Anti-pd-l1 antibodies and their use to enhance t-cell function

-1-

-1- MA 32948Β1

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T and Ashaddamha to improve the functions of vinegar 0 of PD.L1 uncompromising objects d Full Description Reference to requests Alasvad Bwaouat invention Nat eaters to request Oraeh Aloraa 1 Mavt (e) 35 use 119 this request in priority based under No. 61/121092, the depositor 9 Dimbr 2008, has been fully integrated Z 0 n 0 p Total order this request. Technical Ingall: 5, which at that Ziad,, T respect Hedda General invention functions and immune to improve and Zigh immune responses induced cells cells increased controlled and Mamaaljh poor job .T background cells Rhyming: Nmonga disorders acceptable substantially T is common Ackbyh or the introduction of two signals distinct cells . (APCs) static cells provided generators to Tvhat antibody T lymphocyte lymphocyte 1975). It also provides this Alnmong) Lafferty et al., Aust. j. Exp. Biol. Med. Sci. 53: 27-42 Bretscher et al .. Science 169: 1042-1049 .tmiaz probability immune 1 Katie and the two tools Veer Jenkins et al., J. Exp. 1999);) Bretscher, Ρ.Α., PNAS USA 96: 185-190 (1970); and 1987). The shift, Del basic signal or signal the birth of Alopecia antibody) Med. ! 302-319 ΜΑ 32948Β1 are 0 accept Alakharh (T (TCR after the luxury of a polypeptide Mrld F strange submitted in BenQ complex compatibility Alenciha Alradece (MHC). The less the second administration or management in August of 0 Kirkh 1 Li Τ cells molecules common alarm expressed in the picturesque provided to generator antibody (APCs); and urging 0 cells Τ to promote clonal expansion, and the secretion of cytokines and Onaiv Alaatahabh 0 14: 233 .1996) Lenschow et al.) Ann. Rev. Immunol). In the absence of common alarm, can be valid T cells is Mtzhabh to alert antigen, nor Astahabh Water occur Ma; H, and can lead to sinful or replace distrust antibody generators. 0 mm Be that walked Alnmong simple binary signal oversimplification because the signal strength 0 TCR has already raised a quantitative meant trotting activated T and Tma_rha. 106-104: ^ 1996) Viola et al .. Science); 156-159: 3 c 3 1993) Sloan-Lancaster, Nature). ^ Step Eny Zlat 4 0 0 0 possible Chit August Τ even in the absence of common alarm signal if the signal Rngah TCR 0-for'lohm for deletion of the T cells Tsqubl all common alarm signals secondary positive and Almalbh. The Tnghlim this is recalled 0 1 T. and Elbe important leadership injuries immune preventive family of the cell to the hilt, with only J-probability immune system and prevent autoimmunity. And look important secondary signals negative induce referred the cells T, while &amp; quot; lead Alather't allergin 1 Li Therese Scat cells T. Although the simple Alnmong second signal -hdm healthy interpretation of the original lymphocyte, the Alascabh immune cells family p Eml; e Dyadmakih, and can also provide T cells exposed to the generators F-August joint 0 ΜΑ signals 32948Β1 not 5 eT common alarm important therapeutic because Chet to address Akhar't alarm polytheist destroyed up to improve the immune Alascbat that Omasha cells or Aievha 0 Lovell 0 no I 0 &amp; quot; w that by the creations of T cells seen disable 0 happens p expression induced or Aq'm - Shat-me, and Buffy Bbd 1 of apoptosis (1-PD). Nathh Therefore, there is a great importance for 1.PD of loyalty 0 Duff! To Alas other Aldzeetmat 1 t seen 0 sales Clarifier Z Abelat 0 p -PD 1, Mtlriaturabttiya for the death of one of the programmer (PD-L1) and Larry Akr'bti 2 to die one of excruciating PD-L2). Lund Ahtrah inhibition effect 0 T. PD-L1 Ri - 0 Toua Alkhad 0 O T sector Ed 0 c 1 Rzv (the torrent example, immune disorder against tumors) and infection; · than in reminded attic 0 Wei insisted one Ende and times (such as non-Abaktah). However, you must unwind Lord therapeutic I 0 Rjhh Ngo this Anar, an important medical need unmet after-Akoshfoun 1 Achteraaz Lior one current invention Ojame counter for PD-L1, .mma the encryption Zoe acid and Rkat Id 0 No, eBay This Glades anti, It used to Temin cell functions T to Zbadh but ^ s Abaih Almsgesh cells increased controlled and to treat Adarapat ill functions for Khala 0 No 1.0, which in Nellv 0 for Adoy (eg, acute and chronic) disorders of immunity against tumors. I find in Alnmang, Revere invention poly peptide isolated a variable-area series THB - Z. Outgrow 1b HVR-H1; and 2 no-no 7 not HVR..H3J, where: (a) Almto one has HVR-H1 is a GFTFSXiSWIH (successive number:!); -4- -4-ΜΑ 32948Β1 (b) be pipelined HVR-H2 is a AWIX2PYGGSX3YYADSVKG (successive number: 2); (d) Takern successive HVR-H3 is RHWPGGFDY (successive number: 3); where: be | Χ is a d or G; be χ2 an S or L; be [X is a T or S. in one answer for, Xi be a D; be χ2 an S and be χ2 a T. in Gap else, polycarbonate also includes polypeptide sequences framework variable heavy regions chains then Tvier positions between HVRs and Fga formula: - (HC-FR1) - (HVR-H1) - (HC-FR2) (HVR-H2) - (HC-FR3) - (HVR-H3) - (HC-FR4). In another aspect, too, Bstq sequences Framework sequences of human framework Mngq them. Gap in another, sequences serve as a framework Third Khmuah Sub-VH. In Gap else too, be a succession of at least one of the sequences Framework one of the following: The HC-FR1 is EVQLVESGGGLVQPGGSLRLSCAAS (successive number: 4) The HC-FR2 is WVRQAPGKGLEWV (successive number: 5) The HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (successive number: 6) The fact that HC-FR4 is WGQGTLVTVSA (successive number: 7). -5- -5-ΜΑ 32948Β1 on the other side as well, are also Hamad urinary peptide heavy chain variable region with Khgegh series include HVR-Uj HVR-L2, HVR-L1, where: (a) be pipelined HVR-L1 Abbar; for (sequences identities: 8); (b) Tkov successive HVR-L2 is a SASXgLXioS, (sequences identities: 9); (c) be pipelined HVR-L3 is a QQXn Χ | 2 Χ] 3 Χ.4 ΡΧ. 5Τ (Atwala-data gaps: 10); where: be, X is a D or V; be; X is a 7 or 1; be (; X is S or Ν; Χ7 be an A or F; be? X is a 7 or L; χ9 be an F Awa; Χ.Ο be a Y or A; be a Xu F, G, Υ, or S; be 2 [Χ is F, Y, L or W ; Χΐ3 be an F, G, T, A, N, Y, or 1; be 4.Χ is H, T, P, V or 1; be 5 | Χ a P, R, W, A, or. T on the other side also, Χ4 be a D; be; X is 7; be χ5 a S; be Χγ a Α; be? X is a V; be? X is F; be Χίο a Y ; Xu is a Υ; Takern Χΐ2 an L; Χΐ3 be a Υ; 4.Χ be a Η; Χΐ5 be an A. on the other side too, Kqevh series include Oaana sequences Khgegh framework variable regions were Allaml Tvther positions between HVRs according to the formula: - (LC-FR1) - (HVR-L1) - (LC-FR2) - (HVR-L2) - (LC0FR3) - (HVR-L3) (LC-FR4). Gap also in another, sequences derived from sequences Framework Framework human Mngq -6- -6-ΜΑ 32948Β1 them. In another aspect, too, it sequences Framework Khgegh be chains frame him for the first Mngq Kappa VL. In another aspect, too, it is a succession of at least one of the sequences Framework one of the following: LC-be FR1 Abbar; for DIQMTQSPSSLSASVGDRVTITC (successive number: 11) 5 that the LC-FR2 is WYQQKPGKAPKLLIY (successive number: 12) LC-fact FR3 words for GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (successive RFM: 13) Aoun LC-FR4 Abbar; for FGQGTKVEIKR (successive number: 14). In Nmong another, the invention provides an object isolated counter for PD-L1 or fragment Association antigen 10 include succession variable region Khgegh and heavy chain, where: (a) the heavy chain include HVR-H3J HVR-H2, HVR-H1, where: (1) Aoun successive HVR-H1 is a GFTFSXiSWIH; (successive number: 1) (2) Aoun successive HVR-H2 is a Z AWIX2PYGGSX3YYADSVKG (successive number: 2) 15 (3) Aoun successive HVR-H3 is RHWPGGFDY, and ( successive number: 3) (b) Alkhvagh chain on H7R-L3j HVR-L2, HVR-L1, where: ςχ -1- -1-ΜΑ 32948Β1 include (1) be pipelined HVR-L1 is a RASQX4X5X6TX7X8A (sequences identities: 8 )

(2) be pipelined HVR-L2 is a SASXçLXioS; and (sequences identities: 9) (3) be pipelined HVR-L3 is a QQXu Χ | 2 Χ.3 Χ | 4 PXisT; (sequences Lite: 10) where: be (X is a D or G; be Χ2 an S or L; be-Dade is a T or S; be Χ4 a D or 7; be? X is a V or 1; be Χβ an S or N; be Χ7 an A or F; be? X is a V or L; be? X is F Awa; be Χίο a Y or A; be Xu is a F, G, Υ, or S; be 2 | Χ words for F, Y, L, or W; be Χΐ3 an F, G, T, A, N, Y, or 1; be χ14 a Η, 7, T, Ρ or 1; be Χΐ5 a P, R, W , A .T or in a particular Gap, .X be a 5; Χ2 be an S and be Χ3 Ebarh Dha.vi Gap last, be Χ4 a D; Xs be a 7; χ6 be a p S; be? X is a Α; be? X is 7; be? X is F; be 5 | Χ Ebarh for Y; be &amp; quot; X is a Υ; be 2 [Χ is L; be 3 | Χ a Υ ; Χΐ4 be a H; 5.Χ be a Α- in Gap else too, Xi be a D; Χ2 be an S and Χ3 be a T, Χ4 be a D; be; Ebarh X 7; χ6 be a S; Χ7 be a Z A; Χβ be a V; be? X Ajarh for F; be 0 | Χ a Υ; Χιι be a Υ; be 2.Χ phrase p L; be Χΐ3 words for Υ; 4.Χ be a Η and be Χΐ5 a Α. ΜΑ 32948Β1 the other hand, the variable region heavy include the series on one or more of the framework sequences that have been Tvier positions between HVRs the following image: -HC-FR1) - (HVR-H1) - (HC) to include changing areas Khgegh chains on one or more of the framework sequences that have been Tvier positions between HVRs the following image: -LC-FR1) - (HVR-L1) - (LC-FR2) - (HVR-L2) - (LC-FR3) - (HVR-L3) - (LC) (FR4. in another aspect, too, Bstq sequences Framework sequences human framework Mngq them. in another aspect, too, are derived sequences Framework heavy chains Z consecutive first or second or third Hmuah sub-caps. in another aspect, too, be pipelined heavy chains framework framework Thirdly agreed Mahmoah VH subset. in another aspect, too, Tkov one or more Z sequences framework heavy chains and one of the following: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (successive number: 4) HC-FR2 WVRQAPGKGLEWV (successive Rev 0's: 5) HC -FR3 RFTISADTSKNTAYLQ.SLRAEDTAVYYCAR (Relenting number: 6) HC-FR4 WGQGTLVTVSA (successive number: 7). in another aspect, too, are derived sequences Framework Khmoghaigh chains Z succession Kabat Kappa Group parish first, or second or third. In another aspect, too, it sequences Framework Khgegh be chains frame him for the first Mngq Kappa VL. Gap also the last, be one or more of the sequences Framework Khgegh single chains; the following: -9- -9-ΜΑ 32948Β1 LC-FR1 DIQMTQSPSSLSASVGDRVTITC (successive RIP: 11) LC-FR2 WYQQKPGKAPKLLIY (successive number: 12) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (Almto 1 Mechanism RIP: 13) LC-FR4 FGQGTKVEIKR (successive RIP: 14) at an attractive 0 a certain time, the antibody also includes a murine zone or man-of Ybit 0 Jaap R also, it is selected constant human region Anhmuah containing IgGl; and 2 approaches 1; and 02 c 1; and 03 c 1, 04 Gel 0 in a certain aspect, the human region be fixed Abbar; Z IgGl · in love with another, too, are selected fixed Typhimurium region Andjemuah containing 2 AJ, IgGl Hegel, and his 4IgG2 and 03 Gel. In Gap Last Also, the area is fixed Typhimurium is a p. 8 02 Do 0 in particular the other hand, have a resolution of the counter functions nervous Posted diluted or WAFA in 0 certain Hafb Last exuding jobs nerve Sent minimum for Otgrh Fc, which has the functions of nervous / a Ash &amp; quot; Or the removal of Balglicozhel treatment agent. In another Nmong also be Tgrh Fc sorry her tan, P less nervous Mrth a Amtbdal Ν297Α or D2651297 fixed Almtqh. In Nmong else, provides the invention JAMA counterclaim for PD-L1 includes a succession 0 manageable Snap Khgegh and heavy chain, neighborhood 0 w 0 (a), for Alllh Akvelh also on successive HVR-H1, and 2 no-no 7 »HVR-H to be the one of not 0 least 85% with GFTFSDSWJH (Almtuwalia RIP: 15), ΜΑ 32948Β1 1., AWISPYGGSTYYADSVKG (successive Ram: 16) RHWPGGFDYj (Akowalah Rim: 3), respectively, or (b) Tttml series Alhvigh also on successive HVR-L3j H7R0L2j, HVR -L1 that sniff the erosion of at least 85% p 0 RASQDVSTAVA (RTM sequence: 17), SASFLYS (successive number: 18) QQYLYHPATj (successive number: 19), on Althrip. In Ja; b particular, are Almto'lah Pettmakl of 86%, or 87%, or 88%, or 89%, or 90%, or 91%, or 92%, or 93%, or 94%, or 95% , or 96%, or 97./0, or 98%, or 99% or 100%. In Gap else, _imz Almztqh 1 to variable Th 0 him the 0 Dallah on one or more of the framework sequences that have been Tefinr positions between HVRs Bakrrh Altaleh: (HC-FR1) - (HVR-H1) - (HC-FR2) - (HVR-H2) - ( HC-FR3) - (HVR-H3) - (HC-FR4), and include changing areas Khgegh chains on one or more of the framework sequences that have been Tvier positions between HVRs the following manner: (LC-FR3) - (HVR-L3) - (LC-FR4). In another aspect Eva, Stq Framework sequences of the human framework sequences Mngq them. In another aspect, too, are derived sequences Framework heavy chains of the first sequence, or a second or third Tjmuah Kabat subset. In another aspect, too, are the successive Framework heavy chains Third framework agreed Khmuah VH status. In another aspect, too, it is one or more of the sequences Framework heavy chains and one of the following: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (Almto 1 Mechanism Rzm: 4) HC-FR2 WVRQAPGKGLEWV (successive RFM: 5) -11- -11-ΜΑ 32948Β1 HC-FR3 RFTISADTSKNTAYLQ .SLRAEDTAVYYCAR (successive number: 6) HC-FR4 WGQGTLVTVSA (successive number: 7). Gap also in another, derived sequences Framework Khgegh chains of succession Kabat Kappa subset first, or second or third. In another aspect, too, it sequences Framework Khgegh be chains frame him for the first Mngq Kappa VL. In Gap else too, it is one or more of the sequences Framework Khgegh chains and one of the following: LC-FR1 DIQMTQSPSSLSASVGDRVTITC (successive RTM: 11) LC-FR2 WYQQKPGKAPKLLIY (giving birth to RTM: 12) LC-FR3GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (Relenting RTM: 13) LC-FR4 FGQGTKVEIKR (RTM sequence: 14). In Jaz 0 b Sen else, bridles counter also includes Vaerah or human Thalo · area on the side of Oat, Ad Almthh fixed Alpmthreyh Z Amehmuah containing IgGl, and 2 approaches 1, 2 approaches 1,

IgG3j, and 4 Hegel 0 in a particular Gap else, be human region fixed Ara E 3 T's 0 Gel 0 Melt T Also, eBay Almthh Alghaerah fixed z Akhmuah containing IgGl, and 8, IgG2 .ig52 B, and 3 H 8's. In Jabaroaga, to God be the F-La Isla reproach p. 02 Is A 0 0 0 Yi Ja Mabn AAS, be deductible counter functions nervous Posted diluted or bear 0 in Gus with 1 N \ A. Aloza, Dave nerve Sent minimum Z &amp; quot; Fc Tgrh to me Oz 0 d b responded -12- -12-ΜΑ 32948Β1 less' or the removal of Balglicozhel treatment agent. In Nmong else too, Takern Tgrh Fc which has functions less nervous sent a Ν297Α The closing or D265I297 in fixed region. In another Nmong Also, the invention provides an isolated body's counter-PD-L1 includes a succession Khgegh variable region and a heavy chain, where: (a) similar Althagalh.mma consecutive series of at least 85% with heavy chain sequence:

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FDYWGQGTLVTVSA (successive number: 20), or (b) similar succession chain Alkhviqh .mma at least 85% with Alllh Kqevh: (Almto; Maly number: 21). In particular Gap, are successive similarity Ala 86%, or 87%, or 88%; or 89%, or 90 e / e, or 91 e / e, or 92 huh, or 93 e / e, or 94%, or 95%, or 96%, or 97%, or 98%, or 99% or 100%. On the side of R, Tesht 0 for .lmntqh a 0 Kadirah 'âUj 1 to God for one or more of the framework sequences that have been Tvier positions between HVRs image Azib: (HC-FR1) - (HVR-H1) - (HC-FR2) - (HVR-H2) - (HC-FR3) - (HVR-H3) - (HC-FR4), and include changing areas Khgegh chains on one or more of the Twa 7 t, but 0 for exclusive p was Tvier positions between HVRs the following image: ', -13- ΜΑ 32948Β1 (LC- FR3) - (HVR-L3) - (LC-FR4). In another Jaap too, freeing sequences Framework of Toapt framework Bashaah 0 0 0 Zgq Elha the other hand, b Alambrarat Framework heavy chains 0 1 n MTW him first; or a second or Dalah yolk-Muh sub Kabat. Besides coming in as well, but be pipelined 0 heavy exclusive Ylasl &amp; gt; Framework Yltha Mtehgha it Vemoah VH subset. In Gap else too, be one or more of the sequences Framework heavy chains and one of the following: HC-FR1 EVQLESGGGLVQPGGSLRLSCAAS (successive number: 4) HC-FR2 WVRQAPGKGLEWV (successive number: 5) HC-FR3 RFTISADTSKNTAYLQ.SLRAEDTAVYYCAR (Almto 1 Maly number: 6) HC-FR4 WGQGTLVTVSA (successive number: 7). In another aspect, too, derives Almitragliat Framework Khgegh strings of consecutive group Koaat Cap 1 (first ¥; or a second or Thakh 0 c 1 by another father; &amp; quot; Almtwa launched 7 T. Framework Khgegh chains framework first Mngq him to Kappa VL. In Gap else too, be one or \ / of sequences Framework Khgegh chains and one of the following: LC-FR1 DIQMTQSPSSLSASVGDRVTITC (successive number: 1 1) LC-FR2 WYQQKPGKAPKLLIY (successive number: 12) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (successive number: 13) LC-FR4 FGQGTKVEIKR (successive number: 14). -14- ΜΑ 32948Β1 Sas; Alabas,.; piss 1 literature 1 S.phipp Us No, 0 Ttaaty 0 slow a 1 Gorao Study of Ml b de uh ?. '2 AJ hee', Houaaouabasiva ', - the fact that Aklzh S / 0 of | Aaba Ouarh p IgG2 A · in Q 1 j Q 0 Maf, d, as 0 to Aoialeb.ad p Ats ,. Alo 0 thousand b a; 00 d. XY &amp; quot; seen;, F to I Dflam b r Jii &amp; quot; or Ra I 0 for Almagan Algikozhel. in Nmong Last Eva 'Tkdt Ts ;. F Ady functions b Posted Ashe is a Aspd 1 Ν297Α or 0265Α / Ν297 brightest in the S-10's 0

Gap Ed R and IgG2 B in Nmong Last Also, combinations of the invention include any of the Z 1 Assam 1 Hsrlo Oelah's anti PD-L1 0 p provides material and at least one tanker pharmaceutically acceptable. In Nmong else too, invention Hmgo provides nuclear Zola vacancy August 6 flash Almtqh Khgehh or heavy chain rein in anti's PD-L1, where: (a) the heavy chain also on successive HVR-H1, and 2 must and 3 Ad by -15 similarity include at least 85 % with GFTFSDSWIH (successive number: 15); AWISPYGGSTYYADSVKG (RTM .lmtwalah: 16) and RHWPGGFDY (successive RFM: 3), respectively, and

Cx ΜΑ 32948Β1 .. (b) also include Alkhvagh chain on successive HVR-L1, and HVR-L3J H7R-L2 that deaf similarity of at least 85% with RASQDVSTAVA (successive number: 17), SASFLYS (successive RFM: 18) QQYLYHPAT ( successive number: 19), on Althrip. In particular Gap, characterized by successive equal of 86%, or 87%, or 88%, or 89%, or 5% of 90, or 91 e / e, or 92%, or 93%, or 94 e / e, or 95%, or 96%, or 97 e / e, or 98%, or 99% or 100%. In c 1 b Other, T. 0 SHTML 1 Mztqh changing Tghlh ULli on one or more of the framework sequences that have been Tvier positions between HVRs the following manner: (HC-FR1) - (HVR-H1) - (HC-FR2) - (HVR-H2) - ( HC-FR3) - (HVR-H3) - (HC-FR4), and include changing areas Khgegh chains on one or more of the framework sequences that have been 10 Tefinr positions between HVRs image deification: - (LC-FR1) - (HVR-L1 ) - (LC-FR2) - (HVR-L2) (LC-FR3) - (HVR-L3) - (LC-FR4). Gap also in another, Stq sequences Framework sequences of human framework Mngq them. In another aspect, derived sequences Framework heavy chains of the first sequence, or a second or third Nhmuah Kabat subset. Gap also in another, the successive Framework heavy chains Third framework agreed to Hmuah VH parish. In Gap also another 0.15 be one or more of the sequences Framework heavy chains and one of the following: HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS (successive number: 4) HC-FR2 WVRQAPGKGLEWV (successive number: 5) HC-FR3 RFTISADTSKNTAYLQ.SLRAEDTAVYYCAR (successive RFM: 6 )

CY -16- -16-ΜΑ 32948Β1 HC-FR4 WGQGTLVTVSA (successive number: 7). Gap also in another, derived sequences Framework Khgegh chains p. 6 to as Kabat Kappa subset first, or second or third, in another aspect, too, be Almto one bit Framework -alslasl framework first Mngq it kappa VL. On the other side also, &amp; quot; the fact that the birth or A / 0 I sequences Framework Khgegh single strings of the following: LC-FR1 DIQMTQSPSSLSASVGDRVTITC (Marri RIP: 11) LC-FR2 WYQQKPGKAPKLLIY (Murr 1 Mechanism trauma; 12) LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (1 Douala RIP: 13 ) LC-FR4 FGQGTKVEIKR (Almto'lah RIP: 14). In Gap Matn another, the antibody also includes a transient or u 0 confidentiality Thalo 0 area in the z R Aiga, Nur fixed human Almzhlqh of .nhmuah inclusions de IgGl; and 2 H 8's, 2 Hegel; 0IgG4j, IgG3j in a particular attractive else, the fact that one Btqh 'for human Althabh Barr 4 E 0 Q Hegel to 0 in the last Ji P also be selected for one Mztqh antral 1 fixed Aljmuah 1 containing a folding 0 Gel, Gel 02 and 8, and 3 2 H; l, 3 H; l. In 0 August Arla 0 be one slow one Iraa of righteousness; En 28 Hel · In U Oer, Konsmas and 0 for Atfoumas 0 for Aaggloodb.aouadb 0 for pain, p Aloz 1 deletion b Murr 0 d Aldba R &amp; quot; &amp; lt ;; Fc 'Lenny does not Daa b ed a 0 not. ! 0 and Ra as upper Seve Bolchikdrell's. In 0 August seen Oaz 0.0 cold .lar; Fc p does not Lund bb Jst Eouarh 0:00 Abd'l Ν297Α or 0,265,197 in the mother Ed -17- -17-ΜΑ 32948Β1 in an attractive 0 R Also, j 0 SHTML 1 acid 1 to Dhuoa also on the less i 0 B is not 00 e z Avd Ruwi 1 Mchgr any of only 0 Im AAC 1 de d PD-L1 a 7 Q and Sgha 0 Melt r r '0 SHTML 1 also Maql nest Bh as upper 0 Dallah Mga 0 Study of the expression of one of the acid Adroa · in -ar, be bossing one family Ebarh real Bh Auriga one of or primitive Alzuh 0 Melt p wheezy, be bossing eukaryotic cell mammals, confidence 0 n d d o (CHO). In Nmong also seen; invention provides a process for the work gm Z's P.-L1 or DPA generator FM Association, include the cultivation of Bh à- contain nucleic acid mesh &amp; lt; Anyone will Alosam 1 to counter for PD-L1 a 7 bugs or friendlier Study Association for MOQ less in the forms of expression, in Lavrov suitability for the production of this anti bridles or Chettia, and'tdh Ed 1 1 to counter or fibula. In ^ Zj R Also, Alachter 1 GS provides a combination include gm counter for PD-L1 or fragment thereof Association of antigen, according to R. In this Alotijh and 0 birth tasted 0 of one 0 &amp; lt ;, persons sales 0 pharmacist. In Rzj R A i 0; invention provides material digitatio container sales on the amount of therapeutically effective Z

Z Aikirkib 0 of 1 Exposed Egh 1 in this document and instructions refer to the use in the treatment of a disorder ill and Zal, in Hilla T in Rzj R also provides a speeding hypertext Ts 0 some μ0, folding any z wares 1 delegation's PD-LJ a 7 bugs and Sgha 0 G molecule BNCA one Z persons. In lawful 0 1 Answer, ^ Wen RNAi BNCA an antibody; fragment Jays 0 m 0 Gadd ra ^ Duc F; BNCA Urs polypeptide, -18- -18- ΜΑ 32948Β1 Aah Vibes, g! Dt 0 FNLA Ae &amp; quot; 0 Walt 4 x 0 Alae 0 sa 0.1 Fill the Alpsab'dash .Β7 -Η ^ ... to Oabdlez, Ela "d,.: 0 SOS-ml-Fill the Allibanneber; Enbs' Vidonmaegoe 0 Rdasaa Adhssalchaisapemmarb 0 0 0 Asallalhe Amedoo; Aaks &amp; lt; Ib late ^ 0 Rb.vis Adadb, Akondiabalsk Moberhenrhbesksi'q 87. In b Us, bowed molecule AAC 0 Struck Web Z Ml termination Z: CD28) or .1, CDS and CD86, or ICOSACOSL · in E, b seen a twitter, a coded principles August August Lord Bern p o 0 Move r d FR ™. In August R 'z Brighten' to eat 0 but 0 J Akdn p as upper-Dallah TNFR F 0 Rev Isla de:! 0Χ4. / 0Χ 'd &amp; quot; 4 CD30Lj, CD27CD27Lj, ΙΒΒ / 4-ΙΒΒί, HVEM / LIGHTj CD30' Dr. Ed 0 b-s his deputies, and antibodies to help them. Gun in c hampered by another, the invention provides a substance manufactured include any p Alosam convergence above for anti-PD-L1 0 p Anti Z or more. In a Hafb 4 shower 1 Anti Larry Akhmuah eaters of the antiviral factor, or antagonist to the bacterium-termination or harmony 00 for an anti-Guetriaat, or the primary antagonist of the animals. -19- -19-ΜΑ 32948Β1 in &amp; lt; ν'Λ R; Ad Allowaml Anti-Virus from Anhmuah containing Hbtat Achakh! &amp; Gt; -, &amp; lt; Or 0 Htat Breuetaz, or Htat Antijraz, or Htat enter or merge, or Htat Aidaj, such as 0 or authorities viruses, or Mahnat immune response, or sensors support anti Qirsat, or Qah 1 v, or liver aids and herbal treatments. RSS also in the side, connect Alparvinh on one or more of antiviral agents. In Z 3 c R also; invention provides material manufacturing include any of the objects described above for anti-PD-L1 0 G vaccine or eat. In Nmong R Also, Alabraa provides a way to improve the functions of the cell Τ includes giving an impressive amount of any of the objects or structures described above for anti-PD-L1. In one air 0 Melt, makes the body or anti Turka's hidden PD-L1 Τ to Y the light functions work well. In Nmong else too, Alabraa provides a method for treating a disorder light of tan, P Alkhalada Τ Q 0 for the Aetae Marh amount therapeutically from any of the objects or one of Trklt Mosolo Oelah newcomer 4 for PD-L1. In one aspect of 0 to private, it is forced 0 1 b ill cell functions Τ Ebarh Den 1 infection or forced to become one Mmaeh against tumors. In Gap else, be Easyway Idhe or Rlo 'in the c 0 Type R, be' infection 1 Mzmgh uninterrupted, or latent or slow Jaap R A 0 i be a chronic infection caused by Cash MSP for the disease Mentny p .Μ A- de bacteria or a virus, or Yoav initial instinctive. J as Gap, -cald Ily ace disease in August for A-Schgga. J c 1 by another EVA, sales Air-I! Liga &amp; lt ;, S Eadsh 0 -20- -20-ΜΑ 32948Β1 in 0 attractive else too, d Traghoavaely Alalaj.mamadad encompassed 0 in sJU R Aiga, be Alcainabebllmrdebenkpra &amp; lt; Dawhittoyelyataeevl Mdhand bacteria 0 0 Alp else too , p carriag 0 n Μι Aslat Elmy: 1 and Ste Avloveat, and Alaeriaat, and Aq_at, and 1 Qmmyat, WIRE-Ate and Kabaseltat, and Managing Veat 0 1 fragile, and one of Treponema, lobby-DAT pylori. In toured 0 B R Oadhae, &amp; quot; without Cache me for Ouarh p 0 RIP virus, and Eva _iml'ltrivh on Aetae d Mgad for Gero, is coming. In c 1 Melt else too, selected one Fros Z Amehmuh A- de: literary b hepatic web 1 E. Β, or C, or Fros mashing August 1; or -Π 'or a virus u 00 thief urticaria 1, II, or, for Gerus .lamadkhm cells or virus Estienne bar, or ^ will Aberm a 0 Labs, one of the human, or 1 to Gbrosat Hiah u 1 Wet Akabh Abshraeh, -l, -ll, virus or any Ayava 0 on the other side too, Akon'lkash Wasp of the disease fungus, Lucille Tri deer 0 also Z! tender Eoml Anti-Guetriaat. In another aspect, too, selected turmoil as a 2 Qmua 1. Z: Alasrgelos, and Albulasumikoshis, and Kndidaamps Alec S, T T- Dmmitis, and Histoblazmosis, a bar Coxdopkos' and Skro Sordioss. In Gap seen any; be Akain 1 BP Drd 6 Laa, Dr. Al &amp; lt; Ahh lighted to give the primary antagonist of the animals. In another Obga side; Ad Aladalrab of Atjmuah Intmlh on: disease Allaaosmania, inflammation Almtamorat (ie; Aaalria), or d 0 E Shi T. Orag, and diabetes Iqamat, and diabetes Nithabbat, infection appendicitis; Z in Y 7th Tel 0 k resulting from Almtqhobat (such as schistosomiasis) and Eucestoda (eg, diabetes 1 m _kat) of 0 roses (Shell, Trajkanala, and diabetes E; SPA 0 to onshore and Rubiodio-Q) '-21 -21ΜΑ 32948Β1 in Ui b R also 0.0 universe troubled poor job bossing T is a Alnaah against one of the tumors disorder. In Gap last Also, Hamad 1 curb or Levi newcomer PD-for L1 Y also Eshetny on Mentny Q August traditional remedy eaters Ely: 1 for the treatment of radiation, therapy 1 Aoe targeted therapy, the 0 Lage immune, hormone therapy, Chit angiogenesis 5 and treatment Altskyna. In particular R Gap; p 1 for the treatment of Weiwei 1 0 n Anhmroua A-Z: Aljamesitapan, or Alsichaelo Vosmgamd, or Allleksorodbi 0.1 Beveny; Abla-between. In particular Jaap else, be Adz'b 1B also 0 tumors loyalty En Srt'n Mzd of Ahamuah containing Rtan breast: lung, or Alaourn, or August; or 1 tumor Aelabna, or Att 2; or kidney, or liver, or saliva, or kit, or glial tumors, or 0 E. Alderfa 4 or thymus, or Alglhara, or cancer of Arras and convergence 'Lhasa and Bakraas brief description of the shapes and graphics: Akkl 1:00 Hanimv of sample Almiterv T cells Yalallh Β7 liberties cells at the surface. Figure 2 is a graph showing the p largest design-j b like Khala-A A Adam 15 PMEL / B16. Il 3 Ed; Enlm-Atidhar Dhoruai P.-U Ab S RVs Q 7 Kahh, alley 1 P-Q Elaaa; u 0 c IFN-γ in the z Aazla.da in T + PMEL CD8 in Alassap 1 Itid | to Bh | Elaba gpJOO. The birth of each Z August August's + 0 E of S

