presence or absence of a cancer in the patient. Within preferred embodiments, the binding agent is an antibody, more preferably a monoclonal antibody. The cancer may be lung cancer.

The present invention also provides, within other aspects, methods for monitoring the progression of a cancer in a patient. Such methods comprise the steps of: (a) contacting a biological sample obtained from a patient at a first point in time with a binding agent that binds to a polypeptide as recited above; (b) detecting in the

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PCT/US00/08896 sample an amount of polypeptide that binds to the binding agent; (c) repeating steps (a) and (b) using a biological sample obtained from the patient at a subsequent point in time; and (d) comparing the amount of polypeptide detected in step (c) with the amount detected in step (b) and therefrom monitoring the progression of the cancer in the patient.

The present invention further provides, within other aspects, methods for determining the presence or absence of a cancer in a patient, comprising the steps of; (a) contacting a biological sample obtained from a patient with an oligonucleotide that hybridizes to a polynucleotide that encodes a lung tumor protein; (b) detecting in the sample a level of a polynucleotide, preferably mRNA, that hybridizes to the oligonucleotide; and (c) comparing the level of polynucleotide that hybridizes to the oligonucleotide with a predetermined cut-off value, and therefrom determining the presence or absence of a cancer in the patient. Within certain embodiments, the amount of mRNA is detected via polymerase chain reaction using, for example, at least one oligonucleotide primer that hybridizes to a polynucleotide encoding a polypeptide as recited above, or a complement of such a polynucleotide. Within other embodiments, the amount of mRNA is detected using a hybridization technique, employing an oligonucleotide probe that hybridizes to a polynucleotide that encodes a polypeptide as recited above, or a complement of such a polynucleotide.

In related aspects, methods are provided for monitoring the progression of a cancer in a patient, comprising the steps of; (a) contacting a biological sample obtained from a patient with an oligonucleotide that hybridizes to a polynucleotide that encodes a lung tumor protein; (b) detecting in the sample an amount of a polynucleotide that hybridizes to the oligonucleotide; (c) repeating steps (a) and (b) using a biological sample obtained from the patient at a subsequent point in time; and (d) comparing the amount of polynucleotide detected in step (c) with the amount detected in step (b) and therefrom monitoring the progression of the cancer in the patient.

Within further aspects, the present invention provides antibodies, such as monoclonal antibodies, that bind to a polypeptide as described above, as well as diagnostic kits comprising such antibodies. Diagnostic kits comprising one or more oligonucleotide probes or primers as described above are also provided.

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These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.

SEQUENCE IDENTIFIERS

SEQ ID NO: 1 is the determined cDNA sequence for LST-S1-2

SEQ ID NO: 2 is the determined cDNA sequence for LST-S1-28

SEQ ID NO: 3 is the determined cDNA sequence for LST-S1-90

SEQ ID NO: 4 is the determined cDNA sequence for LST-S1-144

SEQ ID NO: 5 is the determined cDNA sequence for LST-S1-133

SEQ ID NO: 6 is the determined cDNA sequence for LST-S1-169

SEQ ID NO: 7 is the determined cDNA sequence for LST-S2-6

SEQ ID NO: 8 is the determined cDNA sequence for LST-S2-11

SEQ ID NO: 9 is the determined cDNA sequence for LST-S2-17

SEQ ID NO: 10 is the determined cDNA sequence for LST-S2-25

SEQ ID NO: 11 is the determined cDNA sequence for LST-S2-39

SEQ ID NO: 12 is a first determined cDNA sequence for LST-S2-43

SEQ ID NO: 13 is a second determined cDNA sequence for LST-S2-43

SEQ ID NO: 14 is the determined cDNA sequence for LST-S2-65

SEQ ID NO: 15 is the determined cDNA sequence for LST-S2-68 SEQ ID NO: 16 is the determined cDNA sequence for LST-S2-72 SEQ ID NO: 17 is the determined cDNA sequence for LST-S2-74 SEQ ID NO: 18 is the determined cDNA sequence for LST-S2-103 SEQ ID NO: 19 is the determined cDNA sequence for LST-S2-N1-1F SEQ ID NO: 20 is the determined cDNA sequence for LST-S2-N1 -2A SEQ ID NO: 21 is the determined cDNA sequence for LST-S2-N1-4H SEQ ID NO: 22 is the determined cDNA sequence for LST-S2-NI-5A SEQ ID NO: 23 is the determined cDNA sequence for LST-S2-N1-6B SEQ ID NO: 24 is the determined cDNA sequence for LST-S2-N1-7B SEQ ID NO: 25 is the determined cDNA sequence for LST-S2-N1-7H

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SEQ ID NO: 26 is the determined cDNA sequence for LST-S2-N1-8A SEQ ID NO: 27 is the determined cDNA sequence for LST-S2-N1-8D SEQ ID NO: 28 is the determined cDNA sequence for LST-S2-N1-9A SEQ ID NO: 29 is the determined cDNA sequence for LST-S2-N1-9E

SEQ ID NO: 30 is the determined cDNA sequence for LST-S2-N1-10A SEQ ID NO: 31 is the determined cDNA sequence for LST-S2-N1-10G SEQ ID NO: 32 is the determined cDNA sequence for LST-S2-N1-11A SEQ ID NO: 33 is the determined cDNA sequence for LST-S2-N1-12C SEQ ID NO: 34 is the determined cDNA sequence for LST-S2-N1-12E

SEQ ID NO: 35 is the determined cDNA sequence for LST-S2-B1-3D SEQ ID NO: 36 is the determined cDNA sequence for LST-S2-B1-6C SEQ ID NO: 37 is the determined cDNA sequence for LST-S2-B1-5D SEQ ID NO: 38 is the determined cDNA sequence for LST-S2-B1-5F SEQ ID NO: 39 is the determined cDNA sequence for LST-S2-B1-6G

SEQ ID NO: 40 is the determined cDNA sequence for LST-S2-B1-8A SEQ ID NO: 41 is the determined cDNA sequence for LST-S2-B1-8D SEQ ID NO: 42 is the determined cDNA sequence for LST-S2-B1-10A SEQ ID NO: 43 is the determined cDNA sequence for LST-S2-B1-9B SEQ ID NO: 44 is the determined cDNA sequence for LST-S2-B1-9F

SEQ ID NO: 45 is the determined cDNA sequence for LST-S2-B1-12D SEQ ID NO: 46 is the determined cDNA sequence for LST-S2-I2-2B SEQ ID NO: 47 is the determined cDNA sequence for LST-S2-I2-5F SEQ ID NO: 48 is the determined cDNA sequence for LST-S2-I2-6B SEQ ID NO: 49 is the determined cDNA sequence for LST-S2-I2-7F

SEQ ID NO: 50 is the determined cDNA sequence for LST-S2-I2-8G SEQ ID NO: 51 is the determined cDNA sequence for LST-S2-I2-9E SEQ ID NO: 52 is the determined cDNA sequence for LST-S2-I2-12B SEQ ID NO: 53 is the determined cDNA sequence for LST-S2-H2-2C SEQ ID NO: 54 is the determined cDNA sequence for LST-S2-H2-1G

SEQ ID NO: 55 is the determined cDNA sequence for LST-S2-H2-4G SEQ ID NO: 56 is the determined cDNA sequence for LST-S2-H2-3H

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SEQ ID NO: 57 is the determined cDNA sequence for LST-S2-H2-5G SEQ ID NO: 58 is the determined cDNA sequence for LST-S2-H2-9B SEQ ID NO: 59 is the determined cDNA sequence for LST-S2-H2-10H SEQ ID NO: 60 is the determined cDNA sequence for LST-S2-H2-12D SEQ ID NO: 61 is the determined cDNA sequence for LST-S3-2 SEQ ID NO: 62 is the determined cDNA sequence for LST-S3-4 SEQ ID NO: 63 is the determined cDNA sequence for LST-S3-7 SEQ ID NO: 64 is the determined cDNA sequence for LST-S3-8 SEQ ID NO: 65 is the determined cDNA sequence for LST-S3-12 SEQ ID NO: 66 is the determined cDNA sequence for LST-S3-13 SEQ ID NO: 67 is the determined cDNA sequence for LST-S3-14 SEQ ID NO: 68 is the determined cDNA sequence for LST-S3-16 SEQ ID NO: 69 is the determined cDNA sequence for LST-S3-21 SEQ ID NO: 70 is the determined cDNA sequence for LST-S3-22 SEQ ID NO: 71 is the determined cDNA sequence for LST-S1-7 SEQ ID NO: 72 is the determined cDNA sequence for LST-S1-A-1E SEQ ID NO: 73 is the determined cDNA sequence for LST-S1-A-1G SEQ ID NO: 74 is the determined cDNA sequence for LST-S1-A-3E SEQ ID NO: 75 is the determined cDNA sequence for LST-S1-A-4E SEQ ID NO: 76 is the determined cDNA sequence for LST-S1-A-6D SEQ ID NO: 77 is the determined cDNA sequence for LST-S1-A-8D SEQ ID NO: 78 is the determined cDNA sequence for LST-S1-A-10A SEQ ID NO: 79 is the determined cDNA sequence for LST-S1-A-10C SEQ ID NO: 80 is the determined cDNA sequence for LST-S1-A-9D SEQ ID NO: 81 is the determined cDNA sequence for LST-S1-A-10D SEQ ID NO: 82 is the determined cDNA sequence for LST-S1-A-9H SEQ ID NO: 83 is the determined cDNA sequence for LST-S1-A-I ID

SEQ ID NO: 84 is the determined cDNA sequence for LST-S1-A-12D SEQ ID NO: 85 is the determined cDNA sequence for LST-S1-A-1 IE SEQ ID NO: 86 is the determined cDNA sequence for LST-S1-A-12E SEQ ID NO: 87 is the determined cDNA sequence for L513S (T3).

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SEQ ID NO: 88 is the determined cDNA sequence for L513S contig 1.

SEQ ID NO: 89 is a first determined cDNA sequence for L514S.

SEQ ID NO: 90 is a second determined cDNA sequence for L514S.

SEQ ID NO: 91 is a first determined cDNA sequence for L516S.

SEQ ID NO: 92 is a second determined cDNA sequence for L516S.

SEQ ID NO: 93 is the determined cDNA sequence for L517S.

SEQ ID NO: 94 is the extended cDNA sequence for LST-S1-169 (also known as L519S).

SEQ ID NO: 95 is a first determined cDNA sequence for L520S.

SEQ ID NO: 96 is a second determined cDNA sequence for L520S.

SEQ ID NO: 97 is a first determined cDNA sequence for L521S.

SEQ ID NO: 98 is a second determined cDNA sequence for L521S.

SEQ ID NO: 99 is the determined cDNA sequence for L522S.

SEQ ID NO: 100 is the determined cDNA sequence for L523S.

SEQ ID NO: 101 is the determined cDNA sequence for L524S.

SEQ ID NO: 102 is the determined cDNA sequence for L525S.

SEQ ID NO: 103 is the determined cDNA sequence for L526S.

SEQ ID NO: 104 is the determined cDNA sequence for L527S.

SEQ ID NO: 105 is the determined cDNA sequence for L528S.

SEQ ID NO: 106 is the determined cDNA sequence for L529S.

SEQ ID NO: 107 is a first determined cDNA sequence for L530S.

SEQ ID NO: 108 is a second determined cDNA sequence for L530S.

SEQ ID NO: 109 is the determined full-length cDNA sequence for L531S short form SEQ ID NO: 110 is the predicted amino acid sequence encoded by SEQ ID NO: 109. SEQ ID NO: 111 is the determined full-length cDNA sequence for L531S long form SEQ ID NO: 112 is the predicted amino acid sequence encoded by SEQ ID NO: 111. SEQ ID NO: 113 is the determined full-length cDNA sequence for L520S.

SEQ ID NO: 114 is the predicted amino acid sequence encoded by SEQ ID NO: 113. SEQ ID NO: 115 is the determined cDNA sequence for contig 1.

SEQ ID NO: 116 is the determined cDNA sequence for contig 3.

SEQ ID NO: 117 is the determined cDNA sequence for contig 4.

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SEQ ID NO: 118 is the determined cDNA sequence for contig 5.

SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO

119 is the determined cDNA sequence for contig 7.

120 is the determined cDNA sequence for contig 8.

121 is the determined cDNA sequence for contig 9.

122 is the determined cDNA sequence for contig 10.

123 is the determined cDNA sequence for contig 12.

124 is the determined cDNA sequence for contig 11.

125 is the determined cDNA sequence for contig 13.

126 is the determined cDNA sequence for contig 15.

127 is the determined cDNA sequence for contig 16.

128 is the determined cDNA sequence for contig 17.

129 is the determined cDNA sequence for contig 19.

130 is the determined cDNA sequence for contig 20.

131 is the determined cDNA sequence for contig 22.

132 is the determined cDNA sequence for contig 24.

133 is the determined cDNA sequence for contig 29.

134 is the determined cDNA sequence for contig 31.

135 is the determined cDNA sequence for contig 33.

136 is the determined cDNA sequence for contig 38.

137 is the determined cDNA sequence for contig 39.

138 is the determined cDNA sequence for contig 41.

139 is the determined cDNA sequence for contig 43.

140 is the determined cDNA sequence for contig 44.

141 is the determined cDNA sequence for contig 45.

142 is the determined cDNA sequence for contig 47.

143 is the determined cDNA sequence for contig 48.

144 is the determined cDNA sequence for contig 49.

145 is the determined cDNA sequence for contig 50.

146 is the determined cDNA sequence for contig 53.

147 is the determined cDNA sequence for contig 54.

148 is the determined cDNA sequence for contig 56.

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SEQ ID NO: 149 is the determined cDNA sequence for contig 57.

SEQ ID NO: 150 is the determined cDNA sequence for contig 58.

SEQ ID NO: 151 is the full-length cDNA sequence for L53OS.

SEQ ID NO: 152 is the amino acid sequence encoded by SEQ ID NO: 151 SEQ ID NO: 153 is the full-length cDNA sequence of a first variant of L514S SEQ ID NO: 154 is the full-length cDNA sequence of a second variant of L514S SEQ ID NO: 155 is the amino acid sequence encoded by SEQ ID NO: 153.

SEQ ID NO: 156 is the amino acid sequence encoded by SEQ ID NO: 154.

SEQ ID NO: 157 is the determined cDNA sequence for contig 59.

SEQ ID NO: 158 is the full-length cDNA sequence for L763P (also referred to as contig 22).

SEQ ID NO: 159 is the amino acid sequence encoded by SEQ ID NO: 158.

SEQ ID NO: 160 is the full-length cDNA sequence for L762P (also referred to as contig 17).

SEQ ID NO: 161 is the amino acid sequence encoded by SEQ ID NO: 160.

SEQ ID NO: 162 is the determined cDNA sequence for L515S.

SEQ ID NO: 163 is the full-length cDNA sequence of a first variant of L524S.

SEQ ID NO: 164 is the full-length cDNA sequence of a second variant of L524S.

SEQ ID NO: 165 is the amino acid sequence encoded by SEQ ID NO: 163.

SEQ ID NO: 166 is the amino acid sequence encoded by SEQ ID NO: 164.

SEQ ID NO: 167 is the full-length cDNA sequence of a first variant of L762P.

SEQ ID NO: 168 is the full-length cDNA sequence of a second variant of L762P.

SEQ ID NO: 169 is the amino acid sequence encoded by SEQ ID NO: 167.

SEQ ID NO: 170 is the amino acid sequence encoded by SEQ ID NO: 168.

SEQ ID NO: 171 is the full-length cDNA sequence for L773P (also referred to as contig 56).

SEQ ID NO: 172 is the amino acid sequence encoded by SEQ ID NO: 171.

SEQ ID NO: 173 is an extended cDNA sequence for L519S.

SEQ ID NO: 174 is the predicted amino acid sequence encoded by SEQ ID NO: 174. SEQ ID NO: 175 is the full-length cDNA sequence for L523S.

SEQ ID NO: 176 is the predicted amino acid sequence encoded by SEQ ID NO: 175.

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SEQ ID NO: 177 is the determined cDNA sequence for LST-sub5-7A. SEQ ID NO: 178 is the determined cDNA sequence for LST-sub5-8G. SEQ ID NO: 179 is the determined cDNA sequence for LST-sub5-8H. SEQ ID NO: 180 is the determined cDNA sequence for LST-sub5-10B.

SEQ ID NO: 181 is the determined cDNA sequence for LST-sub5-lOH. SEQ ID NO: 182 is the determined cDNA sequence for LST-sub5-12B. SEQ ID NO: 183 is the determined cDNA sequence for LST-sub5-l 1C. SEQ ID NO: 184 is the determined cDNA sequence for LST-sub6-lc. SEQ ID NO: 185 is the determined cDNA sequence for LST-sub6-2f.

SEQ ID NO: 186 is the determined cDNA sequence for LST-sub6-2G. SEQ ID NO: 187 is the determined cDNA sequence for LST-sub6-4d. SEQ ID NO: 188 is the determined cDNA sequence for LST-sub6-4e. SEQ ID NO: 189 is the determined cDNA sequence for LST-sub6-4f. SEQ ID NO: 190 is the determined cDNA sequence for LST-sub6-3h.

SEQ ID NO: 191 is the determined cDNA sequence for LST-sub6-5d. SEQ ID NO: 192 is the determined cDNA sequence for LST-sub6-5h. SEQ ID NO: 193 is the determined cDNA sequence for LST-sub6-6h. SEQ ID NO: 194 is the determined cDNA sequence for LST-sub6-7a. SEQ ID NO: 195 is the determined cDNA sequence for LST-sub6-8a.

SEQ ID NO: 196 is the determined cDNA sequence for LST-sub6-7d. SEQ ID NO: 197 is the determined cDNA sequence for LST-sub6-7e. SEQ ID NO: 198 is the determined cDNA sequence for LST-sub6-8e. SEQ ID NO: 199 is the determined cDNA sequence for LST-sub6-7g. SEQ ID NO: 200 is the determined cDNA sequence for LST-sub6-9f.

SEQ ID NO: 201 is the determined cDNA sequence for LST-sub6-9h. SEQ ID NO: 202 is the determined cDNA sequence for LST-sub6-l lb. SEQ ID NO: 203 is the determined cDNA sequence for LST-sub6-l lc. SEQ ID NO: 204 is the determined cDNA sequence for LST-sub6-12c. SEQ ID NO: 205 is the determined cDNA sequence for LST-sub6-12e.

SEQ ID NO: 206 is the determined cDNA sequence for LST-sub6-12f. SEQ ID NO: 207 is the determined cDNA sequence for LST-sub6-l lg.

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SEQ ID NO: 208 is the determined cDNA sequence for LST-sub6-12g. SEQ ID NO: 209 is the determined cDNA sequence for LST-sub6-12h. SEQ ID NO: 210 is the determined cDNA sequence for LST-sub6-II-la. SEQ ID NO: 211 is the determined cDNA sequence for LST-sub6-II-2b. SEQ ID NO: 212 is the determined cDNA sequence for LST-sub6-II-2g. SEQ ID NO: 213 is the determined cDNA sequence for LST-sub6-II-lh. SEQ ID NO: 214 is the determined cDNA sequence for LST-sub6-II-4a. SEQ ID NO: 215 is the determined cDNA sequence for LST-sub6-Il-4b. SEQ ID NO: 216 is the determined cDNA sequence for LST-sub6-II-3e. SEQ ID NO: 217 is the determined cDNA sequence for LST-sub6-II-4f. SEQ ID NO: 218 is the determined cDNA sequence for LST-sub6-II-4g. SEQ ID NO: 219 is the determined cDNA sequence for LST-sub6-II-4h. SEQ ID NO: 220 is the determined cDNA sequence for LST-sub6-II-5c. SEQ ID NO: 221 is the determined cDNA sequence for LST-sub6-II-5e. SEQ ID NO: 222 is the determined cDNA sequence for LST-sub6-II-6f. SEQ ID NO: 223 is the determined cDNA sequence for LST-sub6-II-5g. SEQ ID NO: 224 is the determined cDNA sequence for LST-sub6-II-6g. SEQ ID NO: 225 is the amino acid sequence for L528S.

SEQ ID NO: 226-251 are synthetic peptides derived from L762P.

SEQ ID NO: 252 is the expressed amino acid sequence of L514S.

SEQ ID NO: 253 is the DNA sequence corresponding to SEQ ID NO: 252. SEQ ID NO: 254 is the DNA sequence of a L762P expression construct. SEQ ID NO: 255 is the determined cDNA sequence for clone 23785.

SEQ ID NO: 256 is the determined cDNA sequence for clone 23786.

SEQ ID NO: 257 is the determined cDNA sequence for clone 23788.

SEQ ID NO: 258 is the determined cDNA sequence for clone 23790.

SEQ ID NO: 259 is the determined cDNA sequence for clone 23793.

SEQ ID NO: 260 is the determined cDNA sequence for clone 23794.

SEQ ID NO: 261 is the determined cDNA sequence for clone 23795.

SEQ ID NO: 262 is the determined cDNA sequence for clone 23796.

SEQ ID NO: 263 is the determined cDNA sequence for clone 23797.

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SEQ ID NO: 264 is the determined cDNA sequence for clone 23798. SEQ ÏD NO: 265 is the determined cDNA sequence for clone 23799. SEQ ID NO: 266 is the determined cDNA sequence for clone 23800. SEQ ID NO: 267 is the determined cDNA sequence for clone 23802. SEQ ID NO: 268 is the determined cDNA sequence for clone 23803. SEQ ID NO: 269 is the determined cDNA sequence for clone 23804. SEQ ID NO: 270 is the determined cDNA sequence for clone 23805. SEQ ID NO: 271 is the determined cDNA sequence for clone 23806. SEQ ID NO: 272 is the determined cDNA sequence for clone 23807. SEQ ID NO: 273 is the determined cDNA sequence for clone 23808. SEQ ID NO: 274 is the determined cDNA sequence for clone 23809. SEQ ID NO: 275 is the determined cDNA sequence for clone 23810. SEQ ID NO: 276 is the determined cDNA sequence for clone 23811. SEQ ID NO: 277 is the determined cDNA sequence for clone 23812. SEQ ID NO: 278 is the determined cDNA sequence for clone 23813. SEQ ID NO: 279 is the determined cDNA sequence for clone 23815. SEQ ID NO: 280 is the determined cDNA sequence for clone 25298. SEQ ID NO: 281 is the determined cDNA sequence for clone 25299. SEQ ID NO: 282 is the determined cDNA sequence for clone 25300. SEQ ID NO: 283 is the determined cDNA sequence for clone 25301 SEQ ID NO: 284 is the determined cDNA sequence for clone 25304 SEQ ID NO: 285 is the determined cDNA sequence for clone 25309. SEQ ID NO: 286 is the determined cDNA sequence for clone 25312. SEQ ID NO: 287 is the determined cDNA sequence for clone 25317. SEQ ID NO: 288 is the determined cDNA sequence for clone 25321. SEQ ID NO: 289 is the determined cDNA sequence for clone 25323. SEQ ID NO: 290 is the determined cDNA sequence for clone 25327. SEQ ID NO: 291 is the determined cDNA sequence for clone 25328.

SEQ ID NO: 292 is the determined cDNA sequence for clone 25332. SEQ ID NO: 293 is the determined cDNA sequence for clone 25333. SEQ ID NO: 294 is the determined cDNA sequence for clone 25336.

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SEQ ID NO: 295 is the determined cDNA sequence for clone 25340. SEQ ID NO: 296 is the determined cDNA sequence for clone 25342. SEQ ID NO: 297 is the determined cDNA sequence for clone 25356. SEQ ID NO: 298 is the determined cDNA sequence for clone 25357. SEQ ID NO: 299 is the determined cDNA sequence for clone 25361. SEQ ID NO: 300 is the determined cDNA sequence for clone 25363. SEQ ID NO: 301 is the determined cDNA sequence for clone 25397. SEQ ID NO: 302 is the determined cDNA sequence for clone 25402. SEQ ID NO: 303 is the determined cDNA sequence for clone 25403. SEQ ID NO: 304 is the determined cDNA sequence for clone 25405. SEQ ID NO: 305 is the determined cDNA sequence for clone 25407. SEQ ID NO: 306 is the determined cDNA sequence for clone 25409. SEQ ID NO: 307 is the determined cDNA sequence for clone 25396. SEQ ID NO: 308 is the determined cDNA sequence for clone 25414. SEQ ID NO: 309 is the determined cDNA sequence for clone 25410. SEQ ID NO: 310 is the determined cDNA sequence for clone 25406. SEQ ID NO: 311 is the determined cDNA sequence for clone 25306. SEQ ID NO: 312 is the determined cDNA sequence for clone 25362. SEQ ID NO: 313 is the determined cDNA sequence for clone 25360. SEQ ID NO: 314 is the determined cDNA sequence for clone 25398. SEQ ID NO: 315 is the determined cDNA sequence for clone 25355. SEQ ID NO: 316 is the determined cDNA sequence for clone 25351. SEQ ID NO: 317 is the determined cDNA sequence for clone 25331. SEQ ID NO: 318 is the determined cDNA sequence for clone 25338. SEQ ID NO: 319 is the determined cDNA sequence for clone 25335. SEQ ID NO: 320 is the determined cDNA sequence for clone 25329. SEQ ID NO: 321 is the determined cDNA sequence for clone 25324. SEQ ID NO: 322 is the determined cDNA sequence for clone 25322. SEQ ID NO: 323 is the determined cDNA sequence for clone 25319. SEQ ID NO: 324 is the determined cDNA sequence for clone 25316. SEQ ID NO: 325 is the determined cDNA sequence for clone 25311.

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SEQ ID NO: 326 is the determined cDNA sequence for clone 25310.

SEQ ID NO: 327 is the determined cDNA sequence for clone 25302.

SEQ ID NO: 328 is the determined cDNA sequence for clone 25315.

SEQ ID NO: 329 is the determined cDNA sequence for clone 25308.

SEQ ID NO: 330 is the determined cDNA sequence for clone 25303.

SEQ ID NO: 331-337 are the cDNA sequences of isoforms of the p53 tumor suppressor homologue, p63 (also referred to as L530S).

SEQ ID NO: 338-344 are the amino acid sequences encoded by SEQ ID NO: 331-337, respectively.

SEQ ID NO: 345 is a second cDNA sequence for the antigen L763P.

SEQ ID NO: 346 is the amino acid sequence encoded by the sequence of SEQ ID NO: 345.

SEQ ID NO: 347 is a determined full-length cDNA sequence for L523S.

SEQ ID NO: 348 is the predicted amino acid sequence encoded by SEQ ID NO: 347. SEQ ID NO: 349 is the cDNA sequence encoding the N-terminal portion of L773P.

SEQ ID NO: 350 is the amino acid sequence of the N-terminal portion of L773P.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention is generally directed to compositions and methods for the therapy and diagnosis of cancer, such as lung cancer. The compositions described herein may include lung tumor polypeptides, polynucleotides encoding such polypeptides, binding agents such as antibodies, antigen presenting cells (APCs) and/or immune system cells (e.g., T cells). Polypeptides of the present invention generally comprise at least a portion (such as an immunogenic portion) of a lung tumor protein or a variant thereof. A lung tumor protein is a protein that is expressed in lung tumor cells at a level that is at least two fold, and preferably at least five fold, greater than the level of expression in a normal tissue, as determined using a representative assay provided herein. Certain lung tumor proteins are tumor proteins that react detectably (within an immunoassay, such as an ELISA or Western blot) with antisera of a patient afflicted with lung cancer. Polynucleotides of the subject invention generally comprise a DNA or RNA sequence that encodes all or a portion of

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WO 00/61612 PCT/US00/08896 such a polypeptide, or that is complementary to such a sequence. Antibodies are generally immune system proteins, or antigen-binding fragments thereof, that are capable of binding to a polypeptide as described above. Antigen presenting cells include dendritic cells, macrophages, monocytes, fibroblasts and B-cells that express a polypeptide as described above. T cells that may be employed within such compositions are generally T cells that are specific for a polypeptide as described above.

The present invention is based on the discovery human lung tumor proteins. Sequences of polynucleotides encoding specific tumor proteins are provided in SEQ ID NO: 1-109, 111, 113, 115-151, 153, 154,157, 158, 160, 162-164, 167, 168, 171, 173, 175, 177-224, 255-337, 345,347 and 349.

Lung Tumor Protein Polynucleotides

Any polynucleotide that encodes a lung tumor protein or a portion or other variant thereof as described herein is encompassed by the present invention. Preferred polynucleotides comprise at least 15 consecutive nucleotides, preferably at least 30 consecutive nucleotides and more preferably at least 45 consecutive nucleotides, that encode a portion of a lung tumor protein. More preferably, a polynucleotide encodes an immunogenic portion of a lung tumor protein. Polynucleotides complementary to any such sequences are also encompassed by the present invention. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules include HnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide of the present invention, and a polynucleotide may, but need not, be linked to other molecules and/or support materials.

Polynucleotides may comprise a native sequence (i.e., an endogenous sequence that encodes a lung tumor protein or a portion thereof) or may comprise a variant of such a sequence. Polynucleotide variants may contain one or more substitutions, additions, deletions and/or insertions such that the immunogenicity of the

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PCT/US00/08896 encoded polypeptide is not diminished, relative to a native tumor protein. The effect on the immunogenicity of the encoded polypeptide may generally be assessed as described herein. Variants preferably exhibit at least about 70% identity, more preferably at least about 80% identity and most preferably at least about 90% identity to a polynucleotide sequence that encodes a native lung tumor protein or a portion thereof. The term “variants” also encompasses homologous genes of xenogenic origin.

Two polynucleotide or polypeptide sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A “comparison window” as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M.O. (1978) A model of evolutionary change in proteins - Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J. (1990) Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M. (1989) CABIOS 5:151-153; Myers, E.W. and Muller W. (1988) CABIOS 4:11-17; Robinson, E.D. (1971) Comb. Theor 77:105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4:406425; Sneath, P.H.A. and Sokal, R.R. (1973) Numerical Taxonomy - the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA; Wilbur, W. J. and Lipman, D.J. (1983)Proc. Natl. Acad., Sci. USA 80:126-130.

Preferably, the “percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20

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PCT/US00/08896 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e. gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e. the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

Variants may also, or alternatively, be substantially homologous to a native gene, or a portion or complement thereof. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native lung tumor protein (or a complementary sequence). Suitable moderately stringent conditions include prewashing in a solution of 5 X SSC,

0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridizing at 50°C-65°C, 5 X SSC, overnight;

followed by washing twice at 65°C for 20 minutes with each of 2X, 0.5X and 0.2X SSC containing 0.1% SDS.

It will be appreciated by those of ordinary skill in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encode a polypeptide as described herein. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary due to differences in codon usage are specifically contemplated by the present invention. Further, alleles of the genes comprising the polynucleotide sequences provided herein are within the scope of the present invention. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles may be identified using standard techniques (such as hybridization, amplification and/or database sequence comparison).

Polynucleotides may be prepared using any of a variety of techniques.

For example, a polynucleotide may be identified, as described in more detail below, by screening a microarray of cDNAs for tumor-associated expression (i.e., expression that

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PCT/US00/08896 is at least two fold greater in a lung tumor than in normal tissue, as determined using a representative assay provided herein). Such screens may be performed using a Synteni microarray (Palo Alto, CA) according to the manufacturer's instructions (and essentially as described by Schena et al., Proc. Natl. Acad. Sci. USA £3:10614-10619, 1996 and Heller et ah, Proc. Natl. Acad. Sci. USA 94:2150-2155, 1997). Alternatively, polypeptides may be amplified from cDNA prepared from cells expressing the proteins described herein, such as lung tumor cells. Such polynucleotides may be amplified via polymerase chain reaction (PCR). For this approach, sequence-specific primers may be designed based on the sequences provided herein, and may be purchased or synthesized.

An amplified portion may be used to isolate a full length gene from a suitable library (e.g., a lung tumor cDNA library) using well known techniques. Within such techniques, a library (cDNA or genomic) is screened using one or more polynucleotide probes or primers suitable for amplification. Preferably, a library is size-selected to include larger molecules. Random primed libraries may also be preferred for identifying 5' and upstream regions of genes. Genomic libraries are preferred for obtaining introns and extending 5' sequences.

For hybridization techniques, a partial sequence may be labeled (e.g., by nick-translation or end-labeling with ³²P) using well known techniques. A bacterial or bacteriophage library is then screened by hybridizing filters containing denatured bacterial colonies (or lawns containing phage plaques) with the labeled probe (see Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989). Hybridizing colonies or plaques are selected and expanded, and the DNA is isolated for further analysis. cDNA clones may be analyzed to determine the amount of additional sequence by, for example, PCR using a primer from the partial sequence and a primer from the vector. Restriction maps and partial sequences may be generated to identify one or more overlapping clones. The complete sequence may then be determined using standard techniques, which may involve generating a series of deletion clones. The resulting overlapping sequences are then assembled into a single contiguous sequence. A full length cDNA molecule can be generated by ligating suitable fragments, using well known techniques.

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Alternatively, there are numerous amplification techniques for obtaining a full length coding sequence from a partial cDNA sequence. Within such techniques, amplification is generally performed via PCR. Any of a variety of commercially available kits may be used to perform the amplification step. Primers may be designed using, for example, software well known in the art. Primers are preferably 22-30 nucleotides in length, have a GC content of at least 50% and anneal to the target sequence at temperatures of about 68°C to 72°C. The amplified region may be sequenced as described above, and overlapping sequences assembled into a contiguous sequence.

One such amplification technique is inverse PCR (see Triglia et al., Nucl. Acids Res. 76:8186, 1988), which uses restriction enzymes to generate a fragment in the known region of the gene. The fragment is then circularized by intramolecular ligation and used as a template for PCR with divergent primers derived from the known region. Within an alternative approach, sequences adjacent to a partial sequence may be retrieved by amplification with a primer to a linker sequence and a primer specific to a known region. The amplified sequences are typically subjected to a second round of amplification with the same linker primer and a second primer specific to the known region. A variation on this procedure, which employs two primers that initiate extension in opposite directions from the known sequence, is described in WO 96/38591. Another such technique is known as rapid amplification of cDNA ends or RACE. This technique involves the use of an internal primer and an external primer, which hybridizes to a poly A region or vector sequence, to identify sequences that are 5' and 3' of a known sequence. Additional techniques include capture PCR (Lagerstrom et al., PCR Methods Applic. 7:111-19, 1991) and walking PCR (Parker et al., Nucl. Acids. Res. 79:3055-60, 1991). Other methods employing amplification may also be employed to obtain a full length cDNA sequence.

In certain instances, it is possible to obtain a full length cDNA sequence by analysis of sequences provided in an expressed sequence tag (EST) database, such as that available from GenBank. Searches for overlapping ESTs may generally be performed using well known programs (e.g., NCBI BLAST searches), and such ESTs

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PCT/US00/08896 may be used to generate a contiguous full length sequence. Full length DNA sequences may also be obtained by analysis of genomic fragments.

Certain nucleic acid sequences of cDNA molecules encoding portions of lung tumor proteins are provided in SEQ ID NO: 1-109, 111, 113, 115-151, 153, 154,157, 158, 160, 162-164, 167, 168, 171, 173, 175, 177-224, 255-337, 345, 347 and 349.

Polynucleotide variants may generally be prepared by any method known in the art, including chemical synthesis by, for example, solid phase phosphoramidite chemical synthesis. Modifications in a polynucleotide sequence may also be introduced using standard mutagenesis techniques, such as oligonucleotidedirected site-specific mutagenesis (see Adelman et al., DNA 2:183, 1983). Alternatively, RNA molecules may be generated by in vitro or in vivo transcription of DNA sequences encoding a lung tumor protein, or portion thereof, provided that the DNA is incorporated into a vector with a suitable RNA polymerase promoter (such as T7 or SP6). Certain portions may be used to prepare an encoded polypeptide, as described herein. In addition, or alternatively, a portion may be administered to a patient such that the encoded polypeptide is generated in vivo (e.g., by transfecting antigen-presenting cells, such as dendritic cells, with a cDNA construct encoding a lung tumor polypeptide, and administering the transfected cells to the patient).

A portion of a sequence complementary to a coding sequence (i.e., an antisense polynucleotide) may also be used as a probe or to modulate gene expression. cDNA constructs that can be transcribed into antisense RNA may also be introduced into cells of tissues to facilitate the production of antisense RNA. An antisense polynucleotide may be used, as described herein, to inhibit expression of a tumor protein. Antisense technology can be used to control gene expression through triplehelix formation, which compromises the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors or regulatory molecules (see Gee et al., In Huber and Carr, Molecular and Immunologic Approaches, Futura Publishing Co. (Mt. Kisco, NY; 1994)). Alternatively, an antisense molecule may be designed to hybridize with a control region of a gene (e.g., promoter, enhancer or transcription

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PCT/US00/08896 initiation site), and block transcription of the gene; or to block translation by inhibiting binding of a transcript to ribosomes.

A portion of a coding sequence, or of a complementary sequence, may also be designed as a probe or primer to detect gene expression. Probes may be labeled with a variety of reporter groups, such as radionuclides and enzymes, and are preferably at least 10 nucleotides in length, more preferably at least 20 nucleotides in length and still more preferably at least 30 nucleotides in length. Primers, as noted above, are preferably 22-30 nucleotides in length.

Any polynucleotide may be further modified to increase stability in vivo. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends; the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages in the backbone; and/or the inclusion of nontraditional bases such as inosine, queosine and wybutosine, as well as acetyl- methyl-, thio- and other modified forms of adenine, cytidine, guanine, thymine and uridine.

Nucleotide sequences as described herein may be joined to a variety of other nucleotide sequences using established recombinant DNA techniques. For example, a polynucleotide may be cloned into any of a variety of cloning vectors, including plasmids, phagemids, lambda phage derivatives and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors and sequencing vectors. In general, a vector will contain an origin of replication functional in at least one organism, convenient restriction endonuclease sites and one or more selectable markers. Other elements will depend upon the desired use, and will be apparent to those of ordinary skill in the art.

Within certain embodiments, polynucleotides may be formulated so as to permit entry into a cell of a mammal, and expression therein. Such formulations are particularly useful for therapeutic purposes, as described below. Those of ordinary skill in the art will appreciate that there are many ways to achieve expression of a polynucleotide in a target cell, and any suitable method may be employed. For example, a polynucleotide may be incorporated into a viral vector such as, but not limited to, adenovirus, adeno-associated virus, retrovirus, or vaccinia or other pox virus (e.g., avian pox virus). ). The polynucleotides may also be administered as naked

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PCT7US00/08896 plasmid vectors. Techniques for incorporating DNA into such vectors are well known to those of ordinary skill in the art. A retroviral vector may additionally transfer or incorporate a gene for a selectable marker (to aid in the identification or selection of transduced cells) and/or a targeting moiety, such as a gene that encodes a ligand for a receptor on a specific target cell, to render the vector target specific. Targeting may also be accomplished using an antibody, by methods known to those of ordinary skill in the art.

Other formulations for therapeutic purposes include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. A preferred colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (i.e., an artificial membrane vesicle). The preparation and use of such systems is well known in the art.

Lung Tumor Polypeptides

Within the context of the present invention, polypeptides may comprise at least an immunogenic portion of a lung tumor protein or a variant thereof, as described herein. As noted above, a lung tumor protein is a protein that is expressed by lung tumor cells. Proteins that are lung tumor proteins also react detectably within an immunoassay (such as an ELISA) with antisera from a patient with lung cancer. Polypeptides as described herein may be of any length. Additional sequences derived from the native protein and/or heterologous sequences may be present, and such sequences may (but need not) possess further immunogenic or antigenic properties.

An “immunogenic portion,” as used herein is a portion of a protein that is recognized (i.e., specifically bound) by a B-cell and/or T-cell surface antigen receptor. Such immunogenic portions generally comprise at least 5 amino acid residues, more preferably at least 10, and still more preferably at least 20 amino acid residues of a lung tumor protein or a variant thereof. Certain preferred immunogenic portions include peptides in which an N-terminal leader sequence and/or transmembrane domain have been deleted. Other preferred immunogenic portions may

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PCT/US00/08896 contain a small N- and/or C-terminal deletion (e.g., 1-30 amino acids, preferably 5-15 amino acids), relative to the mature protein.

Immunogenic portions may generally be identified using well known techniques, such as those summarized in Paul, Fundamental Immunology, 3rd ed., 243247 (Raven Press, 1993) and references cited therein. Such techniques include screening polypeptides for the ability to react with antigen-specific antibodies, antisera and/or T-cell lines or clones. As used herein, antisera and antibodies are antigenspecific if they specifically bind to an antigen (i.e., they react with the protein in an ELISA or other immunoassay, and do not react detectably with unrelated proteins). Such antisera and antibodies may be prepared as described herein, and using well known techniques. An immunogenic portion of a native lung tumor protein is a portion that reacts with such antisera and/or T-cells at a level that is not substantially less than the reactivity of the full length polypeptide (e.g., in an ELISA and/or T-cell reactivity assay). Such immunogenic portions may react within such assays at a level that is similar to or greater than the reactivity of the full length polypeptide. Such screens may generally be performed using methods well known to those of ordinary skill in the art, such as those described in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. For example, a polypeptide may be immobilized on a solid support and contacted with patient sera to allow binding of antibodies within the sera to the immobilized polypeptide. Unbound sera may then be removed and bound antibodies detected using, for example, ¹²⁵l-labeled Protein A.

As noted above, a composition may comprise a variant of a native lung tumor protein. A polypeptide “variant,” as used herein, is a polypeptide that differs from a native lung tumor protein in one or more substitutions, deletions, additions and/or insertions, such that the immunogenicity of the polypeptide is not substantially diminished. In other words, the ability of a variant to react with antigen-specific antisera may be enhanced or unchanged, relative to the native protein, or may be diminished by less than 50%, and preferably less than 20%, relative to the native protein. Such variants may generally be identified by modifying one of the above polypeptide sequences and evaluating the reactivity of the modified polypeptide with antigen-specific antibodies or antisera as described herein. Preferred variants include

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PCT/US00/08896 those in which one or more portions, such as an N-terminal leader sequence or transmembrane domain, have been removed. Other preferred variants include variants in which a small portion (e.g., 1-30 amino acids, preferably 5-15 amino acids) has been removed from the N- and/or C-terminal of the mature protein.

Polypeptide variants preferably exhibit at least about 70%, more preferably at least about 90% and most preferably at least about 95% identity (determined as described above) to the identified polypeptides.

Preferably, a variant contains conservative substitutions. A conservative substitution is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged. Amino acid substitutions may generally be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valine; glycine and alanine; asparagine and glutamine; and serine, threonine, phenylalanine and tyrosine. Other groups of amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gin, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, trp, his. A variant may also, or alternatively, contain nonconservative changes. In a preferred embodiment, variant polypeptides differ from a native sequence by substitution, deletion or addition of five amino acids or fewer. Variants may also (or alternatively) be modified by, for example, the deletion or addition of amino acids that have minimal influence on the immunogenicity, secondary structure and hydropathic nature of the polypeptide.

As noted above, polypeptides may comprise a signal (or leader) sequence at the N-terminal end of the protein which co-translationally or posttranslationally directs transfer of the protein. The polypeptide may also be conjugated to a linker or other sequence for ease of synthesis, purification or identification of the

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PCT/US00/08896 polypeptide (e.g., poly-His), or to enhance binding of the polypeptide to a solid support. For example, a polypeptide may be conjugated to an immunoglobulin Fc region.

Polypeptides may be prepared using any of a variety of well known techniques. Recombinant polypeptides encoded by DNA sequences as described above may be readily prepared from the DNA sequences using any of a variety of expression vectors known to those of ordinary skill in the art. Expression may be achieved in any appropriate host cell that has been transformed or transfected with an expression vector containing a DNA molecule that encodes a recombinant polypeptide. Suitable host cells include prokaryotes, yeast, higher eukaryotic and plant cells. Preferably, the host cells employed are E. coli, yeast or a mammalian cell line such as COS or CHO. Supernatants from suitable host/vector systems which secrete recombinant protein or polypeptide into culture media may be first concentrated using a commercially available filter. Following concentration, the concentrate may be applied to a suitable purification matrix such as an affinity matrix or an ion exchange resin. Finally, one or more reverse phase HPLC steps can be employed to further purify a recombinant polypeptide.

Portions and other variants having fewer than about 100 amino acids, and generally fewer than about 50 amino acids, may also be generated by synthetic means, using techniques well known to those of ordinary skill in the art. For example, such polypeptides may be synthesized using any of the commercially available solidphase techniques, such as the Merrifield solid-phase synthesis method, where amino acids are sequentially added to a growing amino acid chain. See Merrifield, J. Am. Chem. Soc. 55:2149-2146, 1963. Equipment for automated synthesis of polypeptides is commercially available from suppliers such as Perkin Elmer/Applied BioSystems Division (Foster City, CA), and may be operated according to the manufacturer's instructions.

Within certain specific embodiments, a polypeptide may be a fusion protein that comprises multiple polypeptides as described herein, or that comprises at least one polypeptide as described herein and an unrelated sequence, such as a known tumor protein. A fusion partner may, for example, assist in providing T helper epitopes (an immunological fusion partner), preferably T helper epitopes recognized by humans,

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PCT/US00/08896 or may assist in expressing the protein (an expression enhancer) at higher yields than the native recombinant protein. Certain preferred fusion partners are both immunological and expression enhancing fusion partners. Other fusion partners may be selected so as to increase the solubility of the protein or to enable the protein to be targeted to desired intracellular compartments. Still further fusion partners include affinity tags, which facilitate purification of the protein.

Fusion proteins may generally be prepared using standard techniques, including chemical conjugation. Preferably, a fusion protein is expressed as a recombinant protein, allowing the production of increased levels, relative to a non-fused protein, in an expression system. Briefly, DNA sequences encoding the polypeptide components may be assembled separately, and ligated into an appropriate expression vector. The 3' end of the DNA sequence encoding one polypeptide component is ligated, with or without a peptide linker, to the 5' end of a DNA sequence encoding the second polypeptide component so that the reading frames of the sequences are in phase. This permits translation into a single fusion protein that retains the biological activity of both component polypeptides.

A peptide linker sequence may be employed to separate the first and the second polypeptide components by a distance sufficient to ensure that each polypeptide folds into its secondary and tertiary structures. Such a peptide linker sequence is incorporated into the fusion protein using standard techniques well known in the art. Suitable peptide linker sequences may be chosen based on the following factors; (1) their ability to adopt a flexible extended conformation; (2) their inability to adopt a secondary structure that could interact with functional epitopes on the first and second polypeptides; and (3) the lack of hydrophobic or charged residues that might react with the polypeptide functional epitopes. Preferred peptide linker sequences contain Gly, Asn and Ser residues. Other near neutral amino acids, such as Thr and Ala may also be used in the linker sequence. Amino acid sequences which may be usefully employed as linkers include those disclosed in Maratea etal., Gene 40:39-46, 1985; Murphy etak, Proc. Natl. Acad. Sci. USA 53:8258-8262, 1986; U.S. Patent No. 4,935,233 and U.S. Patent No. 4,751,180. The linker sequence may generally be from 1 to about 50 amino acids in length. Linker sequences are not required when the first and second

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PCT/US00/08896 polypeptides have non-essential N-terminal amino acid regions that can be used to separate the functional domains and prevent steric interference.

The ligated DNA sequences are operably linked to suitable transcriptional or translational regulatory elements. The regulatory elements responsible for expression of DNA are located only 5' to the DNA sequence encoding the first polypeptides. Similarly, stop codons required to end translation and transcription termination signals are only present 3' to the DNA sequence encoding the second polypeptide.

Fusion proteins are also provided that comprise a polypeptide of the present invention together with an unrelated immunogenic protein. Preferably the immunogenic protein is capable of eliciting a recall response. Examples of such proteins include tetanus, tuberculosis and hepatitis proteins (see, for example, Stoute et al. New Engl. J. Med., 336:86-91, 1997).

Within preferred embodiments, an immunological fusion partner is derived from protein D, a surface protein of the gram-negative bacterium Haemophilus influenza B (WO 91/18926). Preferably, a protein D derivative comprises approximately the first third of the protein (e.g., the first N-terminal 100-110 amino acids), and a protein D derivative may be lipidated. Within certain preferred embodiments, the first 109 residues of a Lipoprotein D fusion partner is included on the N-terminus to provide the polypeptide with additional exogenous T-cell epitopes and to increase the expression level in E. coli (thus functioning as an expression enhancer). The lipid tail ensures optimal presentation of the antigen to antigen presenting cells. Other fusion partners include the non-structural protein from influenzae virus, NS1 (hemaglutinin). Typically, the N-terminal 81 amino acids are used, although different fragments that include T-helper epitopes may be used.

In another embodiment, the immunological fusion partner is the protein known as LYTA, or a portion thereof (preferably a C-terminal portion). LYTA is derived from Streptococcus pneumoniae, which synthesizes an N-acetyl-L-alanine amidase known as amidase LYTA (encoded by the LytA gene; Gene 43:265-292, 1986). LYTA is an autolysin that specifically degrades certain bonds in the peptidoglycan backbone. The C-terminal domain of the LYTA protein is responsible

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PCT/US00/08896 for the affinity to the choline or to some choline analogues such as DEAE. This property has been exploited for the development of E. coli C-LYTA expressing plasmids useful for expression of fusion proteins. Purification of hybrid proteins containing the C-LYTA fragment at the amino terminus has been described (see Biotechnology 70:795-798, 1992). Within a preferred embodiment, a repeat portion of LYTA may be incorporated into a fusion protein. A repeat portion is found in the Cterminal region starting at residue 178. A particularly preferred repeat portion incorporates residues 188-305.

In general, polypeptides (including fusion proteins) and polynucleotides as described herein are isolated. An isolated polypeptide or polynucleotide is one that is removed from its original environment. For example, a naturally-occurring protein is isolated if it is separated from some or all of the coexisting materials in the natural system. Preferably, such polypeptides are at least about 90% pure, more preferably at least about 95% pure and most preferably at least about 99% pure. A polynucleotide is considered to be isolated if, for example, it is cloned into a vector that is not a part of the natural environment.

Binding Agents

The present invention further provides agents, such as antibodies and antigen-binding fragments thereof, that specifically bind to a lung tumor protein. As used herein, an antibody, or antigen-binding fragment thereof, is said to specifically bind to a lung tumor protein if it reacts at a detectable level (within, for example, an ELISA) with a lung tumor protein, and does not react detectably with unrelated proteins under similar conditions. As used herein, binding refers to a noncovalent association between two separate molecules such that a complex is formed. The ability to bind may be evaluated by, for example, determining a binding constant for the formation of the complex. The binding constant is the value obtained when the concentration of the complex is divided by the product of the component concentrations. In general, two compounds are said to bind, in the context of the present invention, when the binding constant for complex formation exceeds about 10³ L/mol. The binding constant may be determined using methods well known in the art.

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Binding agents may be further capable of differentiating between patients with and without a cancer, such as lung cancer, using the representative assays provided herein. In other words, antibodies or other binding agents that bind to a lung tumor protein will generate a signal indicating the presence of a cancer in at least about 20% of patients with the disease, and will generate a negative signal indicating the absence of the disease in at least about 90% of individuals without the cancer. To determine whether a binding agent satisfies this requirement, biological samples (e.g, blood, sera, sputum urine and/or tumor biopsies ) from patients with and without a cancer (as determined using standard clinical tests) may be assayed as described herein for the presence of polypeptides that bind to the binding agent. It will be apparent that a statistically significant number of samples with and without the disease should be assayed. Each binding agent should satisfy the above criteria; however, those of ordinary skill in the art will recognize that binding agents may be used in combination to improve sensitivity.

Any agent that satisfies the above requirements may be a binding agent. For example, a binding agent may be a ribosome, with or without a peptide component, an RNA molecule or a polypeptide. In a preferred embodiment, a binding agent is an antibody or an antigen-binding fragment thereof. Antibodies may be prepared by any of a variety of techniques known to those of ordinary skill in the art. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. In general, antibodies can be produced by cell culture techniques, including the generation of monoclonal antibodies as described herein, or via transfection of antibody genes into suitable bacterial or mammalian cell hosts, in order to allow for the production of recombinant antibodies. In one technique, an immunogen comprising the polypeptide is initially injected into any of a wide variety of mammals (e.g., mice, rats, rabbits, sheep or goats). In this step, the polypeptides of this invention may serve as the immunogen without modification. Alternatively, particularly for relatively short polypeptides, a superior immune response may be elicited if the polypeptide is joined to a carrier protein, such as bovine serum albumin or keyhole limpet hemocyanin. The immunogen is injected into the animal host, preferably according to a predetermined schedule incorporating one or more booster immunizations, and the animals are bled periodically.

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Polyclonal antibodies specific for the polypeptide may then be purified from such antisera by, for example, affinity chromatography using the polypeptide coupled to a suitable solid support.

Monoclonal antibodies specific for an antigenic polypeptide of interest may be prepared, for example, using the technique of Kohler and Milstein, Eur. J. Immunol. 6:511-519, 1976, and improvements thereto. Briefly, these methods involve the preparation of immortal cell lines capable of producing antibodies having the desired specificity (i.e., reactivity with the polypeptide of interest). Such cell lines may be produced, for example, from spleen cells obtained from an animal immunized as described above. The spleen cells are then immortalized by, for example, fusion with a myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal. A variety of fusion techniques may be employed. For example, the spleen cells and myeloma cells may be combined with a nonionic detergent for a few minutes and then plated at low density on a selective medium that supports the growth of hybrid cells, but not myeloma cells. A preferred selection technique uses HAT (hypoxanthine, aminopterin, thymidine) selection. After a sufficient time, usually about 1 to 2 weeks, colonies of hybrids are observed. Single colonies are selected and their culture supernatants tested for binding activity against the polypeptide. Hybridomas having high reactivity and specificity are preferred.

Monoclonal antibodies may be isolated from the supernatants of growing hybridoma colonies. In addition, various techniques may be employed to enhance the yield, such as injection of the hybridoma cell line into the peritoneal cavity of a suitable vertebrate host, such as a mouse. Monoclonal antibodies may then be harvested from the ascites fluid or the blood. Contaminants may be removed from the antibodies by conventional techniques, such as chromatography, gel filtration, precipitation, and extraction. The polypeptides of this invention may be used in the purification process in, for example, an affinity chromatography step.

Within certain embodiments, the use of antigen-binding fragments of antibodies may be preferred. Such fragments include Fab fragments, which may be prepared using standard techniques. Briefly, immunoglobulins may be purified from rabbit serum by affinity chromatography on Protein A bead columns (Harlow and Lane,

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Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988) and digested by papain to yield Fab and Fc fragments. The Fab and Fc fragments may be separated by affinity chromatography on protein A bead columns.

Monoclonal antibodies of the present invention may be coupled to one or more therapeutic agents. Suitable agents in this regard include radionuclides, differentiation inducers, drugs, toxins, and derivatives thereof. Preferred radionuclides include ⁹⁰Y, ¹²³I, ^l25I, ¹³¹I, ¹⁸⁶Re, ¹⁸⁸Re, ²¹ ^t, and ²¹²Bi. Preferred drugs include methotrexate, and pyrimidine and purine analogs. Preferred differentiation inducers include phorbol esters and butyric acid. Preferred toxins include ricin, abrin, diptheria toxin, cholera toxin, gelonin, Pseudomonas exotoxin, Shigella toxin, and pokeweed antiviral protein.

A therapeutic agent may be coupled (e.g, covalently bonded) to a suitable monoclonal antibody either directly or indirectly (e.g., via a linker group). A direct reaction between an agent and an antibody is possible when each possesses a substituent capable of reacting with the other. For example, a nucleophilic group, such as an amino or sulfhydryl group, on one may be capable of reacting with a carbonylcontaining group, such as an anhydride or an acid halide, or with an alkyl group containing a good leaving group (e.g., a halide) on the other.

Alternatively, it may be desirable to couple a therapeutic agent and an antibody via a linker group. A linker group can function as a spacer to distance an antibody from an agent in order to avoid interference with binding capabilities. A linker group can also serve to increase the chemical reactivity of a substituent on an agent or an antibody, and thus increase the coupling efficiency. An increase in chemical reactivity may also facilitate the use of agents, or functional groups on agents, which otherwise would not be possible.

It will be evident to those skilled in the art that a variety of bifunctional or polyfunctional reagents, both homo- and hetero-functional (such as those described in the catalog of the Pierce Chemical Co., Rockford, IL), may be employed as the linker group. Coupling may be effected, for example, through amino groups, carboxyl groups, sulfhydryl groups or oxidized carbohydrate residues. There are numerous references describing such methodology, e.g., U.S. Patent No. 4,671,958, to Rodwell et al.

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Where a therapeutic agent is more potent when free from the antibody portion of the immunoconjugates of the present invention, it may be desirable to use a linker group which is cleavable during or upon internalization into a cell. A number of different cleavable linker groups have been described. The mechanisms for the intracellular release of an agent from these linker groups include cleavage by reduction of a disulfide bond (e.g., U.S. Patent No. 4,489,710, to Spitler), by irradiation of a photolabile bond (e.g., U.S. Patent No. 4,625,014, to Senter etal.), by hydrolysis of derivatized amino acid side chains (e.g., U.S. Patent No. 4,638,045, to Kohn et al.), by serum complement-mediated hydrolysis (e.g., U.S. Patent No. 4,671,958, to Rodwell et al.), and acid-catalyzed hydrolysis (e.g., U.S. Patent No. 4,569,789, to Blattler et al.).

It may be desirable to couple more than one agent to an antibody. In one embodiment, multiple molecules of an agent are coupled to one antibody molecule. In another embodiment, more than one type of agent may be coupled to one antibody. Regardless of the particular embodiment, immunoconjugates with more than one agent may be prepared in a variety of ways. For example, more than one agent may be coupled directly to an antibody molecule, or linkers which provide multiple sites for attachment can be used. Alternatively, a carrier can be used.

A carrier may bear the agents in a variety of ways, including covalent bonding either directly or via a linker group. Suitable carriers include proteins such as albumins (e.g., U.S. Patent No. 4,507,234, to Kato et al.), peptides and polysaccharides such as aminodextran (e.g., U.S. Patent No. 4,699,784, to Shih et al.). A carrier may also bear an agent by noncovalent bonding or by encapsulation, such as within a liposome vesicle (e.g., U.S. Patent Nos. 4,429,008 and 4,873,088). Carriers specific for radionuclide agents include radiohalogenated small molecules and chelating compounds. For example, U.S. Patent No. 4,735,792 discloses representative radiohalogenated small molecules and their synthesis. A radionuclide chelate may be formed from chelating compounds that include those containing nitrogen and sulfur atoms as the donor atoms for binding the metal, or metal oxide, radionuclide. For example, U.S. Patent No. 4,673,562, to Davison et al. discloses representative chelating compounds and their synthesis.

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A variety of routes of administration for the antibodies and immunoconjugates may be used. Typically, administration will be intravenous, intramuscular, subcutaneous or in the bed of a resected tumor, it will be evident that the precise dose of the antibody/immunoconjugate will vary depending upon the antibody used, the antigen density on the tumor, and the rate of clearance of the antibody.

T Cells

Immunotherapeutic compositions may also, or alternatively, comprise T cells specific for a lung tumor protein. Such cells may generally be prepared in vitro or ex vivo, using standard procedures. For example, T cells may be isolated from bone marrow, peripheral blood, or a fraction of bone marrow or peripheral blood of a patient, using a commercially available cell separation system, such as the Isolex™ System, available from Nexell Therapeutics, Inc. Irvine, CA (see also U.S. Patent No. 5,240,856; U.S. Patent No. 5,215,926; WO 89/06280; WO 91/16116 and WO 92/07243). Alternatively, T cells may be derived from related or unrelated humans, non-human mammals, cell lines or cultures.

T cells may be stimulated with a lung tumor polypeptide, polynucleotide encoding a lung tumor polypeptide and/or an antigen presenting cell (APC) that expresses such a polypeptide. Such stimulation is performed under conditions and for a time sufficient to permit the generation of T cells that are specific for the polypeptide. Preferably, a lung tumor polypeptide or polynucleotide is present within a delivery vehicle, such as a microsphere, to facilitate the generation of specific T cells.

T cells are considered to be specific for a lung tumor polypeptide if the T cells specifically proliferate, secrete cytokines or kill target cells coated with the polypeptide or expressing a gene encoding the polypeptide. T cell specificity may be evaluated using any of a variety of standard techniques. For example, within a chromium release assay or proliferation assay, a stimulation index of more than two fold increase in lysis and/or proliferation, compared to negative controls, indicates T cell specificity. Such assays may be performed, for example, as described in Chen et al., Cancer Res. 54:1065-1070, 1994. Alternatively, detection of the proliferation of T cells may be accomplished by a variety of known techniques. For example, T cell

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PCT/US00/08896 proliferation can be detected by measuring an increased rate of DNA synthesis (e.g., by pulse-labeling cultures of T cells with tritiated thymidine and measuring the amount of tritiated thymidine incorporated into DNA). Contact with a lung tumor polypeptide (100 ng/ml - 100 pg/ml, preferably 200 ng/ml - 25 pg/ml) for 3 - 7 days should result in at least a two fold increase in proliferation of the T cells. Contact as described above for 2-3 hours should result in activation of the T cells, as measured using standard cytokine assays in which a two fold increase in the level of cytokine release (e.g., TNF or IFN-γ) is indicative of T cell activation (see Coligan et al., Current Protocols in immunology, vol. 1, Wiley Interscience (Greene 1998)). T cells that have been activated in response to a lung tumor polypeptide, polynucleotide or polypeptideexpressing APC may be CD4+ and/or CD8⁺. Lung tumor protein-specific T cells may be expanded using standard techniques. Within preferred embodiments, the T cells are derived from either a patient or a related, or unrelated, donor and are administered to the patient following stimulation and expansion.

For therapeutic purposes, CD4⁺ or CD8⁺ T cells that proliferate in response to a lung tumor polypeptide, polynucleotide or APC can be expanded in number either in vitro or in vivo. Proliferation of such T cells in vitro may be accomplished in a variety of ways. For example, the T cells can be re-exposed to a lung tumor polypeptide, or a short peptide corresponding to an immunogenic portion of such a polypeptide, with or without the addition of T cell growth factors, such as interleukin2, and/or stimulator cells that synthesize a lung tumor polypeptide. Alternatively, one or more T cells that proliferate in the presence of a lung tumor protein can be expanded in number by cloning. Methods for cloning cells are well known in the art, and include limiting dilution.

Pharmaceutical Compositions and Vaccines

Within certain aspects, polypeptides, polynucleotides, T cells and/or binding agents disclosed herein may be incorporated into pharmaceutical compositions or immunogenic compositions (i.e., vaccines). Pharmaceutical compositions comprise one or more such compounds and a physiologically acceptable carrier. Vaccines may comprise one or more such compounds and an immunostimulant. An immunostimulant

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PCT/US00/08896 may be any substance that enhances or potentiates an immune response to an exogenous antigen. Examples of immunostimulants include adjuvants, biodegradable microspheres (e.g., polylactic galactide) and liposomes (into which the compound is incorporated; see e.g., Fullerton, U.S. Patent No. 4,235,877). Vaccine preparation is generally described in, for example, M.F. Powell and M.J. Newman, eds., Vaccine Design (the subunit and adjuvant approach), Plenum Press (NY, 1995). Pharmaceutical compositions and vaccines within the scope of the present invention may also contain other compounds, which may be biologically active or inactive. For example, one or more immunogenic portions of other tumor antigens may be present, either incorporated into a fusion polypeptide or as a separate compound, within the composition or vaccine.

A pharmaceutical composition or vaccine may contain DNA encoding one or more of the polypeptides as described above, such that the polypeptide is generated in situ. As noted above, the DNA may be present within any of a variety of delivery systems known to those of ordinary skill in the art, including nucleic acid expression systems, bacteria and viral expression systems. Numerous gene delivery techniques are well known in the art, such as those described by Rolland, Crit. Rev. Therap. Drug Carrier Systems 75:143-198, 1998, and references cited therein. Appropriate nucleic acid expression systems contain the necessary DNA sequences for expression in the patient (such as a suitable promoter and terminating signal). Bacterial delivery systems involve the administration of a bacterium (such as Bacillus-CalmetteGuerriri) that expresses an immunogenic portion of the polypeptide on its cell surface or secretes such an epitope. In a preferred embodiment, the DNA may be introduced using a viral expression system (e.g., vaccinia or other pox virus, retrovirus, or adenovirus), which may involve the use of a non-pathogenic (defective), replication competent virus. Suitable systems are disclosed, for example, in Fisher-Hoch et al., Proc. Natl. Acad. Sci. USA #6:317-321, 1989; Flexner et al., Ann. N.Y. Acad. Sci. 569:86-103, 1989; Flexner et al., Vaccine #:17-21, 1990; U.S. Patent Nos. 4,603,112, 4,769,330, and 5,017,487; WO 89/01973; U.S. Patent No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91/02805; Berkner, Biotechniques 6:616-627, 1988; Rosenfeld et al., Science 252:431-434, 1991; Rolls et al., Proc. Natl. Acad. Sci. USA 97:215-219, 1994; Kass-Eisler et al., Proc. Natl.

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Acad Sci. USA 90:11498-11502, 1993; Guzman et al., Circulation 55:2838-2848, 1993; and Guzman et al., Cir. Res. 73:1202-1207, 1993. Techniques for incorporating DNA into such expression systems are well known to those of ordinary skill in the art. The DNA may also be ’’naked, as described, for example, in Ulmer et al., Science 259:1745-1749, 1993 and reviewed by Cohen, Science 259:1691-1692, 1993. The uptake of naked DNA may be increased by coating the DNA onto biodegradable beads, which are efficiently transported into the cells.

While any suitable carrier known to those of ordinary skill in the art may be employed in the pharmaceutical compositions of this invention, the type of carrier will vary depending on the mode of administration. Compositions of the present invention may be formulated for any appropriate manner of administration, including for example, topical, oral, nasal, intravenous, intracranial, intraperitoneal, subcutaneous or intramuscular administration. For parenteral administration, such as subcutaneous injection, the carrier preferably comprises water, saline, alcohol, a fat, a wax or a buffer. For oral administration, any of the above carriers or a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, and magnesium carbonate, may be employed. Biodegradable microspheres (e.g., polylactate polyglycolate) may also be employed as carriers for the pharmaceutical compositions of this invention. Suitable biodegradable microspheres are disclosed, for example, in U.S. Patent Nos. 4,897,268 and 5,075,109.

Such compositions may also comprise buffers (e.g., neutral buffered saline or phosphate buffered saline), carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione, adjuvants (e.g., aluminum hydroxide) and/or preservatives. Alternatively, compositions of the present invention may be formulated as a lyophilizate. Compounds may also be encapsulated within liposomes using well known technology.

Any of a variety of immunostimulants may be employed in the vaccines of this invention. For example, an adjuvant may be included. Most adjuvants contain a substance designed to protect the antigen from rapid catabolism, such as aluminum hydroxide or mineral oil, and a stimulator of immune responses, such as lipid A,

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Bortadella pertussis or Mycobacterium tuberculosis derived proteins. Suitable adjuvants are commercially available as, for example, Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories, Detroit, MI); Merck Adjuvant 65 (Merck and Company, Inc., Rahway, NJ); AS-2 (SmithKline Beecham, Philadelphia, PA);

aluminum salts such as aluminum hydroxide gel (alum) or aluminum phosphate; salts of calcium, iron or zinc; an insoluble suspension of acylated tyrosine; acylated sugars; cationically or anionically derivatized polysaccharides; polyphosphazenes; biodegradable microspheres; monophosphoryl lipid A and quil A. Cytokines, such as GM-CSF or interleukin-2, -7, or -12, may also be used as adjuvants.

Within the vaccines provided herein, the adjuvant composition is preferably designed to induce an immune response predominantly of the Thi type. High levels of Thi-type cytokines (e.g., IFN-γ, TNFoc, IL-2 and IL-12) tend to favor the induction of cell mediated immune responses to an administered antigen. In contrast, high levels of Th2-type cytokines (e.g., IL-4, IL-5, IL-6 and IL-10) tend to favor the induction of humoral immune responses. Following application of a vaccine as provided herein, a patient will support an immune response that includes Thi - and Th2type responses. Within a preferred embodiment, in which a response is predominantly Thi-type, the level of Thi-type cytokines will increase to a greater extent than the level of Th2-type cytokines. The levels of these cytokines may be readily assessed using standard assays. For a review of the families of cytokines, see Mosmann and Coffman, Ann. Rev. Immunol. 7:145-173, 1989.

Preferred adjuvants for use in eliciting a predominantly Thi-type response include, for example, a combination of monophosphoryl lipid A, preferably 3de-O-acylated monophosphoryl lipid A (3D-MPL), together with an aluminum salt.

MPL adjuvants are available from Ribi ImmunoChem Research Inc. (Hamilton, MT) (see US Patent Nos. 4,436,727; 4,877,611; 4,866,034 and 4,912,094). CpG-containing oligonucleotides (in which the CpG dinucleotide is unmethylated) also induce a predominantly Thi response. Such oligonucleotides are well known and are described, for example, in WO 96/02555 and WO 99/33488. Immunostimulatory DNA sequences are also described, for example, by Sato et al., Science 273:352, 1996. Another preferred adjuvant is a saponin, preferably QS21 (Aquila Biopharmaceuticals Inc.,

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Framingham, MA), which may be used alone or in combination with other adjuvants. For example, an enhanced system involves the combination of a monophosphoryl lipid A and saponin derivative, such as the combination of QS21 and 3D-MPL as described in WO 94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol, as described in WO 96/33739. Other preferred formulations comprises an oil-in-water emulsion and tocopherol. A particularly potent adjuvant formulation involving QS21, 3D-MPL and tocopherol in an oil-in-water emulsion is described in WO 95/17210.

Other preferred adjuvants include Montanide ISA 720 (Seppic, France), SAF (Chiron, California, United States), ISCOMS (CSL), MF-59 (Chiron), the SBAS series of adjuvants (e.g, SBAS-2 or SBAS-4, available from SmithKline Beecham, Rixensart, Belgium), Detox (Ribi ImmunoChem Research Inc., Hamilton, MT), RC-529 (Ribi ImmunoChem Research Inc., Hamilton, MT) and Aminoalkyl glucosaminide 4phosphates (AGPs).

Any vaccine provided herein may be prepared using well known methods that result in a combination of antigen, immune response enhancer and a suitable carrier or excipient. The compositions described herein may be administered as part of a sustained release formulation (i.e., a formulation such as a capsule, sponge or gel (composed of polysaccharides, for example) that effects a slow release of compound following administration). Such formulations may generally be prepared using well known technology (see, e.g. Coombes et aL, Vaccine 14\ 1429-1438, 1996) and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain a polypeptide, polynucleotide or antibody dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane.

Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. Such carriers include microparticles of poly(lactide-coglycolide), as well as polyacrylate, latex, starch, cellulose and dextran. Other delayedrelease carriers include supramolecular biovectors, which comprise a non-liquid hydrophilic core (e.g, a cross-linked polysaccharide or oligosaccharide) and, optionally,

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PCT/US00/08896 an external layer comprising an amphiphilic compound, such as a phospholipid (see e.g., U.S. Patent No. 5,151,254 and PCT applications WO 94/20078, WO/94/23701 and WO 96/06638). The amount of active compound contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.

Any of a variety of delivery vehicles may be employed within pharmaceutical compositions and vaccines to facilitate production of an antigen-specific immune response that targets tumor cells. Delivery vehicles include antigen presenting cells (APCs), such as dendritic cells, macrophages, B cells, monocytes and other cells that may be engineered to be efficient APCs. Such cells may, but need not, be genetically modified to increase the capacity for presenting the antigen, to improve activation and/or maintenance of the T cell response, to have anti-tumor effects per se and/or to be immunologically compatible with the receiver (i.e., matched HLA haplotype). APCs may generally be isolated from any of a variety of biological fluids and organs, including tumor and péritumoral tissues, and may be autologous, allogeneic, syngeneic or xenogeneic cells.

Certain preferred embodiments of the present invention use dendritic cells or progenitors thereof as antigen-presenting cells. Dendritic cells are highly potent APCs (Banchereau and Steinman, Nature 392:245-251, 1998) and have been shown to be effective as a physiological adjuvant for eliciting prophylactic or therapeutic antitumor immunity (see Timmerman and Levy, Ann. Rev. Med 59:507-529, 1999). In general, dendritic cells may be identified based on their typical shape (stellate in situ, with marked cytoplasmic processes (dendrites) visible in vitro), their ability to take up, process and present antigens with high efficiency, and their ability to activate naïve T cell responses. Dendritic cells may, of course, be engineered to express specific cellsurface receptors or ligands that are not commonly found on dendritic cells in vivo or ex vivo, and such modified dendritic cells are contemplated by the present invention. As an alternative to dendritic cells, secreted vesicles antigen-loaded dendritic cells (called exosomes) may be used within a vaccine (see Zitvogel et al., Nature Med. 4:594-600, 1998).

Dendritic cells and progenitors may be obtained from peripheral blood,

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PCT/US00/08896 bone marrow, tumor-infiltrating cells, péritumoral tissues-infiltrating cells, lymph nodes, spleen, skin, umbilical cord blood or any other suitable tissue or fluid. For example, dendritic cells may be differentiated ex vivo by adding a combination of cytokines such as GM-CSF, IL-4, IL-13 and/or TNFa to cultures of monocytes harvested from peripheral blood. Alternatively, CD34 positive cells harvested from peripheral blood, umbilical cord blood or bone marrow may be differentiated into dendritic cells by adding to the culture medium combinations of GM-CSF, IL-3, TNFa, CD40 ligand, LPS, flt3 ligand and/or other compound(s) that induce differentiation, maturation and proliferation of dendritic cells.

Dendritic cells are conveniently categorized as immature and mature cells, which allows a simple way to discriminate between two well characterized phenotypes. However, this nomenclature should not be construed to exclude all possible intermediate stages of differentiation. Immature dendritic cells are characterized as APC with a high capacity for antigen uptake and processing, which correlates with the high expression of Fey receptor and mannose receptor. The mature phenotype is typically characterized by a lower expression of these markers, but a high expression of cell surface molecules responsible for T cell activation such as class I and class II MHC, adhesion molecules (e.g., CD54 and CD11) and costimulatory molecules (e.g., CD40, CD80, CD86 and 4-1BB).

APCs may generally be transfected with a polynucleotide encoding a lung tumor protein (or portion or other variant thereof) such that the lung tumor polypeptide, or an immunogenic portion thereof, is expressed on the cell surface. Such transfection may take place ex vivo, and a composition or vaccine comprising such transfected cells may then be used for therapeutic purposes, as described herein. Alternatively, a gene delivery vehicle that targets a dendritic or other antigen presenting cell may be administered to a patient, resulting in transfection that occurs in vivo. In vivo and ex vivo transfection of dendritic cells, for example, may generally be performed using any methods known in the art, such as those described in WO 97/24447, or the gene gun approach described by Mahvi et al., Immunology and cell Biology 75:456-460, 1997. Antigen loading of dendritic cells may be achieved by incubating dendritic cells or progenitor cells with the lung tumor polypeptide, DNA

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PCT/US00/08896 (naked or within a plasmid vector) or RNA; or with antigen-expressing recombinant bacterium or viruses (e.g., vaccinia, fowlpox, adenovirus or lentivirus vectors). Prior to loading, the polypeptide may be covalently conjugated to an immunological partner that provides T cell help (e.g, a carrier molecule). Alternatively, a dendritic cell may be pulsed with a non-conjugated immunological partner, separately or in the presence of the polypeptide.

Vaccines and pharmaceutical compositions may be presented in unitdose or multi-dose containers, such as sealed ampoules or vials. Such containers are preferably hermetically sealed to preserve sterility of the formulation until use. In general, formulations may be stored as suspensions, solutions or emulsions in oily or aqueous vehicles. Alternatively, a vaccine or pharmaceutical composition may be stored in a freeze-dried condition requiring only the addition of a sterile liquid carrier immediately prior to use.

C ancer Therapy

In further aspects of the present invention, the compositions described herein may be used for immunotherapy of cancer, such as lung cancer. Within such methods, pharmaceutical compositions and vaccines are typically administered to a patient. As used herein, a “patient” refers to any warm-blooded animal, preferably a human. A patient may or may not be afflicted with cancer. Accordingly, the above pharmaceutical compositions and vaccines may be used to prevent the development of a cancer or to treat a patient afflicted with a cancer. A cancer may be diagnosed using criteria generally accepted in the art, including the presence of a malignant tumor. Pharmaceutical compositions and vaccines may be administered either prior to or following surgical removal of primary tumors and/or treatment such as administration of radiotherapy or conventional chemotherapeutic drugs.

Within certain embodiments, immunotherapy may be active immunotherapy, in which treatment relies on the in vivo stimulation of the endogenous host immune system to react against tumors with the administration of immune response-modifying agents (such as polypeptides and polynucleotides disclosed herein).

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Within other embodiments, immunotherapy may be passive immunotherapy, in which treatment involves the delivery of agents with established tumor-immune reactivity (such as effector cells or antibodies) that can directly or indirectly mediate antitumor effects and does not necessarily depend on an intact host immune system. Examples of effector cells include T cells as discussed above, T lymphocytes (such as CD8⁺ cytotoxic T lymphocytes and CD4⁺ T-helper tumorinfiltrating lymphocytes), killer cells (such as Natural Killer cells and lymphokineactivated killer cells), B cells and antigen-presenting cells (such as dendritic cells and macrophages) expressing a polypeptide provided herein. T cell receptors and antibody receptors specific for the polypeptides recited herein may be cloned, expressed and transferred into other vectors or effector cells for adoptive immunotherapy. The polypeptides provided herein may also be used to generate antibodies or anti-idiotypic antibodies (as described above and in U.S. Patent No. 4,918,164) for passive immunotherapy.

Effector cells may generally be obtained in sufficient quantities for adoptive immunotherapy by growth in vitro, as described herein. Culture conditions for expanding single antigen-specific effector cells to several billion in number with retention of antigen recognition in vivo are well known in the art. Such in vitro culture conditions typically use intermittent stimulation with antigen, often in the presence of cytokines (such as IL-2) and non-dividing feeder cells. As noted above, immunoreactive polypeptides as provided herein may be used to rapidly expand antigen-specific T cell cultures in order to generate a sufficient number of cells for immunotherapy. In particular, antigen-presenting cells, such as dendritic, macrophage, monocyte, fibroblast and/or B cells, may be pulsed with immunoreactive polypeptides or transfected with one or more polynucleotides using standard techniques well known in the art. For example, antigen-presenting cells can be transfected with a polynucleotide having a promoter appropriate for increasing expression in a recombinant virus or other expression system. Cultured effector cells for use in therapy must be able to grow and distribute widely, and to survive long term in vivo. Studies have shown that cultured effector cells can be induced to grow in vivo and to survive

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PCT/US00/08896 long term in substantial numbers by repeated stimulation with antigen supplemented with IL-2 (see, for example, Cheever et al., Immunological Reviews 157:177, 1997).

Alternatively, a vector expressing a polypeptide recited herein may be introduced into antigen presenting cells taken from a patient and clonally propagated ex vivo for transplant back into the same patient. Transfected cells may be reintroduced into the patient using any means known in the art, preferably in sterile form by intravenous, intracavitary, intraperitoneal or intratumor administration.

Routes and frequency of administration of the therapeutic compositions disclosed herein, as well as dosage, will vary from individual to individual, and may be readily established using standard techniques. In general, the pharmaceutical compositions and vaccines may be administered by injection (e.g., intracutaneous, intramuscular, intravenous or subcutaneous), intranasally (e.g., by aspiration) or orally. Preferably, between 1 and 10 doses may be administered over a 52 week period. Preferably, 6 doses are administered, at intervals of 1 month, and booster vaccinations may be given periodically thereafter. Alternate protocols may be appropriate for individual patients. A suitable dose is an amount of a compound that, when administered as described above, is capable of promoting an anti-tumor immune response, and is at least 10-50% above the basal (i.e., untreated) level. Such response can be monitored by measuring the anti-tumor antibodies in a patient or by vaccinedependent generation of cytolytic effector cells capable of killing the patient’s tumor cells in vitro. Such vaccines should also be capable of causing an immune response that leads to an improved clinical outcome (e.g., more frequent remissions, complete or partial or longer disease-free survival) in vaccinated patients as compared to nonvaccinated patients. In general, for pharmaceutical compositions and vaccines comprising one or more polypeptides, the amount of each polypeptide present in a dose ranges from about 25 pg to 5 mg per kg of host. Suitable dose sizes will vary with the size of the patient, but will typically range from about 0.1 mL to about 5 mL.

In general, an appropriate dosage and treatment regimen provides the active compound(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit. Such a response can be monitored by establishing an improved clinical outcome (e.g., more frequent remissions, complete or partial, or longer disease-free

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PCT/US00/08896 survival) in treated patients as compared to non-treated patients. Increases in preexisting immune responses to a lung tumor protein generally correlate with an improved clinical outcome. Such immune responses may generally be evaluated using standard proliferation, cytotoxicity or cytokine assays, which may be performed using samples obtained from a patient before and after treatment.

Methods for Detecting Cancer

In general, a cancer may be detected in a patient based on the presence of one or more lung tumor proteins and/or polynucleotides encoding such proteins in a biological sample (for example, blood, sera, sputum urine and/or tumor biopsies) obtained from the patient. In other words, such proteins may be used as markers to indicate the presence or absence of a cancer such as lung cancer. In addition, such proteins may be useful for the detection of other cancers. The binding agents provided herein generally permit detection of the level of antigen that binds to the agent in the biological sample. Polynucleotide primers and probes may be used to detect the level of mRNA encoding a tumor protein, which is also indicative of the presence or absence of a cancer. In general, a lung tumor sequence should be present at a level that is at least three fold higher in tumor tissue than in normal tissue

There are a variety of assay formats known to those of ordinary skill in the art for using a binding agent to detect polypeptide markers in a sample. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. In general, the presence or absence of a cancer in a patient may be determined by (a) contacting a biological sample obtained from a patient with a binding agent; (b) detecting in the sample a level of polypeptide that binds to the binding agent; and (c) comparing the level of polypeptide with a predetermined cut-off value.

In a preferred embodiment, the assay involves the use of binding agent immobilized on a solid support to bind to and remove the polypeptide from the remainder of the sample. The bound polypeptide may then be detected using a detection reagent that contains a reporter group and specifically binds to the binding agent/polypeptide complex. Such detection reagents may comprise, for example, a binding agent that specifically binds to the polypeptide or an antibody or other agent

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PCT/US00/08896 that specifically binds to the binding agent, such as an anti-immunoglobulin, protein G, protein A or a lectin. Alternatively, a competitive assay may be utilized, in which a polypeptide is labeled with a reporter group and allowed to bind to the immobilized binding agent after incubation of the binding agent with the sample. The extent to which components of the sample inhibit the binding of the labeled polypeptide to the binding agent is indicative of the reactivity of the sample with the immobilized binding agent. Suitable polypeptides for use within such assays include full length lung tumor proteins and portions thereof to which the binding agent binds, as described above.

The solid support may be any material known to those of ordinary skill in the art to which the tumor protein may be attached. For example, the solid support may be a test well in a microtiter plate or a nitrocellulose or other suitable membrane. Alternatively, the support may be a bead or disc, such as glass, fiberglass, latex or a plastic material such as polystyrene or polyvinylchloride. The support may also be a magnetic particle or a fiber optic sensor, such as those disclosed, for example, in U.S.

Patent No. 5,359,681. The binding agent may be immobilized on the solid support using a variety of techniques known to those of skill in the art, which are amply described in the patent and scientific literature. In the context of the present invention, the term immobilization refers to both noncovalent association, such as adsorption, and covalent attachment (which may be a direct linkage between the agent and functional groups on the support or may be a linkage by way of a cross-linking agent). Immobilization by adsorption to a well in a microtiter plate or to a membrane is preferred. In such cases, adsorption may be achieved by contacting the binding agent, in a suitable buffer, with the solid support for a suitable amount of time. The contact time varies with temperature, but is typically between about 1 hour and about 1 day. In general, contacting a well of a plastic microtiter plate (such as polystyrene or polyvinylchloride) with an amount of binding agent ranging from about 10 ng to about 10 pg, and preferably about 100 ng to about 1 pg, is sufficient to immobilize an adequate amount of binding agent.

Covalent attachment of binding agent to a solid support may generally be achieved by first reacting the support with a bifunctional reagent that will react with both the support and a functional group, such as a hydroxyl or amino group, on the

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PCT/US00/08896 binding agent. For example, the binding agent may be covalently attached to supports having an appropriate polymer coating using benzoquinone or by condensation of an aldehyde group on the support with an amine and an active hydrogen on the binding partner (see, e.g., Pierce Immunotechnology Catalog and Handbook, 1991, at A12-A13).

In certain embodiments, the assay is a two-antibody sandwich assay. This assay may be performed by first contacting an antibody that has been immobilized on a solid support, commonly the well of a microtiter plate, with the sample, such that polypeptides within the sample are allowed to bind to the immobilized antibody. Unbound sample is then removed from the immobilized polypeptide-antibody complexes and a detection reagent (preferably a second antibody capable of binding to a different site on the polypeptide) containing a reporter group is added. The amount of detection reagent that remains bound to the solid support is then determined using a method appropriate for the specific reporter group.

More specifically, once the antibody is immobilized on the support as described above, the remaining protein binding sites on the support are typically blocked. Any suitable blocking agent known to those of ordinary skill in the art, such as bovine serum albumin or Tween 20™ (Sigma Chemical Co., St. Louis, MO). The immobilized antibody is then incubated with the sample, and polypeptide is allowed to bind to the antibody. The sample may be diluted with a suitable diluent, such as phosphate-buffered saline (PBS) prior to incubation. In general, an appropriate contact time (i.e., incubation time) is a period of time that is sufficient to detect the presence of polypeptide within a sample obtained from an individual with lung cancer. Preferably, the contact time is sufficient to achieve a level of binding that is at least about 95% of that achieved at equilibrium between bound and unbound polypeptide. Those of ordinary skill in the art will recognize that the time necessary to achieve equilibrium may be readily determined by assaying the level of binding that occurs over a period of time. At room temperature, an incubation time of about 30 minutes is generally sufficient.

Unbound sample may then be removed by washing the solid support with an appropriate buffer, such as PBS containing 0.1% Tween 20™. The second

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PCT/US00/08896 antibody, which contains a reporter group, may then be added to the solid support. Preferred reporter groups include those groups recited above.

The detection reagent is then incubated with the immobilized antibodypolypeptide complex for an amount of time sufficient to detect the bound polypeptide. An appropriate amount of time may generally be determined by assaying the level of binding that occurs over a period of time. Unbound detection reagent is then removed and bound detection reagent is detected using the reporter group. The method employed for detecting the reporter group depends upon the nature of the reporter group. For radioactive groups, scintillation counting or autoradiographic methods are generally appropriate. Spectroscopic methods may be used to detect dyes, luminescent groups and fluorescent groups. Biotin may be detected using avidin, coupled to a different reporter group (commonly a radioactive or fluorescent group or an enzyme). Enzyme reporter groups may generally be detected by the addition of substrate (generally for a specific period of time), followed by spectroscopic or other analysis of the reaction products.

To determine the presence or absence of a cancer, such as lung cancer, the signal detected from the reporter group that remains bound to the solid support is generally compared to a signal that corresponds to a predetermined cut-off value. In one preferred embodiment, the cut-off value for the detection of a cancer is the average mean signal obtained when the immobilized antibody is incubated with samples from patients without the cancer. In general, a sample generating a signal that is three standard deviations above the predetermined cut-off value is considered positive for the cancer. In an alternate preferred embodiment, the cut-off value is determined using a Receiver Operator Curve, according to the method of Sackett et al., Clinical Epidemiology: A Basic Science for Clinical Medicine, Little Brown and Co., 1985, p. 106-7. Briefly, in this embodiment, the cut-off value may be determined from a plot of pairs of true positive rates (i.e., sensitivity) and false positive rates (100%-specificity) that correspond to each possible cut-off value for the diagnostic test result. The cut-off value on the plot that is the closest to the upper left-hand corner (fe., the value that encloses the largest area) is the most accurate cut-off value, and a sample generating a signal that is higher than the cut-off value determined by this method may be considered

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PCT/US00/08896 positive. Alternatively, the cut-off value may be shifted to the left along the plot, to minimize the false positive rate, or to the right, to minimize the false negative rate. In general, a sample generating a signal that is higher than the cut-off value determined by this method is considered positive for a cancer.

In a related embodiment, the assay is performed in a flow-through or strip test format, wherein the binding agent is immobilized on a membrane, such as nitrocellulose. In the flow-through test, polypeptides within the sample bind to the immobilized binding agent as the sample passes through the membrane. A second, labeled binding agent then binds to the binding agent-polypeptide complex as a solution containing the second binding agent flows through the membrane. The detection of bound second binding agent may then be performed as described above. In the strip test format, one end of the membrane to which binding agent is bound is immersed in a solution containing the sample. The sample migrates along the membrane through a region containing second binding agent and to the area of immobilized binding agent. Concentration of second binding agent at the area of immobilized antibody indicates the presence of a cancer. Typically, the concentration of second binding agent at that site generates a pattern, such as a line, that can be read visually. The absence of such a pattern indicates a negative result. In general, the amount of binding agent immobilized on the membrane is selected to generate a visually discernible pattern when the biological sample contains a level of polypeptide that would be sufficient to generate a positive signal in the two-antibody sandwich assay, in the format discussed above. Preferred binding agents for use in such assays are antibodies and antigen-binding fragments thereof. Preferably, the amount of antibody immobilized on the membrane ranges from about 25 ng to about lpg, and more preferably from about 50 ng to about 500 ng. Such tests can typically be performed with a very small amount of biological sample.

Of course, numerous other assay protocols exist that are suitable for use with the tumor proteins or binding agents of the present invention. The above descriptions are intended to be exemplary only. For example, it will be apparent to those of ordinary skill in the art that the above protocols may be readily modified to use lung tumor polypeptides to detect antibodies that bind to such polypeptides in a

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PCT/US00/08896 biological sample. The detection of such lung tumor protein specific antibodies may correlate with the presence of a cancer.

A cancer may also, or alternatively, be detected based on the presence of T cells that specifically react with a lung tumor protein in a biological sample. Within certain methods, a biological sample comprising CD4⁺ and/or CD8⁺ T cells isolated from a patient is incubated with a lung tumor polypeptide, a polynucleotide encoding such a polypeptide and/or an APC that expresses at least an immunogenic portion of such a polypeptide, and the presence or absence of specific activation of the T cells is detected. Suitable biological samples include, but are not limited to, isolated T cells. For example, T cells may be isolated from a patient by routine techniques (such as by Ficoll/Hypaque density gradient centrifugation of peripheral blood lymphocytes). T cells may be incubated in vitro for 2-9 days (typically 4 days) at 37°C with polypeptide (e.g., 5-25 pg/ml). It may be desirable to incubate another aliquot of a T cell sample in the absence of lung tumor polypeptide to serve as a control. For CD4⁺ T cells, activation is preferably detected by evaluating proliferation of the T cells. For CD8⁺ T cells, activation is preferably detected by evaluating cytolytic activity. A level of proliferation that is at least two fold greater and/or a level of cytolytic activity that is at least 20% greater than in disease-free patients indicates the presence of a cancer in the patient.

As noted above, a cancer may also, or alternatively, be detected based on the level of mRNA encoding a lung tumor protein in a biological sample. For example, at least two oligonucleotide primers may be employed in a polymerase chain reaction (PCR) based assay to amplify a portion of a lung tumor cDNA derived from a biological sample, wherein at least one of the oligonucleotide primers is specific for (i.e., hybridizes to) a polynucleotide encoding the lung tumor protein. The amplified cDNA is then separated and detected using techniques well known in the art, such as gel electrophoresis. Similarly, oligonucleotide probes that specifically hybridize to a polynucleotide encoding a lung tumor protein may be used in a hybridization assay to detect the presence of polynucleotide encoding the tumor protein in a biological sample.

To permit hybridization under assay conditions, oligonucleotide primers and probes should comprise an oligonucleotide sequence that has at least about 60%,

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PCI7US00/08896 preferably at least about 75% and more preferably at least about 90%, identity to a portion of a polynucleotide encoding a lung tumor protein that is at least 10 nucleotides, and preferably at least 20 nucleotides, in length. Preferably, oligonucleotide primers and/or probes will hybridize to a polynucleotide encoding a polypeptide disclosed herein under moderately stringent conditions, as defined above. Oligonucleotide primers and/or probes which may be usefully employed in the diagnostic methods described herein preferably are at least 10-40 nucleotides in length. In a preferred embodiment, the oligonucleotide primers comprise at least 10 contiguous nucleotides, more preferably at least 15 contiguous nucleotides, of a DNA molecule having a sequence recited in SEQ ID NO: 1-109, 111, 113, 115-151, 153, 154, 357, 158, 160, 162-164, 167, 168, 171, 173, 175, 177-224, 255-337, 345, 347 and 349. Techniques for both PCR based assays and hybridization assays are well known in the art (see, for example, Mullis et al., Cold Spring Harbor Symp. Quant. Biol., 51:263, 1987; Erlich ed., PCR Technology, Stockton Press, NY, 1989).

One preferred assay employs RT-PCR, in which PCR is applied in conjunction with reverse transcription. Typically, RNA is extracted from a biological sample, such as biopsy tissue, and is reverse transcribed to produce cDNA molecules. PCR amplification using at least one specific primer generates a cDNA molecule, which may be separated and visualized using, for example, gel electrophoresis. Amplification may be performed on biological samples taken from a test patient and from an individual who is not afflicted with a cancer. The amplification reaction may be performed on several dilutions of cDNA spanning two orders of magnitude. A two-fold or greater increase in expression in several dilutions of the test patient sample as compared to the same dilutions of the non-cancerous sample is typically considered positive.

In another embodiment, the disclosed compositions may be used as markers for the progression of cancer. In this embodiment, assays as described above for the diagnosis of a cancer may be performed over time, and the change in the level of reactive polypeptide(s) or polynucleotide evaluated. For example, the assays may be performed every 24-72 hours for a period of 6 months to 1 year, and thereafter performed as needed. In general, a cancer is progressing in those patients in whom the

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PCT/US00/08896 level of polypeptide or polynucleotide detected increases over time. In contrast, the cancer is not progressing when the level of reactive polypeptide or polynucleotide either remains constant or decreases with time.

Certain in vivo diagnostic assays may be performed directly on a tumor. One such assay involves contacting tumor cells with a binding agent. The bound binding agent may then be detected directly or indirectly via a reporter group. Such binding agents may also be used in histological applications. Alternatively, polynucleotide probes may be used within such applications.

As noted above, to improve sensitivity, multiple lung tumor protein markers may be assayed within a given sample. It will be apparent that binding agents specific for different proteins provided herein may be combined within a single assay. Further, multiple primers or probes may be used concurrently. The selection of tumor protein markers may be based on routine experiments to determine combinations that results in optimal sensitivity. In addition, or alternatively, assays for tumor proteins provided herein may be combined with assays for other known tumor antigens.

Diagnostic Kits

The present invention further provides kits for use within any of the above diagnostic methods. Such kits typically comprise two or more components necessary for performing a diagnostic assay. Components may be compounds, reagents, containers and/or equipment. For example, one container within a kit may contain a monoclonal antibody or fragment thereof that specifically binds to a lung tumor protein. Such antibodies or fragments may be provided attached to a support material, as described above. One or more additional containers may enclose elements, such as reagents or buffers, to be used in the assay. Such kits may also, or alternatively, contain a detection reagent as described above that contains a reporter group suitable for direct or indirect detection of antibody binding.

Alternatively, a kit may be designed to detect the level of mRNA encoding a lung tumor protein in a biological sample. Such kits generally comprise at least one oligonucleotide probe or primer, as described above, that hybridizes to a polynucleotide encoding a lung tumor protein. Such an oligonucleotide may be used,

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PCT/US00/08896 for example, within a PCR or hybridization assay. Additional components that may be present within such kits include a second oligonucleotide and/or a diagnostic reagent or container to facilitate the detection of a polynucleotide encoding a lung tumor protein.

The following Examples are offered by way of illustration and not by 5 way of limitation.

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EXAMPLE 1

ISOLATION AND CHARACTERIZATION OF cDNA SEQUENCES ENCODING LUNG TUMOR POLYPEPTIDES

This example illustrates the isolation of cDNA molecules encoding lung tumor-specific polypeptides from lung tumor cDNA libraries.

A. ISOLATION OF cDNA SEQUENCES FROM A LUNG SQUAMOUS CELL CARCINOMA LIBRARY

A human lung squamous cell carcinoma cDNA expression library was constructed from poly A⁺ RNA from a pool of two patient tissues using a Superscript Plasmid System for cDNA Synthesis and Plasmid Cloning kit (BRL Life Technologies, Gaithersburg, MD) following the manufacturer's protocol. Specifically, lung carcinoma tissues were homogenized with polytron (Kinematica, Switzerland) and total RNA was extracted using Trizol reagent (BRL Life Technologies) as directed by the manufacturer. The poly A⁺ RNA was then purified using an oligo dT cellulose column as described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989. First-strand cDNA was synthesized using the NotI/Oligo-dT18 primer. Double-stranded cDNA was synthesized, ligated with BstXI/EcoRl adaptors (Invitrogen, San Diego, CA) and digested with Noth Following size fractionation with cDNA size fractionation columns (BRL Life Technologies), the cDNA was ligated into the BstXI/Notl site of pcDNA3.1 (Invitrogen) and transformed into ElectroMax E. coli DH10B cells (BRL Life Technologies) by electroporation.

Using the same procedure, a normal human lung cDNA expression library was prepared from a pool of four tissue specimens. The cDNA libraries were characterized by determining the number of independent colonies, the percentage of clones that carried insert, the average insert size and by sequence analysis. The lung squamous cell carcinoma library contained 2.7 x 10⁶ independent colonies, with 100% of clones having an insert and the average insert size being 2100 base pairs. The normal

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PCT/US00/08896 lung cDNA library contained 1.4 x 10⁶ independent colonies, with 90% of clones having inserts and the average insert size being 1800 base pairs. For both libraries, sequence analysis showed that the majority of clones had a full length cDNA sequence and were synthesized from mRNA cDNA library subtraction was performed using the above lung squamous cell carcinoma and normal lung cDNA libraries, as described by Hara et al. (Blood, £4:189-199, 1994) with some modifications. Specifically, a lung squamous cell carcinoma-specific subtracted cDNA library was generated as follows. Normal tissue cDNA library (80 μg) was digested with BamHI and Xhol, followed by a filling-in reaction with DNA polymerase Klenow fragment. After phenol-chloroform extraction and ethanol precipitation, the DNA was dissolved in 133 μΐ of H₂O, heat-denatured and mixed with 133 μΐ (133 pg) of Photoprobe biotin (Vector Laboratories, Burlingame, CA). As recommended by the manufacturer, the resulting mixture was irradiated with a 270 W sunlamp on ice for 20 minutes. Additional Photoprobe biotin (67 μΐ) was added and the biotinylation reaction was repeated. After extraction with butanol five times, the DNA was ethanol-precipitated and dissolved in 23 μΐ H₂O to form the driver DNA.

To form the tracer DNA, 10 pg lung squamous cell carcinoma cDNA library was digested with Notl and Spel, phenol chloroform extracted and passed through Chroma spin-400 columns (Clontech, Palo Alto, CA). Typically, 5 pg of cDNA was recovered after the sizing column. Following ethanol precipitation, the tracer DNA was dissolved in 5 μΐ H₂O. Tracer DNA was mixed with 15 μΐ driver DNA and 20 μΐ of 2 x hybridization buffer (1.5 M NaCl/10 mM EDTA/50 mM HEPES pH 7.5/0.2% sodium dodecyl sulfate), overlaid with mineral oil, and heat-denatured completely. The sample was immediately transferred into a 68 °C water bath and incubated for 20 hours (long hybridization [LH]). The reaction mixture was then subjected to a streptavidin treatment followed by phenol/chloroform extraction. This process was repeated three more times. Subtracted DNA was precipitated, dissolved in 12 μΐ H₂O, mixed with 8 μΐ driver DNA and 20 μΐ of 2 x hybridization buffer, and subjected to a hybridization at 68 °C for 2 hours (short hybridization [SH]). After removal of biotinylated double-stranded DNA, subtracted cDNA was ligated into Notl/Spel site of chloramphenicol resistant pBCSK⁺ (Stratagene, La Jolla, CA) and

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WO 00/61612 PCT/USOO/08896 transformed into ElectroMax E. coli DH10B cells by electroporation to generate a lung squamous cell carcinoma specific subtracted cDNA library (herein after referred to as “lung subtraction I”).

A second lung squamous cell carcinoma specific subtracted cDNA library (referred to as “lung subtraction II”) was generated in a similar way to the lung subtraction library I, except that eight frequently recovered genes from lung subtraction I were included in the driver DNA, and 24,000 independent clones were recovered.

To analyze the subtracted cDNA libraries, plasmid DNA was prepared from 320 independent clones, randomly picked from the subtracted lung squamous cell carcinoma specific libraries. Representative cDNA clones were further characterized by DNA sequencing with a Perkin Elmer/Applied Biosystems Division Automated Sequencer Model 373A and/or Model 377 (Foster City, CA). The cDNA sequences for sixty isolated clones are provided in SEQ ID NO: 1-60. These sequences were compared to known sequences in the gene bank using the EMBL and GenBank databases (release 96). No significant homologies were found to the sequences provided in SEQ ID NO: 2, 3, 19, 38 and 46. The sequences of SEQ ID NO: 1, 6-8, 1013, 15, 17, 18, 20-27, 29, 30, 32, 34-37, 39-45, 47-49, 51, 52, 54, 55 and 57-59 were found to show some homology to previously identified expressed sequence tags (ESTs). The sequences of SEQ ID NO: 9, 28, 31 and 33 were found to show some homology to previously identified non-human gene sequences and the sequences of SEQ ID NO: 4, 5, 14, 50, 53, 56 and 60 were found to show some homology to gene sequences previously identified in humans.

The subtraction procedure described above was repeated using the above lung squamous cell carcinoma cDNA library as the tracer DNA, and the above normal lung tissue cDNA library and a cDNA library from normal liver and heart (constructed from a pool of one sample of each tissue as described above), plus twenty other cDNA clones that were frequently recovered in lung subtractions I and II, as the driver DNA (lung subtraction III). The normal liver and heart cDNA library contained 1.76 x 10⁶independent colonies, with 100% of clones having inserts and the average insert size being 1600 base pairs. Ten additional clones were isolated (SEQ ID NO: 61-70). Comparison of these cDNA sequences with those in the gene bank as described above,

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PCT/US00/08896 revealed no significant homologies to the sequences provided in SEQ ID NO: 62 and 67. The sequences of SEQ ID NO: 61, 63-66, 68 and 69 were found to show some homology to previously isolated ESTs and the sequence provided in SEQ ID NO: 70 was found to show some homology to a previously identified rat gene.

In further studies, the subtraction procedure described above was repeated using the above lung squamous cell carcinoma cDNA library as the tracer DNA, and a cDNA library from a pool of normal lung, kidney, colon, pancreas, brain, resting PBMC, heart, skin and esophagus as the driver DNA, with esophagus cDNAs making up one third of the driver material. Since esophagus is enriched in normal epithelial cells, including differentiated squamous cells, this procedure is likely to enrich genes that are tumor specific rather than tissues specific. The cDNA sequences of 48 clones determined in this subtraction are provided in SEQ ID NO: 177-224. The sequences of SEQ ID NO: 177, 178, 180, 181, 183, 187, 192, 195-197, 208,211, 212, 215, 216, 218 and 219 showed some homology to previously identified genes. The sequences of SEQ ID NO: 179, 182, 184-186, 188-191, 193, 194, 198-207, 209 210, 213, 214, 217, 220 and 224 showed some homology to previously determined ESTs. The sequence of SEQ ID NO: 221-223 showed no homology to any previously determined sequence.

B. ISOLATION OF cDNA SEQUENCES FROM A LUNG ADENOCARCINOMA LIBRARY

A human lung adenocarcinoma cDNA expression library was constructed as described above. The library contained 3.2 x 10⁶ independent colonies, with 100% of clones having an insert and the average insert size being 1500 base pairs. Library subtraction was performed as described above using the normal lung and normal liver and heart cDNA expression libraries described above as the driver DNA. Twenty-six hundred independent clones were recovered.

Initial cDNA sequence analysis from 100 independent clones revealed many ribosomal protein genes. The cDNA sequences for fifteen clones isolated in this subtraction are provided in SEQ ID NO: 71-86. Comparison of these sequences with those in the gene bank as described above revealed no significant homologies to the

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PCT/US00/08896 sequence provided in SEQ ID NO: 84. The sequences of SEQ ID NO: 71, 73, 74, 77, 78 and 80-82 were found to show some homology to previously isolated ESTs, and the sequences of SEQ ID NO: 72, 75, 76, 79, 83 and 85 were found to show some homology to previously identified human genes.

In further studies, a cDNA library (referred to as mets3616A) was constructed from a metastatic lung adenocarcinoma. The determined cDNA sequences of 25 clones sequenced at random from this library are provided in SEQ ID NO: 255279. The mets3616A cDNA library was subtracted against a cDNA library prepared from a pool of normal lung, liver, pancreas, skin, kidney, brain and resting PBMC. To increase the specificity of the subtraction, the driver was spiked with genes that were determined to be most abundant in the mets3616A cDNA library, such as EF1-alpha, integrin-beta and anticoagulant protein PP4, as well as with cDNAs that were previously found to be differentially expressed in subtracted lung adenocarcinoma cDNA libraries. The determined cDNA sequences of 51 clones isolated from the subtracted library (referred to as mets3616A-Sl) are provided in SEQ ID NO: 280-330.

Comparison of the sequences of SEQ ID NO: 255-330 with those in the public databases revealed no significant homologies to the sequences of SEQ ID NO: 255-258, 260, 262-264, 270, 272, 275, 276, 279, 281, 287, 291, 296, 300 and 310. The sequences of SEQ ID NO: 259, 261, 265-269, 271, 273, 274, 277, 278, 282-285, 288290, 292, 294, 297-299, 301, 303-309, 313, 314, 316, 320-324 and 326-330 showed some homology to previously identified gene sequences, while the sequences of SEQ ID NO: 280, 286, 293, 302, 310, 312, 315, 317-319 and 325 showed some homology to previously isolated expressed sequence tags (ESTs).

EXAMPLE 2

DETERMINATION OF TISSUE SPECIFICITY OF LUNG TUMOR

POLYPEPTIDES

Using gene specific primers, mRNA expression levels for seven representative lung tumor polypeptides described in Example 1 were examined in a variety of normal and tumor tissues using RT-PCR.

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Briefly, total RNA was extracted from a variety of normal and tumor tissues using Trizol reagent as described above. First strand synthesis was carried out using 2 pg of total RNA with Superscript II reverse transcriptase (BRL Life Technologies) at 42 °C for one hour. The cDNA was then amplified by PCR with genespecific primers. To ensure the semi-quantitative nature of the RT-PCR, β-actin was used as an internal control for each of the tissues examined. 1 μΐ of 1:30 dilution of cDNA was employed to enable the linear range amplification of the β-actin template and was sensitive enough to reflect the differences in the initial copy numbers. Using these conditions, the β-actin levels were determined for each reverse transcription reaction from each tissue. DNA contamination was minimized by DNase treatment and by assuring a negative PCR result when using first strand cDNA that was prepared without adding reverse transcriptase.

mRNA Expression levels were examined in five different types of tumor tissue (lung squamous cell carcinoma from 3 patients, lung adenocarcinoma, colon tumor from 2 patients, breast tumor and prostate tumor), and thirteen different normal tissues (lung from 4 donors, prostate, brain, kidney, liver, ovary, skeletal muscle, skin, small intestine, stomach, myocardium, retina and testes). Using a 10-fold amount of cDNA, the antigen LST-S1-90 (SEQ ID NO: 3) was found to be expressed at high levels in lung squamous ceil carcinoma and in breast tumor, and at low to undetectable levels in the other tissues examined.

The antigen LST-S2-68 (SEQ ID NO: 15) appears to be specific to lung and breast tumor, however, expression was also detected in normal kidney. Antigens LST-S1-169 (SEQ ID NO: 6) and LST-S1-133 (SEQ ID NO: 5) appear to be very abundant in lung tissues (both normal and tumor), with the expression of these two genes being decreased in most of the normal tissues tested. Both LST-S1-169 and LSTS1-133 were also expressed in breast and colon tumors. Antigens LST-S1-6 (SEQ ID NO: 7) and LST-S2-I2-5F (SEQ ID NO: 47) did not show tumor or tissue specific expression, with the expression of LST-S1-28 being rare and only detectable in a few tissues. The antigen LST-S3-7 (SEQ ID NO: 63) showed lung and breast tumor specific expression, with its message only being detected in normal testes when the PCR was performed for 30 cycles. Lower level expression was detected in some

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PCT/US00/08896 normal tissues when the cycle number was increased to 35. Antigen LST-S3-13 (SEQ ID NO: 66) was found to be expressed in 3 out of 4 lung tumors, one breast tumor and both colon tumor samples. Its expression in normal tissues was lower compared to tumors, and was only detected in 1 out of 4 normal lung tissues and in normal tissues from kidney, ovary and retina. Expression of antigens LST-S3-4 (SEQ ID NO: 62) and LST-S3-14 (SEQ ID NO: 67) was rare and did not show any tissue or tumor specificity. Consistent with Northern blot analyses, the RT-PCT results on antigen LAT-S1-A-10A (SEQ ID NO: 78) suggested that its expression is high in lung, colon, stomach and small intestine tissues, including lung and colon tumors, whereas its expression was low or undetectable in other tissues.

A total of 2002 cDNA fragments isolated in lung subtractions I, II and III, described above, were colony PCR amplified and their mRNA expression levels in lung tumor, normal lung, and various other normal and tumor tissues were determined using microarray technology (Synteni, Palo Alto, CA). Briefly, the PCR amplification products were dotted onto slides in an array format, with each product occupying a unique location in the array. mRNA was extracted from the tissue sample to be tested, reverse transcribed, and fluorescent-labeled cDNA probes were generated. The microarrays were probed with the labeled cDNA probes, the slides scanned and fluorescence intensity was measured. This intensity correlates with the hybridization intensity. Seventeen non-redundant cDNA clones showed over-expression in lung squamous tumors, with expression in normal tissues tested (lung, skin, lymph node, colon, liver, pancreas, breast, heart, bone marrow, large intestine, kidney, stomach, brain, small intestine, bladder and salivary gland) being either undetectable, or 10-fold less compared to lung squamous tumors. The determined partial cDNA sequences for the clone L513S are provided in SEQ ID NO: 87 and 88; those for L514S are provided in SEQ ID NO: 89 and 90; those for L516S in SEQ ID NO: 91 and 92; that for L517S in SEQ ID NO: 93; that for L519S in SEQ ID NO: 94; those for L520S in SEQ ID NO: 95 and 96; those for L521S in SEQ ID NO: 97 and 98; that for L522S in SEQ ID NO: 99; that for L523S in SEQ ID NO: 100; that for L524S in SEQ ID NO: 101; that for L525S in SEQ ID NO: 102; that for L526S in SEQ ID NO: 103; that for L527S in SEQ ID NO: 104; that for L528S in SEQ ID NO: 105; that for L529S in SEQ ID NO: 106;

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PCT/US00/08896 and those for L53OS in SEQ ID NO: 107 and 108. Additionally, the full-length cDNA sequence for L53OS is provided in SEQ ID NO: 151, with the corresponding predicted amino acid sequence being provided in SEQ ID NO: 152. L530S shows homology to a splice variant of a p53 tumor suppressor homologue, p63. The cDNA sequences of 7 known isoforms of p63 are provided in SEQ ID NO: 331-337, with the corresponding predicted amino acid sequences being provided in SEQ ID NO: 338-344, respectively.

Due to polymorphisms, the clone L531S appears to have two forms. A first determined full-length cDNA sequence for L531S is provided in SEQ ID NO: 109, with the corresponding predicted amino acid sequence being provided in SEQ ID NO: 110. A second determined full-length cDNA sequence for L531S is provided in SEQ ID NO: 111, with the corresponding predicted amino acid sequence being provided in SEQ ID NO: 112. The sequence of SEQ ID NO: 111 is identical to that of SEQ ID NO: 109, except that it contains a 27 bp insertion. Similarly, L514S also has two alternatively spliced forms; the first variant cDNA is listed as SEQ ID NO: 153, with the corresponding amino acid sequence being provided in SEQ ID NO: 155. The second variant form of L514S full-length cDNA is provided in SEQ ID NO: 154, with its corresponding amino acid sequence being provided in SEQ ID NO: 156.

Full length cloning for L524S (SEQ ID NO: 101) yielded two variants (SEQ ID NO: 163 and 164) with the corresponding predicted amino acid sequences of SEQ ID NO: 165 and 166, respectively. Both variants have been shown to encode parathyroid hormone-related peptide.

Attempts to isolate the full-length cDNA for L519S, resulted in the isolation of the extended cDNA sequence provided in SEQ ID NO: 173, which contains a potential open reading frame. The predicted amino acid sequence encoded by the sequence of SEQ ID NO: 173 is provided in SEQ ID NO: 174. Additionally, the fulllength cDNA sequence for the clone of SEQ ID NO: 100 (known as L523S), a known gene, is provided in SEQ ID NO: 175, with the corresponding predicted amino acid sequence provided in SEQ ID NO: 176. In further studies, a full-length cDNA sequence for L523S was isolated from a L523S-positive tumor cDNA library by PCR amplification using gene specific primers designed from the sequence of SEQ ID NO: 175. The determined cDNA sequence is provided in SEQ ID NO: **. The amino acid

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PCT/US00/08896 sequence encoded by this sequence is provided in SEQ ID NO: **. This protein sequence differs from the previously published protein sequence at two amino acid positions, namely at positions 158 and 410.

Comparison of the sequences of L514S and L531S (SEQ ID NO: 87 and 88, 89 and 90, and 109, respectively) with those in the gene bank, as described above, revealed no significant homologies to known sequences. The sequences of L513S, L516S, L517S, L519S, L520S and L530S (SEQ ID NO: 87 and 88, 91 and 92, 93, 94, 95 and 96, 107 and 108, respectively) were found to show some homology to previously identified ESTs. The sequences of L521S, L522S, L523S, L524S, L525S, L526S, L527S, L528S and L529S (SEQ ID NO: 97 and 98, 99, 99, 101, 102, 103, 104, 105, and 106, respectively) were found to represent known genes. The determined fulllength cDNA sequences for L520S is provided in SEQ ID NO: 113, with the corresponding predicted amino acid sequence being provided in SEQ ID NO: 114. Subsequent microarray analysis has shown L520S to be overexpressed in breast tumors in addition to lung squamous tumors.

Further analysis has demonstrated that L529S (SEQ ID NO: 106 and 115), L525S (SEQ ID NO: 102 and 120) and L527S (SEQ ID NO: 104) are cytoskeletal components and potentially squamous cell specific proteins. L529S is connexin 26, a gap junction protein. It is highly expressed in lung squamous tumor 9688T, and moderately over-expressed in two others. However, lower level expression of connexin 26 is also detectable in normal skin, colon, liver and stomach. The over-expression of connexin 26 in some breast tumors has been reported and a mutated form of L529S may result in over-expression in lung tumors. L525S is plakophilin 1, a desmosomal protein found in plaque-bearing adhering junctions of the skin. Expression levels for L525S mRNA is highly elevated in three out of four lung squamous tumors tested, and in normal skin. L527S has been identified as keratin 6 isoform, type II 58 Kd keratin, and cytokeratin 13 and shows over-expression in squamous tumors and low expression in normal skin, breast and colon tissues. Notably, keratin and keratin-related genes have been extensively documented as potential markers for lung cancer including CYFRA2.1 (Pastor, A., et al, Eur. Respir. J., 10:603-609, 1997). L513S (SEQ ID NO: 87 and 88)

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PCT/US00/08896 shows moderate over-expression in several tumor tissues tested, and encodes a protein that was first isolated as a pemphigus vulgaris antigen.

L520S (SEQ ID NO: 95 and 96) and L521S (SEQ ID NO: 97 and 98) are highly expressed in lung squamous tumors, and L520S is up-regulated in normal salivary gland and L521S is over-expressed in normal skin. Both belong to a family of small proline rich proteins and represent markers for fully differentiated squamous cells. L521S has been described as a specific marker for lung squamous tumor (Hu, R., et al, Lung Cancer, 20:25-30, 1998). L515S (SEQ ID NO: 162) encodes IGF-P2 and L516S is an aldose reductase homologue and both are moderately expressed in lung squamous tumors and in normal colon. Notably, L516S (SEQ ID NO: 91 and 92) is up-regulated in metastatic tumors but not primary lung adenocarcinoma, an indication of its potential role in metatasis and a potential prognostic marker. L522S (SEQ ID NO: 99) is moderately over-expressed in lung squamous tumors with minimum expression in normal tissues. L522S has been shown to belong to a class IV alcohol dehydrogenase, ADH7, and its expression profile suggests it is a squamous cell specific antigen. L523S (SEQ ID NO: 100) is moderately over-expressed in lung squamous tumor, human pancreatic cancer cell lines and pancreatic cancer tissues, suggesting this gene may be a shared antigen between pancreatic and lung squamous cell cancer.

L524S (SEQ ID NO: 101) is over-expressed in the majority of squamous tumors tested and is homologous with parathyroid hormone-related peptide (PTHrP), which is best known to cause humoral hypercalcaemia associated with malignant tumors such as leukemia, prostate and breast cancer. It is also believed that PTHrP is most commonly associated with squamous carcinoma of lung and rarely with lung adenocarcinoma (Davidson, L.A., et al, J. Pathol., 178: 398-401, 1996). L528S (SEQ ID NO: 105) is highly over-expressed in two lung squamous tumors with moderate expression in two other squamous tumors, one lung adenocarcinoma and some normal tissues, including skin, lymph nodes, heart, stomach and lung. It encodes the NMB gene that is similar to the precursor of melanocyte specific gene Pmell7, wfhich is reported to be preferentially expressed in low-metastatic potential melanoma cell lines. This suggests that L528S may be a shared antigen in both melanoma and lung squamous cell carcinoma. L526S (SEQ ID NO: 103) is overexpressed in all lung

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PCT/US00/08896 squamous cell tumor tissues tested and has been shown to share homology with a gene (ATM) in which a mutation causes ataxia telangiectasia, a genetic disorder in humans causing a predisposition to cancer, among other symptoms. ATM encodes a protein that activates p53 mediated cell-cycle checkpoint through direct binding and phosphorylation of the p53 molecule. Approximately 40% of lung cancer is associated with p53 mutations, and it is speculated that over-expression of ATM is a result of compensation for loss of p53 function, but it is unknown whether over-expression is the cause of result of lung squamous cell carcinoma. Additionally, expression of L526S (ATM) is also detected in a metastatic but not lung adenocarcinoma, suggesting a role in metastasis.

Expression of L523S (SEQ ID NO: 175), was also examined by real time RT-PCR as described above. In a first study using a panel of lung squamous tumors, L523S was found to be expressed in 4/7 lung squamous tumors, 2/3 head and neck squamous tumors and 2/2 lung adenocarcinomas, with low level expression being observed in skeletal muscle, soft palate and tonsil. In a second study using a lung adenocarcinoma panel, expression of L523S was observed in 4/9 primary adenocarcinomas, 2/2 lung pleural effusions, 1/1 metastatic lung adenocarcinomas and 2/2 lung squamous tumors, with little expression being observed in normal tissues.

Expression of L523S in lung tumors and various normal tissues was also examined by Northern blot analysis, using standard techniques. In a first study, L523S was found to be expressed in a number of lung adenocarcinomas and squamous cell carcinomas, as well as normal tonsil. No expression was observed in normal lung. In a second study using a normal tissue blot (HB-12) from Clontech, no expression was observed in brain, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, lung or PBMC, although there was strong expression in placenta.

EXAMPLE 3

ISOLATION AND CHARACTERIZATION OF LUNG TUMOR POLYPEPTIDES BY PCR-BASED SUBTRACTION

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Eight hundred and fifty seven clones from a cDNA subtraction library, containing cDNA from a pool of two human lung squamous tumors subtracted against eight normal human tissue cDNAs including lung, PBMC, brain, heart, kidney, liver, pancreas, and skin, (Clontech, Palo Alto, CA) were derived and submitted to a first round of PCR amplification. This library was subjected to a second round of PCR amplification, following the manufacturer’s protocol. The resulting cDNA fragments were subcloned into the vector P7- Adv vector (Clontech, Palo Alto, CA) and transformed into DH5a E. coli (Gibco, BRL). DNA was isolated from independent clones and sequenced using a Perkin Elmer/Applied Biosystems Division Automated Sequencer Model 373A.