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Walsh 0 5 a Mellh of FACS schemes Althn show in KD-R confidentiality CD8 T cells by antibody to PD-L1 YW243.55 SI in Mgawat reaction mixture. Yum also one for reporting on the percentage of innovation Rasith cells mitigate the severity of CFSE. 1 6 as a whole is a blueprint for the design of Altharia for the treatment of chronic LCMV using images Alehimrah for PD-L1 Ab YW243.55 S70 Almkhad. Raise the stock to Zman 6 doses of PD.L1 starting from day 14 after infection with 2 infection LCMV 13 pfiiClone ^ 10 X. 1 of the two forms 7a and 7b is a two cartoons Pianitin illustrate in Zigh Send sticks CD8 cells Jem neighborhood after treatment of infection LCMV-vivo by PD-L1 Ab almost a 0, YW243.55.S70. The blockage of PD-L1 by YW243.55.S70 to the demise of Alhabayat 0 n b CD8 Alkhalaiaa (as measured by an increase in CD107A Altahi) (Fig. 7a) and increase the ratio 1 Koya t -IFN Ham Althh cells in Alatjabh for peptide LCMV gp33 (Fig. 7b). Was detected recurrence of cells; - gp33 Ptbakimha Boukmasa Allenbabh units H2-Db .gp33 -23- -23-ΜΑ 32948Β1 Figures 8a and 8b illustrate the production of blood and bullets LCMV his father chronic LCMV infection after antibody for PD therapy-L1 inside the body District. In Figure 8a, the viral bullets from various Alonmahh referred to the analysis in the days 21 and 28, after a week or two weeks of treatment Dr. Ab, the Alterpb. In Figure 8b, the bullets viral serological analysis on days 0, 7, 14, 21 and 28, with vaccination 1- LCMV day 0 and the start of treatment per day 14. Figure 9a shows a decline a sign of the growth of the tumor Chrisomh colon MC38.0va result made using the antibody's PD-LI after treatment Almktmhvh tumors (S a ^ c at Aleo 0 AD 14, when the tumor reached 250 mm 3) Figure 9 for a distribution of the frequency of shows Maaat August for PD-L1 Afd milling on MC38.0va cells in Rrah tissue measured scheme .mmkies cells flow. August Yum not for PD-L2 by MC38.0va cells. Bereavement 10 is a graph showing the effect of .lalaj d PD-L1 .dhardh and promised anti-VEGF or gemcitabine on the growth of tumors in MC38.0va Akr'n C57BL6. Figure 11 A-B is a variable sequences Almma 0 Lq and b, bunch R; Z convergence; 11 d L D'da's P.-L1 then see-sa Boss 0 Ne August. -ro Father S CDRs Q; -saat, guardian Toqah's predecessor in August the Dow /; OU any HVRs. Ascla description of the invention has been integrating all bitter one encourages one to incoming in this paper 1 p 1 0 fairway z n .rah this 1 1 Sep. -24- -24-ΜΑ 32948Β1 general techniques -m Tdhz Alaraa Wadley, unless otherwise specified, conventional Tviac Biology 1 Huzeiiah &amp; lt; including the technologies resulting from the return of the link), science Alharah biology, cellular biology, and ironing 0 Lamia Aaaologih and Immunology, all located within this Amehal. These techniques 0 full annotations in the; age-G meth-for Molecular Cloning: A Laboratory Manual, second Sambrook et al., 1989) edition); 1984) Oligonucleotide Synthesis 1.MJ Gait, ed); RI Freshney, ed., 1987 ) Animal Cell Culture); Academie) Methods in Enzymology Press, Inc.); FM Ausubel et al., eds 1987,). Current Protocols in Molecular Biology and periodic updates);, Mullis et al., Ed.,) PCR: The Polymerase Chain Reaction 1994); 1988) A Practical Guide to Molecular Cloning 7.1 Perbal Bernard); Phage Barbas et al., 2001) Display: A Laboratory Manual). I Miah host cells! _ Taiw 0 t Ammoyat and Ageth 1 son of; that the Vawat me no Z T &amp; lt; eaten g stressed &amp; quot; No, &amp; gt; Ende &amp; lt; Akq 0 0 n Laa | for i 0 O Ste these Ad.lala Z Azlaa genie Almkona blood j Aboukhaa Lacey Wei then a ^ m. jis finance Khala-a Alfawih. But some Az 0 0 1 Aailaa father pillowcases d; 0 Majha fled in Alfaw.at ή Τ Β or rather, a 5 Wasdell Abeslo ό'ί 'in Laa termination 0 j. Tnio the cells 0 Τ, loomed Z 1, Z 0 rad I z Lab parchment wit to'til r, blood; for Yakr.lo, bit; and Sarasjsooatelsl. -25- -25-ΜΑ 32948Β1 be one of Mgoyat SSH started 0 Ie Waco Z-H or S-1C in my Hadlat, or a 0 of 0 Aakar, ie 0.0 is the fact that active Ftelia. When dispersed in any blood 0.0 Il This Afaw-0'alosalh s &amp; quot; Or &amp; quot; virgin &amp; quot ;, 4 Li Leiden sources lymphocytes secondary or peripherals, such as the spleen, or contract milk 0 Gaoih or amygdala 0 for most Amgaoiot pristine As short, so die led after 0 0 RCA S or Acotth 0 z A; g r, if this cell had received a signal indicating that there is Generator against, Vanha may Cht and are subject to several Dor't S Study 0 back Z Khalaa 0 applicat applicat to come .lscon to become Khala_a Tj B Fu, s y 1 football 0 dam 0509 Oosah Ashe 1 ^ father with Large 'to alert. The fact that the other strain Fu-Next Steps ^ termination Khalaa 1 b r 0 e fonder days only, but one of the activities carried out Dvaeah · Alopecia refers Mmsheet 1 Mgoyat him to d 0 &amp; lt; p Alodat him; Z which one B 1 Foe hey 0 Z JUP urging them to Acam and Azaj strain that becomes each Mersat neurons · include Alastahabh 1 to complete urged one Vlaaa Z Ouaili &amp; lt; 1 occurs blocks) SPA Z 1 Otev verse 0 -sah one too Nctz when Artat certain associative groups receptors El 0 Z ASAP. Differ! Tkhmuat Aturabhia gw of Khalalo step T, u 1 0 Ddb for suppression resulting physiological Das Alkhala.a. 0 Bmcn Ded Rella 0 v antibody suspicion Matma Chet Almufawat, a private FM generators polymeric 1 Aarh 1 t lead to Alaratat Alchapki of sweet urate immune de thousands c 'or one of Brocivat Alkdlo only / Z Z Aozlaa 1 T. Z Erdem 0 n Zq' not DD &amp; quot; Z Simla 0 F only, even! q as 0 P Bair link any B cells; d 0 Tmahagshlb any '-oda wish this tomorrow dimensions 0 Zly attached to having a B cell count Tama Baro; copies -26- -26- ΜΑ 32948Β1 Ynoalaiya 0.9 Tlotsabnss, crave-Mazha Behrr: a / Z ,; Pakalm 0 Z No, 0 Ahls 0010 E Rowe-bit z a 0, told T that Hael.a Sclat Stahaazla 8 CDP 0 to Ialh Lab 'b 0 Alkhalaiaa to A_sasgoyainanalgeloyopt smarter, Ydloszv-Poprad Diya Barr 0 Plan Pro-bit Tah'sha fled 0 lattes Khala-a (TCR) for Smv this Alablatt Z 0 Rldat' P e a Baltla 0 0 Z or Z Almair Dalal land e 0 Z At Aagla &amp; quot; the S-1 to see. However Alkhalaa1'llthmh'kabarh, Taku Adla n-da Alkhalaal Alod 1 would let him who Metruc Mufaah in induced cells. U 1 to reflect the Z Alkhala_a B, 7 T cells only been discovered jealousies materials in certain contexts only. Z In particular, the T lymphocytes recognize Albroctn Zub if Azhtarh Jp T. Watt Sgarz, including terminals and then on the surface of a host cell a second shot by a cell in advance born newcomer (APC). Can be of many types Ath cells perpetuate 0 and DAT against in some 0 Leno; but &amp; quot; including the harmonization of certain types of private harmonize even more for this Zd and be y 1 t especially in the control of cell T Activity importance, .mma the August cells standing cells and B 0 to another. It depends partly provide antigen on certain proteins called protein complex Labem 1 Vq 1. The main (MHC), and on the surface rendering cells. So, to alert Mahgesh immune cells, could provide peptides suspicion of cells T 0 p peptides MHC, must Amaraf future cell T on this Aillh 0 27- 27-μα 32948Β1 Hmak Mjmutan &amp; lt; Etanellkhalh 1 Lord &amp; lt; any Ouaoo CTLs) or one father T Yea 0 of (&amp; quot ; T) to ^ Acrvelaha-Illely 7 Stobeira; mouth CD8 and 04 € Elystahallaaa.oicon the exception of 0 da El importance of my Agheirosat, and Amkea AKC U Bacrv directly El 2A p peptide 1 T. Algiroseh 1 Bryhaouaystah cells 0 Woody Khala-da Τη to Taiz-DZ parents ;, and Alzdh; and functions Almz 1 Vision Oraa to a Khala-Aryan '&amp; lt;) secretion Amgokeat - in Zhat Allaao Β, and Allaaa large .lmmelthmh and 1 cells Τ toxic to cells. And &amp; quot; shadow 0 Rula 0 Q Amgaoiot Τ pristine and tastier 1 football &amp; lt ;; Tabaiha in Alakh case 4 and Z in these instances significant Zhata to Lha birth or 1 cells nation 0 light of Chitha, Takha these cells delegation cycles of division Feeli to produce nascent cells. Return 0 and j z Allosh these cells to Alsakih like the tastiest 1 cells football cases, but some of them remain Kkhalaaa b / a Las Bhaeb and p Activity 1 Hlaya 1 table or toxic. And this is similar Rrdh cells Aaey: 0 not to Khalaa-A + 4.C produce baskets + CD4 only, while producing cells + baskets CD8 + CD8 0 never. Reflect Τ August Almería cells Mno.at the surface of cells that are not expressed on Khalalo Τ 1 Enlai; 0 W-025's; and 028, and 029, Wa 40 Hh, and 0 acetate Trutd-Q Loro &amp; quot; bit MHC 0 n Algih Sep 0 and when you drag stimuli activation, dims Activity Abamh or cells Almaadh Tdoejia 0 Edh during the days of the dimmest sent neurons or Audtma to sleep, and in a similar way Β activated cells, asking Astahabat Avawat Τ p 0 and 1 authorities CKD two types of stimuli Alemramnh. The first is the antigen, which Yum 0 Li, in &amp; lt; 7L Lord by proteins MHC appropriately to bossing provided Rt F; Akaraf consciousness responded .mmstqublat 1 cells T. 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A-1 to Asagjabh performance 0 of Haw; p 1 includes Ozigah three Alosabh abyss 1 g percent breast that sets it apart net body's defenses: (1) Privacy - Aq 0 Rh identify Alastahabh and not Alassaph individually between a large number of target molecules, and (2) discrimination - Aladra &amp; lt; ) limit-d Ak'ta sa; u in peace 0 p all Albrooavat that countless other organic material, and also Alascabh moon birth Akherih Bear Z bridles, and (3) memory - the ability to remodel experience my lead following the confrontation 0 p Cash Girib Mud insulting a 0 for the disease to Adat 1 Stjaat Oassa and Seychelles Z happened in the initial confrontation. When frustration and Zigh or more of these functions 0, true medical condition. Bam and Besorz navel launch Mgawat Baker of the main lymph sources in the limbs, Hataathmlkmah 0 Ha 0 Stqublat milling AVI Taad on Alaratat.mmoldat F, which Bam in Alhal B z during immune Algeloubeyoloaat associated when milling, while the T cells by -t Algela 0 a T. When activate Almufawat pristine, for he innovation, productive Khala 0 of Wieden we will place after y 7th cycles Chit bigger and multiply. Khdd generally 0 lung response against 0 replies eye buccal Balaztqa tuberculous: The more Khaldaa rose or private Abel increased -29- -29-ΜΑ 32948Β1 against against a given, the greater the number of cells that can luxury Z Almnaadh respond and participate. And JT S-1 by the fact that hourly complex and be a succession of organization events organized m 0 tomorrow, and several types of cells. Wim energize LACK enters RCA 0 August body I felt certain of the cells provided to the antigen (APCs). WTF APCs fulfilled a very small amount Z Elmo LED 0 1 Mghaei and being in 0 Subject to be recognized by the Mgoyat T Almaadh own Jy antibody. And T cells become active emerging after that, for he will then 0 gg Z Tencdt other lattes 0 n 1 Hlaya Seductress, such as 1 to Hlaa B or T cells toxic. Kkar activated lymphocytes and then the specific functions of the nervous kicker. At each stage of this Abe Ah Q 1 of 1 T. equate APCsj 0 p each other direct or Tefr'z 6 in contact Anizh- kyat subject to external starch antibody generators taken by APC series Z Acharat eat dubbed processing antibody generators. And involve such treatment, especially Mok't immune Albrociveh, the disarmament of physical properties and operations Alahtdham Aldzna case of Rotivat 1, b is 1 Azahal t-born immune to the resulting peptides. A limited number of peptides Adatjh d deletion is associated Besolh Tahmah 0 G proteins of MHC Class II and moved to the surfaces of APC, which Azv process by providing antigen. 0 can be activated CD4 T for Mgoomh Atjaadh Almtlamsh i, p 0 Wathrah APC, and it can be done if the expressed protein future of the T cell which can Aderf and 1 Araft .mmakd Ptd 0 of 1 particular been expressed by APC. 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Blood 'and vow -30 - 32948Β1 a signal correlation Mshbl RCA against trait T · Mmakl peptide 0 for MHC ^ antibody on the x-0 surfaces APC Mongol through a complex CD3 routine, and Iatkd to signal the second joint excitatory APC Jl resulting from Arbat separate protein carrier signal on the cell surface of T boat; Abafee qualitative on APC . one of these interactions Almrovh represent the ornament protein, CD28, T and the family of proteins surfaces APC Almrovh the nations Β7. may contribute to other pairs of proteins the 0 Lbh well as in common arousal. described the process of joint arousal, Mmazid of Alngesel with b 0 Yale. gag antibodies for PD- L1 counter the present invention arousal Almstrka p x 0 Lal counter signal common Amttharih negative is provided by criticizing Alavarat through PD-L1-- Alahartan T. T cell help to start the secretion of cytokines Aztrliukin -2 (2-IL) and • the commencement Akalpar Alzh p Stqublat 2-IL Rtfh familiarity quality of the surface. The 2-IL that's specific as upper 0 0 0 GMT active hand in the melodies Algtala cells and T lymphocytes necessary to respond to the staff. L Lech 0 for none T j. To know the effect of 2-IL on the ornament, which is secreted which the nations of the phenomenon of self-Aloethber Alaraz 0:00 it turns out that even in the case of reception of T cell to Athartin, for he does not multiply in 0 pw Aeovh Sthblatt 2-IL Alhlhah one of the private M 2 IL also may affect-the Khala-da Anhaorh 'Z come R. additional 1 | 1 g of cells 1 for deaf Nat' to effect 'to my situation. This is one Altotdhir special importance of one of my Chhl Khala_a Te 1 I do not Wolters General 2-IL enough to stimulate breeding. B 1 to add to the 2 &amp; quot; Al, justifies the exception of 0 Τη Joe 0 Yat other and promote the growth and differentiation of functions h cells and'lkhalaaa macrophages any Dd types Kl 0 aided a! 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Mlle of Category II and mow 0 Liat many adhesion, and thus strengthen Τη cell attachment and support representation Mall 0 0 d antibody. At the same time, make a 1-IL Mtalia influential Baraz endocrine cells Nat Altotar Ardaa on Τη cell to enhance the secretion of 2-IL expression Alorani for the future of the 2-IL. During Cht 0 0 Τη cells in the manner mentioned above, can be associated with some of the cells as well as Β ^ Jenin immune to Z through the antigen receptor Alopecia what, which form images associated with straw 0 termination Z Oham anti produced later. Otherwise Τ cells, Β cells recognize one of Jkn 1 clove in Murth Free untreated. Qualitative Alarabat provides a .mmold antibody types Alair't 1 the one who leads to cell activation Β. Tovernoa are less Τη termination by cells expressing Ray R, for Erottanat Almaadh to activate the cell Β association, Mmstqublat except -t Algeloa Lzn and-1 on the surface of the absorbent. You know these signals derivative Q Τη, Alma; Β Pfhy any of the 0 Zer about the quality of the private generator antibody 4A, factors assistance. - This Awa ^ 0's, but its -IL 2 and 4-A-1, 6- not. But, check the aid effectively Ptlas cell-cell, for \ Bs 0 h on the surface of the Brocvat ornament T Bmlamh fulfilled on the surface of one cell B 0 cercus. To Dthakq p 1 Dadh eaten by contact Totana when a protein known link the mother to eat Abadi CD40 CD40L)), Yum .ltobeir him folding d Τη revitalized Ie Beru'dzn my mother 00 rack CD40 &amp; lt ;; except, of Β. In the name of the gift of Mrovh Chit 1 reserve, say 0 -kon ace .da J Β I Kalia 0 to activate Khala.a Β 1 to Kamzh even in the blood of FH Buy 1 as 1 Doklt August to Tahha generator Anad. -sdadlaa 0 insulting. Z Adthal Allaa 1 1 Tas and Ray Dhald F Alarb de Most Te cells for CD8 not surface, Kalkhalalo infected family infected with Veron 'd -32- -32-ΜΑ 32948Β1 CD4, and therefore recognize the generators antibody associated Berutmat MHC are Algih I Lloyds food-4A II. When you transfer the infection to somatic cell infection, may be subject j 0 Z PRO &amp; quot; Pat Ghabrosh born immunosuppressive treatment within the cell, and peptides resulting Kdat surface 0 p show? LIBAT MHC class 1. It can then identify the complexes MHC Almzkwoh Boillat future of the T cell to Nkh quality generator antibody, and not assume signal 0 n Alatharin 1 Grureten to activate the cell your responsibilities induce first signal and Hdi receptor 2-IL over &amp; quot; radioactive Alolgh cell your responsibilities Yum Anjul Z 1 for calibration second Z during the 2-IL preach from Τη cell faithful neighboring booster. When receiving two signals, the cell requires .Τ anabolic activity cellular allows Z herb ornament a name; Tbth what, Okz 0 you any cells see the same complexes Bptid- MHC class 1. In some Azalat, homicide caused by Araz Tc toxins Rev &amp; lt ;, Alkhalp 1 target, in cases Okhry'stges Tc target cell to commit suicide to fade. Hakka; Jaih Tc Adashth well as allowing the emergence of additional Tc cells of the same-for Vision Doodle F 0 d exhibitionism common to the family of immune globulin Sub-CD28 / CTLA-4 -Β7.1 / Β7.2-1 so discouraged that signals T may be Ovfl common excitatory path was Tocefh cell sniff 0 0 m 0 R Anchal Alathar't B7.1 (CD80) /B7.2 (CD86) -, Hhlal In tolerable. Lahti Necker dual quality - this Uh T 0 Study in Tvhat ornament; Karandikar et al, 1 Neuroimmunol. 89: 10-18 (1998) and 4-Dlahvi CD-28 Alastt 1 Reyn Salomon et al.,; And Oosterwegal et al., Curr. Opin. Immunol. And (1999) 300-294: mil -33- -33-ΜΑ 32948Β1

Sansom, DM, Immunol. 101: 169-177 and '' .Annu. Rev. Immunol. 19: 225-252 (2001) Chambers et ai, Annu. Rev. Immunol. 19: 565-592 (2001) Β7.1 [Freeman et 2000); and) Freedman R. 0.7. Light of, Immunol. 137: 3260-3267; and a /., J. Exp. Med. 174: 625-631 (1991) Yokochi el 57, t. Immunol. 128: 823-827 (1982)] and Β7.2 [Freeman et .7, (1987); and; and Freeman ef .7,1 Exp. Med. 178: 2185-2192 (1993) and,: Science 262: 909-911 (1993) Aruffo el .7. Proc. Natl. Acad. Sci. USA 84: -Azuma et .7, Nature 366: 76-79 (1993)] are expressed .Gross et al., J. Immunol. 144: 3201-3210 (1990) 1987) 8577-8573; and) Gross et .7, t. Immunol. ) T cells on the surface of a structural CD28 on the surface of most cells Please choose a future, genetic expression increases, CTLA-4 1992) 388-380: I, while a) Peach et al, j. Exp. Med. 180: 2049- .T Mraia as a controlled after the activation of the cell Kinsley et .7,; and Linsley et .7, t. Exp. Med. 176: 1595-1604 (1992) (1994) 2058; and reflect the most .Linsley et al, Immunity 4: 535-543 (1996),: Immunity (1994) 801-793: for in a structural low Bemczuaat, increasing the Sriia about Β7.2 and Ray Freeman for APC groups. On some induced later after Β7.1 uncontrolled activation, while expressing 0et al., Science 262: 909-911 (1993); Hathcock et al, j. Exp. Med. 1: 631-640 (1994) is Β7.2 data and deactivate specific genes of the mouse that indicates Β7.2 former genetic expression of the molecule common excitatory importantly to start Alamtahabat immune, but characterized molecules functions .McAdam et .7. Immuno. Rev. 165: 631-640 (1994) .mtdakhlh very Taatotait to promote TCR and 8702 may signal mutually supportive 0 p 0 p Akharh Β7.1 both CD28 Evaal Lanzavecchia; and Lenschow ei .7, Annu. Rev. Immunol. 165: 233-258 (1996) 0τ ornament -34- ΜΑ 32948Β1 (1999) 1-4: 96 Cell 540. In the absence of TCR signal, not a transfer of CD28 importance Vsaolrgih signals. CD28 regulates the transmission of signals organized a threshold value to activate the T cell and reduces to a large degree from the intricacies of TCR number required to activate the cell 0τ: H Science 40 »Viola et (1996) 104-106. Chit CD28 responses ornament T keeps promoting T cell survival and thus allowing for the expansion Buquenat start cloning the T cell and differentiation. .Thompson Et al., Proc (1989) 1333-1337: 86 Acad. Sci. USA mussels / Htm 8; and -5757: 154 .Immunol RO 540 Lucas et (1995) 5768; and SYP 540 Sperling et; (1993) 612-609: 261 Science (04 Shahinian et (1996) 3909-3917: 157 .Immunol; (1995) 98-87: 3 Immunity 540 Boise et. - CD28 as well as the Z Astahabat T in advance Almnmhth, promotes the production of interleukin 2 (2-IL) Obe ornament T. while some responses depends on CD28, it remained unclear whether this dependence in the joint arousal caused by stimuli generated a strong antibody or reliance on 0 skills other common excitatory is Mrovh. ITSP Chial 4-CTLA in a negative signal, which inhibits the transition viewer signals Mai TCR O28-e) Anth for link 4-CTLA inhibition of synthesis 2-IL and progress through the trotting course and Abe 0τ cell responses (405-413 (1994: (a) Immunity 540 Walunas et; and _l 540 Walunas et (1996) 2541-2550: 1 .Exp. Med.} and 466-459: |. Exp. Med 540 for Krummel et (1995); and (1999) 5820-5813: 162 .Immunol RO 540 Brunner et; and, 54 Greenwald et (2001) 145-155: ImmunitylA. Yelp 4-CTLA Doma important in Ttim Astahabat no's, including the possibility of cell T Terminal. despite the lack of clarity in how Aphik Bzn Alather't 0 n slipped Β7 Search 4-CD28j CTLA, chances are Mzho Azd Ely 0 CD28 in a land. &amp; quot; Bhatt b -35- -35-ΜΑ 32948Β1 Stukenat immunosuppressive, and anti-! to direct Aztqal pointed 0 T. CD28 and interpreted by Anchal Alalarat, Mmsahmh TCR.

As a result, you may Tkov anti-CTLA-4 (Kalojdzisam anti-CTLA's anti pilaster) Rao Madsdh B7.1 / B7.2 / CD28 useful in Lhasa Id 1 Alnaaah in the treatment of infections (such as that and chronic) and tumor immunity. 2. transmission of signals ICOS / ICOSL Ihdn La t R to interact yen except! The APC and Khalaa 1 T through Z CD278) ICOS) and ICOSL (Β7-Η2, CD275). Enhances the transmission of signals ICOS / ICOSL Tmaz T cell help and function of the influential, and have Mehta in Alkhaos to produce Aztrliukn -0 a (10-IL), and K P Doma less in regulating gene expression of T cell and the production of 2-IL, including T cells, regulatory, The disparity ornament T and autoimmune.

In exchange for CD28, 0 free Izza is not express Alzh for ICOS as builders Z T cells is not any, but Sges Mraia on T cells after Hutloffe / al correlation., Nature 397: .TCR (1999) 263-266; and (1999) 832 -827: 402 Nature, 04; Y0shinag5e; and 1 .Beier et al, Eur (2000) 3707-3717: 30 .Immunol; and (2000), 105-95 I Coyle et al, Immunity; and (2000) 1040-1047 : 30 .Eur. j. Immunol, 04 Mages et;: 165 .McAdam et ai, j. Immunol (2000) 5035-5040. This raises that ICOS provides a common reference for Amttharih activated T cells. While supporting shared arousal by CD28 gene expression of ICOS, and decreased expression Alzh for ICOS in the absence of Β7.1 and Β7.2, the ICOS does not fully depend on signals McAdam et al., J. Immunol. 165: 5035-5040 (2000) .CD28; and RO, .Aicher et al -36- -36-ΜΑ 32948Β1 Dzdad .Kopfg; al, for; Exp. Med. 192: 53-61 (2000); Immunol. I 4689-4696 (2000) through (Τη2) 2 and (Τη1) 1 help from Τ type as a controlled on ICOS cells goes down El 00 Z Τη2 first phase Z of differentiation, but elevated levels remain Beier cells, in the centers Jertho 0 Yeh T on ICOS cells expression pattern indicates Alzh for .ThI cells

Mages et not 0., Eur. T. Immunol. 30: 1040.; and a /., Eur. j. Immunol. 30: 3707-3717 (2000) .B studies of cells T, have distracting to assist in cell ICOS (2000) 1047 to the role of Jrnan without 6 Behold B on the functional ICOS cells that, but the expression was confirmed Alorava for Tezuka et al., Biochem. Biophys. Res. Commun. 276: 335-345 (2000: objects. From Dong et al, Nature I 97-101; and McAdam et 04, Nature |: 102-105 (2001) Tafuri et 540 Nature 409:; Dong et al, j. Immunol,! 3659-3662 (2001) 2001); f) .105-109 (2001) is 0 regulate the production of one of Stockln (0 z 4-of; ICOS / ICOSL clear that a transmission of signals Hutloffe / al roles., Nature 397: 263- to an impressive 0 'T 1 to 1 Mzhth Makhz as well except 0 da T-O13 the) 0 meanest of Dong et al., Naturel 97-101; Coyle et al, Immunity 13: 95-105 (2000) (1999) 266; 2001). In studies of airway tract disease Alth 0 S; GMT 1 h f) Tesciuba et al, j. Immunol. 167: 1996-2003 .ICOS 4 0 Baz Dad Τη2 4 without Z 0 g Τη2 Jy 1 m n JJ's cfs. ; ThI organized and Zigh 0 Aar ICOS 2001). Referring to the possibility of a) K5pfe; al Ezd 0 re Akeshit at work 0 for 0 ICOS-Ig and 2 "Arutin integration ThI cytokine

Exp. Med. 192: 53-61 (2000) -37- -37-ΜΑ 32948Β1 there another potential role for ICOS to maintenance Bascabat ThI. In the form of drag-J de encephalomyelitis self Alnaah (EAE) multiple sclerosis, \ / disease ΤΗ1 Yeh 0 of exception-a T CD40 quality of Mjelln that the results of disability JCOS has a distinctive Bmon when e-Ouaqh arousal Adskh by urging the cell T, then through one of the developed influential for Dong et al, Nature |: 97-101 .EAE (2001); (2001) 611-605: 2 Rottman et al, Nature Immunol; .Sporici et al., Clin (2001) 277-288: Ji .Immunol . EAE is exacerbated by Almtges Malaf Oolajodindrozt Glicobroc (MOG) very Vir 1 P &amp; quot; /. ICOS to have been an efficient Fshat specific genes where 0.0 p increased production of IFN-α compared to the wild type. Proverb, - Azld'd ICOS in I want to urge ΕΑΕ in Ngovem disease as well, which leads to Zadeh Amaj ΙΕΝ-α- to Oat, lead Assadod ICOS during induction to the polarity ThI response. Thus the mystery of interest that death 0 T mutated TCR quality Mjelln cells in the lab in the presence of ICOS-Ig inhibits Z 0 Roua de h 1 t EAE, and it corresponds to the clear results of peer ICOS-Ig her death for ever in ARR. Sporici et al, supra. Not sacrificed after the reason for the different results in the AMV 0 for additional and in the lab, and yours 0 Ha reflect the role of ICOS in the 10-IL Almenth to Khalaa T regulatory, as well as μ Τ cells; 5 the Azsd'd ICOS in one body neighborhood 0 are one to raise one of the joint through a 10-IL Sabha in the Open 0 Khin Isaiah 1 c 10.IL and mouth any more, but one Maly Z 0 0 Stharh incidents legacy through Hutloffe / al, .CD28 supra. Mamd ring 10 IL-12 and IL-regulatory task in regulating EAE because Viman Ha-AA DWI ./. IL4 Besa b 0- EAE stressed. (1998) 546-537 1.-Segal et al, j. Exp. Med in ICOS Doma another potential is to improve cell responses WHA confirmed by El 1 Z 1 cell T. showed Vir 1 n - /. ICOS and - /. ICOSL that ICOS is required for Asthaat 1 trait B El 1 does not -38- -38-ΜΑ 32948Β1 0τ A \ 1λ 1 to Alao \ a et al .. Nature ?? CYvfisX et al., Nat. Immiol. Ί \ ο (2001) 269-74: of; (2000), 105-95: I Coyle et al., Immunity; McAdam et al., Nature (2001) 102-5: 409 '(2001) 105-9 Nature I 40 »Taftjri et; .Nat. Immunol 40 »Suh et (2003) 899-906: A. Showed, rats &amp; quot; '&amp; quot; ICOS also Rakz bacterial less responsive to immunize five initial, severe defects in Tkows kicker Akltho 0 J Astahabh to do any secondary, and Eao 0 B 1 Zchal I IgG. It s has been emphasizing the role of ICOS in the cell interaction Τ: Β Select has zygote asymmetric ICOS's in T cells in patients with deficient immune Almtver common, which begins appearing in Azehqan. (2003) 68-261: 4 .Nat. Immunol 40 »Grimbacher. Scarcity of Zlat 4 may &amp; quot; Maadh ICOS fact / ICOSL (such as antibodies ICOS help 0.10 and'ra Zad ICOS / ICOSL Habil for Dhupav l) useful in improving the immune response in the treatment of infections (acute and chronic) and / or Mtah ashram 0

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Can! Expression of PD-1 on Kl unilateralism and Dada Ml termination Bucca T cells and Khalaa 1 B and T cells, one of the deadly 1 Study. 1 cm for the expression of PD-1 cells + CD4 and CD8 + T is less without Alkhvzh cells, amyloid, in exchange for less Arrash p less CD28 and 4-Nishimura et al, Int. Immunol 8: 773-80 (1996) .CTLA;: 80 .Boettler et al., J. Virol (2006) 3532-40. This one as a nest persons Rest Photo Hairh Z 1-.Ρ then s z Khala'da T 'human 1 Mzhth, blame .lveskh August to (a) EP 2' (b) ECU 0 rang s, (c) Aksomat 2 and 3, or (d) ipet 2 District 4. (2005) 16-109: 235 Nielsen et al, Cell. Immunol. Ba 0 Sca PD-l5ex3, including less RR 1 Moore F-Rh.mmsuiat ED I 1-PD Ka 0 for 1 for the length of the &amp; lt; L 1 blood 'for both sides Alhah mono Alrah (fi' (PBMCs I Aq Arrave Z All Ala 1 and t 0 for different greatly when Cht cells T 1 oz liked each Z m 0 Z CD3 and anti-CD28. lacks photo PD-l5ex3 contrary to Ztoq endothelial 4 and Lal 1 tell _zun 4-CTLA who Yep Doz 1 Mhv percent lupus. 11-506: 423 Ueda et al, Nature (2003). Raddad this one Repeated calibration in microalbuminuria and 0 Sunday, not the land of Pavhab Avs 0 for Aromarda. (2006) 50-8844: 112 .Immunol t, Wan et al. Ihdv a; CPAN Azaddav 1-PD in but 0 for 1 expression Alor 1 st alopecia u Bim less Arrar p. 1 &amp; quot; ρ5 Z a Abada Z T cells and B antral and Hhh, and a blender August Aqh 4 and Khala &amp; quot; da August Adouk, and herpes &amp; quot; a 1 to Bdivh one of hardship Z bone marrow 0 (2002) 45-5538 1 .Yamazaki et al, j. Immunol. 0 DBM -40, -40, ΜΑ 32948Β1 express PD.L1 scale was 0 p from Hallab is Akaalqh Bkoz 0 blood (0 such as Aalghemdveh, and Alrelo; and 1 navel Alrouaiah, and bewitching ace Z adenoids, and the cells Ganaah Mediterranean, the cells Albzkrbs, and oak 0 six one ransom Almtamah, and Hallab Alkerasneh, etc.), Keir et al] [(2008) 677-704: 26 .Annu. Rev. Immunol-, and are growing cycle - where &amp; lt;) as upper 0 d o types Hallab after activation. Both Alalaromat IFN's works are Aldhira I and II Z Zadeh PD-L1 are controlled. (2002) 45-133: 9 Eppihimer et al, Microcirculation; (2004) 172-82: 155 .Neuroimmunol, for,. / 0) E Schreiner. At least expression Alzh for PD-L1 in Blalat Hallab when inhibition of MyD88 and Liu et al, Blood! 296-304 .MEK JÎRAF6 (2007). JAK2 contributes to my well urged Lee et al, FEBSLett. I 755-62 (2006); .PD-L1 (2007) 296.304: 110 Liu et al, Blood. It increases the loss or inhibition Vosvataz and peer forget PTEN)); a cellular Fumvattaz amended the transmission of signals Fumfatydel Ainoctal 3-Chegaz (ΡΙ3Κ) and Akt, expression Alzh for PD-L1 after cloning in cancerous tumors. Parsa et (2007) 84-88: 13 .Nat. Med ..lm ». Branding Alorani expression of PD-L2 as the most deadens the Z expression Alzh for PD-L1. CM expression of PD-L2 and Ray, are subject to induce, the DCs and Hallab large macrophages, and mast picturesque Nhaa derived from the bone. Yum as well as one to express Alzh for PD-L2 on anywhere from two-thirds to Zcef bewitching Β1 prion inert without bewitching Β2 B traditional. .Zhong El al, EurJ. Immunol (2007) 2405-10: 37. Linked bewitching PD-L2 + Β1 Bgosagatidil Colin Meh may be 0 for a Astahabat immune internal versus bacterial antibody generators. He urged PD-L2 by □ -IFN Nmaa the 5B-NF in &amp; lt; Ba depends. 16-2706: 33 .Liang et al, Eur. j. Immunol -41- -41-ΜΑ 32948Β1

(2003). It can also be urged PD-L2 on single cells and macrophages by GM-CF, 4-A and 1 □ -Immunol,! 5538-45 (2002) .IFN SAL, .Yamaakl et al; Loke et al., PNAS (2003) 0: 5336-41. The transmission of signals PD-1 is typically the biggest impact on the production of cytokines compared Baltkar lighted; p 0 significant impacts on □ -IFN production and □ -IL-2 jTNF- also supports transmission Alamtharat a .mmahmh-PD-1 on the strength of the transmission signals TCR, with inhibition of the largest at low Msuiat excitability TCR. This can be overcome through the decline of common Balamattharh Exp. Med. 192: 1027-34 (2000)] CD28 SAL, .lmh Rah Freeman; or the presence of 2-IL [540 Shake Carter (2002) 634-43: 32 .Immunol SAL .eut]. Raises evidence that the transmission of signals through PD-L1 and PD-L2 may be bidirectional. This suggests that, in addition to modifying the transmission TCR or BCR signals, to the possibility of a second transmit signals to cells that express genetically PD-L1 and PD-L2. Although it proved to be branching cells processing antibody to PD-L2 Bmthrey natural Mzul of patient existence globulin Kjar in the blood of Waldenstrom type no more molecules excitatory Almtturkh MHC II or Β7 be controlled, these cells are produced the largest amount of cytokines inflammatory advance, specifically □ -TOF and 6 1-a and the proliferation of T cell Alkhvz. ! .Exp. Med SAL, .al Rah Nguyen (2002) 1393-98. Treat us as pheasant antibody also led to (1) force the resistance Rrm melanoma bl6 transplate, CTL urged specific tumor Mraia. SAL, .al Rah Radhakrishnan (2003) 1830-38: 4965-72 (2004) Slmmunol. ΙΟ: Glen. Al., Cancer Res Rah Radhakrishnan; -42- ΜΑ 32948Β1; (2) prevent the development of inflammatory disease Heckman et al., Eur. to. Immunol. 37: 1827-35 (2007) Radhakrishnan et «0.40. Immunol. .amalik Alhoobh in Nmong infected mouse asthma Thace

Radhakrishnan et al, for Allergy Clin. Immunol. Π6: 668-74 2004) 65-1360: 173;). (2005) Z Dr'sat ( "DC's") Anth further evidence of the transmission of signals to reverse August cells integrated within the scope of the 1-bit PD-1 EC-wide) PD-1 derived from the bone marrow planted with DC's all sPD-1 Zjt 0 .Kuipers et al, Eur. j. Immunol. 36: 2472-82 (2006). ( "S-PD-1" - Ig 10 15 button activated DC and reviled in the increased production of 10-IL Boutrahh Eko, a giving mg 1 Ed 1-PD. Ah, Z, it showed Turn 1 for many SAT future for PD-L1 or PD-L2 - of &amp; gt; Pi. Β7.1 has been defined as one of the Gal partner Artat for Butte et al, Immunity 27: .PD-L1 :) 111-22. Sat der deny a land. 1 &amp; quot; Bhatt Tadili 1 Kemiana possibility -mad PD-L1 and Β7.1 n blood Ztaca 4) d like to Igv. May urge -hoelat B7-1: PD-L1 signal 0 for none T. Itbb attachments PD-L1 cells, CD4 + T Bo'th Β7.1, or Irv 0 F for '7j de CD4 + Τ Bo 1 middle PD-L1 in 4 RESALE ^ Rh inhibitory. Except for a Rh-da showed Ely) and 4-8ytkatma and Azaj cytokine less Aad Hazi Lal CD3 rice h &amp; quot; .Β7. In Khalaa 1 1 T T--hqr 4 Li collect receptors Β7.1 (ie CD28 d 4 Ha is not inhibiting the multiplication of one of the T cell and hurt 1c .lehtukin .mamadad CD3 0 p Waza 00. "Bashir to the fact that Β7.1 humiliate its impact on the face of pointedness Dalal AAH? E 4 Z, CD28 and 4-CTLA. Ba 0 each,? appeared except 0 O Τ of 0 to Gtqrh gone U- ρ501 E: c 1 PD-T, which reveals 20

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T and Gbri of Khala-a in August Enmoldavch 00 yen 1 Mmaeh 0 Zhalo stromal &amp; lt; acute and Almzmevymehl 1 for examples) Ote 0 of tumor 0 Balaylo to Zlke could Table 0 G between the counter - 1 T. of Ckheoah and PD-L1 1 to counter that 9 first of Alaraa made ​​the Yd't -44- -44-ΜΑ 32948Β1 components p other transmission indicated 1 v 1: PD-L1-P5 ' 0 such as 1 to Assam Aldhadh's 1-.Ρ and antibodies for anti - PD-L2. 4- Β7-Η3 are providing you pointed 0 v 1 Sttharih common Z Zlal 4CD276'B7RP-2) Β7-Η3 PR0352 ) ' Atha , which are expressed widely in August Od father in August. (2001) 269-74: 2 .Chapoval et al, Nat. Immunol in Avir 4 contain Β7-Η3 Z Morh 1 abundant C 41 Exalted 2, with the rule of the picture Gel 4 Baima like the 0 Subject to Amoa-Rh 21g in Akran 0 et Oelaq 2352-59: Qiz .Immunol RO, .Steinberger et al; (2002) 97-6294: a .Immunol for 'al (2003) 365-77: 82 2004); Ling et al., Genomics) 'Recent studies have shown that Β7-Η3 works as one curtain light of the Assapat love for Bam &amp; quot; Donner evidence Z activity 1 Azera 0 n through the following: (1) a combination between them and CD3 counter, Azdmadja 0 B7-H3 / Ig in 1 libra Algtrkh breeding ornament + CD8 + Tj CD4, won activity □ -IFN and Nat. Immunol. 2: 269-74 (2001) JJCD8, .rh Chapoval et; and (2) transpiration R Injection plasmid gene expression Β7-Η3 in tumor lymphatic tumors Nmong 4 EL-R-Dad IT {Pfjh 50% of the tumor, the cells Aatmama CD8 + T well but, der) Net Edablh showed modern role fixative for this Abze. To noon operations deactivate certain genes increase in D Carr ornament reactive T Z differently in the MLR response. I've been discouraged U / .. T Aazlaya CD4 T by anti - CD3 and 28 Hhalamadad in HLA-DR2 transferee infection docking Z Picture 7. Genomics 82: 365-77 (2003) .Β7-Η3 » Shake Ling. Kavt Alentihh is one Nkgad ideas and low □ -IFN production and □ - au - 10-GM-CSF jIL. It can be linked -45- -45-ΜΑ 32948Β1 e 0 these studies as having recipients Β7-Η3's functions opposite, in a similar way to how to regulate CD28 and 4-JUtTLA signals through Β7.1 and Β7.2. The result is that, impeding the transmission of Β7-Η3 to improve the immune response to infection and tumor Fh signals when combined with antibodies may contribute to PD-L1's re - covered by the 5 invention. 5- Β7-Η4 Β7-Η4 represents the latest addition to the family PR01291, VTCNl, Β7-Η.5, B7-S1, Β7χ) Β7), which represents the negative responses ornament Zang et al regulator., Proc. Natl. Acad. Sci. USA 1 .T (2003) 10388-10392, (18); (2003) 679-670, (7) 4, Watanabe et al, Nat, Immunol; 10 (2003) 863-873, (6) 18 Prasad, et al, Immunity; 861-849, (6 ) 8 of Sica et al, Immunity (2003) . (Alzh are expressed both Β7-human Η4 and murine - wide and shiny in each of the lymph Members (spleen and thyroid Altimosah) and lymph include lung, liver, testis, ovary, placenta, skeletal muscle, pancreas, small intestine). Not be detected Β7-Η4 in normal human tissues by IHC or organization Β7-Η4 on Alehtoy Transition. 15 IHC possibility of genetic expression of the strong Β7-Η4 appears in lung and ovarian tumors, it refers Taal analysis of polymerase chain in real Zs (PCR) to express strong Alzh for Β7-Η4 well as in Albroosata and lung cell strains and Tan colon. Β7-Η4 linked to the future of the unknown on T cells activated and not inert Almokhtlgh for 4-ICOSj, CTLA, and 1-PD and the future Β7-Η3. Although Igel BTLA initially Kalmrkp buzz Β7-Η4's, the registered association for mergers B7-H4 / Ig cells from wild - type without - / &amp; quot; BTLA lead to 20 -46- -46-ΜΑ 32948Β1 conclusion that Η7ΕΜ, and not BTLA, is composite Albrabotta Ahlgred for Sedy et al., .Β7-Η4 (2004) 90-98: 6 .Nat. Immunol · Bgher studies using tankers infection Β7-Η4 Wade J ^ t B7-H4 / Ig Z bits that Β7-Η4 sends a signal to the inhibition of cell proliferation .CD4 and CD8 + T .mmsahmh TCR, and-Hdm cell cycle in the G0 phase / G1, and the production of 2-Zang .IL; (2003) 61-849: 18 Sica et al, Immunity (2003) 10388-92: 100 al., Immunity 18: 863-73 (2003) iet al, PNAS production Prasad · can not to overcome common vallum Β7.1 for the inhibition induced by 0B7-H4 / Ig antibody resulted in disability Β7-Η4 for increased innovation and T cell production of 2-IL · hand in the lab to give the antibody Β7-Η4 in vivo for Baehala Keahole Lim-between Bbz; n (KLH) in catch Freund 0 full Bags (CFA) to Mtusalh increase in the production of IgM antibody KLH's, and an increase in innovation Kah T and the production of 2-IL , to a range of two and three times when re - stimulation in the lab using KLH, I Dd to urge 0 Acar of T cell in Adam j-1 mussels in cold Β7-Η4 counterattack. Antibody Aahal crippling anti Β7-Η4's markedly from the start of Woden EAE in .CD4 cells and T 080 Halzaidh, large phagocytic cells' CDllb in the brains Β7-Η4 counter, in Slaj Nmong Iera autoimmune. Altgeraah Anhmah available data indicate Z Β7-Η4 to what may reduce immune Alascabat be controlled in Alonshh Trgh, and bear-Doz 1 in -zm likelihood cell T. may not meet well Altabnr for Β7-Η4 Doma in answer Alaatjabat immune Aldailh in immunity tumor. 54-4650: I .Choi et al, j. Immunol (2003). Whines 7, may Tkon.dhadh Β7-Η4 useful to improve the immune response to infection and 00 Iah rum p 1 Lha between them and antibodies for PD-L1 Olney covered by the invention. -47- 32948Β1

6- RTT .A Htmazl BTLA cent 0 and Ala'lo BTLA-1, CD272) Β7) a 0 I h A- PD and 8 Aae 0 * Taifaal 8 Qasilkdaafidelaala 1, Alaleetmasyydy Kl Smbh. Z 0 and Alalabess 4-CTLA and PD-υ ICOS, including I BTLA Z · T kl Elal Aaet 0 a. And (Be, in 0 Tel ICOS) Lalai Hzl / Tate Z Khalaa 1 Th2 p 0 _il's share 0 Tanmpfi · Thl II, and BTLA i; I z &amp; lt; a Thl Ddn · Îh2 kl k 0 a p 1 CFA August's 1-ιΡ5 Bam Ans Z BTLA CKD ' Lzd &amp; lt ;, Dd'ba B. (3..2) 1236-43: 312 .Commun,? ', Gavrieli et al, Biochem. Biophys. Λ · From then on 'J 30 I whist BTLA z z amassed &amp; lt; Β1 inactive and eat it, Lima is getting 1-.Ρ Bmroh sentenced P 0 Ha z Khala_da Β stimulant. BTLA contain Alttabaan regulators -ΙΤΙΜ Ivo BTLA Ta, beta Tthbytia on each of B lymphocytes well. .Υαί- ../0, Watanabe e (2003) 670-79: 4 .Immunol. Izar cells BLTA &amp; quot; / 'B Astahabh rather for IgM Alvad; yours 0 Ha Tnfihr great response CD3 counter in the lab's. Noon cells BTLA &amp; quot; '&amp; quot; Thl polar increased approximately two-fold in the reproduction in response to exposure to antigen in the lab. In vivo, - &amp; lt; Z 1 n '/' BTLA increase of Ilath fold in Ascabat antibody specific for Hattan, and were hit by Walker's EAE. Similar to the phenotype of Girav &amp; quot; '&amp; quot; BTLA phenotype to turn a blind 1 n / &amp; quot; 1-PD, and show Tarafta largest immune lupus, but virtual patterns section Bonha better cr 1 n 8 &amp; quot; 4-CTLA But, Nzna for his role as an organizer Malb, VFD be impeded BTLA useful to improve the immune response in infection and immunity against the tumor when combined between that and antibodies for PD-L1 to counter dealt invention. -48- -48-ΜΑ 32948Β1 thier attention than it turned out to be Makhana BTLA which represents Edza sub Baih Ig interacts well with fifteen sub-TNFR family 90-98 .HVEM: A. Sedy et al, Nat. Immunol (2005); (2005) 1121-1116; 102 Gonzalez et al., Proc. Natl Acad. Sci. USA. Vhay HVEM are under the scope of the common excitatory factors. (F) Joint Alastiarah of family factors TNFR 1- (OX40 / OX4.L (CD134

Algiran are suffering from a lack of ΟΧ40 been TNFRSF4) and OX40L (XGPl, TNFSF4, GP34, CD252, CD134L) Bastahabat cell CD4 + T ob -lkl of generators viral antibody and common protein, and in the contact-allergy reactions. (1999) 699-708: 11 Kopf et al, Immunity; (1999) 698-689: 11 Chen et al, Immunity; (2000) 365-374: for .Exp. Med, 04 Murata et;: 165 .Immunol d, Gramaglla et al (2000) 3043-3050. Q 0) Tofid less than Almarh T cells specific for the antigen-m recently frequencies in the initial Alastahabh, show less T-cell memory. Gramaglia et al., Supra. In Negotiable 0 0 T cells that suffer from a lack of CD27, it is not impeded early Altkar in CD4 cell groups + T inert 1 t suffer from a lack of ΟΧ40. But, reproduction decreases and cell death to fade after 4-5 days of activation, and produces Enzlkbakaeddkulail 0 n except for a T-long voracious. (2001) 455-445: 15 Rogers et al, Immunity. At 1 h him Khala.a CD8 + T 0 of Manny Z imagines in ΟΧ40, 1 is not affected by the initial Zqam ornament; Om 0 Del Ratm Ella-A Alma; e ops &amp; lt;) about 0 significantly after 3-6 days of face generator tomorrow. : 3 .Croft et al, Nat. Immunol .609-620 (2003) -49- -49-ΜΑ 32948Β1 by branching to T cells or cause cells OX40L expression Alzh mutated and Raya Z Almsjabh to antigen, also produces the symptoms of the monitor Mounaa Almatta CD4 + T cell count increased; Brocker et al, EurJ. Immunol. .: 1610-1616 (1999) .aldhalh T actively linked cell after vaccination, not allow p jet objects .Murata et al, j. Immunol. 169: 4628-4636 (2002) with interactive Mola 0 CD4 + T Maadh counter the accumulation of a greater number of cells ΟΧ40 counter's memory generated. T antibody at the maximum value of the initial Ascabh, improve simultaneously in a number Gramaglla et cells 54, supra., Bansai-Pakala et al., Nature Med. 7: 907-912 (2001), Maxwell Weatherill et al, Cell. Immunol. 209: 63-75 iet 040 j. Immunol. ! 107-112 (2000) Preliminary influential when treating Grand Almstgesh.mmold CTLs 2001). Best Alrakm's happening)