One hundred and sixty two positive clones were sequenced. Comparison of the DNA sequences of these clones with those in the the EMBL and GenBank databases, as described above, revealed no significant homologies to 13 of these clones, hereinafter referred to as Contigs 13, 16, 17, 19, 22, 24, 29, 47, 49, 56-59. The determined cDNA sequences for these clones are provided in SEQ ID NO: 125, 127129, 131-133, 142, 144, 148-150, and 157, respectively. Contigs 1, 3-5, 7-10, 12, 11, 15, 20, 31, 33, 38, 39,41,43,44, 45,48, 50, 53, 54 (SEQ ID NO: 115-124, 126, 130, 134-141, 143, 145-147, respectively) were found to show some degree of homology to previously identified DNA sequences. Contig 57 (SEQ ID NO: 149) was found to represent the clone L519S (SEQ ID NO: 94) disclosed in US. Patent Application No. 09/123,912, filed July 27, 1998. To the best of the inventors’ knowledge, none of these sequences have been previously shown to be differentially over-expressed in lung tumors.

mRNA expression levels for representative clones in lung tumor tissues, normal lung tissues (n=4), resting PBMC, salivary gland, heart, stomach, lymph nodes, skeletal muscle, soft palate, small intestine, large intestine, bronchial, bladder, tonsil, kidney, esophagus, bone marrow, colon, adrenal gland, pancreas, and skin, (all derived from human) were determined by RT-PCR as described above. Expression levels using microarray technology, as described above, were examined in one sample of each tissue type unless otherwise indicated.

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Contig 3 (SEQ ID NO: 116) was found to be highly expressed in all head and neck squamous cell tumors tested (17/17), and expressed in the majority (8/12) of lung squamous tumors, (high expression in 7/12, moderate in 2/12, and low in 2/12), while showing negative expression for 2/4 normal lung tissues and low expression in the remaining two samples. Contig 3 showed moderate expression in skin and soft palate, and lowered expression levels in resting PBMC, large intestine, salivary gland, tonsil, pancreas, esophagus, and colon. Contig 11 (SEQ ID NO: 124) was found to be expressed in all head and neck squamous cell tumors tested (17/17): highly expressed in 14/17, and moderately expressed in 3/17. Additionally, expression in lung squamous tumors showed high expression in 3/12 and moderate in 4/12. Contig 11 was negative for 3/4 normal lung samples, with the remaining sample having only low expression. Contig 11 showed low to moderate reactivity to salivary gland, soft palate, bladder, tonsil, skin, esophagus, and large intestine. Contig 13 (SEQ ID NO: 125) was found to be expressed in all head and neck squamous cell tumors tested (17/17): highly expressed in 12/17, and moderately expressed in 5/17. Contig 13 was expressed in 7/12 lung squamous tumors, with high expression in 4/12 and moderate expression in three samples. Analysis of normal lung samples showed negative expression for 2/4 and low to moderate expression in the remaining two samples. Contig 13 did show low to moderate reactivity to resting PBMC, salivary gland, bladder, pancreas, tonsil, skin, esophagus, and large intestine, as well as high expression in soft palate. Contig 16 (SEQ ID NO: 127) was found to be moderately expressed in some head and neck squamous cell tumors (6/17) and one lung squamous tumor; while showing no expression in any normal lung samples tested. Contig 16 did show low reactivity to resting PBMC, large intestine, skin, salivary gland, and soft palate. Contig 17 (SEQ ID

NO: 128) was shown to be expressed in all head and neck squamous cell tumors tested (17/17): highly expressed in 5/17, and moderately expressed in 12/17. Expression levels in lung squamous tumors showed one tumor sample with high expression and 3/12 with moderate levels. Contig 17 was negative for 2/4 normal lung samples, with the remaining samples having only low expression. Additionally, low level expression was found in esophagus and soft palate. Contig 19 (SEQ ID NO: 129) was found to be expressed in most head and neck squamous cell tumors tested (11/17); with two

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PCT/US00/08896 samples having high levels, 6/17 showing moderate expression, and low expression being found in 3/17. Testing in lung squamous tumors revealed only moderate expression in 3/12 samples. Expression levels in 2/4 of normal lung samples were negative, the two other samples having only low expression. Contig 19 showed low expression levels in esophagus, resting PBMC, salivary gland, bladder, soft palate and pancreas.

Contig 22 (SEQ ID NO: 131), was shown to be expressed in most head and neck squamous cell tumors tested (13/17) with high expression in four of these samples, moderate expression in 6/17, and low expression in 3/17. Expression levels in lung squamous tumors were found to be moderate to high for 3/12 tissues tested, with negative expression in two normal lung samples and low expression in two other samples (n=4). Contig 22 showed low expression in skin, salivary gland and soft palate. Similarly, Contig 24 (SEQ ID NO: 132) was found to be expressed in most head and neck squamous cell tumors tested (13/17) with high expression in three of these samples, moderate expression in 6/17, and low expression in 4/17. Expression levels in lung squamous tumors were found to be moderate to high for 3/12 tissues tested, with negative expression for three normal lung samples and low expression in one sample (n-4). Contig 24 showed low expression in skin, salivary gland and soft palate. Contig 29 (SEQ ID NO: 133) was expressed in nearly all head and neck squamous cell tumors tested (16/17): highly expressed in 4/17, moderately expressed in 11/17, with low expression in one sample. Also, it was moderately expressed in 3/12 lung squamous tumors, while being negative for 2/4 normal lung samples. Contig 29 showed low to moderate expression in large intestine, skin, salivary gland, pancreas, tonsil, heart and soft palate. Contig 47 (SEQ ID NO: 142) was expressed in most head and neck squamous cell tumors tested (12/17): moderate expression in 10/17, and low expression in two samples. In lung squamous tumors, it was highly expressed in one sample and moderately expressed in two others (n=13). Contig 47 was negative for 2/4 normal lung samples, with the remaining two samples having moderate expression. Also, Contig 47 showed moderate expression in large intestine, and pancreas, and low expression in skin, salivary gland, soft palate, stomach, bladder, resting PBMC, and tonsil.

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Contig 48 (SEQ ID NO: 143) was expressed in all head and neck squamous cell tumors tested (17/17): highly expressed in 8/17 and moderately expressed in 7/17, with low expression in two samples. Expression levels in lung squamous tumors were high to moderate in three samples (n=13). Contig 48 was negative for one out of four normal lung samples, the remaining showing low or moderate expression. Contig 48 showed moderate expression in soft palate, large intestine, pancreas, and bladder, and low expression in esophagus, salivary gland, resting PBMC, and heart. Contig 49 (SEQ ID NO: 144) was expressed at low to moderate levels in 6/17 head and neck squamous cell tumors tested. Expression levels in lung squamous tumors were moderate in three samples (n=13). Contig 49 was negative for 2/4 normal lung samples, the remaining samples showing low expression. Moderate expression levels in skin, salivary gland, large intestine, pancreas, bladder and resting PBMC were shown, as well as low expression in soft palate, lymph nodes, and tonsil. Contig 56 (SEQ ID NO: 148) was expressed in low to moderate levels in 3/17 head and neck squamous cell tumors tested, and in lung squamous tumors, showing low to moderate levels in three out of thirteen samples. Notably, low expression levels were detected in one adenocarcinoma lung tumor sample (n=2). Contig 56 was negative for 3/4 normal lung samples, and showed moderate expression levels in only large intestine, and low expression in salivary gland, soft palate, pancreas, bladder, and resting PBMC. Contig 58, also known as L769P, (SEQ ID NO: 150) was expressed at moderate levels in 11/17 head and neck squamous cell tumors tested and low expression in one additional sample. Expression in lung squamous tumors showed low to moderate levels in three out of thirteen samples. Contig 58 was negative for 3/4 normal lung samples, with one sample having low expression. Moderate expression levels in skin, large intestine, and resting PBMC were demonstrated, as well as low expression in salivary gland, soft palate, pancreas, and bladder. Contig 59 (SEQ ID NO: 157) was expressed in some head, neck, and lung squamous tumors. Low level expression of Contig 59 was also detected in salivary gland and large intestine.

The full-length cDNA sequence for Contig 22, also referred to as L763P, is provided in SEQ ID NO: 158, with the corresponding predicted amino acid sequence being provided in SEQ ID NO: 159. Real-time RT-PCR analysis of L763P revealed

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PCT/US00/08896 that it is highly expressed in 3/4 lung squamous tumors as well as 4/4 head and neck squamous tumors, with low level expression being observed in normal brain, skin, soft pallet and trachea. Subsequent database searches revealed that the sequence of SEQ ID NO: 158 contains a mutation, resulting in a ffameshift in the corresponding protein sequence. A second cDNA sequence for L763P is provided in SEQ ID NO: 345, with the corresponding amino acid sequence being provided in SEQ ID NO: 346. The sequences of SEQ ID NO: 159 and 346 are identical with the exception of the Cterminal 33 amino acids of SEQ ID NO: 159.

The full-length cDNA sequence incorporating Contigs 17, 19, and 24, referred to as L762P, is provided in SEQ ID NO: 160, with the corresponding predicted amino acid sequence being provided in SEQ ID NO: 161. Further analysis of L762P has determined it to be a type I membrane protein and two additional variants have been sequenced. Variant 1 (SEQ ID NO: 167, with the corresponding amino acid sequence in SEQ ID NO: 169) is an alternatively spliced form of SEQ ID NO: 160 resulting in deletion of 503 nucleotides, as well as deletion of a short segment of the expressed protein. Variant 2 (SEQ ID NO: 168, with the corresponding amino acid sequence in SEQ ID NO: 170) has a two nucleotide deletion at the 3’ coding region in comparison to SEQ ID NO: 160, resulting in a secreted form of the expressed protein. Real-time RT-PCR analysis of L762P revealed that is over-expressed in 3/4 lung squamous tumors and 4/4 head & neck tumors, with low level expression being observed in normal skin, soft pallet and trachea.

The full-length cDNA sequence for contig 56 (SEQ ID NO: 148), also referred to as L773P, is provided in SEQ ID NO: 171, with the predicted amino acid sequence in SEQ ID NO: 172. L773P was found to be identical to dihydroxyl dehydrogenase at the 3’ portion of the gene, with divergent 5’ sequence. As a result, the 69 N-terminal amino acids are unique. The cDNA sequence encoding the 69 Nterminal amino acids is provided in SEQ ID NO: 349, with the N-terminal amino acid sequence being provided in SEQ ID NO: 350. Real-time PCR revealed that L773P is highly expressed in lung squamous tumor and lung adenocarcinoma, with no detectable expression in normal tissues. Subsequent Northern blot analysis of L773P demonstrated that this transcript is differentially over-expressed in squamous tumors

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PCT/US00/08896 and detected at approximately 1.6 Kb in primary lung tumor tissue and approximately 1.3 Kb in primary head and neck tumor tissue.

Subsequent microarray analysis has shown Contig 58, also referred to as L769S (SEQ ID NO: 150), to be overexpressed in breast tumors in addition to lung squamous tumors.

EXAMPLE 4

SYNTHESIS OF POLYPEPTIDES

Polypeptides may be synthesized on a Perkin Elmer/Applied Biosystems Division 430A peptide synthesizer using FMOC chemistry with HPTU (OBenzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate) activation. A GlyCys-Gly sequence may be attached to the amino terminus of the peptide to provide a method of conjugation, binding to an immobilized surface, or labeling of the peptide. Cleavage of the peptides from the solid support may be carried out using the following cleavage mixture: trifluoroacetic acid:ethanedithiol:thioanisole:water:phenol (40:1:2:2:3). After cleaving for 2 hours, the peptides may be precipitated in cold methyl-t-butyl-ether. The peptide pellets may then be dissolved in water containing 0.1% trifluoroacetic acid (TFA) and lyophilized prior to purification by Cl8 reverse phase HPLC. A gradient of 0%-60% acetonitrile (containing 0.1% TFA) in water (containing 0.1% TFA) may be used to elute the peptides. Following lyophilization of the pure fractions, the peptides may be characterized using electrospray or other types of mass spectrometry and by amino acid analysis.

EXAMPLE 5

PREPARATION OF ANTIBODIES AGAINST LUNG CANCER ANTIGENS

Polyclonal antibodies against the lung cancer antigens L514S, L528S and L531S (SEQ ID NO: 155,225 and 112, respectively) were prepared as follows.

Rabbits were immunized with recombinant protein expressed in and purified from E. coli as described above. For the initial immunization, 400 pg of

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PCT/US00/08896 antigen combined with muramyl dipeptide (MDP) was injected subcutaneously (S.C.). Animals were boosted S.C. 4 weeks later with 200 pg of antigen mixed with incomplete Freund’s Adjuvant (IFA). Subsequent boosts of 100 pg of antigen mixed with IFA were injected S.C. as necessary to induce high antibody titer responses. Serum bleeds from immunized rabbits were tested for antigen-specific reactivity using ELISA assays with purified protein. Polyclonal antibodies against L514S, L528S and L531S were affinity purified from high titer polyclonal sera using purified protein attached to a solid support.

Immunohistochemical analysis using polyclonal antibodies against L514S was performed on a panel of 5 lung tumor samples, 5 normal lung tissue samples and normal colon, kidney, liver, brain and bone marrow. Specifically, tissue samples were fixed in formalin solution for 24 hours and embedded in paraffin before being sliced into 10 micron sections. Tissue sections were permeabilized and incubated with antibody for 1 hr. HRP-labeled anti-mouse followed by incubation with DAB chromogen was used to visualize L514S immunoreactivity. L514S was found to be highly expressed in lung tumor tissue with little or no expression being observed in normal lung, brain or bone marrow. Light staining was observed in colon and kidney. Staining was seen in normal liver but no mRNA has been detected in this tissue making this result suspect.

EXAMPLE 6

PEPTIDE PRIMING OF MICE AND PROPAGATION OF CTL LINES

Immunogenic peptides from the lung cancer antigen L762P (SEQ ID NO: 161) for HLA-A2/K^b-restricted CD8+ T cells were identified as follows.

The location of HLA-A2 binding peptides within the lung cancer antigen L762P (SEQ ID NO: 161) was predicted using a computer program which predicts peptides sequences likely to being to HLA-A*0201 by fitting to the known peptide binding motif for HLA-A*0201 (Rupert et al. (1993) Cell 74:929; Rammensee et al. (1995) Immunogenetics 47:178-228). A series of 19 synthetic peptides corresponding to a selected subset of the predicted HLA-A*0201 binding peptides was prepared as described above.

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Mice expressing the transgene for human HLA A2/K^b (provided by Dr L. Sherman, The Scripps Research Institute, La Jolla, CA) were immunized with the synthetic peptides, as described by Theobald et aL, Proc. NatL Acad. Sci. USA 22:11993-11997, 1995 with the following modifications. Mice were immunized with 50μ3 of L726P peptide and 120pg of an I-A^b binding peptide derived from hepatitis B Virus protein emulsified in incomplete Freund's adjuvant. Three weeks later these mice were sacrificed and single cell suspensions prepared. Cells were then resuspended at 7 x 10⁶ cells/ml in complete media (RPMI-1640; Gibco BRL, Gaithersburg, MD) containing 10% FCS, 2mM Glutamine (Gibco BRL), sodium pyruvate (Gibco BRL), non-essential amino acids (Gibco BRL), 2 x 10‘⁵ M 2-mercaptoethanol, 50U/ml penicillin and streptomycin, and cultured in the presence of irradiated (3000 rads) L762P peptide- (5pg/ml) and 10mg/ml B₂-microglobulin- (3 μg/ml) LPS blasts (A2 transgenic spleens cells cultured in the presence of 7pg/ml dextran sulfate and 25μg/ml LPS for 3 days). After six days, cells (5 x 10⁵/ml) were restimulated with 2.5 x 10⁶/ml peptide pulsed irradiated (20,000 rads) EL4A2Kb cells (Sherman et al, Science 255:815-818, 1992) and 5 x 10⁶/ml irradiated (3000 rads) A2/K^b-transgenic spleen feeder cells. Cells were cultured in the presence of 10U/ml IL-2. Cells were restimulated on a weekly basis as described, in preparation for cloning the line.

Peptide-specific cell lines were cloned by limiting dilution analysis with irradiated (20,000 rads) L762P peptide-pulsed EL4 A2Kb tumor cells (1 x 10⁴cells/well) as stimulators and irradiated (3000 rads) A2/K^b-transgenic spleen cells as feeders (5 x 10⁵ cells/ well) grown in the presence of 1 OU/ml IL-2. On day 7, cells were restimulated as before. On day 14, clones that were growing were isolated and maintained in culture.

Cell lines specific for L762P-87 (SEQ ID NO: 226; corresponding to amino acids 87-95 of SEQ ID NO: 161), L726P-145 (SEQ ID NO: 227; corresponding to amino acids 145-153 of SEQ ID NO: 161), L726P-585 (SEQ ID NO: 228; corresponding to amino acids 585-593 of SEQ ID NO: 161), L762P-425 (SEQ ID NO: 229; corresponding to amino acids 425-433 of SEQ ID NO: 161), L762P(10)-424 (SEQ ID NO: 230; corresponding to amino acids 424-433 of SEQ ID NO: 161) and L762P(10)-458 (SEQ ID NO: 231; corresponding to amino acids 458-467 of SEQ ID

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NO: 161) demonstrated significantly higher reactivity (as measured by percent specific lysis) against L762P peptide-pulsed EL4-A2/K^b tumor target cells than control peptidepulsed EL4-A2/K^b tumor target cells.

EXAMPLE 7

IDENTIFICATION OF CD4 IMMUNOGENIC T CELL EPITOPES DERIVED FROM THE LUNG CANCER ANTIGEN L762P

CD4 T cell lines specific for the antigen L762P (SEQ ID NO: 161) were generated as follows.

A series of 28 overlapping peptides were synthesized that spanned approximately 50% of the L762P sequence. For priming, peptides were combined into pools of 4-5 peptides, pulsed at 20 micrograms/ml into dendritic cells for 24 hours. The dendritic cells were then washed and mixed with positively selected CD4+ T cells in 96 well U-bottomed plates. Forty cultures were generated for each peptide pool. Cultures were restimulated weekly with fresh dendritic cells loaded with peptide pools. Following a total of 3 stimulation cycles, cells were rested for an additional week and tested for specificity to antigen presenting cells (APC) pulsed with peptide pools using interferon-gamma ELISA and proliferation assays. For these assays, adherent monocytes loaded with either the relevant peptide pool or an irrelevant peptide were used as APC. T cell lines that appeared to specifically recognize L762P peptide pools both by cytokine release and proliferation were identified for each pool. Emphasis was placed on identifying T cells with proliferative responses. T cell lines that demonstrated either both L762P-specific cytokine secretion and proliferation, or strong proliferation alone were further expanded to be tested for recognition of individual peptides from the pools, as well as for recognition of recombinant L762P. The source of recombinant L762P was E. coli, and the material was partially purified and endotoxin positive. These studies employed 10 micrograms of individual peptides, 10 or 2 micrograms of an irrelevant peptide, and 2 or 0.5 micrograms of either L762P protein or an irrelevant, equally impure, E. coli generated recombinant protein. Significant interferon-gamma production and CD4 T cell proliferation was induced by a number of L762P-derived

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PCT/US00/08896 peptides in each pool. The amino acid sequences for these peptides are provided in SEQ ID NO: 232-251. These peptides correspond to amino acids 661-680, 676-696, 526-545, 874-893, 811-830, 871-891, 856-875, 826-845, 795-815, 736-755, 706-725, 706-725, 691-710, 601-620, 571-590, 556-575, 616-635, 646-665, 631-650, 541-560 and 586-605, respectively, of SEQ ID NO: 161.

CD4 T cell lines that demonstrated specificity for individual L762Pderived peptides were further expanded by stimulation with the relevant peptide at 10 micrograms/ml. Two weeks post-stimulation, T cell lines were tested using both proliferation and IFN-gamma ELISA assays for recognition of the specific peptide. A number of previously identified T cells continued to demonstrate L762P-peptide specific activity. Each of these lines was further expanded on the relevant peptide and, following two weeks of expansion, tested for specific recognition of the L762P-peptide in titration experiments, as well as for recognition of recombinant E. co/z-derived L762P protein. For these experiments, autologous adherent monocytes were pulsed with either the relevant L762P-derived peptide, an irrelevant mammaglobin-derived peptide, recombinant E. co/z-derived L762P (approx. 50% pure), or an irrelevant E. co/z-derived protein. The majority of T cell lines were found to show low affinity for the relevant peptide, since specific proliferation and IFN-gamma ratios dramatically decreased as L762P peptide was diluted. However, four lines were identified that demonstrated significant activity even at 0.1 micrograms/ml peptide. Each of these lines (referred to as A/D5, D/F5, E/A7 and E/B6) also appeared to specifically proliferate in response to the E. co/z-derived L762P protein preparation, but not in response to the irrelevant protein preparation. The amino acid sequences of the L762P-derived peptides recognized by these lines are provided in SEQ ID NO: 234, 249, 236 and 245, respectively. No protein specific IFN-gamma was detected for any of the lines. Lines A/D5, E/A7 and E/B6 were cloned on autologous adherent monocytes pulsed with the relevant peptide at 0.1 (A/D5 and E/A7) or 1 (D/F5) microgram/ml. Following growth, clones were tested for specificity for the relevant peptide. Numerous clones specific for the relevant peptide were identified for lines A/D5 and E/A7.

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EXAMPLE 8

PROTEIN EXPRESSION OF LUNG TUMOR-SPECIFIC ANTIGENS

a) Expression of L514S in E. coli

The lung tumor antigen L514S (SEQ ID NO: 89) was subcloned into the expression vector pE32b at Ncol and Notl sites, and transformed into E. coli using standard techniques. The protein was expressed from residues 3-153 of SEQ ID NO: 89. The expressed amino acid sequence and the corresponding DNA sequence are provided in SEQ ID NO: 252 and 253, respectively.

b) Expression of L762P

Amino acids 32-944 of the lung tumor antigen L762P (SEQ ID NO: 161), with a 6X His Tag, were subcloned into a modified pET28 expression vector, using kanamycin resistance, and transformed into BL21 CodonPlus using standard techniques. Low to moderate levels of expression were observed. The determined DNA sequence of the L762P expression construct is provided in SEQ ID NO: 254.

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

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SEQUENCE LISTING <110> Corixa Corporation et al.

<120> COMPOUNDS AND METHODS FOR THERAPY AND DIAGNOSIS OF LUNG CANCER <130> 210121.45501PC <140> PCT <141> 2000-04-03 <160> 350 <17O> FastSEQ for Windows Version 3.0 <210> 1 <211> 315 <212 > DNA <213> Homo sapien <220>

<221> misc_feature <222> (1)... ί315) <223> n = A,T,C or G <400> 1 gcagagacag actggtggtt gaacctggag gtgccaaaaa agccagctgc gggcccagga 60 cagctgccgt gagactcccg atgtcacagg cagtctgtgt ggttacagcg cccctcagtg 120 ttcatctcca gcagagacaa cggaggaggc tcccaccagg acggttctca ttatttatat 180 gttaatatgt ttgtaaactc atgtacagtt ttttttgggg gggaagcaat gggaanggta 240 naaattacaa atagaatcat ttgctgtaat ccttaaatgg caaacggtca ggccacgtga 300 aaaaaaaaaa aaaaa 315 <210> 2 <211> 380 <212> DNA <213> Homo sapien <400> 2 atttaggctt aagattttgt ttacccttgt tactaaggag caaattagta ttaaagtata 60 atatatataa acaaatacaa aaagttttga gtggttcagc ttttttattt tttttaatgg 120 cataactttt aacaacactg ctctgtaatg ggttgaactg tggtactcag actgagataa 180 ctgaaatgag tggatgtata gtgttattgc ataattatcc cactatgaag caaagggact 240 ggataaattc ccagtctaga ttattagcct ttgttaacca tcaagcacct agaagaagaa 300 ttattggaaa ttttgtcctc tgtaactggc actttggggt gtgacttatc ttttgccttt 360 gtaaaaaaaa aaaaaaaaaa 380 <210> 3 <211> 346 <212> DNA <213> Homo sapien <220>

<221> mise feature

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PCT/US00/08896 <220>

<221> misc__f eature <222> (1)...(346) <223> n = A,T,C or G <400> 3 ttgtaagtat acaattttag aaaggattaa atgttattga tcattttact gaatactgca catcctcacc atacaccatc cactttccaa taacatttaa tcctttctaa aattgtaagt atacaattgt actttctttg gattttcata acaaatatac catagactgt taattttatt gaagtttcct taatggaatg agtcattttt gtcttgtgct tttgaggtta cctttgcttt gacttccaac aatttgatca tatagtgttg agctgtggaa atctttaagt ttattctata gcaataattt ctattnnnag annccnggnn naaaannann annaaa

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346

<td rowspan="2"> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td colspan="2"> 4 372</td>

<td> DNA Homo</td><td> sapien</td>

<td> &lt;220&gt; &lt;221&gt; &lt;222&gt; &lt;223&gt;</td><td> mise (1) . n = A</td><td> feature .(372) _k,T, C or</td>

<td> &lt;400&gt;</td><td> 4</td><td></td>

actagtctca ttactccaga attatgctct tgtacctgtg tggctgggtt tcttagtcgt tggtttggtt tggttttttg aactggtatg tagggtggtt cacagttcta atgtaagcac tctcttctcc aagttgtgct ttgtggggac aatcattctt tgaacattag agaggaaggc agttcaagct gttgaaaaga ctattgctta tttttgtttt taaagaccta cttgacgtca tgtggacagt gcacgtgcct tacgctacat cttgttttct aggaagaagg ggatgcnggg aaggantggg tgctttgtga tggataaaac gnctaaataa cacaccttta cattttgaaa aaaacaaaac aa

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300

360

372

<td> &lt;210&gt;</td><td> 5</td><td></td>

<td> &lt;211&gt;</td><td> 698</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (l)</td><td> . . (698)</td>

<td> &lt;223&gt;</td><td> n - ,</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 5</td><td></td>

actagtanga tagaaacact gtgtcccgag agtaaggaga gaagctacta ttgattagag cctaacccag gttaactgca agaagaggcg ggatactttc agctttccat gtaactgtat gcataaagcc aatgtagtcc agtttctaag atcatgttcc aagctaactg aatcccactt caatacacac tcatgaactc ctgatggaac aataacaggc ccaagcctgt ggtatgatgt gcacacttgc tagactcaga aaaaatacta ctctcataaa tgggtgggag tattttgggt gacaacctac tttgcttggc tgagtgaagg aatgatattc atatnttcat ttattccatg gacatttagt tagtgctttt tatataccag gcatgatgct gagtgacact cttgtgtata tntccaaatn ttngtncngt cgctgcacat atctgaaatc ctatattaag antttcccaa natgangtcc ctggtttttc cacgccactt gatcngtcaa ngatctcacc tctgtntgtc ctaaaaccnt ctnctnnang gttagacngg acctctcttc tcccttcccg aanaatnaag tgtgngaaga nanccncncn cccccctn.cn tncnncctng ccngctnnnc cncntgtngg

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PCT/US00/08896 gggngccgcc cccgcggggg gacccccccn ttttcccc

698

<td> &lt;210&gt;</td><td> 6</td><td></td>

<td> &lt;211&gt;</td><td> 740</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . - (740)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 6</td><td></td>

actagtcaaa aatgctaaaa taatttggga gaaaatattt catgtttatc ttttattatg tnttgtgaag ttgtgtcttt gccaatattt ccttatatct atccataaca tttatactac gtgaaactta acactttata aggtaaaaat gaggtttcca gttcttgtta tttccaaata gaatggactt ggtctgttaa agataaggtt aaaagttgtt aatgaccaaa cattctaaaa ttttcaagcc ttcgaactat ttaaggaaag caaaatcatt tgagantttc tcantaatat cctgaatcat tcatttcagc atatgtcatc tagggaaagt ctatttcatg gtccaaacct tttcctttaa ntgtgaanta ttnacangaa attttctctt ^a9999tgtgg gaaaagcttc taacaatctg tagtgttncg aatnacggat cgnangaagg actgggtcta tttacangaa gtnnncaact ccngggagcc tttaagtagt tcactaatta atttgtaaga agatttaata ggggctaagg gaaatgcaaa tcctanatgc tnaggcttca gttgccatag tnanagttct tgttatctgt cgaatnatct gttatagttt cctatactat gaatatgcac atctgatcaa gagaagaaga aaaaaattta atatcatttg tgttgactcg ttggtnaggc tnatagggtt ncagaaccan ngttnnntgt

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660

720

740

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 7 670 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (670)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 7</td><td></td>

gctggggagc tcggcatggc ggtccccgct gcagccatgg agcggccccg gctcgatggc cccgtggtgc tcagtgagca cttgggatgc aggagctgtt ccggggccac agcaagaccg ccaaggtgca ctcggtggcc tggagttgcg acgggcgtcg aagacgccac gtcttcttgc tgganaanga ccgttggtca catggggata gtgtggacca ctttgttggc atccaagtaa cgtctggaga taaaaccatt cgcatctggg atgtgaggac tgaacactaa aggggagaac attaatatct gctggantcc tagcnacaag gatgatgtgg tgactttatt gatgccaaga aaacanttcc aanttcgaag tcaccnaaat ctcctggaac tcctgacaat ggnccttggg tgtntcacat cctcagctnc natccacccc &lt;21Q&gt; 8 &lt;211&gt; 689 &lt;212&gt; DNA &lt;213&gt; Homo sapien ggccctcggc gcggcccgtc cgagttcctg cctacctcgg aagaaaacaa tcctgaccta tacaaaatgc tgatgggcan aaccccgttc aatgaacatn cccaaaactg gttgggccag gcgctacgtg gcgcacagcg ggtcttcgac ttatcgggga tttgttacgg attgccactg accattgctg caaagcaaaa aatatnttct aancctgtnc

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PCT7US00/08896 &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; {1) . . . (689) &lt;223&gt; n = A,T,C or G &lt;400&gt; 8 actagtatct aggaatgaac agtaaaagag gagcagttgg ctacttgatt aaatgaagta ctggatttgg gaaaacctgg ttttattaga acatatggaa cacctagcat tgcctactta gccccctgaa ttaacagagc ccaattgaga gcaacaggaa attcaaggga gaaaaagtaa gcaacttggg ctaggatgag tagagcaaag ganagacagc ccccattacc aaataccatt tttgcctggg ctggcagtgt tcctgcccca gcatggcacc ttatngtttt gatagcaact ttcaccaact tattacttga aattataata tagcctgtcc gtttgctgtn gatatatntt cctagtggtt tgactttnaa aataaatnag gtttantttt cnntnctncc nntcnctcrm cnntcccccc cnctcngtcc tccnnnnttn cccccncggn ggacccccct ttggtccctt agtggaggtt natggcccct nggccntann tttccccgtn nnaaatgntt ccccctccca ntcccnccac aagcctaagt ttntaccctg ggggtcccc

<td> acaacagagt</td><td> 60</td>

<td> tgaaagccta</td><td> 120</td>

<td> caaacccctg</td><td> 180</td>

<td> ctgactccct</td><td> 240</td>

<td> gcttgtgcag</td><td> 300</td>

<td> tegttgaatt</td><td> 360</td>

<td> tccaggctgt</td><td> 420</td>

<td> ctccccccnn</td><td> 480</td>

<td> gggggggccn</td><td> 540</td>

<td> ggnnttatcc</td><td> 600</td>

<td> ctcaanccgg</td><td> 660 689</td>

<td> &lt;210&gt;</td><td> 9</td><td></td>

<td> &lt;211&gt;</td><td> 674</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> .. (674)</td>

<td> &lt;223&gt;</td><td> n = -</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 9</td><td></td>

gtccactctc ctttgagtgt actgtcttac tgtgcactct gtttttcaac taaaaaatgc ttgttctata gtggagtaag agctcacaca cccaaggcag gaaaaaagcg aggctttttt gccaccttgg taaaggccag ttcactgcta ataagcctga agggaagtag ctatgagact ttccattttt cttagttctc ccttcatgga aaaaggcttc ctgtaataat tttcacctaa tgaattagca ttctgaaata agagacaaat tgggccgcag agtcttcctg tgatttaaaa aaagttttgt ttggtcttca ccaaaggaca tactctaggg ggtatgttgt caaaaacatt agctgttctg tctttcaatt tcaagttatt ttggagactg agttaattac tttgctctgg aactagcatt attgtcatta tcatcacatt catctgaata atattgtgga tttccccctc tgcttgcatc ttcttttgac anaaatgtca aaaaaaaagg tcgatctact cngcaaggnc catctaatca aggacccnct gccc

<td> tttetagata</td><td> 60</td>

<td> caagataact</td><td> 120</td>

<td> tagaactgct</td><td> 180</td>

<td> ccaataggct</td><td> 240</td>

<td> gtgtgattat</td><td> 300</td>

<td> taaacaaccc</td><td> 360</td>

<td> tgaagacatt</td><td> 420</td>

<td> cctccatgtg</td><td> 480</td>

<td> ctgtcatcat</td><td> 540</td>

<td> tcctctggga</td><td> 600</td>

<td> ctgcgctgga</td><td> 660 674</td>

<td> &lt;210&gt;</td><td> 10</td><td></td>

<td> &lt;211&gt;</td><td> 346</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (346)</td>

<td> &lt;223&gt;</td><td> n - .</td><td> A,T,C or</td>

&lt;400&gt; 10

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PCT/US00/08896 actagtctgc ttctgtctgt ccttaagtgt tttttctttt tgtcagatta aaagggtact tgatagaaag aacaaaaatg ttctgtcatt ccccttataa tattatctaa tttctattan cactatacat tactttatag gttcaagtgt attgtaattc caattgaata nnagnngniui

<td> cctattgttt</td><td> ctttctttcc</td><td> aaaatcagcc</td><td> 60</td>

<td> agatggagga</td><td> aaaggtctaa</td><td> tactacatag</td><td> 120</td>

<td> attttctgta</td><td> acagaaacat</td><td> atttggaatg</td><td> 180</td>

<td> ctgaaatact</td><td> gctgctttaa</td><td> aaagtcccac</td><td> 240</td>

<td> ttgtaaatat</td><td> aettgtetta</td><td> cctctcaata</td><td> 300</td>

<td> gnnnnataaa</td><td> anaaaa</td><td></td><td> 346</td>

&lt;210&gt; 11 &lt;211&gt; 602 &lt;212 &gt; DNA &lt;213 &gt; Homo sapien &lt;400&gt;

actagtaaaa gatgttaagc tgcttccctt ttcaattcca cagttttgca atctgcactt ctgtttgaaa tcttgggatc gtactagcta ctagatggtc aa agcagcattg tttttgaaaa tatctggaat tgacttaagg taattataat tctaaatatc catgagtttt ctgtgtagaa caaattcggt tacttctgtt ccaaataatc gtttaggtta gtggcattag ttggagagct cggcattgta aaaaaaggga atttgcttaa ctgttctcat ttcatattct catataaaaa

<td> cctaattttc</td><td> cactaaaaat</td><td> ataatgaaat</td><td> 60</td>

<td> aacctactgt</td><td> tgttagatta</td><td> atgtatttgt</td><td> 120</td>

<td> cttttttatt</td><td> ttaaccctct</td><td> ttaattetta</td><td> 180</td>

<td> aaacactggg</td><td> atttttggat</td><td> aacagactga</td><td> 240</td>

<td> catagaaagg</td><td> atatggctac</td><td> cttttgttaa</td><td> 300</td>

<td> aatgaagtta</td><td> taaatcaatt</td><td> tttgtataat</td><td> 360</td>

<td> tattaggget</td><td> ttgccccttt</td><td> tctgtaagtc</td><td> 420</td>

<td> taaacaooaa</td><td> acagttaagt</td><td> ccattctctg</td><td> 480</td>

<td> acttaacaat</td><td> ttaaataaac</td><td> tgaaatattt</td><td> 540</td>

<td> caaaacttga</td><td> tttccaaaaa</td><td> aaaaaaaaaa</td><td> 600 602</td>

<td> &lt;210&gt;</td><td> 12</td><td></td>

<td> &lt;211&gt;</td><td> 685</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) ..</td><td> (685)</td>

<td> &lt;223&gt;</td><td> n = A</td><td> ^,Τ,Ο or</td>

<td> &lt;400&gt;</td><td> 12</td><td></td>

actagtcctg attatcatgg gcatgcattt aggtgtttta atatgcatat tttagatatg agaccagtgc angtagtgcc ancanngtga cntntccaat cantntgnta cnnccgccgt tgaaagtaca tattgatgga gtaacatgat tcattatgta agtagagtgc ccttaatnta ctgggtggtg ctcgtaggtg nagtttcncc ngacaatcga accccgcgcc cncnnccccg acfcgaaggca cctaagaaaa tagtagattt aaggaattaa aaaaatatag nnaactgtgc cctccccttg tcacgtggan gtngangcng gtttccnnnc cggatcgctc cnncc

<td> gaaagtgtta</td><td> ggattttgca</td><td> tctaatgttc</td><td> 60</td>

<td> taaaaattag</td><td> actaagcccc</td><td> caaataagct</td><td> 120</td>

<td> gaatatatag</td><td> atgtagtatn</td><td> ttgggtatct</td><td> 180</td>

<td> agtaaaggac</td><td> tttgtagttg</td><td> tttttattaa</td><td> 240</td>

<td> caaaaatana</td><td> aactaaaggt</td><td> agaaaagcat</td><td> 300</td>

<td> caggtggccc</td><td> teggaataga</td><td> tgccaggcag</td><td> 360</td>

<td> tctgcccccc</td><td> tgaagaaett</td><td> ccctcacgtg</td><td> 420</td>

<td> tantggganc</td><td> aggeegnnen</td><td> gtnanaagaa</td><td> 480</td>

<td> aactgtccct</td><td> gngccnnnac</td><td> gctcccanaa</td><td> 540</td>

<td> tccngnaacc</td><td> tngccgnnnn</td><td> cnngcccnnc</td><td> 600</td>

<td> tcnnntcgtt</td><td> ctcncncnaa</td><td> ngggntttcn</td><td> 660</td>

685 &lt;210&gt; 13 &lt;211&gt; 694 &lt;212 &gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

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WO 00/61612

PCT/US00/08896 &lt;221&gt; misc_feature &lt;222&gt; (1) ... (694) &lt;223&gt; n = A,T,C or G &lt;400&gt; 13 cactagtcac tcattagcgt tttcaatagg gctcttaagt ccagtagatt acgggtagtc 60 agttgacgaa gatctggttt acaagaacta attaaatgtt tcattgcatt tttgtaagaa 120 cagaataatt ttataaaatg tttgtagttt ataattgccg aaaataattt aaagacactt 180 tttctctgtg tgtgcaaatg tgtgtttgtg atccattttt tttttttttt taggacacct 240 gtttactagc tagctttaca atatgccaaa aaaggatttc tccctgaccc catccgtggt 300 tcaccctctt ttccccccat gctttttgcc ctagtttata acaaaggaat gatgatgatt 360 taaaaagtag ttctgtatct tcagtatctt ggtcttccag aaccctctgg ttgggaaggg 420 gatcattttt tactggtcat ttccctttgg agtgtactac tttaacagat ggaaagaact 480 cattggccat ggaaacagcc gangtgttgg gagccagcag tgcatggcac cgtccggcat 540 ctggcntgat tggtctggct gccgtcattg tcagcacagt gccatgggac atggggaana 600 ctgactgcac ngccaatggt tttcatgaag aatacngcat ncncngtgat cacgtnancc 660 angacgctat gggggncana gggccanttg cttc 694 &lt;210&gt; 14 &lt;211&gt; 679 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1)...(679) &lt;223&gt; n = A,T,C or G &lt;400&gt; 14 cagccgcctg catctgtatc cagcgccang tcccgccagt cccagctgcg cgcgcccccc 60 agtcccgnac ccgttcggcc cangctnagt tagncctcac catnccggtc aaaggangca 120 ccaagtgcat caaatacctg cngtncggat ntaaattcat cttctggctt gccgggattg 180 ctgtccntgc cattggacta nggctccgat ncgactctca gaccanganc atcttcganc 240 naganactaa tnatnattnt tccagcttct acacaggagt ctatattctg atcggatccg 300 gcnccctcnt gatgctggtg ggcttcctga gctgctgcgg ggctgtgcaa gagtcccant 360 gcatgctggg actgttcttc ggcttcntct tggtgatatn cgccattgaa atacctgcgg 420 ccatctgggg atattccact ncgatnatgt gattaaggaa ntccacggag ttttacaagg 480 acacgtacaa cnacctgaaa accnnggatg anccccaccg ggaancnctg aangccatcc 540 actatgcgtt gaactgcaat ggtttggctg gggnccttga acaatttaat cncatacatc 600 tggccccann aaaggacntn ctcganncct tcnccgtgna attcngttct gatnccatca 660 cagaagtctc gaacaatcc 679 &lt;210&gt; 15 &lt;211&gt; 695 &lt;212&gt; DNA &lt;213&gt; Homo sapien.

&lt;220&gt;

&lt;221&gt; misc_feature

<td> &lt;222&gt;</td><td> (1)</td><td> . . . (695)</td>

<td> &lt;223&gt;</td><td> n =</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 15</td><td></td>

actagtggat aaaggccagg gatgctgctc aacctcctac catgtacagg gacgtctccc 60 cattacaact acccaatccg aagtgtcaac tgtgtcagga ctaanaaacc ctggttttga 120

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ttaaaaaagg gcctgaaaaa aggggagcca caaatctgtc tgcttcctca cnttantcnt 180 tggcaaatna gcattctgtc tcnttggctg cngcctcanc ncaaaaaanc ngaactcnat 240 cnggcccagg aatacatctc ncaatnaacn aaattganca aggcnntggg aaatgccnga 300 tgggattatc ntccgcttgt tgancttcta agtttcnttc ccttcattcn accctgccag 360 ccnagttctg ttagaaaaat gccngaattc naacnccggt tttcntactc ngaatttaga 420 tctncanaaa cttcctggcc acn.attcn.aa ttnanggnca cgnacanatn ccttccatna 480 ancncacccc acntttgana gccangacaa tgactgcntn aantgaaggc ntgaaggaan 540 aactttgaaa ggaaaaaaaa ctttgtttcc ggccccttcc aacncttctg tgttnancac 600 tgccttctng naaccctgga agcccngnga cagtgttaca tgttgttcta nnaaacngac 660 ncttnaatnt cnatcttccc nanaacgatt ncncc 695

<td> &lt;210&gt;</td><td> 16</td><td></td>

<td> &lt;211&gt;</td><td> 669</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> 7. (669)</td>

<td> &lt;223&gt;</td><td> n = ,</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 16</td><td></td>

cgccgaagca gcagcgcagg ttgtccccgt ttcccctccc ccttcccttc tccggttgcc 60 ttcccgggcc ccttacactc cacagtcccg gtcccgccat gtcccagaaa caagaagaag 120 agaaccctgc ggaggagacc ggcgaggaga agcaggacac gcaggagaaa gaaggtattc 180 tgcctgagag agctgaagag gcaaagctaa aggccaaata cccaagccta ggacaaaagc 240 ctggaggctc cgacttcctc atgaagagac tccagaaagg gcaaaagtac tttgactcng 300 gagactacaa catggccaaa gccaacatga agaataagca gctgccaagt gcangaccag 360 acaagaacct ggtgactggt gatcacatcc ccaccccaca ggatctgccc agagaaagtc 420 ctcgctcgtc accagcaagc ttgcgggtgg ccaagttgaa tgatgctgcc ggggctctgc 480 canatctgag acgcttccct ccctgcccca cccgggtcct gtgctggctc ctgcccttcc 540 tgcttttgca gccangggtc aggaagtggc ncnggtngtg gctggaaagc aaaacccttt 600 cctgttggtg tcccacccat ggagcccctg gggcgagccc angaacttga ncctttttgt 660 tntcttncc 669

<td rowspan="2"> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td colspan="2"> 17</td>

<td> 697 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (l) 7</td><td> - - (697)</td>

<td> &lt;223&gt;</td><td> n =</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 17</td><td></td>

gcaagatatg gacaactaag tgagaaggta atnctctact gctctagntn ctccnggcnn 60 gacgcgctga ggagannnac gctggcccan ctgccggcca cacacgggga tcntggtnat 120 gcctgcccan gggancccca ncnctcggan cccatntcac acccgnnccn tncgcccacn 180 ncctggctcn cncngcccng nccagctcnc gnccccctcc gccnnnctcn ttnncntctc 240 cncnccctcc ncnacnacct cctacccncg gctccctccc cagccccccc ccgcaancct 300 ccacnacncc ntcnncncga ancnccnctc gcnctcngcc ccngccccct gccccccgcc 360 cncnacnncg cgntcccccg cgcncgcngc ctcnccccct cccacnacag ncncacccgc 420 agncacgcnc tccgcccnct gacgccccnn cccgccgcgc tcaccttcat ggnccnacng 480 ccccgctcnc nccnctgcnc gccgncnngg cgccccgccc cnnccgngtn ccncncgnng 540

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ccccngcngn cgcccgctgg cnncnctcnc angcngtgcg gggctcccgc gctcngcgcn cnncangncc cncgcggntc cgcccnccnc gngccgnncn ncaccctccg nccnccgccc 600 antccccncc cntncgccca ctntccgntc 660 ccccccc 697

<td> &lt;210&gt;</td><td> 18</td><td></td>

<td> &lt;211&gt;</td><td> 670</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (l)</td><td> . . (670)</td>

<td> &lt;223&gt;</td><td> n = :</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 18</td><td></td>

ctcgtgtgaa ctgacctcca gggacggctg cggcgccgtg catcttcttc cttcaggatc aatctcctcc tctcgaccaa gaacgantgt gncctcacnn acnnaaaagg tttanccacc gggtgcagta gtgccgccgg cccgccgggc gcctacggtg aatcggatcg cttggttcca ctacaggctc tgctcangaa tgccgtccat.

ctgatcnccc gccaaggact cctaagccgg cctcaagatc cccggggcat tgcgcgaatc gtggagtgca gtaccccanc caaagaccta cttcctaaca tgtcacgaag agcggggcca tcccctcatc agcggggtag aggcgggccg gcaccccctt 60 agacatggcc cagaacttga acgacttggc 120 gggcacggcc ctgaagctgt tgctgggggc 180 tgtgttcacc gtggaaggcg ggcncagagc 240 caggacacta tcctgggccg anggccttca 300 atctatgaca ttcgggccag acctcgaaaa 360 cagatggtga atatctccct gcgagtgttg 420 tgttccancg cctaagggct ggactacnaa 480 tgctcaagaa tttnggtggc caagttcaat 540 agttanccct ggttgatccc cgggganccg 600 ctggataatg tggccntcac aaagctcaac 660

670

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 19 606 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (l)</td><td> ..(606)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 19</td><td></td>

actagtgcca tggcctcagt tgtcgccttg ccaggctgtg tcacatgcgt tactatgtgt gggcactagc gagctgctgg cagccaaaag tcttctgtct gagacc acctcagctc tgtccttggt gctcaactgt ccctggaaag cctacctgtg ctgtccactg ctgactttta tttagccttg ctgaatggaa gttttgtttt ccaggccagt tattgatggg ggttgatttg tactacagcc aaactctggg acgactgtca aggcagtgtg cacctgggga aagttnagaa tcaattgaaa tctctgaatg tcgaggagtt ccaggatctc 60 ggacaaattg gggatggcca gagccccgag 120 tctgtgcccg gaaagtttgg catcattcgt 180 atcctccaac agaagtacgg actgctcccc 240 aagcaggaag gcccaagacc tggtgctgga 300 aggcctcatt tgcagaggcc accggagcta 360 tctttctgag cactgtagac caagcccttg 420 aaggatgtat ttatttgtat tttcatatat 480 cattcctagg tggccttatt ctaataagtt 540 agttattaaa taacagattt agaatctagt 600

606 &lt;210&gt; 20 &lt;211&gt; 449 &lt;212&gt; DNA &lt;213&gt; Homo sapien

CA 02369578 2001-10-02

WO 00/61612

PCT/USOO/08896 &lt;400 actagtaaac cagcgccaga ccaccacagc tgccagaaca cttcaagaat tgaagtcaca atttctttag aaaacaaaat • 20 aacagcagca gccgaggaga cgcctgccag tcaaggagtt acaacaacta ccagggcaac tgtcattgcc cttgactgct gaaacatcag acccccgctc gatggactcg cactgcccaa agaaaaggaa tcttggaaga gattttggct tgctcaaaa tatcagcagc gtcgccagca ggagaatatg 60 cctgaggagg acctgtccaa actcttcaaa 120 ctgctcattg caggccagat aaacacttac 180 aaettaggea agctcttcat ggcccaggct 240 gtttccagaa aagaagttaa catgaactct 300 aatatatttg catattgaaa agcacagagg 360 ataacagtgt ctttctagcc ataataaaat 420

449 &lt;210&gt; 21 &lt;211&gt; 409 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400 tatcaatcaa caatgataaa tatgttgagt acagaaataa aaggaaggaa tgtggggata ttgggatgta ctggtgaata aggaacaagc gaaagaacaa aaacagaggc ggaaactcta tacatttgtc aataatacct attaaacaat tgcctatatg acacggagaa aaccaccttt cgctgatgga aaaatttatt caattaaaaa gtgtggtgtg atcatacaaa gggtaccact 60 tggaacaaca tggatgeatt teagaaaett 120 catactatgt ggttctcttt atgtaacatt 180 gaggcagtat ggagtgagat agactggaaa 240 aatgtctgtg tcttcattgg gtggtagtta 300 gaactatata ctaaagaact ctgcatttta 360 gacaaaaaaa aaaaaaaaa 409

<td> &lt;210&gt;</td><td> 22</td><td></td>

<td> &lt;211&gt;</td><td> 649</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;22Q&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (649)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A, T, C or</td>

<td> &lt;400&gt;</td><td> 22</td><td></td>

acaattttca tgataaggat tatttcagtg caaatctaca tcctgaatca agctctgaag aagagagaag ttatatcagt gttgaagcag gatgttttct ctgaagttcn ttatcttaag ggtacttgca gaccaacatt agagaccctg gcagggatgg tgtcacattt aaagaggaag agttctgagg ggtgaataac ttggaatttc tatccatctc cacattgtac tatggtgaat gtggcatggc gttggttttt aangagggta aatatcagtt tgttcacttt tattgatagc taggggcata cggataagtt attacaacaa atttctacag aacctgtgat tattetegea 60 tactactgtt gacagtttcc gcagaaatcc 120 ageaaatgee aacattttgt ggaatagcag 180 cgttttgttt tctttgtttt ttcccccttc 240 gggaagttat gaattactcc ttccagtagt 300 ttttttaaac atgattetag ttnaatgtag 360 tttaatacac tgatttagaa atttgatgtc 420 ttgctttatt tctgccttta cgttgacagt 480 tatatttttt ttttttgtaa gctgtttcat 540 caggaaaaca tctgcatgtt gttatetagt 600 aaacncccag aacggnttg 649 &lt;210&gt; 23 &lt;211&gt; 669 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; mise feature

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 &lt;222&gt; ¢1) . . . (669) &lt;223&gt; n = A,T,C or G &lt;400&gt; 23 actagtgccg tactggctga aatccctgca ggaccaggaa gagaaccagt tcagactttg 60 tactctcagt caccagctct ggaattagat aaattccttg aagatgtcag gaatgggatc 120 tatcctctga cagcctttgg gctgcctcgg ccccagcagc cacagcagga ggaggtgaca 180 tcacctgtcg tgcccccctc tgtcaagact ccgacacctg aaccagctga ggtggagact 240 cgcaaggtgg tgctgatgca gtgcaacatt gagtcggtgg aggagggagt caaacaccac 300 ctgacacttc tgctgaagtt ggaggacaaa ctgaaccggc acctgagctg tgacctgatg 360 ccaaatgaga atatccccga gttggcggct gagctggtgc agcfcgggctt cattagtgag 420 gctgaccaga gccggttgac ttctctgcta gaagagactt gaacaagttc aattttgcca 480 ggaacagtac cctcaactca gccgctgtca ccgtctcctc ttagagctca ctcgggccag 540 gccctgatct gcgctgtggc tgtcctggac gtgctgcacc ctctgtcctt ccccccagtc 600 agtattacct gtgaagccct tccctccttt attattcagg anggctgggg gggctccttg 660 nttctaacc 669 &lt;210&gt; 24 &lt;211&gt; 442 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 24 actagtacca tcttgacaga ggatacatgc tcccaaaacg tttgttacca cacttaaaaa 60 tcactgccat cattaagcat cagtttcaaa attatagcca ttcatgattt actttttcca 120 gatgactatc attattctag tcctttgaat ttgtaagggg aaaaaaaaca aaaacaaaaa 180 cttacgatgc acttttctcc agcacatcag atttcaaatt gaaaattaaa gacatgctat 240 ggtaatgcac ttgctagtac tacacacttt ggtacaacaa aaaacagagg caagaaacaa 300 cggaaagaga aaagccttcc tttgttggcc cttaaactga gtcaagatct gaaatgtaga 360 gatgatctct gacgatacct gtatgttctt attgtgtaaa taaaattgct ggtatgaaat 420 gacctaaaaa aaaaaaaaga aa 442 &lt;21O&gt; 25 &lt;211&gt; 656 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1)...(656) &lt;223&gt; n = A,T,C or G &lt;400&gt; 25 tgcaagtacc acacactgtt tgaattttgc acaaaaagtg actgtaggat caggtgatag 60 ccccggaatg tacagtgtct tggtgcacca agatgccttc taaaggctga cataccttgg 120 accctaatgg ggcagagagt atagccctag cccagtggtg acatgaccac tccctttggg 180 aggcctgagg tagaggggag tggtatgtgt tttctcagtg gaagcagcac atgagtgggt 240 gacaggatgt tagataaagg ctctagttag ggtgtcattg tcatttgaga gactgacaca 300 ctcctagcag ctggtaaagg ggtgctggan gccatggagg anctctagaa acattagcat 360 gggctgatct gattacttcc tggcatcccg ctcactttta tgggaagtct tattagangg 420 atgggacagt tttccatatc cttgctgtgg agctctggaa cactctctaa atttccctct 480 attaaaaatc actgccctaa ctacacttcc tccttgaagg aatagaaatg gaactttctc 540 tgacatantt cttggcatgg ggagccagcc acaaatgana atctgaacgt gtccaggttt 600 ctcctganac tcatctacat agaattggtt aaaccctccc ttggaataag gaaaaa 656

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896

<td> &lt;210&gt;</td><td> 26</td><td></td>

<td> &lt;211&gt;</td><td> 434</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) .7</td><td> - (434)</td>

<td> &lt;223&gt;</td><td> n - A</td><td> l,T,C or</td>

<td> &lt;400&gt;</td><td> 26</td><td></td>

actagttcag actgccacgc caaccccaga aaatacccca catgccagaa aagtgaagtc 60 ctaggtgttt ccatctatgt ttcaatctgt ccatctacca ggcctcgcga taaaaacaaa 120 acaaaaaaac gctgccaggt tttagaagca gttctggtct caaaaccatc aggatcctgc 180 caccagggtt cttttgaaat agtaccacat gtaaaaggga atttggcttt cacttcatct 240 aataactgaa ttgtcaggct ttgattgata attgtagaaa taagtagcct tctgttgtgg 300 gaataagtta taatcagtat tcatctcttt gttttttgtc actcttttct ctctaattgt 360 gtcatttgta ctgtttgaaa aatatttctt ctatnaaatt aaactaacct gccttaaaaa 420 aaaaaaaaaa aaaa 434

<td> &lt;210&gt;</td><td> 27</td><td></td>

<td> &lt;211&gt;</td><td> 654</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> ^feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (654)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 27</td><td></td>

actagtccaa cacagtcaga aacattgttt tgaatcctct gtaaaccaag gcattaatct 60 taataaacca ggatccattt aggtaccact tgatataaaa aggatatcca taatgaatat 120 tttatactgc atcctttaca ttagccacta aatacgttat tgcttgatga agacctttca 180 cagaatccta tggattgcag catttcactt ggctacttca tacccatgcc ttaaagaggg 240 gcagtttctc aaaagcagaa acatgccgcc agttctcaag ttttcctcct aactccattt 300 gaatgtaagg gcagctggcc cccaatgtgg ggaggtccga acattttctg aattcccatt 360 ttcttgttcg cggctaaatg acagtttctg tcattactta gattccgatc tttcccaaag 420 gtgttgattt acaaagaggc cagctaatag cagaaatcat gaccctgaaa gagagatgaa 480 attcaagctg tgagccaggc agganctcag tatggcaaag gtcttgagaa tcngccattt 540 ggtacaaaaa aaattttaaa gcntttatgt tataccatgg aaccatagaa anggcaaggg 600 aattgttaag aanaatttta agtgtccaga cccanaanga aaaaaaaaaa aaaa 654

<td> &lt;210&gt;</td><td> 28</td><td></td>

<td> &lt;211&gt;</td><td> 670</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> .. (670)</td>

<td> &lt;223&gt;</td><td> n = ,</td><td> A,T,C or G</td>

<td> &lt;400&gt;</td><td> 28</td><td></td>

cgtgtgcaca tactgggagg atttccacag ctgcacggtc acagccctta cggattgcca 60

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ggaaggggcg aaagatatgt gggataaact gagaaaagaa nccaaaaacc tcaacatcca 120 aggcagctta ttcgaactct gcggcagcgg caacggggcg gcggggtccc tgctcccggc 180 gttcccggtg ctcctggtgt ctctctcggc agctttagcg acctgncttt ccttctgagc 240 gtggggccag ctccccccgc ggcgcccacc cacnctcact ccatgctccc ggaaatcgag 300 aggaagatca ttagttcttt ggggacgttn gtgattctct gtgatgctga aaaacactca 360 tatagggaat gtgggaaatc ctganctctt tnttatntcg tntgatttct tgtgttttat 420 ttgccaaaat gttaccaatc agtgaccaac cnagcacagc caaaaatcgg acntcngctt 480 tagtccgtct tcacacacag aataagaaaa cggcaaaccc accccacttt tnantttnat 540 tattactaan ttttttctgt tgggcaaaag aatctcagga acngccctgg ggccnccgta 600 ctanagttaa ccnagctagt tncatgaaaa atgatgggct ccncctcaat gggaaagcca 660 agaaaaagnc 670 &lt;210&gt; 29 &lt;211&gt; 551 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) . . . (551) &lt;223&gt; n = A,T,C or G &lt;400&gt; 29 actagtcctc cacagcctgt gaatccccct agacctttca agcatagtga gcggagaaga 60 agatctcagc gtttagccac cttacccatg cctgatgatt ctgtagaaaa ggtttcttct 120 ccctctccag ccactgatgg gaaagtattc tccatcagtt ctcaaaatca gcaagaatct 180 tcagtaccag aggtgcctga tgttgcacat ttgccacttg agaagctggg accctgtctc 240 cctcttgact taagtcgtgg ttcagaagtt acagcaccgg tagcctcaga ttcctcttac 300 cgtaatgaat gtcccagggc agaaaaagag gatacncaga tgcttccaaa tccttcttcc 360 aaagcaatag ctgatgggaa gaggagctcc agcagcagca ggaatatcga aaacagaaaa 420 aaaagtgaaa ttgggaagac aaaagctcaa cagcatttgg taaggagaaa aganaagatg 480 aggaaggaag agagaagaga gacnaagatc nctacggacc gnnncggaag aagaagaagn 540 aaaaaanaaa a 551

<td> &lt;210&gt;</td><td> 30</td><td></td>

<td> &lt;211&gt;</td><td> 684</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) ..</td><td> . (684)</td>

<td> &lt;223&gt;</td><td> n = ί</td><td> l,T,C or</td>

<td> &lt;400&gt;</td><td> 30</td><td></td>

actagttcta tctggaaaaa gcccgggttg gaagaagctg tggagagtgc gtgtgcaatg 60 cgagactcat ttcttggaag catccctggc aaaaatgcag ctgagtacaa ggttatcact 120 gtgatagaac ctggactgct ttttgagata atagagatgc tgcagtctga agagacttcc 180 agcacctctc agttgaatga attaatgatg gcttctgagt caactttact ggctcaggaa 240 ccacgagaga tgactgcaga tgtaatcgag cttaaaggga aattcctcat caacttagaa 300 ggtggtgata ttcgtgaaga gtcttcctat aaagtaattg tcatgccgac tacgaaagaa 360 aaatgccccc gttgttggaa gtatacagcg ggagtcttca gatacactgt gtcctcgatg 420 tgcagaagtt gtcagtggga aaatagtatt aacagctcac tcgagcaaga accctcctga 480 cagtactggg ctagaagttt ggatggatta tttacaatat aggaaagaaa gccaagaatt 540 aggtnatgag tggatgagta aatggtggan gatggggaat tcaaatcaga attatggaag 600

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 aagttnttcc tgttactata gaaaggaatt tgtggtgtgt accgtggatg gaan atgtttattt acatgcagaa aatatanatg

660

684

<td rowspan="2"> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td colspan="2"> 31 654</td>

<td> DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) /</td><td> .. (654)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 31</td><td></td>

gcgcagaaaa aacatcttct tttggcagct agagcctgac ccttggtctt tcatgatcag aagtgcagag ctatggcaga atgatgttgt catgctccac tcaataaagt ggaaccaata cagaatgacc gtgctttcca agaatagttg ggagatacag ggaaagcaaa tggaagagct gcccaatgca gatgggagtt tgactgttgt ttctgtatca tttcagaaac cagaagttat gagatggaag gagaattcct tggaaggtct tcagangttc ttccatcacg aagtttattg cagtacaagg tgcagatggg ctcatttggt aagettaata catcgtggga aaaggtgaca gcagccgggt tgatgcccag agattcctta gaagattcat aaggtgttgt ataaagagac cttttctcca tggettetta ggaacagctg gctggcgtgc gtcattgaga ggttatcatg gttgtaaatg ccctctgtca catgagtctc gttacagtta tgggagatat anttcaggaa tgaagaatgc cctgtacatc ttggctctgc gagaettaaa ttctcaaaga gttacatgat gaaaacaatc cggaaagcag ttagaggaag caaggaactc aagcctggtc nccc

120 180 240 300 360 42 0 480 540 600 654 &lt;210&gt; 32 &lt;211&gt; 673 &lt;212 &gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; mise feature

<td> &lt;222&gt;</td><td> (1)</td><td> ... ¢673)</td>

<td> &lt;223&gt;</td><td> n =</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 32</td><td></td>

actagtgaag tatcacctga ttaaagacca aatgaattga gataaactcc aataaattaa cccgtgactg tgtgggaaat atacctagga aagangtccc gaaattaaaa cagggattag aaaaagaaat caccaggagt cacaaggaag aatcaaaaga tctatccagc tcaaatacat tetatnagee aactgaaaaa tttctactgg aaggtcacca gacgcttcag aaa tetgataegg tttcattgga caaaatcttt atctgacatc agacacacct ccaaattaag aattattaaa gagaccgaga aggtggagaa aattcattga ggagacnccc gacaaaaatg aaaggatttg ctgaaagaag atgacaacaa gttggaaatg tttgttcgtg aaatacacca agaaegaate acagaagaac aggtggtgat catgaaggaa ctcttcaaaa aacctggtgt taaatgatac atggtgtaat atcaactgct gtagcacctt aaatcattga attacaggtc tctgaagaaa ggtctttatt ttgccagcca catcattctt tactaacatt acttctggtg tcatgttgta ggaaataett caaagaaatc tgggagtgcc ctgaaataaa ttgttacaag tgaagatgaa caaaaaaatt

120

180

240

300

360

420

480

540

600

660

673 &lt;210&gt; 33 &lt;211&gt; 673 &lt;212&gt; DNA &lt;213&gt; Homo sapien

CA 02369576 2001-10-02

WO 00/61612

PCT/US00/08896 &lt;220&gt;

&lt;22l&gt; misc_feature &lt;222&gt; (1) . . . (673) &lt;223&gt; n = A,T,C or &lt;400 actagttatt ggatctgttg gaaggttgaa tcttgaagta atcatttaga tgactaaaaa tgaaattatg gaaactttat ctgcacttaa tntattttta aatttatcat ttcgctactg &gt; 33 tactttcctc tttcttttgg aggagcaggg tgatgcatat agggcaagtt tgaacattaa caactttgat aaagcatatg agaagtctaa aatattgtac ttcaanggca tnt cgcttcagaa gtctcacctc aaaagatcca tgcattattt caagaggata tgttnaagac atcatattcc gtcagttatt cagtacaaat tatttatggt ttctatttgg ggtttttcag atcagtgtgc gaagcatgtt tatttgcaaa tgaagatttg ttaagacttt ttgatttaaa tnattaaaaa acctatctat nggtggggct gtttagaagt actgagagcc atagtggcag agttcgacat ctaggaattg agaacttttt aacctgctgg ttgggctttt ggcaaaacct cttagatgga ttcttactaa taagcatact aaattataaa catcatcttt cagtctgagg aactattcat cagtcccaaa gtgattgant gaaccacctt tntatttntt tacacaaatn tgattccaag nantgcatat

120

180

240

300

360

420

480

540

600

660

673

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 34 684 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) ..</td><td> . (684)</td>

<td> &lt;223&gt;</td><td> n = A</td><td> i,T,C or</td>

<td> &lt;400&gt;</td><td> 34</td><td></td>

actagtttat tgatcagggc gaccaaggag ccacagttct ttcaggagga gggcactgtt tgcctggttg gacaattctc gaattggatn cccgcattat gtcttccaag cncagaagga tcaagaaaag tggtgtagca gaaatcacta gagccttaac atctgtgcgg atggctgggt gaaggtacag agtccaagaa catttttgac ctacaagtgg ggcagggtgg atttntttcc aacttactga tccggttcct agacatttga cctgtagttt atagattggc atggagcgga gtgttcagca gaatgcattg cangatnntt tatgaagtcc gttacaccat tccc ttcctctgtt ttagtgcagc gaagcagtgg gcacacaaga tggacttttc cagccccagg ccttcggaaa accattgctg ctnctatgct tgcnnccccc tttacctccc cctaaagcaa taactgcatt tatgaacgtt acgagctcca aatggttctg aatcagagcc aagggcataa gctatttgct ttnttgcaat agagaggctg ctctcccccc gagtggcagg tgtcactgat cttggacaag cctccccttc ggttgcaagt tcagcccggc agtngtgggg tncctagtan gaaatcaaat ttcaggcnat agattatgna

120

ISO

240

300

360

420

480

540

600

660

684

<td> &lt;210&gt;</td><td> 35</td><td></td>

<td> &lt;211&gt;</td><td> 614</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (l) -</td><td> - . (614)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or G</td>

<td> &lt;400&gt;</td><td> 35</td><td></td>

actagtccaa cgcgttngcn aatattcccc tggtagccta cttccttacc cccgaatatt

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ggtaagatcg agcaatggct tcaggacatg ggttctcttc tcctgtgatc attcaagtgc 120 tcactgcatg aagactggct tgtctcagtg tntcaacctc accagggctg tctcttggtc 180 cacacctcgc tccctgttag tgccgtatga cagcccccat canatgacct tggccaagtc 240 acggtttctc tgtggtcaat gttggtnggc tgattggtgg aaagtanggt ggaccaaagg 300 aagncncgtg agcagncanc nccagttctg caccagcagc gcctccgtcc tactngggtg 360 ttccngtttc tcctggccct gngtgggcta nggcctgatt cgggaanatg cctttgcang 420 gaaggganga taantgggat ctaccaattg attctggcaa aacnatntct aagattnttn 480 tgctttatgt ggganacana tctanctctc atttnntgct gnanatnaca ccctactcgt 540 gntcgancnc gtcttcgatt ttcgganaca cnccantnaa tactggcgtt ctgttgttaa 600 aaaaaaaaaa aaaa 614

<td> &lt;210&gt;</td><td> 36</td><td></td>

<td> &lt;211&gt;</td><td> 686</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) ·</td><td> . . (686)</td>

<td> &lt;223&gt;</td><td> n = ,</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 36</td><td></td>

gtggctggcc cggttctccg cttctcccca tcccctactt tcctccctcc ctccctttcc 60 ctccctcgtc gactgttgct tgctggtcgc agactccctg acccctccct cacccctccc 120 taacctcggt gccaccggat tgcccttctt ttcctgttgc ccagcccagc cctagtgtca 180 gggcgggggc ctggagcagc ccgaggcact gcagcagaag ananaaaaga cacgacnaac 240 ctcagctcgc cagtccggtc gctngcttcc cgccgcatgg caatnagaca gacgccgctc 300 acctgctctg ggcacacgcg acccgtggtt gatttggcct tcagtggcat cacccttatg 360 ggtatttctt aatcagcgct tgcaaagatg gttaacctat gctacgccag ggagatacag 420 gagactggat tggaacattt ttggggtcta aaggtctgtt tggggtgcaa cactgaataa 480 ggatgccacc aaagcagcta cagcagctgc agatttcaca gcccaagtgt gggatgctgt 540 ctcagganat naattgataa cctggctcat aacacattgt caagaatgtg gatttcccca 600 ggatattatt atttgtttac cggggganag gataactgtt tcncntattt taattgaaca 660 aactnaaaca aaanctaagg aaatcc 686 &lt;210&gt; 37 &lt;211&gt; 681 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1)...(681) &lt;223&gt; n = A,T,C or G &lt;400&gt; 37 gagacanacn naacgtcang agaanaaaag angcatggaa cacaanccag gcncgatggc 60 caccttccca ccagcancca gcgcccccca gcngccccca ngnccggang accangactc 120 cancctgnat caatctganc tctattcctg gcccatncct acctcggagg tggangccgn 180 aaaggtcgca cnnncagaga agctgctgcc ancaccancc gccccnnccc tgncgggctn 240 nataggaaac tggtgaccnn gctgcanaat tcatacagga gcacgcgang ggcacnnnct 300 cacactgagt tnnngatgan gcctnaccan ggacctnccc cagcnnattg annacnggac 360 tgcggaggaa ggaagacccc gnacnggatc ctggccggcn tgccaccccc ccacccctag 420 gattatnccc cttgactgag tctctgaggg gctacccgaa cccgcctcca ttccctacca 480 natnntgctc natcgggact gacangctgg ggatnggagg ggctatcccc cancatcccc 540

CA 02369578 2001-10-02

WO 00/61612

PCT/USOO/08896 tnanaccaac cggcgcnggc ggactcctcn agcnacngan cttcggtgnt ttgttccctc natnggggct gtcctccntc c

<td> ccccngggtc</td><td> ggngcaacnc</td><td> tcctncaccc</td><td> 600</td>

<td> aacnaattcc</td><td> naaanggegg</td><td> gccccccngt</td><td> 660 681</td>

<td> &lt;210&gt;</td><td> 38</td>

<td> &lt;211&gt;</td><td> 687</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td colspan="2"> &lt;220&gt;</td>

<td> &lt;221&gt;</td><td> misc_feature</td>

<td> &lt;222&gt;</td><td> (l)... (687)</td>

<td> &lt;223&gt;</td><td> n = A,T,C or G</td>

<td> &lt;400&gt;</td><td> 38</td>

canaaaaaaa ctcccggcct gagggcggga atcgcaaggg gggggctgtg aaggananac gcaccccagt cggcgcacna gcccgcccta ctccttgcgc gcncnngtng aactgctgtt aaaacatggc gtgtccggaa cntgccgggg cggcgctaac anaaccgcaa ttccacagan aagttcctgn ^agggg^an9^an ntctgctttt cttcctctna aaattaattc ctgnttactg cgaaaccagn ggtttccctc ccggagctca ctnaggcctc aaanaacgct gcagcgtttc cggggaagct ggcangangc gtgaatctcc ccttaanaac ggtccnccgg cngtccc

<td> aagctgcgcg</td><td> atggcgccac</td><td> ggcccctctt</td><td> 60</td>

<td> cgaggcgccc</td><td> cggctcccgc</td><td> aageggagga</td><td> 120</td>

<td> naggccctgg</td><td> ggccgctctg</td><td> ctctcccgcc</td><td> 180</td>

<td> cccgcaaagg</td><td> tccccnangc</td><td> ggnggcggcg</td><td> 240</td>

<td> gggegegeng</td><td> cgaacccgtc</td><td> cacccccgcg</td><td> 300</td>

<td> cacagcccan</td><td> agccacnttt</td><td> ctagggtgat</td><td> 360</td>

<td> caccgctgtc</td><td> aaaaaanctc</td><td> ttcgctccac</td><td> 420</td>

<td> tgccgcccgc</td><td> acaggtcatc</td><td> tgatcacgtc</td><td> 480</td>

<td> actttgttca</td><td> accccacccg</td><td> ccgttctctc</td><td> 540</td>

<td> cagcttcctc</td><td> tacccnatng</td><td> tanttnetet</td><td> 600</td>

<td> aacctcttnc</td><td> ctgtggcaac</td><td> tgetnaaaga</td><td> 660 687</td>

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 39 695 DNA Homo</td><td> sapien</td>

<td> &lt;22Q&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> .. (695)</td>

<td> &lt;223&gt;</td><td> n = j</td><td> ft.,T,C or</td>

<td> &lt;400&gt;</td><td> 39</td><td></td>

actagtctgg tagaaaaacg tgacccctgc cttattagtt ccaaactttt gttgttatgg ttagtttaaa aanaaatcna atttgaaatc ntccaaatct tggaatggcc naatatatat cctacaatag tatacagatt gctagactgt ataacatgat ttttttaact gtagaaaaaa attaggggta ngaacangat anacacggca tnttggaaac ctatttaang ccttggtccc tgtgattcat atataagtag ggaaagggag aggtgctgaa gtagatcatg ccacatgcct tgtttccagt ttngaaantt ccttccgttt ngtccnttta ttaaaagggg ccaaaattta

<td> gtaggaette</td><td> tttcatcaat</td><td> tcaaaacccc</td><td> 60</td>

<td> ggataagatt</td><td> tctaacattt</td><td> ctgggctctc</td><td> 120</td>

<td> tattattata</td><td> gtatacaaca</td><td> ctgctgttgc</td><td> 180</td>

<td> ttgtgattca</td><td> caatttaaaa</td><td> acactgtaat</td><td> 240</td>

<td> catgtgaatg</td><td> ttaatgttaa</td><td> tttgttcaan</td><td> 300</td>

<td> taaaatttta</td><td> aaaagcaggg</td><td> cccaaactta</td><td> 360</td>

<td> ttgttattaa</td><td> ntggttatag</td><td> ctctgtttag</td><td> 420</td>

<td> aagntgacat</td><td> tatttnccag</td><td> tgacttgtta</td><td> 480</td>

<td> tggtnctatt</td><td> ggnntttgaa</td><td> tccaancngg</td><td> 540</td>

<td> acttttttac</td><td> nanatettat</td><td> ttttttattt</td><td> 600</td>

<td> ggggnnccac</td><td> naccattcnt</td><td> gaataaaact</td><td> 660</td>

<td> aggng</td><td></td><td></td><td> 695</td>

&lt;210&gt; 40 &lt;211&gt; 674 &lt;212&gt; DNA

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 &lt;213 &gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) . - (674) &lt;223&gt; n = A,T,C or G &lt;400&gt; 40 actagtagtc agttgggagt ggttgctata ccttgacttc atttatatga atttccactt 60 tattaaataa tagaaaagaa aatcccggtg cttgcagtag agttatagga cattctatgc 120 ttacagaaaa tatagccatg attgaaatca aatagtaaag gctgttctgg ctttttatct 180 tcttagctca tcttaaataa gtagtacact tgggatgcag tgcgtctgaa gtgctaatca 240 gttgtaacaa tagcacaaat cgaacttagg atgtgtttct tctcttctgt gtttcgattt 300 tgatcaattc tttaattttg ggaacctata atacagtttt cctattcttg gagataaaaa 360 ttaaatggat cactgatatt taagtcattc tgcttctcat ctnaatattc catattctgt 420 attagganaa antacctccc agcacagccc cctctcaaac cccacccaaa accaagcatt 480 tggaatgagt ctcctttatt tccgaantgt ggatggtata acccatatcn ctccaatttc 540 tgnttgggtt gggtattaat ttgaactgtg catgaaaagn ggnaatcttt nctttgggtc 600 aaantttncc ggttaatttg nctngncaaa tccaatttnc tttaagggtg tctttataaa 660 atttgctatt cngg 674

<td> &lt;210&gt;</td><td> 41</td><td></td>

<td> &lt;211&gt;</td><td> 657</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> raise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (657)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 41</td><td></td>

gaaacatgca agtaccacac actgtttgaa ttttgcacaa aaagtgactg tagggatcag 60 gtgatagccc cggaatgtac agtgtcttgg tgcaccaaga tgccttctaa aggctgacat 120 accttgggac cctaatgggg cagagagtat agccctagcc cagtggtgac atgaccactc 180 cctttgggag gctgaagtta aagggaatgg tatgtgtttt ctcatggaag cagcacatga 240 atnggtnaca ngatgttaaa ntaaggntct antttgggtg tcttgtcatt tgaaaaantg 300 acacactcct ancanctggt aaaggggtgc tggaagccat ggaagaactc taaaaacatt 360 agcatgggct gatctgatta cttcctggca tcccgctcac ttttatggga agtcttatta 420 naaggatggg ananttttcc atatccttgc tgttggaact ctggaacact ctctaaattt 480 ccctctatta aaaatcactg nccttactac acttcctcct tganggaata gaaatggacc 540 tttctctgac ttagttcttg gcatggganc cagcccaaat taaaatctga cttntccggt 600 ttctccngaa ctcacctact tgaattggta aaacctcctt tggaattagn aaaaacc 657

<td> &lt;210&gt;</td><td> 42</td><td></td>

<td> &lt;211&gt;</td><td> 389</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (389)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or G</td>

&lt;400&gt; 42

CA 02369578 2001-10-02

WO 00/61612

PCT/USOO/08896 actagtgctg aggaatgtaa acaagtttgc tgggccttgc gagacttcac caggttgttt cgatagctca cactcctgca ctgtgcctgt cacccaggaa tgtctttttt aattagaaga caggaagaaa acaaaaacca gactgtgtcc cacaatcaga aacctccgtt gtggcagang ggccttcacc gccaccaggg tgtcccgcca gacagggaga gactccagcc ttctgaggcc atcctgaaga attcctgttt gggggttgtg aaggaaaatc acccggattt aaaaagatgc tgttgcctgc ccgcgtngtn gggaagggac tggtttcctg gtgaatttct taaaagaaaa atattttaag ttaagaaaaa aaaaaaaaa

120

180

240

300

360

389

<td colspan="2"> &lt;210&gt; 43 &lt;211&gt; 279 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt;</td><td> 43</td>

actagtgaca agctcctggt cttgagatgt cttctcgtta aggagatggg ccttttggag gtaaaggata aaatgaatga gttctgtcat gattcactat tctagaactt gcatgacctt tactgtgtta gctctttgaa tgttcttgaa attttagact ttctttgtaa acaaataata tgtccttatc attgtataaa agctgttatg tgcaacagtg tggagatcct tgtctgattt aataaaatac ttaaacactg aaaaaaaaaa aaaaaaaaa

120

180

240

279

<td> &lt;210&gt;</td><td> 44</td><td></td>

<td> &lt;211&gt;</td><td> 449</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . ¢449)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 44</td><td></td>

actagtagca tcttttctac aacgttaaaa ttgcagaagt agcttatcat taaaaaacaa caacaacaac aataacaata aatcctaagt gtaaatcagt tattctaccc cctaccaagg atatcagcct gttttttccc ttttttctcc tgggaataat tgtgggcttc ttcccaaatt tctacagcct ctttcctctt ctcatgcttg agcttccctg tttgcacgca tgcgttgtgc aagantgggc tgtttngctt ggantncggt ccnagtggaa ncatgctttc ccttgttact gttggaagaa actcaaacct tcnancccta ggtgttncca ttttgtcaag tcatcactgt atttttgtac tggcattaac aaaaaaagaa atnaaatatt gttccattaa actttaataa aactttaaaa gggaaaaaaa aaaaaaaaa

120

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240

300

360

420

449

<td> &lt;210&gt;</td><td> 45</td><td></td>

<td> &lt;211&gt;</td><td> 559</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (l) ·'</td><td> .. (559)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 45</td><td></td>

actagtgtgg gggaatcacg gacacttaaa gtcaatctgc gaaataattc ttttattaca cactcactga agtttttgag tcccagagag ccattctatg tcaaacattc caagtactct ttgagagccc agcattacat caacatgccc gtgcagttca aaccgaagtc cgcaggcaaa tttgaagctt tgcttgtcat tcaaacagat gaaggcaaga gtattgctat tcgactaatt

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CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ggtgaagctc tgtattttgt tgatggatat aatattatgt tgtgtttgca aaaaaaaaaa ttggaaaaaa taactttatc ctataattgt atctagccca ttgattatga aaaaaggaa ttnactagaa tttctacact agattttgtt tagtattgta tattctgaat tactttttgt acaattatgc tttacaagct cttaactttt aaatatggga gttaagttaa ttttgtatat aatactgaag acagggtgaa atatatttta ttacataagt atattttgta actcgactga aaaaaaattc atgtgggtaa

300

360

420

480

540

559

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 46 731 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> - . (731)</td>

<td> &lt;223&gt;</td><td> n ss .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 46</td><td></td>

actagttcta gtaccatggc tgtcatagat gcaaccatta tattccattt agtttcttcc 60 tcaggttccc taacaattgt ttgaaactga atatatatgt ttatgtatgt gtgtgtgttc 120 actgtcatgt atatggtgta tatgggatgt gtgcagtttt cagttatata tatattcata 180 tatacatatg catatatatg tataatatac atatatacat gcatacactt gtataatata 240 catatatata cacatatatg cacacatatn atcactgagt tccaaagtga gtctttattt 300 ggggcaattg tattctctcc ctctgtctgc tcactgggcc tttgcaagac atagcaattg 360 cttgatttcc tttggataag agtcttatct tcggcactct tgactctagc cttaacttta 420 gatttctatt ccagaatacc tctcatatct atcttaaaac ctaaganggg taaagangtc 480 ataagattgt agtatgaaag antttgctta gttaaattat atctcaggaa actcattcat 540 ctacaaatta aattgtaaaa tgatggtttg ttgtatctga aaaaatgttt agaacaagaa 600 atgtaactgg gtacctgtta tatcaaagaa cctcnattta ttaagtctcc tcatagccan 660 atccttatat ngccctctct gacctgantt aatananact tgaataatga atagttaatt 720 taggnttggg c 731

<td> &lt;210&gt;</td><td> 47</td><td></td>

<td> &lt;211&gt;</td><td> 640</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (640)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 47</td><td></td>

tgcgngccgg cgttaataac gtacaccaaa anacgactnc ggagcagcat ttggtatgtc caganattgc tacatacntt acanctacac cccagtgggt ntggcnttnt tttggccctt tcctcaggtc tgtgacatcc aacaattttt ggacctgtcn ttactgaaag caatgccaag gtccccgaaa ctggtgcttg tttnccttgg nttgggacca ctttgtanga cctgcctgca tttcaccaat tgatnacccn gcnactaang anagaaacat tccgagcggt nanaagatgc ganaacanac cacctanctt ntcttctcac cactttcatc cagggttttt atngattnct aaanactggg gaacaanagt gcttctnncc tagatcaggt cctaanggct tctttggaag accanatcna aactgnaccc cgccctgaaa tcttantttg tcataccaca ggctnnaana nntgaacatt ctagaccacg aatacattcc tcttcanact atcatctggc ttcggaancc tcttcccgat ttgcctaaca tcntcnatgg agtacantct tacacaacct aggncaaccg atggatgcat ggtccngaaa acaagttccc attctttgcc

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360

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600

640

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 &lt;210&gt; 48 &lt;211&gt; 257 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt;

actagtatat ccaccttgag tgattttctt ttatatttgt aaaaaaaaaa gaaaatgtaa cagccttgga tgttcctgaa atatgtatca aaaaaaa atatcacttg aacctaacct aaagtgattt tcataaaata

<td> tgtactcaaa</td><td> caaaagttgg</td><td> tettaagett</td><td> 60</td>

<td> gcctctttta</td><td> gcataatcac</td><td> attttctaaa</td><td> 120</td>

<td> gtattagttt</td><td> tacatttgtt</td><td> ttttggaaga</td><td> 180</td>

<td> tttaaataaa</td><td> aagtatcttt</td><td> agagtgaaaa</td><td> 240 257</td>

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 49 652 DNA Homo</td><td> sapien</td>

<td> &lt;22Q&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> .. (652)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 49</td><td></td>

actagttcag tccacttatt gttgacacta tggggaaaaa taaacttctt ttttcaaagc ttctttaaag aacagcangg tttattgtat gatgcttttc cgcataactg atgagtggct tgaactctta gaaactgccc aatcttattt tctgtttcca tttcctcaca cagctatatc ttattgaagc ttgtanaata atatagagtg cacaaatgaa gctgaagggg agtcataaat atttctgtat taaaatggct aaacttgaaa tttttaaagt ccaacccatg agctttctca caatttttgt aaatatccca cagtgtatac

<td> cccccttgtc</td><td> attttcatta</td><td> taacccaatt</td><td> 60</td>

<td> gtataatgac</td><td> ttatgaatta</td><td> gcacagttaa</td><td> 120</td>

<td> tacactatca</td><td> aataggaaac</td><td> attggaaaga</td><td> 180</td>

<td> tagaaagttt</td><td> tcagattact</td><td> ttgaaaattc</td><td> 240</td>

<td> atatgtagat</td><td> ggactcatgc</td><td> attaagactg</td><td> 300</td>

<td> gtgattttcc</td><td> ttttaatata</td><td> catatttatt</td><td> 360</td>

<td> actttggaga</td><td> tatacctatn</td><td> aaaccaatat</td><td> 420</td>

<td> aatgttgctt</td><td> cagatgtgca</td><td> agttgcaaat</td><td> 480</td>

<td> ttcaaactgt</td><td> atttcaatct</td><td> atttctccaa</td><td> 540</td>

<td> ngataactgc</td><td> ttctgtgtcg</td><td> tcgcatttga</td><td> 600</td>

<td> ctcttggttg</td><td> tgcattnacc</td><td> cc</td><td> 652</td>

&lt;210&gt; 50 &lt;211&gt; 650 &lt;212 &gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt;

&lt;222&gt;

&lt;223&gt;

&lt;400&gt;

ttgcgctttg tgttgagtaa gactccgtgt gctttctttt ctccccaaac ggctcctgga ccaggactac ctctggagta attcccantt misc_feati (l) . . . (65¹n = A,T,C atttttttag aaaggagatg aactgtgtga ttgggttctt acacaagctc nggctgcctg aatgtcttta ccgtctgccc agggggtgcc )

or G ggcttgtgcc cccaatattc acacttggga tctagaagat tcagccacan ggggaggcag tttttaactg canacaagtg taactgaaca

<td> ctgtttcact</td><td> tatagggtct</td><td> agaatgettg</td><td> 60</td>

<td> aaagctgcta</td><td> aatgttctct</td><td> ttgccataaa</td><td> 120</td>

<td> tttttctcct</td><td> ctgtcccgag</td><td> gtegtegtet</td><td> 180</td>

<td> tgagaaatgc</td><td> atatgacagg</td><td> ctgagancac</td><td> 240</td>

<td> gcagcttctc</td><td> cacagcccca</td><td> gcttcgcaca</td><td> 300</td>

<td> acatgggagt</td><td> gccaaggtgg</td><td> ccagatggtt</td><td> 360</td>

<td> tttgccactg</td><td> ctgccctcac</td><td> ccctgcccgg</td><td> 420</td>

<td> ggantgaaat</td><td> gggggtggsg</td><td> gggaacactg</td><td> 480</td>

<td> gtagggatan</td><td> aaggtgtgaa</td><td> cctgngaant</td><td> 540</td>

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 gcttttataa attatnttcc ttgttanatt tattttttaa tttaatctct gttnaactgc ccngggaaaa ggggaaaaaa aaaaaaaaat tctntttaaa cacatgaaca

600

650

<td colspan="3"> &lt;210&gt; 51</td>

<td> &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td colspan="2"> 545 DNA Homo sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> .. (545)</td>

<td> &lt;223&gt;</td><td> n = ,</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 51</td><td></td>

tggcgtgcaa ccagggtagc tgaagtttgg gtctgggact ggagattggc cattaggcct cctganattc cagctccctt ccaccaagcc cagtcttgct acgtggcaca gggcaaacct gactcccttt gggcctcagt ttcccctccc cttcatgana tgaaaagaat actacttttt cttgttggtc taacnttgct ggacncaaag tgtngtcatt attgttgtat tgggtgatgt gtncaaaact gcagaagctc actgcctatg agaggaanta agagagatag tggatganag ggacanaagg agtcattatt tggtatagat ccacccntcc caacctttct ctcctcagtc cctgcncctc atgtntctgg tntggtgagt cctttgtgcc accanccatc atgctttgca ttgctgccat cctgggaagg gggtgnatcg tctcacaact tgttgtcatc gtttganatg catgctttct tnatnaaaca aanaaannaa tgtttgacag ngtttaaaat aaaaaanaaa caaaa

120

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300

360

420

480

540

545

<td> &lt;210&gt;</td><td> 52</td>

<td> &lt;211&gt;</td><td> 678</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td colspan="2"> &lt;220&gt;</td>

<td> &lt;221&gt;</td><td> mise feature</td>

<td> &lt;222&gt;</td><td> (1) .. -(678)</td>

<td> &lt;223&gt;</td><td> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 52</td>

actagtagaa gaactttgcc gcttttgtgc ctctcacagg cgcctaaagt cattgccatg ggaggaagac gatttggggg gggagggggg gggggcangg tccgtggggc tttccctant ntatctccat ntccantgnn cnntgtcgcc tcttccctcg tcncattnga anttantccc tggnccccnn nccctctccn ncctncncct cccccctccg ncncctccnn ctttttntan ncttccccat ctccntcccc cctnanngtc ccaacnccgn cagcaatnnc ncacttnctc nctccncncc tccnnccgtt cttctnttct cnacntntnc ncnnntnccn tgccnntnaa annctctccc cnctgcaanc gattctctcc ctccncnnan ctntccactc cntncttctc ncncgctcct nttcntcnnc ccacctctcn ccttcgnccc cantacnctc nccncccttn cgnntcnttn nnntcctcnn accncccncc tcccttcncc cctcttctcc ccggtntntc tctctcccnc nncncnncct cnncccntcc nngcgnccnt ttccgccccn cnccnccntt ccttcntcnc cantccatcn cntntnccat nctncctncc nctcacnccc gctncccccn ntctctttca cacngtcc &lt;210&gt; 53 &lt;211&gt; 502 &lt;212&gt; DNA &lt;213&gt; Homo sapien

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660

678 &lt;220&gt;

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 &lt;221&gt; misc__feature &lt;222&gt; (1) ... (502) &lt;223&gt; n = A,T,C or G &lt;400&gt; 53 tgaagatcct ggtgtcgcca tgggccgccg ccccgcccgt tgttaccggt attgtaagaa 60 caagccgtac ccaaagtctc gcttctgccg aggtgtccct gatgccaaaa ttcgcatttt 120 tgacctgggg cggaaaaang caaaantgga tgagtctccg ctttgtggcc acatggtgtc 180 agatcaatat gagcagctgt cctctgaagc cctgnangct gcccgaattt gtgccaataa 240 gtacatggta aaaagtngtg gcnaagatgc ttccatatcc gggtgcggnt ccaccccttc 300 cacgtcatcc gcatcaacaa gatgttgtcc tgtgctgggg ctgacaggct cccaacaggc 360 atgcgaagtg cctttggaaa acccanggca ctgtggccag ggttcacatt gggccaattn 420 atcatgttca tccgcaccaa ctgcagaaca angaacntgt naattnaagc cctgcccagg 480 gncaanttca aatttcccgg cc 502

<td> &lt;210&gt;</td><td> 54</td><td></td>

<td> &lt;211&gt;</td><td> 494</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) - .</td><td> . (494)</td>

<td> &lt;223&gt;</td><td> n = ί</td><td> i, T, C or</td>

<td> &lt;400&gt;</td><td> 54</td><td></td>

actagtccaa gaaaaatatg cttaatgtat attacaaagg ctttgtatat gttaacctgt 60 tttaatgcca aaagtttgct ttgtccacaa tttccttaag acctcttcag aaagggattt 120 gtttgcctta atgaatactg ttgggaaaaa acacagtata atgagtgaaa agggcagaag 180 caagaaattt ctacatctta gcgactccaa gaagaatgag tatccacatt tagatggcac 240 attatgagga ctttaatctt tccttaaaca caataatgtt ttcttttttc ttttattcac 300 atgatttcta agtatatttt tcatgcagga cagtttttca accttgatgt acagtgactg 360 tgttaaattt ttctttcagt ggcaacctct ataatcttta aaatatggtg agcatcttgt 420 ctgttttgaa ngggatatga cnatnaatct atcagatggg aaatcctgtt tccaagttag 480 aaaaaaaaaa aaaa 494

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 55 606 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (606)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 55</td><td></td>

actagtaaaa agcagcattg ccaaataatc cctaattttc cactaaaaat ataatgaaat 60 gatgttaagc tttttgaaaa gtttaggtta aacctactgt tgttagatta atgtatttgt 120 tgcttccctt tatctggaat gtggcattag cttttttatt ttaaccctct ttaattctta 180 ttcaattcca tgacttaagg ttggagagct aaacactggg atttttggat aacagactga 240 cagttttgca taattataat cggcattgta catagaaagg atatggctac cttttgttaa 300 atctgcactt tctaaatatc aaaaaaggga aatgaagtat aaatcaattt ttgtataatc 360 tgtttgaaac atgantttta tttgcttaat attanggctt tgcccttttc tgttagtctc 420 ttgggatcct gtgtaaaact gttctcatta aacaccaaac agttaagtcc attctctggt 480

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 actagctaca aattccgttt catattctac anatggtcta cttctgtcnt ataaaaacna aaaaaa ntaacaattt aacttgantt aaattaactg nccaaaaaaa aaatatttct aaaaaaaaaa

540

600

606 &lt;210&gt; 56 &lt;211&gt; 183 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 56 actagtatat ttaaacttac aggcttattt aattaacatg gttataatac gtacaatcct gtgtgataaa ctgattttgg tttgcaataa aaa gtaatgtaaa tccctcatcc aaccttgaaa ccaccatttt catcacacaa aataaaaaaa aatgtactgt ctttttttgt aaaaaaaaaa

120

180

183

<td> &lt;210&gt;</td><td> 57</td><td></td>

<td> &lt;211&gt;</td><td> 622</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> ¢1)</td><td> .. (622)</td>

<td> &lt;223&gt;</td><td> n = ,</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 57</td><td></td>

actagtcact gcagtggaga aatcagtgag ctgggtcaaa agagaacctg agggatcttc tctacaanaa gaganaccan atatatattt gaaacctgaa aaacttgaaa actgtcttct gtgctgctgg cactgttctg gctgcatgaa acttctcttt tgagcttgtt gcagcccttc aagcctctga ctttnaatnt ttaaaaccat aaaaaaaaaa ccttgtagct gtgtacgctg ctcagagctc accaggccct ccctctccct tccctgctgg tttgtcctct tttttaattt ttgagtcttt gaanaaaaat aa aatcaatcaa cacctgccca ctgatctacc ggcagcaacc cctccaacat gtgggacaga ggggttaatg ccntnaaatg gatatgtctt gtttncctta tattcttccc ctgagttggg ccacccccta tgggaatggc tactggaact agacaaagga agcttgacct tttgaagtnt aaaatccant aagatgttan ttgcctgtgg gaaagaggat ggatccagga tggaggtggg ctatcctgtt gaagggangg ananttcatg atatntacat ccctctgccn taattaattg

120

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540

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622

<td colspan="2"> &lt;210&gt; 58 &lt;211&gt; 433 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt;</td><td> 58</td>

gaacaaattc gtgtggaagc tcctttcagc accagcttta catatttgtg tgacagtaaa ttatccacca aaaaaaaaaa tgattggtta gttgaaaatt tgccagtgtt agctgaacca actttaatcg cctgtccatt aagacttcat aaa tgtaccgtca gaaagttact gaataatgta ttttatgaat tgctgcttgg atgaatggcc ttgtgtatca aaagacttga gcttttccac tcatccagag accaaataaa atagaaatat tactgttcta tcaataaagt agaaatttca ttgctcatat tgatgttatc tagacctctt ttttactggt ttatttgttt tgtatgtttc tgattttgca agtaaaggga tgtgacagtc gtactgaaaa tcttctgaat tgacttgaat aactgaaaaa

120

180

240

300

360

420

433 &lt;210&gt; 59 &lt;211&gt; 649

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1).,.(649) &lt;223&gt; n = A,T,C or G &lt;400&gt;

actagttatt tgtcatttgg ttggccatat attaggcgtn gacccttatc ctttatcgat ggctgtgcaa atcatatgan tacnaaaaat ggangctgan atcatgccag atctgacttt atttgcattt gtgtatgttc tgtcttttta agatacatgg aatgtcctta ggtgggctca gangctagga acaaaaatta gcacaaggat ggcaacaaaa cnggttataa ctctgatgag cctggagaag ttactgagtt tttgcaaata gacatataat cgcttgtaat gttcgaggtc gtcaggcatg cacttgaacc atgagaactt tcattctaat tgatgctatc tgtctgtgct gtaaganttc ttttctccca aaatttgtat cccagcactt agcctggcca gtggtgcacg ccagaangaa gtttaaaaaa gagtgtgaag aagcaccttt gagccttggc tttatatatt ttctgtgggt tttaaaagtg tgggagactg gcatagcgaa tctgtaatac gangttgcag aaaaaaaaa tagcctctgg gctggtgctg ccacttttta ctggattcta tgtgttttca acttgatttg aggtgggtgg aacttgtctc cagcttctca tganctgaag

120

180

240

300

360

420

480

540

600

649

<td colspan="3"> &lt;210&gt; 60 &lt;211&gt; 423 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) -</td><td> .. (423)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A₍T,C or</td>

<td> &lt;400&gt;</td><td> 60</td><td></td>

actagttcag acctggcagt gaagtgagcg tcttctgtat tgtcttacaa aggaatggcc caacccatta aaa gccttccagt gataccatca ctgggctgtt tttttttttc ggcagggctt tgagttggcg atcttttgta tcactgacaa agcctgatgt ttagtgccag cattagtana tcctacaggg ttgtgggcag gtttgtatna acatggggaa ccaaaagagc gctgcggtgg acacaagact ggtgganaaa gctactggtt aacttganct gtgtgcccag aaagaatatt gcagccatga cngattcagc acagcctttc tgtatgatgt gagaccttaa ctggctggaa tctccaagca gaacaaaacc cgaattgtgg ttcctttggt attagtagag acaaaaaaaa

120

180

240

300

360

420

423

<td> &lt;210&gt;</td><td> 61</td><td></td>

<td> &lt;211&gt;</td><td> 423</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) -</td><td> . . (423)</td>

<td> &lt;223&gt;</td><td> n =</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 61</td><td></td>

cgggactgga tccctcccca caggtctgag atgtaaagtg gaccccagag tatggctggg aagttcggag ggagaggccc agtcgggggc ctctgagcac accccgccca cacaggcctc gggctcttcc gccccgcccc tagctgtgct cgccgggtcc agcccctgct gctcaagaag

120

180

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 actggatcag ggtanctaca agtggccggg ccttgccttt gggattctac cctgttccta 240 atttggtgtt ggggtgcggg gtccctggcc cccttttcca cactncctcc ctccngacag 300 caacctccct tggggcaatt gggcctggnt ctccncccgn tgttgcnacc ctttgttggt 360 ttaaggnctt taaaaatgtt annttttccc ntgccngggt taaaaaagga aaaaactnaa 420 aaa 423

<td> &lt;210&gt;</td><td> 62</td><td></td>

<td> &lt;211&gt;</td><td> 683</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (683)</td>

<td> &lt;223&gt;</td><td> n - j</td><td> A,T,C or G</td>

<td> &lt;400&gt;</td><td> 62</td><td></td>

gctggagagg ggtacggact ttcttggagt tgtcccaggt tggaatgaga ctgaactcaa 60 gaagagaccc taagagactg gggaatggtt cctgccttca ggaaagtgaa agacgcttag 120 gctgtcaaca cttaaaggaa gtccccttga agcccagagt ggacagacta gacccattga 180 tggggccact ggccatggtc cgtggacaag acattccngt gggccatggc acaccggggg 240 ggatcaaaat gtgtacttgt ggggtctcgc cccttgccaa aaccaaacca ntcccactcc 300 tgtcnttgga ctttcttccc attccctcct ccccaaatgc acttcccctc ctccctctgc 360 ccctcctgtg tttttggaat tctgtttccc tcaaaattgt taatttttta nttttngacc 420 atgaacttat gtttggggtc nangttcccc ttnccaatgc atactaatat attaatggtt 480 atttattttt gaaatatttt ttaatgaact tggaaaaaat tnntggaatt tccttncttc 540 cnttttnttt ggggggggtg gggggntggg ttaaaatttt tttggaancc cnatnggaaa 600 ttnttacttg gggcccccct naaaaaantn anttccaatt cttnnatngc ccctnttccn 660 ctaaaaaaaa ananannaaa aan 683

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 63 731 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) ..</td><td> .(731)</td>

<td> &lt;223&gt;</td><td> n = ί</td><td> l,T,C or</td>

<td> &lt;400&gt;</td><td> 63</td><td></td>

actagtcata aagggtgtgc gcgtcttcga cgtggcggtc ttggcgccac tgctgcgaga 60 cccggccctg gacctcaagg tcatccactt ggtgcgtgat ccccgcgcgg tggcgagttc 120 acggatccgc tcgcgccacg gcctcatccg tgagagccta caggtggtgc gcagccgaga 180 ccgcgagctc accgcatgcc cttcttggag gccgcgggcc acaagcttgg cgcccanaaa 240 gaaggcgtng ggggcccgca aantaccacg ctctgggcgc tatggaangt cctcttgcaa 300 taatattggt tnaaaanctg canaanagcc cctgcanccc cctgaactgg gntgcagggc 360 cncttacctn gtttggntgc ggttacaaag aacctgtttn ggaaaaccct nccnaaaacc 420 ttccgggaaa attntncaaa tttttnttgg ggaattnttg ggtaaacccc ccnaaaatgg 480 gaaacntttt tgccctnnaa antaaaccat tnggttccgg gggccccccc ncaaaaccct 540 tttttntttt tttntgcccc cantnncccc ccggggcccc tttttttngg ggaaaanccc 600 cccccctncc nanantttta aaagggnggg anaatttttn nttncccccc gggncccccn 660 ggngntaaaa nggtttcncc cccccgaggg gnggggnnnc ctcnnaaacc cntntcnnna 720 ccncnttttn n 731

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 64 313 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> , . (313)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 64</td><td></td>

actagttgtg gttagagatg taaagttgat gattagagat aaatgttgat aaaaaaaaaa caaaccacga gttgctacac agagaatatg aagtatgaga catgtatata aaa ctgaagaaag atgttgggtc aagaatgcat agaaagctac tatccatagt acgaaaagtg tgtagagaaa gtcagaagat tctaattaag gaataaaatt ggaaataact catcttgagg ctctcggaaa tcttctgaag gtctcagtaa tgcaacgtct agcagattgc atattaaaga aatgaagatn agttgtaaaa

120

180

240

300

313

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 65 420 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . ¢420)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 65</td><td></td>

actagttccc caggaagctg tctgggaggt gtagatactg ctccgtgctc atttgtttta acacaaatta tggcaggcaa gcagtggcag tggagggaag ccttaacact actaatttat acattttcat atgatattaa gggcttccaa cttctgtgtc aatctaggcc ccctcctctc ttccaggaaa tgcaagtatt aaagcatcca ctgaggcagt tagggagggg ttagcttgcc tcagctgtgg ggtgtgtgga gaccatcatc aacaaagccn gcatgtgtgg tgtggctccc ctcctgccac ctgccaccca agacatgagc cttggttgtg annnnnaana cagagagagg tccttccctg ccttcccctt agccaggttt cgtgtataat tatcgttgta nnannngaaa

120

180

240

300

360

420

<td> &lt;210&gt;</td><td> 66</td><td></td>

<td> &lt;211&gt;</td><td> 676</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) </td><td> (676)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 66</td><td></td>

actagtttcc cctcaatttg aaataaactc aacaaggaat actgttttta gtagttttta gttagaaacc tatgatcatt tacttcatca acaaatctgg aatcccacaa aggatttgcg aatgtgagct tgttctcttg aaactcattc ataagttttt atgcatttct tatacctagc cttacttgtg tatagatngg ttatctgaat tcagggttaa gaagagtgca aaattctgca tacctaatac gctgaggaaa aaacagaata cttgattgca gaaaggaatg gatttttagt aatgtttcct atggagctgg aataagtagt tcaacttaat attactattg taaatttctg caggtcttaa ggggtgactt ggctcaaccc tccgagggaa tatggaaatt tactggatag

120

180

240

300

360

420

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 actccagccc ctttttaaga tttttggtga ccctggaaaa ttaaagggaa attgcaaagt aaaaattgga aaaanaatca anttgttaat aactta ctcagatatc gtttnaaaga tcccgcaggg taaatgggga ttanctgtgt aataaacccc cttattgttt aaatgntggg agttgaattc tttgttaaat aaaaanggaa naaaaattat cttggaaatt gaagcttggc ttttaagcct ccgttagggt

480

540

600

660

676

<td> &lt;210&gt;</td><td> 67</td><td></td>

<td> &lt;211&gt;</td><td> 620</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> -feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (620)</td>

<td> &lt;223&gt;</td><td> n = J</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 67</td><td></td>

caccattaaa gaattgtgag acattccatt taggggaaaa agattgtagt cccaaagaga cacttttgaa ctaaaaaaaa tctttactgg ttgcatgggc ccccnttttn gctgcttacc caggtgatag taatgaaggg aaatctgatc gctgtggtgg ggaaattata gtgttttgtt agggatatca aanttatggg cccttaaaat aaaatttgga aagaacttcc aagagccttt gttacatctg agaacgcatc tttattccgt ggttagttaa ttttattttt atctctaatt actttttaag tgttgaangg ccagcatttt ctagttgaac ttacgaagct aaactcacat tgtgcagaac acattgtaat ggtttgtctg cagtgcccac ctccaggtnt cattcctgcc gacttccttg atacagataa actaagaagg gtgccccctc ttgcaagctg cccaggaact atttactttg taaaagttgt tttggtcctc tctaagtttg tttgatagct tttgctgaat agcaagagca tactacaaac agtcactaaa aagtttaatt ggggaaaang ccctaaaaag caaattaacc gggaaaattc

120

180

240

300

360

420

480

540

600

620

<td> &lt;210&gt;</td><td> 68</td><td></td>

<td> &lt;211&gt;</td><td> 551</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> λ (551)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 68</td><td></td>

actagtagct ctaatgctag ttagaacaga gtattggggt tctgagactg actcggcacc tacagctgat ttaaacctaa cctatgtgct nannnannna ggtacataat accagtattt cctctctgtg tgcaatgact tggtgaaact actttgatat ggaactcaat ttacatttgt cccctccccc a

cactgaggag aagggctaat caataacttg cccaagggcc ccttccaagg tcaacaagcc ttgaaccttc ctagcattgg nnatcttaat

<td> etatttetta</td><td> acatgctttt</td><td> atagaccatg</td><td> 60</td>

<td> ctcacacctc</td><td> cttagctgta</td><td> agagtctggc</td><td> 120</td>

<td> tggccactgg</td><td> aaatccctgg</td><td> gccggcattt</td><td> 180</td>

<td> aaaagagtta</td><td> aaggcacgac</td><td> tgggatttct</td><td> 240</td>

<td> ctgagggggt</td><td> cagtangtgc</td><td> tctgggaggg</td><td> 300</td>

<td> aettgaagee</td><td> caattataaa</td><td> attgttattt</td><td> 360</td>

<td> aaaaetttgt</td><td> tagtttatcc</td><td> tattatattg</td><td> 420</td>

<td> atttggttcc</td><td> tgtngcatat</td><td> gtttttttcn</td><td> 480</td>

<td> ttaaaccnca</td><td> attttgcnat</td><td> tcnccnnnnn</td><td> 540 551</td>

&lt;210&gt; 69 &lt;211&gt; 396 &lt;212&gt; DNA &lt;213&gt; Homo sapien

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1)...(396) &lt;223&gt; n = A,T,C or G &lt;400&gt; 69 cagaaatgga aagcagagtt ttcatttctg tttataaacg tctccaaaca aaaatggaaa 60 gcagagtttt cattaaatcc ttttaccttt tttttttctt ggtaatcccc tcaaataaca 120 gtatgtggga tattgaatgt taaagggata tttttttcta ttatttttat aattgtacaa 180 aattaagcaa atgttaaaag ttttatatgc tttattaatg ttttcaaaag gtatnataca 240 tgtgatacat tttttaagct tcagttgctt gtcttctggt actttctgtt atgggctttt 300 ggggagccan aaaccaatct acnatctctt tttgtttgcc aggacatgca ataaaattta 360 aaaaataaat aaaaactatt nagaaattga aaaaaa 396

<td> &lt;210&gt;</td><td> 70</td><td></td>

<td> &lt;211&gt;</td><td> 536</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> ..(536)</td>

<td> &lt;223&gt;</td><td> n = ,</td><td> A,T,C or G</td>

<td> &lt;400&gt;</td><td> 70</td><td></td>

actagtgcaa aagcaaatat aaacatcgaa aaggcgttcc tcacgttagc tgaagatatc 60 cttcgaaaga cccctgtaaa agagcccaac agtgaaaatg tagatatcag cagtggagga 120 ggcgtgacag gctggaagag caaatgctgc tgagcattct cctgttccat cagttgccat 180 ccactacccc gttttctctt cttgctgcaa aataaaccac tctgtccatt tttaactcta 240 aacagatatt tttgtttctc atcttaacta tccaagccac ctattttatt tgttctttca 300 tctgtgactg cttgctgact ttatcataat tttcttcaaa caaaaaaatg tatagaaaaa 360 tcatgtctgt gacttcattt ttaaatgnta cttgctcagc tcaactgcat ttcagttgtt 420 ttatagtcca gttcttatca acattnaaac ctatngcaat catttcaaat ctattctgca 480 aattgtataa gaataaaagt tagaatttaa caattaaaaa aaaaaaaaaa aaaaaa 536

<td> &lt;210&gt;</td><td> 71</td><td></td>

<td> &lt;211&gt;</td><td> 365</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) /</td><td> .. (865)</td>

<td> &lt;223&gt;</td><td> n = -</td><td> A,T,C or G</td>

<td> &lt;4Q0&gt;</td><td> 71</td><td></td>

gacaaagcgt taggagaaga anagaggcag ggaanactnc ccaggcacga tggccncctt 60 cccaccagca accagcgccc cccaccagcc cccaggcccg gacgacgaag actccatcct 120 ggattaatct nacctctntc gcctgnccca ttcctacctc ggaggtggag gccggaaagg 180 tcncaccaag aganaanctg ctgccaacac caaccgcccc agccctggcg ggcacganag 240 gaaactggtg accaatctgc agaattctna gaggaanaag cnaggggccc cgcgctnaga 300 cagagctgga tatgangcca gaccatggac nctacncccn ncaatncana cgggactgcg 360 gaagatggan gacccncgac nngatcaggc cngctnncca nccccccacc cctatgaatt 420 attcccgctg aangaatctc tgannggctt ccannaaagc gcctccccnc cnaacgnaan 480

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 tncaacatng acaanctctc cacgccaagn ganggttatc ccncctatnt ttngttgncc aagggtgntt ggattanang ccnaanaaac aantataaaa cnccttgcgt cnagccgaac cngccctttc ggccccctcc ctgggaactg tggggcncct ggggggcccc accatggtnc tcnnatttnc cgncggaacn ctccc naaggggcaa catnggtggn tccncggnng ccnnttctgt ^cc99999tgc cgtttccccg ancctnnaat accaactatt accccctttt ntgnatgttt natcnantng ttantaacgg atccccagaa aactaaaccg gtcccttaat ccnctcccct tncncctttn cacccggggn

540

600

660

720

780

840

865

<td rowspan="2"> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td colspan="2"> 72</td>

<td> 560 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> ¢1)</td><td> . . (560)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 72</td><td></td>

cctggacttg aaaagacagt ccatgcccaa tcnaantgct cagcagtgga gcaccacaaa ngcctgtnaa cctgaaagga actgatnctt cttccntttc tcttggttcc gtccagtgct cttctctggc gggggtgaat gatcnaacag gattaacttc aacctggtga gaaggccccc gaaccctgaa cccaaaaaaa agaacctgac ccngcctagg aactggaaaa gtgatgctna gagggagaca nnngttgggg aatgggagaa anaactcctg cgggcgggat gacccggcga agtctacggg tcatccgatc ngaanattgc ctttctacat aggantttga tganaataaa gaccngaaaa ganccttttt cggcgacgtc gaccgcctcc ggaaaacttc tgtggctgca caaaacctcc ggancaaact atggt.ctgtg actgacccnc tnttgccncc tcttttgact cgcgccgcca gangaattgc gcgtccaagc accaccgtgc gtggatngga ancanaaact cnatngggga naangggttc

120

180

240

300

360

420

480

540

560

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 73 379 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (379)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 73</td><td></td>

ctggggancc aaccgcncaa gnanngagga ttggccacnn ataagngacc tnccacgtan ttgttcaaaa ggcggtnngc naaacatgcc acanaacaaa gtggaattaa ctttatttca agntggaant aaaaaataa nccatntcnn naagatatgg ctcnangagc gaaatctggc tctgtattta anttgttgtc gncgcgaagg acgaggaaga tctcaagcta aaanngtann aacctctctn ttggactgtt tggcaataaa tngngctttc atgccgcggg tgttccttgt ttccctgnca gtncatttta aanccnctga nngnacaanc gaaggggccc gcctnangag taacttcttt gannaaactt

120

180

240

300

360

379 &lt;210&gt; 74 &lt;2ll&gt; 437 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

CA 02369578 2001-10-02

WO 00/61612

PCT/USOO/08896 &lt;221&gt; misc_feature &lt;222&gt; (1) . . . (437) &lt;223&gt; n = A,T,C or G &lt;400&gt;

actagttcag ctaggtgttt acaaaaaaac caccagggtt aatcactgaa gaataagtta gtcatttgta aaaaaaaaaa actgccacgc ccatctatgt gctgccaggt cttttgaaat ttgtcaggct taatcagtat ctgtttgaaa aaaaaaa caaccccaga ttcaatctgt tttanaagca agtaccacat ttgattgata tcatctcttt aatatttctt

<td> 30</td><td></td><td></td><td></td>

<td> aaatacccca</td><td> catgccagaa</td><td> aagtgaagtc</td><td> 60</td>

<td> ccatctacca</td><td> ggcctcgcga</td><td> taaaaacaaa</td><td> 120</td>

<td> gttctggtct</td><td> caaaaccatc</td><td> aggatcctgc</td><td> 180</td>

<td> gtaaaaggga</td><td> atttggcttt</td><td> cacttcatct</td><td> 240</td>

<td> attgtagaaa</td><td> taagtagcct</td><td> tctgttgtgg</td><td> 300</td>

<td> gttttttgtc</td><td> actcttttct</td><td> ctctnattgt</td><td> 360</td>

<td> ctataaaatt</td><td> aaactaacct</td><td> geettaaaaa</td><td> 420 437</td>

<td> &lt;210&gt;</td><td> 75</td><td></td>

<td> &lt;211&gt;</td><td> 579</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) .. </td><td> -(579)</td>

<td> &lt;223&gt;</td><td> n = A</td><td> i, T, C or G</td>

<td> &lt;400&gt;</td><td> 75</td><td></td>

ctccgtcgcc gacccagcac ccctgtgttt caaggtgcac tgaaaacaag gacctatttc cctccgtcta ccttggggtg gtgttgattc gatatatttt gccaagatga atcgccgacc aaggccgtgt gtcggcgacg cccttgacct tgatcctgac ccagagcgtg gaaggggcan tttccttcca naaaatcctt tgtgcggggc aggtgaggtc cattcaagag aggacttcgt tatctaacta tttggacaag cacttgtgat gatctgcact ataggtgatc aaaaaaaaaa

<td> gccctccgcc</td><td> acgcagccgg ccaccgccga</td><td> 60</td>

<td> ccagcttgaa</td><td> gagaaagaaa acaagaagtt</td><td> 120</td>

<td> ccaggtggtc</td><td> gcggggacaa actacttcat</td><td> 180</td>

<td> acacctgcga</td><td> gtgttccaat ctctccctca</td><td> 240</td>

<td> ccagaccaac</td><td> aaagccaagc atgatgaget</td><td> 300</td>

<td> gcccttcagc</td><td> cagaagactg acaaagtcat</td><td> 360</td>

<td> cctaaaataa</td><td> gcttcatctc cgggctgtgc</td><td> 420</td>

<td> gcttttgcat</td><td> ttctcttcct aaatttcatt</td><td> 480</td>

<td> ttnattaett</td><td> tcagaatatt ttccaaatna</td><td> 540</td>

<td> aaaaaaaaa</td><td></td><td> 579</td>

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 76 666 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) - .</td><td> .(666)</td>

<td> &lt;223&gt;</td><td> n = A</td><td>_t,T,C or</td>

<td> &lt;400&gt;</td><td> 76</td><td></td>

gtttatccta tccctgtttc ttgatgttgt ttcctggcta ctcactacag cagcttctcc taaaaaatat cagccagtga tctctccaac ttccacagtg tatgggcagg ctccatgttg ggaccaggga aacaataaaa acagtttacc acaacctttt cagattgtca cctaataata atggcaacca gctagcctct tgatgcaaca agcacgtggt gaaaatcata cccaccatac

<td> gctccttgag</td><td> ggcaagagcc</td><td> acagtatatt</td><td> 60</td>

<td> ctgtggaact</td><td> aggttttaat</td><td> aattttttaa</td><td> 120</td>

<td> gaccattgtc</td><td> tcagagcagg</td><td> tgctggctct</td><td> 180</td>

<td> ggtaacctct</td><td> taettattat</td><td> cttcaggaca</td><td> 240</td>

<td> teettgtett</td><td> tttatgacag</td><td> gatgtttgct</td><td> 300</td>

<td> aaaacacttg</td><td> eggatattet</td><td> ggactgtttt</td><td> 360</td>

<td> ttatcttaca</td><td> atgaaaagga</td><td> ntttatagat</td><td> 420</td>

<td> aaaaattcct</td><td> tttcccgaan</td><td> gaaaangget</td><td> 480</td>

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ttctcaataa tcattttagg atatcaatta cttaaa ncctcacttt caaatatgan ccacccccat cttaanatct ttttattgtn ctcccatgaa tacaagatag cgttacttgt anaaanggga ccccganatc ttcaaaattt aanggtgaan ttatcgaaac ggtattgtga ttcntaancg

540

600

660

666

<td rowspan="2"> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td colspan="2"> 77 396</td>

<td> DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> .. ¢396)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or G</td>

<td> &lt;400&gt;</td><td> 77</td><td></td>

ctgcagcccg atcattgccc catanganta tggtccacag attaagtgag gaagtttttt aatacttcta ggggatccac aaagttgcac tgccanaata cataacangc aagggagact aaacctctga atgggaacaa taatctacca ttgctggtct aattccattt actgcctcct ctcagccttc atttgtacac aaaaaaaaaa nggttatttg cttgggattt ttttgaaaat tacctgtgag agcttcctaa atttaaaatt aaaaaa gcagctaatt ggccttggaa canctccntg gaatgcaaaa attctgtgtc tcaagtgtac ctanatttgg aggtatcata gggctggttt taaagcatgg tgtgactttc tttaaaataa

120

180

240

300

360

396

<td> &lt;210&gt;</td><td colspan="2"> 78</td>

<td> &lt;211&gt;</td><td> 793</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> ¢1)</td><td> ..(793)</td>

<td> &lt;223&gt;</td><td> n = j</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 78</td><td></td>

gcatcctagc gaaaattcca taccacagtc gaccctctcc atataaatcc acacagtcna gcagtttgtc ccagtatgtc ggaagatatt atgaaaaagc tctgtcggct gacacctgat ttggttcaat aataatnttt cgccgactca gtgtcagcat aaacctggag agaggttggg aagacaagca gctttaaaga ctcctcaatc ccaggattat cnaaccgtct tctcaagttg tgaaaattga taggttttgg tntctttttn ggc cacaaggcag tcttgctcct ccaaaaagga gtgaccaact acaaaccctt aagtgtttgc tggtttatga gtttgttgac ctatgcttac ctnaaaatga aaccagaaaa ttatgttcac aaacaatntg