De Smedt et al, j. Immunol. 168: 661-670 .ΟΧ40 antibody antibody qualitative assistant's. (2002), a late effect signal will allow the survival of the newly influential resulting cells when Oqmy value ΟΧ40 Leoz -CD28 ΟΧ40 after the initial immune response. There is also good evidence that the functions and functional analysis, CD28 Mmsahmh signals. ΟΧ40 addition to increasing the initial Altabar Alzh be obstructed in T that ornament responses ΟΧ40 against the bottoms of CD28 deficiency but are impeded late Alascabat in the absence of signals, CD28 markedly in the absence of signals

Bertram et 54, j. Immunol. ; Rogers et 54) Immunity 15: 445-455 (2001) .vguet ΟΧ40 .168: 3777-3785 (2002) 50 50ΜΑ 32948Β1 applying anti Maadh antibodies, useful when, OX40 / OX40L result is that, it may be counter-activate covered by the invention Moghaima for the treatment of PD-L1 combined with antibodies Wayne's career .T palaces disorders of the cell 4-1ΒΒ (CD137) / 4-lBBL-2 4-1ΒΒ Olney suffer from a lack of T cells appear, OX40 / OX40L as is the case for reactive 0 Amold CD8 + T accumulated less Hlaya (TOFSF9) 4-lBBLj (TOFRSF9, CD137) .llmakrh T 1-4 and the emergence of fewer cells BBL antibody in the initial responses in the absence of Tan et al, t. Immunol. ; DeBenedette et al, j, Immunol. 163: 4833-4841 (1999) as well, not to Atim 0 .Tan et al., J. Immunol. 164: 2320-2325 (2000) 1999) 4868-4859;) CTLs but suppressed accumulation, CD8 + T 1-4 preliminary Alastahabh reproductive cells BBL disability Almarh at the maximum value of the initial response after 3-6 days, due to erosion of the cells that split transpiration for objects .Cooper et al, Eur. j. Immunol 32: 521-529 (2002) .adh 1-4 times a similar anti Ntaikha: BBL infection kU.APCs 1-4 counter help and ΒΒ's anti Melero et al, 0. On some of Hoz in the neighborhood of El Jem CD4 + T ^ and CTL responses Raddad ; Melero et al, Eur. t. Immunol. 28: 1116-1121 (1998); Nature Med. 3: 682-685 (1997) Guinn et al, t. Immunol. 162:; Takahashi et al, j. Immunol. 162: 5037-5040 (1999) Takahashi et; Halstead et al, Nature Immunol 3: 536-541 (2002) 1999) 5010-5003;) Bansal-Pakala et al, j. Immunol. 169: 5005- (· .al, Immunol Lett.. 76: 183-191 (2001) 1-4 Alastahabh initial proliferative, which ΒΒ 2002) 5009. No antibody specific for the well) -51- -51-ΜΑ 32948Β1 Ds 1 Asset r disability 4-1BBL experiences and refers to Alnmthat Uttar 4-1ΒΒ's in the rack; Cell survival signals. 0 otherwise ΟΧ40, Ratkd 4-1ΒΒ that provides late to influence the effect signal will allow the survival of cells resulting Marh Hdia Afd realistic value of the primary immune response. There is also good evidence that the Z 1 Escherichia 4-ΙΒΒ after CD28- addition to increasing the genetic expression of the 4-lBBj ΟΧ40 .mmsahmh CD28 signals; and functional analysis of the inadequacy of CD28 versus palaces 4-1ΒΒ that the cell responses to T Initial be hampered significantly in the absence of CD28 signals , but are impeded late responses in the absence of thrills ΟΧ40 only. 455-445: 15 Rogers et al, Immunity (2001); (2002) 3785-3777: 168 .Immunol RO, Bertram et al. It can urge the antibody to CD137 anti Almaad rebound in tumor cancer, which fell short of CD8 + CTLs Doma / whatever. , Melero et al, Nat. Med. 3: 682-5 (1997); Hirano et al (2005) 1089-96: (3) 65 .Cancer Res. It gives expression Alzh Banaani and stainless to induce PD-L1 for resistance in these tumors, reversible when disability Hirano et al .PD-L1. As a result, it may be activated 4-1BB / 4-BBL, the application of anti assistance antibodies, for example, in particular 0 p anti-PD-L1 (Kaljsm counter for PD-L1 counter) Moghaima in the treatment of the cell functional disorders for 3- (CD27 / CD27L (CD70 father Antphal were looking S152 signals, TNFRSF7) CD27) and CD70) CD27L, TNFSF7) in the initial stages of T cell Amtahabh in disability Studies in the lab, he urged Yum objection interactions Oshima et al, Int. Immunol. Ο: 517-526 (1998) .CD27 / CD70; 52- 52-ΜΑ 32948Β1 (1994) 1421-1429: 153 .Immunol RO, .Agematsu et al;: 154 .J. Immunol 540 Hintzen et

(1995) 2612-2623. Tnqm T cells lacking CD27 initially normal, then includes .mmadl weak after three or more days of activation. : A. Hendriks et al., Nature Immunol (2000) 433-440. This indicates that CD27 involved in promoting the first extension Nhmuah cell T 5 inert, either early Balkat to death Ornament T or Baltothr ornament on course to allow continuous Balannagam after 2-3 days of Altvhat. This is confirmed by studies that forced the on Algiran that suffer from a lack of CD27, and where fewer numbers of responses to specific antigen appeared (4-8 days) and a few T-cell memory during the three weeks or more. Hendriks et al, supra. Increases Altabar for CD27 gene are controlled Mpkina after activating the cell T, before the value of the 10 most influential response. As a result, 'is believed to activate CD27 / CD27L, and include the application of antibodies Saadenn Specifically 0 G antibody to PD-L1 counter Almnkurh in this 0 document, is useful in the treatment of the cell functional disorders T. 4- (C.30 / CD30L ( CD153 15 are transmission signals Ki-1, TOFRSF8) CD30) and TNFSF8, CD153) CD30L) dowry excitatory common to many T cell functions in the laboratory. : Qqa. Del Prete et al, 7. Exp. Med (1995) 442-449: 156 .1655-1661 (1995), Bowen et al, j. Immunol. Taatbb reactants crippling for CD30L in suppressing the development of Th2 cells and improve the growth of Thl cells in the lab. Toad these activities 0 p data that describes the genetic Altabar manner Mgdil for CD30 20 by Th2 cells and Tc2 toxic type 2. Del Prete et .7. supra, Nakamura et

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-53- -53-ΜΑ 32948Β1 (1996) 2090-2098: 158 .Immunol RO, al. The Laker Anorave p CD30 after 3 days 4 0 0 n h perimeter Khala 0 O T carrier in an initial non-polar culturing. Nakamura ef al, supra, Z Shaw that his role is not limited to Alastahabat which governs the Stockzn Q S 02 despite Edm clarity Apt Antal Ajarat CD30 / accurately CD30L, believed similar Ava both ΟΧ40 and Hh1-4. When you move the CD8 + T cells specific for Mull 0 to F-printed with Fr'n ^ ne JJ lack of CD30L Abatha, do not wrap the accumulation of numbers KERA UP- Fall 0 Z b for Avahabh literature; and show little Z T-cell memory. As a result, as well as CD30 may provide a 'cadre Rao Mah survival signals to produce large numbers of Khalalo T Aluaah RCA FM hands of 0 to a maximum initial responses.

As a result, LED is Chit CD27 / CD27L; and -0 Tbaiq AGEs 13:00 anti Saadh, specifically when combined with Glades l Anti-PD-L1 counter Levi Abaovo invention is useful for the treatment of functional limitations of the cell T. disorders 5_ HVEM / LIGHT complicated effect TNFRSF14, LIGHTR, ATAR, HEA) HVEM; PRO509) and LIGHT (CD258; TR2, HVEML; PR0726, TNFSF14) on exhibitionism common to T cell Bo 0 mode 1 Irh LIGHT on Alaratjat well as the future of Amgootokman- □ (LTQR), and (2) the ability of HVEM on Alarabat d LT53 Negotiable Dhupav. So, Anpfi be recommended into account the influence of others Alarabat system signals the partners in any Drai D &amp; quot; R HVEM / LIGHT. LIGHT has been attached to having a disability and early Altkar trait T and Araz Afiatokzn in Thalat cell lymphocytes mixed heterogeneous Aljiv-data (Immunol.. (MLRs RO, .Tamada et al -54- -54-ΜΑ 32948Β1

Harrop 2000) 4110-4105: 164;), Kwon et al, t. Biol. Chem. 272: 14272-14276 (1997) Tamada et al., Nature Med. 6: 283-289 (· .et al., J. Immunol. 161: 1786-1794 (1998) in Oraa Aallm LIGHT 2000). Kate is the production of cytokines the prior Alakeab Ezl 0 0 Aouaqh) .Ye et ai, j. Exp. Med. 195: 795-800 (2002) .MHC navel 7 defaming non-compliant as well, is dismissed types of skin graft Taarh skills in case of larg 0 / Azas Larry in Scheu et al, j. Exp. .CD28 And LIGHT Co 1 M1 Levin z ^ Nun shortcomings in both believe that the other land to kraurosis 0) p 0 0 indicates to me you .Med. 195: 1613-1624 (2002) (!) Or the production of Alstokin. This Altaatihh Idam thus T aided Alamte cell A- light laboratory dramas which showed that the cells of the money one t and Danny ZZ in Okz 7th Zh 0 framework ΤΗ2 bear and ΤΗ1 generator 1 tomorrow 1 to hetero deaf Baztoj weak Szrat; and (2) Adt 1 pamphlets z one body [sheu et al , supra] (CTL) Poor Mama T to Moghaih Tamada 540 production Nature Med. .vaalah Different &amp; quot; CTLs 0 paralysis Z Azaj LIGHT 1 neighborhood loyal to its 0.6 3: 283-289 (2000) Anti Madsdh z i III fUÎ Tq - HVEM / LIGHT result is that, it may be Advantaged 0 masculinity in this Alutehga 50 &amp; quot; Dr. PD-L1 in Al_khaso 0 Z with Aja «a counter for .T in the treatment of functional disorders of the cell 2. Definitions indicates &amp; quot; MOQ 1 to Haceh &amp; quot; Or &amp; quot; 1 to August 1 Jane E. &amp; quot; 1 Li any molecule d I August Mei 0 in this paper 0.0 tried Almhtalh! Molecule Mok antibody itself, or Dora 'bear Qah or Vchor Ahiomat or g ^ P insect or food product 0 Khalaz 0, the sucking 0 indicates Talh 0 Amoll 0 Aq to

UK -.- Dzeemcn Walt 0 rack consciousness Teach Aoasitl Geloyolzt z ed for &amp; quot; '&amp; quot; 1' S Waddell's &amp; quot; Foreigeh.ekzha I CI 0.0 any RCA 0 &amp; lt; _ father d. Pearl Ed Z wanted Alitapl Adhi of 0 Didzz | t only 0's, pp Asve b Ba 0 I 0 Dldh father and my wad Alkimjaa 0 of a (Agola externa 0 PayPal S; &amp; lt; Z Allzl-SAT, in Yab.d 0 no x 3 U ou j A; At Lasry 0 B, and'rad Lhasa p acid-d for A'v Evynju 0 Gogol h 0 ESL night Waddle 0 Τ. in Z,% ίύ Z I Z Ur literature to Osokserasalha 00 H.kadibmaddhark Avas 0 Balamc 0 arduous or provoking or eaten 0 Q dermal 0 Agbr 0 assists 0 0 Ouav AHAs 0 DDS p 4 g equ Lalai Ed d kV. Almhills age bane 1 t Akai Y Z Alabe and A'd Adderall Atdetm 1 | winding meant Mok F-4 and u -en equ Lalai agents Dslavi August; de LED or growth Alorm- to fetch 0 Al.a if 0 Ahalis 0 Aleglalj 0 as SV 'of 00 del! Li F1 anyone except 5000 or Zaia , Z does not attack Roe-b El-la Ett 0, Lund -kon I Seve F Tkdn Las Z standing of Aljhaz Las Fiat Azlarkli; l-H'astal-H.vii August Alpes Zdla 10 Mtef Alvhao 6 cells Altasfsharkat S 0. j 0 to fend off one of Y.hl sales 0 Fa -eia thoughts 0 Ml- Tkov Az 0 Aa 0 of my impact Iha 0 Loua a 0 Q Aalpartyaaly blood Az de Rkat I ever. S in August -56- 32948Β1 terminal, and occur after Ndokh T cells and 8 and entry to Amehat. these operations include inhibition of 0 cells y 0 Taath interaction by T cells and regulatory production Astahabh deficient (Haceh) in the cells of one concept facing the antigen in the absence of excitatory signals Akatrkh associated with inflammation. Alter the probability &amp; quot; the office or induced to adapt to the immune system with external antibody generators, which are the lack of an interactive qualitative lymph tissues of the birth against certain conditions in Atabb see to urge immunity Khalosh Oo.mmahmh ornament as possible. In Albalven, could be urged probability clinically Balaatta repeated large doses extremely antigen or ο small doses touched on the threshold value required to induce an immune response, the antibody as giving generators soluble infusion into a vein or under the tongue. It facilitates immunosuppression as well as one unpleasant possibility. Anmear may lead to the possibility of self-immune milk 0 come. Change &amp; quot; improve and Zigh cell τ &amp; quot; To induce or stimulate or pay Ornament T to Zigh biological or continuous glass, or renew or activate cells infected Τ enemies or inert. Taatdd 1 Ohlh to improve and ornament Zigh T: increase Araz □ -antrveron of CDS T cells, Zadeh Alai ;, and increase the response to antigen (to get rid of overuse or pathogen dragged on 1 Thal) for the pre-intervention levels. In a Alnmans Ebag PM 0 level optimization El 0 Z 1 of the AFL 50%, or 60%, or 70%, or 80 e / e, or 90 huh, or 00 A%, or 20 A%, or 150%, or 200%. Aware 'of well-seasoned in Hedda Egal Cguih Ias this population 0 indicates &amp; quot; resulting from the lack of ornament turmoil τ &amp; quot; To DAP or state Tq CON T Eadsl weak Alastahabh to stimulate antibody-born. In Nmong Mann, Z Alad &amp; lt; August Aloziga - Ί Adtrza is linked to the face, to determine the increase is 0 melted in the transition effect 1 t 0 n 0 Halal PD-Ι. μα 32948Β1 -1 Do in Nmong else, represents our per- turmoil career palaces of T cell Adtaraia Tkov in which T cells Nat inert or less on the ability of the secretion of cytokines or Altkar Tngiv activity or if cells. In a particular aspect, Anth lower Alastahabh is effectively control the pathogen or a tumor that expresses the antigen. Examples include the Altatjh career Palaces Ornament T characterized by failure and Zigh T cell acute incurable infection, chronic infection and tumor immunity disorders. -illr &amp; Quot; chronic infection &amp; quot; To infection is where the transmission factor (Kmspbat disease 0 Thell viruses, bacteria, parasites and a single ornament, fungi, etc.) discuss causes of the disease Menaih in shame patient infection, has not yet been removed from the host as HR case during LED sharp 0 may -kon Addoy chronic imams or latent or slow. While the machine overcomes 1 vs. de 0 for DWI sharp pattern within a few days or Osaba (such as influenza) VFD Umrah Aldayo infection 0 only low news for months or years or decades or a lifetime (such as hepatitis 0 1 n predilection B). On the other hand, are latent infection actively asymptomatic football To-da t 0 Irdha Irh Zadeh terrible infection from high-class levels of MPB RIP R'dgah (dl A &amp; lt; Q inst) 0 Okhana, are slow infection gradual increase continuously in Oer'd of light Hg 0 Azh Delh followed clinically advanced therapeutic system along the term begins after the appearance of only; Z 1 Aklsa. Unlike the latent infection and permanent, it may not slow the infection began a sharp Bgmh from 1 to Carr viral (such as viruses Allbeckornaoah infection; and 00 Werls data Vezina Waller Dfairs 1 and 0 Dotzveld- Jakob disease). Include infection factors Wasp 1 block de I 0 infection 0 g 0 These Karosat (such as cytomegalovirus, and Fberos Este 0 bar, -58- -58-ΜΑ 32948Β1 and Neros! Hepatic inflammation of the type B, and hepatitis Z type c, and Fberos 0 to mash 1 Bit Z Alzuall Oll, and HIV immune Z type 1 and 2, and Werls tumor! mortal Khalima, and Agheiromat pets fabric lymphatic type 1 and 2, and Evros Alalahi 1 Dahi, etc.), and bacteria (Mil Almtfrh Althleeh, and the platoon Alvestrah, to | for &amp; gt; 1 a,.. ; 4 pneumoniae, and meningococcal pneumonia chapman, gold Angodih 'WAP Alorlh, and Helicobacter pylori, etc.), parasites and unicellular (Shell August Alchammab' and Plasmodium falciparum, the species Schistosoma, and a platoon arched, and species Trypanosoma, evil j 0 for E: etc.) and Alaftrat (such as client Alrkhashih, and Awhith Awhita, and Aldodu coli and 0 b Hidh hit this, but for how long and 0 pulmonary reminded carinii etc.). Sneda 0 for Maqlh stromal Riomat or Pro-same Mhloahelynhos -ar &amp; lt ;, 0 brain or August b affliction, mistaken for Ali Katrutin in this father, causing Tkout Saih to the moon guu; and &amp; quot; children per 'the NIJ and another death. Alytjlo diseases z ^ de .ardon E 1 Yslavl: Sd / messengers Jaab Las 0 Asgaa, for milk containing 0. Six-Sdomd-d 0 Kerr (GSS), and; to Arles Arrash less (sFI) 'and Alex, da; As, and &amp; quot; S 0's termination | Lacey 1 Berri (BSE) J (RIP; Ka &amp; quot; Darren a ^ &amp; quot;) 'Ldi p Oraa 0 to Atlal | of the brain etc. 0 Wani many 5 [&amp; lt ;, Alaelal foundations Ladki Aspell diarrhea (ΜΕ) Aacurialmzs (are) Veasldiaclalodaua 9 Aualobdt Alozs; for Aylal a father &amp; lt; j a 0 C Akkl, and Alaihl Asey prese &amp; lt; j Reyes Ehab 00 Aaobya, 0 * &amp; quot ;, Dssd of an ostrich. -59. -59.ΜΑ 32948Β1 Ahbr Otah tumor &amp; quot; Tumors to escape immune recognition and removal process. So, as a concept -ris /) '&amp; quot; LED committees 0 &amp; quot; 0 Iah tumor at the limit of the escape Almnkurh process and identify tumors and attack them by the immune system. Examples include the Altparv tumor link the tumor, and the shrinkage of the tumor, and removing the tumor. 5 raises &amp; quot; Mkhad common excitatory negative BNCA) Β7) to factor reduces or impairs or Dthbt or - or z intersect at Alaszerah common signal routines Salh contribute to the cell that sniff Ackbyr them and Raia cells Allmoghaiha.mmsahmh in a family Β7 member · in one Ajeranb, you may curse BNCA alone or in Tolegh 0 G antibodies; -PD daad of the invention to Ahraa to transform the T cell deficient Alozigh to a cell-free Aloziga palaces 0 10 in the side R; may be BNCA factor inhibits DNA and / or synthesis of ^ u Rao .kaabar Asher 1 st and / or transmission of signals and / or treatment after the expression of Alorava Huzeie Alastora 1 Thk Adalb Β7. In another aspect, BNCA Gesta fluorescence, or part of an anti Mrtbt.mmuk one cheek, Ookulail polypeptide BNCA, or BNCA or of RNAi; or molecule BNCA represents -spb in Khgd or impede or discourage or Altkhalay Z or overlap in 1 Achal 1 Dard 15 signals by Re Asthari common negative Β7. Part 0 of 1 includes Aborah Sukh one of the Elbe Β7 1 following: 4-Β7.1, PD-1, PD-L1, CTLA (including 1 Kaabar Z and Ray de &amp; lt; a Β7-Η3, PD-L2, (T; Β7-Η4. Alters a ' Bags of one common Rey positive &amp; quot; to the molecule increases or improves or - or supports reference 'for the excitatory' for joint 1 t contribute to the Brocivat Z cell 1 T-Bam additional 20 and Ray nest .llaaa 1 Moghaih T. in one aspect, it may 0 fact that one molecule 1 Azera 1 Kirk a -60- -60-ΜΑ 32948Β1 1 to Mouhb Zalai 1 6 c cell or origin of part Fabl soluble or antibody helped activates excitatory joint 0 Lord of the path. - only 0 trust &amp; lt ;, molecules Alatrah August! to positively received one of the family of one of Graeh Β7; &amp; lt; a Β7.1 and C0S / IC0SL jCD28 jB7.2 '-alo 0 handful Aladahah BL 0 joint Advisory Zt family TNFR, such as OX40 / .X40L and-a 4 CD27 / CD27L BB / 41-BBL and CD30 / C530Lj CD30 / CD30L and H7EM / LIGHT. Athber &amp; quot; molecule whistling &amp; quot; or &amp; quot; molecule Afar Sgar'a to the molecule Assay '&amp; lt ;, p. 6 to 500 Dalton 0 indicates &amp; quot; RNA nested &amp; quot;' RNAi 'to the RNA length extends ranges for-10 to 50 nucleotides, running on -kulail expression Warrar for Jenin Sadaf; urged to Dkon Adela Tkami parts 0 eBay him adequately &amp; lt; matching ratio of at least 80% target) for a while. Method of RNA interference refers to the suppression of expression Alzh for the gene, one thief lah-tune (ie containing 0 1 tattooed to silent), which is in the level of post-reproduction (such as translation) and includes all the mechanisms of teratogenicity and post-cloning to inhibit gene expression Algin.mmsahmh RNA, all your Almnkurh in (2002) 1265: 296 PD Zamore, Science, and Hannan and Rossi, Nature t (2004) 371-378. In this 5 Aloqh, may Atakn image RNAi RNA whistling nested (siRNA), and / or RNA Qsber a clip (shRNA), and / or micro RNA (miRNA). 0 Dkon mow; RNAi categories Almnkurh usually Rdouhh stranded RNA complexes can be expressed in the form of Raya and Jaddah separate complementary RNA or RNA complementary to the wall of our part. There are ways in Aarova 0 i 0 of 1 Nahal manufacturing complexes 0 Zdugh stranded RNA. The torrent example, can be found on the design, synthesis and slA Λτ-bsiRNA, at (2005) 224-215: 39 Sandy et al., BioTechniques. 32948Β1 Sher &amp; quot; i Mud Dam &amp; quot; Or Q | 0's Ghaev 1 Zdug a 4 night (dsl) .od length; Lyi% to triple strands p. 10! Li 50 Buqueotb, Aslevytvblaks Aye 0 z u z Fouptdhan, Eza, Ziaaalooly-Aeliadhanmukav (Tg 1 x 80% nest 0 humiliated for 0 yen a-q). Designed sils Z c. Hhab Alaltib 0 y U Sch to -tm Takbak Atia's? Bsld and specific z z Adrae foundations, Laos RNA but _sp 0 J E, J de Azhal! Rate and 'no 1 I 1 S

Idsh. (2002) .8-1443: (3) 99 · Paddison et al, Proc Natl AcadSciUSA

Raises Giver &amp; quot; MBC &amp; quot; ; ^ For Hlaa, the ranges p. 7! Li 20 A 1'rna Se SEC &amp; quot; ! F shl! Li RNA Bio 0 de Aljdela, Dradh &amp; lt; of 0 n 10 to 50 Bokpotd 0 mm B1 willing Bkllal 0 Nafber Arash ZZ DD 'B to Oilrd names are &amp; lt; Dlz Aihpav (.tabnh J Hee 0 t ° DSL B, aims eBay Q 0 for Wael). Raises &amp; quot; Jna- yu, 'to Anduaj against MSAS cent-a pair Algele Bkoan double helix is ​​why the right of z; z to Zddoua, each with a 0 so Ben Z form of a stick in Hasha piece of candy will be managed by 0 (Srov 0 Abi a 3 Amos); Garhrl p. 6 to 10 to 70 Naokpobd and then to give it in the first p; d I; "p 3 bears &amp; quot; Eza-Tgh &amp; quot ;, and Tmt ~, for Haa Adzssmelal less literature in August by Aard Rise) RNA).

E-Dt &amp; quot; BNCA RNA Sa 'Ao &amp; quot;,! ... Opportunities Z RR BNCA Aluwadsabaravay.-Ddv; for Y'n Deshrs'vee -62- -62-ΜΑ 32948Β1 not a valid 0 0 Kirk Β7 less negative when there BNCA RNAi expression compared Alzh for one molecule common excitatory negative Β7 in existence compared to no where BNCA RNAi. Can be defined and synthesis BNCA RNAi known ways ((2003), 12-9 (1) and Shi Y, Trends in Genetics, W02002 / 044321, W02001 / 075164, W02003064621, W02003056012). Harm &amp; quot; BNCA Ooleiho peptide &amp; quot; Ooleihrbptid linked to, in a manner Noaia Mgdil, Bbola polypeptide joint Asari negative Β7, or a compound that includes the future of Associative or transmission of signals Created, &amp; lt ;, Althrip, as mentioned in this document. It can be synthesized chemically Oolajobptidat Almnkurh using the method of synthesis Oolajobptidat Mrovh, or Thoudbrha and purified using the result of the return of the genetic link technology. The length of the Oolajobptidat Almnkurh usually about 5 amino acids nest one for less, or Atgadd 1 acids 1 to Omatah 6 U, 7 or 8 or 9 or 0, 1, 11, 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 23 or 33 or 34 or 35 or 36 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 16 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 seen 70 or 71 or 72 or 73 or 74 or 75 or 76 or 77 or 78 or 79 or 80 or 81 or 82 or 83 or 84 or 85 or 86 or 87 or 88 or 89 or 90 or 91 or 92 or 93.94, or 95 or 96 or 97 or 98 or 99 or 100 Oookther.amkintarev Oolajobptidat Almnkurh without testing unnecessary using techniques Mrovh. Many of us, it should be advised that sort Oolajobptidat libraries techniques to Ooleihobptidat able to link -63- -63-ΜΑ 32948Β1 Noja Yadav poly peptide known in this Anhal (see, for the third US patent Alaraa No. 5,556,762, and 5,750,373, 708,871 and a 4, 4 , 833,092 and 5,223,409; Geysen et; W084 / 03564 and No. PCT wo 84/03506 and 5,403,484, and 5,571,689; and bulletins to Ahhlahma et .1., P10oc. Natl. Acad,? al ,, p35c. Natl. Acad . Sel. USA,;? VAtil Geysen et al, in Synthetic Peptides as Antigens, 130-149 (· Sci. USA, 3: 178-182 (1985)? »choofeet al., J. Immunol, 0,1 Sathlolaj 25. a., j. Immunol. Meth., 1259-Π4 (\? 's 61 &amp; lt ;? a (, D' 140: 611-616 (1988), Cwirla, s. E. et al. Proc. Natl. Acad. £ 4 E USA, 3: 6378 (1990) Clackson, T. &amp; lt;? 54; Nature, 352: 624; Lowman, Η.Β. et 5 /. Biochemistry, 30: 10832 (1991) Kang, AS et 5 /, Proc. Natl.; (1991); Marks, j. D. et 54, j. Mol. Biol, 1991) 581: of) Acad. Sci. USA, 3: 8363 (1991), and Smith, G. p.1 Current Opin. Biotechnol., 2: 668. (1991) to -e j El 0 a - BNCA whistling or molecule BNCA refers Anti molecule Ooleihobptid or antibody, as mentioned in this Aluthh, Shatt Crown Sep 1 Sthari 0 Czk Noaia manner Mgdil. Preferably makes Chit 0 Anchal reference excitatory 1 Msark Β7 negative Qasra BNCA 1 and 0 w Ostagibh to stimulate antigen. Can determine Dznot T vinegar; its Β7 1 for SAP No. PCT 1 biography Walla Tkhalchha so 0 means rejecting 0 Gh Mrovh (Anzer-, for example, bulletins 1 Kgbrh this E 0 birth Z BNCA mow-Zt r shower. (W02000 / 39585 and W02000 / 00823 200 ho 1 Lee 2000 d 1 to Tun, or .qlenhawwala 1500 or 750 or 500 or 250 or Daqone Wei 1 Kara &amp; lt ;, a land. "sessile Noja on Z Mgdil, Bbola Itid excitatory minus 7 h as it has since / t in this deposit, and 0 straw extended without experiments Gner necessary using Tkabbat -64- -64-ΜΑ 32948Β1 Mbrovh. 4 the one for the process, is why knowing that 0 at gg Mjmuot Aldziqat organic to stand de 1 Dzeot that I one's ability meant a land. &amp; quot; duck PDF early tightens 0 Harovh in this 1 1 Fall (Ashe indicators WOOO / 00823 numbers: PCT and 39585 / WOOO). the term &amp; quot refers; antibiotic &amp; quot; any bold facilitated the withered or p jj Al-Kafat Aldhava, Kagheiros or hit-0 a or Algarat seen a single animal cell, but it is not fatal to the host when Akirkizzat and Hoasl 1 Jrouat given. in this Aloqh, Sdmn the term &amp; quot; antibiotic antagonist bacteria, and factor anti-virus; Ua 0's with 1 Ed for Htraat, Ua 0 for anti Moo 1 s up cell 0 in Ji Neb specified, not the fact that the antibiotic SATA high at concentrations breaks doses given 0 can Tstev Akadat brigades 1 Kadh of 0 Ktrella or anti Baktlao Z Za 7 s Uah on but microbicide (kill them directly) or that inhibit Hrasm &amp; lt; society Amsamaa) ·'s -alamadadat bio-destructive test for Hrathim chicks Ktaq Dq (ie &amp; quot; War Hattelyvih small Q b subset of bacteria, bacteria negative gram, etc.) or the scope of plenty (War folding Hak% /) 'examples of antibiotics included: ( 1) Ominojlecosadat, &amp; lt; a amikacin, and Jdzisamesen, and C.s.esen, and neomycin, and Nitilmesen, and Estreptobin, and Oada-; and Arrow-E and (2) Onsamsavat, such Geldanamesan, and Herbyman, and (3) Carpaceveat, ml Orakark 4 (4) Carpabasmat, such as Artabinyum, and Dorippinim, and Svem / Sellattin, and Mirobiv 0 me 0 m, and (A) Sfawsborenat (first generation), such as Svadrokhl, Rsevasulbn, amid the Lin E and cephalexin, and (6) Cevallosoranat (second generation), such as -klr 4 and, Dagaizdol; and cefoxitin, and Safberozhel and Bguruksam, and (6) Bgalosoranat (Wallach generation) E eg 0 for cefixime, and Svdgnier, and Badettoran, and Svobarazon, and Sfotaksm, and cefpodoxime, -65- -65-ΜΑ 32948Β1 and 0 Sigtasidem, and Seviabionn, and Seviizoxim, for Sevzaaksov, and (7) Cevallosporaiat (generation IV), such as Siem, and (8) Cephalosporins (fifth generation), such as Savetobrreaul, and (9) Glicobptidat like Hkoppelanin, and Qancomisan, and (. 1) Macroledat like Okaamtheromaimin, and Kalrtheroamasin, and Dertheromitin, and Aarairomitin, and Roxy Theromitin, and Trulaandomitin 0.5 and Teleietrossin, and Smictinocn, and (11) Monubaktamat, such Ockstraonnamm, and (12) Pensilinat such as amoxicillin and ampicillin, and Oklosselln, and Kriencelin, and cloxacillin, and dicloxacillin, and Vleclukacelin and Mazlosselln, and Metesylin, and nafcillin, and oxacillin, and Beracelin, and Tekarcelin, and (13) poly peptide antibiotic such as Pasiramen, and colistin, poly Maksen B, and (14) Kinolonat like Mrreaulokmamin, and Annoxasin 0.10 and Catigluckasin, but Averwlocaman, but Imovlocazin, and 0 RCA »for such as coffee ; and Norvlocaman, and Oorvluxasin, and Trovavloxasan, and (15) SKU 0 Sat 0 g 0 Afaj of, and Rontosal, and Mfassitamad, and Silvamethyzul, and Slvanal forever; and Svalazln 4 Silvesoxasul, and trimethoprim, and Tremesoubram- Slwamytokmasul (TMP-SMX), and (16) Taatraseklinat such as demeclocycline and doxycycline, and Msuschaelin, and Oak 1C Taz 1 Seclen 0.15 and tetracycline, and (7a) others such as Orsiamin, and chloramphenicol, and Rv'bn; and ^ CAT and Aithambuotol, and Vosgomitin, and acid Vosidik, and Horazoldon, and Ooomaza 0; and Lord; and metronidazole, and Mubirosin, and Natrovoraos, and platinum -e and Ouazs and start a Kenobristin / Dalgoperden, Ragambyn / Rabgaban, and Dddasul. It guarantees the term &amp; quot; antagonist-virus &amp; quot; Re or any lit 0 Ea r and / or 0 trauma and / or survival of 20 viruses. Wingman that drugs Fros introduction reverse Hthel (!) Htat incentives 0) -66- -66-ΜΑ 32948Β1 reverse transcription, which include, for example, (a) Htat enzyme reverse tissue Zir Nyukljubd (NRTIs) (6 Kicleor Shell / Osacleor (®ZOVIR ®, Z OVIRAX), and Sdopovir, Ozido Thi 0 condemns / Zidodhus (RETROVIR®, AZT), and Didanocn (VIDEX®, ddl; Zalesitapan (HIVID®, ddc); and Stacodn (ZERIT®, d4T; for Ammivodn (EPIVIR®, 3TC); Obakahenr ZIAGEN®)); and Amitriahabin (®EMTRJVA); and Brifudan (®HELPW); and Askavir 1 Aodotxoreden; and Kiramaidin (Taryafferin by Valeant '2 inhibitor polymerase peer Sastidin nucleoside 6130-PCI, Mvazh and pictures from the initial property (eg R7128) by PharmasseVRoche; Shatt Tir Naoassad 0.0 middle 0608-Merck / Isis Pharmaceuticals - ΜΚ, (b) Htat Ezim introduction A- 1 Fezrh for Nyukljubd (NtRTIs) (such as Sovaufer (®VIREAD); Odipovir (®PREVEON, ®HEPSEI ^ A); Fumiversen (®VITRAVENE); (c) Htat reverse transcriptase b Nyukljubd (JNRTIs ^, Aavaverniz (®STOCRW®, SUSTIVA); and-S (®VIRAMtWE), and d ^ Shades (®RESCRIPTOR), wa-Darshan (®INTELENCE); and Auferad; Shatt except nucleoside enzyme polymerase RNA-dependent HCV RNA Ra-759- ViroChem Pharma - VCH, and the inhibitor except nucleoside inhibitor Bolimbraz RNA Ra- 868554-Pfizer - PF; and (d) Htat polymerase, ensure polymerase RNA-based Z RNA to Gerus hepatitis C by 1941-Boehringer Ingelheim - BILB; wth Bollymharraz RNA Boath Roche-R1626; Shatt Ralicaz 0137171-ACH Po 1 Plan Achillion Pharmaceuticals, R7128 - inhibitor polymerase by 333-Roche / Pharmasset, ΑΒΤ 'and 072-ΑΒΤ- Htat polymerase by 207127 Abbott, BI - - Solmiraz Ra- -67- -67-ΜΑ 32948Β1 7851-Boehringer Ingelheim, PSI- Shatt Bolmar 0 BL by Pharmasset, ΑΝΑ598- 0 w-i 0 polymerase by 3281-Anadys Pharmaceuticals, ΜΚ- Shatt 0 and by model, Merck IDX184- Shatt polymerase by 625,433 Idenix, GSK- Dazs and facilitated the R'sth Glaxo 189-Smith Kline, ^ Χ- Mtt polymerase by Inhibitex, ΝΜ283- facilitated the Bolm 9 Laz Bo'th Idenix, HCV796 - u 2 for polymerase by GL60667, Wyeth and GS9190- Mthbad polymerase by 0 00868554-Gilead , PF- Shatt polymerase by VCH759, Pfizer and J7CH916 2 x 7 and VX759- Htot polymerase by IDX184, Virochem and IDX375- Htat Bollymaraz by Idenix, BMS650032- polymerase inhibitor by Bristol Myers Squibb; (2) protease inhibitors include, for example: saquinavir (® FOROVASE® / lNVIRASE), and Reznaver (®NORVIR), and indinavir (®CRIXIVAN), and Nelvinaver (®VIRACEPT), and amprenavir (®AGENERASE), and lopinavir (®LJ &amp; gt; &amp; quot; ^, (KALETRA; REYATAZ®) j), and Vwambrenawer ( ®LEXIVA), and Tibranaver (®APTIVUS), and Daronafner (®PREZISTA), and Telabraver (950-VX); second-generation HCV Htat Brubaz by VX-500 - Vertex Pharmaceuticals and -7χ 813; Shatt Rrutiaz NS3 / 4A by 7227-Intermune / Roche - IT.-191 / R, Bos; / crosses, the Shatt al-Brubaz by 503034 Schering-Plough -SCH, comb HCV NS3 / 4A Rowe &amp; quot; Buzz by Medivir / Tibotec - TMC435 / TMC435350, Mtt 1625-ACH Rubaz by Achillion ACH -806, Pharmaceuticals- Shatt protease by ΒΙ201335, Achillion / Gilead and BILN 2061- Hhlat Brubaz by 900518 / SP900518, Boehringer Ingelheim, SCH (Narlaperfir) - protease inhibitor by ΜΚ-7009, Schering-Plough- Mtbaal Rrutiaz by Merck, and 650,032 ^ BMS-791325, BMS-790Q52, BMS - Htat Rowe &amp; quot; Buzz Boishlh Bristol -68- -68-ΜΑ 32948Β1 R7227, Myeres Squibb- Mtbaal Rrutiaz by ΡΗΧ1766, Roche- protease inhibitor by AVL-181, Phenomix- Shatt protease by CTS- , AviJa Therapeutics, biliverdin 1027 - Mthbad protease by VX985, Roche Biosciences- by Rrutiaz inhibitor, Vertex 759-VCH and 917-VCH- torches protease by IDX-136, VirochemWertex and 316-Htat protease Boath 450-Idenix, ΑΒΤ- Htat protease by VBY 376, Abbott- Shatt protease by virobay; (3) Htat Atejraz include, for example: Raltejraver (®ISENTRESS), Alfitrakir; (4) therapeutic methods of synthesis inhibitors fly Nyukliossidanzir Nyukljubd, pea (Sovohar + Zmempersetapin + Aagaferiz), Kombiver ( lamivudine; Zbdovodan), (5) input or integration Htat which include, for example: Maraierroc, and Aengwertad, and Djelkosanol, and the antibody for CD4 counter, and the antibody for gpl20 counter, and the antibody for CCR5 counter, and anti-HCV NS5a; (a) 831 -Α and 689-8o AZD 2836 by Arrow Therapeutics, (b) 790052-BMS and 824393-Bristol Myers Squibb ^^ BMS, (c) 625433-GSK by Glaxo Smith Kline, (d) anti-1095-NS4a ACH; (5) Htat maturity Olney included, for example: Bifarmat and Vivicu; t (6) inhibitors launch Vnrosah Kdmn for money, zanamivir (®RELENZA), and oseltamivir (®TAMIFLU), and Orbidol; and (7) and improvers immune response, which included, for example, interferon a (such as the 883-BLX and BLX 883 CR by Biolex Therapeutics, and Bellerophon by Nautilus IFN-α, Biotech outstretched persons, IFN-aSR Boath LG Life Sciences, and IFN-a2b CR extended influence, and IFN-a2b XL by IFN-α , Flamel Technologies processor Bbola Aithiln glycol (such as PEGASYS®, PEG-IFN-a-2a; PEG ^ TRON®, PEG-IFN-a-2b), and the integration of Roche -69- -69-ΜΑ 32948Β1 Olberman Marie serum IFN-a2b 1 Antervirov-? . The same IFN-P-lb

BETASERON®)), and Aztrveron 3, Aztrveron-d, and Antreron- λ (0 such as 29-PEG-rIL Bo'sth ZymoGenetics / Novo Nordisk), Aztrveron-him / globule white II interferons (such as Intarcia Therapeutics), and aid the future of the 7-like Bnaqos included Ammekmbod, and Oizzaturien, a different image from the initial property of which (such as the 975-ΑΝΑ and 971-Anadys (ΑΝΑ Pharmaceuticals, and Oocalophanid (L-Glu-L-Trp-ΟΗ, ΙΜ862) and the image of a different fatty or 0 accompanied h Glicosel them by 205-Implicit Bioscience , NOV (such ®Molixan- antiviral peptide by. Novelos Therapeutics, Inc), and anti Assadsa EHC18 by Enzo Biochem, gamma-D- and L- Gelothamil- Trepettuphav (such as 07-SciClone, SCV and Oloviron (Mtheloloviron-1- HGVSGHGQHGVHG; Olrveron_2 - CPG 10101, (GVSGHGQHGVHG- E 0 9-TLR dilemmas Coley Pharmaceuticals / Actilon; (8) synergistic anti-Aguero-data; any U frying-for Alhawwas anti-virus and Mahnat or not what any of them, but it improves the effect of anti-virus Aryan; like Korruken, juice and grapefruit, and hydroxyurea, but Ngrnopd, Y Makouwenolak, and Rasgeiratrul, and Rretnava, as well as drugs laze anti-Agherusat jju Ama_ak_in, and Odjelkods; and Vokulovar (®FAMVIR), and Pennekikolover, and Vskarnett, and Vosgoonit, and Mkulovar (®VITRASERT®, CYMEVENE®, CYTOVENE ); and Gardasil, and Aibasitapin, and Nmmonovir, and Morruksidin, and Teixafner, and Baramihir, but Ouaril 4 Baudovelooudin, and ribavirin, and rimantadine, and Trigloradhn, and &amp; quot; Bzhar; and Troayd-Q; and &amp; quot; pioneers; and Valakiklovir, and Valjankiklovir, and vidarabine, and improvers Anrzn 0 such as ΕΜΖ702 Po 1 "&amp; quot; -7 Glance. -7.ΜΑ 32948Β1