<td> gtgggtgagg</td><td> aaatccagag</td><td> ttgccatgga</td><td> 60</td>

<td> tgtggccctc</td><td> tcctacactc</td><td> tggccagaga</td><td> 120</td>

<td> cacaaaggac</td><td> tctcgaccca</td><td> aactgcccca</td><td> 180</td>

<td> catctggact</td><td> cagacatatg</td><td> aagaagetet</td><td> 240</td>

<td> gatgattatt</td><td> catcacttgg</td><td> atgagtgccc</td><td> 300</td>

<td> tgaaaataaa</td><td> gaaatccaga</td><td> aattggcaga</td><td> 360</td>

<td> aacaactgac</td><td> aaacaccttt</td><td> ctcctgatgg</td><td> 420</td>

<td> ccatctctga</td><td> cagttgaagc</td><td> cgatatcctg</td><td> 480</td>

<td> aaactgcaga</td><td> tacgctctgt</td><td> tgcttgacac</td><td> 540</td>

<td> attgtaagaa</td><td> aaaaaatctc</td><td> cagccttctg</td><td> 600</td>

<td> atgtgaaaaa</td><td> tggctattgt</td><td> ggaacanatn</td><td> 660</td>

<td> cactattttt</td><td> aanaaaanan</td><td> nttttaaaat</td><td> 720</td>

<td> tttetaentt</td><td> gnganctgat</td><td> ttctaaaaaa</td><td> 780 793</td>

&lt;210&gt; 79 &lt;211&gt; 456 &lt;212&gt; DNA &lt;213&gt; Homo sapien

CA 02369578 2001-10-02

WO 00/61612

PCT/USOO/08896 &lt;220&gt;

&lt;221&gt; miSC—feature &lt;222&gt; {1)...(456) &lt;223&gt; n = A,T,C or G &lt;400&gt; 79 actagtatgg ggtgggaggc cccacccttc tcccctaggc gctgttcttg ctccaaaggg 60 ctccgtggag agggactggc agagctgang ccacctgggg ctggggatcc cactcttctt 120 gcagctgttg agcgcaccta accactggtc atgcccccac ccctgctctc cgcacccgct 180 tcctcccgac cccangacca ggctacttct cccctcctct tgcctccctc ctgcccctgc 240 tgcctctgat cgtangaatt gangantgtc ccgccttgtg gctganaatg gacagtggca 300 ggg9^ct99^aa atgggtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gcnccccccc 360 tgcaagaccg agattgaggg aaancatgtc tgctgggtgt gaccatgttt cctctccata 420 aantncccct gtgacnctca naaaaaaaaa aaaaaa 456

<td> &lt;210&gt;</td><td> 80</td><td></td>

<td> &lt;211&gt;</td><td> 284</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) . -</td><td> . (284)</td>

<td> &lt;223&gt;</td><td> n = Ά</td><td> l,T,C or</td>

<td> &lt;400&gt;</td><td> 80</td><td></td>

ctttgtacct ctagaaaaga taggtattgt gtcatgaaac ttgagtttaa attttatata 60 taaaactaaa agtaatgctc actttagcaa cacatactaa aattggaacc atactgagaa 120 gaatagcatg acctccgtgc aaacaggaca agcaaatttg tgatgtgttg attaaaaaga 180 aataaataaa tgtgtatatg tgtaacttgt atgtttatgt ggaatacaga ttgggaaata 240 aaatgtattt cttactgtga aaaaaaaaaa aaaaaaaaaa aana 284

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 81 671 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (U ·’</td><td> - . (671)</td>

<td> &lt;223&gt;</td><td> n = J</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 81</td><td></td>

gccaccaaca ttccaagcta ccctgggtac ctttgtgcag tagaagctag tgagcatgtg 60 agcaagcggt gtgcacacgg agactcatcg ttataattta ctatctgcca agagtagaaa 120 gaaaggctgg ggatatttgg gttggcttgg ttttgatttt ttgcttgttt gtttgttttg 180 tactaaaaca gtattatctt ttgaatatcg tagggacata agtatataca tgttatccaa 240 tcaagatggc tagaatggtg cctttctgag tgtctaaaac ttgacacccc tggtaaatct 300 ttcaacacac ttccactgcc tgcgtaatga agttttgatt catttttaac cactggaatt 360 tttcaatgcc gtcattttca gttagatnat tttgcacttt gagattaaaa tgccatgtct 420 atttgattag tcttattttt ttatttttac aggcttatca gtctcactgt tggctgtcat 480 tgtgacaaag tcaaataaac ccccnaggac aacacacagt atgggatcac atattgtttg 540 acattaagct ttggccaaaa aatgttgcat gtgttttacc tcgacttgct aaatcaatan 600 canaaaggct ggctnataat gttggtggtg aaataattaa tnantaacca aaaaaaaaan 660

671 aaaaaaaaaa a

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 82 217 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> ^feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (217)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or G</td>

<td> &lt;400&gt;</td><td> 82</td><td></td>

ctgcagatgt ttcttgaatg ctttgtcaaa ttaanaaagt taaagtgcaa taatgtttga agacaataag tggtggtgta tcttgtttct aataagataa acttttttgt ctttgcttta tcttattagg gagttgtatg tcagtgtata aaacatactg tgtggtataa caggcttaat aaattcttta aaaggaaaaa aaaaaaaaaa aaaaaaa

120

180

217

<td> &lt;210&gt;</td><td> 83</td>

<td> &lt;211&gt;</td><td> 460</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td colspan="2"> &lt;220&gt;</td>

<td> &lt;221&gt;</td><td> mise feature</td>

<td> &lt;222&gt;</td><td> (1)... ¢460)</td>

<td> &lt;223&gt;</td><td> n = A, T, C or</td>

<td> &lt;400&gt;</td><td> 83</td>

cgcgagtggg agcaccagga tctcgggctc ggaacgagac tgcacggatt gttttaagaa aatggcagac aaaccagaca tgggggaaat cgccagcttc gatnaggcca agctgaanaa aacggagacg caggagaaga acaccctgcc gaccaaagag accattgagc angagaagcg gagtgaaatt tcctaagatc ctggaggatt tcctaccccc gtcctcttcg agaccccagt cgtgatgtgg aggaagagcc acctgcaaga tggacacgag ccacaagctg cactgtgaac ctgggcactc cgcgccgatg ccaccggcct gtgggtctct gaagggaccc cccccaatcg gactgccaaa ttctccggtt tgccccggga tattatacaa nattatttgt atgaataatg annataaaac acacctcgtg gcancaaana aaaaaaaaaa

120

180

240

300

360

420

460

<td> &lt;210&gt;</td><td> 84</td><td></td>

<td> &lt;211&gt;</td><td> 323</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (323)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 84</td><td></td>

tggtggatct tggctctgtg gagctgctgg gacgggatct aaaagactat tctggaagct gtggtccaan gcattttgct ggcttaacgg gtcccggaac aaaggacacc agctctctaa aattgaagtt tacccganat aacaatcttt tgggcagaga tgcctatttt aacaaacncc gtccctgcgc aacaacnaac aatctctggg aaataccggc catgaacntg ctgtctcaat cnancatctc tctagctgac cgatcatatc gtcccagatt actacanatc ataataattg atttcctgta naaaaaaaaa aaa

120

180

240

300

323

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896

<td colspan="2"> &lt;210&gt; 85</td>

<td> &lt;211&gt;</td><td> 771</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td colspan="2"> &lt;220&gt;</td>

<td> &lt;221&gt;</td><td> misc_feature</td>

<td> &lt;222&gt;</td><td> (1) . . - (771)</td>

<td> &lt;223&gt;</td><td> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 85</td>

aaactgggta ctcaacactg agcagatctg ttctttgagc aanagtttgc tcctggctgc tttgatgtca gtgctgctac gaagcaagca actttgactg ctgtcttgga tacacagacc attgtgggct tcacacggca gctggccaat gaaggctgtg cacacaaaga aaaagttgtc tgtgtgcgca aatccaaaac gtgcgtctcc tcagtaaaaa agtcaagaac atgtaaaaac attggacata gcccaagaac agaaagaact tgctggggtt atgganggtt tagtgcttat cttatttgtg cctcctggac atcatattgc atcatanttt gctttgttta acatcacatt gttatttata gctntaggtt ttctgtgttt aactttttat ttggtntant gcaanttaaa aattatattt ggggggggaa gccacaagct ttttttaaaa aaccantaca nccnngttaa tttgcttttn antagaaaat ttnttagaac natttgaaaa

<td> &lt;210&gt;</td><td> 86</td><td></td>

<td> &lt;211&gt;</td><td> 628</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (1) /</td><td> ..(628)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 86</td><td></td>

actagtttgc tttacatttt tgaaaagtat tatttttgtc cttgtgttag gtaagaatgg aatttattaa gtgaatcagt attatcttaa agctgaagcc aaaatatgct tcaaaagaaa agttcataca ttcaaagcat ctgaactgta gtttctatag gtggagaang aaatagatta atgtcnaagt atgattggtg aatctggggt tgaaattttc tagttttcat tctgtacatt gaaatattaa tgtttacctt tcaatgtgtg gtatcagctg ttccctnggg gatggggaat ggattattgg aaaatggaaa tcctttcnca gtttctggct cctaccctac tgatttancc catcntctgc tttattccca ttaatnaant tttgatgaat ccaaggaatt nagtggnttc ntcnttgt &lt;21Q&gt; 87 &lt;211&gt; 518 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; mise feature

<td> taaaaaccat</td><td> gtgctgtacc</td><td> 60</td>

<td> tccacctctg</td><td> eggegaatea</td><td> 120</td>

<td> gtattettea</td><td> tcctaaattt</td><td> 180</td>

<td> acatcaatgc</td><td> tatcatcttt</td><td> 240</td>

<td> agacttgggt</td><td> gaaatatatt</td><td> 300</td>

<td> tgtggctttt</td><td> ctggaatgga</td><td> 360</td>

<td> ggaggtttca</td><td> cttgcacatc</td><td> 420</td>

<td> ttgtccaatt</td><td> natgaagtta</td><td> 480</td>

<td> naaattaaac</td><td> tgtattttat</td><td> 540</td>

<td> acnaantttc</td><td> ctaaactatt</td><td> 600</td>

<td> taaatattgg</td><td> antttctgca</td><td> 660</td>

<td> atggtnggtc</td><td> ccnaatggtt</td><td> 720</td>

<td> aaaaaaaaaa</td><td> a</td><td> 771</td>

<td> caagtgctta</td><td> tcaactaaac</td><td> 60</td>

<td> gtgacccttc</td><td> ttgtcataag</td><td> 120</td>

<td> angaetttat</td><td> tgttcattgt</td><td> 180</td>

<td> caagcqaatt</td><td> acatccataa</td><td> 240</td>

<td> gagggagcaa</td><td> ggttgaagat</td><td> 300</td>

<td> tttagttnga</td><td> catcagattt</td><td> 360</td>

<td> gactcantaa</td><td> cacccctttc</td><td> 420</td>

<td> gaaaaaagta</td><td> cttaaagcct</td><td> 480</td>

<td> agaataagaa</td><td> aacattttat</td><td> 540</td>

<td> aaatctgctt</td><td> ttatgcnnac</td><td> 600 628</td>

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 &lt;222&gt; (1)...(518) &lt;223&gt; n = A,T,C or G &lt;400&gt; 87 ttttttattt tataacaaca agtagtacag ttttacatgg aaacacattt ctacagttta ggttaaaatg naatttaacc taaaancgag tttttagaga ttatactgtt ttttaaaatt caaatcaatt aatttcaatt acaatgcagc ctttgaggat ctcatgccat ccccccgttg gtagttcagc tatggtttaa ttatgcttaa tttaagtcat tctctcttat aaaattccca cctnaatacc aagcagaagc aaaaagcaaa ttttatttat aaatttattg cctgttttat 60 tacatatggt tcaaaatgta taatacatca 120 aacaagtttt gtgtaaaaaa tgcagataca 180 cctaaaaatt gatttttttt tgaaatttaa 240 ataaccttta ttactatagc atggtttcca 300 tttcacggta aattgggttt taagcggcaa 360 ctttgaactt caaatgaagg ttatggttgt 420 acaagtttag ctgcattttg ctctaaactg 480 agggaccc 518 &lt;21O&gt; 88 &lt;211&gt; 1844 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400 gagacagtga tattttattt ggtatttgct ttccatcttc agcttatgtg gaaatagaaa taatcccttt tctcagtaac tagatgtagc ttgtaggaat acatagggca taattttcaa ccttgctttt taataatgtt aatgcagctc gcaccctacc tccattattc accatattca gctttcacct ggtgctcctc agtgcagcag ccatcttagg attgctcttc catgcagcta atttgaagtt ccaatttacc tagtaataaa aaaatcaatc ttacacaaaa ttttgaacca aaatttataa atcctagtat tatttttcga aaagcatttt ttggtgctgg ttgaatttgc tatcatagaa gaagggatct agatcctgtg atacatatga acaaaacatg atctgtgaat gtcaaaaagg aaattaaacg aggttagcaa ttcgagtcat tcacctgctt cttactgtat aaacctaaat agaagggtgt cttccctggt cctgtgcttc gggagaagct ctgctgctgt acttgtgcct caaaggtgta gtgaaatggg ggttatataa tttaggatga cttgttttaa tatgtattaa ataaaagctg caaaggattt gactccgtct gagctgcttg gaagccatat tacatctata catttaagaa atccaaagaa ttagtctttg tgtataatga gcctttttta atgtattata gatatggaaa ctacagccat aggtttagat ttctggtcat actgacattg ataaaataca ttgtttttgc ggtcctgaag accctgacta cacagatggg agatcctgtg cctttgcttc ctgcttatgc ttcaggatcc aattttgctg gagagaaatt cttaaaaatt gcataaaatt accataaaca aaaaaaaaaa ttggcctcag aaaaagttgt tgattatttt 60 caaaaaaaaa aaaaaaaaaa agaatcacaa 120 gaaaaaggga agtagttgca gtagagtttc 180 atgtgtcttt tactcaagct aaggggtata 240 tttcacatat tctcacaata agagaatttt 300 agtttagtat aaataatatt ttgtgtgttt 360 aatattttac actgagctcc ttcctacacg 420 aaaatagctc attttttaaa tgtcagtgag 480 cgtgtattat gttaacaatg tctgcagatt 540 taagcaaaac gggccaatga ctagaataac 600 agcagcattc cagaaaagta gttggtgaaa 660 gggaattatg agtaacctct attttttaag 720 ttaagccttg aggataataa agcttgagag 780 gtatcacttc atgcatgcta ccatgatagt 840 tcaagatatt cacccttttg cccatagaaa 900 tcttagctga tcacaagatc attatcagcc 960 gagttttata ttttcctttc ttcgtttttc 1020 agatggaatg caaagtaatc aagtgttcgt 1080 gaaagaggtc cctaaatatc ccccaccctg 1140 ccagaagtca ggtgctagag cagctggaga 1200 ggtgctgctg caacaaggct ttcaatgtgc 1260 cagcagcctg gtaagtcctg aggaggttcc 1320 tcaacggggc tcgctctaca gtctagagca 1380 atgagggtta aattaacaac cataaccttc 1440 tcaaagcatt ttaaccttgc cgcttaaaac 1500 cattgttaaa ctgtagtgga aaccatgcta 1560 gaaattaaat gtgtttttaa atttcaaaaa 1620 gatttgccat gtaaaatgta tctgcatttt 1680 ttaaaactgt actacttgat gtattataca 1740 gtataatgtt gttataataa aacaggcaat 1800 aaaaaaaaaa aaaa 1844 &lt;210&gt; 89 &lt;211&gt; 523 &lt;212&gt; DNA

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) . . . (523) ' &lt;223&gt; n = A,T,C or G &lt;400 tttttttttt gggataaaga acaatatgat tcaccttgtc ctccccactg gccctggcat actttgatna ggtgctcaag taattgaatg &gt; 89 tttttttagt tgactgttag gtagaaaatg tttccacatc cagatcccct gacttgaacc gaaaacacat aaaagtttgc gtggctcaat caatccacat tcactcacag ctaagccaga cctacccttc gggattttgc caaccacaga agggaattga agaatggata aagaatgact ttattgatca taaggaagaa gatatagaaa acaggccttc ctagagctaa ctgggaaagg agagaaantc aatgaaggat ncnttgaatg cttattatgt aactagcaaa ggtcctattg cctccagctt acgagganat gagcctttcg cccaaatggc caagggaatt acc accaggcact taagacgatt ggtccttctg cctgcccccg gggccccctg anagtggatc cacccgtgct aatanatgaa

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300

360

420

480

523

<td> &lt;210&gt;</td><td> 90</td><td></td>

<td> &lt;211&gt;</td><td> 604</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) - .</td><td> . (604)</td>

<td> &lt;223&gt;</td><td> n = Λ</td><td> l,T_zC or</td>

<td> &lt;400&gt;</td><td> 90</td><td></td>

ccagtgtggt gcaaaggaaa ctcacccacc gggagccttc ctctttcctc ctggaatgca cactgcattg ^a9999tggta accactaatg ccctaattgc cccc ggaatgcaaa tagccaatat aactaaatcc aagggcatgt tctgatcctt attgtttgca gtgataggac cacctgtttg gggagggcag tgaaattccc gattaccccg gtgtcgtttc caaagtcaaa agaaaatcag ttcctcttta acaccgaagg acggtaattt gtaaaatgag attattactg ctnggcaggc gaagctttcg tatgaaatga agcttcagcc ctgttcagat cggcacaaca atttcctgcg gattcacatt aagcctcgga ggatttctcc tccagttttc agaagctggg agccagaccg agtttatctc aggcctctgc ttcatgtttg gtcgcctctt taacttgcta aacttgggag tggggtgaat tcaactgcat attccctgca agatgtcaat agagaaccag accacacagc acagaacatg cagtaggaag gttagtgata cttctctcct taatttcaag tgcaaaattc

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604

<td> &lt;210&gt;</td><td> 91</td><td></td>

<td> &lt;211&gt;</td><td> 858</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> .. (858)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> &amp;,T,C or</td>

<td> &lt;400&gt;</td><td> 91</td><td></td>

tttttttttt ttttttttta tgattattat tttttttatt gatctttaca tcctcagtgt 60 tggcagagtt tctgatgctt aataaacatt tgttctgatc agataagtgg aaaaaattgt 120 catttcctta ttcaagccat gcttttctgt gatattctga tcctagttga acatacagaa 180

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ataaatgtct aaaacagcac ctcgattctc gtctataaca ggactaagtt cactgtgatc 240 ttaaataagc ttggctaaaa tgggacatga gtggaggtag tcacacttca gcgaagaaag 300 agaatctcct gtataatctc accaggagat tcaacgaatt ccaccacact ggactagtgg 360 atcccccggg ctgcaggaat tcgatatcaa gcttatcgat accgtcgacc tcgagggggg 420 gcccggtacc caattcgccc tatagtgagt cgtattacgc gcgctcactg gccgtcgttt 480 tacaacgtcg tgactgggaa aaccctggcg ttacccaact taatcgcctt gcagcacatc 540 cccctttcgc cagctggcgt aatagcgaan agcccgcacc gatcgccctt ncaacagttg 600 cgcagcctga atggcgaatg ggacgcgccc tgtagcggcg cattaaagcg cggcngggtg 660 tggnggntcc cccacgtgac cgntacactt ggcagcgcct tacgccggtc ntt.cgctt.tc 72 0 ttcccttcct ttctcgcacc gttcgccggg tttccccgnn agctnttaat cgggggnctc 780 cctttanggg tncnaattaa nggnttacng gaccttngan cccaaaaact ttgattaggg 840 ggaaggtccc cgaagggg 858 &lt;210&gt; 92 &lt;211&gt; 585 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) - - . (585) &lt;223&gt; n = A,T,C or G &lt;400&gt; 92 gttgaatctc ctggtgagat tatacaggag attctctttc ttcgctgaag tgtgactacc 60 tccactcatg tcccatttta gccaagctta tttaagatca cagtgaactt agtcctgtta 120 tagacgagaa tcgaggtgct gttttagaca tttatttctg tatgttcaac taggatcaga 180 atatcacaga aaagcatggc ttgaataagg aaatgacaat tttttccact tatctgatca 240 gaacaaatgt ttattaagca tcagaaactc tgccaacact gaggatgtaa agatcaataa 300 aaaaaataat aatcatnann naaanannan nngaagggcg gccgccaccg cggtggagct 360 ccagcttttg ttccctttag tgagggttaa ttgcgcgctt ggcgttaatc atggtcatag 420 ctgtttcctg tgtgaaattg ttatccggct cacaattccn cncaacatac gagccgggaa 480 gcntnangtg taaaagcctg ggggtgccta attgagtgag ctnactcaca ttaattgngt 540 tgcgctccac ttgcccgctt ttccantccg ggaaacctgt tcgnc 585 &lt;210&gt; 93 &lt;211&gt; 567 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) . . . (567) &lt;223&gt; n = A,T,C or G &lt;400&gt; 93 cggcagtgtt gctgtctgcg tgtccacctt ggaatctggc tgaactggct gggaggacca 60 agactgcggc tggggtgggc anggaaggga accgggggct gctgtgaagg atcttggaac 120 ttccctgtac ccaccttccc cttgcttcat gtttgtanag gaaccttgtg ccggccaagc 180 ccagtttcct tgtgtgatac actaatgtat ttgctttttt tgggaaatan anaaaaatca 240 attaaattgc tantgtttct ttgaannnnn nnnnnnnnnn nnnnnnnggg ggggncgccc 300 ccncggngga aacnccccct tttgttccct ttaattgaaa ggttaattng cncncntggc 360 gttaanccnt gggccaaanc tngttncccg tgntgaaatt gttnatcccc tcccaaattc 420 ccccccnncc ttccaaaccc ggaaancctn annntgttna ancccggggg gttgcctaan 480 ngnaattnaa ccnaaccccc ntttaaatng nntttgcncn ccacnngccc cnctttccca 540

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 nttcggggaa aaccctntcc gtgccca

567

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 94 620 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) /</td><td> . . (620)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 94</td><td></td>

actagtcaaa catgtttatc gccaatattt gtgaaactta gttcttgtta ataaggttaa tttcaagcct gagaatttct atgtctctaa tttcccttaa agggttaagg aatgctaaaa ttttattatg ccttatatct acactttata tttccaaata aagttgttaa tcgaactatt cattaatatc gaaagtacta gtgtgaaant gtgttgggga taatttggga ttttgtgaag atccataaca aggtaaaaat gaatggactt tgaccaaaca taaggaaagc ctgaatcatt tttcatggtc atttaaaatg gaaaatattt ttgtgtcttt tttatactac gaggtttcca ggtctgttaa ttctaaaaga aaaatcattt catttcacta caaacctggt aaattttcct tttaagtagt tcactaatta atttgtaana anatttaata gggctaagga aatgcaaaaa cctaaatgca aggctcatgt tgccatantt ctttttaaaa gttatagttt cctatactat naatatgcac atctgatcaa gaagaggaag aaaagtttat tatcatttgt tnactccgat gggtaaaggc attctttana

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620 &lt;210&gt; 95 &lt;211&gt; 470 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) ... (470) &lt;223&gt; n = A,T,C or G &lt;400&gt;

ctcgaccttc nactttntgc gaaacatgag agcaggtgaa agccatgcca ccaaggtccc gagccaggat ccaagggcct tctgcacagc ttaattcang ttcttaccag acaacccatc ctcaaaggtt tgagccaggg gtaccaaggt gngccaggca ggatgaaccc agcttacang cagaagcaga cagcctccac ccacaacctg ctgtaccaan ccctgancca gcatcaangt tgagcagctg attcttcaaa cctttacccc ctnaggaaat naaacacaaa gtccctgagc ggttgtccaa ccctgaccaa aagaccagaa gagtgngtcc accacctcag atttgttccc nattccagag caggttgtac ggtccctgag ggcttatcaa aagccactat agcatccttt cttcaacagc acaaccaagg ccaggctgta caangtccct ccaggctaca

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420

470

<td> &lt;210&gt;</td><td> 96</td><td></td>

<td> &lt;211&gt;</td><td> 660</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (l)</td><td> . . (660)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A, T,C or G</td>

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 &lt;400&gt; 96 tttttttttt tttttttttt ggaattaaaa gcaatttaat gagggcagag caggaaacat gcatttcttt tcattcgaat cttcagatga accctgagca gccgaagacc agaaaagcca tgaagacttt ctgcttaatt caggggctta caggattctt cagagtgtgt gtgaacaaaa gctttatagt acgtattttt aggatacaaa taagagagag actatggctt ggggtgagaa tgtactgatt acaaggtcta cagacaatta agacacagaa acagatggga agagggtgnc cagcatctgg nggttggctt ctcaagggct tgtctgtgca ccaaattact tctgcttggn cttctgctga gctgggcctg gagtgaccgt tgaaggacat ggctctggta cctttgtgta gcctgncaca ggaactttgg tgtatccttg ctcaggaact ttgatggcac ctggctcagg aaacttgatg aagccttggt caagggacct tgatgcttgc tggctcaggg accttggngn ancctgggct canggacctt tgncncaacc ttggcttcaa gggacccttg gnacatcctg gcnnagggac ccttgggncc aaccctgggc ttnagggacc ctttggntnc nanccttggc

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240

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360

420

480

540

600

660

<td> &lt;210&gt;</td><td> 97</td><td></td>

<td> &lt;211&gt;</td><td> 441</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td colspan="3"> &lt;220&gt;</td>

<td> &lt;221&gt;</td><td> misc_</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (l)</td><td> . - (441)</td>

<td> &lt;223&gt;</td><td colspan="2"> n - A, T, C or</td>

<td> &lt;400&gt;</td><td> 97</td><td></td>

gggaccatac anagtattcc tctcttcaca ccaggaccag ccactgttgc agcatgagtt cccagcagca gaagcagccc tgcatcccac cccctcagct tcagcagcag caggtgaaac agccttgcca gcctccacct caggaaccat gcatccccaa aaccaaggag ccctgccacc ccaaggtgcc tgagccctgc caccccaaag tgcctgagcc ctgccagccc aaggttccag agccatgcca ccccaaggtg cctgagccct gcccttcaat agtcactcca gcaccagccc agcagaanac caagcagaag taatgtggtc cacagccatg cccttgagga gccggccacc agatgctgaa tcccctatcc cattctgtgt atgagtccca tttgccttgc aattagcatt ctgtctcccc caaaaaaaaa a

120

180

240

300

360

420

441

<td> &lt;210&gt;</td><td> 98</td><td></td>

<td> &lt;211&gt;</td><td> 600</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . ¢600)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 98</td><td></td>

gtattcctct cttcacacca ggaccagcca ctgttgcagc atgagttccc agcagcagaa gcagccctgc atcccacccc ctcagcttca gcagcagcag gtgaaacagc cttgccagcc tccacctcag gaaccatgca tccccaaaac caaggagccc tgccacccca aggtgcctga gccctgccac cccaaagtgc ctgagccctg ccagcccaag gttccagagc catgccaccc caaggtgcct gagccctgcc cttcaatagt cactccagca ccagcccagc agaanaccaa gcagaagtaa tgtggtccac agccatgccc ttgaggagcc ggccaccana tgctgaatcc cctatcccat tctgtgtatg agtcccattt gccttgcaat tagcattctg tctcccccaa aaaagaatgt gctatgaagc tttctttcct acacactctg agtctctgaa tgaagctgaa ggtcttaant acaganctag ttttcagctg ctcagaattc tctgaagaaa agatttaaga tgaaaggcaa atgattcagc tccttattac cccattaaat tcnctttcaa ttccaaaaaa

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CA 02369578 2001-10-02

WO 00/61612 PCT/USOO/08896

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 99 667 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> .. (667)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 99</td><td></td>

actagtgact gagttcctgg caaagaaatt tgacctggac cagttgataa ctcatgtttt 60 accatttaaa aaaatcagtg aaggatttga gctgctcaat tcaggacaaa gcattcgaac 120 ggtcctgacg ttttgagatc caaagtggca ggaggtctgt gttgtcatgg tgaactggag 180 tttctcttgt gagagttccc tcatctgaaa tcatgtatct gtctcacaaa tacaagcata 240 agtagaagat ttgttgaaga catagaaccc ttataaagaa ttattaacct ttataaacat 300 ttaaagtctt gtgagcacct gggaattagt ataataacaa tgttnatatt tttgatttac 360 attttgtaag gctataattg tatcttttaa gaaaacatac cttggatttc tatgttgaaa 420 tggagatttt taagagtttt aaccagctgc tgcagatata ttactcaaaa cagatatagc 480 gtataaagat atagtaaatg catctcctag agtaatattc acttaacaca ttggaaacta 540 ttatttttta gatttgaata tnaatgttat tttttaaaca cttgttatga gttacttggg 600 attacatttt gaaatcagtt cattccatga tgcanattac tgggattaga ttaagaaaga 660 cggaaaa 667

<td> &lt;210&gt;</td><td> 100</td><td></td>

<td> &lt;211&gt;</td><td> 583</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (l)</td><td> .. (583)</td>

<td> &lt;223&gt;</td><td> n = ,</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 100</td><td></td>

gttttgtttg taagatgatc acagtcatgt tacactgatc taaaggacat atatataacc 60 ctttaaaaaa aaaatcactg cctcattctt atttcaagat gaatttctat acagactaga 120 tgtttttctg aagatcaatt agacattttg aaaatgattt aaagtgtttt ccttaatgtt 180 ctctgaaaac aagtttcttt tgtagtttta accaaaaaag tgcccttttt gtcactggat 240 tctcctagca ttcatgattt ttttttcata caatgaaatt aaaattgcta aaatcatgga 300 ctggctttct ggttggattt caggtaagat gtgtttaagg ccagagcttt tctcagtatt 360 tgattttttt ccccaatatt tgatttttta aaaatataca catnggtgct gcatttatat 420 ctgctggttt aaaattctgt catatttcac ttctagcctt ttagttatgg caaatcatat 480 tttactttta cttaaagcat ttggtnattt ggantatctg gttctannct aaaaaaanta 540 attctatnaa ttgaantttt ggtactcnnc catatttgga tcc 583

<td> &lt;210&gt;</td><td> 101</td><td></td>

<td> &lt;211&gt;</td><td> 592</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) ·</td><td> .· (592)</td>

<td> &lt;223&gt;</td><td> n = ,</td><td> A,T,C or G</td>

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 &lt;400 gtggagacgt gggaaacgca ggagtgactg gagctcgatt gattctgtaa aaatgcattg tgaatatttt attttgtcca tttttgtaca gtgncncnan

101 acaaagagca aggagcagga ggagtgggct cacggaggca tagtgaacat gaataaaact tttttttgcc ttgatgtatt taatgcnttt ttggnggttg gccgctcaag aaagaaaaaa agaaggggac ttgaaatttt atggaaagta gtctccccca aaggctaatc tattttgtaa anatatacct aatttaatga acacctggga cggcgaactc cacctgtctg cagcaganac ttagaaatat ttgctctatg caattattat atgtatcttg atcaagtttg atgcctaatt agaaaaagaa gctctgcctg acacctccac cttccaagga ttattgtctg aaactgcaca tatcacattt gtgctgctga ttgataaatg ttattatccc aggcaagccc gttagactct aacgtcgctg catattgcag taaatactgt ttggtcattg accataattt atttctatat acncaatgaa aa

120

180

240

300

360

420

480

540

592

<td colspan="2"> &lt;210&gt; 102 &lt;211&gt; 587 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;220&gt;</td><td></td>

<td> &lt;221&gt;</td><td> misc_feature</td>

<td> &lt;222&gt;</td><td> (1)...(587)</td>

<td> &lt;223&gt;</td><td> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 102</td>

cgtcctaagc gcttatgttt gggctgtgca ccaggcggat cctcccacct ggcagccttc gacactgccc ttcctttgaa ctttgccagg gcctccactt acttagacta tctggaagaa ntccggtcag gccccttccc tcaaanaatg caaaactcag attccctctc aaagggcaaa gcttcnntnt accnggggcn catcagggaa agtggagacc ggcgggaagg ttagcactac aanaacccca gggctgaagc agggcagctc actgaaaagg taccaaaacn atgccccaaa gaacacagac nagtccttgg gaaatgcacc ctggcctcct tgggcccagc anactattag angtcacccn gcttttccta ncttctcnng attaanaatt cacatccctg ctttagggct gctgcatgtg gcatcccctc cccttgccct ggcaggggct ggnctcttga naaaaagaaa gatttttaat tcccatc tcctcatgcg ccccggctgg aacttacagc gcctcatgtt ggggaaccaa gactttgggt acccagcctg aaccagggaa tccccattng

120

180

240

300

360

420

480

540

587

<td> &lt;210&gt;</td><td> 103</td><td></td>

<td> &lt;211&gt;</td><td> 496</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (496)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 103</td><td></td>

anaggactgg ctgcanccct gcggtgggtc actggcagga cccttaacat ttgcctacag tgggctgacc gangcttgcc ggaaaagaaa ccctacntgc tggncactgc tccaccacaa tggaccttan gatataatcc aatttcattc gcaaaaggtg tcctccttct caaaac tctctctcgt anatggaaac ccactttgac ccnacatatc acccatgcaa agtctacact ccttacacac gattnncccc cctacctatc ctctcagtgt tctgtggtcc cctctgttcc ntngctactg ttggcattct tggcccccac catgttggat aatgcccaac cttgacatca ctgnanggtg ctctgctnag gcccagctac ctctggcgat cctcaaccgt atcagggtgc atggcagaac ccctacccnt gnttctcctg anaaagaatt catttaccat agagtgtggc tgacncatca tcnagggatt

120

180

240

300

360

420

480

496

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896

<td> &lt;210&gt;</td><td> 104</td><td></td>

<td> &lt;211&gt;</td><td> 575</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) </td><td> . - ¢575)</td>

<td> &lt;223&gt;</td><td colspan="2"> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 104</td><td></td>

gcacctgctc tcaatccnnc tctcaccatg atcctccgcc tgcanaaact cctctgccaa 60 ctatggangt ggtttcnggg gtggctcttg ccaactggga agaagccgtg gtgtctctac 120 ctgttcaact cngtttgtgt ctgggggatc aactnggggc tatggaagcg gctnaactgt 180 tgttttggtg gaagggctgg taattggctt tgggaagtng cttatngaag ttggcctngg 240 gaagttgcta ttgaaagtng ccntggaagt ngntttggtg gggggttttg ctggtggcct 300 ttgttnaatt tgggtgcttt gtnaatggcg gccccctcnc ctgggcaatg aaaaaaatca 360 ccnatgcngn aaacctcnac nnaacagcct gggcttccct cacctcgaaa aaagttgctc 420 cccccccaaa aaaggncaan cccctcaann tggaangttg aaaaaatcct cgaatgggga 480 ncccnaaaac aaaaancccc ccntttcccn gnaanggggg aaataccncc cccccactta 540 cnaaaaccct tntaaaaaac cccccgggaa aaaaa 575

<td> &lt;210&gt;</td><td> 105</td>

<td> &lt;211&gt;</td><td> 619</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;220&gt;</td><td></td>

<td> &lt;221&gt;</td><td> mise feature</td>

<td> &lt;222&gt;</td><td> (1) . . . (619)</td>

<td> &lt;223&gt;</td><td> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 105</td>

cactagtagg gcctaaccca tgcataaagc tcaatacaca tgcacacttg gacaacctac gacatttagt tttccaaatt aatgaagtcc cttaaaacat aagtggtggg atagaaacac ggttaactgc caatgtagtc ctcatgaact ctagactcan tttgcttggc tagtgctttt tttgtacagt ctggtttttc ctactatatn gaaaaaaaa tgtgtcccga aagaagaggc cagtttctaa cctgatggaa aaaaaatact tgagtgaagg tatataccag cgctgcacat atggcaactt gttnanatga gagtaaggag

HBBatacttt gatcatgttc caataacagg actctcataa aatgatattc gcatgatgct atttgaaatc gatcagtaaa aattcctttt agaagctact cagctttcca caagctaact cccaagcctg atgggtggga atatattcat gagtgacact atatattaag ggattcncct ccccncctcc attgattaga tgtaactgta gaatcccact tggtatgatg gtattttggt ttattccatg cttgtgtata acttccaaaa ctgtttggta cgaaaaaana

120

180

240

300

360

420

480

540

600

619

<td> &lt;210&gt;</td><td> 106</td>

<td> &lt;211&gt;</td><td> 506</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;220&gt;</td><td></td>

<td> &lt;221&gt;</td><td> mise feature</td>

<td> &lt;222&gt;</td><td> ¢1)...(506)</td>

<td> &lt;223&gt;</td><td> n = A, T, C or</td>

CA 02369578 2001-10-02

WO 00/61612 PCT/USOO/08896 &lt;400&gt; 106 cattggtnct ttcatttgct ntggaagtgt nnatctctaa cagtggacaa agttcccngt 60 gccttaaact ctgtnacact tttgggaant gaaaanttng tantatgata ggttattctg 120 angtanagat gttctggata ccattanatn tgcccccngt gtcagaggct catattgtgt 180 tatgtaaatg gtatntcatt cgctactatn antcaattng aaatanggtc tttgggttat 240 gaatantnng cagcncanct nanangctgt ctgtngtatt cattgtggtc atagcacctc 300 acancattgt aacctcnatc nagtgagaca nactagnaan ttcctagtga tggctcanga 360 ttccaaatgg nctcatntcn aatgtttaaa agttanttaa gtgtaagaaa tacagactgg 420 atgttccacc aactagtacc tgtaatgacn ggcctgtccc aacacatctc ccttttccat 480 gactgtggta ncccgcatcg gaaaaa 506 &lt;210&gt; 107 &lt;211&gt; 452 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) .. . (452) &lt;223&gt; n = A,T,C or G &lt;400&gt; 107 gttgagtctg tactaaacag taagatatct caatgaacca taaattcaac tttgtaaaaa 60 tcttttgaag catagataat attgtttggt aaatgtttct tttgtttggt aaatgtttct 120 tttaaagacc ctcctattct ataaaactct gcatgtagag gcttgtttac ctttctctct 180 ctaaggttta caataggagt ggtgatttga aaaatataaa attatgagat tggttttcct 240 gtggcataaa ttgcatcact gtatcatttt cttttttaac cggtaagant ttcagtttgt 300 tggaaagtaa ctgtganaac ccagtttccc gtccatctcc cttagggact acccatagaa 360 catgaaaagg tccccacnga agcaagaaga taagtctttc atggctgctg gttgcttaaa 420 ccactttaaa accaaaaaat tccccttgga aa 452

<td> &lt;210&gt;</td><td> 108</td>

<td> &lt;211&gt;</td><td> 502</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;220&gt;</td><td></td>

<td> &lt;221&gt;</td><td> mise feature</td>

<td> &lt;222&gt;</td><td> (1)...(502)</td>

<td> &lt;223&gt;</td><td> n = A,T,C or</td>

<td> &lt;400&gt;</td><td> 108</td>

atcttcttcc cttaattagt tnttatttat ntattaaatt ttattgcatg tcctggcaaa 60 caaaaagaga ttgtagattg gcttctggct ccccaaaagc ccataacaga aagtaccaca 120 agaccncaac tgaagcttaa aaaatctatc acatgtataa tacctttnga agaacattaa 180 tanagcatat aaaactttta acatntgctt aatgttgtnc aattataaaa ntaatngaaa 240 aaaatgtccc tttaacatnc aatatcccac atagtgttat ttnaggggat taccnngnaa 300 naaaaaaagg gtagaaggga tttaatgaaa actctgcttn ccatttctgt ttanaaacgt 360 ctccagaaca aaaacttntc aantctttca gctaaccgca tttgagctna ggccactcaa 420 aaactccatt agncccactt tctaanggtc tctanagctt actaancctt ttgacccctt 480 accctggnta ctcctgccct ca 502 &lt;210&gt; 109 &lt;211&gt; 1308

CA 02369578 2001-10-02

WOOO/61612 PCT/US00/08896 &lt;212 &gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 109 acccgaggtc tcgctaaaat catcatggat tcacttggcg ccgtcagcac tcgacttggg 60 tttgatcttt tcaaagagct gaagaaaaca aatgatggca acatcttctt ttcccctgtg 120 ggcatcttga ctgcaattgg catggtcctc ctggggaccc gaggagccac cgcttcccag 180 ttggaggagg tgtttcactc tgaaaaagag acgaagagct caagaataaa ggctgaagaa 240 aaagaggtga ttgagaacac agaagcagta catcaacaat tccaaaagtt tttgactgaa 300 ataagcaaac tcactaatga ttatgaactg aacataacca acaggctgtt tggagaaaaa 360 acatacctct tccttcaaaa atacttagat tatgttgaaa aatattatca tgcatctctg 420 gaacctgttg attttgtaaa tgcagccgat gaaagtcgaa agaagattaa ttcctgggtt 4B0 gaaagcaaaa caaatgaaaa aatcaaggac ttgttcccag atggctctat tagtagctct 540 accaagctgg tgctggtgaa catggtttat tttaaagggc aatgggacag ggagtttaag 600 aaagaaaata ctaaggaaga gaaattttgg atgaataaga gcacaagtaa atctgtacag 660 atgatgacac agagccattc ctttagcttc actttcctgg aggacttgca ggccaaaatt 720 ctagggattc catataaaaa caacgaccta agcatgtttg tgcttctgcc caacgacatc 780 gatggcctgg agaagataat agataaaata agtcctgaga aattggtaga gtggactagt 840 ccagggcata tggaagaaag aaaggtgaat ctgcacttgc cccggtttga ggtggaggac 900 agttacgatc tagaggcggt cctggctgcc atggggatgg gcgatgcctt cagtgagcac 960 aaagccgact actcgggaat gtcgtcaggc tccgggttgt acgcccagaa gttcctgcac 1020 agttcctttg tggcagtaac tgaggaaggc accgaggctg cagctgccac tggcataggc 1080 tttactgtca catccgcccc aggtcatgaa aatgttcact gcaatcatcc cttcctgttc 1140 ttcatcaggc acaatgaatc caacagcatc ctcttcttcg gcagattttc ttctccttaa 1200 gatgatcgtt gccatggcat tgctgctttt agcaaaaaac aactaccagt gttactcata 1260 tgattatgaa aatcgtccat tcttttaaat ggtggctcac ttgcattt 1308 &lt;210&gt; 110 &lt;211&gt; 391 &lt;212&gt; PRT &lt;213&gt; Homo sapien

<td></td><td colspan="2"> &lt;400&gt;</td><td colspan="13"> 110</td>

<td> Met</td><td> Asp</td><td> Ser</td><td> Leu</td><td> Gly</td><td> Ala</td><td> Val</td><td> Ser</td><td> Thr</td><td> Arg</td><td> Leu</td><td> Gly</td><td> Phe</td><td> Asp</td><td> Leu</td><td> Phe</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Lys</td><td> Glu</td><td> Leu</td><td> Lys</td><td> Lys</td><td> Thr</td><td> Asn</td><td> Asp</td><td> Gly</td><td> Asn</td><td> He</td><td> Phe</td><td> Phe</td><td> Ser</td><td> Pro</td><td> Val</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> lie</td><td> Leu</td><td> Thr</td><td> Ala</td><td> lie</td><td> Gly</td><td> Met</td><td> Val</td><td> Leu</td><td> Leu</td><td> Gly</td><td> Thr</td><td> Arg</td><td> Gly</td><td> Ala</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Thr</td><td> Ala</td><td> Ser</td><td> Gin</td><td> Leu</td><td> Glu</td><td> Glu</td><td> Val</td><td> Phe</td><td> His</td><td> Ser</td><td> Glu</td><td> Lys</td><td> Glu</td><td> Thr</td><td> Lys</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Ser</td><td> Arg</td><td> lie</td><td> Lys</td><td> Ala</td><td> Glu</td><td> Glu</td><td> Lys</td><td> Glu</td><td> Val</td><td> He</td><td> Glu</td><td> Asn</td><td> Thr</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Ala</td><td> Val</td><td> His</td><td> Gin</td><td> Gin</td><td> Phe</td><td> Gin</td><td> Lys</td><td> Phe</td><td> Leu</td><td> Thr</td><td> Glu</td><td> He</td><td> Ser</td><td> Lys</td><td> Leu</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Thr</td><td> Asn</td><td> Asp</td><td> Tyr</td><td> Glu</td><td> Leu</td><td> Asn</td><td> He</td><td> Thr</td><td> Asn</td><td> Arg</td><td> Leu</td><td> Phe</td><td> Gly</td><td> Glu</td><td> Lys</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Thr</td><td> Tyr</td><td> Leu</td><td> Phe</td><td> Leu</td><td> Gin</td><td> Lys</td><td> Tyr</td><td> Leu</td><td> Asp</td><td> Tyr</td><td> Val</td><td> Glu</td><td> Lys</td><td> Tyr</td><td> Tyr</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td> His</td><td> Ala</td><td> Ser</td><td> Leu</td><td> Glu</td><td> Pro</td><td> Val</td><td> Asp</td><td> Phe</td><td> Val</td><td> Asn</td><td> Ala</td><td> Ala</td><td> Asp</td><td> Glu</td><td> Ser</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td> Arg</td><td> Lys</td><td> Lys</td><td> lie</td><td> Asn</td><td> Ser</td><td> Trp</td><td> Val</td><td> Glu</td><td> Ser</td><td> Lys</td><td> Thr</td><td> Asn</td><td> Glu</td><td> Lys</td><td> He</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td> Lys</td><td> Asp</td><td> Leu</td><td> Phe</td><td> Pro</td><td> Asp</td><td> Gly</td><td> Ser</td><td> He</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Val</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896

<td> Leu</td><td> Val</td><td colspan="2"> Asn Met 180</td><td> Val</td><td> Tyr</td><td> Phe</td><td> Lys</td><td> Gly 185</td><td> Gin</td><td> Trp</td><td> Asp</td><td> Arg</td><td> Glu 190</td><td> Phe</td><td> Lys</td>

<td> Lys</td><td> Glu</td><td> Asn</td><td> Thr</td><td> Lys</td><td> Glu</td><td> Glu</td><td> Lys</td><td> Phe</td><td> Trp</td><td> Met</td><td> Asn</td><td> Lys</td><td> Ser</td><td> Thr</td><td> Ser</td>

<td></td><td></td><td> 195</td><td></td><td></td><td></td><td></td><td> 200</td><td></td><td></td><td></td><td></td><td> 205</td><td></td><td></td><td></td>

<td> Lys</td><td> Ser</td><td> Val</td><td> Gin</td><td> Met</td><td> Met</td><td> Thr</td><td> Gin</td><td> Ser</td><td> His</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Phe</td><td> Thr</td><td> Phe</td>

<td></td><td> 210</td><td></td><td></td><td></td><td></td><td> 215</td><td></td><td></td><td></td><td></td><td> 220</td><td></td><td></td><td></td><td></td>

<td> Leu</td><td> Glu</td><td> Asp</td><td> Leu</td><td> Gin</td><td> Ala</td><td> Lys</td><td> He</td><td> Leu</td><td> Gly</td><td> He</td><td> Pro</td><td> Tyr</td><td> Lys</td><td> Asn</td><td> Asn</td>

<td> 225</td><td></td><td></td><td></td><td></td><td> 230</td><td></td><td></td><td></td><td></td><td> 235</td><td></td><td></td><td></td><td></td><td> 240</td>

<td> Asp</td><td> Leu</td><td> Ser</td><td> Met</td><td> Phe</td><td> Val</td><td> Leu</td><td> Leu</td><td> Pro</td><td> Asn</td><td> Asp</td><td> He</td><td> Asp</td><td> Gly</td><td> Leu</td><td> Glu</td>

<td></td><td></td><td></td><td></td><td> 245</td><td></td><td></td><td></td><td></td><td> 250</td><td></td><td></td><td></td><td></td><td> 255</td><td></td>

<td> Lys</td><td> lie</td><td> lie</td><td> Asp</td><td> Lys</td><td> lie</td><td> Ser</td><td> Pro</td><td> Glu</td><td> Lys</td><td> Leu</td><td> Val</td><td> Glu</td><td> Trp</td><td> Thr</td><td> Ser</td>

<td></td><td></td><td></td><td> 260</td><td></td><td></td><td></td><td></td><td> 265</td><td></td><td></td><td></td><td></td><td> 270</td><td></td><td></td>

<td> Pro</td><td> Gly</td><td> His</td><td> Met</td><td> Glu</td><td> Glu</td><td> Arg</td><td> Lys</td><td> Val</td><td> Asn</td><td> Leu</td><td> His</td><td> Leu</td><td> Pro</td><td> Arg</td><td> Phe</td>

<td></td><td></td><td> 275</td><td></td><td></td><td></td><td></td><td> 280</td><td></td><td></td><td></td><td></td><td> 285</td><td></td><td></td><td></td>

<td> Glu</td><td> Val</td><td> Glu</td><td> Asp</td><td> Ser</td><td> Tyr</td><td> Asp</td><td> Leu</td><td> Glu</td><td> Ala</td><td> Val</td><td> Leu</td><td> Ala</td><td> Ala</td><td> Met</td><td> Gly</td>

<td></td><td> 290</td><td></td><td></td><td></td><td></td><td> 295</td><td></td><td></td><td></td><td></td><td> 300</td><td></td><td></td><td></td><td></td>

<td> Met</td><td> Gly</td><td> Asp</td><td> Ala</td><td> Phe</td><td> Ser</td><td> Glu</td><td> His</td><td> Lys</td><td> Ala</td><td> Asp</td><td> Tyr</td><td> Ser</td><td> Gly</td><td> Met</td><td> Ser</td>

<td> 305</td><td></td><td></td><td></td><td></td><td> 310</td><td></td><td></td><td></td><td></td><td> 315</td><td></td><td></td><td></td><td></td><td> 320</td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Leu</td><td> Tyr</td><td> Ala</td><td> Gin</td><td> Lys</td><td> Phe</td><td> Leu</td><td> His</td><td> Ser</td><td> Ser</td><td> Phe</td><td> Val</td>

<td></td><td></td><td></td><td></td><td> 325</td><td></td><td></td><td></td><td></td><td> 330</td><td></td><td></td><td></td><td></td><td> 335</td><td></td>

<td> Ala</td><td> Val</td><td> Thr</td><td> Glu</td><td> Glu</td><td> Gly</td><td> Thr</td><td> Glu</td><td> Ala</td><td> Ala</td><td> Ala</td><td> Ala</td><td> Thr</td><td> Gly</td><td> He</td><td> Gly</td>

<td></td><td></td><td></td><td> 340</td><td></td><td></td><td></td><td></td><td> 345</td><td></td><td></td><td></td><td></td><td> 350</td><td></td><td></td>

<td> Phe</td><td> Thr</td><td> Val</td><td> Thr</td><td> Ser</td><td> Ala</td><td> Pro</td><td> Gly</td><td> His</td><td> Glu</td><td> Asn</td><td> Val</td><td> His</td><td> Cys</td><td> Asn</td><td> His</td>

<td></td><td></td><td> 355</td><td></td><td></td><td></td><td></td><td> 360</td><td></td><td></td><td></td><td></td><td> 365</td><td></td><td></td><td></td>

<td> Pro</td><td> Phe</td><td> Leu</td><td> Phe</td><td> Phe</td><td> He</td><td> Arg</td><td> His</td><td> Asn</td><td> Glu</td><td> Ser</td><td> Asn</td><td> Ser</td><td> He</td><td> Leu</td><td> Phe</td>

<td></td><td> 370</td><td></td><td></td><td></td><td></td><td> 375</td><td></td><td></td><td></td><td></td><td> 380</td><td></td><td></td><td></td><td></td>

<td> Phe</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Pro</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 385</td><td></td><td></td><td></td><td></td><td> 390</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

ggagaactat ccagccacca ggcgccgtca ggcaacatct acccgaggag agctcaagaa attgagaaca ctcactaatg ttccttcaaa gattttgtaa acaaatgaaa gtgctggtga actaaggaag cagagccatt ccatataaaa gagaagataa atggaagaaa ctagaggcgg tactcgggaa gtggcagtaa &lt;210&gt; 111 &lt;211&gt; 1419 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 111 aaattaagga ccgtctctcc gcactcgact tcttttcccc ccaccgcttc taaaggctga cagaagcagt attatgaact aatacttaga atgcagccga aaatcaagga acatggttta agaaattttg cctttagctt acaacgacct tagataaaat gaaaggtgaa tcctggctgc tgtcgtcagg ctgaggaagg tcccagctac aaaaacccga tgggtttgat tgtgggcatc ccagttggag agaaaaagag acatcaacaa gaacataacc ttatgttgaa tgaaagtcga cttgttccca ttttaaaggg gatgaataag cactttcctg aagcatgttt aagtcctgag tctgcacttg catggggatg ctccgggttg caccgaggct ttaattgact ggtctcgcta cttttcaaag ttgactgcaa gaggtgtttc gtggtaagaa ttccaaaagt aacaggctgt aaatattatc aagaagatta gatggctcta caatgggaca agcacaagta gaggacttgc gtgcttctgc aaattggtag ccccggtttg ggcgatgcct tacgcccaga gcagctgcca tatgcttcct aaatcatcat agctgaagaa ttggcatggt actctgaaaa taaaggctga ttttgactga ttggagaaaa atgcatctct attcctgggt ttagtagctc gggagtttaa aatctgtaca aggccaaaat ccaacgacat agtggactag aggtggagga tcagtgagca agttcctgca ctggcatagg agttcgttgc ggattcactt aacaaatgat cctcctgggg agagacgaag aggaaaagag aataagcaaa aacatacctc ggaacctgtt tgaaagcaaa taccaagctg gaaagaaaat gatgatgaca tctagggatt cgatggcctg tccagggcat cagttacgat caaagccgac cagttccttt ctttactgtc

120

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1020

1080

1140

1200

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 acatccgccc caggtcatga aaatgttcac tgcaatcatc ccttcctgtt cttcatcagg 1260 cacaatgaat ccaacagcat cctcttcttc ggcagatttt cttctcctta agatgatcgt 1320 tgccatggca ttgctgcttt tagcaaaaaa caactaccag tgttactcat atgattatga 1380 aaatcgtcca ttcttttaaa tggtggctca cttgcattt 1419 &lt;210&gt; 112 &lt;211&gt; 400 &lt;212&gt; PRT &lt;213&gt; Homo sapien &lt;400&gt; 112

<td> Met</td><td> Asp</td><td> Ser</td><td> Leu</td><td> Gly</td><td> Ala</td><td> Val</td><td> Ser</td><td> Thr</td><td> Arg</td><td> Leu</td><td> Gly</td><td> Phe</td><td> Asp</td><td> Leu</td><td> Phe</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Lys</td><td> Glu</td><td> Leu</td><td> Lys</td><td> Lys</td><td> Thr</td><td> Asn</td><td> Asp</td><td> Gly</td><td> Asn</td><td> He</td><td> Phe</td><td> Phe</td><td> Ser</td><td> Pro</td><td> Val</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> lie</td><td> Leu</td><td> Thr</td><td> Ala</td><td> He</td><td> Gly</td><td> Met</td><td> Val</td><td> Leu</td><td> Leu</td><td> Gly</td><td> Thr</td><td> Arg</td><td> Gly</td><td> Ala</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Thr</td><td> Ala</td><td> Ser</td><td> Gin</td><td> Leu</td><td> Glu</td><td> Glu</td><td> Val</td><td> Phe</td><td> His</td><td> Ser</td><td> Glu</td><td> Lys</td><td> Glu</td><td> Thr</td><td> Lys</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Ser</td><td> Arg</td><td> He</td><td> Lys</td><td> Ala</td><td> Glu</td><td> Glu</td><td> Lys</td><td> Glu</td><td> Val</td><td> Val</td><td> Arg</td><td> He</td><td> Lys</td><td> Ala</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Glu</td><td> Gly</td><td> Lys</td><td> Glu</td><td> He</td><td> Glu</td><td> Asn</td><td> Thr</td><td> Glu</td><td> Ala</td><td> Val</td><td> His</td><td> Gin</td><td> Gin</td><td> Phe</td><td> Gin</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Lys</td><td> Phe</td><td> Leu</td><td> Thr</td><td> Glu</td><td> He</td><td> Ser</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Asn</td><td> Asp</td><td> Tyr</td><td> Glu</td><td> Leu</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> lie</td><td> Thr</td><td> Asn</td><td> Arg</td><td> Leu</td><td> Phe</td><td> Gly</td><td> Glu</td><td> Lys</td><td> Thr</td><td> Tyr</td><td> Leu</td><td> Phe</td><td> Leu</td><td> Gin</td><td> Lys</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Asp</td><td> Tyr</td><td> Val</td><td> Glu</td><td> Lys</td><td> Tyr</td><td> Tyr</td><td> His</td><td> Ala</td><td> Ser</td><td> Leu</td><td> Glu</td><td> Pro</td><td> Val</td>

<td></td><td> 13C</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 340</td><td></td><td></td><td></td><td></td>

<td> Asp</td><td> Phe</td><td> Val</td><td> Asn</td><td> Ala</td><td> Ala</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Arg</td><td> Lys</td><td> Lys</td><td> lie</td><td> Asn</td><td> Ser</td><td> Trp</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td> Val</td><td> Glu</td><td> Ser</td><td> Lys</td><td> Thr</td><td> Asn</td><td> Glu</td><td> Lys</td><td> He</td><td> Lys</td><td> Asp</td><td> Leu</td><td> Phe</td><td> Pro</td><td> Asp</td><td> Gly</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td> Ser</td><td> He</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Val</td><td> Leu</td><td> Val</td><td> Asn</td><td> Met</td><td> Val</td><td> Tyr</td><td> Phe</td>

<td></td><td></td><td></td><td> 180</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td> 190</td><td></td><td></td>

<td> Lys</td><td> Gly</td><td> Gin</td><td> Trp</td><td> Asp</td><td> Arg</td><td> Glu</td><td> Phe</td><td> Lys</td><td> Lys</td><td> Glu</td><td> Asn</td><td> Thr</td><td> Lys</td><td> Glu</td><td> Glu</td>

<td></td><td></td><td> 195</td><td></td><td></td><td></td><td></td><td> 200</td><td></td><td></td><td></td><td></td><td> 205</td><td></td><td></td><td></td>

<td> Lys</td><td> Phe</td><td> Trp</td><td> Met</td><td> Asn</td><td> Lys</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Val</td><td> Gin</td><td> Met</td><td> Met</td><td> Thr</td>

<td></td><td> 210</td><td></td><td></td><td></td><td></td><td> 215</td><td></td><td></td><td></td><td></td><td> 220</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Ser</td><td> His</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Leu</td><td> Glu</td><td> Asp</td><td> Leu</td><td> Gin</td><td> Ala</td><td> Lys</td>

<td> 225</td><td></td><td></td><td></td><td></td><td> 230</td><td></td><td></td><td></td><td></td><td> 235</td><td></td><td></td><td></td><td></td><td> 240</td>

<td> lie</td><td> Leu</td><td> Gly</td><td> He</td><td> Pro</td><td> Tyr</td><td> Lys</td><td> Asn</td><td> Asn</td><td> Asp</td><td> Leu</td><td> Ser</td><td> Met</td><td> Phe</td><td> Val</td><td> Leu</td>

<td></td><td></td><td></td><td></td><td> 245</td><td></td><td></td><td></td><td></td><td> 250</td><td></td><td></td><td></td><td></td><td> 255</td><td></td>

<td> Leu</td><td> Pro</td><td> Asn</td><td> Asp</td><td> He</td><td> Asp</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Lys</td><td> He</td><td> He</td><td> Asp</td><td> Lys</td><td> He</td><td> Ser</td>

<td></td><td></td><td></td><td> 260</td><td></td><td></td><td></td><td></td><td> 265</td><td></td><td></td><td></td><td></td><td> 270</td><td></td><td></td>

<td> Pro</td><td> Glu</td><td> Lys</td><td> Leu</td><td> Val</td><td> Glu</td><td> Trp</td><td> Thr</td><td> Ser</td><td> Pro</td><td> Gly</td><td> His</td><td> Met</td><td> Glu</td><td> Glu</td><td> Arg</td>

<td></td><td></td><td> 275</td><td></td><td></td><td></td><td></td><td> 280</td><td></td><td></td><td></td><td></td><td> 285</td><td></td><td></td><td></td>

<td> Lys</td><td> Val</td><td> Asn</td><td> Leu</td><td> His</td><td> Leu</td><td> Pro</td><td> Arg</td><td> Phe</td><td> Glu</td><td> Val</td><td> Glu</td><td> Asp</td><td> Ser</td><td> Tyr</td><td> Asp</td>