Transiti.n Therapeutics, and Dai Hebroklorad 0 b of the &amp; lt; Ely i 1 for example, Ceplene® t IFN-a); and (9) anti-viral variety or Gner classified, such as: (.ΚΡΕ-02003002 (Artenimo Q Kemin Pharmaceuticals, and Metukenon- common enzyme Q10 Anti assistant to oxidation of the Antipodes Pharmaceuticals, and Htat Olga- Ezim Gelokosidaz i (for example, 3253-ΜΧ- Sljobgar of Migenix Pharmaceuticals, and Kamtanocirmin, anti Geloko Cortikoid (for example, Htat HCV 1RES, 0 Afberdston, VGX-410C from VGX Pharmaceuticals) , and 0 proceeds Kadah (&amp; lt;) Jfj, 1 for money; ΡΥΝ17 Z Phynova Pharmaceuticals), and factors of anti Kiro-data derived 0 n conventional treatments Baloosab, the torrent example, ΡΥΝ18 by Phynova Pharmaceuticals, and Htat Cabacaz (eg, 84451-LB- from LG Life Sciences, and Aericasan- 6556-PF-03491390 / IDN of Pfizer), and principals Sklo Spourin that inhibit Alacakh viral by preventing Arbat Spklo feelin a (for example, SDZΝΙΜ911 of Novartis, and 025 -. (Debiopharm, / Debio includes expression &amp; quot ; antagonist for Guetriaat &amp; quot; any molecule Athbad or stop the growth, and the death of wa or survival of fungi. this includes, for example, to (1) polyene anti-Guetriaat like Natamen factors, Rimobidin, and the Philippines, and nystatin, and the Amphotericin, and Kak-; (2 ) and knees Imidazole such as miconazole, and ketoconazole (®LOTRIMIN), and econazole, and Begonasul, and Biotokonasul, and Vntekonasul, and Isoconazole, and Oaks 8 Mazule and Mbrtakonasul (®ERTACZO), and Solkonasul, and Bokonasul, (3) and knees Rasul, such as fluconazole, and Aarakounasul, and Oazafokonasul, and Ravokonasul Busako 0 Zeul, and Forekonasul, and Terkonasul; (4) and knees allele Secretary like Rbinavenn (®LAMISIL), -71- -71-ΜΑ 32948Β1 and Omorruken, and Mavtigain (®Naftin), and Bewoosav 1 n (LOTRIMIN ultra); (5) and Akpat Snuka NDS, such as Onadolafungen, and Kapsovongen, and Makavongenn and rad see Z't properties of anti-Guetriaat such as acid Bmzeljk, and Scilopeix and flus 1 Worsen, and Jrpso griseofulvin, and Jtaataan Bnfja, and Halodojzn, and Tolmaullac, TINACTIN) (®DESENEX®, AFTATE, and acid Oozdeklvek, Ozat B1 Kai 4730 ISO (oil Z Melaleuca, from type Taerbinin -4 ~ first) and oil Alozra and &amp; lt; AA lemon, orange oil, and oil Palmarosa, and patchouli, lux lemon, corn oil E Ozat coconut Aq 'includes expression &amp; quot; antagonist of firsts' or cook Dad primitives factor any molecule that inhibits or prevents without growth, or the death or survival of living wa cups of primitives. Y 0 except for 0 Gh on anti-firsts factors, to (1) anti-malarial agents, for filler Kzzn, and Chegamax, and quinidine, and Kinimacs, and chloroquine (®ARALEN), and "Rocky Klurkin (®PLAQUENIL), and amodiaquine, and pyrimethamine (®DA ^ PRIM) ; and Solgadoudi, and Brojoinel, and Meglukin (®LARIAM), and Halovantren, and t &amp; quot; Ikin; and Ortemesen, and its derivatives (for example, and artemether, and Ortenssonat, and Dai Hedroortemasinyin, and Ortther), and clindamycin and combinations of them; (2) and Mhtat loans; and drugs, Bernidoual, and Bobarfacun and Carparson, and clioquinol, and Dai Sogheiram, and Aaglorenethein, and Nmmetin, and Vuorasulidon, and Mihlomin and meglumine, and ^ 0.6 Role and Mironadasul (®FLAGYL), and Milleteghosen, and Negortimoks, and Nettazoxanad, and Oorindasul, and sulfate crestomycin, and pentamidine, and pyrimethamine ^ ®DARAPRIM); and Sidasul, and tinidazole. MA 32948Β1 -Il- Do Ackbyr &amp; quot; I 1 &amp; quot; Will not be calm 0 of 0 s Alhlap semantic folding any World 0 0 teleological p Krd and'lve, Atd Haggai 0 in Ouail, stimulates Aate 0 Cash Allowab0..d a Z 0 0 Eet Ekt &amp; quot; -oeg 1 1 yards Lke p Soo. To .ekn to 0 the fact that the (categories ^ because for almost Chal 0 West | LHD Study h Alkatn | Drd, Z Z in the end an intelligent not be p 0 A (z &amp; quot; Jr as 1's, Renew r. T, Ekn Tmge thousand-categories Kzv 0 n Ka 'P examination Hdl (z i Ailo Qah Salk to Bahan end Il Alotyl &amp; gt; ed loomed Z (0 LED Justice 0:00-term disease-Ersl 1 FEL, examination Sabin Sass must tighten exponent' 0 Ih fitting for Y Lhasa-data from Ez.zt large T; Manodq 0 n insulted S 'z aluminum' in which good fJb (Z 0 Bill 1 mile, Adtaos · but-.ge-a) to 4 alone Z August Bam and Ken Kerry y 1 El FOB 1 n - I Yerbe Φ; Ij termination 0 m 4 Z Om PS1 Abah to Opkyr 0 of Al_bah. and Yu Haha 0 Alodh Adi (z 0 resolve 0 for ^ o August 4 industriousness 5) Z Reds 0 born p against pannier 0 n Ace Alsd p ugh 0 M. link Asahot A'itralqh h Aaan Bkdrber't B'o was not &amp; quot; Zlaola 'Saa p Elk 0 will not trauma specific Alavym for Awad Adallala Aldldh category 4 Lal b Bam bin. Taatkhadd. this topic Aladabassa! S HI a * to Or'lah 6 Z | rein | FD, and 1 t hard d Zq ZZ less literature j D'd No, .. you &amp; lt; Kltse; for Yltssslanima four of the six TEN Wei can Acrv b 0 a, Y ¥ and Alalttab 0 I Bois 0 to only 00 these laze Azad breadwinners. -73- -73-ΜΑ 32948Β1 Tesfl Lqa 0 panels acid DNA family cell's ability to absorb and Desertification for DNA acid that there is a vacancy proteins object pathogen that is injected into the muscle. Examples of anti-viral vaccines that can be used in Tolegh with Glades anti include for PD-L1 of the ways that have been described in the request made comment on: goods-Bio HCV (Verasom) By .Pevion Biotech, and 4040 ha (MVA-HCV Bois 0 waist see Den transformation; t Anzh designed to enhance the response of cellular Abaih (lymphocytes T, but 0 of cells CD4; and CD8 +) against -, NS3, NS4 and NS5B - shameless NS3 / 4a DNA enhanced Eodon by Inovio Biomedical, and almost HCV / CpG Bo 1 middle Novartis, for Hah GI-5005 - an HCV by Globeimmune, and a mixture IC41 synthetic for peptides containing peaks adhesive HCV CD4 and 8 T j inauguration h poly -L- Arsene Bo 1 middle .Intercell walked enhance Ascabat tenth of generators HIV if administered as a mixture with the adjuvant. the working materials immune help with one or more Z of the following methods: (1) extend the Ahthaz engorgement 1 Shi and submit it to the big) Almmelthmat, (3) Hgz stream large Almmelthmat or other immune cells to the injection site, or (4) of Taiz; 0 g Andaj S Ken topical and Alozhalh Aaeeh

0 Tttml and other examples of the adjuvant: a substance full assistance for Freund S (CFA); and aluminum salts, and proteins derived from bacteria such as muscle bilateral or trilateral peptides to Muramil. Lychee 0 for the term 'antibody &amp; quot; The monoclonal antibodies Silat (.mma the Alosam 1 Kadh Nat Full length containing the Fc region of immunoglobulin), and combinations -74- -74-ΜΑ 32948Β1 Jem anti Nat specifically multi Aqh lenses, and Glades anti-N-1 Uah (z torrent example objects anti-quality bilateral and Glades anti Akaiah, and'losam I barely 0 multiple qualitative and molecules Nat Aceh single as well as fragments of one rein 0 FD &amp; lt; Ely ijf example, 21 ( 'Fab, F (ab and Fv). We use I cut &amp; quot; globulin Mmaea'a (Ig) 0 p 5 &amp; quot; Jem counter &amp; quot; in the current demand. the unit Lean anti quad Alllh basal in glycoprotein Tldd 1 parts Z homogeneous Created z two of Alkhviqh matched chains (L) and Igbin 0 n buzzing August matched (H) (the resolution of an anti IgM consists x 5 units Duration only 6 termination Z Mottagash Tad 0 O to Polly Gap additional peptide Lemmy series for, and thus contains 10 R'da responded Mull 0 10 against, while can be polymerized 'for the antibody IgA Akrzh Kko; n mg 0 and bodies filled one Hafa _il to 2-5 units quad chain base next to the chain's.) in the 0 state igGs, be quad unit Alllh generally about 150,000 Dalzen 0 blood of restitution of all sales 0 uh L with H series by disulfide -sash Association, while Yum responded A- H 0 p each other by one or \ / Roaz Danny Z / Z Itid needs new equipments 1 1 Adoa Tule 15 H. cough and each views H wa also the Faroe second Kritid Yin conduction Nat skunk breaks. And each basket H I Aderf N, mg 1 to 0 Tz 1 t (Vh) bear 3 Alan Dalla (Ch) each one of the chains JJ a 4 room 0 T. Ch to Oraa Almma &amp; lt; of μ and 06 and Cullen each L IL Z 1 party N ^ for Mtaar (VL) Yep mg 1 Li, consistently (Cl) at &amp; lt; hee R 'are 0 DD 0 of Vl 0 p d VH and matching the Cl 0 p Egal Althat first heavy God (ChI) - led to the DAT 20 Niah Kha 10 of acid asset Deuteronomy 0 each and i home between machines Cguirh to any ΜΑ 32948Β1 E- 1 - The series Ivilh. Pairing of Vu Vh together constitute the subject of linking against an individual generator 0 of the structure and properties of Algiat Almokhtlgh of antibodies, see, for example 1! Basic an .8th edition, Daniel p. Stites, Abba I. Terr and Tristram G AA 0 Aa1- Clinical 6 Appleton &amp; amp; Lange, Norwalk, CT, 1994, page 71 and Chapter 1 (.Parslow (eds. 0 Memkt 0 allocation for Dallah L of any Fdarah to one or Abyan strains 0 n Aloraa 0 we identify A clear, and one T-Qomi kappa or lambda, based on the sequences Ahamven 'of amino Valay S 0 1 Ted; apolipoprotein MTW 1 has one of the acid .lomana Like 0 for fixed Suha .lthagalh (Ch), walked Tkhmzs Gelopulimat practically unknown to Giot Mokhtlgh or Oraa Mma &amp; lt; of 0 Ik 5 its Algeloblaat Alaeh: IgA; IgD; IgE; IgM,, IgG, Nat heavy chains Tami », c, γ, and d 40 &amp; lt ;, Akowala 0 Bam thus not one of Giat OLJ y to Hraeh &amp; lt categories ;, basis Alarouk Alarla a p in the Z 1 Mechanism and function Ch, Elysilalmt one evil j ^ Wen p 1 ft August Akabt: to Ehgl 0.2 satirized, 81, IgG4, IgG3 Hello 82 Gel. and 0 restrain 0 CAD &amp; quot; 0 to isolated &amp; quot; is one almost Alaepm determined up and interpreted by one Ted * p one Mkumat 1 Raih Tjieih own and his. the Almkozot contaminated n 1 Study 0 j material to 0 to enter 0 p ISA 0 s Allajah UI B1 rein counter, may include Alabat, and Herrat; From then 0 Pat Brocatah or GTR Brocatah. at 0 Tzj Aceh, Bam will b Table 3 Asad to Izhs 0 Pfysatifibdwab

Akrn 99./ Id. Ba! Assay, and (2) to der 0 a k 1 humiliation de 0.15 Rev any of, any 1 N z least! And Mab insisted 0 z only 0 Ji Akaelll Padam μ-Α Evyhklk; Q Mudbq, μα 32948Β1 him 6 for 3) Î) for Azaom p SDS-PAGE p. Dalal Alibov Almkhos Ad Z Ed 0 Q Bathaddam marginalized / d Aayla,! and sales of 0 since August Ab- TB original Amoadh Akrla Z 1 rein SV 1 most fragile 0 p u; g any b; Alalebat for that! extent Almkozot z least Sabalatab newcomer g Tkdt Lord; - However, only Z 0 War Ad.z be Thfou | Oham to Alfdl cobra 1 j z z ash and SSH. Ahbr b &amp; quot; Dtgh Z; &amp; quot; ! F &amp; quot; * d &amp; lt; H S! * Li was fitting &amp; lt; b camels Z't, 1, ;;., Li dam lion. Winch reference to Il Add 1 0 n Aceh Coterie in Hrrh &amp; quot; VH &amp; quot ;. And walked Alaiarh Il AAC p 0 for p Asz August in PL; A'a 7 &amp; quot; 0 0 Dtkdt this Ayalat in E 0 Rh is! Conner Ojr'e Jem Assad TeX; for Tanda Z Rey ducks Rla 0 antibody. Mstth &amp; quot ;. refers Afber &amp; quot; To Hakqhon parts 0 Aghmn energies Cgdhirh Ifoulynho 0 0 Grt in Almto Mechanism within 1 to counter anti-radiation used in a land. Duck-and-all r o Anti RCA | Cal private. And 0 p deletion 0.7 Wei &amp; lt does not distribute one elbow A; the Ala 7 qat August Z Glades anti 0 is a 5 concentration in Thelabh barriers 1 E called Amatq excessive Dd in every Q! Bands changing Qllh Alhvigh and one of the Dallah Ivilh. Tami Alodz'e No, 0 many Eolah from 1 to Ztaqat 1 KERA 0 Ttq 1 frame (μ. (FRs energies Alamadh p o Alosat 1 n 1 Khgegh West Rabaa FRs nest, Takhar meant about how M Old'h PII, August three is 0 Lq excessive Alnghr, and one I pose loops shut; and - &amp; quot; pose 0 of Oluah_ environment structure. Yum a 0 detention Abatq excessive one change in each Sete, and 0 p neighborly adhesive ΜΑ 32948Β1 -66- by FRs frameworks and with excessive areas Altver of one other instrument, contribute to Tkows 0 signed antigen antibodies link (Azfr Kabat et al, Sequences of Proteins of, Immunological Interest, 5th Ed. Public Health Service, Nati.nal Institutes of Health (1991) .Bethesda, MD). fixed ranges not be directly linked to the Arqat &amp; lt; r Anti 0 p antigen, but appears and a variety of functions induced, such as body Almkhad participate in based on antibody cells poisoning. the term &amp; quot; antibody and a monoclonal antibody according to Amthaddamh in this Aloiaha to Eads 0 m anti obtained from the bodies of groups of anti Mthansh to h L 0 T.r, that Alosam individual anti started Voat include matching with Eda 1 Tat A- 'because it carries 0 Taimkn to be present your 0 Yat Ssth · the Palaly, the resolution of August Almail 0 0 0 Infer curb Avdwisskhalit! Alosam of anti downloaded. Typically, the stunts 1 antibody single vegetation cover Jsme 0 Dhado Z August 6 Edidh Pia 0 the tying goal, t have been obtained Z August 6 Edel 0 Aq Link Target 0 P z Trivamb T. 0 screwed 1 selection MTW; Maly one master Aq wanted to target ZZ b r 0 Toagliat polypeptide 0 Afty for example, the b choice m 0 each Z 1 Khtar b unique from Zsa range 0 del, Mather b 0 n means 0 Hhea tumor, or lar burden or the DNA y 1 Tjh about the return of a land.-Bhatt Genie 0 up to without de 0 a to August 6 Rplt 1 Vdv 1 Mztyh.memkn CDC Tvieri, Mthelae Kh 0 1 yen to Mel for goal 0, or 0 land liberal linking S 0 p asses, Oolsasafearerias 'Olghablas Sam'dhar'! Sdialoraak.o, Npfhsdmirh -78- -78-ΜΑ 32948Β1 goal is also the antibody contained in this invention. Unlike antibody preparations which include multi monoclonal antibodies typically Mokhtlgh directed against determinants Mokhtlga (adhesive tops), it is directed each Ham Anti single Alveselh Set against a single generator on the cheek. Furthermore Z select them, the antibody single distinct liquidity in God are not contaminated other immune Bgelobolinat. Change and the rate of a monoclonal antibody that the body of the reported property as can be obtained from antibodies Mthansh group to a large extent, and should not be understood as a god require antibody production in any particular way. For example, the production of antibodies and monoclonal required can be used according to the present invention by way of Kohler et al .. Nature, 256: 495 (1975); Harlow et al .. Antibodies: A, hybrid tumor (eg Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., In: Monoclonal Antibodies and T-Cell hybridomas 563.681 (Elsevier, Ν.Υ ., recurrent link (see, for example, US demand RFM DNA 1981); or can be produced in ways) Clackson et al.,, 4,816,567), and Tnaat display phagocytic cells (see the torrent example Nature, 352: 624-628 (1991); Marks et al., j. Mol. Biol. 222: 581-597 (1992); Sidhu et al., j. Mol. Biol. 338 (2): 299-310 (2004); Lee et al.) j. Mol. Biol. 340 (5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101 (34): 12467-12472 (2004); and Lee et 4 and &amp; quot; chat Lac 1 c Glades Algadh (al., j. Immunol. Methods 284 (1-2): 119-132 (2004), human or semi-human in animals that O portions of the positions 0 0 Gelobolin absorber or genes that symbolizes Jawpaulin sequences in the human immune system (see, to insult; for Adale Adrah Jakobovits j; W.98 / 24893; W.96 / 34096; W096 / 33735; W091 / 10741: international numbers -79- -79-ΜΑ 32948Β1 -255: 362 Jakobovits et al .. Nature; (1993) 2551: 90 et al., Proc. Natl. Acad. Sci. USA (1993) 7:33 .Bruggemann et al .. Year in Immunol; (1993) 258; and patent applications However 0 Rey numbers: 5,661,016; 5,633,425; 5,625,126; 5,569,825; 5,545,806; 5,545,807; and 856-859: 368 Marks et al., Bio.Technology 10: 779-783 (1992); Lonberg et al .. Nature: 14 .FishWld et al .. Nature Biotechnol; (1994) 813-812: 368 Morrison, Nature; (1994) 845-851 (1996); Neuberger, Nature Biotechnol. 14: 826 (1996) and Lonberg and. (1995) 65-93: 13 .Huszar, Intern. Rev. Immunol 0 indicates &amp; quot; Lean anti Anhard &amp; quot; to Jehm Advantaged non-conjugated portion Sam cellular or Akhaaa No. 0 using an anti deaf Terms full length &amp; quot ;, or &amp; quot; r Anti b; r E or c 00 m Anti Tam'a to denote the same as any and ^ pounds to the body 1 FD in Sour'dh Alaamh, not fragments Table 30 daad. Lucille Glades anti S. Z nor Akhdid Z 0 Talh contain Ouay μ Thagiq and Eag 0 contain &amp; lt ;, Fc Ί was recalled to shackle Sete agents b; p Ntanat Napto to Likh 0 Air Alosa 1 &amp; lt; Eay Q 0 for Alil of machinery 0 Apte of 0 Dhalel ILA) or passed Vgea janitor Ahamvy Alosna. In E 0 z equations 'Oh'n Akdn Q 3 a 0 CAD father wa «de Walker or / and Zalv disease ACPI' p A'feza, including S 0 Ouayez, Reds additional Asad my Daal 5 d. 0 Ti for i 0 and Dgdto /; for ESL fledgling Z Adam equ literature · μ equ z Ilaa 0 0 Bam 0 FD Z Fab and 'Fab and 2 (' p (ab and Fv for Alag ~ or oxidation S 0 and (no F, E A.abl (Aarme; Alosyib; 2 Ouaeads \ E · 0.87 4 is not as upper 5 as p5tent

MA 32948Β1 [1995; 1062-1057: - .Zapata et al, Protein Eng); and antibody molecules Nat single chain antibodies and multi-specific, which was formed from .hzaaa Jem counterattack. Anth digest Alababaian two antibody fragments bind antigen matched, called fragments &amp; quot; Fab &amp; quot; And Hvlah &amp; quot; Fc &amp; quot; Residual, reflects the ability to digest Altbar easily. The Fab fragment consists of a series L College as well as the area of ​​the region Almngirh of God Vh) H) and JAL hard the first heavy chain (ChI). Each Fab fragment is monovalent for linking antigen, which is a subject of linking generator against pink. Address pepsin antibody give large fragment rosy 2 ( 'F (ab which traveled roughly Hzita Fab Mrbttin Boisalh disulfide them Activity linking - generator against divalent and remain able to Akthaka 0 born Ala 01 d 0 Link fragments' Fab fragments Fab its proximity to the units Ghada vary Hliah one additional E 0. grew 0 de Alkrboxa for shops ChI .mma in that one or more of the Alsistinat Z Algsaldh antibody. the Fab '- SH is labeled here's' Fab 1 Collapse Ih 0 for the 1 Rahdh (units) Alababh of cysteine ​​fixed Paljalat Scholl set free. the Azaj Chg 7 O r anti 2 ( 'F (ab authentically spouses of the fragments' Fab and &amp; quot; Taq -t Hema and there are also other chemical Aranat known for fragments of the antibody. Sliver include Fc the literal parts carboxy both chains H Almthbh of Boas 00 Plan compounds I sulfide. is determined Functions 1 to Mar objects 1 to counter 0 Mapt in μ the Fc, also represent those 1 to Mztqh distinctive part receptors (FcR) and c 0 Dely types PS cells 0 &amp; quot; Fv &amp; quot; is a fragment gm Mie less sister and that Thuzei Z Rzaa y stated number b '0 P, to Hvlah: Weimar ^ d Mtfenrh area of ​​heavy chain and one I see Khgagh one in ΜΑ 32948Β1

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.lssalh Of H and one of God L) units -ohmal my father Ldh 0 and 0 Zh dissolved Art framework 0 0 born 1 P meat counter. However, even bosom 1 Fv supplemented Iedy 3 «CDR see RCA j) No one Kara Z j 0 y responded Rla antibody, but rather be less familiarity 0 n 0 r 0 Sir Ark Ace &amp; quot; Fv 4 individual &amp; quot; | One who also A_khasr Kazla &amp; quot; sFv &amp; quot; Or &amp; quot; scFv &amp; quot; It Ebarh r antibody fragments ride from the areas of the body with a 1 Ed VH wa 7 Mthla No, Worley Bbbl 0 d individually. In Mgdil, also includes poly peptide sFv Rak T. Worley areas because 7Η wa 7 and T-1 Ih 1 for sFv Q Tgk 0 for McCall required bind antigen for a review of sFv, see PJuckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and, 1995 Borrebaeck; (1994) 315 - 269 .Moore eds .. Springer - Verlag, New York, pp include &amp; quot; Functional fragments of antibodies raw invention are fully counter-part lime, and generally include linking antigen region or variable Z proper antibody or Fc region of the antibody that retain the ability Link Alopecia d FcR. Tttml examples of antibody fragments on the longitudinal antibodies and antibody molecules mono God and the antibody multiple quality that has been configured Tzaaa antibody. -82- -82-ΜΑ 32948Β1 raises Almhtalh A'ojdzisam Tha'bho to Hz 0 none as 0 or ^ Dz a 0 T. trauma response Ed where x 0 for 1 Tgalaya Iymjolamad LLJ Thaghilal (No 7) &amp; lt; Mmhal Z -as (a 7) Vilasesloalooliyjd &amp; lt; Vh-Vl) . ; R r Shahla, a 1 meat of 0 to small Baz 0 W Hza_da sFv (claimed one thief one of the preceding) the pioneers of short &amp; lt; about 5-10 Palimpsest 0 E Levy) between the areas of Vh wa 7 Search Yum achieve Adawj Z S Almkhk wares for any epigallocatechin 7 Mmahtjezhishglah young parity, ie d Z 0 r Rt 0 Nike T may be one of the objects of (Tmabh to that point 1 cent 1 to equal or 0 Zdugh August 'and the father aka 0 No Reply, ^ August is da 0 corridors is in-line 0 of Lachin Z fragments sFv' '1 Stand &amp; quot; SPS b presence areas Vh wa 7 Ashtn z Sunday, 13:00 Althaeadsh Z poly strings Bptidmokhtlgh. is described objects okapi more Aldil z, z Mr. Lacalle 4 in Alber'eh Alou ΕΡ404097; SPA 1 Cooley RTM wo 93/11161; and 134-9: 129 .Hudson et al. (2003) Nat. Med, and .Hollinger et a .., proc (1993) 90: 6444-6448 Natl. Acad. Sel. Usa- contain one of the bodies of one delegation and a single in August ha z father 0 antagonist &amp; quot; b &amp; quot; and to be as part of the chain Aatgalh and / or Alkhvaah Mmach or Mdjansh 0 p 0 Zabt Mtzerh in Ojaa counter derived from the special strains or maximum of the I or P 4 him by a private counter, Yep 0 a be remaining Allslh (hope) Mmach or homogeneous 0 p MTW 0 Apt what &amp; lt; of Assam's counter derivative Q Ilalan I see or am to class or subclass other anti-body 'to Gap fragments doubt antibodies, as long as the &amp; quot; y Kthat Albaulogi required (see, - 81: 6851 .Natl. Acad. Sci. USA .ei, .and Morrison et al; 4,816,567 .US · Patent No (1984) 6855). 1 to include Agam 1 to counter one of the father Khemarah Z 1 Kadh ®privatized '-83 -83ΜΑ 32948Β1 Hst is Achtakkake bind antigen from the antibody region that has been one Sagh p &amp; lt; Coordination parental Alamdod that have been Dhanha Bamthaddam antigen Alaguenm Mahal. I and 0 for use in the current Alab, quot is made using Altabar &amp; ;. Ham anti .tuaq 0 p humans &amp; quot; -i &amp; Lt; p Vision Alosam anti chimerism. 5 images are &amp; quot; compatible with humans &amp; quot; Objects delegation 1 z 1 to human &amp; lt; For Ely &amp; gt; 1 Phil E rodent) antibodies Jimrah Txtoa the minimum Z insoluble 1 Chh Z Algeloubeyolzn Almmaea G1 R. Adi 0 in a Avang; the fact that antibodies compatible 0 p humans globulinaemia immune human (antibody recipient) where the delegation in August 0 of Aahd 1 T. politicians 0 n HVR for the most important one for the recipient and i 1 T. constructivism Z HVR of the types of non-human (antibody given) 10 0 Aqer such as; or Jerne or Alorab or heads of non-human describe precisely, tilt, wa or ability required. In some cases, it is replaced by the structural units of the FR 1 1 Haloubeyolzn human colostric structural units of non-human debate. Moreover Yum 4 1 Be that T. Hsal 0 1 0 Assam anti-compliant p evil on the units in the building, no one antibody to the recipient or the giver Adam. This is made 0 amendments to revise the antibody's performance towards the Z plus. Z as upper 0 H 0.15 Bstml antibody compatible with pustulation largely &amp; lt ;, one &amp; lt ;, least, Nmda &amp; lt ;, WAH SHIN 0 n collect 1 Flat changing, where the collection or largely agree all excessive episodes shaming 0 GS those antibodies specific Paljloubeyolv Almai Z human without 0 All or all of the FRs to a large extent is the aim of 0 to private 0 Ywalah Algeloubeyolzn Afoua Labrie 0 -aljm anti Almto 0 Vq 0 p humans choice on at least one portion of the fixed area 20 Haloubeyoln immune (Fc); and typically includes a special zone Paljlopulin HIV.

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Jones et 540 Nature 321: 522-525 (1986); Riechmann et Altagaesel For more, see 540 332: 323-329 Nature (1988); and Presta, Cun. Op. Struct. Biol. 2: 593-596 (1992). See also, eg, Vaswani and Hamilton, Ann. Allergy, Asthma &amp; amp; Immunol. 1: 105-115 (1998); Harris, Biochem. Soc. Transactions 23: 1035-1038 (1995); Hurle and Gross, Cun. Op. . Biotech. 5: 428-433 (1994); and US Pat. Nos. 6,982,321 and 7,087,409 &amp; gt; be &amp; quot; human antibody &amp; quot; A body which includes a succession Hmor 0 aa as those of anti-body, which was produced by a human and / or has been a Nhouder 0-or any Tagafih to prepare the bodies of men, as has been described in this document. - Is a 0 1 private antibody Krad urticaria particular antibody compatible 0 p needles that do not j 0 on the small units of special linking antigen is human building. .memkn Produce corrosive Bastbhaddam multiple objects known in JAL techniques which include Er libraries 0 Z August. Hoogenboom and Winter, j. Mol. Biol., 227: 381 (1991); Marks et 54, J. Mol. , 0.5404 1991) 222: 581. There are also ways to prepare monoclonal antibodies August and'la). Cole et 54., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. It is described in van Dijk and; (1985) 77, see A; Amos Boerner et 54., j. Immunol., 147 (1): 86-95 (1991) 0 1 as possible to prepare for Agam one delegation. van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001) Z Bam Azj a] needle by giving the antigen to an animal name Adra Taatadel directed me antibodies Almnkurh in response to the test generator tomorrow but Ke father have I internal placement is Afaqadh ability, for example , for deafness A- 1 Faraji Spr'n Langer, for example Aleraouah Emiri No. 6,075,181. 6,150,584 to assemble Adish b) -85- -85-ΜΑ 32948Β1 XENOMOUSE ™ technology), see, for example, sales also .Proc's. Natl 540 Li et '(2006) 103: 3557-3562, Acad. Sci. USA in connection Baalq human objects that have been synthesized through the hybrid tumor of B cell technology. The term &amp; quot refers; excessive Acfhiro area, or &amp; quot; HVR &amp; quot ;, or &amp; quot; HV, ', Ed 0 resulted in this Alogh to Ingall Almtfihr antibody regions, which would be excessive in Akaaar Almto'lah Wa or Alafat Anjaddedh down Constructivism. In general, the antibodies consist of a six-Z 1 Taq excessive Altefiar; three in Η3, Η2, HI) VH), and three in the L3, L2, LI) VL). In the original anti Glades Η3 and 3 show the most diversity of excessive Altvehr six areas, Od Almhakd that Η3 on Jih specifically meet Rida role in the transfer of precise determination of the anti-radiation countermeasures. See, for example, Johnson and Wu, in; (2000) 45-13: 37 Xu et al .. Immunity (2003, Methods in Molecular Biology 248: 1-25 (Lo, ed .. Human Press, Totowa, NJ. indeed, the antibody-like El Jem camel natural be heavy chain Hamers-, only functional and stable in the absence of Khgegh series, see, for example

Casterman et al .. Nature 363: 446-448 (1993); Sheriff et al .. Nature Struct. Biol. 3: 733. .736 (1996) and fill areas determine Alasal .HVR are in this Aloqh use a number of projections, (Kabat et al.,) For &amp; quot; Kabat &amp; quot; On successive Mtngarah a common-but Shaddam (CDRs)

Sequences Rh Rh Proteins Immunological Interest, 5th Ed. Public Health Service, and instead z Zlri 0 0 indicates Koia'a 1 Li. (National Institutes of Health, Bethesda, MD. (1991) and Tmid. (Chothia and Usk re- Mol. Biol. 1 Hearing, S Father ((1587) 7 of? A- 0 and: your responsibilities ΜΑ 32948Β1 areas AbM HVRs thing capacity between CDRs d &amp; quot; Kabat &amp; quot; loops constructivism, according to Cuba, which is used in the computer program Oxford Molecular's AbM antibody modeling. and dressing areas &amp; quot; contact HVRs for the crystalline structures of complex analysis of available. the following are the units of the building Per Mnalqh of this 0 areas for HVRs. 5 Episode Kabat AbM Kuthia Altas L30-L36 L26-L32 L46-L55 L50-L52 L89-L96 L91-L96 Η30-Η35Β Η26-Η32 L24-L34 L24-L34 L50-L56 L50-L56 L89-L97 L89-L97 Η26-Η35Β Η31-Η35Β LI L2 L3 Η1 10 (numbering Kabat) Η30-Η35Η26-Η32 Η26-Η35 Η31-Η35 Η1 (Trqimkuthia) Η47-Η58 Η50-Η65 Η50-Η58 Η53-Η55 Η2 15 Η96-Η101 Η93-Η101 Η95-Η102Η95-Η102 Η3 areas may be HVRs of &amp; quot; HVRs extended &amp; quot; as follows: 36-24 or 1 (a) 34-24 .56-46 or -50

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The term &amp; quot; numbered B units of the field Almtfihr according to Kabat or Trhi 0 m subject of one of the acid 5 amino also reported Kabat'a, photographs Almokhtlgh of it, refers to the numbering system used for the areas of changing Nat Ivilh authority or Akhalat changing Nat Alkhvagh series -alojdzisam anti As reported by Kabat et al. , Sequences of Proteins of Immunological Interest, 5'h Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). And Bamthaddam this Alfezam for Ezkim, the .twalah acid exponent of sin may sound 0 &amp; lt ;, 10 amino acids or less in line E0 Mavih 0 p Khgd, or insert, FR or HVR 1 1 Il Kerr. Z For 1 example, it is doubtful whether Almtver heavy Mttslh may include adding r a 0 seen and'hd (Alouha 0 H 1 to Bmaah 52a according to the numbering of Kabat) after unification Albmaah 52 Η2 for WAP 1 T. Abeb listed (such as .louhdat Albaah 82a, and 82, and 82c, etc. Tabghae to Kabat ) squandered Alouha of externa 0 82 0 framework y 1 t 1 for God .ltvilh. Will 'to identify possible Kabat numbering of Ouhyt 1 PSAT -15 anti given by Anhaz 0 of 0 when Iatq .lttabq for Oft 1 0 p I barely restrain August 6 A'b' Ezkim according to Kabat. 1 n Aahd 1 v 1 to Bmaah &amp; quot; 1 for a framework &amp; quot; Or &amp; quot; FR &amp; quot; It is one of the units for shops Albmabh Alls secret units of the building HVR Z has been devoted to this Aaud Sir A'alatar Perry Overdrive E 0 &amp; quot; Walked to the window unit Adgy exponent August 7 eating.

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Barbas et al. Proc Nat. Acad. Sci. USA 91: 3809-3813 (1994); Schier et al. Gene 169: 147-155 (1995); Yelton et al. J. Immunol. 155: 1994-2004 (1995); Jackson et al., T. • Immunol. 154 (7): 3310-9 (1995); and Hawkins et al, J. Mol. Biol. 226: 889-896 (1992) according to its use in the current demand, indicating expression specifically linked to or be specified for interactions measurable and reproducible , such as the link between the objective and the blood of antifreeze,'lve Iike - Wen checked for the presence of the target in the presence of a total of Mthansh is one of the chat me to mow p 0 come biological weapons . On Mbil example, be an antibody which specifically correlated Vdv (and'vi. Ifs to be top of the adhesive) an antibody which correlated our goal familiarity, and should be larger; more easily, and t Oo.mamdh greater than linked to other objectives. In a "fairly Zmazj 1; be the extent of the antibody target link is associated with less than about 10 0 a i 1 z convergence of lava Khal goal love measurement, for example, by a radioactive Mphaa experience (RJA). In certain Vazj, an antibody that specifically associated MDF what Butapt separation is (Kd) AFL M &amp; lt ;, or equal to 1 micro Molar, or less than or equal to 100 nano Rlar; or Ashe 0 n or Levi 10 7 a Molar, or AFL Z 0 or equal to 1 b .rlar, or Ash than or equal to 0.1 nano Molar. And in certain Nmang, specifically summit adhesive Z Rowe &amp; quot antibody linked; religion is conservative -91- -91-ΜΑ 32948Β1 yen 0 Rowen z Mokhtlgh types. In Nmong else, can Alarabat Anhdd includes, and did not not require Hamri link. I barely Adaic Lean &amp; quot; Or &amp; quot; antibody &amp; quot; Jem is a counter which Hbt or reduces biological Algshat generator F which Efum linking. There snag antibodies or antibody to the biological activity of the antibody to the extent Maud Kerr or completely. Tparvy anti Glades for AA &amp; quot; e? Z Verde 1 GS send a signal through the PD-1 to restore a functional response by Khalaa 1 0 ml a case of Nat dysfunction to stimulate Mo LED 0 0 F A'alhm anti Anaad &amp; quot; Or meat counter is activated Jem counter that enhances or Aral begins each one Rh middle Bo 1 antigen , which is linked to it. In Kazj D 1; Ta 0 for 1 to 1 Agam Vdhadh table to make or activate Arzel 1 without impact and 6 d 1 to Marie Akrati 0 aims to provide care and natural expression of mutant Sep &amp; quot; System is Ieb can Alts 0 s r j the equ Alachter 1 GS 1 for a present. And _iml.lomthelh the only 0 solid - Loire to fold them Aladraa Z 0 Lemke 1 t been Tzqhlha Dzit or pronation of one of the glass (for Speed ​​1 Similarly, glass with AD 0000 Sam -ver), or the number of sugar, s &amp; lt; Ely Syed example 0, a 0 Tros) 'or early Repeat amides or * me Esther! n, or alcohol polyvinyl and Celikoma 0 In certain models, coprophrasia BTS Daphne 'Imkl 00 N. 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IgG is at Asn297 in the CH2. Offers and position Paljlakojin N existing J Lal 0 antibody treatment, Glades anti processing Amthaddam present invention also genicula Z rad 0 and Aldioimtie? Barsssle 0 Bamagmhoobod.slsyalbulala can U besetting Is 0 a s | Tdal Α297Ν 'SPA Agh Smells -zd Arbat fought Rungh A; sales |' s (&amp; quot ; y 6 c Darren Fc without Arles Y &amp; quot;) fay 03 Gadl He H2. M E ΤΗΐΐς.ίρ ût ni çun, TB 0 fairway Q, for Amaalhala Sdah.bhmaviaveaalndehql CHO any treatment gel 0 Kul and, God consequential lupus 1 turn up RIP TP 1 Hgmh Ao E. U about Bdid, can -thbd and malleable Send health M 3 Asz without Ab'l CH2 Z g dl expression in mammalian cells 1 t 0 such as rush Lalai. Ahbr the term &amp; quot; Please choose a a land. &amp; Quot; Bhatt "in general to force Bh 0 light of the total Z Altd Aadima parity Ird link the position of a molecule (z b 1 for money; c 0 a Dmad) and by a land.-Duck (z example E generator against). Unless cm otherwise specified, according to its use in one of request, Tber 'link to Olga 0 indicates 1 to fasten thousand 1 Tia 1 t's * jS T &amp; lt ;, 1: 1 between the members of a pair link (for example, an antibody generator against). It can generally walk to Wallach 0 0 of molecule X for its partner Y by a fixed separation (Kd). Familiarity can be measured by public roads .arovh in Athal, .mma those that are described in the application. And objects tend Akadh Nat familiarity Alnkhvdh generally to the link in the antigen slowly and tend to decay Spolh, while objects Aldhadh Nat high familiarity in Aamh.mmold linked antibody faster and tend to stay / Tbth to GTR 0 longer. There are many ways to measure Almrovh Please choose a link -98- -98-ΜΑ 32948Β1 in Anhal, and can use any of them for the purposes of the present invention. And are described below Nmang illustrative Maevh below. Is measured &amp; quot; κά &amp; quot; Or &amp; quot; The value of Kd &amp; quot; According to this invention by antigen numbered link radioactively experience (RIA), which are made by using a copy of the Fab antibody of interest 5 and the birth of its own antibody according to what has been described by the following experiment. Is measured Please choose a link to the solution of Fabs for antigen Boamatth Fab balancer using a lower concentration of antigen No. AA (25-A) in the presence of Mellh calibration of the antigen is numbered, and then are captured generator against linked using covered slab antibody anti's Fab &amp; lt; Azzer, for example, bless, (1999) 881-293: 865, .j. Mol. Biol 1.Chen et al). Lst one of the conditions of alopecia Bakhrbh 0.10 are covered dishes rubber-precise Z (DYNEX Technologies, Inc) throughout the bass: Khaddam's micro grams of ml of capture antibody's (Fab (Cappel Labs in 50 0 any Mola 0 R. Dunn carbonate sodium (No. pH 9.6) , O'd Wasa after deletion Bamthaddam 2% (weight of size) albumin bovine serum in PBS for ranged Q Maafeen to Z Saouat I Dre heat weddings (23 m secret.) in the non-adsorbed plate (269620 # unc ^ 'and the mother mixing 0100 Bheco 15 Molar seen 26 Pico Molar generator stressed 125η] Bastkhadd 0 m Idl Takhaiev · IL Z Fab shop taking care of 0 or (Elyslabal, Dh 0 Dsaljm Akad for VEGF, and -Fab 12, in the (1997) 4599-57: 4593, .Presta et al .. Cancer Res) {^ Zlat, including Baal 0 then Z Fab portion specific thousands of 0 or to one's alll, and can still S ball cock oral Ah ^ 1 for example 0.65 Tah) to ensure the one to get Alzazn. of it, including Zgl one of the mixtures to Doh 20 assembly Tahven at temperatures free 1 Rh room &amp; lt; Ely PM 0 Gel 1 such as' for a period of loyalty to one) 0 WPM Ava 0 -99- -99-ΜΑ 32948Β1 Zvaz 0 him one cell and Tmgslatabqosman Aat Bastkhadd 13:00 0.1% 1 m n ™ 20-TWEEN in PBS. and Andi are draining one for dishes, the uncle of adding 150 micro liters / Ezns 0 birth kj \ j (MICROSCINT-20 ™; Packard), and u 0 E. counting only 0 for staying Z Ed 1 d ja 0 a ^ TOPCOUNT ten minutes 0 Wim 1 selection concentrations of each Fab give Ash or z Tawi 20 percent are a land. &amp; quot; Bhatt Aloqmy for use in a net correlation experiments. According to Nmong Last Bam measure the value of Kd or Kd by Assadam LjJ Rs 1 VII 1 for superficial Bamtkhadd 13:00, .03000 instrument (BIAcore, Inc®BIACORE -2000 or a BIACORE (Piscataway, NJ at 25 m using slices CM5 to Mull 0 F Father 0 T. I 10 units causes of the disease (RU ). in short Hoih 20 Dexter 1 n are Scat sliced ​​way sensor Erboxa methyl processor (.CM5, BIAcore Inc) and that Adam Ν- ith 0 for - '3) -Ν- Dai-methyl amino propyl) - calc Dai amide hydrochloride (EDC) and N- Hill 0 Rolci Sakseamad (NHS) according to the instructions of the supplier. And it is diluted antigen using 10 mM Molar sodium acetate, No. pH 4.8, to 5 micro g / ml (0.2 milli Molar) prior to injection when the flow of 5 microseconds rate liters a minute to 10 units in response to almost (RU) of the associated protein. After injection .mmold antibody, is injected d 1 Mrlar of ethanol Secretary of Hhab Atjmoat Pollack Almtagaelh.balzsph measurements kinetic, including injection using solutions ease doubled from 0.78) Fab nano Molar to 500 nano Molar) in PBS using 0.05% of the surface tension reducers ™ 20 TWEEN at 25 m at the flow rate of 25 micro liters of about a minute. This is strabismus rates Alarabat (kon) and rates of 1 Lyle (k5ff) using Nmong Alaratat simple one-to-one Langmuir of -100- -100-ΜΑ 32948Β1 (3.2 BIAcore® Evaluation Software version by the simultaneous installation schemes sensor correlation and separation. This is strabismus a fixed separation just 0 weigher ( kd) j image ratio 0k5flk5n see, for example, a flood, (1999) 881-293: 865, .j. Mol. Biol 1.Chen et al. If Z extended operating Ena 0 of 1-1.6 Μ by ringing Albulasmon Altahi a 7 bugs, and by experience * d that 0.0 Bmcn select the operating rate by Tagafih benefit and move measures the increase or Nfan in y; emission Alumied (excitation = 295 nano Molar; and emission = 340 Madhu lar, and 6 of nano Molar for Ztaq) Ezd 25 m from 20 nano Molar Z Jem anti-generator antibody (Picture Fab) in PBS; No. pH 7.2, in the presence of mounting pylons of the antigen according to the measured j Tiga scale, such as the Tiga scale provided Bmahbs flow (Aviv Instruments) or photometers Tiga (8000-series SLM-AMINCO ™ spectrophotometer (ThermoSpectronic a-M Cguiteqlb 0 can also identify '' the rate of ESL &amp; quot; or &amp; quot; a land. duck-&amp; quot; or &amp; quot; drawing the duck-a land. &amp; quot; a &amp; quot; K &amp; quot; According to this Lahraa according to what has been described as Mbak using 2000-BIAcoreTM or 3000-BIAcoreTM of (BIAcore, Inc., Piscataway, NJ) at 25 m using slices CM5 0 to weld 1 CKD Akabt when / 1 10 units Astahabh (RU). In short segments are activated sensor and a basket of vital mm Dkaatran Erboxa methyl processor (.CM5, BIAcore Inc) Onv using ethyl Ν- - '3) -Ν- Dai Shell A 0 Ivo propyl) for / Bo Dai-standing Hedroklor-LED (EDC) and Ν- Adroxa Sakseamed (NHS) according to the instructions of the supplier. And is diluted antigen using a 10-year lar Q Osdat 1 of sodium, Drdm b 0 Ruginy 4.8; 5 Lao g / t (~ 0.2 milli Molar) Tell injection when the flow of 5 micro liters accurate -101- -101-ΜΑ 32948Β1 rate to achieve 10 units Astahabh Triba (RU) of the perpetrator protein. After injection .mmold tomorrow 'is injected d 1 Molar of ethanol a 0 bin blocking Anhmoat Pollack Almtagaelh.balzbh measurements motor, the injection Bamthaddam solutions ease doubled from 0.78) Fab nano Molar to 500 nano Molar) in PBS using a 0.05% (Tween 20 (PBST at 25 when Ted rate of 0 s 25 micro liters almost a minute. This is calculated link rates (k0n) and rates of separation (k5ff) using Nmong link Wasit one to brigade Langmuir of BIAcore) (3.2 Evaluation Software version by the simultaneous installation schemes sensor correlation and separation. This is fixed account of the balance of separation (Kd) in ^ Rh ratio k5f ^ k5n · Ashe 'for example, 881-293: 865 Mol Biol RO (1999) (.Chen, Y., et al. If oz 0 operating justice En 0 1 ΙΟ6 Μ-1 S by ringing surface Albulasmon previous experience, after which 'can select the operating rate by Tagafih soak and move measures the increase or decrease in the delegation emission! to Ombi (excitation = 295 nano Molar; and Alazat = 340 Madhu Molar, 16 Madhu 0 lar jlkU, ) Id 25 m from 20 Madhu 0 0 Rlar of El Jem anti-antigen (Picture Fab) in PBS; No. pH 7.2, in the presence of increasing concentrations of the World said Ot for Ayala in 0 measure Tiga, such as Tiga Rod .mmahbs scale flow (Aviv Instruments) or Tds Ana Lenny (8000-series SLM-Aminco (ThemioSpectronic using 0 Cguit canned 0 Bo 13:00 forgotten my ringing for Asmo 0 Anh described previously using -BIAcoreTM (2000 or aBIAcoreTM-3000 (BIAcore, Inc., Piscataway, NJ 0 p. needle &amp; quot; Essentially similar &amp; quot ;, WA Mtmac to an end with a 0 Ed &amp; quot; ' And Haa fi a Ashaddak in demand, to a high degree sufficiently Z similarities between Qimbin Addetyn (z No 1 Thal '-102 -102ΜΑ 32948Β1

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This can be achieved process Anhanah No, &amp; lt; additional identification 0 August 1 percentage fun-H sequence of the amino acid in several 0 Slavery fall within Almrsenn skills i 1 Egal, Z b 1 for example, Baskhadd 13:00 Dmamah computer 0 came up Bhari Mtd Barr 0 mg BLAST; or 2-BLAST; or ALIGN, or DNASTAR) Megalign). _memkn To the owners of skill in this 0 0 Gal Thdel 0 Almtd't 1 Lap Im 1 Mahe .i in Nelly any Formulate sports are necessary Khakiq additional Mahaz'h &amp; lt ;, round, length! For the whole of 0 Toagliat 0 t are Mgarztay 0 and land Father in this Father 'Bam; Ij August 1 Boiv Aata 0 A Yum maximum of August 16th ace exponent Ad'm Perla 0 c Aael &amp; quot; t 0 is not a termination of Pam 0 0 T. Atwaa. BC-term khat b QtmecWnc Q; the player Alosh b Alive, Buser pyright I. "; rather 2.555 ..Washington DC 'such as then-C 0 j n RTM d &amp; lt; 1 of only &amp; quot; P / No. II Alhsolerbery 0 ^ At Hlaabiklimsdk 1 ,, ",, to Oeeadsela 0. B. ,. Yum ESL |, some Ilasesaasa Ard.vtamadds 0 0 * Dhataszosaatrapt peered Mla.j All Schlesla and 0 p. One of two scenarios applies for the duration of 13:00 2-ALIGN has been one of Mirat in 6 Apt 1 of the amino acid,;: T 0; 0 Elas 00 to name; E: * AA Egta:; broadcast:;: Amini what (a) have or Tesht 0 for p 0 p e 0 for Amhi (b)) Delisit -104- 100 /. * N quantum γ Ιχ de 0 Yhadrad o ^; Elorb "Anm'v P 0 to Oaala) and (b) Visi B3, B2 Ydeillalayla Sladha ^ (b) 'and Brma 4 Ilaarleb Addd; (d) b) Zspbimasd;, .. 0 ¥ ^ Bs 0 B-Y No, 0 ppg 0 Edjd 0 of the p a 0 Lali was in the light of an ace; λ least to Adam Ra 0 h PC 2-ALIGN- neighborhood 0 Add III "Roller &amp; quot; Alzs 0 forgive only 0 or yummiest in Father Wadley p Barr 4 z molecule p Ndoye Bam vs 0 della Z Re p ace rang else R'loh not 0 J connects ~ 0 Butkleadifa Waller 0 i Lucky name! Lar n u z sales 0 for coded III 1 Drywall 0 Ra 0 n a land.-Bhatt h BJ excise a ; slower framework Alaloj. Be Ja 0; 4 T. insisted 0 Z III Albrell 1 to bite Abdla Bgdat and'lobm Wireless Performance in 0 Medicine Sass; Ed 1 Dar and ^ Hecdnpfia 'Las Uh Add III Adrola g' Dd Lacey Lalai .s Adila T'td'losam Amoadh in 1 'request to present the existing E Medicine ; Aa in cells 0 -105- -105-ΜΑ 32948Β1 and change Akalpar &amp; quot; &amp; quot Suwaliat comparison sample; To sequences as DNA necessary Zds Z Mbr'bh 1 Chgar 1 connected by 6 N. Emaho in k 1 In 0 Ouail neighborhood 0 Mkhms 0 and 6 Apt b Almgarzh 1 Mmasph the cells must be 1 Vision mouths 4 z For example, cell 0 Z 6 'and August 6 Chg; l b 0 shaped me; and a hotbed linking Rebarsom. Almrov will be Oocauaotik cells -m, surgeons 4 signals polyurethane processing Odinan, and Adzac 0 and 0 be a nuclear acid &amp; quot; operationally linked &amp; quot; When it is placed in Boua 0 p MTW one relationship with acid 0 other nuclear 0 Qash for 0 example, DNA absorbent .mmtwalah primary or commander secreting it can be linked functionally 0 p DNA for a multi-dam if fatigue 1 t Z OPEN initial .Δρ in Azaz dissipated Abbd, and the blood of a catalyst or the tribulations of functional connectivity. Mmto Mechanism 1 0 Shaffer If -a; Z y garage 0 for 4 or 0 compaction was linked Paribusum linked with a Ohd Mralah Chg 1 t if k 0 and 1 Zt fainter Q Eml 0 of loss. Generally means pegged functionally DNA sequences that are linked Oad JSwj 0 mirth; In the case of the commander Mistir, be Mcharbh In &amp; lt; t Alaraeh. Q u balances, do not Ddzim Amehsnat be contiguous. WPM Art Z through the link in my .rah type 0 In Ί Ed 0 m The reason such as e 0 these sites, is made using air conditioners or active links few Alkluotad A- .mma p 0 corresponds to traditional practices. Expression &amp; quot; the top of the adhesive blow &amp; quot; When I use it refers to the early polypeptide 0 j Joshua's 0 &amp; quot; * early for peptide or antibody-ROM 0 p &amp; quot; poly strain marker &amp; quot ;. And-Dkon to the Crown Bill 0 S constructivism and Hd't sufficient to provide the top-stick against which can Akhaj body 1 FD; and to me also short enough Njt not impede urinary Activity polypeptide which is 0 for incorporated with 0 will Amodil A-Kha that poly is polypeptide tag is also unique so do not It barely reacts Adam 0 instead largely 106-1 with its 948 contract | Syndicate Agqh Aloay. And Epeshkd harmony be for 0 Crown Atda 0 Lalai termination 0 J &amp; lt ;, all-Habitat; n o 00 lost, Iimala 8 and 50 (and Epeshkd Sila between about 10 and 20 does not Dhabi 0 to Damadaloba) · I, Ie, Dyyt &amp; lt; Almazt-to Abadmssadola d linking, fine for perl-Q besides Me 0 No (&amp; quot; No 00 s &amp; quot;) Aufla 0 P .rkl p on No, Sai Ibbbs.b.d. P Boy link your .rgob W Wali Kov.omz 'replies D'merf Z Smld (p: J fact &amp; quot; is 0 Tjazsho) and metric attained Wendt to Gelobjulzn Mtea 0 DD, I Alive Ais Nmti in Tral 0 y exhorted son, z; cells Z 0 Rga t. .JtU All persons or 0.1 Pt. Can Alhaol Z August 6 the field of data each 0 ^ q Is the Alayq Azoea any z 0 Olhls Las each 'Alaraa every 6' Houa &amp; quot; d 3. Houa, Ao4- IgG,! And IgA (.i in the deletion IgAI O2- Α; Ι) 'Ad E 8 termination Ad Heead IgM Z 0 0 Gogol include Azdlaot Ig Mahmoah Alabal p .M T't E 3 Invavi 0 Cansera will; z' Lash in any 6 Joel E 0 'in Audj 0 Gogol folding Logie Aked.d, Azd includes 0 production Ablariol; N. 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Imkz 0 that the blood Ar'bt one of the two parts 0 Amos is 0 Mbaa p Harika Association of peptide and ; solo extent or Z during Rabahl peptide 0 j; 4 for each birth or eat Ahdat Z 1 1 1 Bgaiah for alopecia ^ acid amoebic. And as upper Besgh 0 H, rack "that the fleecing 5 yen and pain de Alr'sh 1 0 G in reading each other's frame. Character &amp; quot universe; fixed &amp; quot; It is that I kept 1 0 Byrutin basis of a Bthbash. Non-Nia and'bna and 0 full Z Storage 0 Arfer Alyd_lad of Alosalb analytical measurement Sat protein in Anhal and are reviewed in

Peptid and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York 'New York, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993). _ekn Haas Althat degree temperatures selected certain period of time. Rapid examination, can keep the formula Id 40 m Jd; sickest to one month, and the CM measurement stability. Where will Tkhoz_s 1 Sgh Ed 0 ° 2.8 m, it builds in general Aoun formula fixed at 30 m or 40 for a period of one month or less Me Wa E 0 0 2-8 to extend Aas all persons. W b Zs Almigh Z 30 m; Beni Aoun Mgh broadly stable for at least two years when 30 -108- -108-ΜΑ 32948Β1 War Q or 40-K; 6 Thor Aaloh- Z Pray aluminum 'R Adam de 0 All 1 Mae'szyn ¥ Z 0 Odense bit 'Dblala' * 0 L'n Kdn August Alai p August that Aadbaa! regurgitation of 6 to 0% and Dr. Ashe 0 6 n s 0 Rh tougher Z &amp; quot; XY in b. In Zj ^ 1 Rey, Poke Z to any except in coded 0 All Alaa S 'B &amp; quot; recycled Btaah 1 &amp; quot; P August Ashe then bb; melted 1 b Ryans Aamtdy, SPD in a dilute solution in -ev Er Aye 0 Q 0 Kdn August equ Levi Lab Atale (m; Etale g is through grief) to the RIP did 0 to Albrdtv Z Alasam 'On SS models 0 g captivity 1 GS, that the Kha 0 Kdn August any Tkdn Lab Alaehlae I Ed M y | t &amp; quot; Vguet 1 maximum of DDL Q outgrow &amp; quot; PO Eddie 0.0 pellets Alas h Ne mother alerted Alheiguet! To Osmona. Listen E 1; Meh Hcef brain to one, but A'losa B's 0 Auza ranged pp 250 to 350 Vguet] simony. The 0 Bh overabundance Aiotr .stkhaddm Description 0 of 0 of y 0 v Vguet Odzi Ashe Z ESL Alotmve Adam buckets Z Zq 'nebulae 0 Htalh number Walter-t if 00 AP with P 0 i a 0 Nmve Ash SB mother d walked Las similar Algguet osmotic Amdam b Afor Ao days in August only 0 Sze Z dilatable dimensions 0 d Bobad, &amp; lt ;, i Wael. 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Light of 1 v 0 of -kon Ladd; Adad August -109- -109-ΜΑ 32948Β1 Vsaolojtha a Manny solution Structured No. Alehtdrugiy 0 0 Dml a 0 of Arad, the carrier accepted Fssolojia on Alkhalal organization such as phosphates, reportedly 1 T. and other Q 0 to metabolize organic; and antioxidants, making the acid 1 to Oskorsk ; Lord Lapid T. 0 juicy Wazzv Aldzeaa (less than 10 building blocks hornier); and the one Rosat 0.0 such as Olbumv S or gelatin or Algelopuliot immune; and polymers familiarity water 0 such as Crown Whipple Birob 0 Wen; and amino acids such as glycine or glutamine or Alosarajnn or Alors or 0 lysine; and Mono Scared, and Dai Scared, and the other one for Klohdarat completed by 1 to Jaragoz or mannose or Aldickstren; factors Alkhalabah such as EDTA; and Kehopt sugar 0 such as Almantbol or 1 Rrbdil; and Alarat nation-forming salts such as sodium; and / or tension 0 C z 'to Oaonh Shell ®TWEEN reducers; poly E. &amp; quot; Young Chang glycol (PEG), ® PLURONICS. According to the Interior Alfsharat to fatigue T that is placed Bach 1 all unusual in As't Akharih own Baltjat therapeutic, which contain 0 Alomat private land and Alatkhadd'm and or Akaaa 0 me and / or lateral and / or Althnrat concerning the use of this therapeutic Alenthat of symptoms. It includes pay &amp; quot; pharmaceutically acceptable acid &amp; quot; Z acids Z Edo; E and Edo-H g h 0 of the 0; kHz and Balhleriqh I &amp; quot; formulated M, for example, include inorganic acids pouring Agrokhlorik acid, Barakneryk 4 Hdrrom; k, and Rrooodfou and Break, and Kprhk, and sulfonic, and Solfenik, and Hosgourak, and Krbovek , K- a-1 to acids 1 Foe 0 BP alkyl downer chain and branched acids of the &amp; lt; Yeh, and congenital, wa-Olagatih, and aryl Olfatyh, and an annular Gther homogeneous, and saturated and unsaturated, mono and Krbokcelik, but I am, and Thelash 4 .mma in, for example, acid Algurmak, and acetic, -110- -110-ΜΑ 32948Β1 2-hydroxy-acetic, and Tri Maoro optic, and Phil acetic, G Shell Ossek, and; butyl, and acetic, and Onranilak, and Brobbanwick, 2-Hedrkba Roazin 'step oxo Robanwick, and Robanduwik, and cyclo Pttan PRWEB; and Vek, and Sdhu ^ n Rubio't &amp; quot; &amp; quot; k, O3-phenyl Rubionak, Butanwick, Botandwek, and Bgzoak, 3 (4 ^ Ro-Broil) Bazhoyk; 2-Ostuke-Broeck, Oschorbak, and Cinnamic, and low; for Sagurak, and Amtaarik, and Mcconnek, and Mendilak, and Saksenak, and Amponik, and Vuora- 'and Maleatt, and Maliak, and hydroxy Maliak, and Malonek, and lactic, and-d' and Irtareatt, and Jalaako 5 Iike, and Gelykolak, and Geleconak, and Gelokonyk, and Rovz 4 me Oocalix, oxalic, your machine, salicylic and terephthalic, and Bmobah, Woden; and Tallosanak, and methane Solgonak; and Ian Solgonak, wa 0.2-Ian Dai Assay 2-hydroxy-e; second Solgonak, Jordan Srlfinuc 0.4-Klrobrin Skozz, allocating -2-Solgonak, e-toluene Solgonak, and Kmgorsolgonak , Sithil any Spklo [2.2.2] -oocc-2-S-1-Klopte Dko Veke ^ 4; 4 '~ Mittin Y-3- (Hdrox-2-in-1-acid Krbokcelik), hydroxy Adik 0 ensure a' Qguaed pharmaceutically acceptable '. Z'ed Z b Od 1 Lisa and y 0 I started for U. on the torrent of money, include appropriate rules Nick problem Q 0 Aden problem Gu 1 Ed inorganic 0 such as lithium, Akod-Ome and Albota 0, and Almaviom, and Alkaviom, and 1 to Omoveom, and one of iron, and Zk; Wade; Wade; and Alohvdm 4 Gelocam 1 n, Moervolln, and Beradash and the rules of non-toxic Aazavih.mma the Secretary R'ae Alobat Althazah and 0 for triple and 1 Omivat 1 t-Pei The closing and only 0 Sat ringed Ram 1 Tadl basic Alorna [&amp; lt ;, 1 Ihr «Den .Jr as 0 Fill the 010 (.R days 0 Kdn t: 0 'aa: 0 Tate, :: Ddddh for: Aai; s g 000000 Zst d 0 Lite Uorin De'zs and Edn and Lal; Gal Eds for Abett Worley, d 0 j pulling a 0 yen I.zdhul else; and a 506 Dd'a 8 d AS Das edge 10 reminded, s Sleep a 4:00 Alohama 0, b ZZ SS 0 and literature of 0's atrium and acid Asarbak acid Edh 00 as Dallas and satisfied 'the basis of 1 &amp; quot; deceiver 1 Yedlai "and Alolahoud-Vsosmaizbiskls 15 Alohad will ... hearts p Aloead for mite S name Todee 4, Aelah. 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Includes protection vehicles fatty illustrations glycerin and gelatin pellets and Alumblyboz and Alumblyzioz and raffinose and Alumblyboz and Allizioz and raffinose and Almanrioz and Alsakyuz. Examples of sugars which have been reduced to glucose, maltose, lactose and maltose and oak Alambroz include. Examples of non-reducing sugars include non-reductive compounds Gelaicosadat of knees poly hydroxy been selected from sugar alcohols and other early alcohols Nat straight series. Sugar alcohols include preferred compounds Gelaicosadat mono and a special form of compounds that have been obtained through the pellets 0 Khral young man like Alambroz, maltose and Alaktuluz and Almaletiloz. Could be the fact that Agmo 0 cent of the applicable Hlaakosidik or Jlambro Siddeek. Illustrations sugars from alcohol sugars include Jlosetol and maltitol and Akebzl and Arrow Maltuluz 0 Avkriaat to the fact that one of Mabbolh pharmaceutically Oa- phrase pellets Z is shorthand such as Walter Yaalon or sucrose. GT 1 1 addition to Kiryat pharmaceutically acceptable to the formula in &amp; quot; the amount of fatty protect &amp; quot; (For example, Akh 0 hands Packer; d tactless 1), which would mean that the protein is captured mainly in Alkemiana or Agheizayani stability and integration when I am one Crane &amp; lt; Ely · l example, Althelml or storage). Be 00 expatriate brain, Gh &amp; quot; Mahal 0 residency in this document is for one or more of the material accepted Shehadlai (a safe substance Od sa 0 of En 0 Aehlaih 1 Λ7) and &amp; quot; the fact Mgedh in z 113 113ΜΑ 32948Β1 Anailh formula mesh own melting formula, after freeze-drying. 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This is a true &amp; quot; Isla &amp; quot; E ZZ aluminum 'Adam Abe; Wireless Performance for P..LI Alkha 0 of invention if R-Duck will show or 1 / r 6, but G Dub 06 Alozihh Alopecia T cell has been moving. An inch Akibir &amp; quot; effective amount &amp; quot; The amount of effective &amp; lt ;, persons Z 0 0 T. certain bold, &amp; lt; &amp; gt; Sehl example to irrigate Vroryh order to achieve the desired or ether shown that effect included 0 z Iedj MP or protective. Be effective quantity, Z easy example, Q 1 to 1 Agam hospitality for PD-L1 present invention Ebarh Z Ashe R'Kiz result in inhibition Akharh L1 &amp; quot; P5 either 0 through n 1_PD on T cells or Β7.1. -kon &amp; Quot; Elk Yeh 0 1 Gaalh cure &amp; quot; It is less R'Kiz b to influence Z Akin stainless LDs or effective one particular Disturbance. 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Administration by &amp; quot; intermittent &amp; quot; An address is not made in connection without interruption, but they are in the nature of an annular. Refers mammal for the purposes of treatment of any animal is classified as a mammal Letts 0 for those animals on Almrlah animals and animals Zerah and Ahiomat Hadimh one of the animal or animals used in sport or pets Shell Aloclab and'ljul and Alorab, cattle and Alahnazd and hamsters and Aerbua, mice and ferrets, cats, etc 0 for Dalal S to be a human one. Aie Aklah &amp; quot; b Alsdlanao &amp; quot; ! Li - 8 n in b 0 survey lion Asea of ​​0 fact Laval me being Salé nor 0 cell {for Kdlat lib Tabrd Lk 1 effective helplessly | one who Bam Hetau rack 0 B.-Escherichia pumping Skdl 0 U raises Almhtk &amp; quot; Cm &amp; quot; To PS of 0! 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Teogoanin; Mkhrkaptoubeyors; and ^ t Fashio 0 yen 0 such as Sazbiladnn; and Okalablatyn, and Krpoblatin; and Fblastnn (®VELBAN) and Latour b (16-VP); and Avosgamed; and Metcntron; and vincristine (®ONCOVW); Ooksil platinum to Konavnn, Ffigorlpin (®NAVELBINE); and Novntron; Aadarkat; Dionomaysan; aminopterin; Aabandronat, retarder cream Tobooizumiraz 2000 RES; Dai Floro 0 Ithil cited (DMFO); and compounds Rataguid such as retinoic acid; and salts or acids or derivatives 1 Rkat Almapah -121- -121-ΜΑ 32948Β1 accepted pharmacist; and also combinations z two or more of the former, such as CHOP, an abbreviation joint Laage Q Sdkulovosgamed, and doxorubicin, and Vinchrisan, and Brdnimolon, FOLFOXj, which A_khasar to Izam treatment 0 Aooxalemen (™ EGXATIN) jointly with -5 FU and Aukuvuran. Therapeutic factor Amodil be on a special form of objects in Tolegh 5 Dean Z PD-L1 0 n invention, particularly in immune against the disease treatment is a Jamestapin. 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Applied Biosystems, Foster City, CA), or "possible one to get it commercially (z i example, from Life Technologies, Rockville, MD). And Bakali; Nur 0 m mg 0 lung lunulae Alakluot; d 1 t be intimidated by what a particular set of coupons typically number; 0 n Platt Akiokluotad 0 to I Huwaliat Mokhtlgh, b cm consolidate Gharwq by one group Mdomat Z 0 n Mab 5 .lajamalih. And have Koleilat Alioukluotad, I love to use 0.0 Toapt 0 aj Akehv to Negotiable DNA Mtver scale can also be less Ngm positions Alaremyh to Ogr'd cloning. In my love .ltrq, it can be prepared 1 MTW lei vulnerable Adwoa told the Tech 1 0 goers additional Aq Q 0 to Ohad amino happening by accident by a few Tgrh Altioukluotad. And tell the machine Maroiz 0 for good; the outputs 1's, as described by, .Zoller et al .. Nucleic Acids Res (1987) 10: 6487-6504. And Baahaz, CM prepare sequences Alobaiq acids 0 d Alor 1 magnify from 1 to Ohamas amino Pthhan Z Koleilat group Alioukluotad 0 which JÂA3 b 1 Kodomat Allergobesc 0 Aalyyb DNA Hat be less s Z Morh affirm 1 1 cue Q Ablazmid .thtoa Z 0 Twalh S 0 acid Roy was 0 their, hauled half way 0 d A- '0 15 Askhadd 13:00 Azz &amp; quot; m DNA buffer 1 g Kkhanq grandfather-a me ka 0 No 0 n one heart, which - Zlala prefix Head Althukl 0 Ot 0 d, contains groups search right coupons that are Tauferi -ί \ γ Koleilat Alnyukljub group.

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îRRS Se h 1 Li 1 10 in Ouamh 4 cm of 0 using vectors Albulaz 0 hands! Nhtoah multiplier and 6 Apt b Compare snitch is one Stakkakha of 1 compliant to Ozua with .lkhalih one to chew on in a relationship with this etc. ^ a Alamadagh 0 Ih 0 for at least normally double the site, as well as sequences numbered be Vadrh &amp; lt ;, Duffy 1 outwardly similar option in Anholh cells. For waffle 4 Bim are Nmtdh converter Ahurc 0 0 15 using a Lalai PBR322, a plasmid 0 incision Q Oraa Pay 0 Fa E. coli. PBR322 E 4 Z contain genes symbolize Mttqat ampicillin (Amp) and Turabkeatin, or may also contain Er 0 E plasmids microbial or bacterial omnivorous, or cm modified K 6 J on, boosters walked to Yum A-August 0.1 Plan object microbial to show endogenous routines. Yum Khrah examples of derivatives pBR322 0 Staydmh No, Zbr Abam counter specific detail in the Alpes - American reading No. 5648237 20 (Carter, and Aaron) - -135- 32948Β1 En is used vector macrophages 1 Nhtoah on Mphaaf and So'pt 'Li Ka :: 010 ... 'Q 1 flour 1 host Tmacgralvielaqh 0 0 Ahzh the control cells; Alibzha 0 Wael 0.9 n to be a lion 13:00 Z avaricious mesh 11-.λΟΕΜ. ΤΜ j r: maximum of ; a 0 hands trimming. Can S 0 Qm.l exception; a chew. B Mesh E. coli .LE392 Aa. Z password for Aladaa Ndjen Ed Aktar Petrdn p m? Each Mikdiat 0 n k. )B. Melt 1 RH for succession Mouhodh organization before ( '5) Petron SPA | Akonalmazz of Lake 0'; White nucleus typically fall into two categories, urging the problem. Be Adzz a &amp; quot; to Khatt Azaarh.thaszzatdab 0 j | of the hand in excessive levels of Alanta PVC Petron under Amitr &amp; quot; Ende in E, a ball for b and Lalai h Astahabh Cgui 1 Rat 1 Mzrah, for example , the presence or absence of feed or Tver in Drlo heat. Be Eddkir 0 n Alrzac perceived by a variety of chewing gum cells as well Mrovh. Can be p; Haalh Tohta Adzz 1 Mkhar to -on DNA seen 0 g 1 Study 1 Hgegh and heavy Almzz by removing the source of the DNA by T. b Karim Waddell succession Almzz isolated in the vector of the invention. May be Amthaddam grass Q 0 Iraliq August his father and Alktnr Z Almzzac heterogeneous to amplify and direct the display or the target Hayat. In some Alnmang, it is used Almzzac is Almottagash, but where p. &amp; Lt; λλνζ General Bantsakh more and higher earnings from gene Almtahedv appearance compared to 0 p 1 booster Fule Bill natural target. -136- -136-UK 0ϋ \ I Q 1 n .vu Lalla 0 long as the PSC Ola-A 0 x 0 ants de August &amp; lt ;, Ay Z 0 Zz ΡΗ5Α g P- Elaa 0 BL Y, Harmony &amp; lt; y Ratid m) d 0 Armat Q; n 0 Il Adrn tac or 1 to Marz ire. Z! J JW, Tkov Szac see D'la 0 CDT me at (t Zat Alknya or Shmh known only / j) j 0 B Valley: S and M 6 Apt Labeau-bound Z, Z walked deny H - Z; Z Wei Y; Lala Zly Dilah seen the 0 to 1 ESL Study wor 0 No (269: 2011 I (1580) .ah termination termination;? Se; s) Sd'm Smmlat Ed Mhavat to supply any Muaba restriction is required.

In one of the attributes Alachter 1 GS, J 0 small all prone inside the S-Ij Audh Algia Union z Created Mtwab Araz signal that directs' Los 1 allowances for Adola peptides Mabarrah p cover 0 d Ouamh, may-Kunmtwalah 1 to impact Ouarh for a component of the vector, or it may be a part of the DNA-peptide Afahadv which Bim entered me a land. 'must be August 6 1 to impact one Dtrh Nrd this one Alakharaa .twalah cm recognized and processed (ie her hair by Bbtidiz pointed 0) by a 0 to aunt Aagafz 0 Balssh cells the guest prokaryotic that do not understand and address the 6 Apt 0 to effect a; faithful to the peptides is Almottaganh, it is replaced by a succession Alakharh Boishlh 0 Twalh 4 Wathrah Eiarh, the torrent example Mq Anhmuah consisting of alkaline phosphatase (f) Ippj or introductions Anteroteixein II constant temperature (PelBj PhoEj LamBj (STII MBPj OmpAj. in a Nmang invention, the sequences reference used in both one of the instruments for ^ m the display is a sequences STII signal or Mtgbrh including types. in another aspect, it can produce immunoglobulins happens according to the invention in the cytoplasm of the guest cell, so they do not short-0 request and 6 d 6 machines 4 pounds Alaraz eating all Don 0 in -137- -137- 1015 20 μα 32948Β1 this regard, is shown Khgegh and heavy chains Hlopulin immune, folded and assembled Edn Geloubeyolinat immunological and functional within the cytoplasm. The availability of particular strains of chewing gum (the one i fell, strains &amp; quot; E. Coli trxB) Sd conditions ^ Zam be Mgdilh Kko; n dilemmas L-Cutter must Tnana, which so tight folding and gathering correct units 1 Deah Amoherh routine. Probaand 5 (1995) 159: 203, Pluckthun Gene). Yum also darker Zzj Almnadh objects of the invention can express Bashaddam Yum b enumeration 1 Zsph quantitative Mkodt guardian tomorrow or a Z &amp; lt system; Tahlim 0 1 1 Labem Haj delegation 1 1 Krzh canker Bhorh true of the invention. Bam Ngiv such amendment at least part by Tadbl Alantagal forces in the Z time to Mkumat Shelley Bbbd 1 0 0 ppm to detect one of the Alachua 0 Kaad; the power of one of Akqal's the only Arraz / Lycia RTM 5,840,523 (Simmons any 0). T. 0 Tim types of e z d commencement of Ed (HR) Dad Bzon. 0 Sbh TIR's known, can condemn 0 z D. Quinn IL August 6 0 acid 1B 0 of 0 0 acid Roy, Z 0 Z Annagalah strong, giving it a way to Mlalh Nbt this Celle

Framework 0 0 a presser for a Azaal; overcame Q helm · 0 Ekn Ann Dm'ob Dar il * TR e characteristics that -oda Aq 0 Sat Adon and Ezdan mounts d &amp; lt; Dd 0 neither in Zj ^ j, j Atfihrat Alidkpobd silent. Imkn't sales of hundreds E 4 Z torrent 0 example, Z Tairat in the number or spacing .toagliat Shine- Dalgamo, 1 but Alacharh 0 0 n &amp; lt; s Wood Akho-der 0 J born 0 Bzk 0 codon in Dap 0 Atgieratvee 6 &amp; quot; "alters 6 see him urging Alobo to pro excitement (ie '0 fact Agheirat Hat) -0 y Dhirarlochaudaaddklopalaflaklkdddd; d; Zi 'Sd 138- 138-ΜΑ 32948Β1 amino acids, pulling for two days, and facilitators, and Ordne multiplicity n 0 and 1 Almwama first bend and could add to the complexity of the work of the bank. Yum Rah u 0 &amp; lt; 0 Aiqa generate Almhecr Dinh A- in 4: 151.158 .hmttHm) mHODS: ACornpanlQntoMethQdslnEmwol · y &amp; lt; And 0 -ob Mjmo; 1, from Alzuql.mamdy forces TIR each will see it. This Atjmuah Anhdrdh provide Ssuiat compared to the display each series Wa-b .sat also completed daad Land 0 0 B Z and languages ​​0 z TIR strength. Yum can determine the forces of TIR by level 1 of the Air 1 for a quantitative committee rapporteur k 0 is the explanations in detail in US Patent No. 5,840,523 (Simmons et al.). On the basis of comparable strength to move, 1 cm Khtar the TIRs Klelyhdh would have been incorporated into the expression vector of the invention facilities. B) the cells start of his parents, the family 7! -al Family of primitive cells nucleus of suitability to express Glades anti-invention of the bacteria and the bacteria up uncontroversial, such as gram-negative bacteria to positive or Gram. Ohlh to Xie 1 delegation &amp; lt include;) (on Mbil example, E. coli), or bacillary (for example, B. subtilis), or Akosh_da Enterobacter, or pseudo-types (for example, p. Aeruginosa), or Amonilla t · . And Serratia marcescans, or Klebsiella, or Proteus, or Shigella, or

Wlizobia; or Vitreoscill, or Paracoccus- in a Alnmang, is used as a negative cells &amp; lt; M in a Laghmanj, are made using E. coli cells Kmoghaivat of the invention. It includes strains of E p 0 on KR 2 .W3J10 (Bachmann, Cellular and Molecular Biology, vol

(Washington, DC: American Society for Microbiology, 1987), PP. 1190-1219; ATCC -139- -139-ΜΑ 32948Β1 (27,325 .Deposit No and Mstqatma, .mma the 33D3 Nat W3110A / k4 genotype strain (5,639,635 .AtonA) ptr3 lac Iq lacL8 AompTA (nmpc-fepE) degP41 kanR ( US Pat. No). be strains see and Mstagafa Shell 1776 coliBjE. colk .e, (31,446 E. 294 (ATCC (31,608 ATCC 31,537) and E. coli RV358 (ATCC) suitable EVA. this be 5 Alohlh 5 illustrative and not specific. be ways to create dispersant T. any of the bacteria referred to Frizzle Nat genetic Aloraa specific known in Laval and Mtherouhh, for example, in, .Bass et al (1990) 309-314: a. Proteins · be necessary to generally choose the appropriate bacteria. Sa lightest in mind the possibility of doubling Ariblikun in bacterial cells. for example, it can be an appropriate use of E. coli or Serratia or types of Salmonella Kacf Afdma including 10 made using plasmids are well known Shell pBR322, or PBR325, or PACYC177, or ρΚΝ410 to supply Riblikun . stereotype must -hrz the guest amounts few cell Alabat evidence of Brocnn, Lund is an Rgobh integrate Mbtat additional Broctaz in cell culture. c) antibody production 15 sniff converter Alla_da 1 of chewing gum by vectors described Akaabar of the NL and a button Vf in central Taz &amp; quot; a funky love appropriate alpha rate of 0 to urge Adrzac, or 1 Khtar wanted Agolh, or p Algiat 1 Ytoagliat color-coded, to desirable. -mna Kho.l introduction of DNA in the initial host Alo 0 of Bhat -kon from 1 to possible Iaf of DNA, E. 0 A - 0 Kromo Rs Wagners or Bo'th Mk 1 Del chromosomal. Atmada ornament on August Adad, including Z 0 for Akhoil Bathaddam Tviac