<td></td><td> 290</td><td></td><td></td><td></td><td></td><td> 295</td><td></td><td></td><td></td><td></td><td> 300</td><td></td><td></td><td></td><td></td>

<td> Leu</td><td> Glu</td><td> Ala</td><td> Val</td><td> Leu</td><td> Ala</td><td> Ala</td><td> Met</td><td> Gly</td><td> Met</td><td> Gly</td><td> Asp</td><td> Ala</td><td> Phe</td><td> Ser</td><td> Glu</td>

<td> 305</td><td></td><td></td><td></td><td></td><td> 310</td><td></td><td></td><td></td><td></td><td> 315</td><td></td><td></td><td></td><td></td><td> 320</td>

<td> His</td><td> Lys</td><td> Ala</td><td> Asp</td><td> Tyr</td><td> Ser</td><td> Gly</td><td> Met</td><td> Ser</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Leu</td><td> Tyr</td><td> Ala</td>

<td></td><td></td><td></td><td></td><td> 325</td><td></td><td></td><td></td><td></td><td> 330</td><td></td><td></td><td></td><td></td><td> 335</td><td></td>

<td> Gin</td><td> Lys</td><td> Phe</td><td> Leu</td><td> His</td><td> Ser</td><td> Ser</td><td> Phe</td><td> Val</td><td> Ala</td><td> Val</td><td> Thr</td><td> Glu</td><td> Glu</td><td> Gly</td><td> Thr</td>

<td></td><td></td><td></td><td> 340</td><td></td><td></td><td></td><td></td><td> 345</td><td></td><td></td><td></td><td></td><td> 350</td><td></td><td></td>

CA 02369578 2001-10-02

WO 00/61612 PCT/US0O/O8896

<td> Glu</td><td> Ala</td><td> Ala 355</td><td colspan="2"> Ala Ala</td><td> Thr</td><td> Gly</td><td> He 360</td><td> Gly</td><td> Phe</td><td colspan="2"> Thr Val</td><td> Thr 365</td><td colspan="2"> Ser Ala</td><td> Pro</td>

<td> Gly</td><td> His</td><td> Glu</td><td> Asn</td><td> Val</td><td> His</td><td> Cys</td><td> Asn</td><td> His</td><td> Pro</td><td> Phe</td><td> Leu</td><td> Phe</td><td> Phe</td><td> He</td><td> Arg</td>

<td></td><td> 370</td><td></td><td></td><td></td><td></td><td> 375</td><td></td><td></td><td></td><td></td><td> 380</td><td></td><td></td><td></td><td></td>

<td> His</td><td> Asn</td><td> Glu</td><td> Ser</td><td> Asn</td><td> Ser</td><td> He</td><td> Leu</td><td> Phe</td><td> Phe</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Pro</td>

<td> 385</td><td></td><td></td><td></td><td></td><td> 390</td><td></td><td></td><td></td><td></td><td> 395</td><td></td><td></td><td></td><td></td><td> 400</td>

&lt;210&gt; 113 &lt;211&gt; 957 &lt;212 &gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 113 ctcgaccttc tctgcacagc ggatgaaccc tgagcagctg aagaccagaa aagccactat 60 gactttctgc ttaattcagg agcttacagg attcttcaaa gagtgtgtcc agcatccttt 120 gaaacatgag ttcttaccag cagaagcaga cctttacccc accacctcag cttcaacagc 180 agcaggtgaa acaacccagc cagcctccac ctcaggaaat atttgttccc acaaccaagg 240 agccatgcca ctcaaaggtt ccacaacctg gaaacacaaa gattccagag ccaggctgta 300 ccaaggtccc tgagccaggc tgtaccaagg tccctgagcc aggttgtacc aaggtccctg 360 agccaggatg taccaaggtc cctgagccag gttgtaccaa ggtccctgag ccaggctaca 420 ccaaggtccc tgagccaggc agcatcaagg tccctgacca aggcttcatc aagtttcctg 480 agccaggtgc catcaaagtt cctgagcaag gatacaccaa agttcctgtg ccaggctaca 540 caaaggtacc agagccatgt ccttcaacgg tcactccagg cccagctcag cagaagacca 600 agcagaagta atttggtgca cagacaagcc cttgagaagc caaccaccag atgctggaca 660 ccctcttccc atctgt.ttct gtgtcttaat tgtctgtaga ccttgtaatc agtacattct 720 caccccaagc catagtctct ctcttatttg tatcctaaaa atacggtact ataaagcttt 780 tgttcacaca cactctgaag aatcctgtaa gcccctgaat taagcagaaa gtct.tcatgg 840 cttttctggt cttcggctgc tcagggttca tctgaagatt cgaatgaaaa gaaatgcatg 900 tttcctgctc tgccctcatt aaattgcttt taattccaaa aaaaaaaaaa aaaaaaa 957 &lt;210&gt; 114 &lt;211&gt; 161 &lt;212&gt; PRT &lt;213&gt; Homo sapien &lt;400&gt; 114

<td> Met</td><td> Ser</td><td> Ser</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Gin</td><td> Thr</td><td> Phe</td><td> Thr</td><td> Pro</td><td> Pro</td><td> Pro</td><td> Gin</td><td> Leu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Gin</td><td> Gin</td><td> Gin</td><td> Gin</td><td> Val</td><td> Lys</td><td> Gin</td><td> Pro</td><td> Ser</td><td> Gin</td><td> Pro</td><td> Pro</td><td> Pro</td><td> Gin</td><td> Glu</td><td> He</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Phe</td><td> Val</td><td> Pro</td><td> Thr</td><td> Thr</td><td> Lys</td><td> Glu</td><td> Pro</td><td> Cys</td><td> His</td><td> Ser</td><td> Lys</td><td> Val</td><td> Pro</td><td> Gin</td><td> Pro</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Asn</td><td> Thr</td><td> Lys</td><td> He</td><td> Pro</td><td> Glu</td><td> Pro</td><td> Gly</td><td> Cys</td><td> Thr</td><td> Lys</td><td> Val</td><td> Pro</td><td> Glu</td><td> Pro</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Cys</td><td> Thr</td><td> Lys</td><td> Val</td><td> Pro</td><td> Glu</td><td> Pro</td><td> Gly</td><td> Cys</td><td> Thr</td><td> Lys</td><td> Val</td><td> Pro</td><td> Glu</td><td> Pro</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gly</td><td> Cys</td><td> Thr</td><td> Lys</td><td> Val</td><td> Pro</td><td> Glu</td><td> Pro</td><td> Gly</td><td> Cys</td><td> Thr</td><td> Lys</td><td> Val</td><td> Pro</td><td> Glu</td><td> Pro</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Gly</td><td> Tyr</td><td> Thr</td><td> Lys</td><td> Val</td><td> Pro</td><td> Glu</td><td> Pro</td><td> Gly</td><td> Ser</td><td> He</td><td> Lys</td><td> Val</td><td> Pro</td><td> Asp</td><td> Gin</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Gly</td><td> Phe</td><td> lie</td><td> Lys</td><td> Phe</td><td> Pro</td><td> Glu</td><td> Pro</td><td> Gly</td><td> Ala</td><td> He</td><td> Lys</td><td> Val</td><td> Pro</td><td> Glu</td><td> Gin</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td> Gly</td><td> Tyr</td><td> Thr</td><td> Lys</td><td> Val</td><td> Pro</td><td> Val</td><td> Pro</td><td> Gly</td><td> Tyr</td><td> Thr</td><td> Lys</td><td> Val</td><td> Pro</td><td> Glu</td><td> Pro</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td> Cys</td><td> Pro</td><td> Ser</td><td> Thr</td><td> Val</td><td> Thr</td><td> Pro</td><td> Gly</td><td> Pro</td><td> Ala</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Thr</td><td> Lys</td><td> Gin</td>

CA 02369578 2001-10-02

WO 00/61612

PCT7US00/08896

145

Lys

150

155

160

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 115 506 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) . .</td><td> .(506)</td>

<td> &lt;223&gt;</td><td> n = A</td><td> .,T,C or</td>

<td> &lt;400&gt;</td><td> 115</td><td></td>

cattggtnct ttcatttgct ntggaagtgt nnatctctaa cagtggacaa agttcccngt 60 gccttaaact ctgtnacact tttgggaant gaaaanttng tantatgata ggttattctg 120 angtanagat gttctggata ccattanatn tgcccccngt gtcagaggct catattgtgt 180 tatgtaaatg gtatntcatt cgctactatn antcaattng aaatanggtc tttgggttat 240 gaatantnng cagcncanct nanangctgt ctgtngtatt cattgtggtc atagcacctc 300 acancattgt aacctcnatc nagtgagaca nactagnaan ttcctagtga tggctcanga 360 ttccaaatgg nctcatntcn aatgtttaaa agttanttaa gtgtaagaaa tacagactgg 420 atgttccacc aactagtacc tgtaatgacn ggcctgtccc aacacatctc ccttttccat 480 gactgtggta ncccgcatcg gaaaaa 506

<td> &lt;210&gt;</td><td> 116</td>

<td> &lt;211&gt;</td><td> 3079</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 116</td>

ggatccccgg ggtcaaaggg aaagaggtca cttgcaggca tgtgcacaaa cagattgcct gcagatcact gtttcctaaa cagaaaaaat aagtggttta gatctgccca aggatgaaac ttcccagagg ggggaatcgt caggtgctca gcatgtaccg ccaggacact gccatgccaa gccccagcct ctatggtgaa atcagtgctc gaaggcaagg tgcaccccac accactgtgc ccagcccact taatcatcac taaaaagggg catcaccgtt gttctctcca gcacctccca ccaccatgtc tcgccagtca ccgcctctgc ggggtggcgg gctatggcag gtggtggcag gtggtgccgg gcggagctgg gtatccaaga ccagcatcca catcaccccg tggtggtggc ccggagcctc cttcaggaac tagtggattt ctttggaggt ggtcactgtc gagggtgagg ccccccacag gctgagttag tagggggcgc gtgggctctg tctattttcc gaaaaccctg ttgccccccg tactgggatg tgccccctca gacatacttg ttatttctaa aggtgtgacc agctcgacag cctgggtaac acccactagt agtgtgtctt tctgtctccc ttcggcaggg tacaacctgg cggtttggtg ggtttcggcg ggcttcggtg aaccagagtc accgaggagc agtcctgccc gaggagctat tgagggcttc ggatagctgt ctctagcaca cagcaacctg ctgatggaca gttgtcaata gttcctggca ctagcagcgt ctgagcagag ggtgagctca ctctctcgcc agagccacct gcctggttct ccggagcggg gcaccagctt tcagccttgc ggggctccaa ctggtgctgg gtggagctgg gccctggctt tcctgactcc gcgagcagat aggccaaaga ggaaggataa ccacattctc gccttcccta taaccaagaa ctgcctggaa gcttccccaa ctcctggtcc tcctttttgg caccaacttg cctgccagga cagctgcccc cagcccagtt tctgcgtcct cttgctccac gggcagtcgt cacctccgtg gggtgcttgt gaggatatcc aggcggctat tggtggcttt tcctgtctgc cctcaacctg caagaccctc gcaaggaaaa acctggcctt tggcctaaac acaaaaaaat tataaggcta aagtgtaaga gctccaaggg tgtaagagtc gctgctcaca ttgccaagag agaaagcgtt ccaggcatgc ctggaaggga gctgagctct caggaacaag agcttcagca tcccggtccg ggagtgggtg atcagcacta ggctttggag gggctcggtg cctcctggag caaatcgacc aacaataagt

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CA 02369578 2001-10-02

WO 00/61612 PCT/USOO/08896 ttgcctcctt catcgacaag gtgcggttcc tggagcagca gaacaaggtt ctggaaacaa 1500 agtggaccct gctgcaggag cagggcacca agactgtgag gcagaacctg gagccgttgt 1560 tcgagcagta catcaacaac ctcaggaggc agctggacag catcgtgggg gaacggggcc 1620 gcctggactc agagctgaga aacatgcagg acctggtgga agacttcaag aacaagtatg 1680 aggatgaaat caacaagcgt accactgctg agaatgagtt tgtgatgctg aagaaggatg 1740 tagatgctgc ctacatgaac aaggtggagc tggaggccaa ggttgatgca ctgatggatg 1800 agattaactt catgaagatg ttctttgatg cggagctgtc ccagatgcag acgcatgtct 1860 ctgacacctc agtggtcctc tccatggaca acaaccgcaa cctggacctg gatagcatca 1920 tcgctgaggt caaggcccag tatgaggaga ttgccaaccg cagccggaca gaagccgagt 1980 cctggtatca gaccaagtat gaggagctgc agcagacagc tggccggcat ggcgatgacc 2040 tccgcaacac caagcatgag atctctgaga tgaaccggat gatccagagg ctgagagccg 2100 agattgacaa tgtcaagaaa cagtgcgcca atctgcagaa cgccattgcg gatgccgagc 2160 agcgtgggga gctggccctc aaggatgcca ggaacaagct ggccgagctg gaggaggccc 2220 tgcagaaggc caagcaggac atggcccggc tgctgcgtga gtaccaggag ctcatgaaca 2280 ccaagctggc cctggacgtg gagatcgcca cttaccgcaa gctgctggag ggcgaggaat 2340 gcagactcag tggagaagga gttggaccag tcaacatctc tgttgtcaca agcagtgttt 2400 cctctggata tggcagtggc agtggctatg gcggtggcct cggtggaggt cttggcggcg 2460 gcctcggtgg aggtcttgcc ggaggtagca gtggaagcta ctactccagc agcagtgggg 2520 gtgtcggcct aggtggtggg ctcagtgtgg ggggctctgg cttcagtgca agcagtagcc 2580 gagggctggg ggtgggcttt ggcagtggcg ggggtagcag ctccagcgtc aaatttgtct 2640 ccaccacctc ctcctcccgg aagagcttca agagctaaga acctgctgca agtcactgcc 2700 ttccaagtgc agcaacccag cccatggaga ttgcctcttc taggcagttg ctcaagccat 2760 gttttatcct tttctggaga gtagtctaga ccaagccaat tgcagaacca cattctttgg 2820 ttcccaggag agccccattc ccagcccctg gtctcccgtg ccgcagttct atattctgct 2880 tcaaatcagc cttcaggttt cccacagcat ggcccctgct gacacgagaa cccaaagttt 2940 tcccaaatct aaatcatcaa aacagaatcc ccaccccaat cccaaatttt gttttggttc 3000 taactacctc cagaatgtgt tcaataaaat gttttataat ataagctggt gtgcagaatt 3060 gttttttttt tctacccaa 3079 &lt;210&gt; 117 &lt;211&gt; 6921 &lt;212 &gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 117 gaattctgac tgtccactca aaacttctat tccgatcaaa gctatctgtg actacagaca 60 aattgagata accatttaca aagacgatga atgtgttttg gcgaataact ctcatcgtgc 120 taaatggaag gtcattagtc ctactgggaa tgaggctatg gtcccatctg tgtgcttcac 180 cgttcctcca ccaaacaaag aagcggtgga ccttgccaac agaattgagc aacagtatca 240 gaatgtcctg actctttggc atgagtctca cataaacatg aagagtgtag tatcctggca 300 ttatctcatc aatgaaattg atagaattcg agctagcaat gtggcttcaa taaagacaat 360 gctacctggt gaacatcagc aagttctaag taatctacaa tctcgttttg aagattttct 420 ggaagatagc caggaatccc aagtcttttc aggctcagat ataacacaac tggaaaagga 480 ggttaatgta tgtaagcagt attatcaaga acttcttaaa tctgcagaaa gagaggagca 540 agaggaatca gtttataatc tctacatctc tgaagttcga aacattagac ttcggttaga 600 gaactgtgaa gatcggctga ttagacagat tcgaactccc ctggaaagag atgatttgca 660 tgaaagtgtg ttcagaatca cagaacagga gaaactaaag aaagagctgg aacgacttaa 720 agatgatttg ggaacaatca caaataagtg tgaggagttt ttcagtcaag cagcagcctc 780 ttcatcagtc cctaccctac gatcagagct taatgtggtc cttcagaaca tgaaccaagt 840 ctattctatg tcttccactt acatagataa gttgaaaact gttaacttgg tgttaaaaaa 900 cactcaagct gcagaagccc tcgtaaaact ctatgaaact aaactgtgtg aagaagaagc 960 agttatagct gacaagaata atattgagaa tctaataagt actttaaagc aatggagatc 1020 tgaagtagat gaaaagagac aggtattcca tgccttagag gatgagttgc agaaagctaa 1080 agccatcagt gatgaaatgt ttaaaacgta taaagaacgg gaccttgatt ttgactggca 1140 caaagaaaaa gcagatcaat tagttgaaag gtggcaaaat gttcatgtgc agattgacaa 1200

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 caggttacgg gacttagagg gcattggcaa atcactgaag tactacagag acacttacca 1260 tcctttagat gattggatcc agcaggttga aactactcag agaaagattc aggaaaatca 1320 gcctgaaaat agtaaaaccc tagccacaca gttgaatcaa cagaagatgc tggtgtccga 1380 aatagaaatg aaacagagca aaatggacga gtgtcaaaaa tatgcagaac agtactcagc 1440 tacagtgaag gactatgaat tacaaacaat gacctaccgg gccatggtag attcacaaca 1500 aaaatctcca gtgaaacgcc gaagaatgca gagttcagca gatctcatta ttcaagagtt 1560 catggaccta aggactcgat atactgccct ggtcactctc atgacacaat atattaaatt 1620 tgctggtgat tcattgaaga ggctggaaga ggaggagatt aaaaggtgta aggagacttc 1680 tgaacatggg gcatattcag atctgcttca gcgtcagaag gcaacagtgc ttgagaatag 1740 caaacttaca ggaaagataa gtgagttgga aagaatggta gctgaactaa agaaacaaaa 1800 gtcccgagta gaggaagaac ttccgaaggt cagggaggct gcagaaaatg aattgagaaa 1860 gcagcagaga aatgtagaag atatctctct gcagaagata agggctgaaa gtgaagccaa 1920 gcagtaccgc agggaacttg aaaccattgt gagagagaag gaagccgctg aaagagaact I960 ggagcgggtg aggcagctca ccatagaggc cgaggctaaa agagctgccg tggaagagaa 2040 cctcctgaat tttcgcaatc agttggagga aaacaccttt accagacgaa cactggaaga 2100 tcatcttaaa agaaaagatt taagtctcaa tgatttggag caacaaaaaa ataaattaat 2160 ggaagaatta agaagaaaga gagacaatga ggaagaactc ttgaagctga taaagcagat 2220 ggaaaaagac cttgcatttc agaaacaggt agcagagaaa cagttgaaag aaaagcagaa 2280 aattgaattg gaagcaagaa gaaaaataac tgaaattcag tatacatgta gagaaaatgc 2340 attgccagtg tgtccgatca cacaggctac atcatgcagg gcagtaacgg gtctccagca 2400 agaacatgac aagcagaaag cagaagaact caaacagcag gtagatgaac taacagctgc 2460 caatagaaag gctgaacaag acatgagaga gctgacatat gaacttaatg ccctccagct 2520 tgaaaaaacg tcatctgagg aaaaggctcg tttgctaaaa gataaactag atgaaacaaa 2580 taatacactc agatgcctta agttggagct ggaaaggaag gatcaggcgg agaaagggta 2640 ttctcaacaa ctcagagagc ttggtaggca attgaatcaa accacaggta aagctgaaga 2700 agccatgcaa gaagctagtg atctcaagaa aataaagcgc aattatcagt tagaattaga 2760 atctcttaat catgaaaaag ggaaactaca aagagaagta gacagaatca caagggcaca 2820 tgctgtagct gagaagaata ttcagcattt aaattcacaa attcattctt ttcgagatga 2880 gaaagaatta gaaagactac aaatctgcca gagaaaatca gatcatctaa aagaacaatt 2940 tgagaaaagc catgagcagt tgcttcaaaa tatcaaagct gaaaaagaaa ataatgataa 3000 aatccaaagg ctcaatgaag aattggagaa aagtaatgag tgtgcagaga tgctaaaaca 3060 aaaagtagag gagcttacta ggcagaataa tgaaaccaaa ttaatgatgc agagaattca 3120 ggcagaatca gagaatatag ttttagagaa acaaactatc cagcaaagat gtgaagcact 3180 gaaaattcag gcagatggtt ttaaagatca gctacgcagc acaaatgaac acttgcataa 3240 acagacaaaa acagagcagg attttcaaag aaaaattaaa tgcctagaag aagacctggc 3300 gaaaagtcaa aatttggtaa gtgaatttaa gcaaaagtgt gaccaacaga acattatcat 3360 ccagaatacc aagaaagaag ttagaaatct gaatgcggaa ctgaatgctt ccaaagaaga 3420 gaagcgacgc ggggagcaga aagttcagct acaacaagct caggtgcaag agttaaataa 3480 caggttgaaa aaagtacaag acgaattaca cttaaagacc atagaggagc agatgaccca 3540 cagaaagatg gttctgtttc aggaagaatc tggtaaattc aaacaatcag cagaggagtt 3600 tcggaagaag atggaaaaat taatggagtc caaagtcatc actgaaaatg atatttcagg 3660 cattaggctt gactttgtgt ctcttcaaca agaaaactct agagcccaag aaaatgctaa 3720 gctttgtgaa acaaacatta aagaacttga aagacagctt caacagtatc gtgaacaaat 3780 gcagcaaggg cagcacatgg aagcaaatca ttaccaaaaa tgtcagaaac ttgaggatga 3840 gctgatagcc cagaagcgtg aggttgaaaa cctgaagcaa aaaatggacc aacagatcaa 3900 agagcatgaa catcaattag ttttgctcca gtgtgaaatt caaaaaaaga gcacagccaa 3960 agactgtacc ttcaaaccag attttgagat gacagtgaag gagtgccagc actctggaga 4020 gctgtcctct agaaacactg gacaccttca cccaacaccc agatcccctc tgttgagatg 4080 gactcaagaa ccacagccat tggaagagaa gtggcagcat cgggttgttg aacagatacc 4140 caaagaagtc caattccagc caccaggggc tccactcgag aaagagaaaa gccagcagtg 4200 ttactctgag tacttttctc agacaagcac cgagttacag ataacttttg atgagacaaa 4260 ccccattaca agactgtctg aaattgagaa gataagagac caagccctga acaattctag 4320 accacctgtt aggtatcaag ataacgcatg tgaaatggaa ctggtgaagg ttttgacacc 4380 cttagagata gctaagaaca agcagtatga tatgcataca gaagtcacaa cattaaaaca 4440 agaaaagaac ccagttccca gtgctgaaga atggatgctt gaagggtgca gagcatctgg 4500

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 tggactcaag aaaggggatt tccttaagaa gggcttagaa ccagagacct tccagaactt 4560 tgatggtgat catgcatgtt cagtcaggga tgatgaattt aaattccaag ggcttaggca 4620 cactgtgact gccaggcagt tggtggaagc taagcttctg gacatgagaa caattgagca 4680 gctgcgactc ggtcttaaga ctgttgaaga agttcagaaa actcttaaca agtttctgac 4740 gaaagccacc tcaattgcag ggctttacct agaatctaca aaagaaaaga tttcatttgc 4800 ctcagcggcc gagagaatca taatagacaa aatggtggct ttggcatttt tagaagctca 4860 ggctgcaaca ggttttataa ttgatcccat ttcaggtcag acatattctg ttgaagatgc 4920 agttcttaaa ggagttgttg accccgaatt cagaattagg cttcttgagg cagagaaggc 4980 agctgtggga tattcttatt cttctaagac attgtcagtg tttcaagcta tggaaaatag 5040 aatgcttgac agacaaaaag gtaaacatat cttggaagcc cagattgcca gtgggggtgt 5100 cattgaccct gtgagaggca ttcgtgttcc tccagaaatt gctctgcagc aggggttgtt 5160 gaataatgcc atcttacagt ttttacatga gccatccagc aacacaagag ttttccctaa 5220 tcccaataac aagcaagctc tgtattactc agaattactg cgaatgtgtg tatttgatgt 5280 agagtcccaa tgctttctgt ttccatttgg ggagaggaac atttccaatc tcaatgtcaa 5340 gaaaacacat agaatttctg tagtagatac taaaacagga tcagaattga ccgtgtatga 5400 ggctttccag agaaacctga ttgagaaaag tatatatctt gaactttcag ggcagcaata 5460 tcagtggaag gaagctatgt tttttgaatc ctatgggcat tcttctcata tgctgactga 5520 tactaaaaca ggattacact tcaatattaa tgaggctata gagcagggaa caattgacaa 5580 agccttggtc aaaaagtatc aggaaggcct catcacactt acagaacttg ctgattcttt 5640 gctgagccgg ttagtcccca agaaagattt gcacagtcct gttgcagggt attggctgac 5700 tgctagtggg gaaaggatct ctgtactaaa agcctcccgt agaaatttgg ttgatcggat 5760 tactgccctc cgatgccttg aagcccaagt cagtacaggg ggcataattg atcctcttac 5820 tggcaaaaag taccgggtgg ccgaagcttt gcatagaggc ctggttgatg aggggtttgc 5880 ccagcagctg cgacagtgtg aattagtaat cacagggatt ggccatccca tcactaacaa 5940 aatgatgtca gtggtggaag ctgtgaatgc aaatattata aataaggaaa tgggaatccg 6000 atgtttggaa tttcagtact tgacaggagg gttgatagag ccacaggttc actctcggtt 6060 atcaatagaa gaggctctcc aagtaggtat tatagatgtc ctcattgcca caaaactcaa 6120 agatcaaaag tcatatgtca gaaatataat atgccctcag acaaaaagaa agttgacata 6180 taaagaagcc ttagaaaaag ctgattttga tttccacaca ggacttaaac tgttagaagt 6240 atctgagccc ctgatgacag gaatttctag cctctactat tcttcctaat gggacatgtt 6300 taaataactg tgcaaggggt gatgcaggct ggttcatgcc actttttcag agtatgatga 6360 tatcggctac atatgcagtc tgtgaattat gtaacatact ctatttcttg agggctgcaa 6420 attgctaagt gctcaaaata gagtaagttt taaattgaaa attacataag atttaatgcc 6480 cttcaaatgg tttcatttag ccttgagaat ggttttttga aacttggcca cactaaaatg 6540 tttttttttt tttacgtaga atgtgggata aacttgatga actccaagtt cacagtgtca 6600 tttcttcaga actccccttc attgaatagt gatcatttat taaatgataa attgcactcg 6660 ctgaaagagc acgtcatgaa gcaccatgga atcaaagaga aagatataaa ttcgttccca 6720 cagccttcaa gctgcagtgt tttagattgc ttcaaaaaat gaaaaagttt tgcctttttc 6780 gatatagtga ccttctttgc atattaaaat gtttaccaca atgtcccatt tctagttaag 6840 tcttcgcact tgaaagctaa cattatgaat attatgtgtt ggaggagggg aaggattttc 6900 ttcattctgt gtattttccg g 6921

<td> &lt;210&gt;</td><td> 118</td>

<td> &lt;211&gt;</td><td> 946</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 118</td>

cttctgactg ggctcaggct gacaggtaga gctcaccatg gcttcttgtg tccttgtccc 60 ctccccatca cagctgtggt gcagtccacc gtctccagtg gctatggcgg tgccagtggt 120 gtcggcagtg gcttaggcct gggtggagga agcagctact cctatggcag tggtcttggc 180 gttggaggtg gcttcagttc cagcagtggc agagccattg ggggtggcct cagctctgtt 240 ggaggcggca gttccaccat caagtacacc accacctcct cctccagcag gaagagctat 300 aagcactaaa gtgcgtctgc tagctctcgg tcccacagtc ctcaggcccc tctctggctg 360 cagagccctc tcctcaggtt gcctgtcctc tcctggcctc cagtctcccc tgctgtccca 420

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ggtagagctg gagcacccat tggagcttca gagcattata ttcagaacaa tgaaccccca gcctgtatct atttataata acttttttat gggatgaatg tgctcaccat ctgttactaa agaaaatgac cttccactta cccaggcagt ctgtgatgat catatattct ctgataagtg cttagtgccc cagatcaacc attattaatt ctctgctcct ctttccactg atccatgaaa ttctgtgctc tttactttgc aatagttgtt tcacttcttc tctgatttta tcttgcctcc tttcattgca gctctcaaac gcacaagtga ttcactgttt cttgctttgg tttaaaagat tctctctctc catcatgatg agtgttctat gaaaattgcc tctctaactt ctagtcctat gcaattgcta ggccaaagtt aatcta tataccatct taatcaccac ctctgaggct aggggcttat ataagtgttg gatgtacaaa aataaagcag ttgggcttaa

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946 &lt;210&gt; 119 &lt;211&gt; 8948 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 119 tcaacagccc acaccaacac tttcctcccg ggcccaggta gtccgcctat gcgctgagcc ggatcaacac tgaccagcgg accagaactc ccatccagga agcctgaatt gttttgccca agatgggcca gagcccttta gaggctacac aatgtttggg acctggcctc actatcgctg agttggagga gacagctgca aggaggagga aggccttctc aacaagaaag atatggacac ttcatctgaa catacctgaa ccctgcagca aatacaagcg ctcgtaaccc aacaagatca gcagcaagtg tgatcatccc acgaagccat ggcactactg caatgcggca tcatcagaaa ctcagttcac cccagcacca accataataa ctgctccttg ccagctccga ctcctgcccc gcgagcagcg ccttggcccc gctctcccga tctgggccgc cggcgggggc ggacggctac gctgctgcag gaagtatgga ggccaatgac gccctgtgat taaagccatc ttgtcagagt gtggatgagg agtggagcag gcagctggac ggagtatgaa gaacatcatt gctgctgtac catacgcatg tgaccaactt tctgcagacg agaaaatgct ggggctccag cctgctggaa tcaggtgcag agactacaga gaaaatcgtg gtacgtgacg tcctccgaac cttggctctg catgattgac ggaagattac tagccaaggc cgatgcccag gacagtgacc agtaattgaa ggcccctcca cgcagctcct cggcccgtcg acctcgcgag ctccgctttc ttgcccgccg atgatccgcg accagcagga tgtcaaaccg aactgctccg gatggaatac caaatggaaa gcttaccaga agtgtccctc ggctctggct cagcaaaggg cacattaaca aaaatcaaag aacctgctga caggccacgt gactggagcg agtcaactgg gtcctcaatc cagtggagtt gcctactttc gactccatca cagatcaagg aacttggtaa agcaataaac cataaggggg ggcccgggag ccactggccg tggaaccagc atagagaaga atgaagacga tcagagatgt aagcattacc acaactgaaa accaacagag tgccatgccg ctgcgccctt ccgtctccgc ccttccgcac tccgcgccgg acatgagctg ccgagtctgg tgtactattc gcacgatgtc actgcttgat aactgactcg tcctcgacag aaaggcttct gagtccgcag gggatgagtt cggagatgga gccaccgggg ccgacctgcg aagcgtcctt ccagggagat acaagaacac aagttaaaga agcatccagc ggattcttca agttttttga ggaagaagta agctggagaa acaagtctaa ccattattct atgagtgtat gcgttgacat tggacctctc tctacatcaa tcagggccat tagccgacct ttggagatga agaccctggt tcactcatca aaaatgacaa taatctctcc gccgccctcc gctcgcagcg tcccgcccgg cccgcctcgc caacggaggc cccggacctg tcggcgcggc caggcaccag gcgagcagag gagtcgagaa cttgatcaga tcagctccaa ggccagctcc caccaaacat catggtggcc catccacaac cgagaaatct tgagaggatg catgtggatc caacatcgct aaaagagctc ttcagacaaa gatcaccaag agaggcgcag cccctgcgac agaacgagag gaagattgta cagagctctc cctgaaggac gcttgttccc ttgcaagatt catgaagagc gacaatcgcc tgagttacat tgacaagcgg cattcagctc tggaacctgc gcaagaaaca cacccgacca gagccacagc gcctcgggag ttccccggcc ttatgcctcg tcccacccgc cgctacgagg gtgatcaccg aaccagaaca ctcatcgtgc ttggatgagt gagatgcggc gagcaaatgc aagggtggtg gtcaccagtg tggggtgtgg tccatcggcg gcgatctacc gatcacctgc aatgactgcg cagaaacagg aataagctga attgaggcct tgcattgatg tctactgaag aagaacatgc aaaatccttg cagctgaagc tgtgactaca aacaacgagc tctgtggggc gagcagtact ctggtgtcct aagctgaaaa taccaagagt aaaatacagt cctggctatc caagatgtca tggatgctga

120

180

240

300

360

420

480

540

600

660

720

780

840

900

960

1020

1080

1140

1200

1260

1320

1380

1440

1500

1560

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1800

1860

1920

1980

2040

2100

2160

2220

2280

2340

CA 02369578 2001-10-02

WO 00/61612

PCT/USOO/08896 tggagctgca gaagattcgc aggcagatag agcactgcga gggcaggatg actctcaaaa 2400 acctccctct agcagaccag gggtcttctc accacatcac agtgaaaatt aacgagctta 2460 agagtgtgca gaatgattca caagcaattg ctgaggttct caaccagctt aaagatatgc 2520 ttgccaactt cagaggttct gaaaagtact gctatttaca gaatgaagta tttggactat 2580 ttcagaaact ggaaaatatc aatggtgtta cagatggcta cttaaatagc ttatgcacag 2640 taagggcact gctccaggct attctccaaa cagaagacat gttaaaggtt tatgaagcca 2700 ggctcactga ggaggaaact gtctgcctgg acctggataa agtggaagct taccgctgtg 2760 gactgaagaa aataaaaaat gacttgaact tgaagaagtc gttgttggcc actatgaaga 2820 cagaactaca gaaagcccag cagatccact ctcagacttc acagcagtat ccactttatg 2880 atctggactt gggcaagttc ggtgaaaaag tcacacagct gacagaccgc tggcaaagga 2940 tagataaaca gatcgacttt agattatggg acctggagaa acaaatcaag caattgagga 3000 attatcgtga taactatcag gctttctgca agtggctcta tgatcgtaaa cgccgccagg 3060 attccttaga atccatgaaa tttggagatt ccaacacagt catgcggttt ttgaatgagc 3120 agaagaactt gcacagtgaa atatctggca aacgagacaa atcagaggaa gtacaaaaaa 3180 ttgctgaact ttgcgccaat tcaattaagg attatgagct ccagctggcc tcatacacct 3240 caggactgga aactctgctg aacataccta tcaagaggac catgattcag tccccttctg 3300 gggtgattct gcaagaggct gcagatgttc atgctcggta cattgaacta cttacaagat 3360 ctggagacta ttacaggttc ttaagtgaga tgctgaagag tttggaagat ctgaagctga 3420 aaaataccaa gatcgaagtt ttggaagagg agctcagact ggcccgagat gccaactcgg 3480 aaaactgtaa taagaacaaa ttcctggatc agaacctgca gaaataccag gcagagtgtt 3540 cccagttcaa agcgaagctt gcgagcctgg aggagctgaa gagacaggct gagctggatg 3600 ggaagtcggc taagcaaaat ctagacaagt gctacggcca aataaaagaa ctcaatgaga 3660 agatcacccg actgacttat gagattgaag atgaaaagag aagaagaaaa tctgtggaag 3720 acagatttga ccaacagaag aatgactatg accaactgca gaaagcaagg caatgtgaaa 3780 aggagaacct tggttggcag aaattagagt ctgagaaagc catcaaggag aaggagtacg 3840 agattgaaag gttgagggtt ctactgcagg aagaaggcac ccggaagaga gaatatgaaa 3900 atgagctggc aaaggtaaga aaccactata atgaggagat gagtaattta aggaacaagt 3960 atgaaacaga gattaacatt acgaagacca ccatcaagga gatatccatg caaaaagagg 4020 atgattccaa aaatcttaga aaccagcttg atagactttc aagggaaaat cgagatctga 4080 aggatgaaat tgtcaggctc aatgacagca tcttgcaggc cactgagcag cgaaggcgag 4140 ctgaagaaaa cgcccttcag caaaaggcct gtggctctga gataatgcag aagaagcagc 4200 atctggagat agaactgaag caggtcatgc agcagcgctc tgaggacaat gcccggcaca 4260 agcagtccct ggaggaggct gccaagacca ttcaggacaa aaataaggag atcgagagac 4320 tcaaagctga gtttcaggag gaggccaagc gccgctggga atatgaaaat gaactgagta 4380 aggtaagaaa caattatgat gaggagatca ttagcttaaa aaatcagttt gagaccgaga 4440 tcaacatcac caagaccacc atccaccagc tcaccatgca gaaggaagag gataccagtg 4500 gctaccgggc tcagatagac aatctcaccc gagaaaacag gagcttatct gaagaaataa 4560 agaggctgaa gaacactcta acccagacca cagagaatct caggagggtg gaagaagaca 4620 tccaacagca aaaggccact ggctctgagg tgtctcagag gaaacagcag ctggaggttg 4680 agctgagaca agtcactcag atgcgaacag aggagagcgt aagatataag caatctcttg 4740 atgatgctgc caaaaccatc caggataaaa acaaggagat agaaaggtta aaacaactga 4800 tcgacaaaga aacaaatgac cggaaatgcc tggaagatga aaacgcgaga ttacaaaggg 4860 tccagtatga cctgcagaaa gcaaacagta gtgcgacgga gacaataaac aaactgaagg 4920 ttcaggagca agaactgaca cgcctgagga tcgactatga aagggtttcc caggagagga 4980 ctgtgaagga ccaggatatc acgcggttcc agaactctct gaaagagctg cagctgcaga 5040 agcagaaggt ggaagaggag ctgaatcggc tgaagaggac cgcgtcagaa gactcctgca 5100 agaggaagaa gctggaggaa gagctggaag gcatgaggag gtcgctgaag gagcaagcca 5160 tcaaaatcac caacctgacc cagcagctgg agcaggcatc cattgttaag aagaggagtg 5220 aggatgacct ccggcagcag agggacgtgc tggatggcca cctgagggaa aagcagagga 5280 cccaggaaga gctgaggagg ctct.ct.tctg aggtcgaggc cctgaggcgg cagttactcc 5340 aggaacagga aagtgtcaaa caagctcact tgaggaatga gcatttccag aaggcgatag 5400 aagataaaag cagaagctta aatgaaagca aaatagaaat tgagaggctg cagtctctca 5460 cagagaacct gaccaaggag cacttgatgt tagaagaaga actgcggaac ctgaggctgg 5520 agtacgatga cctgaggaga ggacgaagcg aagcggacag tgataaaaat gcaaccatct 5580 tggaactaag gagccagctg cagatcagca acaaccggac cctggaactg caggggctga 5640

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 ttaatgattt acagagagag agggaaaatt tgagacagga aattgagaaa ttccaaaagc 5700 aggctttaga ggcatctaat aggattcagg aatcaaagaa tcagtgtact caggtggtac 5750 aggaaagaga gagccttctg gtgaaaatca aagtcctgga gcaagacaag gcaaggctgc 5820 agaggctgga ggatgagctg aatcgtgcaa aatcaactct agaggcagaa accagggtga 5880 aacagcgcct ggagtgtgag aaacagcaaa ttcagaatga cctgaatcag tggaagactc 5940 aatattcccg caaggaggag gctattagga agatagaatc ggaaagagaa aagagtgaga 6000 gagagaagaa cagtcttagg agtgagatcg aaagactcca agcagagatc aagagaattg 6060 aagagaggtg caggcgtaag ctggaggatt ctaccaggga gacacagtca cagttagaaa 6120 cagaacgctc ccgatatcag agggagattg ataaactcag acagcgccca tatgggtccc 6180 atcgagagac ccagactgag tgtgagtgga ccgttgacac ctccaagctg gtgtttgatg 6240 ggctgaggaa gaaggtgaca gcaatgcagc tctatgagtg tcagctgatc gacaaaacaa 6300 ccttggacaa actattgaag gggaagaagt cagtggaaga agttgcttct gaaatccagc 6360 cattccttcg gggtgcagga tctatcgctg gagcatctgc ttctcctaag gaaaaatact 6420 ctttggtaga ggccaagaga aagaaattaa tcagcccaga atccacagtc atgcttctgg 6480 aggcccaggc agctacaggt ggtataattg atccccatcg gaatgagaag ctgactgtcg 6540 acagtgccat agctcgggac ctcattgact tcgatgaccg tcagcagata tatgcagcag 6600 aaaaagctat cactggtttt gatgatccat tttcaggcaa gacagtatct gtttcagaag 6660 ccatcaagaa aaatttgatt gatagagaaa ccggaatgcg cctgctggaa gcccagattg 6720 cttcaggggg tgtagtagac cctgtgaaca gtgtcttttt gccaaaagat gtcgccttgg 6780 cccgggggct gattgataga gatttgtatc gatccctgaa tgatccccga gatagtcaga 6840 aaaactttgt ggatccagtc accaaaaaga aggtcagtta cgtgcagctg aaggaacggt 6900 gcagaatcga accacatact ggtctgctct tgctttcagt acagaagaga agcatgtcct 6960 tccaaggaat cagacaacct gtgaccgtca ctgagctagt agattctggt atattgagac 7020 cgtccactgt caatgaactg gaatctggtc agatttctta tgacgaggtt ggtgagagaa 7080 ttaaggactt cctccagggt tcaagctgca tagcaggcat atacaatgag accacaaaac 7140 agaagcttgg catttatgag gccatgaaaa ttggcttagt ccgacctggt actgctctgg 7200 agxtgctgga agcccaagca gctactggct ttatagtgga tcctgttagc aacttgaggt 7260 taccagtgga ggaagcctac aagagaggtc tggtgggcat tgagttcaaa gagaagctcc 7320 tgtctgcaga acgagctgtc actgggtata atgatcctga aacaggaaac atcatctctt 7380 tgttccaagc catgaataag gaactcatcg aaaagggcca cggtattcgc ttattagaag 7440 cacagatcgc aaccgggggg atcattgacc caaaggagag ccatcgttta ccagttgaca 7500 tagcatataa gaggggctat ttcaatgagg.aactcagtga gattctctca gatccaagtg 7560 atgataccaa aggatttttt gaccccaaca ctgaagaaaa tcttacctat ctgcaactaa 7620 aagaaagatg cattaaggat gaggaaacag ggctctgtct tctgcctctg aaagaaaaga 7680 agaaacaggt gcagacatca caaaagaata ccctcaggaa gcgtagagtg gtcatagttg 7740 acccagaaac caataaagaa atgtctgttc aggaggccta caagaagggc ctaattgatt 7800 atgaaacctt caaagaactg tgtgagcagg aatgtgaatg ggaagaaata accatcacgg 7860 gatcagatgg ctccaccagg gtggtcctgg tagatagaaa gacaggcagt cagtatgata 7920 ttcaagatgc tattgacaag ggccttgttg acaggaagtt ctttgatcag taccgatccg 7980 gcagcctcag cctcactcaa tttgctgaca tgatctcctt gaaaaatggt gtcggcacca 8040 gcagcagcat gggcagtggt gtcagcgatg atgtttttag cagctcccga catgaatcag 8100 taagtaagat ttccaccata tccagcgtca ggaatttaac cataaggagc agctcttttt 8160 cagacaccct ggaagaatcg agccccattg cagccatctt tgacacagaa aacctggaga 8220 aaatctccat tacagaaggt atagagcggg gcatcgttga cagcatcacg ggtcagaggc 8280 ttctggaggc tcaggcctgc acaggtggca tcatccaccc aaccacgggc cagaagctgt 8340 cacttcagga cgcagtctcc cagggtgtga ttgaccaaga catggccacc agcgtgaagc 8400 ctgctcagaa agccttcata ggcttcgagg gtgtgaaggg aaagaagaag atgtcagcag 8460 cagaggcagt gaaagaaaaa tggctcccgt atgaggctgg ccagcgcttc ctggagttcc 8520 agtacctcac gggaggtctt gttgacccgg aagtgcatgg gaggataagc accgaagaag 8580 ccatccggaa ggggttcata gatggccgcg ccgcacagag gctgcaagac accagcagct 8640 atgccaaaat cctgacctgc cccaaaacca aattaaaaat atcctataag gatgccataa 8700 atcgctccat ggtagaagat atcactgggc tgcgccttct ggaagccgcc tccgtgtcgt 8760 ccaagggctt acccagccct tacaacatgt cttcggctcc ggggtcccgc tccggctccc 8820 gctcgggatc tcgctccgga tctcgctccg ggtcccgcag tgggtcccgg agaggaagct 8880 ttgacgccac agggaattct tcctactctt attcctactc atttagcagt agttctattg 8940

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ggcactag

<td> &lt;210&gt;</td><td> 120</td><td></td>

<td> &lt;211&gt;</td><td> 587</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> .. (587)</td>

<td> &lt;223&gt;</td><td> n = -</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 120</td><td></td>

8948 cgtcctaagc acttagacta catcagggaa gaacacagac cacatccctg tcctcatgcg gcttatgttt tctggaagaa agtggagacc nagtccttgg ctttagggct ccccggctgg gggctgtgca ntccggtcag ggcgggaagg gaaatgcacc gctgcatgtg aacttacagc ccaggcggat gccccttccc ttagcactac ctggcctcct gcatcccctc gcctcatgtt cctcccacct tcaaanaatg aanaacccca tgggcccagc cccttgccct ggggaaccaa ggcagccttc caaaactcag gggctgaagc anactattag ggcaggggct gactttgggt gacactgccc attccctctc agggcagctc angtcacccn ggnctcttga acccagcctg ttcctttgaa aaagggcaaa actgaaaagg gcttttccta naaaaagaaa aaccagggaa ctttgccagg gcttcnntnt taccaaaacn ncttctcnng gatttttaat tccccattng gcctccactt accnggggcn atgccccaaa attaanaatt tcccatc

120

180

240

300

360

420

480

540

587

<td> &lt;210&gt;</td><td> 121</td><td></td>

<td> &lt;211&gt;</td><td> 619</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> ^feature</td>

<td> &lt;222&gt;</td><td> (1)</td><td> . . (619)</td>

<td> &lt;223&gt;</td><td> n = .</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 121</td><td></td>

cactagtagg atagaaacac tgtgtcccga gagtaaggag agaagctact attgattaga gcctaaccca ggttaactgc aagaagaggc gggatacttt cagctttcca tgtaactgta tgcataaagc caatgtagtc cagtttctaa gatcatgttc caagctaact gaatcccact tcaatacaca ctcatgaact cctgatggaa caataacagg cccaagcctg tggtatgatg tgcacacttg ctagactcan aaaaaatact actctcataa atgggtggga gtattttggt gacaacctac tttgcttggc tgagtgaagg aatgatattc atatattcat ttattccatg gacatttagt tagtgctttt tatataccag gcatgatgct gagtgacact cttgtgtata tttccaaatt tttgtacagt cgctgcacat atttgaaatc atatattaag acttccaaaa aatgaagtcc ctggtttttc atggcaactt gatcagtaaa ggattcncct ctgtttggta cttaaaacat ctactatatn gttnanatga aattcctttt ccccncctcc cgaaaaaana aagtggtggg gaaaaaaaa

120

180

240

300

360

420

480

540

600

619

<td colspan="2"> &lt;210&gt; 122 &lt;211&gt; 1475 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt;</td><td> 122</td>

tccacctgtc cccgcagcgc cggctcgcgc cctcctgccg cagccaccga gccgccgtct agcgccccga cctcgccacc atgagagccc tgctggcgcg cctgcttctc tgcgtcctgg

120

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 tcgtgagcga ctccaaaggc agcaatgaac ttcatcaagt tccatcgaac tgtgactgtc 180 taaatggagg aacatgtgtg tccaacaagt acttctccaa cattcactgg tgcaactgcc 240 caaagaaatt cggagggcag cactgtgaaa tagataagtc aaaaacctgc tatgagggga 300 atggtcactt ttaccgagga aaggccagca ctgacaccat gggccggccc tgcctgccct 360 ggaactctgc cactgtcctt cagcaaacgt accatgccca cagatctgat gctcttcagc 420 tgggcctggg gaaacataat tactgcagga acccagacaa ccggaggcga ccctggtgct 480 atgtgcaggt gggcctaaag ccgcttgtcc aagagtgcat ggtgcatgac tgcgcagatg 540 gaaaaaagcc ctcctctcct ccagaagaat taaaatttca gtgtggccaa aagactctga 600 ggccccgctt taagattatt gggggagaat tcaccaccat cgagaaccag ccctggtttg 660 cggccatcta caggaggcac cgggggggct ctgtcaccta cgtgtgtgga ggcagcctca 720 tcagcccttg ctgggtgatc agcgccacac actgcttcat tgattaccca aagaaggagg 780 actacatcgt ctacctgggt cgctcaaggc ttaactccaa cacgcaaggg gagatgaagt 840 ttgaggtgga aaacctcatc ctacacaagg actacagcgc tgacacgctt gctcaccaca 900 acgacattgc cttgctgaag atccgttcca aggagggcag gtgtgcgcag ccatcccgga 960 ctatacagac catctgcctg ccctcgatgt ataacgatcc ccagtttggc acaagctgtg 1020 agatcactgg ctttggaaaa gagaattcta ccgactatct ctatccggag cagctgaaga 1080 tgactgttgt gaagctgatt tcccaccggg agtgtcagca gccccactac tacggctctg 1140 aagtcaccac caaaatgctg tgtgctgctg acccacagtg gaaaacagat tcctgccagg 1200 gagactcagg gggacccctc gtctgttccc tccaaggccg catgactttg actggaattg 1260 tgagctgggg ccgtggatgt gccctgaagg acaagccagg cgtctacacg agagtctcac 1320 acttcttacc ctggatccgc agtcacacca aggaagagaa tggcctggcc ctctgagggt 1380 ccccagggag gaaacgggca ccacccgctt tcttgctggt tgtcattttt gcagtagagt 1440 catctccatc agctgtaaga agagactggg aagat 1475

<td> &lt;210&gt;</td><td> 123</td>

<td> &lt;211&gt;</td><td> 2294</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 123</td>

cagcgccggc tcgcgccctc ctgccgcagc caccgagccg ccgtctagcg ccccgacctc 60 gccaccatga gagccctgct ggcgcgcctg cttctctgcg tcctggtcgt gagcgactcc 120 aaaggcagca atgaacttca tcaagttcca tcgaactgtg actgtctaaa tggaggaaca 180 tgtgtgtcca acaagtactt ctccaacatt cactggtgca actgcccaaa gaaattcgga 240 gggcagcact gtgaaataga taagtcaaaa acctgctatg aggggaatgg tcacttttac 300 cgaggaaagg ccagcactga caccatgggc cggccctgcc tgccctggaa ctctgccact 360 gtccttcagc aaacgtacca tgcccacaga tctgatgctc ttcagctggg cctggggaaa 420 cataattact gcaggaaccc agacaaccgg aggcgaccct ggtgctatgt gcaggtgggc 480 ctaaagccgc ttgtccaaga gtgcatggtg catgactgcg cagatggaaa aaagccctcc 540 tctcctccag aagaattaaa atttcagtgt ggccaaaaga ctctgaggcc ccgctttaag 600 attattgggg gagaattcac caccatcgag aaccagccct ggtttgcggc catctacagg 660 aggcaccggg ggggctctgt cacctacgtg tgtggaggca gcctcatcag cccttgctgg 720 gtgatcagcg ccacacactg cttcattgat tacccaaaga aggaggacta catcgtctac 780 ctgggtcgct caaggcttaa ctccaacacg caaggggaga tgaagtttga ggtggaaaac 840 ctaatcctac acaaggacta cagcgctgac acgcttgctc accacaacga cattgccttg 900 ctgaagatcc gttccaagga gggcaggtgt gcgcagccat cccggactat acagaccatc 960 tgcctgccct cgatgtataa cgatccccag tttggcacaa gctgtgagat cactggcttt 1020 ggaaaagaga attctaccga ctatctctat ccggagcagc tgaaaatgac tgttgtgaag 1080 ctgatttccc accgggagtg tcagcagccc cactactacg gctctgaagt caccaccaaa 1140 atgctgtgtg ctgctgaccc acagtggaaa acagattcct gccagggaga ctcaggggga 1200 cccctcgtct gttccctcca aggccgcatg actttgactg gaattgtgag ctggggccgt 1260 ggatgtgccc tgaaggacaa gccaggcgtc tacacgagag tctcacactt cttaccctgg 1320 atccgcagtc acaccaagga agagaatggc ctggccctct gagggtcccc agggaggaaa 1380 cgggcaccac ccgctttctt gctggttgct attttgcagt agagtcatct ccatcagctg 1440 taagaagagc tgggaatata ggctctgcac agatggattt gcctgtgcca ccaccagggc 1500

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 gaacgacaat agctttaccc tcaggcatag gcctgggtgc tggctgccca gacccctctg 1560 gccaggatgg aggggtggtc ctgactcaac atgttactga ccagcaactt gtctttttct 1620 ggactgaagc ctgcaggagt taaaaagggc agggcatctc ctgtgcatgg gctcgaaggg 1680 agagccagct cccccgaccg gtgggcattt gtgaggccca tggttgagaa atgaataatt 1740 tcccaattag gaagtgtaag cagctgaggt ctcttgaggg agcttagcca atgtgggagc 1800 agcggtttgg ggagcagaga cactaacgac ttcagggcag ggctctgata ttccatgaat 1860 gtatcaggaa atatatatgt gtgtgtatgt ttgcacactt gtgtgtgggc tgtgagtgta 1920 agtgtgagta agagctggtg tctgattgtt aagtctaaat atttccttaa actgtgtgga 1980 ctgtgatgcc acacagagtg gtctttctgg agaggttata ggtcactcct ggggcctctt 2040 gggtccccca cgtgacagtg cctgggaatg tattattctg cagcatgacc tgtgaccagc 2100 actgtctcag tttcactttc acatagatgt ccctttcttg gccagttatc ccttcctttt 2160 agcctagttc atccaatcct cactgggtgg ggtgaggacc actcctgtac actgaatatt 2220 tatatttcac tatttttatt tatatttttg taattttaaa taaaagtgat caataaaatg 2280 tgatttttct gatg 2294 &lt;210&gt; 124 &lt;211&gt; 956 &lt;212 &gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 124 gatgagttcc gcaccaagtt tgagacagac caggccctgc gcctgagtgt ggaggccgac 60 atcaatggcc tgcgcagggt gctggatgag ctgaccctgg ccagagccga cctggagatg 120 cagattgaga acctcaagga ggagctggcc tacctgaaga agaaccacga ggaggagatg 180 aacgccctgc gaggccaggt gggtggtgag atcaatgtgg agatggacgc tgccccaggc 240 gtggacctga gccgcatcct caacgagatg cgtgaccagt atgagaagat ggcagagaag 300 aaccgcaagg atgccgagga ttggttcttc agcaagacag aggaactgaa ccgcgaggtg 360 gccaccaaca gtgagctggt gcagagtggc aagagtgaga tctcggagct ccggcgcacc 420 atgcaggcct tggagataga gctgcagtcc cagctcagca tgaaagcatc cctggagggc 480 aacctggcgg agacagagaa ccgctactgc gtgcagctgt cccagatcca ggggctgatt 540 ggcagcgtgg aggagcagct ggcccagctt cgctgcgaga tggagcagca gaaccaggaa 600 tacaaaatcc tgctggatgt gaagacgcgg ctggagcagg agattgccac ctaccgccgc 660 ctgctggagg gagaggatgc ccacctgact cagtacaaga aagaaccggt gaccacccgt 720 caggtgcgta ccattgtgga agaggtccag gatggcaagg tcatctcctc ccgcgagcag 780 gtccaccaga ccacccgctg aggactcagc taccccggcc ggccacccag gaggcaggga 840 cgcagccgcc ccatctgccc cacagtctcc ggcctctcca gcctcagccc cctgcttcag 900 tcccttcccc atgcttcctt gcctgatgac aataaaagct tgttgactca gctatg 956

<td> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td> 125 486 DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> _feature</td>

<td> &lt;222&gt;</td><td> (l)</td><td> . . ¢486)</td>

<td> &lt;223&gt;</td><td> n - -</td><td> A,T,C or</td>

<td> &lt;400&gt;</td><td> 125</td><td></td>

aaattatata tagtgnttca gctcccattg tggtgttcat agtcttctag gaacagataa 60 acttaagtat tcaattcact cttggcattt tttctttaat ataggctttt tagcctattt 120 ttggaaaact gcttttcttc tgagaacctt attctgaatg tcatcaactt taccaaacct 180 tctaagtcca gagctaactt agtactgttt aagttactat tgactgaatt ttcttcattt 240 tctgtttagc cagtgttacc aaggtaagct ggggaatgaa gtataccaac ttctttcaga 300 gcattttagg acattatggc agctttagaa ggctgtcttg tttctagcca agggagagcc 360

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 agcgcaggtt ttggatacta gagaaagtca tttgcttgta ctattgccat tttagaaagc 420 tctgatgtga attcaaattt tacctctgtt acttaaagcc aacaatttta aggcagtagt 480 tttact 486 &lt;210&gt; 126 &lt;211&gt; 3552 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 126 cggcaggcag gtctcgtctc ggcaccctcc cggcgcccgc gttctcctgg ccctgcccgg 60 catcccgatg gccgccgctg ggccccggcg ctccgtgcgc ggagccgtct gcctgcatct 120 gctgctgacc ctcgtgatct tcagtcgtgc tggtgaagcc tgcaaaaagg tgatacttaa 1B0 tgtaccttct aaactagagg cagacaaaat aattggcaga gttaatttgg aagagtgctt 240 caggtctgca gacctcatcc ggtcaagtga tcctgatttc agagttctaa atgatgggtc 300 agtgtacaca gccagggctg ttgcgctgtc tgataagaaa agatcattta ccatatggct 360 ttctgacaaa aggaaacaga cacagaaaga ggttactgtg ctgctagaac atcagaagaa 420 ggtatcgaag acaagacaca ctagagaaac tgttctcagg cgtgccaaga ggagatgggc 480 acctattcct tgctctatgc aagagaattc cttgggccct ttcccattgt ttcttcaaca 540 agttgaatct gatgcagcac agaactatac tgtcttctac tcaataagtg gacgtggagt 600 tgataaagaa cctttaaatt tgttttatat agaaagagac actggaaatc tattttgcac 660 tcggcctgtg gatcgtgaag aatatgatgt ttttgatttg attgcttatg cgtcaactgc 720 agatggatat tcagcagatc tgcccctccc actacccatc agggtagagg atgaaaatga 780 caaccaccct gttttcacag aagcaattta taattttgaa gttttggaaa gtagtagacc 840 tggtactaca gtgggggtgg tttgtgccac agacagagat gaaccggaca caatgcatac 900 gcgcctgaaa tacagcattt tgcagcagac accaaggtca cctgggctct tttctgtgca 960 tcccagcaca ggcgtaatca ccacagtctc tcattatttg gacagagagg ttgtagacaa 1020 gtactcattg ataatgaaag tacaagacat ggatggccag ttttttggat tgataggcac 1080 atcaacttgt atcataacag taacagattc aaatgataat gcacccactt tcagacaaaa 1140 tgcttatgaa gcatttgtag aggaaaatgc attcaatgtg gaaatcttac gaatacctat 1200 agaagataag gatttaatta acactgccaa ttggagagtc aattttacca ttttaaaggg 1260 aaatgaaaat ggacatttca aaatcagcac agacaaagaa actaatgaag gtgttctttc 1320 tgttgtaaag ccactgaatt atgaagaaaa ccgtcaagtg aacctggaaa ttggagtaaa 1380 caatgaagcg ccatttgcta gagatattcc cagagtgaca gccttgaaca gagccttggt 1440 tacagttcat gtgagggatc tggatgaggg gcctgaatgc actcctgcag cccaatatgt 1500 gcggattaaa gaaaacttag cagtggggtc aaagatcaac ggctataagg catatgaccc 1560 cgaaaataga aatggcaatg gtttaaggta caaaaaattg catgatccta aaggttggat 1620 caccattgat gaaatttcag ggtcaatcat aacttccaaa atcctggata gggaggttga 1680 aactcccaaa aatgagttgt ataatattac agtcctggca atagacaaag atgatagatc 1740 atgtactgga acacttgctg tgaacattga agatgtaaat gataatccac cagaaatact 1800 tcaagaatat gtagtcattt gcaaaccaaa aatggggtat accgacattt tagctgttga 1860 tcctgatgaa cctgtccatg gagctccatt ttatttcagt ttgcccaata cttctccaga 1920 aatcagtaga ctgtggagcc tcaccaaagt taatgataca gctgcccgtc tttcatatca 1980 gaaaaatgct ggatttcaag aatataccat tcctattact gtaaaagaca gggccggcca 2040 agctgcaaca aaattattga gagttaatct gtgtgaatgt actcatccaa ctcagtgtcg 2100 tgcgacttca aggagtacag gagtaatact tggaaaatgg gcaatccttg caatattact 2160 gggtatagca ctgctctttt ctgtattgct aactttagta tgtggagttt ttggtgcaac 2220 taaagggaaa cgttttcctg aagatttagc acagcaaaac ttaattatat caaacacaga 2280 agcacctgga gacgatagag tgtgctctgc caatggattt atgacccaaa ctaccaacaa 2340 ctctagccaa ggtttttgtg gtactatggg atcaggaatg aaaaatggag ggcaggaaac 2400 cattgaaatg atgaaaggag gaaaccagac cttggaatcc tgccgggggg ctgggcatca 2460 tcataccctg gactcctgca ggggaggaca cacggaggtg gacaactgca gatacactta 2520 ctcggagtgg cacagtttta ctcaaccccg tctcggtgaa aaattgcatc gatgtaatca 2580 gaatgaagac cgcatgccat cccaagatta tgtcctcact tataactatg agggaagagg 2640 atctccagct ggttctgtgg gctgctgcag tgaaaagcag gaagaagatg gccttgactt 2700