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-140- -140-ΜΑ 32948Β1 record appropriate to such cells. Is in general use to address one of Kasam Cdi chloride 1 calcium to a solution, da 0 for bacteria 1 t containing ho 0 mow grandfather 0 R cellular material 0 'blood and other Atrigh convertible polyethylene Jykola 180 be' other Shih will serve him a-Ddha are Alascherad electrophoresis. -tm Ministers and Hlaya initial 0 to Zuh .lmstkhaddmh to produce peptides .lbola expedite the Ooot Maroh in outputs 1 and is suitable for the cultivation of cells selected the guest. Examples include among August Z Ravi urea (LB) in addition to the necessary care supplements. In Bakhr 0 Alnmang 0.1 for circles as upper Oaia Z 0 4 Aiar hotter on the basis of the establishment of the expression vector, to allow the growth of cells beginning eloah Athtoah the carrier of expression Antvaiah's. For filler sniff A. Add to the media for the growth of undeveloped cells to Mgarm gene for ampicillin. Eva may be the inclusion of any supplements Dharor: Its addition to Alkrbo 0 n, and Albaojzn, and 0 issued inorganic phosphate concentration of 1 T. appropriate Dz 0 Mmordha or z b d 0 i Mkmad or with another medium, such as a source Natroyjnn complex. B Ajerih DD contain and i 0 Arrah &amp; lt ;; D reduced to one or more selected from the August Almkoh for-for JLo 0 Datyon and-and Sstas and Hocalakulat and Dai Yu Ordzl and Dai Rormel 0:00 PL 1 cent Khalaa one scary Ouen Auriga one of the Derst Hraoh Yep 0 At ^ Zj me, in August to Z brother 0 Rchia E. coli, 1 Cor happening in 0 de seam temperature 0.0 n 6 to 20 m to Hldali 39 m, ho 1 Lee 25 m to Ho'la 37 me and Dr. 6 to 30 m 0 DD Den Artem Ydero 0 c 0 Ne Lal 0 i Ouar; p any number Madrdjna 8 Adh 0 n 6 to 5 Ely B'la and '-141- -141-ΜΑ 32948Β1 imam depends on the host Cache. In ^ Zj Q, spyware to Ihrge 1 E. coli 0.0 Ekn be a; Am Alfdrugiy 0 n about 6.8 to Mdaly 7.4, or &amp; lt; and to 7. If you have been made using an enhanced retractable induce in Zoh additional to the invention, Yum District ÙÏJ? Ml P &amp; lt; 0 Iasph Z of rice. In one of the features of the invention, it is used as boosters PhoA control) Shakh 'for poly peptide, T.. Uj 7 y Te Dadam ministers cells A- 1 skinnier and i specified in Balgosvat to induce. Lang stomach in 0.0 the fact that one Hest Aye Bolgosgat Ebarh z center CRAP (see, for example, -263: 133, (2002) Immunol. Methods RO ,. Simmons et al 147). It may be Amajhaddam Mtvuah other Amehot lineup, according to the Taku; n Abakl Madm; as it is known in Atjal. In a 1 Bzj, the Araz urinary peptides mouthpiece of the present invention in the drawn Z 6 cell cells the guest. Amtkhalas includes protein typically on Tmzd Cache Aldhaievy, generally by means such as Tadhah or treatment shock waves Waco-friendly or Aekhall 0, that is listed Yum Tmzh cells, you may be removed gestures cells or whole cells Bucca Central Eldad or filtrate. May Yum Moreover pious proteins, for example, Boisalo chromatograph Rath familiarity. Alternatively, you can transfer Yum Albrocaat in Aoit 1 Mzri and played in it. How could whoosh 1 H.llaaa farm WPM -rchih and Rkiz.lmadh father of &amp; lt; p additional lung proteins produced. Can yum Moreover urinary isolate Pasha 0 Yat Almazemh and set using 0 slavery known commonly thrive, such as' the electrolyzer to Hl poly 0 / "for amide (PAGE) and Western experience spot. -142- -142-ΜΑ 32948Β1 0 toward the Qin antibody production with large amounts by fermentation process. Be E 0 1 that P 0 seen Mkhzmh nest widely fed batch code to produce Rwinat product return Alathak Aayna0.kon to my uncle t! Brewing on Ntafy widely Energy 1000 Carr St. Alofairs u o 0 for example 0 Rally capacity of 10,004 Li 100,000 liters. Use these intelligence services ranged driving 5 to Osea Lassen and singers, especially Jlucrz (source Krbozr Energy popularized) 0 -d border of 1 t z ^ s whistling generally to fermentation in the uncured not Zaid 100 cr Tzda in one his first of volumetric, and can -waoj 0 n to 1 g to Wali 100 cr 0 E 0 core brewing; are typically begin urged show Adrutn after being hydrated have focused &amp; lt cells; of 0 Gash 1 Li desirable density 'on torrent example 0.550 from about 180 to 220.10 you 0 n 1 Hlaya at this stage in the phase Akabt Abkar . It may be used Den range 0 to Alith materials, according to the user's carrier, as is Mbrov in Anhal explanations and 0 0 n ago 0 0 has included B-1 cells to Fsat Avenge VPL induction. Yum usually urged the cells for about 12-50 hours, Bargm you can use yum urged longer or shorter. To improve the outcome and quality of the production of polyurethane peptides of the invention, the less blood Taa 0 0 Yale J Rosa jyJ 15 Mokhtlgh. The torrent example, to improve Althamia will health; while the Crown Bjaddat one body Alhad one feature, it can be a-M vectors additional show Bazat proteins Habbirov, such as proteins Dsb (DsbBj DsbA and 0 of 8 e DsbDj Rao DsbG) or FkpA (replaces Rundle p. 4 Zad -oizumraz actively Chaperon) joint transform cells prokaryotic Alamadagh. I've sacrificed routines Chaperon but Ali and facilitates the correct solubility of Brocavat heterogeneous Almenthh 20 bacterial cells in the guest. 19605-274: 19601 Chem H / hr (1999) .Chen et al; Gorgiou -143- -143-ΜΑ 32948Β1 and others, US Patent No. 6,083,715; Gorgiouj and others, however, the patent 0 Rakoua opportunities 6,027,888; and Ramm; 17105-275: 17100. Biol. Chem RO (2000) Bothmann and Pluckthun .Arie et al. (2001) Mol; 17113-275: 17106 .Biol. Chem RO (2000) and Pluckthun 39: 199-210 .0Microbiol a few routine decomposition of proteins is Almthansh expressive (and in particular those that are sensitive Ekhall Alrwin); chewing gum can be made using certain strains is effective for enzyme hydrolysis routine Choose 1 GS current. For example, you may be modified Mlalat gum cells to make a transgene (Abat) Alzhh in the genes for the enzymes antitragus Brocez bacterial Mrovh like Broctaz III Tspj DeqPj OmpO and Breueaz and I Brocez Mi and Brociaz Brocez V and VI and combinations of them. Some strains of E. coli Atrchia be limited to Brocez available and are described, for example, Joly et al. (1998), supra ·, Georgiou et al; US Arrah No. 5,264,365 nations of Gorgiou and others; and US Patent No. 5,508,192 on behalf Gorgiou and others; and Haraet 1 for% and \) 11-Y 0 of .10, Microbial Drug Resistance 1. \ him. The use of strains of E. coli Ahurcaa Ballenbh deficient enzymes to proteolysis and converted by excessive expression plasmids for protein Habarouk one or more Kkhalaaa chewing gum in the expression system that there is a vacancy Glades anti-invention. D) Tiqah antibody in a Tang, purified antibody protein Aptj are further in this specification for Sshoudrat be Mthansh somewhat Kbehr tests and additional uses. Can be 144- 144-ΜΑ 32948Β1 Bim use methods of purifying protein known record in Anhal. The following actions be a Amraat purification suitable ideal: count on Please choose a column immunological or ion exchange, or precipitation of ethanol, or HPLC phase inverted, or chromatograph on silica or Ratj Capone exchange such as DEAE, and focus chromatography, and £ H 8? E- 0 H, and deposition ammonium sulfate, and the use of HLA Rchih 0 me, the torrent example 75-Sephadex G. in one of the SAT, is Amthaddam a routine Gner moving on &amp; lt; t d Kqah familiarity Achaaah Kh v 1 antibody of the invention. Rod is A Libra p protein indisputable vinegar 0 of 41 kilometers d 1 Ton. Staphylococcus aureas and T-1 link the gods p 0 - Fc of AGEs 13:00 1 delegation. 62: 1-13 .Immunol. Afeth RO (1983) Llndmark et al. Could be the Euro-steel that is topical form of the Russian Movement A Ara p Emod Licht 0 &amp; lt's ;, Shlh g 0 Laage or silica, or Emod codified glass pores or acid column Sask- in Z but-Ott;, Γ black paint by reactive material, such as Jkierul ; let Aagafy 1 to 1 g t Ozdd b-picture of the two of Melo, is coming. No. betrays Ezde 7 μ for solid phase to remove contaminants tie indefinitely to Alhlor Alhtab. Ads in the end is the body burden of pain equ m3 n S Ala 00 core by sequential liquidation. 2-results JUII μ »ι for [β \ father of Fousalj 2 1 Mgad cryptic if; 'Q 0 for z 0 Kdlat Wallach 0 Z b Almiol, Alhar, Z Benefits or mother Z t: August 6; shawl; for Ad R R Ad Dsad Walker Z births gravy 0 of , or m ^ y 'Ed Sz, Ao August 6; esophagus t' -145- -145- ΜΑ 32948Β1 (a) Hecongbebblaharh may contain vector for use in chewing gum prokaryotic cell on the continuum signal or several peptides R has the same Mopa fission specified when martial -N Nadh protein or many Albbbdat 0 0 Alahishlam infants should preferably be the signal sequence is selected Almthansh known and are Dljtha (ie, Bim 1 Iarha by the enzyme signal peptide) by the host cell. Altabar in all mammalian cells, Tu &amp; lt; 6 mechanisms of signal mammary secretion as well as pioneers Virus, the torrent example, a 0 is not exciting

Simple gD linking 0 Mtqh Article Almttjh DNA DNA under Akrah DNAJ thousand -rr-term 13:00 Amo 9 birth of Akhozaa 0 Ai d not be inhabited Emkov) Lennkh WA Lars Ahs IP (z i 'Ladd' 0 possible a 0 Tmahlam out SV40 only typically because it contains &amp; lt ;, enhanced by all ). C) Maclnhg 0 Bmcn En grate and Alasfaj Jane Antghae, and it is also called a stylus to Waddle ^ v 00 for PBT only 0 Imae of 0 Ta z 0 Rsz Albroobat Levi (a) Dh article 0 A to Lhasa Adobe 1 Hao 0 Tweet .lokhry 0.0 h, loyalty or or Z or Ee or (b) ' del Answer 1 age in Cgz &amp; quot; of 1 to table Het 0 of Mathotrick 0 h 0 0 I;, or (c); and Dr. foodstuffs a &amp; lt; JH Z 1 Kahh in complex media 0 z -0 Bill 1 for the money, one of Jane pain 1 Td t-Sez d -olas b 0 Talmq d Bacilli -146 -146ΜΑ 32948Β1 0 if the blood of one of the examples Zzam Aimae a drug to stop the growth of a host cell. Reach those cells that are converted 1 Bzhoh Bastkhadd 13:00 0 #NAME d Akkoan &amp; lt ;, Azaj Ross Bam 0 Zhaomh Lahr and eternal - 0 G6 Alaztqa. Evolution 0 J examples of 0 such as the selection of the jungle on the use Alakagahr like Bomsn, and acid Makouwenov and-and _ as examples only 0 other on Almno.at negotiable Azh 1 E 1 to Mabm to exception-a mammal 0 you 1 t Z discrimination capable of absorbing a cell-to not take Adwoa for-m counter, Mt- for DHFR; RIM Aamaidin Kivaz, and Matalooven ~ Ra Ra 1 2; and; Gdil G 0 data Mtalothopf Lord; and Azz, including adenosine Dimiiaz, and Ezim Ooosnn d "Krrkilaze etc. Syed 1 Presentation for example, is highlighted Alkhalada 1 transform &amp; amp; Ù Achthar DHFR first Ispat p 1 lice in and i farm contain folding 0 Dtrkat (Μχ) 4 and ^ d Yahsai for DHFR · in - one Bzj; host cell is critical when using DHFR of Ra Z .arv r, contain important Slalabhd 0 goers brown (CHO) r Taku 0 z effective in Fetat DHFR · &amp; lt; Nthela, 9096-ATCC CRL). Z Iho alternative, walked selection of host cells (specifically, the host cells of scruples Azib that has presented an internal DHFR established) Anholh or Anholh jointly Assadam 6 Apt 1 Resolution 1 of the WWE 1 t denotes' to the antibody, and brooch DHFR type Azibe WPM if Lash of Aloqa 0 such as Veo Gelaikob 3 for Kareem turning Algosgour (ΑΡΗ) Onv b 0 and the cells in the center of the presentation contain Oua.l Aimae numbered 1 to Say Lalla E ^ z 1 to counter one of the vital Gelaicosd Us, for example, Kgasn, or neomycin, or G418. 1 Zgler mainland cent only 0 blades Ram 4965199 '-147- -147- ΜΑ 32948Β1 d) and h Ouadh contain Noac Ads and Asak on Mzz Bam Acrv Ne Iwas 0 him Cache wn and be over-Dta constitute E 0 t Aluwa acid which symbolizes sequences antibody required. Sequences Almzz be Mrovh normal cells Alnoah.d sales money 4 containing p 1 0 Giat Fieh Auriga one of the area rich B-- ΑΤ found nearly 25 to 30 captain Tmraba Hubble Almoha 1 0 0 B outfit a pumping heh. The / Ztralh see from 70 to 80 base before the start of copying Alkt 1 t Z gene which CNCAAT area where. Ifs that N any Zhoklho 0 HD 0 1 Add 1 to a third of the most natural Algievat nucleus 0 Be Zap AATAAA 1 Lee 0 Bmcn be excitement (for alopecia added many A final on 3rd party 0 n 0 0 Pmab Waller Az- in Zj ^ m 0 No, _tm enter g 0 p these sequences in a manner Mnab Showers Almar Ne Rush in additional natural nucleus.

P 0 for Adz 1 v 1 to see Mufasph for use 0 p flawed ornament Bdabh nucleus gg PhoA E and Aki 0 BL and Ozzmh d lactose and Mzz Voseviaz alkaline system booster Repettovan &amp; lt; 4φ &amp; gt; And an enhanced 1 T. hybrid Mtd enhanced tac. Although Z that 0.0 Anez the fact that 1 v 1 to Kirya Almaarova Mmash 0 v 0 SHTML one of the boosters 1 t g C 0 mother in real time Bakeereya also &amp; lt ;, Zap -Shine SD)) 5a, gi0 Acirbtabeklsla-Q 0 C Yesh &amp; lt; Beileihd Aljm'vd 'is Akzalbdlibglab r not Azah Aluud; j the cells 1 S 0 No β mammal, Z Cecil 0 example, by Anhfsat that are obtained from the genome, such as 1 Fros Tdd tumor, and 0 Ira 0 Li Rtan dorsal dam Tertat glands (0 Tel Verdes No 2), -148- Msoscmassad, Bs 0 to Dsssm Q 0 u 0.0 bears 0 Dscs 0 Dersdaysp »Mzd! Demlaramadv 0.0 grew 0 Founder 0 Deddahahdsfouys host cells systems. Htm Alharl Z airplanes toil; and Aisalsdos SV40 in Y; Me b .SV4 Sahadihes-Dmsayibs; Hee Q 0 for Labem dam Ouayblohozvvira; Alosertme 44 A44.amis. 0 Im in a ra; Alosaa RFM 78., 0.46. August principles: 297 Reyes et al., Nature (1982) 598-601 Lahoud Assa p termination; painstaking v SV Ela'a 'I Lahr 6 Wigger Znzim discriminate Sass Z in the 4 x herpes August. T r-bound for 'Lash Adam Z x, y Ont long Aljzeasefi ^ g. Abar Created pain Zz Ib 0 0 0 A Zkh insisted Z Adi DNA 'Lenny compact Jem Assad della Wallace a Galaya 0 0 0 x 0 to Mah Oeay cachexia Badech 0 for August 6 in the Z Wallach. Esd thousands Alkd Z 6 Apt I a 0 laps Aceh (Aljhan, l; Tz, and Albers 'and mothers who Ed 0 Yaffe' father). Zlat 0.0 Ikn Uax to use Marz of Guah normal cell virus. Examples Taatfmn on -149- -149-ΜΑ 32948Β1 reminded enhanced SV40 existing one for an attractive Adokhr virus Z continued etc. (100,270); and Marz 1 Thgz 1 Bakr cell hyperplasia virus, and Mzz multiple tumor on late GAP originally Afaj 4 and 0 Zzac to Proman glands 0 0 Zgler Esha (1982) 18-17: 297 Yaniv, Nature Lahoud pardoned grate boosters to activate the natural Anhfsat nucleus. Ekn 0 0 1 _esgm trismus into slices at least for the position 5 'or 3 position' on the succession seen outclass T. Worley 0 love one newcomer 4 Om blood &amp; lt; a position that when there are five of Anhvz. F) Created Faye annulment Z vectors Altaber used in the picturesque family Hmcha Lavoie 0 (August and Alguetr-DAT, insects, plants, animals or humans or Hallab 1 t U with 0 s in the cups to; U multiple years) are typically the sequences necessary for Aie y 00 x Wei mRNA- without this one of the sequences was one fairway in Ha'da from position 5 'F-3' and u ^ 0 z translation and rap n DNAs or cDNAs natural nucleus or viral. Containing Te S z Obe Theclo 0 must hatchery on Hagh treatment with numerous cyclase parts at the Z Almitrj 0 of bridging mRNA JJ 1 the one who symbolizes one of the antibody 0 fact a Mkumat Aie 1 squirt F Barr 5:00 * uk Adnal many! To adenyl my hormone bovine growth. See Wasp 1 Cooley Rzm 94/11026 and B F, which has been disclosed there. G) selection of host cells and turning Tttml exception, da as upper) suitable for transcription or Dallah 'for the expression of DNA in Alzuql I z exception-not a doctor nucleus highest described in this specification, .mma the picturesque exponentially 0 0 as MSI deployment 1 a -150- -150 -ΜΑ 32948Β1 vertebrate on the farm (implant Nchristah) action routine. Of the term on the family cell lines, Kdaah 'for useful 0 strain CV1 to college one monkey 1 Khawla By (1651 SV40 (COS-7, ATCC CRL; and strain embryonic Faculty of mankind (293 or 293 cells cloned Hroua for (in 0 Zri hanging, (1651 COS-7, ATCC CRL); and cells Hamsr Jenin College (10 BHK, ATCC CCL), and the cells 5 whitener Hamitr Sha / - 4216: 77 DHFR (CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA ((1980); and cells Srtola rat, ((1980) 251-243: 23 .ΤΜ4, Mather, Biol. Reprod) E cells College monkey ((70 CVl ATCC CCI); and except 0 a college one monkey Alonrdwi original -VERO) (1587-76, ATCC CRL; and cells Rtan cervical pustular (HELA, ATCC CCL2); and bewitching Faculty of one of the dogs (34 MDCK, ATCC CCL); and cells 0 CKD Zz Ja 0 Lucy, BRL 3Α) 10 (1442 ATCC CRU; and bewitching human lung (75 W138, ATCC CCL); and cells CKD Mery (8065 Hep G2, HB); and tumor breast Murine (MMT 060562, ATCC CCL51); and Khalaa-a TRI ((1982) 44-68: 383 .Mather et al .. Annals N. Y Acad. Sci); and 5 cells MRC ; and exception-da FS4; and breed a human renal tumor (Hep G2).; r shift-for Khala-a family -t \ y Ads Alzh Almnkur above or vectors of cloning to produce antibody and'hm button ^ on or ^ i diet 15 traditional Kt is adjusted appropriately to urge the boosters, and ran Au'ml Akhoil, or longer, for 1 ft .lmharh to Amato .lmtalobh one bit. The examples of additional 1 rose 6 for the machines in August cells Almoghaid 0 h) cultivation Hallab family not take Button 1 cent 1 milkman 1 family Almtsh to produce the antibody of this invention in Bhmuah Mokhtlgh Q Alooat 0 -wUj 1 for media Akahh traders like (Minimal Essential, Ham's Flo (Sigma 20 (RPMI-1640 (Sigma '() Sigma)' Medium ((MEM, and Dulbecco's Modified Eagle's

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-151-

-151-1hahlo UK

Medium ((DMEM), Sigma) suitable for cultivation of host cells. Machines »y to the 7th," Ic Astkhadd 13:00 any of the Aws 1 i! The lighthouse in, .Hi et al, Meth. Enz. 58:44 (1979), Bames et al (1980) 102: 255 .anal. Biochem Bara 1 T. Aladraa Urdu Z't 1 to Kareem 4.767,704; 4,657,866; 4,927,762; 4,560,655; and 5,122,469; S 1 Cooley RIP 90/03430 WO; 1 to request one for an international RIP 87/00195 WO; or reading Aladraa only 0 Rey RIP 30.985 Ka-framework Button 1 cent cells family. Can supplement any of these 1 to Ooyt Il 0 necessary by Amomat and / or your responsibilities 1 ml other growth (such as' to insulin; more substantial; Dunn, as upper 0 for the growth of the skin), a 0 loomed (0 such as chloride, 0 sodium, Kalium, magnesium, and phosphate), solvents 0 blow (0 such as HEPES) ; Veokluotedat (0 such as Odivoszn and thymidine), d 1 T. vital (such as Afar ™ genamycin), a contemporary of scarce (identified Kbarakbat non-membership of the found usually when &amp; quot; Rkez't Haiah the extent Micro Molar), and glucose or unequal power source. Q ik as any other necessary supplements included when; Kizat appropriate known to the owners of skill in Amehal. Such as p 0 &amp; lt; of Azraah, such as temperature, pH land, Wei young 0 in the DC Almatkhaddmh PM 0 Sakka with the host cell that has been selected to express Alorani, and will be clear to the owners of skill in Amehal. 1) purification Jem counter when using recurrent genetic correlation techniques, the antibody can be produced Bzn the cell, in the space righteousness: and, _lazem cell, or can Arazh directly in the middle. In the case of the production of solder between the cell counter, Kkhaloh Oo, not removal of particulate debris, either family or fragments Anhllh cells, for Eyal; Boamth a Aerd; Xie Algaiq or filtration. Describes Carter et al, Bio / Technology (1992) 10: 163-167 a procedure for isolating antibodies that are counter to Arazha into the cytoplasm of the cell -152- -152-ΜΑ 32948Β1 of Escherichia coli. In short, it is thawed cell paste in the presence of sodium acetate (pH 3.5), EDTA, and tends Snonal methyl fluoride (PMSF) for about 30 minutes. When the secretion of anti bridles at the national, the concentration of materials is first floating Onglmh Z gene expression in general, using a filter protein concentration Tjaria available, for example, filtration unit deceitful Millipore Pellicon or Amicon. It can be included comb. Rrutiaz such as PMSF in any previous Z Alahtoat to discourage hydrolyzed protein and can include antibiotics to prevent the spin-off of pollutants growth. It can antibody combination that was prepared from cells using purification, for example, chromatograph Hidroxl Obapt, Alamichrad electrophoresis, dialysis, and analysis Alkromato Graffy of familiarity 0.0 p fact chromatography analysis of intimacy is the preferred purification technique. Adopt adequate protein A compound Associative of familiarity on the species and type like any Fc domain of Hlopulinat immune exists in the antibody. A protein can be used to purify antibodies that rely on human immunoglobulins which contain 1, 2, or 4 heavy chains ((1983) 13-62: 1 .Lindmark et al, j. Immunol. Meth). (Agherah are routine G z similar types of Giran and Inan 3 (1986) 5: 15671575 .Guss et al., EMBO j). Matrix composite U Cleat be familiar buzz of a Oquz, but all matrices longer available. Allow the collection of fixed Mikhanykl matrices such as controlled pore glass or PU 0 Lee (styrene-Dai Phil) Pazin -mmadlat flowing faster and shorter processing times than those that can be achieved by Oquz. Where Jem counter includes a range of Cm3, is Bakerbond (T. Baker, Phillipsburg, NJ -l) ABX ™ resin 0 guide for purification. Lamas is also the Aryan Q -153- -153-ΜΑ 32948Β1 Albroc 1 n Akhzih such as the Saddle Show me a column, deposition Alaaonol, HPLC developed Exi, Eml 0 / Rmatogerava silica, chromatography get on Kromatur'v heparin ™ SEPHAROSE on Rasnh ionic exchange or Capone ( such as acid column early Osnar'nat) E repeat chromatography, SDS-PAGE, and ammonium deposition major Ne Square; Z palpation 0 m 5 it barely is deduced. Longer any step (steps) purification preliminary, can expose the mixture which includes one of the antibody of interest and contaminants to chromatograph the reaction is endothermic water - Artem pH using separate sequential buffer solution when Hedrugiy number ranging from ho me 2.5 to 4.5; preferably conducting at concentrations of salt low (on torrent money 'Mah burden 0 Aeh 10 Ttr'ouh Z &amp; lt; Wali smelting 0 to 0.25 and lar) · c. Prepare antibody 1) many antibodies reproduction in general, is increased several anti Glades alveoli in living organisms 0 n many injections subcutaneously (sc) or within the peritoneum (ip) to a 15-antigen or material Maadh. It may be useful accompanied generator private antibody protein Mull 0 L "efficiency of the species to be incubation, for example hemocyanin Mokhoun of a major hole in the 0 Haut clams (KLH); misery serum, Gelobolin thyroid beef, or Shatt Tricin soybean Hall Aste &amp; lt; perpetuated as upper 0 1 Chgaq or dual-Alozigh, for example torrent Amitr Malamido Bzuel Sksenemed (accompanied by structural laid Liben); no-Brooks -

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-154- -154-ΜΑ 32948Β1 (Q B units of Jessen), Gelothar aldehyde, hydrides Sksinak, SOCh, or r1n == c = NR, R and urged to be 'No independently an alkyl Bhmoat small 0 Pray examples contained about Almaadh materials that can Amthaddamha material assistance and complete Freund Wei assist MPL-TDM (fat Mono Vosgourl a, Trewazz Dai Keller 5 0 Dermakulat Taklegue). Immunization protocol may be selected by the owners of skill in Khal Ajr'e without unnecessary experiments. Bam animals immunized against the antigen, escorts generator does not; or derivatives Iwashlh d 0 c; a torrent money 0.10 micro gram or 5 0 Kro Jr'm or PRO &amp; quot; Q or Mlkha &amp; lt ;, (of Arab or Algiran, Z respectively) h 3 Hajj 13:00 article Alkhaadh Freund's or injection Alakhlul in Alodi 10 when multiple Muaba. A month later, it is enhanced Alehio 1 with a 0.1 waist 5/1 or 10/1 x 0 quantity, to the original peptide or seen one article fabricated by helping Elka 0 Weapons for Freund ^ '^ n 1 Alhan skin lest 0 Moi multiple. After 4 d 14 days, it is less one of Ahiomat WPM S News of the caliber Alhhami to resolve one of the counterattack. Cm promote Alehio 1 with until you reach the cases Alaszer'r Alzspa 7 Alkhsai Z 0 cm work caliber Mk 1 A deals in Rrah) for one cell to resume a land. Turn Z &amp; quot; Bhatt additional Kazdm 1 c 15 Brocnn. The bloc also like Alpes desperately to Taiz factors; g Ala'tabh performance of 0 0 of 2) monoclonal antibodies are Alharl Z! I. 0 Ghada 1 Hadiv b Z mg 0 light of Z father imported Aktlo fairly Ke, ie be one of Agam Lion; 'Nnrdh Azs 0 Z BTO 0 y burden Tgrat Memkh occur Butkl Tabe 0 me and AUO -medilat 0 nomadic loyalty (D.-for Alale Azra' -155- -155-ΜΑ 32948Β1 the introduction of an amide group) which may ecstasy in small quantities. Thus suggesting unilateral expression of monoclonal antibody to Study where there is a mixture of antibodies outstanding. &amp; Lt; a torrent example, not work Alosam anti mono night Bachkdam way hybrid tumor mentioned for the first time by (1975) 256: 495, Kohler et al., Nature, or it can be made by 5 Ways DNA resulting from the resumption of the genetic link (US Patent No. 4,816,567). In the way the hybrid tumor, are immunized mouse or animal host another convenient, on sales Ahio'n rodent example, as mentioned above to stir lymphocytes that produce be able to see one Zj antibodies that are associated specifically protein used for immunization. Instead, the lymphocytes can be immunized in the lab. Later Hamad spyware is 0 p cells tumor cells Behold medulloblastoma Bashaddam Hamad appropriate factor, such as poly Aithilnn glycol, Kko; n Khaldah tumor - (, Goding, Monoclonal Antibodies: Principles and Practice, pp.59-103 (Academic Press 1986). Includes immunization factor Nmtia protein generator antibody or Mtver merger o · are Ouamh, Bim use either the lymphocytes in the blood filamentous (&amp; quot; PBLs &amp; quot;) if Ashe land exist except 0 a Z 15 human origin, or are used spleen cells or cells I b if S land responded mammalian sources of non-human. later left Hamad lymphocytes with Ψ H live Amdam Hamad factor Mnab, such as polyethylene glycol, to form vinegar; and tumor Hhan., Goding · ress (VtM? &amp; quot; Monoclonal Antibodies: Principles and Practice , AcÉéi.

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-156- -156-ΜΑ 32948Β1 be 0 to 1 for machines Hlaya 1 Beard 0 0 Ouadh righteous Z-except for a TD; Yeh transferred, Ely face Akhdid 0 0% *} tumor Kaaa 1, bless Gu 0 RIP, beef and Shri. Ouadh,, r strains Khalaha Qiaa use of font tumor or lar. It is grown &amp; lt; no ear tumor, which then Thouderi and growing up in Lj Rrah Mgab preferably contain Z and tastier or \ / o wanted one for me Ti 1 i t or except 0 da 'tumor 1 for Haj' illiteracy is' to CDs. The sales example, if k 1 Zt Khala_da Aderm 1C original impoverish the enzyme Hipxantin guanine z ^ Riromta 0 Rasdhaz (HGPRT or HPRT), include the center of the farm to tumor hybrid Nmata pardoned Hipxantv, a 0-soo sur-n; and semolina; n (center HAT), substances that regales growth of 1 to Khalaa to Ahsa .HGPRT the preferred myeloma cells live in those that integrate are returned, Ham-term supports anti-static high-level produced by the meat counter cells that have been selected, and k ^ n sensitive to the middle of the center, such as HAT. Including, Ngdil myeloma murine strains, such as those derived from Ur 13:00 Grand 21-MOPC and 11-MPC available from the Salk Institute Cell Distribution Center, San Diego, California USA, and the cells 2-SP (and Mstqalha, for example, 653-X63 -Ag8) available from the American Type Culture Collection, Manassas, Virginia USA. The description of the human myeloma and strains of myeloma cells heterogeneous murine-human to produce objects of human anti-monoclonal (, .Immunol RO, Kozbor et alM Monoclonal Antibody Production Techniques and the one hee 0 if fy1 \) \ AA (1987,. (Applications, pp. 51-63 (Marcel Dekker, Inc., New York blood Adahjar central 0 1 Mzrah 1 t 0 v 0 m j, Â (Arrm Alhhan cells for the production of monoclonal antibodies monoclonal antibody directed against the antigen. preferably determine the quality of R-es Glades 1 delegation mono 1b -157- -157 -ΜΑ 32948Β1 produced by Alhhan tumor cells by the immune precipitation or by link test in the lab, such as the immune radiation test (RIA) or test enzyme-linked immunosorbent assay (ELISA). can Akhmtbar the center of the farm Olney is the cultivation of hybrid tumor for the presence of antibodies cells anti five monoclonal directed against the antigen required. preferably identify Please choose a quality link antibody monoclonal by immune sedimentation or Boishlh one hot link in the lab, such as the one for the Upper C radiation (RIA) or associated Balazam test (ELISA). this is the technology and Alabr 1 T. Mbrovh in Athal. For example, you can select Please choose a link by analyzing

Special Scatchard Mm et al., Anal. Biochem107: 220 (1980) H · 10 unresolved 0 Ladd hybrid tumor cells that are produced Glades anti qualitative NAT, and / or familiarity, and / or the desired activity, can clone a 7 Il μ 0 visions Boishah 1 limit z Ame't Altkhvpf can grow PO through standard methods ( Goding, supra). 1 among the farm include PSAT Lhz one purpose, z torrent example, the center of D-MEM or 1640-RPMI. In addition, we can grow Alhhan tumor cells in Ovem seen in the image tumors in Ka'n mammal 0 15 are Fml Glades Mufadh supported "the August that was Afrazi Bo'sth Abel August to one convenient form of central ale ^ E 0 Aia ascites, or yolk 0 for by Ad'e b 0 Taiwiopt traditional Hteiq, such as protein-Searoze 8 / and Matogerav Brook 0 d Aba &amp; quot; six 0.1 to Amichard Alkahrbana gel 0.1 to Dazh, or Algsal chromatography of the Nation 0 -158- -158-ΜΑ 32948Β1

How can one work of monoclonal antibody produced by DNA Z worm ways a land. &amp; Quot; genetic es, such as those Almnkurh in US Patent No. 4,816,567 and as 0 and has since / t Oelah. Are isolated DNA encrypted for antibody monoclonal -Your and &amp; quot; Dallah Bamthaddam conventional procedures (for example, using the bars Koleilat 1 Liu Kluotad 5 appreciate 5 to Alaratat specifically genes encoded heavy and light chains of antibodies 1 pad Typhimurium). Alhhan tumor cells act as a source Mgdil DNAJ, .mmejrd Ezlha, · 0 Ekn .DNAJ put in the vectors of expression Alzh, which are later transmission referred to in 1 Hlaya family such as Escherichia coli cells, individual cos cells, cells Mbhi Hawwan a Chinese land (CHO ); or cell tumor medulloblastoma do not produce a protein Geloubeyolinat immune to Tkhaltq objects 10 1 Kadh mono-0 in this family AAC cells 1 Tjh Y with one quality of a land. &amp; quot; duck genetic 0 Yesh 0 for AST 0 satisfied one of the articles about prisoner Aozh Almatj p worm 1 to fasten one of Jenny in Bmutair-a DNA Olathe 0 unawares the- .. 0.1 'counter on (1993) 262-256: of, Skerra et al, Curr. Opinion in Immunol (1992) 0: 151-188 .and Pliickthun, Immunol. Revs. - In one! Other Nmang, can isolate the Glades Akadh 0 n b 6 Apt 0 to Ilaya McCafferty et al, Nature, 15 cm 1 for anti generated Bastkhadd 13:00 A 1 Chat mentioned in Marks et and Clackson et all Nature, 3 (1990) 554-552: vomiting. Ste (1991) 628-624: vomiting isolated murine antibodies and Alepeshrla, &amp; lt ;, al, Mol t. Biol, (1991) 597-581: fry Akowaly, iPad 13:00 group sequences to cells Mmelthmh- describe subsequent Algtherat production Agam

Marks termination al,) lu. Anti-human Eolah .lolvh (0 de 7 a Rlar) Rak I and Oevia Altit fusion and try Alarkat 1 Gyi, (Bio / Technology, 20 (1992) 783-779: I -159- -159-ΜΑ 32948Β1 in vivo as a way to create a group sequences cells 0 accused Aq Jet 1 (Waterhouses (1993) 2265-2266: No ,. Nucl. Acids Res,. / 0). automatic; is 0 this Heat Bd'il Ybla to Ktb 0 Z technologies tumor Alhhan to curb anti mono Eshidiya August Alohussam 1 Kadh monoclonal 0.5 can also be amendment IaJ for example, Bo 1 middle replace Mud 1 No 1 Chgar fixed ranges and heavy Khviqh Alpmthreyh series instead Q sequences lin; Yeh 1 Azerh (reading Alaraa Alorakih No. 4,816,567; (1984) 6851: a 8, Morrison, et al, Proc. Natl Acad. Sci. USA ) or by connecting all or part of the sequence encoding the poly peptide E 1 t Geloubeyol ;; j 0 Tea Epeshkla covalently .mmtwalah Ttver Gelopuliiat immune. The poly replace strain Z JLo 0 Pulia 0 to Seychelles 10 energies Althabh deductible counter, or are replaced by bands changing signed Hamad V d vs 0 and one for body Anti synthesis antibody Khemara divalent includes Rukh d 0 c hook against its quality and location of the generator against Hamad generator against another quality of the generator against various &amp; quot; Antibodies may be monoclonal Almnkurh in this mono Altkaha innocence, it is known in the preparation doubtful. The torrent example, one of insomnia &amp; lt ;, include one Kaabar Alrr'na 15 per- for the resumption of the genetic link to a series Khgegh immune Geloubeyolinat heavy chain and a modified 0 in bowl is amputated heavy Alllh at any point in the Fc region commodities link Akeshakhmo heavy chain. Instead, they can replace the building blocks of a Sstnn 0 for private Rahd't Bnabh to another amino acid or is deleted to prevent Alarabat Alchapki. Roads is also father of suitability for the preparation of monoclonal antibodies parity. It can digest antibody fragments Alag 20, specifically Fab fragments, using conventional techniques in Mbrovh Anhal.

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160- 160-ΜΑ 32948Β1 also can be prepared antibody chimerism or August in the lab using a wineskin m / loofah in synthetic protein chemistry, Mtdmia to include those Alchapki correlation factors. In the form of example, can be created by using a binary toxin immune sulphide exchange reaction or by formation Theo ether bond. Alohlh contained include Alkashgh on appropriate materials for this purpose Zmemino Theolat and 5-methyl-4-Mrkpto Biotir Dmmedat. 3) antibodies are compatible with humans Ka Yum 0 Be antibodies include the Agiraa on anti-radiation anti-human or compatible with Escher. 0 images compatible 0 p represents human antibody non-human (the torrent example, Akorah) in immunoglobulins chimerism, immunoglobulins or fragments of them chains (such as 10 Fv; Fab; 'Fab; 2 (' F (ab or other Allantkh to link generator Allenbd objects anti) containing Jp lowest grill derived from Geloeulen immunotherapy is a human. include antibodies compliant | mention z Geloubeyolinat immune human (Jassam anti future) where Aspdal building blocks of complementary selection area (HVR) (CDR as used in this patent) the acceptor by the structural units of CDR types G1 t human (g Anti 15 0 brother) &amp; lt; a mouse, barn, or Alorb containing the required quality, and familiarity machine. in some Aaala 0 t; is Ambdal units of the building of the structure of human Hlopulinat immune by Ashe 0 scourge of Abia two non-human Almnafflerh. as &amp; quot; possible that the antibodies compatible 0 p of 0 include the evil of E 0 Lei building blocks do not Iojd in El Jem counter for the future or in the CDR emulsified or sequences structure. in general, the antibody includes Alo's with needles Ap largely on the 20 every 0 n scale Mtver at least one, and Taqan Nmtia, broadcast corresponding to each or all of the pretty -161- -161-ΜΑ large 32948Β1 regions CDR those of the immune Paljlopulinat human Ghr the all Z or all largely Z regions FR in those special, Mmtwalah identical Tmaia immune Hlopulinat. The antibody includes compatible with humans to show a little, at least from a fixed area of ​​immune Geloubeyolinat (Fc), a pattern that alopecia Paljlopulinat human immune. : 321 Jones et al, Nature 5 .522-525 (1986); Riechmann et al, Nature 332: 323-329 (1988) and Presta, Curr. Opin (1992) 593-596: of. Struct. Biol. The consensus of non-human antibodies 0 p ways humans known in Khal. In general, the antibody compatible 0 p humans contains one or more of the building blocks of the amino acid which entered the non-human source. Usually done Alacharh B units to 10 amino acid human Ghr on God and building blocks emulsifier, derived pattern of the band Almtver &amp; quot; emulsion &amp; quot ;. You can conduct compatibility 0 p humans mainly by following the method of Winter &amp; Co., -323 :. Jones et al., Nature .522-525 (1986); Riechmann et al, Nature (1988) 327; (1988) 1536-1534 :. Verhoeyen et al, Science, or through made using rodent CDRs or CDR sequences instead of sequences corresponding to resolve the anti-human. 15 Thus, the antibody is compatible 0 p humans in antibody chimerism (US Patent No. 4,816,567 .No), where he was replaced less than a human scale Mtfr properly by successive Almnachrh of non-human species. In practice, the antibody is compatible with the pattern of human antibodies in human anti where some units are replaced by the building CDR and some units of the building FR Bannabh by units from the corresponding locations in 20 antibodies for rodents.