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 tttaaataat tcacagtgct aaagttcaat ctcaccaatt ttaaaacaga ctgctctttt aacaatagct aaaaataaac gaagactgaa actaccaaat ttttctatag aatatttaaa tatagtttgt gcattataac ttgtaaataa ttggaaccca acaattaggt ttcaacatgt tatattttta caactggtaa ttttttttac aagttatgct aagaaatatt ttaaattaaa tcatttgact gaatatagtt tgaaatgaga cctacaatag tgagtctatg at aatttattac ctttgtcaga atgtatatga aagcaagttg atctcaaact agatatttta aatatcacat gagtatcact aatgttgcag ttggaggcaa ggaaataaat acaaagagga aaaaaagaga aggaaatagt

<td> attagcagaa</td><td> gcatgcacaa</td><td> agagataatg</td><td> 2760</td>

<td> cattctggag</td><td> gtttccaaaa</td><td> ataatattgt</td><td> 2820</td>

<td> tgattttttt</td><td> ctcaattttg</td><td> aattatgcta</td><td> 2880</td>

<td> ttgcttatct</td><td> tttccaaaaa</td><td> gtgaaaaatg</td><td> 2940</td>

<td> ccagcactgg</td><td> aattaaggtc</td><td> tctaaagcat</td><td> 3000</td>

<td> gtaataaata</td><td> tgctggataa</td><td> atattagtcc</td><td> 3060</td>

<td> tattatgtat</td><td> tcactttaag</td><td> tgatagttta</td><td> 3120</td>

<td> atgtgaagaa</td><td> agttttggaa</td><td> aagaaacaat</td><td> 3180</td>

<td> ctcataaaga</td><td> attggactca</td><td> cccctactgc</td><td> 3240</td>

<td> aatgtgttga</td><td> agtgccctat</td><td> gaagtagcaa</td><td> 3300</td>

<td> gtgtgtgtgt</td><td> atattattat</td><td> taatcaatgc</td><td> 3360</td>

<td> aaatggtaaa</td><td> aacttgaaat</td><td> gaggctgggg</td><td> 3420</td>

<td> gagcttccta</td><td> ggcctgggct</td><td> cttaaatgct</td><td> 3480</td>

<td> tcctgtccaa</td><td> tttgtgtaat</td><td> ttgtttaaaa</td><td> 3540 3552</td>

<td> &lt;210&gt;</td><td> 127</td>

<td> &lt;211&gt;</td><td> 754</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 127</td>

tttttttttt gcctttcaaa gctctagtgt ggacacgtga gaagacatac acctatatta aacgtttgta cctttatggt gaatcaagac tggtcctcaa accaccttct ctcatctgta atgatgtcga ttgtcattgt ggtcacacag ccatgcttct aatgtatccg acaaaaataa aaatgtaagg ggggsgcaca tggatcatct tgcaatatcg agtaaaaccc aatactttta aagctgtgct acctgcccgg tcattgattt aagtaagtga caaccattat gtattttact tggttacaat cttttgatat ctcctgcatg tgtcattaaa cctgcttttc ctgtgtcagt atacccaatc tcaaaatagt gcggccgctc

<td> taatgagaaa</td><td> gctaagagag</td><td> gaaataagta</td><td> 60</td>

<td> cagatccagg</td><td> attcatatcc</td><td> aagcattctg</td><td> 120</td>

<td> gacccaatat</td><td> tcaaccaaat</td><td> caatactgaa</td><td> 180</td>

<td> attacaaaca</td><td> aaaatccaat</td><td> gaacattctt</td><td> 240</td>

<td> agaagttact</td><td> ggaattgaaa</td><td> ttttggttca</td><td> 300</td>

<td> agctaataga</td><td> tttttgaaat</td><td> gatcagtctt</td><td> 360</td>

<td> gggaaaagat</td><td> tcactgtgaa</td><td> gcacagagca</td><td> 420</td>

<td> gttcaggcgt</td><td> tatctatcct</td><td> gtaagtggca</td><td> 480</td>

<td> tttttaactc</td><td> atgttttccc</td><td> ttgactacac</td><td> 540</td>

<td> gtactattca</td><td> tggaatactc</td><td> tgcaattata</td><td> 600</td>

<td> aaaatttatt</td><td> atacatatgt</td><td> atcatagata</td><td> 660</td>

<td> gatctcttcc</td><td> caacattaca</td><td> atatatatta</td><td> 720</td>

<td> gaag</td><td></td><td></td><td> 754</td>

&lt;210&gt; 128 &lt;211&gt; 374 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt;

aggttttgat gaaggagtaa ttcccctgcc aaaaaacaga ggtttaattg tttcttcctt aacttaaaaa

128 taaaaaggca aattaaagat cttggtaagt gccagctaat aataaaacta agttaaggca gctg aatgatttta gaaagatgat aactcttgat catttccaaa tatgttcata ttataagggc

<td> ttgttcgata</td><td> atcttttaaa</td><td> aaaataagag</td><td> 60</td>

<td> ttttatttcc</td><td> ttgtgacctc</td><td> tatatccccc</td><td> 120</td>

<td> ggagaaagga</td><td> ttaaagactc</td><td> ttatttaacc</td><td> 180</td>

<td> ggttagtatc</td><td> tccctgctga</td><td> cctcttcttt</td><td> 240</td>

<td> tatgtattaa</td><td> aacaactcag</td><td> aataacatct</td><td> 300</td>

<td> tatactatca</td><td> tccataataa</td><td> ccaaggcaat</td><td> 360</td>

374 &lt;210&gt; 129 &lt;211&gt; 546 &lt;212&gt; DNA &lt;213&gt; Homo sapien

CA 02369578 2001-10-02

WOOO/61612 PCT/US00/08896 &lt;400&gt; 129 agtgtgatgg atatctgcag aattcgggct aagcgtggtc gcggcccgag gtctggaact 60 tcccagcacy tgaaaaggag cctcctgagc tgactcggct aaagccccac tttcgctcct 120 cctcatttct gcctactgat ttccttggag cattcatctg aatattaccg tttgctgtgt 180 aacctggtac atacatagca tgactccctg gaatagagtg ggctggggtg cttatgctgg 240 gagagtgatt gacatgcact ttcaagctat atctaccatt tgcagcaaag gagaaaaaat 300 acctcgagta aattccatca ttttttataa catcagcacc tgctccatca tcaaggagtc 360 tcagcgtaac aggatctcca gtctctggct caactgtggc agtgacagtg gcattaagaa 420 tgggataaaa tccctgtttc acattggcat aaatcatcac aggatgagga aaatggaggc 480 tgtctctttc cacaaaggct tccacagtgg ctgggggcac agacctgccc gggcggccgc 540 tcgaaa 546

<td colspan="2"> &lt;210&gt; 130 &lt;211&gt; 5156 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt;</td><td> 130</td>

accaaccgag gcgccgggca gcgacccctg cagcggagac agagactgag cggcccggca 60 ccgccatgcc tgcgctctgg ctgggctgct gcctctgctt gtcgctcctc ctgcccgcag 120 cccgggccac ctccaggagg gaagtctgtg attgcaatgg gaagtccagg cagtgtatct 180 ttgatcggga acttcacaga caaactggta atggattccg ctgcctcaac tgcaatgaca 240 acactgatgg cattcactgc gagaagtgca agaatggctt ttaccggcac agagaaaggg 300 accgctgttt gccctgcaat tgtaactcca aaggttctct tagtgctcga tgtgacaact 360 ccggacggtg cagctgtaaa ccaggtgtga caggagccag atgcgaccga tgtctgccag 420 gcttccacat gctcacggat gcggggtgca cccaagacca gagactgcta gactccaagt 480 gtgactgtga cccagctggc atcgcagggc cctgtgacgc gggccgctgt gtctgcaagc 540 cagctgtcac tggagaacgc tgtgataggt gtcgatcagg ttactataat ctggatgggg 600 ggaaccctga gggctgtacc cagtgtttct gctatgggca ttcagccagc tgccgcagct 660 ctgcagaata cagtgtccat aagatcacct ctacctttca tcaagatgtt gatggctgga 720 aggctgtcca acgaaatggg tctcctgcaa agctccaatg gtcacagcgc catcaagatg 780 tgtttagctc agcccaacga ctagaccctg tctattttgt ggctcctgcc aaatttcttg 840 ggaatcaaca ggtgagctat ggccaaagcc tgtcctttga ctaccgtgtg gacagaggag 900 gcagacaccc atctgcccat gatgtgattc tggaaggtgc tggtctacgg atcacagctc 960 ccttgatgcc acttggcaag acactgcctt gtgggctcac caagacttac acattcaggt 1020 taaatgagca tccaagcaat aattggagcc cccagctgag ttactttgag tatcgaaggt 1080 tactgcggaa tctcacagcc ctccgcatcc gagctacata tggagaatac agtactgggt 1140 acattgacaa tgtgaccctg atttcagccc gccctgtctc tggagcccca gcaccctggg 1200 ttgaacagtg tatatgtcct gttgggtaca aggggcaatt ctgccaggat tgtgcttctg 1260 gctacaagag agattcagcg agactggggc cttttggcac ctgtattcct tgtaactgtc 1320 aagggggagg ggcctgtgat ccagacacag gagattgtta ttcaggggat gagaatcctg 1380 acattgagtg tgctgactgc ccaattggtt tctacaacga tccgcacgac ccccgcagct 1440 gcaagccatg tccctgtcat aacgggttca gctgctcagt gatgccggag acggaggagg 1500 tggtgtgcaa taactgccct cccggggtca ccggtgcccg ctgtgagctc tgtgctgatg 1560 gctactttgg ggaccccttt ggtgaacatg gcccagtgag gccttgtcag ccctgtcaat 1620 gcaacaacaa tgtggacccc agtgcctctg ggaattgtga ccggctgaca ggcaggtgtt 1680 tgaagtgtat ccacaacaca gccggcatct actgcgacca gtgcaaagca ggctacttcg 1740 gggacccatt ggctcccaac ccagcagaca agtgtcgagc ttgcaactgt aaccccatgg 1800 gctcagagcc tgtaggatgt cgaagtgatg gcacctgtgt ttgcaagcca ggatttggtg 1860 gccccaactg tgagcatgga gcattcagct gtccagcttg ctataatcaa gtgaagattc 1920 agatggatca gtttatgcag cagcttcaga gaatggaggc cctgatttca aaggctcagg 1980 gtggtgatgg agtagtacct gatacagagc tggaaggcag gatgcagcag gctgagcagg 2040 cccttcagga cattctgaga gatgcccaga tttcagaagg tgctagcaga tcccttggtc 2100 tccagttggc caaggtgagg agccaagaga acagctacca gagccgcctg gatgacctca 2160 agatgactgt ggaaagagtt cgggctctgg gaagtcagta ccagaaccga gttcgggata 2220

CA 02369578 2001-10-02

WO 00/61612

PCT/USOO/08896 ctcacaggct acactaacat aggaggccac caagggaaac aaggagtcgg aattggagaa ttgaagcaga agggagtcag attcactctc tgggaaactg aatcagatca gtatgggcaa acctgcaggt tcagccagaa gcgctgctgc gtgagattga ccttggccat agctggaaag cagaagccca tcaacacatt ggctggtctt ggcccatgat tggagacaag acctgccccc atttctcaac tgggtgggat cccattcctg tgctgggcaa gaatagactg gtggagtcct tgtgactaaa cagagtgcaa caagcttctt attttcaagc agagctatgg tttcttttaa agcaaagcaa gcttgggcat ttagaacacc tctttcctcc tccctccatt tatatttatt tgccctcata acttacaaac tctttgctca aggctgacag ttctacaact gaaccagagg ccttggattt catcactcag tcctgcctca aagattagca tgaggactat aagcggaagc aaccaagtcc taggtcttat tgatcagtcc aagcctggta gaaagaagaa gctgctttcc tgccactttt ggacaacaga ggtttcagat tgatgcacag acaggagatt ggaaaaggga gaaggagctg gaaggttgat agacggcctc actggagcag gtcagagctg catagatggg aggctgctac tgaggttctt ggggacattt atcccatggc tgaggcagat gatggaaaga ggaatttgga ggaaaaaact cccagtcaca gctgatcaga tggaagaagt tgcttgctgg tgatgccatg atgttgggaa tgaaagaggt aaaaatgatg acccataata catccttcca gagtacctac gagttgattg tttgtttgtc acagaacata agctctgggt gattgcaaca cacttccacc tcctgaaagt atgcagctga gaccactacg gaaagccacg tccaaacaag ggtagcccgg ctggcccagc cagcacagtc tttcaggtgg accaggcata gcacagcagc cgtgccaatc tatgaagttg aaagcagaag gccagtgaca agggcaaaga gggagtctga ctggcctctc gagtttgaca accagagcca ctgcatctga aagctttccc gaagagaggg attctggctg aatacccagg gggatacaga gaacatgttt caggtggttg agcactgggt caaactgcac caagtgctgt ttgactttgc ctgtggccag gttcctccta gagcagtgtt tgcctgccac gcaacttaga agtatttact aaaattctct cgcatcaatg agagaatgtt tccatctttc tgtgtgccag tctagtgagg acaagtggtg tgttgcaaga tgtgcacatt gactgttgag ttggctggga gtttttaaat gcctggcaga tggggccaaa ttgagtcagc ccctctcact acggtgctgt agttgacaag tccgcctcct aagaagcaaa tggatgagtt tcttacagaa ttgctaaaag agagcatcct ctgaagaagc agacccagca atggggccgg acttggaagc tgaagagtga cgaatatgga agaacgctgg tggaccagcc gagccaagac cacgtcagca atgtgaagaa ctcttgagca tctcagggct aatgggtatg tcttattgca gtgagaatga aggcagatgt tgggatatag ccaggcatga taaaatacta cttacaaccc ggagtgagga cttcaagttc gattgcattt ttttcggttt agatttatta tattttatct cctactcaca catccattac gggctggtgg aagacaagca tttattgcaa ccctcccatg tctttgcatt ttatgataac agactatggt aaagaacaat aagtgaagct tggctttaaa cagtaacatg ggtgcgcaag ggtgcaaggg ggaggccact ggattcagtg gaggatcaaa caagcgtaca tggaaaaagt cagagcacaa taaaaacctc catgaagaga agcagaaaga ggaggccctg caatgtgaca gatgagggaa tgcagtacag ggttacaatc tctcagtgta ccagatcaac gaggggccac cttggagaac acagtgaagc cgggagccat ctcaggtcaa ccatactcct tcaaggatct ttgcctcata tcaacttatt aattcttcct ttgcctcata agggtgtgaa cctgtaaggc tggacctggg ttattaaagc caaagtgata gtcctaattc tattttctca cttcagctgg ctccatccat gacagtggtg tttttaaaaa taaccgcttg ggggcacttg ccagctgtca accagtggga gctgccttgc tgttagaaaa tccttgggaa agtctggctc gagcaactga gccctgcatg cttgtggaaa caagcggaaa tctcggcttc caaaaagcgg cagaagaatc gggagagaga gaagcactga agagagtttg ctctcctaca gccctgggga gaaatctcca gcagatggag gtggaaggag atggtgatta caagacacac gatgaagagg agccaactgc ctccatttgc attagggaca tgccataaat gtcatgtgag ctgacctgac tgcttcctga ggaccccaaa atagtcgtaa ctttgagtaa aatgtcagaa ttgtcctctg catgttctcc aggcccattc catgacatcc atttcctacc gaaaagtgtg aatcctactt atctcctctc gtcacatcca ccttccaaca acatagtctc ataaatttaa gtttgcaacc agttttggca ctctgtgcct attgctggag ttctgtattt aaaaaa

2280

2340

2400

2460

2520

2580

2640

2700

2760

2820

2880

2940

3000

3060

3120

3180

3240

3300

3360

3420

3480

3540

3600

3660

3720

3780

3840

3900

3960

4020

4080

4140

4200

4260

4320

4380

4440

4500

4560

4620

4680

4740

4800

4860

4920

4980

5040

5100

5156 &lt;210&gt; 131 &lt;211&gt; 671 &lt;212&gt; DNA &lt;213&gt; Homo sapien

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 aggtctggag ttttgcatcc cctgggcagc tcccgatgct ccattgcgct agaatgaggg tgcctagaag aggatgtcgc gaatttttct cctgaccctt cgtgacaccg ttaactgcta

131 ggcccacagc cggttgcagt caycacgagg ggtggagtgt ggtttatccc caagatccct ccaatgggtg ctggaatatt ttcgccatac cctgctcccc gagacaggtc t

cggatgtggg gtgttgcaga atcatgactc ttgttgacac tgagtcctgt ctgcgagggt cacagtgatg caaattgaat agaaattgtt aggaagggag ttcttcaccg acaccgggaa aaagtggtca tagcacacat 60 cgaagtcctc ttgetegtea ccccacactt 120 ggaaaataaa gatgactgtg atccacacct 180 ccccgatgaa agtgtgcagc gtcccccaat 240 ttccaacgac tgccagtgtt tcagacccaa 300 ttcagacctc cttctcctac cccactggag 360 ataegaatgt caatctttgc tcggtcagtg 420 tacagatgca tgaagagggc gtacaagtta 480 tagccagatc ttctgtactt cttttccttc 540 gtcagccccg tttgcaaaac acaggatgcc 600 acaggaagtg ccttctggtg cctgcacgtt 660

671

<td colspan="2"> &lt;210&gt; 132 &lt;211&gt; 590 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt;</td><td> 132</td>

ctgaatggaa cttggcaatt ggttcatctg tttgttccag ggaactggag cctcaccatc tttctagtta cgaaaatact attccaggaa ctgcaagccc aagcttatgg gcttacccac cagccccaaa atatatcaaa acattttcca aattgaaaaa cgtggcaggc acacaaataa cagctaagcc tgaaagtgac ctctgtgatg tgtgctcagc tctggaggaa ctccaatagc gcaacatatt cacagtgact cagtggtcct ttttatcacc tgggcactgg agtgacctct atattagtga ccagcggaga tgataagett 60 agtggttcaa caattcactc cattgccctg 120 ttatcacgtc ttacaggagg tttaaagttc 180 atgattgatg ctttcagtag aatttcctct 240 cagcttgaaa gtacaggtga aaatgtcaaa 300 gtggataata ctgtgggcaa cgacactatg 360 cctgagatta tattatttga tcctgatgga 420 aatetaaett ttcggacagc tagtctttgg 480 acttacaccc tgaacaatac ccatcattct 540 cgcgcctcca actcagacct 590

<td> &lt;210&gt;</td><td> 133</td>

<td> &lt;211&gt;</td><td> 581</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 133</td>

aggtcctgtc actgtgggcc ctgtcctcat atgctctggg tgggccaggg gggggagaac tggctggata aatccaaacc cctcctagac ggctgaggag ^cgggsg^cact tggagataaa ctctgcaaag gagctcatgg atgaatattt agagaggagc tctggtacta atagctgtct tctgtccctg agtgtgacat gagaactccc acttgtctcc ttcagcttcc gtggaggagt gagggataaa tgggctatgg aaaaagggtc gtccagtgct ggctagggca gtggggagag tctggaattc ttggggggtg ttggggagag 60 tctaccacca ccctgtaccc tagcctgcac 120 ttccccaggt ctctgtgcac tctgtcttgg 180 ctccaccaga gggaggetea ggggactggt 240 aattgtgtaa gagccaaaga attggtagta 300 gaaatgattt gaataatgga gctgggaata 360 tttaagaacc tacttcctaa tctcttcccc 420 ctcttcctgc ctccagctct gccccaggct 480 ggggaggagg gagagcaggg ttgggggaga 540 gaccagacct c 581 &lt;210&gt; 134 &lt;211&gt; 4797 &lt;212&gt; DNA &lt;213 &gt; Homo sapien &lt;220&gt;

&lt;221&gt; mise feature

CA 02369578 2001-10-02

WO 00/61612 PCT/USOO/08896 &lt;222&gt; (1) . . . (4797) &lt;223&gt; n = A,T,C or G &lt;400&gt; 134 cctgggacca aagtgctgcc cagagctgag ggtcctggag ccacatgaga aggcttctcc 60 ctgtgtacct gtgcagcaca gggtagggtg agtccactca gctgtctagg agaggaccca 120 ggagcagcag agacncgcca agcctttact cataccatat tctgatcctt ttccagcaaa 180 ttgtggctac taatttgccc cctgaagatc aagatggctc tggggatgac tctgacaact 240 tctccggctc aggtgcaggt gaggttgtca tgggggcccc ccccacccaa gacggcaaca 300 ggtcatgcct gggggcagtg gtcaggcagt ctcctgtgtt tactgagcat gtactgagtg 360 caccctgcct gccctgtctc cacccagctg gctccaaagg gcaatgctga ggagaggaat 420 ggggtcgtga gctgctgtta aggagagctc atgcttggag gtgaggtgaa ggctgtgagc 480 tccagaaggc cccagggcgc nctgctgcac gcaggctcat attcactagg aatagcttta 540 ctcactaaga aacctctgga acccccttca gaaggttatt tgactcctga gcctctattt 600 tctcatctgc aaaatgggaa taataccttg acctgataag cttgtggagc tgtaaggcag 660 cacagagcca gctggggtgt agctcttcca tccaagctcc cttccttact tcccctttcc 720 tgtggggact gggggagaga agtccctgag ctggaggtgg tcagggaagc ttcacagagg 780 aggtggctct tgagtggacc tcaggaagag gggtgagaga gctaaggaag gaggctgagg 840 tcatccctgg ggaagtgacc tagcggaggc ctgagagctg caaggtagga tatctgttgt 900 tggaagtgtc tgttgttgga agtgggggcc tttttttcag ggagggtggg gccagagaag 960 tgtgtgccct gggataagta ggataaccac agtagttatg cccctaaggg atgcccaccc 1020 cacccctgtg gtcacagaaa agctttccca ggtggcctag gcacctgtct cgtggctcca 1080 gagacaggct gcacctgaca cacacaatgg aaggacagct ctccttgtcc attttccaag 1140 gagcttagcc tcagctgcct tgtccaggta ctagcctccc tcatagcctg agcttggcca 1200 gcccaggtgc tctggagcct cccccgaccc acccaacaca ctctgcttct ggtcctcccc 1260 accccccacc tccccaacac actctgcttc tggtcctgca ggtgctttgc aagatatcac 1320 cttgtcacag cagaccccct ccacttggaa ggacacgcag ctcctgacgg ctattcccac 1380 gtctccagaa cccaccggcc tggaggctac agctgcctcc acctccaccc tgccggctgg 1440 agaggggccc aaggagggag aggctgtagt cctgccagaa gtggagcctg gcctcaccgc 1500 ccgggagcag gaggccaccc cccgacccag ggagaccaca cagctcccga ccactcatca 1560 ggcctcaacg accacagcca ccacggccca ggagcccgcc acctcccacc cccacaggga 1620 catgcagcct ggccaccatg agacctcaac ccctgcagga cccagccaag ctgaccttca 1680 cactccccac acagaggatg gaggtccttc tgccaccgag agggctgctg aggatggagc 1740 ctccagtcag ctcccagcag cagagggctc tggggagcag gtgagtggcc tctgcattcc 1800 ttgggaaatt gagtgggttg gtcctaatgc ctggcacttg gcaggcccta cacctgtgcc 1860 ctgcgcgatc tcgtattcct caccaggaag acagggcaca ggggccgcct tcccctaccc 1920 ccagggcctc gcagagcagg acagactaac tatgagatca gagcagaagc acccttaaag 1980 atcacccaag agagggctcc caaactcaca atccaaactt gcagccctcg tcgaagagtg 2040 aacgttatac cagtcatttt atttatagct tcgtggattt acgcttacac taaatagtct 2100 gctattcata caaaatgtgt gctttgtatc actttttgtg atatccatgc catggtccag 2160 ccagggtccg gagttgatgt ggcaagaagg cctggctttc gggccctgtg cgatcctggt 2220 ttgggtgcat ctgagtgggt ggtggcaaag atcagggagg caggagctgc ttctgggtct 2280 gtagtggagc tggttgctgc tgctggcggt gacctggcca acccaatctg cccctgccct 2340 cccacaggac ttcacctttg aaacctcggg ggagaatacg gctgtagtgg ccgtggagcc 2400 tgaccgccgg aaccagtccc cagtggatca gggggccacg ggggcctcac agggcctcct 2460 ggacaggaaa gaggtgctgg gaggtgagtt ttctttcagg ggggtagttt ggggtgaatt 2520 gctgctgtgg ggtcagggtg gggctgacca cagccaaggc cactgctttg ggagggtctg 2580 cacgagagcc caaggagccg ctgagctgag ctggccccgt ctacctgccc taggggtcat 2640 tgccggaggc ctcgtggggc tcatctttgc tgtgtgcctg gtgggtttca tgctgtaccg 2700 catgaagaag aaggacgaag gcagctactc cttggaggag ccgaaacaag ccaacggcgg 2760 ggcctaccag aagcccacca aacaggagga attctatgcc tgacgcggga gccatgcgcc 2820 ccctccgccc tgccactcac taggccccca cttgcctctt ccttgaagaa ctgcaggccc 2880 tggcctcccc tgccaccagg ccacctcccc agcattccag cccctctggt cgctcctgcc 2940 cacggagtcg tgggtgtgct gggagctcca ctctgcttct ctgacttctg cctggagact 3000 ^tagggcacca ggggtttctc gcataggacc tttccaccac agccagcacc tggcatcgca 3060

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 ccattctgac tcggtttctc caaactgaag cagcctctcc ccaggtccag ctctggaggg 3120 9^a99999atc cgactgcttt ggacctaaat ggcctcatgt ggctggaaga tcctgcgggt 3180 9999^ctt999 gctcacacac ctgtagcact tactggtagg accaagcatc ttgggggggt 3240 ggccgctgag tggcagggga caggagtcac tttgtttcgt ggggaggtct aatctagata 3300 tcgacttgtt tttgcacatg tttcctctag ttctttgttc atagcccagt agaccttgtt 3360 acttctgagg taagttaagt aagttgattc ggtatccccc catcttgctt ccctaatcta 3420 tggtcgggag acagcatcag ggttaagaag actttttttt ttttttttaa actaggagaa 3480 ccaaatctgg aagccaaaat gtaggcttag tttgtgtgtt gtctcttgag tttgtcgctc 3540 atgtgtgcaa cagggtatgg actatctgtc tggtggcccc gttctggtgg tctgttggca 3600 ggctggccag tccaggctgc cgtggggccg ccgcctcttt caagcagtcg tgcctgtgtc 3660 catgcgctca gggccatgct gaggcctggg ccgctgccac gttggagaag cccgtgtgag 3720 aagtgaatgc tgggactcag ccttcagaca gagaggactg tagggagggc ggcaggggcc 3780 tggagatcct cctgcaggct cacgcccgtc ctcctgtggc gccgtctcca ggggctgctt 3840 cctcctggaa attgacgagg ggtgtcttgg gcagagctgg ctctgagcgc ctccatccaa 3900 ggccaggttc tccgttagct cctgtggccc caccctgggc cctgggctgg aatcaggaat 3960 attttccaaa gagtgatagt cttttgcttt tggcaaaact ctacttaatc caatgggttt 4020 ttccctgtac agtagatttt ccaaatgtaa taaactttaa tataaagtag tctgtgaatg 4080 ccactgcctt cgcttcttgc ctctgtgctg tgtgtgacgt gaccggactt ttctgcaaac 4140 accaacatgt tgggaaactt ggctcgaatc tctgtgcctt cgtctttccc atggggaggg 4200 attctggttc cagggtccct ctgtgtattt gcttttttgt tttggctgaa attctcctgg 4260 aggtcggtag gttcagccaa ggttttataa ggctgatgtc aatttctgtg ttgccaagct 4320 ccaagcccat cttctaaatg gcaaaggaag gtggatggcc ccagcacagc ttgacctgag 4380 gctgtggtca cagcggaggt gtggagccga ggcctacccc ncagacacct tggacatcct 4440 cctcccaccc ggctgcagag gccaganncc agcccagggt cctgcactta cttgcttatt 4500 tgacaacgtt tcagcgactc cgttggccac tccgagagtg ggccagtctg tggatcagag 4560 atgcaccacc aagccaaggg aacctgtgtc cggtattcga tactgcgact ttctgcctgg 4620 agtgtatgac tgcacatgac tcgggggtgg ggaaaggggt cggctgacca tgctcatctg 4680 ctggtccgtg ggacggtncc caagccagag gtgggttcat ttgtgtaacg acaataaacg 4740 gtacttgtca tttcgggcaa cggctgctgt ggtggtggtt gagtctcttc ttggcct 4797

<td colspan="2"> &lt;210&gt; 135 &lt;211&gt; 2856 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt;</td><td> 135</td>

tagtcgcggg tccccgagtg agcacgccag ggagcaggag accaaacgac gggggtcgga 60 gtcagagtcg cagtgggagt ccccggaccg gagcacgagc ctgagcggga gagcgccgct 120 cgcacgcccg tcgccacccg cgtacccggc gcagccagag ccaccagcgc agcgctgcca 180 tggagcccag cagcaagaag ctgacgggtc gcctcatgct ggctgtggga ggagcagtgc 240 ttggctccct gcagtttggc tacaacactg gagtcatcaa tgccccccag aaggtgatcg 300 aggagttcta caaccagaca tgggtccacc gctatgggga gagcatcctg cccaccacgc 360 tcaccacgct ctggtccctc tcagtggcca tcttttctgt tgggggcatg attggctcct 420 tctctgtggg ccttttcgtfc aaccgctttg gccggcggaa ttcaatgctg atgatgaacc 480 tgctggcctt cgtgtccgcc gtgctcatgg gcttctcgaa actgggcaag tcctttgaga 540 tgctgatcct gggccgcttc atcatcggtg tgtactgcgg cctgaccaca ggcttcgtgc 600 ccatgtatgt gggtgaagtg tcacccacag cctttcgtgg ggccctgggc accctgcacc 660 agctgggcat cgtcgtcggc atcctcatcg cccaggtgtt cggcctggac tccatcatgg 720 gcaacaagga cctgtggccc ctgctgctga gcatcatctt catcccggcc ctgctgcagt 780 gcatcgtgct gcccttctgc cccgagagtc cccgcttcct gctcatcaac cgcaacgagg 840 agaaccgggc caagagtgtg ctaaagaagc tgcgcgggac agctgacgtg acccatgacc 900 tgcaggagat gaaggaagag agtcggcaga tgatgcggga gaagaaggtc accatcctgg 960 agctgttccg ctcccccgcc taccgccagc ccatcctcat cgctgtggtg ctgcagctgt 1020 cccagcagct gtctggcatc aacgctgtct tctattactc cacgagcatc ttcgagaagg 1080 cgggggtgca gcagcctgtg tatgccacca ttggctccgg tatcgtcaac acggccttca 1140

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 ctgtcgtgtc gctgtttgtg gtggagcgag caggccggcg gaccctgcac ctcataggcc 1200 tcgctggcat ggcgggttgt gccatactca tgaccatcgc gctagcactg ctggagcagc 1260 taccctggat gtcctatctg agcatcgtgg ccatctttgg ctttgtggcc ttctttgaag 1320 tgggtcctgg ccccatccca tggttcatcg tggctgaact cttcagccag ggtccacgtc 1380 cagctgccat tgccgttgca ggcttctcca actggacctc aaatttcatt gtgggcatgt 1440 gcttccagta tgtggagcaa ctgtgtggtc cctacgtctt catcatcttc actgtgctcc 1500 tggttctgtt cttcatcttc acctacttca aagttcctga gactaaaggc cggaccttcg 1560 atgagatcgc ttccggcttc cggcaggggg gagccagcca aagtgataag acacccgagg 1620 agctgttcca tcccctgggg gctgattccc aagtgtgagt cgccccagat caccagcccg 1680 gcctgctccc agcagcccta aggatctctc aggagcacag gcagctggat gagacttcca 1740 aacctgacag atgtcagccg agccgggcct ggggctcctt tctccagcca gcaatgatgt 1800 ccagaagaat attcaggact taacggctcc aggattttaa caaaagcaag actgttgctc 1860 aaatctattc agacaagcaa caggttttat aattttttta ttactgattt tgttattttt 1920 atatcagcct gagtctcctg tgcccacatc ccaggcttca ccctgaatgg ttccatgcct 1980 gagggtggag actaagccct gtcgagacac ttgccttctt cacccagcta atctgtaggg 2040 ctggacctat gtcctaagga cacactaatc gaactatgaa ctacaaagct tctatcccag 2100 gaggtggcta tggccacccg ttctgctggc ctggatctcc ccactctagg ggtcaggctc 2160 cattaggatt tgccccttcc catctcttcc tacccaacca ctcaaattaa tctttcttta 2220 cctgagacca gttgggagca ctggagtgca gggaggagag gggaagggcc agtctgggct 2280 gccgggttct agtctccttt gcactgaggg ccacactatt accatgagaa gagggcctgt 2340 gggagcctgc aaactcactg ctcaagaaga catggagact cctgccctgt tgtgtataga 2400 tgcaagatat ttatatatat ttttggttgt caatattaaa tacagacact aagttatagt 2460 atatctggac aagccaactt gtaaatacac cacctcactc ctgttactta cctaaacaga 2520 tataaatggc tggtttttag aaacatggtt ttgaaatgct tgtggattga gggtaggagg 2580 tttggatggg agtgagacag aagtaagtgg ggttgcaacc actgcaacgg cttagacttc 2640 gactcaggat ccagtccctt acacgtacct ctcatcagtg tcctcttgct caaaaatctg 2700 tttgatccct. gttacccaga gaatatatac attctttatc ttgacattca aggcatttct 2760 atcacatatt tgatagttgg tgttcaaaaa aacactagtt ttgtgccagc cgtgatgctc 2820 aggcttgaaa tcgcattatt ttgaatgtga agggaa 2856 &lt;210&gt; 136 &lt;211&gt; 356 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 136 ggtggagcca aatgaagaaa atgaagatga aagagacaga cacctcagtt tttctggatc 60 aggcattgat gatgatgaag attttatctc cagcaccatt tcaaccacac cacgggcttt 120 tgaccacaca aaacagaacc aggactggac tcagtggaac ccaagccatt caaatccgga 180 agtgctactt cagacaacca caaggatgac tgatgtagac agaaatggca ccactgctta 240 tgaaggaaac tggaacccag aagcacaccc tcccctcatt caccatgagc atcatgagga 300 agaagagacc ccacattcta caagcacaat ccaggcaact cctagtagta caacgg 356

<td rowspan="2"> &lt;210&gt; &lt;211&gt; &lt;212&gt; &lt;213&gt;</td><td colspan="2"> 137 356</td>

<td> DNA Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) - -</td><td> - (356)</td>

<td> &lt;223&gt;</td><td> n = A</td><td>_L,T,C or G</td>

<td> &lt;400&gt;</td><td> 137</td><td></td>

gcaggtggag aagacatttt attgttcctg gggtctctgg aggcccattg gtggggctgg 60

CA 02369578 2001-10-02

WO 00/61612

PCT/USOO/08896 gtcactggct gcccccggaa cagggcgctg ctccatggct ctgcttgtgg tagtctgtgg 120 ctatgtctcc cagcaaggac agaaactcag aaaaatcaat cttcttatcc tcattcttgt 180 cctttttctc aaagacatcg gcgaggtaat ttgtgccctt tttacctcgg cccgcgacca 240 cgctaaggcc aaanttccag acanayggcc gggccggtnc nataggggan cccaacttgg 300 ggacccaaac tctggcgcgg aaacacangg gcataagctt gnttcctgtg gggaaa 356

<td> &lt;210&gt;</td><td> 138</td>

<td> &lt;211&gt;</td><td> 353</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 13B</td>

aggtccagtc ctccacttgg aatagacact tagatttctc tacattgatg tggaaattgc aatgccagcc atcttggcat ctccagccgt gtctttatgt gcatcggagc tcactcagac cctgatgaga tcttgtggga tgctgctacc cctggccctc caagcagcat ctcgsccgsg gtggggagtg agaaaccacc accacctcct gagcaggctg cttgtactcc mssmcgctam gcaagggacg tgtccatcca gaagaggctt cggtaagtag tggttctgag gccgaattcc tttctcctgc ctgactcttc ccctgatgcc cgatctcctg cctccatctc age

120

180

240

300

353

<td> &lt;210&gt;</td><td> 139</td>

<td> &lt;211&gt;</td><td> 371</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 139</td>

agcgtggtcg eggeegaggt agacatattc tacacttcaa agccttggaa aggtcactga ttttccagtg tctgtaaagc actatttgac acagtggatc aggattggac ctgcccgggc actagtggat c ccatccgaag agctttggtg aaaatettea caggtgagga tctgtgccac ggccgctcga caagattgca caattcccat attggattat agtgatccca gtgggaggcc aageegaatt gatggcagtg cgaccagagt gttgacctct aaagatgaaa gtggagaagt ccagcacact tgaagagaga tggtccgacc accttattca atggaaaaat gtaaagatgc ggcggccgtt

120

180

240

300

360

371

<td> &lt;210&gt;</td><td> 140</td>

<td> &lt;211&gt;</td><td> 370</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 140</td>

tagcgtggtc geggeegagg tccatctccc tttgggaact agggggctgc tggtgggaaa 60 tgggagccag ggcagatgtt gcattccttt gtgtccctgt aaatgtggga ctacaagaag 120 aggagetgee tgagtggtac tttctcttcc tggtaatcct ctggcccagc ctcatggcag 180 aatagaggta tttttaggct atttttgtaa tatggettet ggteaaaate cctgtgtagc 240 tgaattccca agccctgcat tgtacagccc cccactcccc tcaccaccta ataaaggaat 300 agttaacact caaaaaaaaa aaaaaacctg cccgggcggc egetegaaag ccgaattcca 360 gcacactggc 370

<td> &lt;210&gt;</td><td> 141</td>

<td> &lt;211&gt;</td><td> 371</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 141</td>

tagcgtggtc geggeegagg tcctctgtgc tgcctgtcac agcccgatgg taccagcgca 60 gggtgtaggc agtgcaggag ccctcatcca gtggcaggga acaggggtca tcactatccc 120

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 aaggagcttc agggtcctgg tactcctcca cagaatactc ggagtattca gagtactcat 180 catcctcagg gggtacccgc tcttcctcct ctgcatgaga gacgcggagc acaggcacag 240 catggagctg ggagccggca gtgtctgcag cataactagg gaggggtcgt gatccagatg 300 cgatgaactg gccctggcag gcacagtgct gactcatctc ttggcgacct gcccgggcgg 360 ccgctcgaag c 371 &lt;210&gt; 142 &lt;211&gt; 343 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 142 gcgttttgag gccaatggtg taaaaggaaa tatcttcaca taaaaactag atggaagcat 60 tgtcagaaac ctctttgtga tgtttgcttt caactcacag agttgaacat tccttttcat 120 agagcagttt tgaaacactc ttttgtagaa tttgcaagcg gatgattgga tcgctatgag 180 gtcttcattg gaaacgggat acctttacat aaaaactaga cagtagcatt ctcagaaatt 240 tctttgggat gtgggcattc aacccacaga ggagaacttc atttgataga gcagttttga 300 aacacccttt ttgtagaatc tacaggtgga catttagagt get 343 &lt;210&gt; 143 &lt;211&gt; 354 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 143 aggtctgatg gcagaaaaac tcagactgtc tgcaacttta cagatggtgc attggttcag 60 catcaggagt gggatgggaa ggaaagcaca ataacaagaa aattgaaaga tgggaaatta 120 gtggtggagt gtgtcatgaa caatgtcacc tgtactcgga tetatgaaaa agtagaataa 180 aaattccatc atcactttgg acaggagtta attaagagaa tgaccaagct cagttcaatg 240 agcaaatctc catactgttt ctttcttttt tttttcatta ctgtgttcaa ttatctttat 300 cataaacatt ttacatgcag ctatttcaaa gtgtgttgga ttaattagga teat 354 &lt;210&gt; 144 &lt;211&gt; 353 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 144 ggtcaaggac ctgggggacc cccaggtcca gcagccacat gattctgcag cagacaggga 60 cctagagcac atctggatct cagccccacc cctggcaacc tgcctgccta gagaactccc 120 aagatgacag actaagtagg attctgccat ttagaataat tctggtatcc tgggcgttgc 180 gttaagttgc ttaactttca ttctgtctta egatagtett cagaggtggg aacagatgaa 240 gaaaccatgc cccagagaag gttaagtgac ttcctcttta tggagccagt gttccaacct 300 aggtttgcct gataccagac ctgtggcccc acctcccatg caggtctctg tgg 353 &lt;210&gt; 145 &lt;211&gt; 371 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 145 caggtctgtc ataaactggt ctggagtttc tgacgactcc ttgttcacca aatgcaccat 60 ttcctgagac ttgctggcct ctccgttgag tccacttggc tttctgtcct ccacagctcc 120 attgccactg ttgatcacta gctttttctt ctgcccacac cttcttcgac tgttgactgc 180 aatgcaaact gcaagaatca aagccaaggc caagagggat gccaagatga tcagccattc 240

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 tggaatttgg ggtgtcctta taggaccaga ggttgtgttt gctccacctt cttgactccc 300 atgtgagacc tcggccgcga ccacgctaag ccgaattcca gcacactggc ggcccgttac 360 tagtggatcc g 371

<td> &lt;210&gt;</td><td> 146</td>

<td> &lt;211&gt;</td><td> 355</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 146</td>

ggtcctccgt cctcttccca gaggtgtcgg ggcttggccc cagcctccat cttcgtctct 60 caggatggcg agtagcagcg gctccaaggc tgaattcatt gtcggaggga aatataaact 120 ggtacggaag atcgggtctg gctccttcgg ggacatctat ttggcgatca acatcaccaa 180 cggcgaggaa gtggcagtga agctagaatc tcagaaggcc aggcatcccc agttgctgta 240 cgagagcaag ctctataaga ttcttcaagg tggggttggc atcccccaca tacggtggta 300 tggtcaggaa aaagactaca atgtactagt catggatctt ctgggaccta gcctc 355

<td> &lt;210&gt;</td><td> 147</td>

<td> &lt;211&gt;</td><td> 355</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 147</td>

ggtctgttac aaaatgaaga cagacaacac aacatttact ctgtggagat atcctactca 60 tactatgcac gtgctgtgat tttgaacata actcgtccca aaaacttgtc acgatcatcc 120 tgacttttta ggttggctga tccatcaatc ttgcactcaa ctgttacttc tttcccagtg 180 ttgttaggag caaagctgac ctgaacagca accaatggct gtagataccc aacatgcagt 240 tttttcccat aatatgggaa atattttaag tctatcattc cattatgagg ataaactgct 300 acatttggta tatcttcatt ctttgaaaca caatctatcc ttggcactcc ttcag 355

<td> &lt;210&gt;</td><td> 148</td>

<td> &lt;211&gt;</td><td> 369</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 148</td>

aggtctctct ccccctctcc caccttcctt catgatgtgg agggagtgtg atgtggcagc gctgcagcag gaaaagatga acttcttca ccgagggctt ccctcttctt cctccatcca gagaagttac ctctcctgcc gaagagtgct ctgagaaggt caagtggctc gcctgaggat agactctcct agccaagtga gcaacccagc ttctctcaca ttgtcctgtt gacatcaata gggcgacccc agacatgctt cctagccaac tctagaaaga gccctgggag cacagaggaa gagagcttac acttcccctt accgcatgag agcgcttaag ttctcaaatt gaagagtcag cattcctcag

120

180

240

300

360

369

<td> &lt;210&gt;</td><td> 149</td><td></td>

<td> &lt;211&gt;</td><td> 620</td><td></td>

<td> &lt;212&gt;</td><td> DNA</td><td></td>

<td> &lt;213&gt;</td><td> Homo</td><td> sapien</td>

<td> &lt;220&gt;</td><td></td><td></td>

<td> &lt;221&gt;</td><td> mise</td><td> feature</td>

<td> &lt;222&gt;</td><td> (1) - -</td><td> . (620)</td>

<td> &lt;223&gt;</td><td> n = A</td><td> l,T,C or</td>

&lt;400&gt; 149

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 actagtcaaa catgtttatc gccaatattt gtgaaactta gttcttgtta ataaggttaa tttcaagcct gagaatttct atgtctctaa tttcccttaa agggttaagg aatgctaaaa ttttattatg ccttatatct acactttata tttccaaata aagttgttaa tcgaactatt cattaatatc gaaagtacta gtgtgaaant gtgttgggga taatttggga ttttgtgaag atccataaca aggtaaaaat gaatggactt tgaccaaaca taaggaaagc ctgaatcatt tttcatggtc atttaaaatg gaaaatattt ttgtgtcttt tttatactac gaggtttcca ggtctgttaa ttctaaaaga aaaatcattt catttcacta caaacctggt aaattttcct tttaagtagt tcactaatta atttgtaana anatttaata gggctaagga aatgcaaaaa cctaaatgca aggctcatgt tgccatantt ctttttaaaa gttatagttt cctatactat naatatgcac atctgatcaa gaagaggaag aaaagtttat tatcatttgt tnactccgat gggtaaaggc attctttana

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360

420

480

540

600

620

<td> &lt;210&gt;</td><td> 150</td>

<td> &lt;211&gt;</td><td> 371</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 150</td>

ggtccgatca aaacctgcta cctccccaag actttactag tgccgataaa ctttctcaaa 60 gagcaaccag tatcacttcc ctgtttataa aacctctaac catctctttg ttctttgaac 120 atgctgaaaa ccacctggtc tgcatgtatg cccgaatttg yaattctttt ctctcaaatg 180 aaaatttaat tttagggatt catttctata ttttcacata tgtagtatta ttatttcctt 240 atatgtgtaa ggtgaaattt atggtatttg agtgtgcaag aaaatatatt tttaaagctt 300 tcatttttcc cccagtgaat gatttagaat tttttatgta aatatacaga atgttttttc 360 ttacttttat a 371

<td> &lt;210&gt;</td><td> 151</td>

<td> &lt;211&gt;</td><td> 4655</td>

<td> &lt;212&gt;</td><td> DNA</td>

<td> &lt;213&gt;</td><td> Homo sapien</td>

<td> &lt;400&gt;</td><td> 151</td>

gggacttgag gggttggcaa acatgttgta tggggctcct ataacacaga ccaccttcga cgcacagttt ttctgttatc aatcctggag cctggaaaac gaacagcatg ccacgcgcag tgctctctct cgacgtgtcc attccactga actgaagaaa aggtgatgac cccacctcct ctgagcacgt cacggaggtg acgagggaca gattgcccct agtatgtaga agatcccatc aggttggcac tgaattcacg gagggatgaa ccgccgtcca tcctgggccg acgctgcttt cggatgaaga tagcatcaga cgaagcgccc gtttcgtcag gatccccaga tgatgaactg tggtgaagat caaagagtcc cgtacaggca acagcaacag agtctccatc ttcatatggt agctgccttc tgtgagccag ccattcctga tggcatggga ttcttaagta ccagaagaaa aatgcccaga gaccagcaga aacagcgtca ccatcacccg ttccagcagt ctctactgcc cagggagctg gtgaagcggt yctagtcatt acaggaagac acagtcttgt attttaatca gaggcccgga aagcagcaag aacacacatg gtatacttac ctggaactca cagcagcacc aacagctccc cttatcaacc gccaacattc gattcatatt ggacagcagc ctcaatttag ttcagaacgg cggcgccctc ccatcccctc cgagcaccgc aaattgcaaa ttatccgcgc gccccaacca tgattcgagt agagtgtgct acaatttcat ttgttactct tctgtgcttg tttcggacag gtatccagat cagtgagggg tgcagtacct agcacttact cacctctgaa ctcagcagcg ccatgatggg gtaagggtct attgatcaat tgagccacag ctcctcgtcc gccctacgca caacaccgac caagtcggcc gacatgcccc catgcctgtc tgagctgagc agaggggaac ggtaccttat gtgtaacagc ggaaaccaga cccaggaaga tacaaagaac gacatccatc ccgtgagact tcttcagcac tcagaaacag caaaatgaac caacgccctc cacccacatg cggggtgggg cttacagcta tacacgaacc accagtccct cagcccagct tacccaggcc acctggacgt atccagatca tacaaaaaag cgtgaattca agccatgccc gagccacccc agttgtgttg gatgggcaag gacaggaagg ggtgatggta aagaaacgaa tatgaaatgc acaattgaaa acctcaatac agcatgaaca actcctacaa ccaatggctg

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1380

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 gagacatgaa tggactcagc cccacccagg cactccctcc cccactctcc atgccatcca 1440 cctcccactg cacaccccca cctccgtatc ccacagattg cagcattgtc agtttcttag 1500 cgaggttggg ctgttcatca tgtctggact atttcacgac ccaggggctg accaccatct 1560 atcagattga gcattactcc atggatgatc tggcaagtct gaaaatccct gagcaatttc 1620 gacatgcgat ctggaagggc atcctggacc accggcagct ccacgaattc tcctcccctt 1680 ctcatctcct gcggacccca agcagtgcct ctacagtcag tgtgggctcc agtgagaccc 1740 ggggtgagcg tgttattgat gctgtgcgat tcaccctccg ccagaccatc tctttcccac 1800 cccgagatga gtggaatgac ttcaactttg acatggatgc tcgccgcaat aagcaacagc 1860 gcatcaaaga ggagggggag tgagcctcac catgtgagct cttcctatcc ctctcctaac 1920 tgccagcccc ctaaaagcac tcctgcttaa tcttcaaagc cttctcccta gctcctcccc 1980 ttcctcttgt ctgatttctt aggggaagga gaagtaagag gcttacttct taccctaacc 2040 atctgacctg gcatctaatt ctgattctgg ctttaagcct tcaaaactat agcttgcaga 2100 actgtagctt gccatggcta ggtagaagtg agcaaaaaag agttgggtgt ctccttaagc 2160 tgcagagatt tctcattgac ttttataaag catgttcacc cttatagtct aagactatat 2220 atataaatgt ataaatatac agtatagatt tttgggtggg gggcattgag tattgtttaa 2280 aatgtaattt aaatgaaaga aaattgagtt gcacttattg accatttttt aatttacttg 2340 ttttggatgg cttgtctata ctccttccct taaggggtat catgtatggt gataggtatc 2400 tagagcttaa tgctacatgt gagtgacgat gatgtacaga ttctttcagt tctttggatt 2460 ctaaatacat gccacatcaa acctttgagt agatccattt ccattgctta ttatgtaggt 2520 aagactgtag atatgtattc ttttctcagt gttggtatat tttatattac tgacatttct 2580 tctagtgatg atggttcacg ttggggtgat ttaatccagt tataagaaga agttcatgtc 2640 caaacgtcct ctttagtttt tggttgggaa tgaggaaaat tcttaaaagg cccatagcag 2700 ccagttcaaa aacacccgac gtcatgtatt tgagcatatc agtaaccccc ttaaatttaa 2760 taccagatac cttatcttac aatattgatt gggaaaacat ttgctgccat tacagaggta 2820 ttaaaactaa atttcactac tagattgact aactcaaata cacatttgct actgttgtaa 2880 gaattctgat tgatttgatt gggatgaatg ccatctatct agttctaaca gtgaagtttt 2940 actgtctatt aatattcagg gtaaatagga atcattcaga aatgttgagt ctgtactaaa 3000 cagtaagata tctcaatgaa ccataaattc aactttgtaa aaatcttttg aagcatagat 3060 aatattgttt ggtaaatgtt tcttttgttt ggtaaatgtt tcytttaaag accctcctat 3120 tctataaaac tctgcatgta gaggcttgtt tacctttctc tctctaaggt ttacaatagg 3180 agtggtgatt tgaaaaatat aaaattatga gattggtttt cctgtggcat aaattgcatc 3240 actgtatcat tttctttttt aaccggtaag agtttcagtt tgttggaaag taactgtgag 3300 aacccagttt cccgtccatc tcccttaggg actacccata gacatgaaag gtccccacag 3360 agcaagagat aagtctttca tggctgctgt tgcttaaacc acttaaacga agagttccct 3420 tgaaactttg ggaaaacatg ttaatgacaa tattccagat ctttcagaaa tataacacat 3480 ttttttgcat gcatgcaaat gagctctgaa atcttcccat gcattctggt caagggctgt 3540 cattgcacat aagcttccat tttaatttta aagtgcaaaa gggccagcgt ggctctaaaa 3600 ggtaatgtgt ggattgcctc tgaaaagtgt gtatatattt tgtgtgaaat tgcatacttt 3660 gtattttgat tatttttttt ttcttcttgg gatagtggga tttccagaac cacacttgaa 3720 accttttttt atcgtttttg tattttcatg aaaataccat ttagtaagaa taccacatca 3780 aataagaaat aatgctacaa ttttaagagg ggagggaagg gaaagttttt ttttttatta 3840 tttttttaaa attttgtatg ttaaagagaa tgagtccttg atttcaaagt tttgttgtac 3900 ttaaatggta ataagcactg taaacttctg caacaagcat gcagctttgc aaacccatta 3960 aggggaagaa tgaaagctgt tccttggtcc tagtaagaag acaaactgct tcccttactt 4020 tgctgagggt ttgaataaac ctaggacttc cgagctatgt cagtactatt caggtaacac 4080 tagggccttg gaaatccctg tactgtgtct catggatttg gcactagcca aagcgaggca 4140 ccccttactg gcttacctcc tcatggcagc ctactctcct tgagtgtatg agtagccagg 4200 gtaaggggta aaaggatagt aagcatagaa accactagaa agtgggctta atggagttct 4260 tgtggcctca gctcaatgca gttagctgaa gaattgaaaa gtttttgttt ggagacgttt 4320 ataaacagaa atggaaagca gagttttcat taaatccttt tacctttttt ttttcttggt 4380 aatcccctaa aataacagta tgtgggatat tgaatgttaa agggatattt ttttctatta 4440 tttttataat tgtacaaaat taagcaaatg ttaaaagttt tatatgcttt attaatgttt 4500 tcaaaaggta ttatacatgt gatacatttt ttaagcttca gttgcttgtc ttctggtact 4560 ttctgttatg ggcttttggg gagccagaag ccaatctaca atctcttttt gtttgccagg 4620 acatgcaata aaatttaaaa aataaataaa aacta 4655

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 &lt;21Q&gt; 152 &lt;211&gt; 586 &lt;212&gt; PRT &lt;213&gt; Homo sapien &lt;400&gt; 152

<td> Met 1</td><td> Leu</td><td> Tyr</td><td> Leu</td><td> Glu 5</td><td> Asn</td><td> Asn</td><td> Ala</td><td> Gin</td><td> Thr 10</td><td> Gin</td><td> Phe</td><td> Ser</td><td> Glu</td><td> Pro 15</td><td> Gin</td>

<td> Tyr</td><td> Thr</td><td> Asn</td><td> Leu</td><td> Gly</td><td> Leu</td><td> Leu</td><td> Asn</td><td> Ser</td><td> Met</td><td> Asp</td><td> Gin</td><td> Gin</td><td> He</td><td> Gin</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Pro</td><td> Tyr</td><td> Asn</td><td> Thr</td><td> Asp</td><td> His</td><td> Ala</td><td> Gin</td><td> Asn</td><td> Ser</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Ala</td><td> Pro</td><td> Ser</td><td> Pro</td><td> Tyr</td><td> Ala</td><td> Gin</td><td> Pro</td><td> Ser</td><td> Ser</td><td> Thr</td><td> Phe</td><td> Asp</td><td> Ala</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Leu</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Pro</td><td> Ala</td><td> He</td><td> Pro</td><td> Ser</td><td> Asn</td><td> Thr</td><td> Asp</td><td> Tyr</td><td> Pro</td><td> Gly</td><td> Pro</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> His</td><td> Ser</td><td> Phe</td><td> Asp</td><td> Val</td><td> Ser</td><td> Phe</td><td> Gin</td><td> Gin</td><td> Ser</td><td> Ser</td><td> Thr</td><td> Ala</td><td> Lys</td><td> Ser</td><td> Ala</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Thr</td><td> Trp</td><td> Thr</td><td> Tyr</td><td> Ser</td><td> Thr</td><td> Glu</td><td> Leu</td><td> Lys</td><td> Lys</td><td> Leu</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> He</td><td> Ala</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Lys</td><td> Thr</td><td> Cys</td><td> Pro</td><td> He</td><td> Gin</td><td> He</td><td> Lys</td><td> Val</td><td> Met</td><td> Thr</td><td> Pro</td><td> Pro</td><td> Pro</td><td> Gin</td><td> Gly</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td> Ala</td><td> Val</td><td> lie</td><td> Arg</td><td> Ala</td><td> Met</td><td> Pro</td><td> Val</td><td> Tyr</td><td> Lys</td><td> Lys</td><td> Ala</td><td> Glu</td><td> His</td><td> Val</td><td> Thr</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td> Glu</td><td> Val</td><td> Val</td><td> Lys</td><td> Arg</td><td> Cys</td><td> Pro</td><td> Asn</td><td> His</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Arg</td><td> Glu</td><td> Phe</td><td> Asn</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td> Glu</td><td> Gly</td><td> Gin</td><td> He</td><td> Ala</td><td> Pro</td><td> Ser</td><td> Ser</td><td> His</td><td> Leu</td><td> He</td><td> Arg</td><td> Val</td><td> Glu</td><td> Gly</td><td> Asn</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td> Ser</td><td> His</td><td> Ala</td><td> Gin</td><td> Tyr</td><td> Val</td><td> Glu</td><td> Asp</td><td> Pro</td><td> He</td><td> Thr</td><td> Gly</td><td> Arg</td><td> Gin</td><td> Ser</td><td> Val</td>

<td></td><td></td><td></td><td> 180</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td> 190</td><td></td><td></td>

<td> Leu</td><td> Val</td><td> Pro</td><td> Tyr</td><td> Glu</td><td> Pro</td><td> Pro</td><td> Gin</td><td> Val</td><td> Gly</td><td> Thr</td><td> Glu</td><td> Phe</td><td> Thr</td><td> Thr</td><td> Val</td>

<td></td><td></td><td> 195</td><td></td><td></td><td></td><td></td><td> 200</td><td></td><td></td><td></td><td></td><td> 205</td><td></td><td></td><td></td>

<td> Leu</td><td> Tyr</td><td> Asn</td><td> Phe</td><td> Met</td><td> Cys</td><td> Asn</td><td> Ser</td><td> Ser</td><td> Cys</td><td> Val</td><td> Gly</td><td> Gly</td><td> Met</td><td> Asn</td><td> Arg</td>

<td></td><td> 210</td><td></td><td></td><td></td><td></td><td> 215</td><td></td><td></td><td></td><td></td><td> 220</td><td></td><td></td><td></td><td></td>

<td> Arg</td><td> Pro</td><td> lie</td><td> Leu</td><td> He</td><td> He</td><td> Val</td><td> Thr</td><td> Leu</td><td> Glu</td><td> Thr</td><td> Arg</td><td> Asp</td><td> Gly</td><td> Gin</td><td> Val</td>

<td> 225</td><td></td><td></td><td></td><td></td><td> 230</td><td></td><td></td><td></td><td></td><td> 235</td><td></td><td></td><td></td><td></td><td> 240</td>

<td> Leu</td><td> Gly</td><td> Arg</td><td> Arg</td><td> Cys</td><td> Phe</td><td> Glu</td><td> Ala</td><td> Arg</td><td> He</td><td> Cys</td><td> Ala</td><td> Cys</td><td> Pro</td><td> Gly</td><td> Arg</td>