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-162- -162-ΜΑ 32948Β1 The choice of human variable ranges, each of Alhvigh and heavy, to be used in the work of antibodies compatible with the evil Jana important to reduce antibody formation. According to the most appropriate way ', it is examined succession Alntata Almtver to curb anti-rodent against a total sequences of human sequences Mtfihrh Alntaly known. Later it accepted human successive Alorb to those Alopecia rodents as a structure of mortal (FR) to curb anti-compatible with humans. , Sims et al (1987) 196: 901, Mol. Biol RO, Chothia et al; (1993) 151: 2296, .Immunol SAL 'serve other way specified structure is derived from the sequence matched Tmaia to Jmaa objects of human anti Q a specific subset of Alkhvagh or heavy chains. You can use the same structure for many Z antibodies compatible 0 p Almokhtlgh humans. , Carter et al, Proc. Natl. Acad. Sci. USA (1993) 151: 2623, .Immunol SAL ..lm 0, E 4285 (1992); Presta: Ge. The Oevia consensus antibody p 0 Mehta humans is by maintaining a high familiarity of the antigen and other biological properties. To achieve this goal, and Ovia of one of my favorite Firecracker, does the preparation of antibodies compatible with bitter by the process of analyzing the original Mtwayat and Shat compatible 0 p humans cognitive Nmang fabricated using a three-dimensional sequences from 1 to Osah compliant 0 p bitter. The Nmang immunoglobulins three-dimensional code in a common and familiar to owners of skill in Anhal. Alahab automated programs that show presents the formal mechanisms of three-dimensional sequences immunoglobulins candidate is purified. These operations allow for analysis of infant Amehtml role of the structural units in the recruitment of succession immunoglobulins Arahh, ie, the analysis of the structural units that affect the ability of immunoglobulins candidate Z linked to the birth of what the private antibody. In this case, you can choose the building blocks and integrated FR -163- -163-ΜΑ 32948Β1 of the ways and Lavaux 0 1 1 bit of emulsified Bgess 0 1 Athgaksmat rein in Assad Tlobh, &amp; lt; Increase! For intimacy for MOQ 1 P (MOST 1 antibody) .lmstahedv. Der; Ouamh 0.0 Ham 0 Ddman mud 0 s August 0 by CDR .0 cercus and Zly greatly influence the Artat 0 Nike 0 antibody 0 'from one of the unexpected presence Mokhtlgh images of the body I barely Almtwah 0 p Evil 0 z i example 0.0 Bmcn be! Body! Get Almto! Vq 0 Aalepeshrouarhenczihjsm Anti 0.0 such as Fab 'to the blood seen! jurisprudence is 0 Optional with and! extent or ACSH Z Awa 0 for 1 for the nation p Doadd Mitr'vvy Tea 0 instead, it can be! body 1 of the Anti Ato! Vq 0 p 1 for humans libra Ens 20 Amadadslam, such as bridles anti IgGl painful. 4) antibodies mankind as a substitute for compatibility 0 p! For human beings, can -ord Assam counter b 0 Z E example 0.0 now possible Zzj Ahiomat mutate and heal &amp; lt; Ely torrent example, mice) capable, when vaccinated, to produce the glory Ka 0 for 0 n | of Assam Akadh rich in the absence of domestic production of immunoglobulins I. Z · il example, has been and Assany that Alhanaf Almottagad gene linkage area of ​​heavy Aceh meat counter (JH) in the mutant mice 0 n strain traction; Mieh to Althbyt Elka 0 for harmed c Adam counter internal origin. A turn Jane To any z ^ bit Ί Jrthomhh Dred in food-Ran Ta &amp; lt; Jeroobh of the strain to produce human antibodies when testing anti antigen. Langer, for example,, Jakobovits et al, Proc. Natl. Acad. Sci. USA (1993) 2551; Ha; (1993) 258-362: 255, Jakob.vits et al., Nature;, .Bruggermann et al -164- -164-ΜΑ 32948Β1 (1993) 33: iYear in Immuno .. î overland, only data Alanmaa / .da Nran Alorlam 5591669 international demand RFM 97/17852 WO. Instead Y, the .memkn a 0 da J trauma except 0 of 0 B to Akaj objects 1 to counter one wild and 0 Chglaya 1 Agam 1 Mgadh in one of the plant, from the records of the substance of pelagic z Globe 0 for the same (7) Z ZZ Iasnin. Hoogenboom; (1990) 553-552: Qz Nature, 04 G McCafferty (1991) 381: 227 .Mol. Biol -r, and Winter. Ozi this Heh, the blood of one fraternity c 0 Yt Ihlaq Dad 7 in the frame in either gene protein Rabbani proceeds 0 J or Madhua to exception-da August for the air-a nematode, such as Μ13 or fd, and displayed cultch r Mgad Y Z Dh c 3 .lmmelthmh cells. Where .lchim contain Heer 0 Z DNA Benefits &amp; quot; No, Ed-Ah Q c 0 Rum 1 Hlaya macrophages, &amp; quot; lead 0 acquitted by a dam on the functional properties of the meat counter to the selection of the gene encoded for meat counter, which  these 0 Bras. Bakali, Tha /, MySQL August D R. 1:00 cell B. not take RIP ornament macrophages Almokhtlgh many forms, which in the name Asradha; z sales example, Curr. Opin E.l Johnson, Kevin s. and Chiswell, David (1993) 3: 564-571 .Struct. Biol. Can be made using many sources of parts Almokhtlgh Jane 7

Infants Allthmh cells. Singles (1991) 628-352: 624 Nature 1.Clackson et al Mokhtlgh matrix of Glades 1 Kadh for Ooxazulun Mahmoah of random sequences or genes Sfenrh V - Z spleen Algiran that was incubation. You can create dragged seven of the genes of the donor z z 0 evil Anhsnin Rimkn isolate antibodies Mokhtlgh matrix of antibody generators (Mtdmia generator self-Ghad) generally follow Almtqanyat Almnkurh by .j. Mol 1.Marks et al -165- -165-ΜΑ 32948Β1 (1991) 222: 581-597 .Biol, or (1993) 734-12: 725 .Griffith et al., EMBO J. see Oania, US Patent Nat numbers 5565332 and 905 of 5573. The Oevia do techniques. Cole et and somebody has 0 Boerner et available to prepare monoclonal antibodies and human monoclonal antibody (, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, .lmh Cole et (1991) 86-95: 11) 147 .j. Immunol ..lmh p. 77 (1985) and Boerner et). Z A similar, -cfs prepare human antibodies by entering the human immune Geloubeyolinat sites animals Almtehorh me and Ray, for example, Algiran where inhibition of genes immunoglobulins endogenous partial or Klia. When the test is, are observed human antibody production, which is similar to a large extent that it has seen in humans in all bursa, Mtdmia gene re-arrangement, the antibody and Altbah record. Is described this way, for example, the procedures US Patent Nat 5,545,807 numbers; 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,661,016 and in the following journals: -779: 0 of Marks et al., Bio / Technology (1992) 783; (1994 ) 859-856: 368 Lonberg et al., Nature; -812: 368 Morrison, Nature Nature Biotechnology 14: 845-51 (1996), Neuberger, Nature, .lmh 13 (1994), Fishwild et -65: Say .Biotechnology 14: 826 (1996) and Lonberg and Huszar, Intern. Rev. Immunol (1995) 93. Okhanna, Oifta can generate human antibodies in the lab by anti-activated B cells (Langer procedures Nat US Patent 5,567,610 and 5,229,275) numbers. 5) antibody fragments -166- -166-ΜΑ 32948Β1 in Maevh cases, ecstasy advantages to using fragments Jem counter, unlike Glades 1 whole delegation. Wheat Ohham fragments Elsafarh liquidation terrible, and could lead to the arrival of yolk 0 n solid tumors. -taiwir Been Tviac Mokhtlgh Khzaaa to produce the antibody. Traditionally, it was Aiav this Alchglaya 5 through digestion case of protein antibody painful (see, &amp; lt ;, μ, for example,, Biochem Biophys. Method 24: 107-117. (1992); and Brennan et ai's, Morimoto et ai ((1985) 229: 81 Science)., 0 GS, the _memkn-term this one Saa directly Bo'h cells 1 to the family of one of Matjh all with one quality of a land. &amp; quot; Bhatt 'to Jenny. can .ltobeir Y Z 0 n Shatha-a \ μ 1 CAD Fv, Fab and scFv and Ratha in and not take E. &amp; lt; Azha 0 n Aichirt E. coli 4 jj 0 Mmah '1 c 10 0 for Atahi large amounts of this one to fragments 0.0 Bmcn when for Hzada palpation 0 m counter Q Bh 0 R. sequences omnivorous cell of the body 1 of the Anti Mnawh above. della Z so 4 0 Bmcn &amp; quot; p 0 fragments Fab'-δΗ including 0 Wathrah from Aagarh 0 of E. coli and-Ekn Anray ς7 m &amp; quot; Q Gza 0 2 ( 'Carter et al., Bio / Technology 0: 163167 (1992)) F (ab). Thi to one of the other Lahr s 4 can Azd 0 Tzaaa 2 (' F (ab 0 cercus 0 n Rri trotting family Lalai Z TAWD 5151 to link one to Jenny. is described Fab and 2 ( 'F (ab Zadeh in GnRH DTMF 0 Ala 0 R in R-R in 0.1 cent hottest 1 GS Alohrkh RFM 5,869,046. in other models, the Adam counter that name one selection Ouarh for Dr. Fv a ^ 1 de Study (scFv). see demand Cooley 1 RTM .W 93/16185; the righteousness of one cent Alachter 1 GS 1 to Osaa No. 5,571,894 behind Asa Lahr 4 &amp; quot; S 0 5,587,458 for. In as 0 to j d additional 1 FD Barr 5 b Z Z Z Khhli

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-167, -167, ΜΑ 32948Β1 Ssilakal, Yhotklrphipprah Alachter'a Alomreierz 0 of 5,641,870. 0 Ekn be Chg 7 Aa.ljsm 1 Mgad'kti unilateral one of Uah or de 6) Elaj Egar initial mm in Hdoth'landzim j 0-term z additional Assad can Oehta Astkhadd 13:00 objects S 0 for Akharaa Made in ADEPT * \ A 0.0 s Table 0 m Almmad Bazzim Cht s 1.1 for the initial | the one who turns an initial (z E 1 for example, as upper &amp; lt ;, r ke 00 avi Tdel, a &amp; lt ;, international demand RFM 81/01145 WO) to an effective anti-drug because of R. 0. Azhler nest master of one of the example, demand .ta Rzm 88/07378 behind one of the invention Urdu RFM 4,975,278. U 0 for Alazz Created &amp; quot; Bam CZ 1 Vq.baa 1 Moghaid ADEPTJ &amp; lt ;, any enzyme Dader &amp; lt ;, persons Z initial drug that converts into the toxic image of the cell 1 to ACSH effective. Useful blastulae include the method of this invention, for example DDS summarizes, &amp; lt ;, Gelokosidaz, glucose oxidase, to Azzouzbm Shri, Ichaelrob 0 BL human, Olcalzn Fumvattaz useful to convert initial properties contain phosphate to drugs free; Arles late useful to convert an initial drugs containing sulfate to drugs free; Satosen to Aamnz useful for converting 5-Floro Stosn nontoxic to the drug anti-Rtan 5-Floro Rrussel; proteases, such Serai protease, Tarmolcn, Stellesn, carboxy Beptadaz (on ways instance, carboxy Beptadaz G2 and carboxy Beptadaz a) for the Kayiban (such as Kataatsn B wa), useful for the transformation of primary real estate that contains a peptide to drugs free; e-Alozl carboxy Beptadaz, is useful for the transformation of primary real estate one I Kaddoa on Amtbdal groups -168- -168-ΜΑ 32948Β1 0 to Hmany 0-Omivo; Azz-devitalized as 0 clever Alkrbohal 0 Rat such as β- Jlambrosidaz and neuraminidase useful for converting primary Paljlecosl processing real estate to estate 0 Rh; β -laki what j useful Khoil Assarat A- Bo 1 middle β- lactam to drugs free; and penicillin amidase, such as Bveselyn Wamydaz or Z 0 Meilen G a 0 Adaz, useful for converting Almmttqh real estate when Natroyjanat Secretary what own by phenoxy acetyl groups or phenyl acetyl, respectively, to drugs free. Instead, you can use the antibodies that the enzymatic activity, Almrovh Oevia in Amehal, as antibodies Hgxih to convert the primary real estate of the invention to drugs effective free (see, for example, (1987) 458-457: 328 Massey, Nature). -memkn Prepare Mtravqat catalytic antibody as described in these opinions to send the body to one Tad catalytic Alrrmah cell group. Almnkurh enzymes can be linked to the above is an international Tas peptide or 1 to 1 Agam delegation Almnkurh in this Alrah by Almrovh techniques such as Pam Amehal 0 6 hope-a land. Bhatt .lchapki bilateral Alozigh heterogeneous Almnkurh above. Dalla Z that 0.0 Ekn as 0 W Daou ^ t Alazdmaj which include linking generator 1 tomorrow Ely persons H 1 area almost the Akht'a A; Tbth effectively part Epeshkd and Zid at least Arim Alakht'a Assad'm Tviac 5ΝΛ any of the ~ Uhde a land.-Bhatt. Jenny 1 Mrovh in 1 shops (see, Z E money 4, al Ee Neuberger (1984) 604-608: 312 Nature). 7) bilateral antibodies quality and multiple 1 Uah -169- -169-ΜΑ 32948Β1 7 / - [) .losam anti bilateral quality (BsAbs) in Alosam counterattack. To &amp; quot; e Ptuaat responded no, #NAME least Nest z peaks adhesive Almokhtlgh, Mi 0 Talh t r LaRouche or another routine. Instead Z, it can be linked to Nraa and Ahd.mmold antibody Afahadv, and 0 as possible Dh Nraa R Dhar; p 0 correlated molecule running on a white ball like molecule 0 Thbl F A (Russell 5 0 Thal, CD3) 'concentration and the concentration of cellular defense mechanisms Study F sticky one Hrah AM 0 born He 0 can Ashakkak this Alosam counter of Adam anti Kah one level or occupied the post-a and 0 antagonist (for money, bilateral antibodies Auriga 0 Vision 2 ( 'F (ab). K. 0 of walked Asnhaddam bilateral antibodies' to the quality of Thmrkz Wadhwa 0 for any P cells that 0 express and Ray z antigen Almtahedv.thtoa this Glades 1 delegation Z Nraa Wade 10 connects the antibody generator Almallo 0 b and arm wa Art worker of 19:00 7 trait &amp; lt; Ely 0 sales 0 for example, Zrran; Anti Anrverov a, FINCA colloid, Mellh R.sin a, 0 Z 2 Hhsad FcgRIII (0 to request Azdola Ram 96/16673 wo) '0 Gadd FcgRI ïU * lEvbB2 (Raz Alanm'a 0 to Omraa No. 5,837,234), anti-CD3 ^ ErbB2 (patent Alaraa Aryan Wareham 5,821,337) 0.15 CAD methods for preparation of antibodies bilateral quality Mrovh in Amehal · Ih 0 d 1 to Azj S Lalla .jam 1 to counter Tgaiah 'full-length to the quality Z Akaabar Eshr'h 1 Kirk to Zuahan Eqil Alllh / Khgev 1 Study Susul; n s, b Cove - Aauhat Q' (1983) 30: 537-539, Millstein et al., Nature. As a result Category Ashoana heavy and light ESL immunoglobulin, are produced these 5 hybrids tumors mixture hinted 0 L x 0 a t-Zt -20 of the antibody, among them have only one bilateral Alinh Laalou; correct 0 be I t 170. 170.ΜΑ 32948Β1 1 correct molecule, which has been conducted by steps already Algsal chromatography of affinity / Ehgh, and Dkon low Almenth ways. The detection of similar actions in the international application 93/08829 wo In Ram (1991) 3659-0: 3655 [, Traunecker et αΙ., ΕΜΒΟΙ.

According to one of the terminal Almokhtlgh, Hamad is variable ranges antibody binding qualities required for 1 &amp; lt; Hamad sites antigen antibody), Mmtoagliat scale fixed for sweet Pioline immune. Preferably integration constant scope Tgal chain Hlopulin immune, and includes at least a portion of the articulated Maftqh, CH2 areas, and CH3. Preferably to found heavy chain constant region (CHI) Olney contain too much fun connecting Alkhvagh series, in a Alandemahat at least. DNAs are introduced Almtfr heavy chain of mergers Hlopulin immune, and if it Astzm, Alkhvagh chain Hlopulin immune vectors Altabnr Arrash separate, and are infected her jointly in the host organism appropriately. This provides great flexibility in adjusting the mutual proportions of the three peptide fragments of polyethylene in Alnmang LACK Torre ratios is equal to the three hope urinary peptide used in the construction Alnoakh Almh. However, it can enter sequences coding for the branches or urinary collecting three peptide chains in one expression vectors Alzh when Alzh expression leads to at least two Mlasl Arola Itid equal proportions to the results as high or when they are not big Alfb. In a Alnmang favorite this way, antibodies are Tnabh 1 Dhueah Z IL heavy Gelobujin immune Hhan her quality Ardat first in a Alonra, the husband of 0 yen LL shop 0 H Mellh Khgegh to Jrabeulen inevitable Sun (Lior quality confusing seconds) in Aldhir'a R 'found 0 that this Charisma is Alemtemath touched composite dual-quality desired Q separation Tolhgat LL -171- -171-ΜΑ 32948Β1 1 to Geloeulenabas Gararupb 'b-RIP and 6 Ddlaod 0 to Alade 0 days 0 Teyvi 0 row referred I Q Alhuzeiia 0 bilateral quality easy way to washing 0 is detected p this Alri Ne bristles but 0 Crown RTM 9404690 AijJl .wo p Ashish's 6 0 0 Adam Dube milk Azzer, &amp; lt ;, Ethel 4: 121 Suresh et ai, Methods in Enzymolosv Mfmmadh Tnash Alrah E ... Ed (1986) 210. Rack not ^ Z 0 I 0, the other one for masculinity j 0 to request one Cooley RTM 96.7011 WO Ed reading Alahachaa Aloaaa RTM 5.731,168; can Salja loyalty 0 h Ebi z Nog z h-It the IPA Oooh 7 d; August parental the Daemrat is applicat any been Maha p farm Study p. 0 recurrence of a land.-duck literary to Ed 'for S-del S states of ESL Eraz, Eralolsud CH3 fitting for 0 s Hi SV Al 0 Aldikh, including a 0 instead and, Ed; or | cr z Wallach Gaibah H exponent Ed; /, S Ed 0 j &amp; lt; Joel, , a lion, for the first baskets for E 0, j uh &amp; lt; Ouay aluminum Q '' Eds Ed D_ptoyn). Done Takbak &amp; quot; Tj, In &amp; quot; 0 C I r equ I 9 &amp; lt; Ola 00's; loaned; folding Anh RNAi molecule bridles of the reported Lalani Bdat Mal non 0 for any Saao; Atmb (S. Chall cited). Q Laz of 0 0 of; Ilyamadsdhestabllosyeira; Upb like Aldaamrat is Altjansh. Htm Osev At Jupp Aloim newcomer Tala irrigation 0 0 n-occupied the post of the SS in the ESL · z 0 i waffle, not only incite 0 or newcomer; 0 Zbh Atmi Sd'm pioneers Y.a. F. Brennan et ai. Science 229: 81 (1985) λ to result &amp; lt; 0 'of Bam LL -172- -172-ΜΑ sound 32948Β1 in the case of protein to generate fragments 2 (' F (ab. Is reduced these fragments in the presence of as upper 0 complexity Dai thiol's is sodium firming Feminal Dai thiol laid flashed configuration Q 1 E sulfides within the molecule. later fragments' Fab that has been generated to Eadso Nero O't (TNB) derivatives later was re-convert a derivative Fab'-ΤΝΒ to derivative Fab'-ΤΝΒ for Taku. ; n 5 Jem anti-dual awareness. can Amthaddam Glades anti bilateral Aldhub Ashe was Aijha agents to install Alantghani enzymes. can be extracted fragments' Fab directly from Aachkrchia E. coli can be peers Kimpay Ku-n antibodies bilateral quality. describes (1992) 225-217: Qto .Exp. Med SAL, Shalaby et al production of antibody molecules Tgana quality compatible 0 Ta humans Tmaia 2 (F (ab. was Azaz all Dt ^ 10 'Fab problem of Mngdil Z Aithirxia E. coli and are exposed to the separation Alkemiaeda in Waddle to form Lean counter binary quality. is Jem counter, Tia Aluah formed and his father 0 Ely Allat that cross-ray excessively about the future, ErbB2 and blender of regular human T, and Odz run analytical activity of the cells of the lymph toxic for the cell in August 0 Harih Z 0 d Akkadian as family 0 k 0 a is described Mokhtlgh techniques to prepare and isolate fragments of objects Akadh bilateral Akkava tumors Beshrh 15 Z implant resulting from the resumption of the genetic link cells. The torrent waffle 4 is Anaj parents &amp; quot; Rat good bilateral Acansh parity using Bbtdat link to Lucien. , Kostelny et al, j. Immunol (1992) 51: 1547-1553) 148. Been linked Bbtdat link to Lucien from Pro &amp; quot; bit Fos and Jun parts' Fab for two antibodies Almokhtlgh by fusion gene. The Athleel AKA &amp; quot; Rat Almthans. The resolution of the counter when Aceh A- ^ Den .rnorat then vilified Aouadh Oksdiva tack ^ 20 yen parents &amp; quot; Erat is Almottagash antibody. Bilateral A'alosam mentioned technology provides Boatq -173- -173-ΜΑ 32948Β1 (1,53) 6444-6448: 90, Hollinger et ai, Proc. Natl. Acad. Soi. USA less b-Tal Dd Hzaa 0 m 0 Mhmad I think Alau 6 / AKC Levy, of. · Μ, I, Z Zhlaq &amp; lt; of 0 to 1 for God (Vh) linked blown 0, Hl Ba 7) Boishla rad Klljmabutla Ih Balazdo 1c between Aihlaven ZZ 'Guide 0 · automated blood of the warmth of the S &amp; quot; 7 d' 7 5 for a Alggalay 0 for Azdo | c Olztaguen VL and Vh for the meteor to Isy, Z Dodi Ely 0 0 Kdln refused to link the park against. The description &amp; lt; 0 Yi ary code 0; Hzot m I 0.0 Til Ka / night AKC 1 is Ü hope Dabrat Q, a S (1 .Fv (sFv Zzer SAL, a &amp; quot; b0r et al .Immunol, 152: 5368 (1994) of 1 Koha having a 3 Yum counter I Wacker 0 n Tkavin. Z i example, Lash Z 2 Sam -Tutt etal, R. 147: 60. Immunol (1991) 10 anti triple Aldhueah 0 walked linking | to Agam AAC 1 quality illustrations bilateral de Bakmtin contact lenses Mokhtlgtin on a specific Re. instead Q, it can Hamad Nraa anti-protein arm linked Bhuzeie Akz z

Plight 0 such as acceptor part of the cell T (the torrent example, CD28, CD3, CD2 or Β7) 'or receptor-Fc d F9R) IgG), 0 such as CD64) FcyRI) 4 CD32) Fc2RII) and FcyRIII 15 (CD16) Rk 0 g suppression of cellular defense cells that cross saw her for protein Anhdd. As Lash added Sunday, 0 or AAC 0 birth Tnaah quality of concentration factors Anamh cell cells Ashe v 0 Aer Ray for Bruin Set 0 this Glades anti contain Nraa linking protein and arm 0 Lrt Eoml Sam B or .rkp grapple from Yukluotad Atmaai, such as dota, DPTA, EOTUBE or TETA. 1 connects to curb anti dual-quality protein of interest other of interest and Drt

20 O_t tissue factor (&amp; quot; (TF

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-174- -174-ΜΑ 32948Β1 8) polyvalent anti Alosam polyvalent antibody may be affected with a 0 internal format (Rao Yum Thagweidah) faster than the antibody Tgaia parity by cell expressed and Ray Z Mull 0 antibody associated with anti Glades. F can be Glades anti present invention is a polyvalent 5 antibodies (other than those of the Bakh IgM) What three or more sites linking antigen (eg, Assam 0 antagonist Rbaah parity), can be produced Charge by expression Alorani output r resume Alaratat Abaaa DNA labia chains urinary peptide meat counter. It can polyvalent antibody includes Ntafy switch to Dagat and Eladh or two linking many of tomorrow's generator sites. Scale shift to include Daemrat Amodil (or be /), Z 10 Oomntqh Fc region Mgmlah. In this 5 case, antibody includes Mzthh Fc-machine or more z bind antigen sites on the edge of amino region Fc, includes Adam 1 FD polyvalent Amodil in this patent (or Itakern of) what ranges from 3 to Delly 8; shower omits 4 , connect the generator against the sites. Multi-antibody includes Altka &amp; lt; Z H poly peptide and one persons (preferably poly peptide) two series, where x 0 for IL &amp; lt; chains) 15 urinary peptide on two or more Alguetaqat! To variable. On asset Athale -cfs that u 0 for an advance (chains) urinary peptide on VDl- (Xi) n-VD2- (X2) n-Fc 'where 0 fact that his 7 Ebalh scope Mtver up, and be VD2 a Mtver Dan scale, and be Fc Dz pp poly peptide chain and one of the Fc region, and represents XI and Χ2 Omzna acid or poly Bbbd, and Ecot &amp; quot; Brhensgroo1.dsl 1 to Thal, IL _imr can (lar) Polyurethane ^ Ely: 20 IL VH-CHl-Fc region j 1 Peter Ryan VH-CH1; IL î 0 Lacquer - VH-CH1-VH-CH1

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-175- -175-ΜΑ 32948Β1

Fc. Preferably polyvalent in these views &amp; lt antibody includes Aelonn ;, &amp; lt; the persons (preferably four) of poly peptides scale Mtfr Khgev Coterie. -cfi that e 0 for additional anti polyvalent in this patent, for example torrent; Z 0 of Draouh Q is about 2 to 1 ho me 8 poly peptide 1 T. Ztaq Mtver Khgev Aceh. 0 Tut's Adola Bhdat 7 Tai monastery Khgev 1 Study 1 for the unexpected T. Nalaq .tver Khgev Coterie, and in news 0, o 0 for Oevia the CL range. 9) antibodies to facilities heterogeneous Glades 1 located to counter of 0 accompanies is one of Mottagazs a-also in Alaraa S 'not be the' M 1 to counter of 0 accompanies is one of Mottagazs Z Atnnn Z 1 for anti-radiation oxidation of; -0 cent are 0 Tas 0 z 0 pannier 1 Thal, can Aguetr 1 P A 0 end-term 0 or 1 Kadh in Anras Z Akhac Bovid 0 Ane and R Sotnn. The Agherah this one to Agam one delegation, from 0 torrent 1 for money; for Stahed 0 P Khala_da 1 device S for except 0 a Gtho 0 to undesirable, 0.0 cent Alakhc 0 p Urdu RTM 4,676,980; and Dlaj 1 Pui HIV. Altab milk 0 Crown RTM 91/00360 Wo, demand Andolee RTM 92/200373 WO father and one of the European RTM 0308936 EP. P 1 Almtautam these I Z for any one ascend in the S Aikhadda 2 Alhlerq Almrolo in my Albrday Cdb 0, I 0 Tk Ashe age of a land. Edaml-duck Aazah. I sales z, x sector 'ace Father Q 0 m' Lad exchange 0 J. Mahdloboata-Kdanrabottlh; -r-Slalomaradd; 6 Sep I wanted a 0 A z .ar Rlat and .gl-4-achievement -ooa Db't D-P S m So.eayt waffle 4 J T, E; Alanm'a only / Yi Rzm 0 of 676.9 4 'spray Ha z y iPad, m: j r dl only 4 Bhatt Ski' Lhasa. For 0 d 6'l -176- -176-ΜΑ 32948Β1 Alarabat Alchapki appropriate Mrohh in Anhal, and are disclosed in reading Lahraa land ^ No. 4,676,980, in addition to a number of Alarabat Alttopky techniques. 10) functional treatment of 0 tendon might Q 0 term land modified antibody of the invention with respect to Bozigh tendon Fc, for 5 example, to an infringement (for example, promote or get rid of) Shih cell that contributes to the occurrence ornament 1 that rely on F (ADCC generator) and / Shih or 1 to 1 Ornament me simmering 0 z 1 to complement (CDC) to curb the counter. In a Alnmang favorite, it is reduced and Zigh strung Fc antibody for PD.L1 or the basis of it. This can be achieved by the introduction of one or eat Z Mjmuat Alasenbdal acid! Amini to the Fc region to curb the counter. Instead it or Z addition 0.10 ^ can Ed's unit (s) in the building of the Sistine Fc region, I shoveled lead to Petco; n Association of apolipoprotein D 1 sulfides within 1 to Dth in this region. May have to rein I barely father Emari 1 1 D that has been generated an improved ability to influence internal and interpreted by any increase each

1 one who BASIS 25 per occurrence complementary and fulfilled cellular wounds Jem Al Akad (ADCC). ate . . B Caron é176: 1191-1195 (1992) and Shopes, P 15 (1992) 2922. Z 0 possible exhorted; 0.1 to Agam 1 Kadh AKA »Dah 1 Mjavh eating Z Zhat anti-tumor lion; m Rowe 1 Pet Tech 1 Bugeh Enabh Alozigh is 0 and p 0 males J (1993 ) 53: 2560-2565 al., Cancer Research production Wolff. Dalla 0 n Zq '0 possible de Gisele's 0 mg 0 0 as upper and Ed have done Dtguetnn Fc and automatic HD Cove 1:00 0 0 x 0 m reinforced Wa ^ with

Stevenson et al., Anti-Cancer Drue Design 3: 219-230 (1989)} 'Λ .ADCC.

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Ki can be a 0 instead of any unit , vu among the Ga I in Cvaz, Valley Alapm cm Celle, nakedness Mo Bean, to improve Machinery for Valley Ee Dh Alarabat Aatthad Gallic 0 z around 0 Aaky, individuals can (and Wade) 0 coop, Li Adam only for Thin Pat 0 (t Rs specifically LACK Likud Aljmm daad Ara p Shatha 0 c 3 Td 15 such fragment Fv). includes Mgdil type E 0 Li face Akjdid for Mtver Alaspdali replace one or a 0 massively multiplayer Z units constructivism of the area too Altvehr deductible counter the original (the torrent money 'Jess 0 m 0 \ 182- 182-ΜΑ 32948Β1 6 Ashe with Wigger or human .) are Ouamh 4 have Mtver (Aberat) trafficking in which growth needle Nioar fight biological improved door to resolving anti Alasfi Azve then generated 0ο | was fitting 'for suitable for Toledhnh .lmtvnrat the replacement one to get to the father Z Tarif include Ahdy'klq Ku 0 show the cells 0 Uflil ;. B, Haal, Blood; units Presentation 0 &amp; gt; S, d * z conscious only 1 S 0 St Akaao (U 0 6-7 0 Gel Waffle Rahe) to generate bolted substitutions forever all the data I E. Bam has shown 1 t Tirat Lean the reporting that has been generated in the tire unilateral Akkavo p Jessie 0 data cells Mkemh filamentous Kandemajat.mmentj gene M13J III Anjae in each particle 0 P 0 A after 0 Bam survey Almtfihrat that 'displayed by phagocytic cells of the activity Lange 0 Logie (z sales Lacalle, a land.-Duck) were also disclosed in this patent. To determine the c? \ Y Mzhlqh b Acfhir Hrahh gdyel, you can make Tgrh Balh Balolanin to identify the building blocks of the area Grth 0 1 as a non--mm in Arbat antigen to a large extent. Alternatively, or in addition to, the HD Leko 0 n z useful to analyze the crystal structure of a complex body of daad born antibody to determine the points 1 clams between the antibody and its target (for example, Β7.1, PD-L1). &amp; Quot; the fact that these units 1 1 Bebh agents and structural units adjacent filters Aspdal according to the techniques in this Almnkurh Repeat 1 cent. Once &amp; quot; Walid these five variables are exposing a large list of variables to the survey as a 0 Manar is in this patent can choose antibodies that have properties superior to an end and 1 or more Q NAT tests relevant to the development. Another type works to change the amino acid for the resolution of the counter alternative treatment Nmong Paljlecosal original antibody. It is intended to express switch clubfoot and one or more of the cracks -83, - -83, -ΜΑ 32948Β1 Alklahilra 0 presence 0 in El Jem 1 to Z, and / or lighted, e'hd or \ a Z 0 fantastic one to address Alglicosl is in pregnancy recycled · Counting i Glades ! Mgadh to me one of the Jbkul pattern associated with either Ν-Π R B0- Ds d 'Aaat N &amp; quot; To attach the Coordination Alkrbuhedrat bales Gaven Rev Father Lalla, production; n. Tkov Aamapt Nlabh IBD S cripple the Abrad-la-Eads - Z '- - Hmt Takern X righteous about any security acid Aie Rock' Laar; 0 Toalat perception of Armaq Alazz.ey trotted | Krboumdarat to Palmdd Abai to land. Aal Td the presence of each of these sequences Zlab 0 Albbbd in the urinary seem dy Ba_loa 0 0 Amos's sales. Change the expression Study B'lchikrblmertbt some Ely! Dlov Dai seen a p Alkdaat Î-Ν ^ 0 lactose Lin, Gelakters, or Vadz Sd Aros B and as upper 0 of Sen or Riod, E 0 No Land 0 n p lar I Adam 5-Bdrokhly Brolin or 5 Ahedroxa to Azin 0 Yum Ayz 1 0 Rala ^ abyss gel 0 Cosml M prevailed Butkl Mlalm valley indicate 6 s r Alobna P Takhtra Z wa 0 d; seen! / o Adapt humiliation 0 b lesions Akdharh Oela 0 (if one Qa 0 Sale Ablakcos 0's, for, provided Rs. k 0 a no NL Ngm Badah; Ghafa, Wu Abal Boath, one Oooknrmen united 'v 0 Alin'r t-rays father! 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Examples of non-Anhdodh contained about Albulirat soluble in water include, for example, not to Har, a poly Acelin glycol (PEG); common polymers of ethylene Glicodaroehlin glycol, carboxy methyl cellulose, dextrin, alcohol polyvinyl, early Viphel ^ Rodon; Bulela, 3 Daiuksolan's, poly -1.3, 6 Rayooyn; Bo 0 to pass 0 Strk Z Aithilenzamaliak Atmydrid, acids poly-amino (both polymers homogeneous or polymers Hishturkh Icoaiah), and Dbmstran or poly (AA-Ivel Pirollidon) poly Aatdn glycol, and Pratt Mthach Q Crown Brobelf glycol, common polymers of any of the Crown Brobelf / Aithilzn oxide, hydroxyl Aadidat address Balbola OXY asset (for small Male drooled) 4 Crown vinyl alcohol, and mixtures of them. You may Bmon for polyethylene glycol Ahellen Bropon Oldhad attributes in Aksba result of persistence in water 0 has the fact that the polymer any weight to drag &amp; quot; Z; and possible-be or Z Mzera. _tkn That number varies Alprli 0 Rat attached antibody, in the case Arvavy eat p polymer and 1 extent, could be the fact that mow ^ v identical or Mokhtlgh. An I 0 He 0 Ekn determine 0 Edd -185- Rao type Alolmma | T. Alskhaddmh for Achtqath prostitution on considerations include, the torrent example Yassin limitation, Elj 0 of properties Anhddh or functions of the antibody to be improved, both will be Assadam Trust Table 0 m counter in the treatment under specific conditions, etc. The Alkmhv this one Ds 01 t d \ to MTG \ u 1 Sa \ no one burned P, Pharmacy  0 Remington: The Science ad Practice 5 (2000) 20th Ed., Alfonso Gennaro, Ed., Philadelphia College of Pharmacy and Science. D) Samag Pharmaceutical Yum prepare therapeutic formulations for Tkhozs 0.1 Plan vinegar * 1 component 1 fell a degree Aqe 1 Mallobh 0 p carrier materials; or Su 1 languages ​​or stabilizers acceptable Shehadlania, (Remington: The Science and, .Practice of Pharmacy, 20th Ed., Lippincott Williams &amp; amp; Wiklins, Pub., Gennaro Ed 10 2000 Philadelphia, PA). The fact that he wanted termination; or Adr'ite or Alambat accepted z I receptor at doses and 1 concentrations' to Tdmh, and &amp; quot; such as z solutions Mnglmh, and 0 antagonists antioxidant Mtdt acid Oschorbak, Mathonv, Villa 0 Khin E; Sd_om b Yai Zd; rad Hahzh, your responsibilities 1 ml &amp; quot; Levi 'tension, complexes Vlz.lo (z · l a 0 Cal DAT KJÿjs.-zη your responsibilities 1 ml Khalash such as EDTA Rao-reducing factors surfactant Torre is Ubah 0.15 when the worker .lalaja phrase p linear Jays 0 m Anti 0.0 Gml smaller occupancy 0 of 0 Bahlh started 0 linked to the face. to determine the scope of the Artat Arotn Almedf. z sales example, B z MTW 1 lei 1 Mguetqh 'for a changing of the body 1 to counter, - · l stigmatize 18:00 Tza 0 of Adam counter or Z Jr'lot' for peptide 1 t retain the ability to bind 0 Twalah 1 Shoten adv. can be 0 Tkhalehg this At't

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T. 0 SHTML Elmo 0 d Alhaf 0 Adash for Escmahd 13:00 Ot to Araa Wadley Z Oocta Dessel Dai-methyl puncture a 0 and Veom Kaorzd; 0 chloride my blood; halides Bralkuniom (for example, chlorine, rum; Re); ^ echoed Ddondaum; Bmrosal, Verl, butyl or alcohol Brill; Olkml lands 0 such as &amp; lt ;, or Rupel land; Ka &amp; quot; El; Rearersenaul; Michaelo Hecanol 0.3 -bntanol, and m / Lesolle create Aua 0 0 ·'s strong, sometimes rack b &amp; quot; stabilizers &amp; quot; To adjust or keep strengthening the liquid in the &amp; quot; Re. Z for servants with Dzevat vital Mthonh, big 0 such as proteins and antibodies, commonly referred to as &amp; quot; stabilizers' where any 0 Bmcn that Tng-Wael 0 p mg 0 and the bodies of seven sales side of the Hmvy amino charged, Z -ada to Y E0 Kaveh Addq D'khal Aldzeat 0 -187- - 187-ΜΑ 32948Β1 has 0 There Relay factors Mamraouh any amount of 0.1 H / H to 25% weight; and Ahil Q 1 to 5% 0.0 p 0 Elk taking Yat prophetess other Kkonat in mind. Your responsibilities p. 1 mL of a 1 Mgdilh for Ke 6 lattes Skr.h Edid 0 August 0 0 J Royza ml alcohols Skr'dh Lab | Hdroxl to or higher, such as Algelesrs, erythrol, arabitol, za 0 words, Sorierl, and mannitol. _imd Alier 1 Languages ​​1 for additional Z Auaml Ta 0 for Ko'hd or \ a Z Denny: (!) Au'ml tireless, (2) boosters Hablah melting, (3) Statoil and (4) Tmta factors that natural or pests, but 0 adhesion wall of the container. This 5 excipients include nest: alcohols Sugar 0 of Edidh) to Hedrokel (.lmnkurh above); Alomigth &amp; acids lt ;, Alolas, glycine, Algelotamanan, Osarajen, histidine, R-E of Sunan, Urhai; for Osev 0.2-Pas Olad; p Glo-AMEC, Rionen, etc; Almkriaat organic or alcohols sugary, such as one for the cruise; lactose, Allaktatol, Altrewazz, Stashiwz, mannose, Morpuz, Vadzne R., Port; Stoel, Mewenisam, Mewenisatol, Gelakouz, Gelaktatol, glycerol, Sichaelidol (ZZ example, Inositol) Aaialin poly glycol; sulfur containing Loral a 6 th; 0 4 Glutathione such as urea, Theoktek acid: sodium Theo Glicullac, tho glycerol, a .odhu; Gelerol and Sodrom Shu major; low protein molecular Wazzv such misery 1 every human, albumin wild susp, gelatin or Geloubeyolinat in living Ozzy; and Br't lighter water such as polyvinyl Bnroledon; Mono Maxinat (for ethyl 4 Zadozn; Madhuz, Rkioz, glucose; disaccharide (for example, lactose 0.0 Altoz, Auz));, Dlana Aekaredat like Raveguz; and Adeel Alskaredat such as dextrin or Dekshran. -188- -188-ΜΑ 32948Β1 found Alraml Alhafdh Lahr; Surfactants non-ionic or detergent (known Oevia factors doubt &amp; quot;) 7 by a Z-soluble therapeutic factor Oifta to protect the therapeutic protein against agglomeration Aqi Basb, Z Ash Oifta exposing formula to stress surfaces mowing without turning natural pest Brod .lalaja effective or Adam Alamadad- Mmujd Aqua 0 antihypertensive's Ku-0 R. 1 Tahi is! Arne to the extent -raouh n 0 6 0 0.05 Bhma for about 1 Mjmaml, and Aggls 6 to 0:07 Bhm / 0 to 6 to 0.2 Mjma 0 for 0 Sz antihypertensive agents just; Non-ionic surfactants deputized on poly Sourat (20.60; 60; 65; 80; etc.) E Oocamar poly (184.188, etc.), Aadidat Mdrokhll ®PLURONIC; ®TRITON, poly oxy asset 1 n sorbitan mono point (20- TWEEN, 80-.TWEEN, etc.) E to Aoroiho 6 for 400; Crown Ouwayt 40 Sar'te g-one at a &amp; lt; Ua 10; 50 and 60 1 hydrogenated by poly oxy ethylene, glycerol .rdhu Sarate Jeremiah stearic acid Cruz, methyl Bhuluz and / Puxi 0 tighten Selauluz 0 x 0's Adzgat one of AARP a (t 0 Bmcn used on Sodom Laurel sulfate, Dai ukelele intentional-Om a Dah Wad 1 j Ookel sodium Slgomat 0 μ 1 to Mtgat Z Klr'd Bralkoa 0 Om or chloride Brjubom. but Adam 1 Lsg in vivo, Z be sterilized. loves the blood of one of the formulas Dah 1 candidacy Z Lal father Akrfairsh AST 0:00; as upper 0 of mode! for Rukayat therapeutic in this patent in h 1 priority U blight arrival I Z Speed ​​1 nights, bag or vial in Asher-d U Sd'dh Lab * i'j needle r under the skin. -189- - 189-ΜΑ 32948Β1 0 fact &amp; lt; Aiqa | to Aetae and art methods Almrovh and accepted, for example by one or Aseel Z Jerouat the command of one or infusion impetus for a long period of time in an appropriate manner, the Q 0 Yale example 0.1 to inject or Althrip under the skin, my vein, inside the membrane Albraimona, within Alodil, in 1 Hrse inside pests, within the joints, giving a topical, inhalation or means a, but 0 for fitting for dates or less agents. 0 also walked that trait my acquittal on more than one active compound and one in Lori 1 glands wanted to be cured; preferably those Nat complementary activities that do not affect u 0 j Presentation - other, rather 0 n that, or in addition to, you can structure Z as upper include 0 for Mam cell , cytokine inhibitor seen tiger factor. Bojd these molecules appropriately Do in Tolegh quantities are Sd of 0 Stand 0 0 also walked the mobilization of the active ingredients in Deghivh capsules have been prepared, for example, by gui Tucker 0 molecules or by surface polymerization interfaces, for example, the b-Rocky Mceli cellulose or minute capsules Algelowin capsules minutes 0 n Rla- (0 Hthel Bthasellat), respectively, to give the drug Rvani systems (for money; Alojs 0 or 5 Aldhettih's, objects Arkzah of albumin, minute particles Althlebatt sized nano-capsules Bhhm nanotechnology), or in a large Tlebatt. The disclosure of this one was suspended in Remington's Pharmaceutical Sciences 18th edition, supra. Can &amp; quot; slated firming Arro &amp; quot; Cut and antibodies Almnkurh in this patent through the use of multiple Vzah Akkava salts are soluble in water &amp; quot; Non-toxic. Examples include .Fe3 +, Fe2 +, Zn2 ', Mg2. , Ca2, 20 .Al2,, sn. , Sn2. , Cu2 and 0.86. Anions to include illustrations that can Dashkl salts Z -190-