<td></td><td></td><td></td><td></td><td> 245</td><td></td><td></td><td></td><td></td><td> 250</td><td></td><td></td><td></td><td></td><td> 255</td><td></td>

<td> Asp</td><td> Arg</td><td> Lys</td><td> Ala</td><td> Asp</td><td> Glu</td><td> Asp</td><td> Ser</td><td> He</td><td> Arg</td><td> Lys</td><td> Gin</td><td> Gin</td><td> Val</td><td> Ser</td><td> Asp</td>

<td></td><td></td><td></td><td> 260</td><td></td><td></td><td></td><td></td><td> 265</td><td></td><td></td><td></td><td></td><td> 270</td><td></td><td></td>

<td> Ser</td><td> Thr</td><td> Lys</td><td> Asn</td><td> Gly</td><td> Asp</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Arg</td><td> Pro</td><td> Phe</td><td> Arg</td><td> Gin</td><td> Asn</td><td> Thr</td>

<td></td><td></td><td> 275</td><td></td><td></td><td></td><td></td><td> 280</td><td></td><td></td><td></td><td></td><td> 285</td><td></td><td></td><td></td>

<td> His</td><td> Gly</td><td> He</td><td> Gin</td><td> Met</td><td> Thr</td><td> Ser</td><td> lie</td><td> Lys</td><td> Lys</td><td> Arg</td><td> Arg</td><td> Ser</td><td> Pro</td><td> Asp</td><td> Asp</td>

<td></td><td> 290</td><td></td><td></td><td></td><td></td><td> 295</td><td></td><td></td><td></td><td></td><td> 300</td><td></td><td></td><td></td><td></td>

<td> Glu</td><td> Leu</td><td> Val</td><td> Tyr</td><td> Leu</td><td> Pro</td><td> Val</td><td> Arg</td><td> Gly</td><td> Arg</td><td> Glu</td><td> Thr</td><td> Tyr</td><td> Glu</td><td> Met</td><td> Leu</td>

<td> 305</td><td></td><td></td><td></td><td></td><td> 310</td><td></td><td></td><td></td><td></td><td> 315</td><td></td><td></td><td></td><td></td><td> 320</td>

<td> Val</td><td> Lys</td><td> He</td><td> Lys</td><td> Glu</td><td> Ser</td><td> Leu</td><td> Glu</td><td> Leu</td><td> Met</td><td> Gin</td><td> Tyr</td><td> Leu</td><td> Leu</td><td> Gin</td><td> His</td>

<td></td><td></td><td></td><td></td><td> 325</td><td></td><td></td><td></td><td></td><td> 330</td><td></td><td></td><td></td><td></td><td> 335</td><td></td>

<td> Thr</td><td> lie</td><td> Glu</td><td> Thr</td><td> Tyr</td><td> Arg</td><td> Gin</td><td> Gin</td><td> Gin</td><td> Gin</td><td> Gin</td><td> Gin</td><td> His</td><td> Gin</td><td> His</td><td> Leu</td>

<td></td><td></td><td></td><td> 340</td><td></td><td></td><td></td><td></td><td> 345</td><td></td><td></td><td></td><td></td><td> 350</td><td></td><td></td>

<td> Leu</td><td> Gin</td><td> Lys</td><td> Gin</td><td> Thr</td><td> Ser</td><td> He</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Ser</td><td> Tyr</td><td> Gly</td><td> Asn</td><td> Ser</td>

<td></td><td></td><td> 355</td><td></td><td></td><td></td><td></td><td> 360</td><td></td><td></td><td></td><td></td><td> 365</td><td></td><td></td><td></td>

<td> Ser</td><td> Pro</td><td> Pro</td><td> Leu</td><td> Asn</td><td> Lys</td><td> Met</td><td> Asn</td><td> Ser</td><td> Met</td><td> Asn</td><td> Lys</td><td> Leu</td><td> Pro</td><td> Ser</td><td> Val</td>

<td></td><td> 370</td><td></td><td></td><td></td><td></td><td> 375</td><td></td><td></td><td></td><td></td><td> 380</td><td></td><td></td><td></td><td></td>

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896

<td> Ser</td><td> Gin</td><td> Leu</td><td> He</td><td> Asn</td><td> Pro</td><td> Gin</td><td> Gin</td><td colspan="2"> Arg Asn</td><td> Ala</td><td> Leu</td><td> Thr</td><td> Pro</td><td> Thr</td><td> Thr</td>

<td> 385</td><td></td><td></td><td></td><td></td><td> 390</td><td></td><td></td><td></td><td></td><td> 395</td><td></td><td></td><td></td><td></td><td> 400</td>

<td> lie</td><td> Pro</td><td> Asp</td><td> Gly</td><td> Met</td><td> Gly</td><td> Ala</td><td> Asn</td><td> He</td><td> Pro</td><td> Met</td><td> Met</td><td> Gly</td><td> Thr</td><td> His</td><td> Met</td>

<td></td><td></td><td></td><td></td><td> 405</td><td></td><td></td><td></td><td></td><td> 410</td><td></td><td></td><td></td><td></td><td> 415</td><td></td>

<td> Pro</td><td> Met</td><td> Ala</td><td> Gly</td><td> Asp</td><td> Met</td><td> Asn</td><td> Gly</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Thr</td><td> Gin</td><td> Ala</td><td> Leu</td><td> Pro</td>

<td></td><td></td><td></td><td> 420</td><td></td><td></td><td></td><td></td><td> 425</td><td></td><td></td><td></td><td></td><td> 430</td><td></td><td></td>

<td> Pro</td><td> Pro</td><td> Leu</td><td> Ser</td><td> Met</td><td> Pro</td><td> Ser</td><td> Thr</td><td> Ser</td><td> His</td><td> Cys</td><td> Thr</td><td> Pro</td><td> Pro</td><td> Pro</td><td> Pro</td>

<td></td><td></td><td> 435</td><td></td><td></td><td></td><td></td><td> 440</td><td></td><td></td><td></td><td></td><td> 445</td><td></td><td></td><td></td>

<td> Tyr</td><td> Pro</td><td> Thr</td><td> Asp</td><td> Cys</td><td> Ser</td><td> He</td><td> Val</td><td> Ser</td><td> Phe</td><td> Leu</td><td> Ala</td><td> Arg</td><td> Leu</td><td> Gly</td><td> Cys</td>

<td></td><td> 450</td><td></td><td></td><td></td><td></td><td> 455</td><td></td><td></td><td></td><td></td><td> 460</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Ser</td><td> Cys</td><td> Leu</td><td> Asp</td><td> Tyr</td><td> Phe</td><td> Thr</td><td> Thr</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Thr</td><td> Thr</td><td> He</td><td> Tyr</td>

<td> 465</td><td></td><td></td><td></td><td></td><td> 470</td><td></td><td></td><td></td><td></td><td> 475</td><td></td><td></td><td></td><td></td><td> 480</td>

<td> Gin</td><td> He</td><td> Glu</td><td> His</td><td> Tyr</td><td> Ser</td><td> Met</td><td> Asp</td><td> Asp</td><td> Leu</td><td> Ala</td><td> Ser</td><td> Leu</td><td> Lys</td><td> He</td><td> Pro</td>

<td></td><td></td><td></td><td></td><td> 485</td><td></td><td></td><td></td><td></td><td> 490</td><td></td><td></td><td></td><td></td><td> 495</td><td></td>

<td> Glu</td><td> Gin</td><td> Phe</td><td> Arg</td><td> His</td><td> Ala</td><td> He</td><td> Trp</td><td> Lys</td><td> Gly</td><td> He</td><td> Leu</td><td> Asp</td><td> His</td><td> Arg</td><td> Gin</td>

<td></td><td></td><td></td><td> 500</td><td></td><td></td><td></td><td></td><td> 505</td><td></td><td></td><td></td><td></td><td> 510</td><td></td><td></td>

<td> Leu</td><td> His</td><td> Glu</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Pro</td><td> Ser</td><td> His</td><td> Leu</td><td> Leu</td><td> Arg</td><td> Thr</td><td> Pro</td><td> Ser</td><td> Ser</td>

<td></td><td></td><td> 515</td><td></td><td></td><td></td><td></td><td> 520</td><td></td><td></td><td></td><td></td><td> 525</td><td></td><td></td><td></td>

<td> Ala</td><td> Ser</td><td> Thr</td><td> Val</td><td> Ser</td><td> Val</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Glu</td><td> Thr</td><td> Arg</td><td> Gly</td><td> Glu</td><td> Arg</td><td> Val</td>

<td></td><td> 530</td><td></td><td></td><td></td><td></td><td> 535</td><td></td><td></td><td></td><td></td><td> 540</td><td></td><td></td><td></td><td></td>

<td> He</td><td> Asp</td><td> Ala</td><td> Val</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Arg</td><td> Gin</td><td> Thr</td><td> He</td><td> Ser</td><td> Phe</td><td> Pro</td><td> Pro</td>

<td> 545</td><td></td><td></td><td></td><td></td><td> 550</td><td></td><td></td><td></td><td></td><td> 555</td><td></td><td></td><td></td><td></td><td> 560</td>

<td> Arg</td><td> Asp</td><td> Glu</td><td> Trp</td><td> Asn</td><td> Asp</td><td> Phe</td><td> Asn</td><td> Phe</td><td> Asp</td><td> Met</td><td> Asp</td><td> Ala</td><td> Arg</td><td> Arg</td><td> Asn</td>

<td></td><td></td><td></td><td></td><td> 565</td><td></td><td></td><td></td><td></td><td> 570</td><td></td><td></td><td></td><td></td><td> 575</td><td></td>

<td> Lys</td><td> Gin</td><td> Gin</td><td> Arg</td><td> He</td><td> Lys</td><td> Glu</td><td> Glu</td><td> Gly</td><td> Glu</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 580</td><td></td><td></td><td></td><td></td><td> 585</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 153 &lt;211&gt; 2007 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 153 gaattcgtcg ctgctccagg gaaagttctg ttactccact gactctctct tttcctgata 60 acatggccag caagaaagta attacagtgt ttggagcaac aggagctcaa ggtggctctg 120 tggccagggc aattttggag agcaaaaaat ttgcagtgag agcagtgacc agggatgtga 180 cttgaccaaa tgccctggag ctccagcgcc ttggagctga ggtggtcaaa ggtgacctga 240 atgataaagc atcggtggac agtgccttaa aaggtgtcta tggggccttc ttggtgacca 300 acttctggga ccctctcaac caagataagg aagtgtgtcg ggggaagctg gtggcagact 360 ccgccaagca cctgggtctg aagcacgtgg tgtacagcgg cctggagaac gtcaagcgac 420 tgacggatgg caagctggag gtgccgcact ttgacagcaa gggcgaggtg gaggagtact 480 tctggtccat tggcatcccc atgaccagtg tccgcgtggc ggcctacttt gaaaactttc 540 tcgcggcgtg gcggcccgtg aaagcctctg atggagatta ctacaccttg gctgtaccga 600 tgggagatgt accaatggat ggtatctctg ttgctgatat tggagcagcc gtctctagca 660 tttttaattc tccagaggaa tttttaggca aggccgtggg gctcagtgca gaagcactaa 720 caatacagca atatgctgat gttttgtcca aggctttggg gaaagaagtc cgagatgcaa 780 agattacccc ggaagctttc gagaagctgg gattccctgc agcaaaggaa atagccaata 840 tgtgtcgttt ctatgaaatg aagccagacc gagatgtcaa tctcacccac caactaaatc 900 ccaaagtcaa aagcttcagc cagtttatct cagagaacca gggagccttc aagggcatgt 960 agaaaatcag ctgttcagat aggcctctgc accacacagc ctctttcctc tctgatcctt 1020 ttcctcttta cggcacaaca ttcatgttga cagaacatgc tggaatgcaa ttgtttgcaa 1080 caccgaagga tttcctgcgg tcgcctcttc agtaggaagc actgcattgg tgataggaca 1140 cggtaatttg attcacattt aacttgctag ttagtgataa gggtggtaca actgtttggt 1200 aaaatgagaa gcctcggaac ttggagcttc tctcctacca ctaatgggag ggcagattat 1260 actgggattt ctcctgggtg agtaatttca agccctaatg ctgaaattcc cctaggcagc 1320

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 73 tccagttttc tcaactgcat tgcaaaattc ccagtgaact tttaagtact tttaacttaa 1380 aaaaatgaac atctttgtag agaattttct ggggaacatg gtgttcaatg aacaagcaca 1440 agcattggaa atgctaaaat tcagttttgc ctcaagattg gaagtttatt ttctgactca 1500 ttcatgaagt catctattga gccaccattc aattattcat ctattaattc cttgatcctt 1560 catttatcca ttctgcaaac ttttcttgag caccagcacg ggtggccatt tgtggacttc 1620 tcttcattcc tatgtgtttt cttatcaaag tgatccactc tcgaaaggct cctttccagt 1680 ctgtggttgg gttcaagtca tgccagggcc agggggccca tctcctcgtt tagctctagg 1740 caaaatccag gggatctgca gtggggagcg ggggcaggaa gctggaggga aggcctgtga 1800 agggtaggga tgtggaaaga caaggtgaca gaaggaccca ataggacctt tctatatctc 1860 tggcttagca ttttctacat catattgtaa tcgtcttatt tgctagtttt cttccttact 1920 gtgagtgact aacagtcatc tttatcccag tgcctggtac ataataagtg atcaataaat 1980 gttgattgac taaaaaaaaa aaaaaaa 2007

<td colspan="2"> &lt;210&gt; 154 &lt;211&gt; 2148 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt;</td><td> 154</td>

gaattcgtcg ctgctccagg gaaagttctg ttactccact gactctctct tttcctgata 60 acatggccag caagaaagta attacagtgt ttggagcaac aggagctcaa ggtggctctg 120 tggccagggc aattttggag agcaaaaaat ttgcagtgag agcagtgacc agggatgtga 180 cttgaccaaa tgccctggag ctccagcgcc ttggagctga ggtggtcaaa ggtgacctga 240 atgataaagc atcggtggac agtgccttaa aaggggaagc tggtggcaga ctccgccaag 300 cacctgggtc tgaagcacgt ggtgtacagc ggcctggaga acgtcaagcg actgacggat 360 ggcaagctgg aggtgccgca ctttgacagc aagggcgagg tggaggagta cttctggtcc 420 attggcatcc ccatgaccag tgtccgcgtg gcggcctact ttgaaaactt tctcgcggcg 480 tggcggcccg tgaaagcctc tgatggagat tactacacct tggctgtacc gatgggagat 540 gtaccaatgg atggtatctc tgttgctgat attggagcag ccgtctctag catttttaat 600 tctccagagg aatttttagg caaggccgtg gggctcagtg cagaagcact aacaatacag 660 caatatgctg atgttttgtc caaggctttg gggaaagaag tccgagatgc aaagactatc 720 tgtgctatag atgaccagaa aacagtggaa gaaggtttca tggaagacgt gggcttgagt 780 tggtccttga gggaacatga ccatgtatag acagaggagg catcaagaag gctggcctgg 840 ctaattctgg aataaacacg acaaaccaga ggcagtacgg gaaggaggca aattctggct 900 ctgcctctat ccttgattac cccggaagct ttcgagaagc tgggattccc tgcagcaaag 960 gaaatagcca atatgtgtcg tttctatgaa atgaagccag accgagatgt caatctcacc 1020 caccaactaa atcccaaagt caaaagcttc agccatttta tctcagagaa ccagggagcc 1080 ttcaagggca tgtagaaaat cagctgttca gataggcctc tgcaccacac agcctctttc 1140 ctctctgatc cttttcctct ttacggcaca acattcatgt tgacagaaca tgctggaatg 1200 caattgtttg caacaccgaa ggatttcctg cggtcgcctc ttcagtagga agcactgcat 1260 tggtgatagg acacggtaat ttgattcaca tttaacttgc tagttagtga taagggtggt 1320 acaactgttt ggtaaaatga gaagcctcgg aacttggagc ttctctccta ccactaatgg 1380 gagggcagat tatactggga tttctcctgg gtgagtaatt tcaagcccta atgctgaaat 1440 tcccctaggc agctccagtt ttctcaactg cattgcaaaa ttcccagtga acttttaagt 1500 acttttaact taaaaaaatg aacatctttg tagagaattt tctggggaac atggtgttca 1560 atgaacaagc acaagcattg gaaatgctaa aattcagttt tgcctcaaga ttggaagttt 1620 attttctgac tcattcatga agtcatctat tgagccacca ttcaattatt catctattaa 1680 ttccttgatc cttcatttat ccattctgca aacttttctt gagcaccagc acgggtggcc 1740 atttgtggac ttctcttcat tcctatgtgt tttcttatca aagtgatcca ctctcgaaag 1800 gctcctttcc agtctgtggt tgggttcaag tcatgccagg gccagggggc ccatctcctc 1860 gtttagctct aggcaaaatc caggggatct gcagtgggga gcgggggcag gaagctggag 1920 ggaaggcctg tgaagggtag ggatgtggaa agacaaggtg acagaaggac ccaataggac 1980 ctttctatat ctctggctta gcattttcta catcatattg taatcgtctt atttgctagt 2040 tttcttcctt actgtgagtg actaacagtc atctttatcc cagtgcctgg tacataataa 2100 gtgatcaata aatgttgatt gactaaatga aaaaaaaaaa aaaaaaaa 2148

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 &lt;210&gt; 155 &lt;211&gt; 153 &lt;212 &gt; PRT &lt;213&gt; Homo sapien &lt;400&gt; 155

<td> Met</td><td> Thr Ser</td><td> Val</td><td> Arg</td><td> Val</td><td> Ala</td><td> Ala</td><td> Tyr</td><td> Phe</td><td> Glu</td><td> Asn</td><td> Phe</td><td> Leu</td><td> Ala</td><td> Ala</td>

<td> 1</td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Trp</td><td> Arg Pro</td><td> Val</td><td> Lys</td><td> Ala</td><td> Ser</td><td> Asp</td><td> Gly</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Thr</td><td> Leu</td><td> Ala</td><td> Val</td>

<td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Pro</td><td> Met Gly</td><td> Asp</td><td> Val</td><td> Pro</td><td> Met</td><td> Asp</td><td> Gly</td><td> Ile</td><td> Ser</td><td> Val</td><td> Ala</td><td> Asp</td><td> Ile</td><td> Gly</td>

<td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ala</td><td> Ala Val</td><td> Ser</td><td> Ser</td><td> Ile</td><td> Phe</td><td> Asn</td><td> Ser</td><td> Pro</td><td> Glu</td><td> Glu</td><td> Phe</td><td> Leu</td><td> Gly</td><td> Lys</td>

<td></td><td> 50</td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ala</td><td> Val Gly</td><td> Leu</td><td> Ser</td><td> Ala</td><td> Glu</td><td> Ala</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Gin</td><td> Gin</td><td> Tyr</td><td> Ala</td><td> Asp</td>

<td> 65</td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Val</td><td> Leu Ser</td><td> Lys</td><td> Ala</td><td> Leu</td><td> Gly</td><td> Lys</td><td> Glu</td><td> Val</td><td> Arg</td><td> Asp</td><td> Ala</td><td> Lys</td><td> Ile</td><td> Thr</td>

<td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Pro</td><td> Glu Ala</td><td> Phe</td><td> Glu</td><td> Lys</td><td> Leu</td><td> Gly</td><td> Phe</td><td> Pro</td><td> Ala</td><td> Ala</td><td> Lys</td><td> Glu</td><td> He</td><td> Ala</td>

<td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Asn</td><td> Met Cys</td><td> Arg</td><td> Phe</td><td> Tyr</td><td> Glu</td><td> Met</td><td> Lys</td><td> Pro</td><td> Asp</td><td> Arg</td><td> Asp</td><td> Val</td><td> Asn</td><td> Leu</td>

<td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td> Thr</td><td> His Gin</td><td> Leu</td><td> Asn</td><td> Pro</td><td> Lys</td><td> Val</td><td> Lys</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Gin</td><td> Phe</td><td> Ile</td><td> Ser</td>

<td></td><td> 130</td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td> Glu</td><td> Asn Gin</td><td> Gly</td><td> Ala</td><td> Phe</td><td> Lys</td><td> Gly</td><td> Met</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 145</td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> &lt;210&gt;</td><td> 156</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> &lt;211&gt;</td><td> 128</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> &lt;212&gt;</td><td> PRT</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> &lt;213&gt;</td><td colspan="3"> Homo sapien</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> &lt;400&gt;</td><td> 156</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> Met</td><td> Thr Ser</td><td> Val</td><td> Arg</td><td> Val</td><td> Ala</td><td> Ala</td><td> Tyr</td><td> Phe</td><td> Glu</td><td> Asn</td><td> Phe</td><td> Leu</td><td> Ala</td><td> Ala</td>

<td> 1</td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Trp</td><td> Arg Pro</td><td> Val</td><td> Lys</td><td> Ala</td><td> Ser</td><td> Asp</td><td> Gly</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Thr</td><td> Leu</td><td> Ala</td><td> Val</td>

<td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Pro</td><td> Met Gly</td><td> Asp</td><td> Val</td><td> Pro</td><td> Met</td><td> Asp</td><td> Gly</td><td> Ile</td><td> Ser</td><td> Val</td><td> Ala</td><td> Asp</td><td> lie</td><td> Gly</td>

<td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ala</td><td> Ala Val</td><td> Ser</td><td> Ser</td><td> Ile</td><td> Phe</td><td> Asn</td><td> Ser</td><td> Pro</td><td> Glu</td><td> Glu</td><td> Phe</td><td> Leu</td><td> Gly</td><td> Lys</td>

<td></td><td> 50</td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ala</td><td> Val Gly</td><td> Leu</td><td> Ser</td><td> Ala</td><td> Glu</td><td> Ala</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Gin</td><td> Gin</td><td> Tyr</td><td> Ala</td><td> Asp</td>

<td> 65</td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Val</td><td> Leu Ser</td><td> Lys</td><td> Ala</td><td> Leu</td><td> Gly</td><td> Lys</td><td> Glu</td><td> Val</td><td> Arg</td><td> Asp</td><td> Ala</td><td> Lys</td><td> Thr</td><td> Ile</td>

<td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Cys</td><td> Ala Ile</td><td> Asp</td><td> Asp</td><td> Gin</td><td> Lys</td><td> Thr</td><td> Val</td><td> Glu</td><td> Glu</td><td> Gly</td><td> Phe</td><td> Met</td><td> Glu</td><td> Asp</td>

<td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Gly Leu</td><td> Ser</td><td> Trp</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Glu</td><td> His</td><td> Asp</td><td> His</td><td> Val</td><td> Ala</td><td> Gly</td><td> Ala</td>

<td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td></td><td> &lt;210&gt;</td><td> 157</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> &lt;211&gt;</td><td> 424</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> &lt;212&gt;</td><td> DNA</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> &lt;213&gt;</td><td colspan="3"> Homo sapien</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 &lt;220&gt;

&lt;221&gt; misc_feature &lt;222&gt; (1) .. . (424) &lt;223&gt; n = A,T,C or G &lt;400&gt; 157 ctgcagcccg ggggatccac tagtccagtg tggtggaatt cattggtctt tacaagactt 60 ggatacatta cagcagacat ggaaatataa ttttaaaaaa tttctctcca acctccttca 120 aattcagtca ccactgttat attaccttct ccaggaaccc tccagtgggg aaggctgcga 180 tattagattt ccttgtatgc aaagtttttg ttgaaagctg tgctcagagg aggtgagagg 240 agaggaagga gaaaactgca tcataacttt acagaattga atctagagtc ttccccgaaa 300 agcccagaaa cttctctgcn gnatctggct tgtccatctg gtctaaggtg gctgcttctt 360 ccccagccat cgagtcagtt tgtgcccatg aataatacac gacctgctat ttcccatgac 420 tgct 424

<td colspan="2"> &lt;210&gt; 158 &lt;211&gt; 2099 &lt;212&gt; DNA &lt;213&gt; Homo sapien</td>

<td> &lt;400&gt;</td><td> 158</td>

ccgcggttaa aaggcgcagc aggtgggagc cggggccttc acccgaaacc cgacgagagc 60 ccgacagccg gcggcgcccg agcccgacct gcctgcccag ccggagcgaa gggcgccgcc 120 ccgcgcagag cccgcgccag ggccgccggc cgcagagcag ttaaaacgtg caggcaccag 180 aaggcacttc ctgtcggtga agaagacctg tctccggtgt cacgggcatc ctgtgttttg 240 caaacggggc tgacctccct tcctggggag caggaagggt cagggaagga aaagaagtac 300 agaagatctg gctaaacaat ttctgtatgg cgaaagaaaa attctaactt gtacgccctc 360 ttcatgcatc tttaattcaa tttgaatatt ccaggcgaca tcctcactga ccgagcaaag 420 attgacattc gtatcatcac tgtgcaccat tggcttctag gcactccagt ggggtaggag 480 aaggaggtct gaaaccctcg cagagggatc ttgccctcat tctttgggtc tgaaacactg 540 gcagtcgttg gaaacaggac tcagggataa accagcgcaa tggattgggg gacgctgcac 600 actttcatcg ggggtgtcaa caaacactcc accagcatcg ggaaggtgtg gatcacagtc 660 atctttattt tccgagtcat gatcctcgtg gtggctgccc aggaagtgtg gggtgacgag 720 caagaggact tcgtctgcaa cacactgcaa ccgggatgca aaaatgtgtg ctatgaccac 780 tttttcccgg tgtcccacat ccggctgtgg gccctccagc tgatcttcgt ctccacccca 840 gcgctgctgg tggccatgca tgtggcctac tacaggcacg aaaccactcg caagttcagg 900 cgaggagaga agaggaatga tttcaaagac atagaggaca ttaaaaagca gaaggttcgg 960 atagaggggt cgctgtggtg gacgtacacc agcagcatct ttttccgaat catctttgaa 1020 gcagccttta tgtatgtgtt ttacttcctt tacaatgggt accacctgcc ctgggtgttg 1080 aaatgtggga ttgacccctg ccccaacctt gttgactgct ttatttctag gccaacagag 1140 aagaccgtgt ttaccatttt tatgatttct gcgtctgtga tttgcatgct gcttaacgtg 1200 gcagagttgt gctacctgct gctgaaagtg tgttttagga gatcaaagag agcacagacg 1260 caaaaaaatc accccaatca tgccctaaag gagagtaagc agaatgaaat gaatgagctg 1320 atttcagata gtggtcaaaa tgcaatcaca ggttcccaag ctaaacattt caaggtaaaa 1380 tgtagctgcg tcataaggag acttctgtct tctccagaag gcaataccaa cctgaaagtt 1440 ccttctgtag cctgaagagt ttgtaaatga ctttcataat aaatagacac ttgagttaac 1500 tttttgtagg atacttgctc cattcataca caacgtaatc aaatatgtgg tccatctctg 1560 aaaacaagag actgcttgac aaaggagcat tgcagtcact ttgacaggtt ccttttaagt 1620 ggactctctg acaaagtggg tactttctga aaatttatat aactgttgtt gataaggaac 1680 atttatccag gaattgatac gtttattagg aaaagatatt tttataggct tggatgtttt 1740 tagttctgac tttgaattta tataaagtat ttttataatg actggtcttc cttacctgga 1800 aaaacatgcg atgttagttt tagaattaca ccacaagtat ctaaatttgg aacttacaaa 1860 gggtctatct tgtaaatatt gttttgcatt gtctgttggc aaatttgtga actgtcatga 1920 tacgcttaag gtggaaagtg ttcattgcac aatatatttt tactgctttc tgaatgtaga 1980

CA 02369578 2001-10-02

WO 00/61612 PCT/US00/08896 cggaacagtg tggaagcaga aggctttttt aactcatccg tttgccaatc attgcaaaca 2040 actgaaatgt ggatgtgatt gcctcaataa agctcgtccc cattgcttaa aaaaaaaaa 2099 &lt;210&gt; 159 &lt;211&gt; 291 &lt;212&gt; PRT &lt;213&gt; Homo sapien

<td></td><td colspan="2"> &lt;400&gt;</td><td colspan="13"> 159</td>

<td> Met</td><td> Asp</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Leu</td><td> His</td><td> Thr</td><td> Phe</td><td> He</td><td> Gly</td><td> Gly</td><td> Val</td><td> Asn</td><td> Lys</td><td> His</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Thr</td><td> Ser</td><td> lie</td><td> Gly</td><td> Lys</td><td> Val</td><td> Trp</td><td> He</td><td> Thr</td><td> Val</td><td> lie</td><td> Phe</td><td> He</td><td> Phe</td><td> Arg</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Val</td><td> Met</td><td> He</td><td> Leu</td><td> Val</td><td> Val</td><td> Ala</td><td> Ala</td><td> Gin</td><td> Glu</td><td> Val</td><td> Trp</td><td> Gly</td><td> Asp</td><td> Glu</td><td> Gin</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Glu</td><td> Asp</td><td> Phe</td><td> Val</td><td> Cys</td><td> Asn</td><td> Thr</td><td> Leu</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Cys</td><td> Lys</td><td> Asn</td><td> Val</td><td> Cys</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Tyr</td><td> Asp</td><td> His</td><td> Phe</td><td> Phe</td><td> Pro</td><td> Val</td><td> Ser</td><td> His</td><td> He</td><td> Arg</td><td> Leu</td><td> Trp</td><td> Ala</td><td> Leu</td><td> Gin</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> He</td><td> Phe</td><td> Val</td><td> Ser</td><td> Thr</td><td> Pro</td><td> Ala</td><td> Leu</td><td> Leu</td><td> Val</td><td> Ala</td><td> Met</td><td> His</td><td> Val</td><td> Ala</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Tyr</td><td> Arg</td><td> His</td><td> Glu</td><td> Thr</td><td> Thr</td><td> Arg</td><td> Lys</td><td> Phe</td><td> Arg</td><td> Arg</td><td> Gly</td><td> Glu</td><td> Lys</td><td> Arg</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Asn</td><td> Asp</td><td> Phe</td><td> Lys</td><td> Asp</td><td> He</td><td> Glu</td><td> Asp</td><td> He</td><td> Lys</td><td> Lys</td><td> Gin</td><td> Lys</td><td> Val</td><td> Arg</td><td> He</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td> Glu</td><td> Gly</td><td> Ser</td><td> Leu</td><td> Trp</td><td> Trp</td><td> Thr</td><td> Tyr</td><td> Thr</td><td> Ser</td><td> Ser</td><td> He</td><td> Phe</td><td> Phe</td><td> Arg</td><td> He</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td> lie</td><td> Phe</td><td> Glu</td><td> Ala</td><td> Ala</td><td> Phe</td><td> Met</td><td> Tyr</td><td> Val</td><td> Phe</td><td> Tyr</td><td> Phe</td><td> Leu</td><td> Tyr</td><td> Asn</td><td> Gly</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td> Tyr</td><td> His</td><td> Leu</td><td> Pre</td><td> Trp</td><td> Val</td><td> Leu</td><td> Lys</td><td> Cys</td><td> Gly</td><td> He</td><td> Asp</td><td> Pro</td><td> Cys</td><td> Pro</td><td> Asn</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td> Leu</td><td> Val</td><td> Asp</td><td> Cys</td><td> Phe</td><td> He</td><td> Ser</td><td> Arg</td><td> Pro</td><td> Thr</td><td> Glu</td><td> Lys</td><td> Thr</td><td> Val</td><td> Phe</td><td> Thr</td>

<td></td><td></td><td></td><td> 180</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td> 190</td><td></td><td></td>

<td> He</td><td> Phe</td><td> Met</td><td> lie</td><td> Ser</td><td> Ala</td><td> Ser</td><td> Val</td><td> He</td><td> Cys</td><td> Met</td><td> Leu</td><td> Leu</td><td> Asn</td><td> Val</td><td> Ala</td>

<td></td><td></td><td> 195</td><td></td><td></td><td></td><td></td><td> 200</td><td></td><td></td><td></td><td></td><td> 205</td><td></td><td></td><td></td>

<td> Glu</td><td> Leu</td><td> Cys</td><td> Tyr</td><td> Leu</td><td> Leu</td><td> Leu</td><td> Lys</td><td> Val</td><td> Cys</td><td> Phe</td><td> Arg</td><td> Arg</td><td> Ser</td><td> Lys</td><td> Arg</td>

<td></td><td> 210</td><td></td><td></td><td></td><td></td><td> 215</td><td></td><td></td><td></td><td></td><td> 220</td><td></td><td></td><td></td><td></td>

<td> Ala</td><td> Gin</td><td> Thr</td><td> Gin</td><td> Lys</td><td> Asn</td><td> His</td><td> Pro</td><td> Asn</td><td> His</td><td> Ala</td><td> Leu</td><td> Lys</td><td> Glu</td><td> Ser</td><td> Lys</td>

<td> 225</td><td></td><td></td><td></td><td></td><td> 230</td><td></td><td></td><td></td><td></td><td> 235</td><td></td><td></td><td></td><td></td><td> 240</td>

<td> Gin</td><td> Asn</td><td> Glu</td><td> Met</td><td> Asn</td><td> Glu</td><td> Leu</td><td> He</td><td> Ser</td><td> Asp</td><td> Ser</td><td> Gly</td><td> Gin</td><td> Asn</td><td> Ala</td><td> He</td>

<td></td><td></td><td></td><td></td><td> 245</td><td></td><td></td><td></td><td></td><td> 250</td><td></td><td></td><td></td><td></td><td> 255</td><td></td>

<td> Thr</td><td> Gly</td><td> Ser</td><td> Gin</td><td> Ala</td><td> Lys</td><td> His</td><td> Phe</td><td> Lys</td><td> Val</td><td> Lys</td><td> Cys</td><td> Ser</td><td> Cys</td><td> Val</td><td> He</td>

<td></td><td></td><td></td><td> 260</td><td></td><td></td><td></td><td></td><td> 265</td><td></td><td></td><td></td><td></td><td> 270</td><td></td><td></td>

<td> Arg</td><td> Arg</td><td> Leu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Pro</td><td> Glu</td><td> Gly</td><td> Asn</td><td> Thr</td><td> Asn</td><td> Leu</td><td> Lys</td><td> Val</td><td> Pro</td>

<td></td><td></td><td> 275</td><td></td><td></td><td></td><td></td><td> 280</td><td></td><td></td><td></td><td></td><td> 285</td><td></td><td></td><td></td>

<td> Ser</td><td> Val</td><td> Ala</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 290</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

&lt;210&gt; 160 &lt;211&gt; 3951 &lt;212&gt; DNA &lt;213&gt; Homo sapien &lt;400&gt; 160 tctgcatcca tattgaaaac ctgacacaat gtatgcagca ggctcagtgt gagtgaactg

CA 02369578 2001-10-02

WOOO/61612 PCT/USOO/08896 gaggcttctc tacaacatga cccaaaggag cattgcaggt cctatttgca acctgaagtt 120 tgtgactctc ctggttgcct taagttcaga actcccattc ctgggagctg gagtacagct 180 tcaagacaat gggtataatg gattgctcat tgcaattaat cctcaggtac ctgagaatca 240 gaacctcatc tcaaacatta aggaaatgat aactgaagct tcattttacc tatttaatgc 300 taccaagaga agagtatttt tcagaaatat aaagatttta atacctgcca catggaaagc 360 taataataac agcaaaataa aacaagaatc atatgaaaag gcaaatgtca tagtgactga 420 ctggtatggg gcacatggag atgatccata caccctacaa tacagagggt gtggaaaaga 480 gggaaaatac attcatttca cacctaattt cctactgaat gataacttaa cagctggcta 540 cggatcacga ggccgagtgt ttgtccatga atgggcccac ctccgttggg gtgtgttcga 600 tgagtataac aatgacaaac ctttctacat aaatgggcaa aatcaaatta aagtgacaag 660 gtgttcatct gacatcacag gcatttttgt gtgtgaaaaa ggtccttgcc cccaagaaaa 720 ctgtattatt agtaagcttt ttaaagaagg atgcaccttt atctacaata gcacccaaaa 780 tgcaactgca tcaataatgt tcatgcaaag tttatcttct gtggttgaat tttgtaatgc 840 aagtacccac aaccaagaag caccaaacct acagaaccag atgtgcagcc tcagaagtgc 900 atgggatgta atcacagact ctgctgactt tcaccacagc tttcccatga acgggactga 960 gcttccacct cctcccacat tctcgcttgt agaggctggt gacaaagtgg tctgtttagt 1020 gctggatgtg tccagcaaga tggcagaggc tgacagactc cttcaactac aacaagccgc 1080 agaattttat ttgatgcaga ttgttgaaat tcataccttc gtgggcattg ccagtttcga 1140 cagcaaagga gagatcagag cccagctaca ccaaattaac agcaatgatg atcgaaagtt 1200 gctggtttca tatctgccca ccactgtatc agctaaaaca gacatcagca tttgttcagg 1260 gcttaagaaa ggatttgagg tggttgaaaa actgaatgga aaagcttatg gctctgtgat 1320 gatattagtg accagcggag atgataagct tcttggcaat tgcttaccca ctgtgctcag 1380 cagtggttca acaattcact ccattgccct gggttcatct gcagccccaa atctggagga 1440 attatcacgt cttacaggag gtttaaagtt ctttgttcca gatatatcaa actccaatag 1500 catgattgat gctttcagta gaatttcctc tggaactgga gacattttcc agcaacatat 1560 tcagcttgaa agtacaggtg aaaatgtcaa acctcaccat caattgaaaa acacagtgac 1620 tgtggataat actgtgggca acgacactat gtttctagtt acgtggcagg ccagtggtcc 1680 tcctgagatt atattatttg atcctgatgg acgaaaatac tacacaaata attttatcac 1740 caatctaact tttcggacag ctagtctttg gattccagga acagctaagc ctgggcactg 1800 gacttacacc ctgaacaata cccatcattc tctgcaagcc ctgaaagtga cagtgacctc 1860 tcgcgcctcc aactcagctg tgcccccagc cactgtggaa gcctttgtgg aaagagacag 1920 cctccatttt cctcatcctg tgatgattta tgccaatgtg aaacagggat tttatcccat 1980 tcttaatgcc actgtcactg ccacagttga gccagagact ggagatcctg ttacgctgag 2040 actccttgat gatggagcag gtgctgatgt tataaaaaat gatggaattt actcgaggta 2100 ttttttctcc tttgctgcaa atggtagata tagcttgaaa gtgcatgtca atcactctcc 2160 cagcataagc accccagccc actctattcc agggagtcat gctatgtatg taccaggtta 2220 cacagcaaac ggtaatattc agatgaatgc tccaaggaaa tcagtaggca gaaatgagga 2280 ggagcgaaag tggggcttta gccgagtcag ctcaggaggc tccttttcag tgctgggagt 2340 tccagctggc ccccaccctg atgtgtttcc accatgcaaa attattgacc tggaagctgt 2400 aaaagtagaa gaggaattga ccctatcttg gacagcacct ggagaagact ttgatcaggg 2460 ccaggctaca agctatgaaa taagaatgag taaaagtcta cagaatatcc aagatgactt 2520 taacaatgct attttagtaa atacatcaaa gcgaaatcct cagcaagctg gcatcaggga 2580 gatatttacg ttctcacccc aaatttccac gaatggacct gaacatcagc caaatggaga 2640 aacacatgaa agccacagaa tttatgttgc aatacgagca atggatagga actccttaca 2700 gtctgctgta tctaacattg cccaggcgcc tctgtttatt ccccccaatt ctgatcctgt 2760 acctgccaga gattatctta tattgaaagg agttttaaca gcaatgggtt tgataggaat 2820 catttgcctt attatagttg tgacacatca tactttaagc aggaaaaaga gagcagacaa 2880 gaaagagaat ggaacaaaat tattataaat aaatatccaa agtgtcttcc ttcttagata 2940 taagacccat ggccttcgac tacaaaaaca tactaacaaa gtcaaattaa catcaaaact 3000 gtattaaaat gcattgagtt tttgtacaat acagataaga tttttacatg gtagatcaac 3060 aaattctttt tgggggtaga ttagaaaacc cttacacttt ggctatgaac aaataataaa 3120 aattattctt taaagtaatg tctttaaagg caaagggaag ggtaaagtcg gaccagtgtc 3180 aaggaaagtt tgttttattg aggtggaaaa atagccccaa gcagagaaaa ggagggtagg 3240 tctgcattat aactgtctgt gtgaagcaat catttagtta ctttgattaa tttttctttt 3300 ctccttatct gtgcagaaca ggttgcttgt ttacaactga agatcatgct atatttcata 3360

CA 02369578 2001-10-02

WO 00/61612

PCT/US00/08896 tatgaagccc ctaatgcaaa gctctttacc tcttgctatt ttgttatata tattacagat 3420 gaaatctcac tgctaatgct cagagatctt ttttcactgt aagaggtaac ctttaacaat 3480 atgggtatta cctttgtctc ttcataccgg ttttatgaca aaggtctatt gaatttattt 3540 gtttgtaagt ttctactccc atcaaagcag ctttttaagt tattgccttg gttattatgg 3600 atgatagtta tagcccttat aatgccttaa ctaaggaaga aaagatgtta ttctgagttt 3660 gttttaatac atatatgaac atatagtttt attcaattaa accaaagaag aggtcagcag 3720 ggagatacta acctttggaa atgattagct ggctctgttt tttggttaaa taagagtctt 3780 taatcctttc tccatcaaga gttacttacc aagggcaggg gaagggggat atagaggtcc 3840 caaggaaata aaaatcatct ttcatcttta attttactcc ttcctcttat ttttttaaaa 3900 gattatcgaa caataaaatc atttgccttt ttaattaaaa acataaaaaa a 3951 &lt;210&gt; 161 &lt;211&gt; 943 &lt;212&gt; PRT &lt;213&gt; Homo sapien

<td></td><td colspan="2"> &lt;400&gt;</td><td> 161</td><td></td><td></td><td></td><td></td>

<td> Met 1</td><td> Thr</td><td> Gin</td><td> Arg</td><td> Ser 5</td><td> He</td><td> Ala</td><td> Gly</td>

<td> Thr</td><td> Leu</td><td> Leu</td><td> Val 20</td><td> Ala</td><td> Leu</td><td> Ser</td><td> Ser</td>

<td> Val</td><td> Gin</td><td> Leu 35</td><td> Gin</td><td> Asp</td><td> Asn</td><td> Gly</td><td> Tyr 40</td>

<td> Pro</td><td> Gin 50</td><td> Val</td><td> Pro</td><td> Glu</td><td> Asn</td><td> Gin 55</td><td> Asn</td>

<td> lie 65</td><td> Thr</td><td> Glu</td><td> Ala</td><td> Ser</td><td> Phe 70</td><td> Tyr</td><td> Leu</td>

<td> Phe</td><td> Phe</td><td> Arg</td><td> Asn</td><td> lie 85</td><td> Lys</td><td> He</td><td> Leu</td>

<td> Asn</td><td> Asn</td><td> Ser</td><td> Lys 100</td><td> He</td><td> Lys</td><td> Gin</td><td> Glu</td>

<td> Val</td><td> Thr</td><td> Asp 115</td><td> Trp</td><td> Tyr</td><td> Gly</td><td> Ala</td><td> His 120</td>

<td> Tyr</td><td> Arg 130</td><td> Gly</td><td> Cys</td><td> Gly</td><td> Lys</td><td> Glu 135</td><td> Gly</td>

<td> Phe 145</td><td> Leu</td><td> Leu</td><td> Asn</td><td> Asp</td><td> Asn 150</td><td> Leu</td><td> Thr</td>

<td> Val</td><td> Phe</td><td> Val</td><td> His</td><td> Glu 165</td><td> Trp</td><td> Ala</td><td> His</td>

<td> Tyr</td><td> Asn</td><td> Asn</td><td> Asp 180</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Tyr</td>

<td> Val</td><td> Thr</td><td> Arg 195</td><td> Cys</td><td> Ser</td><td> Ser</td><td> Asp</td><td> He 200</td>

<td> Gly</td><td> Pro 210</td><td> Cys</td><td> Pro</td><td> Gin</td><td> Glu</td><td> Asn 215</td><td> Cys</td>

<td> Gly 225</td><td> Cys</td><td> Thr</td><td> Phe</td><td> He</td><td> Tyr 230</td><td> Asn</td><td> Ser</td>

<td> Met</td><td> Phe</td><td> Met</td><td> Gin</td><td> Ser 245</td><td> Leu</td><td> Ser</td><td> Ser</td>

<td> Thr</td><td> His</td><td> Asn</td><td> Gin 260</td><td> Glu</td><td> Ala</td><td> Pro</td><td> Asn</td>

<td> Arg</td><td> Ser</td><td> Ala 275</td><td> Trp</td><td> Asp</td><td> Val</td><td> He</td><td> Thr 280</td>

<td> Phe</td><td> Pro 290</td><td> Met</td><td> Asn</td><td> Gly</td><td> Thr</td><td> Glu 295</td><td> Leu</td>

<td> Pro</td><td> He 10</td><td> Cys</td><td> Asn</td><td> Leu</td><td> Lys</td><td> Phe 15</td><td> Val</td>

<td> Glu 25</td><td> Leu</td><td> Pro</td><td> Phe</td><td> Leu</td><td> Gly 30</td><td> Ala</td><td> Gly</td>

<td> Asn</td><td> Gly</td><td> Leu</td><td> Leu</td><td> He 45</td><td> Ala</td><td> He</td><td> Asn</td>

<td> Leu</td><td> lie</td><td> Ser</td><td> Asn 60</td><td> He</td><td> Lys</td><td> Glu</td><td> Met</td>

<td> Phe</td><td> Asn</td><td> Ala 75</td><td> Thr</td><td> Lys</td><td> Arg</td><td> Arg</td><td> Val 80</td>

<td> He</td><td> Pro 90</td><td> Ala</td><td> Thr</td><td> Trp</td><td> Lys</td><td> Ala 95</td><td> Asn</td>

<td> Ser 105</td><td> Tyr</td><td> Glu</td><td> Lys</td><td> Ala</td><td> Asn 110</td><td> Val</td><td> He</td>

<td> Gly</td><td> Asp</td><td> Asp</td><td> Pro</td><td> Tyr 125</td><td> Thr</td><td> Leu</td><td> Gin</td>

<td> Lys</td><td> Tyr</td><td> He</td><td> His 140</td><td> Phe</td><td> Thr</td><td> Pro</td><td> Asn</td>

<td> Ala</td><td> Gly</td><td> Tyr 155</td><td> Gly</td><td> Ser</td><td> Arg</td><td> Gly</td><td> Arg 160</td>

<td> Leu</td><td> Arg 170</td><td> Trp</td><td> Gly</td><td> Val</td><td> Phe</td><td> Asp 175</td><td> Glu</td>

<td> He 185</td><td> Asn</td><td> Gly</td><td> Gin</td><td> Asn</td><td> Gin 190</td><td> He</td><td> Lys</td>

<td> Thr</td><td> Gly</td><td> He</td><td> Phe</td><td> Val 205</td><td> Cys</td><td> Glu</td><td> Lys</td>

<td> He</td><td> He</td><td> Ser</td><td> Lys 220</td><td> Leu</td><td> Phe</td><td> Lys</td><td> Glu</td>

<td> Thr</td><td> Gin</td><td> Asn 235</td><td> Ala</td><td> Thr</td><td> Ala</td><td> Ser</td><td> He 240</td>

<td> Val</td><td> Val 250</td><td> Glu</td><td> Phe</td><td> Cys</td><td> Asn</td><td> Ala 255</td><td> Ser</td>

<td> Leu 265</td><td> Gin</td><td> Asn</td><td> Gin</td><td> Met</td><td> Cys 270</td><td> Ser</td><td> Leu</td>

<td> Asp</td><td> Ser</td><td> Ala</td><td> Asp</td><td> Phe 285</td><td> His</td><td> His</td><td> Ser</td>

<td> Pro</td><td> Pro</td><td> Pro</td><td> Pro 300</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Leu</td>

CA 02369578 2001-10-02

WO 00/61612 PCT/USOO/08896

<td> Val</td><td> Glu</td><td> Ala</td><td> Gly Asp</td><td> Lys</td><td> Val</td><td> Val</td><td> Cys</td><td> Leu</td><td> Val</td><td> Leu</td><td> Asp</td><td> Val</td><td> Ser</td><td> Ser</td>

<td> 305</td><td></td><td></td><td></td><td> 310</td><td></td><td></td><td></td><td></td><td> 315</td><td></td><td></td><td></td><td></td><td> 320</td>

<td> Lys</td><td> Met</td><td> Ala</td><td> Glu Ala</td><td> Asp</td><td> Arg</td><td> Leu</td><td> Leu</td><td> Gin</td><td> Leu</td><td> Gin</td><td> Gin</td><td> Ala</td><td> Ala</td><td> Glu</td>

<td></td><td></td><td></td><td> 325</td><td></td><td></td><td></td><td></td><td> 330</td><td></td><td></td><td></td><td></td><td> 335</td><td></td>

<td> Phe</td><td> Tyr</td><td> Leu</td><td> Met Gin</td><td> lie</td><td> Val</td><td> Glu</td><td> lie</td><td> His</td><td> Thr</td><td> Phe</td><td> Val</td><td> Gly</td><td> He</td><td> Ala</td>

<td></td><td></td><td></td><td> 340</td><td></td><td></td><td></td><td> 345</td><td></td><td></td><td></td><td></td><td> 350</td><td></td><td></td>

<td> Ser</td><td> Phe</td><td> Asp</td><td> Ser Lys</td><td> Gly</td><td> Glu</td><td> lie</td><td> Arg</td><td> Ala</td><td> Gin</td><td> Leu</td><td> His</td><td> Gin</td><td> He</td><td> Asn</td>

<td></td><td></td><td> 355</td><td></td><td></td><td></td><td> 360</td><td></td><td></td><td></td><td></td><td> 365</td><td></td><td></td><td></td>

<td> Ser</td><td> Asn</td><td> Asp</td><td> Asp Arg</td><td> Lys</td><td> Leu</td><td> Leu</td><td> Val</td><td> Ser</td><td> Tyr</td><td> Leu</td><td> Pro</td><td> Thr</td><td> Thr</td><td> Val</td>

<td></td><td> 370</td><td></td><td></td><td></td><td> 375</td><td></td><td></td><td></td><td></td><td> 380</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Ala</td><td> Lys</td><td> Thr Asp</td><td> lie</td><td> Ser</td><td> lie</td><td> Cys</td><td> Ser</td><td> Gly</td><td> Leu</td><td> Lys</td><td> Lys</td><td> Gly</td><td> Phe</td>

<td> 385</td><td></td><td></td><td></td><td> 390</td><td></td><td></td><td></td><td></td><td> 395</td><td></td><td></td><td></td><td></td><td> 400</td>

<td> Glu</td><td> Val</td><td> Val</td><td> Glu Lys</td><td> Leu</td><td> Asn</td><td> Gly</td><td> Lys</td><td> Ala</td><td> Tyr</td><td> Gly</td><td> Ser</td><td> Val</td><td> Met</td><td> He</td>

<td></td><td></td><td></td><td> 405</td><td></td><td></td><td></td><td></td><td> 410</td><td></td><td></td><td></td><td></td><td> 415</td><td></td>

<td> Leu</td><td> Val</td><td> Thr</td><td> Ser Gly</td><td> Asp</td><td> Asp</td><td> Lys</td><td> Leu</td><td> Leu</td><td> Gly</td><td> Asn</td><td> Cys</td><td> Leu</td><td> Pro</td><td> Thr</td>

<td></td><td></td><td></td><td> 420</td><td></td><td></td><td></td><td> 425</td><td></td><td></td><td></td><td></td><td> 430</td><td></td><td></td>

<td> Val</td><td> Leu</td><td> Ser</td><td> Ser Gly</td><td> Ser</td><td> Thr</td><td> lie</td><td> His</td><td> Ser</td><td> lie</td><td> Ala</td><td> Leu</td><td> Gly</td><td> Ser</td><td> Ser</td>

<td></td><td></td><td> 435</td><td></td><td></td><td></td><td> 440</td><td></td><td></td><td></td><td></td><td> 445</td><td></td><td></td><td></td>

<td> Ala</td><td> Ala</td><td> Pro</td><td> Asn Leu</td><td> Glu</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Arg</td><td> Leu</td><td> Thr</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Lys</td>

<td></td><td> 450</td><td></td><td></td><td></td><td> 455</td><td></td><td></td><td></td><td></td><td> 460</td><td></td><td></td><td></td><td></td>

<td> Phe</td><td> Phe</td><td> Val</td><td> Pro Asp</td><td> lie</td><td> Ser</td><td> Asn</td><td> Ser</td><td> Asn</td><td> Ser</td><td> Met</td><td> He</td><td> Asp</td><td> Ala</td><td> Phe</td>

<td> 465</td><td></td><td></td><td></td><td> 470</td><td></td><td></td><td></td><td></td><td> 475</td><td></td><td></td><td></td><td></td><td> 480</td>

<td> Ser</td><td> Arg</td><td> lie</td><td> Ser Ser</td><td> Gly</td><td> Thr</td><td> Gly</td><td> Asp</td><td> lie</td><td> Phe</td><td> Gin</td><td> Gin</td><td> His</td><td> He</td><td> Gin</td>

<td></td><td></td><td></td><td> 485</td><td></td><td></td><td></td><td></td><td> 490</td><td></td><td></td><td></td><td></td><td> 495</td><td></td>

<td> Leu</td><td> Glu</td><td> Ser</td><td> Thr Gly</td><td> Glu</td><td> Asn</td><td> Val</td><td> Lys</td><td> Pro</td><td> His</td><td> His</td><td> Gin</td><td> Leu</td><td> Lys</td><td> Asn</td>

<td></td><td></td><td></td><td> 500</td><td></td><td></td><td></td><td> 505</td><td></td><td></td><td></td><td></td><td> 510</td><td></td><td></td>

<td> Thr</td><td> Val</td><td> Thr</td><td> Val Asp</td><td> Asn</td><td> Thr</td><td> Val</td><td> Gly</td><td> Asn</td><td> Asp</td><td> Thr</td><td> Met</td><td> Phe</td><td> Leu</td><td> Val</td>

<td></td><td></td><td> 515</td><td></td><td></td><td></td><td> 520</td><td></td><td></td><td></td><td></td><td> 525</td><td></td><td></td><td></td>

<td> Thr</td><td> Trp</td><td> Gin</td><td> Ala Ser</td><td> Gly</td><td> Pro</td><td> Pro</td><td> Glu</td><td> lie</td><td> He</td><td> Leu</td><td> Phe</td><td> Asp</td><td> Pro</td><td> Asp</td>

<td></td><td> 530</td><td></td><td></td><td></td><td> 535</td><td></td><td></td><td></td><td></td><td> 540</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Arg</td><td> Lys</td><td> Tyr Tyr</td><td> Thr</td><td> Asn</td><td> Asn</td><td> Phe</td><td> lie</td><td> Thr</td><td> Asn</td><td> Leu</td><td> Thr</td><td> Phe</td><td> Arg</td>

<td> 545</td><td></td><td></td><td></td><td> 550</td><td></td><td></td><td></td><td></td><td> 555</td><td></td><td></td><td></td><td></td><td> 560</td>

<td> Thr</td><td> Ala</td><td> Ser</td><td> Leu Trp</td><td> lie</td><td> Pro</td><td> Gly</td><td> Thr</td><td> Ala</td><td> Lys</td><td> Pro</td><td> Gly</td><td> His</td><td> Trp</td><td> Thr</td>

<td></td><td></td><td></td><td> 565</td><td></td><td></td><td></td><td></td><td> 570</td><td></td><td></td><td></td><td></td><td> 575</td><td></td>

<td> Tyr</td><td> Thr</td><td> Leu</td><td> Asn Asn</td><td> Thr</td><td> His</td><td> His</td><td> Ser</td><td> Leu</td><td> Gin</td><td> Ala</td><td> Leu</td><td> Lys</td><td> Val</td><td> Thr</td>

<td></td><td></td><td></td><td> 580</td><td></td><td></td><td></td><td> 585</td><td></td><td></td><td></td><td></td><td> 590</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Ser</td><td> Arg Ala</td><td> Ser</td><td> Asn</td><td> Ser</td><td> Ala</td><td> Val</td><td> Pro</td><td> Pro</td><td> Ala</td><td> Thr</td><td> Val</td><td> Glu</td>

<td></td><td></td><td> 595</td><td></td><td></td><td></td><td> 600</td><td></td><td></td><td></td><td></td><td> 605</td><td></td><td></td><td></td>

<td> Ala</td><td> Phe</td><td> Val</td><td> Glu Arg</td><td> Asp</td><td> Ser</td><td> Leu</td><td> His</td><td> Phe</td><td> Pro</td><td> His</td><td> Pro</td><td> Val</td><td> Met</td><td> He</td>

<td></td><td> 610</td><td></td><td></td><td></td><td> 615</td><td></td><td></td><td></td><td></td><td> 620</td><td></td><td></td><td></td><td></td>

<td> Tyr</td><td> Ala</td><td> Asn</td><td> Val Lys</td><td> Gin</td><td> Gly</td><td> Phe</td><td> Tyr</td><td> Pro</td><td> He</td><td> Leu</td><td> Asn</td><td> Ala</td><td> Thr</td><td> Val</td>

<td> 625</td><td></td><td></td><td></td><td> 630</td><td></td><td></td><td></td><td></td><td> 635</td><td></td><td></td><td></td><td></td><td> 640</td>

<td> Thr</td><td> Ala</td><td> Thr</td><td> Val Glu</td><td> Pro</td><td> Glu</td><td> Thr</td><td> Gly</td><td> Asp</td><td> Pro</td><td> Val</td><td> Thr</td><td> Leu</td><td> Arg</td><td> Leu</td>

<td></td><td></td><td></td><td> 645</td><td></td><td></td><td></td><td></td><td> 650</td><td></td><td></td><td></td><td></td><td> 655</td><td></td>

<td> Leu</td><td> Asp</td><td> Asp</td><td> Gly Ala</td><td> Gly</td><td> Ala</td><td> Asp</td><td> Val</td><td> lie</td><td> Lys</td><td> Asn</td><td> Asp</td><td> Gly</td><td> lie</td><td> Tyr</td>

<td></td><td></td><td></td><td> 660</td><td></td><td></td><td></td><td> 665</td><td></td><td></td><td></td><td></td><td> 670</td><td></td><td></td>

<td> Ser</td><td> Arg</td><td> Tyr</td><td> Phe Phe</td><td> Ser</td><td> Phe</td><td> Ala</td><td> Ala</td><td> Asn</td><td> Gly</td><td> Arg</td><td> Tyr</td><td> Ser</td><td> Leu</td><td> Lys</td>

<td></td><td></td><td> 675</td><td></td><td></td><td></td><td> 680</td><td></td><td></td><td></td><td></td><td> 685</td><td></td><td></td><td></td>

<td> Val</td><td> His</td><td> Val</td><td> Asn His</td><td> Ser</td><td> Pro</td><td> Ser</td><td> lie</td><td> Ser</td><td> Thr</td><td> Pro</td><td> Ala</td><td> His</td><td> Ser</td><td> lie</td>

<td></td><td> 690</td><td></td><td></td><td></td><td> 695</td><td></td><td></td><td></td><td></td><td> 700</td><td></td><td></td><td></td><td></td>

<td> Pro</td><td> Gly</td><td> Ser</td><td> His Ala</td><td> Met</td><td> Tyr</td><td> Val</td><td> Pro</td><td> Gly</td><td> Tyr</td><td> Thr</td><td> Ala</td><td> Asn</td><td> Gly</td><td> Asn</td>

<td> 705</td><td></td><td></td><td></td><td> 710</td><td></td><td></td><td></td><td></td><td> 715</td><td></td><td></td><td></td><td></td><td> 720</td>

<td> lie</td><td> Gin</td><td> Met</td><td> Asn Ala</td><td> Pro</td><td> Arg</td><td> Lys</td><td> Ser</td><td> Val</td><td> Gly</td><td> Arg</td><td> Asn</td><td> Glu</td><td> Glu</td><td> Glu</td>

<td></td><td></td><td></td><td> 725</td><td></td><td></td><td></td><td></td><td> 730</td><td></td><td></td><td></td><td></td><td> 735</td><td></td>

<td> Arg</td><td> Lys</td><td> Trp</td><td> Gly Phe</td><td> Ser</td><td> Arg</td><td> Val</td><td> Ser</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Val</td>

CA 02369579 2001-10-02

WO 00/61612

PCT/US00/08896

<td></td><td colspan="6"> 740</td><td colspan="2"> 745</td><td colspan="7"> 750</td>