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C' so Hoo (100 mg) 0 Mmerml Ely: for less, instead of about 200 Bhma 0 for r d 00 ¥ y,» .- t p Ase'a ( '1 to that point t Ta p I Sz, Μ μ Q 0 M..550 Ss.o h / PR 0 o, Α not;' d t Alolega-Study within this 1 1 Crieff Pkwy Ohama 0 Ne Rrb and 2 JP Oogdhir, '0 Zmthel acids Mutu and Dai water 0 Akrboye exponent 0) 0 Eay 0 Slas, Slsd Arrow Krbokciec tastiest 0 Zjth that &amp; quot; effective within this Akaarev &amp; lt ;, acids RIP / Lo saturated Mtd 0 lion Doroud and Rrz and'sv and Alcaroak and Alayabk and Alcabr_ak Balargeovek and / Aosk acids Mono / Boksilh .c20 Z b t acrylic and Robriuek Mithakr .ak and Krorzdk wa-Ro / and Tozhec 0 x 0 for acids Dai Krboxti .vozjah Z Us Dai / Boxela and &amp; quot; Te b 0 such as 0 acid 1 Tugging and 1 Ksvek and 1 Botharik and forever and'babut; Z 0 of 0 included Ohmahy Dai / Boksila c29 b z rays on malic Algiyumarik and Alsstrcconnek Wade acid 8 shabby 0 Tesht 0's acids tea / Rksila Azzb Z Us Ray / Boksila? &amp; quot; 2 h Z 0 such as acid; no; the I Brigade 2; 3. Pto &amp; quot; Dan Ray / Boksila 0 to that 0.0 Bmcn that shui acids Alkrbokelah that fall within this haemorrhage on one or Amehn ΜΑ 32948Β1 -Ι91 of hydroxyl groups Kko Den-Protect 1-hydroxy-Z / Boksilah. Al carnivorous 0 1 Z machine; proxy 1 Mboksilh Akmongeh glycolic and lactic Algelesarak and the acid &amp; lt; Tromat and Almabut and buil &amp; lt; Iike and Alserick. And include aromatic acids that fall within this haemorrhage on Albrooak Sorry acid and 0:00 0 0 only for loomed | Gzayh for STA Elka 0 &amp; lt; Soluble AVI water and commonly used, which can be one Suha of 0 utility to spend the night urinary Bhd't any contained in this Alakhar'ae &amp; lt ;, i TB, U follows: (1) salts Fflerah acid Z enemy uncooked applicat (&amp; lt ;, equ Land CKD e Alcassom) E and caper-Zt and Aarat and'lladat Dalla b; Ta 2 (d) salts, Szyh mussels 0 z / Bdia; youthful (z i aluminum 'by Ace tonsil Aztk and Roberaozot 1 Kaedm and Jkdlat Azzk 59 Z Dlae Land &amp; lt; Rat Zzv a) and (3) No 1 h r, a shower / 0 Dmamd Ehve Rih Albdat (z Broat 1 Zec) and salicylate. (D) ways 1 to treat Dhalsjsi 0 Z 0 Begin 1 VI 0 Aloeliseadssdilla 0 t wanted Ela 0, Z name specified Oelah, rather a; Sdsrh, commencement Ema name for Ezouasl No, &amp; lt; additional Ashia 1! D Alahj, 'q Z 0 commencement and Aledj S d Dalai Atth Q 0 and Ba_meysalj, -am; Te Aladib; for Yardd and 1 or Z de Mlesslh round of treatment times. -192- Μα 32948Β1 in a specific Nmong, comment invention stimulation Almmtturk output Z ease Azslh signals across 1.PD; especially through Amthaddam antibody PD-L1 Olney some Alaratat d 1-PD Rao Β7.1; and Knlry attached treating functional deficiency disorders in Khalalo 0τ 1 - 5 infections fell short of PDI and its own relational Arkpat (&amp; quot; PD-1: PD-L &amp; quot;) Doma cradle Qzim in cases of immune defense against Mbbat acute infection and these Elms 0. WAP Irv's Air 1 T. PD-i: PD-L Doma Ri in regulating the balance Pugh 0 Kia Adas waffle newcomer microbes subsequent snitch semen runoff contributes to the damage the immune system. For example, while scrape Akran Daddy then P 0 Ha A.chav expression Alorava p 1 0 PD-1 infection n cheese F 0 de Seh a / z 10 Nzarha Q wild-type, but it has evolved Phones hepatic injury more severe. SAL, Iwai et al (2003) 39.50: 198 .Exp. Med In ^ Zj land Zd 1 to inflammation Alqrveh Addoy Hellani 4 exacerbate disability Jem counter for PD-L1 Z unit inflammatory disease 1 consecrated; Z over Z Ladd Khalaoua CD4 T of 0 nervous messengers run correctly; - 1-HSV and the production of IFN-α and Bakak. FEBS ..rh et un's (2005) 6259-64: 579. · Lett 15 s 1 Stead Alcaett one minute that Taatbb in chronic infection path Send to answer the immune responses to infection Woody times of the dissolution. PD-1: PD-L after 1 T. quality T can Woody Alfberusat causing the infection to the times of Mark Barber et cells antiviral. , .rh T for Gbros Wenger effective and thus suppress Astahabh ornament is Astrav .Nature 439: 682-87 (2006); Wherry et T, .rh. Virol. 78: 5535-45 (2004) 20 sa Mehta to control viral ineffective during infection CD8 + T or i 1 Ge cells I cells -193 -193ΜΑ 32948Β1 HIV 1 to Mzmzh in Akr'v and CDC Edoy LCMV 1 to Mzmzh a z Alao 1 mL 1 t distinguish infection in Rabsaat. And Ddh that Ik-fighting to SIV infection in Alanan HTLVj and 7 solution HBV.J Adlo Adoa to Gerus, with CDS. T gradually .lozivh d 1 Vinegar of 0 Ua virtual bewitching First, .tboia Bazj Setczn A; sales Alaa 1B 0 IL-2 loss of cellular Mieh production soon Altvhat 0.0 p maintain Altabutr Alzh I Q6 Z 0 Oual PD-1 5 are Akmkm in increasing, Barber et al. .by LCMV to Mstervh in Akran infected loud! CD8 + T cells through to 1 Harl Z PD-1: PD-L1 above. It has given antibodies that hinder the link d improved and a significant reduction in the burden Algirose · In Algiran Almhala T Ascabat cell PD-LPD-cells L1 ineffective, regained disability CD40 Τη 0 Das form which Z Ascabh the case of functional deficiencies which led to Ka; Wa; BL Alstoknat u cells CD8 + Τ 10 infected and reduce the load Algarosa which strongly suggests Ashaddamha way therapeutic for the treatment of AAC 0 Wei chronic viral. Decoding focused one to set up the Ai'v this one in the House, LCMV in PD-1: PD-L and the result of the role of quality T nibble on a breathtaking PD-1 treatment of the infection; Mzh in evil. The fact Altabar Alzh for Petrovas et al., T. Exp. Med. ; (2006) 92-2281: A Day et 040 Nature 443:] HIV 15 for bearing for T; (2006) 54-350]; and Khalada Traumann et al, Nat. Med. 12: 1198-202 (2006)

Boettler et al .. t. Virol. 80: 3532-40 (2006); Boni et 540 J. Virol. 81: 4215-25] HBV. [Urbani et al, t. Virol. 80: 11398-403 (2006)] HCV Adoaah for T (2007)]; and breathtaking u e 0 DCj blood Anhaiti CD14. The picturesque single-PD-L1 is controlled butter Chen et al, j. Immunol. 6634-41] chronic HBV in a 20 Kai; Doanh 1 shows Bddoy

CX 194- 194-ΜΑ 32948Β1 T cells and CD14 +; (2007)], and the cells Geng et al, l. Viral Hepat. 13: 725-33 (2006) v 0 pussy disability interactions. [Trabattoni et al, Blood 2003) 20-2514: for)] HIV in the supply and the parish's quality of HIV CD4 + and T CD8 + in the lab Astray cells PD-1: P5.L1 Petrovas et .otsaid proliferation and cytokine production of SIV and qualitative HCV y and quality for HBV al., for. Exp. Med. 203: 2281-92 (2006); Day et al, supra-, Trautmann et al, supra-, Boni -et al., Supra; Urbani et al, supra-, Velu et «R. 40, Virol. 81: 5819-28 (2007) Aluah CD8 + T proof Alajtha Moghaima Oifta the PD-1 HD p cells degree Altaboukr Alzh the unity of the land. Ertt level AAC 0 1 Hravi Bear T-virus to denote the degree Astrav Waddle cells Ashe-J; Mmaigmnedd by 0 h, HIV's quality! CD8.T the PD-1 cells in the lab for 0 and Asyjabh HIV on Altkar 1 Stahabz RCA against CD8 + T and closes the ability of cells, &amp; gt; PD! Cache observations within the neighborhood, there is a direct relationship of exchange Bzn 1 Oraia p 5 Souza et «0.40. Immunol. And one specific to pregnancy. -1979: Guetd HIV consciousness for! CD4 + T except 0 a period of 0 Ralh without lines have echoed HIV (2007) 87, have Ki 1 for people living with 0 p Altabar Arrash A- b 0 form 0 Dhoz Z HIV Nakrh quality for CD8.T AIDS cells and in contrast to the .lmassaban 1 Tkulaidatn Areros and'kin 0 Chet K 'burden of DWI, P.-J is? Adad and Oni after 0 d PD-Ι 1 to AIDS and 1 Ken happen to have an expression for the Raby

CD8 and Add Wei Khala_a; CD4 + T low, the Z leads gone 1 Nkgadedd except 0 of CD4 + T Zhang 0 p Zadeh Waddle Asus in plasma 0, HIV AAC 1 football sender Uncle 9 me, the quality of T .et al, Blood 109: 4671-78 (2007) -195- -195 -ΜΑ 32948Β1 branching walked PD-1: PD-L Light my whoosh 0 F Easyway Abkesel. MP Helicobacter pylori in Alayabh Aakeab, a contagious; Azs and Nrah S, otherwise 0 Zny ten Om longer Q Erar S; not to wonder 0 b t! Injury parliament pain 0 Ende. Ata Edoy pylori infection », TAT Z; t the cells 1 T is WOC 0 of Sze z, infection; Z leads to Atbrar Ocoee. 0 P's a '&amp; quot; / z to &amp; quot; , Pyior in one or all of the Ka 0 Q bad it was Z; PDII Ddlar Aaqla 0 2 Aiharri infectious. -s Khala 0 da (infectious Nlharah and Ray molecules r any MHC II Odd Ava b Doz 1 in Zigh APC job I want Ή infection. Pylori Z 1 Agam one delegation's PD.L1 which p .ltvaal to convert 1-PD to PD-L1 proliferation except for &amp; quot; A a &amp;; Zj 2 &amp; quot; two thousand Ps 0 Ra Allaaa .lzaarah infectious prone to pylori .lmr cells CD4 T. p. 4 Ouayz PD-L1 0 Amthaddam Glades anti or siRNA production of T regulatory cells, which benefits Study that 1 gg PD-L1 Z Aqobeir genetic cells T and the continuation of the infection through Akgm in Aldyadmique yen T cells Almnglmh nerve and sent I want infection pylori .lmlm 0 .Beswick et al, Infect (2007) 4334-41: 75 .Immun. FZ 0 Tech Aldeddan parasitic Oehta PD-track 1: PD-L1 induce the command of August cells that suppress the immune response. during infection Taenia crassiceps (ie downright 1 n tapeworm) in Algiran, be increased one-PD and PD.L2 are controlled on the large phagocytic cells are activated, and express except 0 da CD4 + T and Ratha Z 1-PD. Ngll disability 1-PD or PD-L1 or PD-L2 largely leveled Z suppress T cells in the lab by Allthmh Kabarh cells from mice infected with worms Harialah. (2005) 58-1349: 35 .Terrazas et al., Int. j. Parasitol. And I Oete 0 Wei Shistosoma mansoni in Grand, express phagocytic cells Kabarh for high Msuiat of Aya- PD levels -196- -196-ΜΑ 32948Β1 modest PD-L2. Antibodies have ruled for PD-L1 on the ability of these cells to suppress large macrophages T cell proliferation in vitro, while no antibody PD-L2 for any effect. The genetic expression of PD-L1 has fallen on the phagocytic cells of infected Kabjrh Ghabran after 12 weeks of infection, which is accompanied by a decrease in energy cells, T &amp; quot; 5 (2004) 1240-48 .Smith et al, j. Immunol. 2. immunization against tumor includes empirical evidence for immunization against tumor on the following (1) Note mitigation Allqash, (3) and (2) the existence of Ascabh immune to shame are disclosed but is not effective against 0 tumors; and the growing presence of primary and secondary malignant cases in patients with one repeat S; and (4) any (5) in 0 RIP tumors; and T 10 for mounting Vnoat antibodies and cells Note the possibility of testing animals vaccinated against many 0 n Oraa tumors. Studies have shown that most human tumors express Laura. R Mo 0 0 0 DAT against her ^ Rum and thus be able to induce T Alitzhabh discernible Boismalh cells (TAAs) have to dat experiences of 0 Rereh .Boon et al, Immunol. Today 16: 334-336 (1995) .almnaaah or specialized picturesque BL TAA -! 15 at an early stage through vaccinate cancer patients Dudley et not 0 .. Science 298: 850-854 (2002): .TAA presented antigen gating Dr. Gajewski et al, Clin. Cancer Res. T. 895s-901s (2001); Marincola et al, Adv. Immunol. 2000) 273-181: 24. Lund was 0 g h): Peterson et al, j. Clin. Oncol. 21: 2342-2348 (2003) Mackensen et al., .alnoaah Generator against Arrm in many z Akjarb these CD8 + T cells Oelah. And ^ was LADIS p-except for a Œur. Cytokine Netw 10: 329-336 (1999): Peterson et al. 20 (Λ ΜΑ 32948Β1 -1.7- T awareness of the generator against tumor disease has been detected harboring Khalana T Allahmgaoih 1 not 0 of the cells! To expansive (CTLs) to the ashram sites 0 -2161: 170 1 Immunol 0.Meidenbauer et al (2003) 2169. and 0 p it . for forced z R "Th 1 Special Rrm Balkhala" a \ {a August immune, Vadna what Yum control tumor growth. will Agqq already that Z is possible to protect Adakktqh environment of the tumor tumor cells from functioning Almmaea 0: 75 [.Ganss et al. , Cancer Res. 58: 4673-4681 (1998): Singh et al, 1 Exp. Med (1992) 139-146. We have found that Bam Walser Arrash Z Awa 0 Ablh soluble for, and ^ P molecules associated Basha.mma the factor additional β 1 alcohol (TGF-β) and Aztrrk 1 N. 10- (IL); and Pro 0 Mtagelazdan 2 GS, FASL, and 0 for compounds Accra 0 4-CTLA 'and 0 for compound Akrabotta Lazne Ih 0 T. Tlathi associated factor of tumor necrosis cells (TRAIL) and composite Alr'ti 4A 1 to apoptosis 1 (akaB7- hl, PD-L1) by the tumors and lead 0 any RasGas in Adro Walles 0 so, is 0 impede these signals Altzimih immune pulposus on Arrb &amp; lt cells; - Gh and birth Khassann age of CD8 + T cells specific for the tumor in the Cache neighborhood. the Alorani expression of PD-L1 many Q MCU tumors; not yours; T and Z .memkn be in harmony with other departments immunosuppressive. PD-L1 regulated captivity Aar't acceptor ornament T. has been shown to express Alzh for PD-L1 in Almoha on ¥ Er, Why g solid tumors ,, which the cancers of the breast, lung, colon, metabolism and Arrm pain ;; to Avea and Almtozh, liver, saliva and stomach and glial tumors and the Euro-0 m thyroid shape and thymus and Alglharah and Arras and neck. -793: 8 .Brown et al, 1 Immunol. 170: 1257-66 (2003): Dong et al, Nat. Med .800 (2002): Hamanishi et al, PNAS1 3360-65 (2007): Strome et al, Cancer Res -198- -198-ΜΑ 32948Β1 2003) 5-6501: Qq); Inman et al, Cancer 109: 1499-505 (2007); Konishi et al., Clin.

Cancer Res. O: 5094-100 (2004); Nakanishi et al, Cancer Immunol. Immunother. 56: 1173-82 (2007); Nomi et al, Clin. Cancer Res. Il: 2151-57 (2004); Thompson et al., • PNAS1: 17174-79 (2004); Wu et al, Acta Histochem. 108: 19-24 (2006) Oraa JA Z many PD-l.PD-L 5 reveals mottling immune Oania express Alzh cancer.

Coussens et al, .ually surprisingly, .memkn discrimination Oevia cancer as a disease and inflammatory Zs while the ratio ml to 5% of Q Oraa cancer in .Nature 420: 860-867 (2002), [Kuper et al, j. Intern. Med. 248: 171-183 (2000)] worldwide infectious origin of halitosis Zou et al, Ntu. Rev. 0.10, many human tumors and inflammation related Bakeaj 1 for chronic .Cancer 5: 263-274 (2005) on tumors Adatj p land that Akaabar PD-L1 expression studies on Alzh expectations about the strength of Mir land is favorite in kidney cancer and the land PD- show L1 Alzh p Hamanishi et .oualemthanh, breast, stomach, pancreas, but not Rtan lung cells Secret al) Proc. Natl. Acad. Sci. USA 104: 3360-65 (2007), Inman et al, Cancer 109: 1499- 15 505 (2007), Konishi et al, Clin. Cancer Res. 0: 5094-100 (2004); Nakanishi et al,

Cancer Immunol. Immunother. 56 .. \\ 160-% τ çiy.lià et al .. Clin. Cancer Res. vv. 2151-57 (2007); Thompson et 540 Proc. Natl. Acad. USA I: 17174-79 (2004); In addition, these Walker 0 Sat, Wu et al., Acta Histochem. O: 19-24 (2006)

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.199- .199-Μα 32948Β1 that high Centennials Z expression Alorava p PD-L1 Z tumors 0 Bmcn that P Thassann stage of the tumor and invasion to Christianity exponent structures can not meet marched PD-1: PD-L Aissa role in land 1km August 0 Rarely 0 A Bam Altabnr Asher 1:00 u PD-1 or PD-L1 in cases of malignant cell of, but left over 1 Kaabar Alor 1:00 u PD_L2 in one of the cases of malignant cell Almttqh fiddle. ; Brown et al, supra (2003) 851-62.Exp Med 'and, Rosenwald et al · -d additional a 7:00 L1 &amp; quot u; P5 {, Naadid Z except &amp; quot; Da 1 tumor 1 Zkhas, and 1 to Ylselykhalaa plasma August' and-age stretch

1 to T cell Lhasa 0 y Hla.da tumor Sass any p sprayed decent Ikelal, Blood .PD-L1 (2007) 296-304 0 of 0 Yum) Kaabar Alzh for PD-L1 on some tumors Alpmgaoih ops faithful T and Khaha 1 tumors 1 to Amgaoih for trait T any of; repast, WPM Akaabar Arrash p -PD LI meant grid cells | Balzoa'd Aalash related to a &amp; lt; the Libyan oasis 0 0 1 .Dorfman et al, Am

(2006) 802-10: 30 .Surg. Pathol. P 2 Akdv Adakkah explain any of that i 0 0 T 'Q 0 in Rrm Bweide 0 ../»^Chemnitz (2007) 3226-33: 110 Blood. Yum ales 0 Rrash p 1-PD and PD-L1 Z in Alluki 0 O and 1 tumor 1 Amgaoi Viabhaldy Ablz 1 n 0 him who the most important in 0 Haddth 1 7 Alla 0 (2007) 2585.90: 121 Cancer RO. Shimauchi et al, Int- 'the fact that these 0 to Kelaiah b ..... . &amp; quot; 1 Ascabh for after 1 T. TCR, and exacerbate Aouaqh 1-PD 0 n prisoner Arrash Enhe □. 0 appear to studies conducted Me 1 to Zmazj Alehio'veh that 1 Ltd. Arrash ZZ tumors Shatt activated 0 to T cell and deviate a herpes-1 Orbm In some cases Doe -200- -200-ΜΑ 32948Β1 a clean-shaven Akuh U tumor. Nat. Med. 8: 793-800 (2006); Hirano et al., Cancer 0.Dong et al (2005) 1089-96 .'qh Res'

Akal 0 A, leads to the Aral Alaharrat cross-PD-L1 Sdam Aloham Mufadh P PD-LI contained in Alagiraa, and Y 7th to improve and Zigh cell T, to the weakness of immunization against tumor, and as a result of SEC can be the fact that Z not Vartan 0-and-parchment Amlaj Aaoabla could Table 0 G between Atrigh Alakharaa and other ways V] infection pranks or ABF 'either in the form of step 1 Telajp or Aykhh or Kmkumat 4 type b j' 1-CANCER: I Thin Aloz Gh Mae 0 0 of 0 Q for P Aloodam R. Larry g father 'p.

Herqh termination amicably 0 1) U) Mi APC, &amp; lt; (A) additional in alarm 0 Rldat I E 0 worker know MHC strange Mtfrh and DNA,!, (B), p Asli Dalai 1 trail Lord Bjat 0 replies 0 n; - Adhlak Mok 0 leaved, P (Il 0.0 6 H Q, Ib, GM-CSF, and Z Eadsh apt Β7.2, Β7.1) to Orme, and (3) the 0 Wallace Larry Lage principles, Ed Elajpkhala-termination 1 0 Dhue of Naourm. Aao the 0 Lage Ais Kheir stinging Z slipped Khallaal 0000 0 amicably a Almertha 1 Sorm, and the expansion of B; in Ischl &amp; lt; R t 2-1 cheek 'Ed toss' d #U Z 0 Elail. Bszlalyzs, to Tkintguetela, Aaadila Alaymadrdbny rad rush out; M. Alaa 0 or Alhmad; d PD-L1 Adhardh in Alaraa P eat 'd 0 Ekt; Id 5; Etae T cells that have been Q 0 Hlha 0 to Adael d so 0 -201- -201-ΜΑ 32948Β1 include wineskin treatment Alhleydah for Rtan on the following: (1) radiation therapy (eg, radiation therapy, X-rays, and radiation exposure) or Amthaddam ionizing radiation both cancer cells and reduce tumor size. You can be given radiation therapy, either external through radiation external beam therapy (EBRT) or internally via the nicknames treatment; and, (2) chemotherapy, or Amthaddam drug mmm cells which is based Bøjer in Bshim cells Burah; and (3) methods of targeted therapy , or factors that particularly affect the proteins irregular cancer cells (for example, kinase Altaromen inhibitors such as Ammatetip and Geevitinnib and antibodies monoclonal dynamic phototherapy); and (4) Aklaj immune, or improve Alassaph immune to shame (such as pollen); and (5) treatment Baher 0 Watt; 10 or hinder Mormon (for example, when the tumor Hnt thief 0 Ryan) E (6) 0 Shatt al-Duc vessels, or obstruction of blood vessels and growth of the composition, and (7) the possible care or a ^ c directed to improve the quality Araih to reduce pain, nausea, vomiting and 1 to Estelle and rush. And-Ekn be permissible Aehlae drugs &amp; quot; knife pain, such as morphine and oxy codon and anti 1 v 0 Neutral such as Ood'zsdhiron and Opripatant the most aggressive treatment regimens. 15 in the treatment of cancer, you can use any methods of treatment Takidah Muldh 0 Hema Z Dulag immunization against cancer, before or after or jointly h Atae one of Assam's Lhasa -PD LI contained in the invention. In addition, it can Aehlae Alai m newcomer 5 for P.-L1 Alo 1 Rose in the invention VPL or after or jointly 0 p ways% ί 1 Pugh S '&amp; lt ;, Aaala Glades | for anti-Murr-duck tumor (such as Alosnm one his aide-de August and 'to Assam 20 Almnadh mono indigo associated Palm) and / or give Awalo 1 Klaj Levy 0 -202- -202-ΜΑ 32948Β1 12 infection in the treatment of F 0 Wei (0 Similarly, LED Elms 0 these Rao acute), can be combined to give Alosam Mufadh for PD-L1 Azurdh in the invention Ozk 1 traditional Lage in addition to or in place of Z-defense stimulating the natural S Anel against infection. Cases defense immune natural include the host against infection, the Q 0 Bill but not limited to, inflammation, fever and defense breadwinner induced in the body of the reported cases of defense breadwinner induced cell .llimgaoih T .mma the secretion Allimvukin and T cells Almmmh cells (especially during Agheirosh infection) and decomposition induced Balemtemm and Alopsonah (preparation bacteria Balobrnin to devour the cell are easy) and Adad Bakt 1 RIA Balopsoven to devour the Khoi 0 and SKU 0 as much as 5 Alojs 13:00 1 counter for PD-L1 contained in the invention to re Cht bewitching T Olney what Z meets Mvidz in the treatment of the 0 chronic DWI, especially those in which Akrn immunization Aahm the occurrence ornament Mehta factor for the completion of healing. A Bakterya: p mussels, lattes Lhasa 0 Z Trafficking 1 Z Easyway bacterial, could dimensions in assets oxidation for PD-L1 contained my Alachter 1 p 0 n slipped Ahilalhl b; every road 0 n or Blob 0 DD &amp; lt; s S b p Lhasa 0 Z Joey. The HTM m Zlah Easyway Allekeao the Father in Li Ba 0 harmony Gadat b Assad; d-termination for; n Ka 5 eat Addie 0 Yi father's birth, Foy bit of; Zlawa- Q Edatl U Dtaa 0 'Ç Z -kon Arkierha' Ne t 0 RD commencement of the land Ih 1 Lars fell 2 Ά Study), and swam to Hmsyl CFA; Ehlae D'0l j '..m j S' -203- -203-ΜΑ 32948Β1 (the torrent example, serum many offshoots and Alosam Akadh and antibiotics, etc.). These organisms include Clostridium spp and .bacillus spp and Corynebacterium spp. D vibrio chloerae Bordetella pertussis d d d .Staphylococcus spp Streptococcus spp. And include positive bacteria gram that Tsthabb typically Oevia to methods of treatment 5 traditional Almnkurh on Aloke bacteria (such as Escherichia and Klebsiella and Proteus and Yersinia and Erwina ^ d Salmonella d Pseudomonas aerugluosa. Include one Bkzd 1 01 lakh that are resistant cases preparing Bakthraa Balobsonin cellular Alopsonah of gorging, and thus enjoy the jungle immune liquidation as follows: .Streptococcus spp and .Haemophilus spp and .Neisseria spp d .Klebsiella spp d BacterioidesJragillis. 10 RIP bacteria S. Tru cases defense breadwinner by invading cells to invade the bridles of the reported except for the complementary Thdia Maaia. dependent filtering infections Almnkurh mostly on a cushion, which contribute to the occurrence of lymphocytes T, which is the fact that in one meet / Dh valid because his time infection. the examples given about that on typhi) Salmonella include.? ,, .S S. enteritidis, choleraesuis).) a .Legionella spp d .Listeria spp a .Brucella spp d 15 Mycobacterium .mma the M. tuberculosis and M. avium and I leprae bacteria is twisted like .Treponema spp and .Borrelia spp and .Leptospira spp bacteria caused permanent and latent infection. The Treponema palladium, which is the virus that causes syphilis, Reza transmitted through sexual promiscuity, which could have severe consequences if the nurse did not Bam treatment. Vialor disease through a distinctive late. The initial clinical stage in 20 or peptic ulcers at the vaccination site lobby. Following that stage comes the presence of the blood spirochetosis -204- -204-ΜΑ 32948Β1 Wayuu Secret 7 Kate Adz Aldziv 1 1 Ead one who .i in Zq Noire Laurent Li alleles of the three I know of syphilis Aazdhua. Rack alleles (Li Z (a Alzhra Alaida 0.0 Del RIP abundance Kern Ede 1 Aloer'd and'la Z r ^ do not see 'for agents tuck Dallah i; and we Yeh's the 0 Alps. Z Henri Anyone appears in (1) F at me; Ab 5 Aloord 0 p roasted Aloua one father 0 priority and Nearer in Ala 0 or Aloaurer Ahia; or (2) Aalaba Arkli (o see 'evil r h) E or (3) in August &amp; lt; Assab automated Alarlo!) and 4 (1) of the ear (cm Aloehab). type Herr Z Amolll Z Adlar Adrlo to Asdl printed with b, and b to Ail.nalal Jui Abir number August 'o d U land | Z Hdih (T. pallidum subp. pertenue) Ot ( "'" E'hm 0-3 ') D. 9's (' Τ 10 . (pallidum subsp, endemicum AM 0 ways to Elaj Azeri Z A- (0 t b 0 N-5) Dara - d r -ÙÂ ..bra 6 Aern and Aziirobin. omits to give Glades newcomer; for the Alhe der; in Alakhaddraa to Laage period of latent infection. the Azno RIP Lyme; but -dh because of Borrelia burgdorferi, the Escher Pollack Adlo a land. Â 15 1 disease in b-1 commencement 1 is in the form of 0 Lgh de topical E 0 befell Oer 0 z my land μ * includes Akuk and 1 D and 1 Kdaa and stiff Alao pain Akasal 0 to'gman land Aryan one of inflammation 1 Mgasal Akql 0 and 1 season as 0 a guarantee land any father that "with cases of Sha 0 for the 0 pour 0 to Qahga and 0 Elal one of the roots of b and Akeab Eg 0 him less and Dap Alzglm 0 valid to some &amp; lt; machines RIP Lyme permanent, Z &amp; quot; lead to inflicting Ashe Z &amp; quot; 20 reversible as I keep 0 Aahehriaklathi.

CX -205- -205- ΜΑ 32948Β1 are Mbdna to give vital Akadat. Lyme can repel &amp; lt; 0 Pied the current Laage disease Ouala 0 0 of 7 lats resistance Mvadat vital using hydroxychloroquine or Ka 0 v. Patients can be treated non-Asepen antibiotics and tucking suffering from Matho; 0 as a &amp; quot; &amp; Quot; C Almtakhr / chronic Lyme 1 0 pain to pain me by one of Jababztin. It can help Mino Doxycycline in the treatment of trauma PD-L1 1 0 Meh one who neurological symptoms or other inflammatory. Preferably giving antibodies for the treatment of latent infection atom. 3 3 and hermsii and B. recurentis d see .lburelaat of the disease, such as those resulting Ttahobrar 0 n 0 n 0 DD as well as leptospirosis B.persica and B. duttonii 5 and disease. hispanica and B. parikeri. And turicata Bach 0 per Ts unless and y balls 1 km; k 0 Zat me at (L. interrogans (0 such as the occurrence subsidy liver Dad 0 B1 opportunities 1; Asli | to Atjo p 0 s SA, Bacon dimensions in Alosam ESL; ρ5 contained s except for, lost from T. 0 Lal a 0 t 0 mother airing 0 all? s with or NL 1a 0 1 d Atedam the 0 Lage Ip's 0 Laage% ù led d ue Adlaj F-6A; visits Dr. R. Ra Srds. Adlan '0 Ic 8 n Ahouasargareadihoymsadh (0.8; for Ohe 0) Dhirasausyla. Bdyabr 0 Alyalbiwalolmsokaaadazekos 0 Ot s aluminum that Aloolo, to the bezel. Aloionra are encouraged as well as XY :: L *: ;; Saloakoi, Ilak &amp; gt ;, Basgoake, duck; Alfdtlaz.a -206- -206-ΜΑ 32948Β1

Goodpasture and Falz 0 of Reye. TCT influenza infection cases Oehta Adaa defense against bacterial pneumonia, which increases the risk of injury to the land of Z Alochlozza Akeab bacterial pneumonia. PRO &amp; quot show; the same .lstahih to Gerus Alozgaura a ^ q 0 to Hovl generator P 0 4 0 5 Ztj Q Tgr 1 T. and the return of a land. &amp; Quot; Bhatt! Jenny. A 1.0 Father T Afaw-A; the fact that the I 7 cells p 1 0 delegation Adaqlh basis of SA's 0 to eliminate the virus after infection. Influenza classified into three main types cloudy namely: (a) and (b) and (c) · r Alozgluzza (a) 0 n types Ahlgredh Hat EQ infect both Alp one evil and a lot of live Alcalot Aryan &amp; lt; like Alhaz 0 R. Warhol and the Euro-and Ahio 0 P Algq 0 s) It is one of literature Rey injury Balontonza epidemic. And Kzv 4 Ed 0 Ibb 10 strains cell Mokhtlgtin of .lonflonza (t I rum RNA waza 1 clove Zs 1 Boss indigenous Otghae teratogenicity to create Nkh Hajaf, &amp; quot; lead to Z strains and Aelah new · Do not Bstnsch Influenza Type B in Arwanat and eternal, it Moreh J Ash WAP influenza type (c) it has one Fal tea type 0 representing most treatment methods .ltkulaidah in relievers land Altatjh Z infection, b 1 what p.15 Alastahabh immune to shame the disease 0 form 0 pardoned. However Zlat, darker to 0 Sbb certain strains (Mtd 1 Ozgluzza from 1 to Dhua a) in the Ala 1 for both the Lord of line 1 Rh gulch lead to 1 priority 'can Elaj Alozzawzz 1 x 1 Zaa (a) in a manner t-confidential and Oaaih 0 N. Dalal Aeta 0 E 0 Tdt exponent 1 toroidal; 1 Omaztadin and R.mmaidan started 0 Shatt 1 latex Asse 0 and with y 7 Te Aladam 1 to my bed for this one to drugs is limited by one of the occurrence of one of the big j Selat no 'and'lotf 20 1 Ldq Amo 0 Ed for Gero, bit 1 the one who p. 9 (Oba 1 DEF) B1 SOS because the p level 0 X? -207- -207-ΜΑ 32948Β1 can prevent giving contraceptive anti-serum IgG to Brocbat St 6 Lord of the Loire 0's share one of the deadliest and Aldhuromived 1 g ! infection .lrioah, Iv 0 a be Ik for IgA Mokha 0 me to the pleasures of infection 1 Qmah 1 Tngsh.lalloah and Title aerobic 0 and the fact ÿ] only 0 eating Haalah No, ^ Zza is a vaccine 0 p give comb virus Bgurmalin or β Rowe ^ for the most valuable 0.2) Vnros measles after, Nhvin de M. , and h Q 9; for Yaa fulfilled, the development of any Allalatlab Z August! satisfied insisted 4 0 0 Z Walk Ewalzk 0 m and'khab August. In Dadam Ad z bad I Ham 1 GS listed rash soldier Bfie 0 demeaning to me, quickly scatter off Z in Table 3 Ba 0 Kmvl 'd &amp; lt; Fitting for a (infection T Ait Avhaan 1 Khalra, the fact T.l 18:00 Rev r ob Eldy bacterial guardian, Sun 1 to inflammation, nose Alo 0 folding and Alakouab R-Wei D'bb widely Las 0 August 0 d awing UUC 0 DWI. Afraid of Easyway | for the birth of Plan Z Land female-d and see; 'and b in teenagers Alnin malnourished 0.0 TB g, Lugg Alhao Z 1 Atae captivity d IgG Shui Mjme, the Dalai Eknand 0 n except 0 father B1 windows in one Nlat Ir Study, right if; to 0 extensible 0 0 encouraged not 0 for Alammap 0' 0 'E Zqe 0 indifferent Hrus Pugh is, the method of eating M * SJ Father RIP will in! ZZ 95% p infant Sen. and .oua Ann Pfaff pattern six watts' P virus, Bodhi Sen 0 or presser Backlish; Li Q-a p Father Kada t; Asass: Manal 0 Atelakabh, .ekn; P-Z Hoss 0 of E. a case of 0 SSPE, and boring; o r Dub -drd burden p Alamay 1 Aldalmh to Ahaaz Lacey Arai · PO Box 1 -208-

SSPE BPB images Nailah defective Gerus measles and that income with a group Algiriun and budding. For these patients, it will be re-Amodil Kachit T-cell antibody to PD-L1 contained in the invention to facilitate viral filter. 3) hepatitis B virus is Vhrus hepatitis ΗΒ-ν) Β) of more pathogens in the blood stromal August. One of the basic causes of acute liver injury and inflammation insured and liver cancer, as well as chronic infected for life. After the injury, infection, short-reproducing virus in liver cells, which then Ngsal for HBsAg antigen Salha. And it is used Ulkipv process for excess levels of serum HBsAg and record as a way to diagnose the infection, for hepatitis B. It can be turned on or severe infections can develop at a lasting chronic infection. Current methods of treatment for chronic HBV include the a- Acrvrone which increases the August Alzh generator against human leukocytes Class HIA) I) on the surface of liver cells, and the next, but recognized by T cells Alaamg-Ouen poisoned for Khalaa 0 addition. 4 to deletion has led Zg 7; Alu / Sep, Janakulovar and 1 Gamskulovar and Amagodin, some effectiveness in the treatment of HBV infection in Mrerah experience. Knock additional treatment and HBV include a- interferon and Odenovaufer and entecavir and Tdddan 0 0 international Aithilzt glycol 0 Bima can be achieved fortified captivity through the administration Z Gore spray Addh and Abe to Lugg 0 or anti serological for HBsAg treated, it can &amp; quot; lead in August to HBsAg Mbt 0 or height Audh -209 - a land. &amp; quot; duck! Jenny to resist infection. It can be combined with antibodies for PD.L1 1 moiety in Alatiraa and methods of conventional therapy for hepatitis B infection to achieve a therapeutic advantage I see.

4) Veros.lalthab hepatitis C infection walked to lead Vnros hepatitis HC-V) C) to an image Ps 0 of NH Alakeab hepatic, Ta 0 de cystic injury. While the similarity of symptoms with infections Alatjh Q | to Akeab hepatic Β, the distinctive compared d ΗΒ-ν, can not land on the families 1 infected show for hovered z 10 to 20 Szh 0 .μ Elaj infection HC-V z Aetae -ob 0 yen a- Arvnron and Rsafberan. Will the parties promising treatment for the infection HC-V use the Shatt Albrooaaz; -elabraver (960-VX). Additional treatment methods include the following: antibody for 1-Medarex, MDX-1106) PD), and Pavaoudimap (antibody associated Baumvatidil Starr; n lipid Fumgori anionic Barivh rely on Β2- glycoprotein 1, Peregrine Pharmaceuticals), and the resolution of an anti (antibodies counter) Ε2 protein robe viral counter for HPV (the i Adal; XTL Pharmaceuticals, ATL 6865 - Ab68 + Ab65), and ®Civacir (Geloubeyolzn immune human anti-HCV for many clones). It can be combined with antibodies for PD-L1 contained in the invention with one or more of the methods of treatment of hepatitis C infection to achieve a therapeutic advantage. 5) Human immunodeficiency virus (HIV) attacks the HIV cells + CD4, .mma the T-cell lymphocytes, are binge large phagocytic cells and mononuclear and Allaaa dendritic follicular cells of Langerhans and Allaaa table / Almtgesh + CD4-and-so, catch a tenth defect Kadid immunization induced cells. And lead -210- -210-ΜΑ 32948Β1 HIV infection to infection to AIDS in a ratio of at least 50% of the individuals, and sexually transmitted, or give infected blood or contaminated blood transfusions Menthat, and trustees Rattler, my infected, or the use of needles or syringes containing on the blood, and transmitted Z infected mother to fetus offended childbirth. Symptoms can not be on the infected d HIV, or can develop has a case of nurse eleventh resemble the large subunit 'fever, headache, sore throat, malaise and rashes show host. Symptoms can develop into a state Qmor immune Advanced, .mma the permanent fever, night sweat, weight loss, without the grace of Assab, eczema, psoriasis, seborrheic dermatitis and diabetes Alntafa herpes and oral candidiasis and oral dowry. And transmission of parasitic infections are more common in opportunities Alzs patients developed infections to have AIDS. Methods include the treatment of HIV ways anti therapy Verosat.mma the nucleoside analogues, zidovudine (AST) either alone or in conjunction 0 p Didanocn or Zalesitapan, Dai deoxy Anocn, Dai deoxy cytidine, to Amedvodan, stavudine; Hbtat reverse transcription such as Delaverdin, Nagiraban, to Auferad, and Htat Albrocnz like Sakoenawer, ritonavir, indinavir, and Veldhaver. .memkn Combine Glades l Anti-PD-LI contained in the invention and conventional methods of treatment for HIV infection to achieve 0 Lise Elajah 0 6) mass of cells the virus missed 1 0 a concomitant cytomegalovirus infection (CMV) permanent infection and latent and frequent. CMV virus infects one of Hlaya Ohaddh land one of the'lkhalaaa ops cells Ahad, of inductors and'lkhalaaa for granular and remains Kat O. Land 1 Krereh to Gero 0 Q CMV &amp; lt include ;, land b wagging -211 ΜΑ 32948Β1 subunit (Oe one skinny and one to inflammation one of the glands and you fall) and 0 Yale because JjkJ to i 0 Lgh Gelml 0 J 7 Tjh all insisted 0 Aceh of 0 vital Gadat. Scatters the virus contacted preach 0 Odd A_es in .lbol; and saliva, semen and to some extent in the Z fluids other bridles. Lash occur E 0 Les Alataal of one mother and one of the infected 4 Li Profiling 1 Owoldi Through Shell 0 blood ministers equ do my CMV Alykhalleamve Althamin cellular virus infection 'Eetmd Alasyahabat drag; Mieh Abe to the newly invented! To kill non-specific and generator against CMV gup, Z leads to p 1 apple of Z 0 cm cells and increase the number of CD8 lymphocytes in Alkhala.a who Gaoih 0 + CD4 · ways to treat CMV infection include Mmada't 1 Ssat &amp; lt; Jasseklohir, and Hoscarzt, and Bdovar, but it is recommended Asuhar Ehgt in 0 RIP Z Azi. Lash Table 1 0 p between objects' for anti-PD-L1's Alo'rdh in the invention Ozk Elaj 0 0 Wei Se-Q name of the virus to cells - Alagda suit.

Epstein-Barr 0 Neros walked Af leads virus EBV) Epstein-Barr) to the rates ^ Wei Dalla Dhaka 0 No Rum 0 or Bikd Las Gela; a B. -oda 1 presser ^ o EBV in Adla S, a Presentation; Digdat AAC, A, Ralph 0 Sun led inflammation Alhak, languages ​​capacities, and Sekhemkhet F Alimdh the only 0 and 1 to Aldal. It found off Alakeab Kadi to Htdr to, and because

Satkon rack 0 of 0 No Akkhal ^ de ί EVB to the land 'z EBV is accompanied by the evolution of the cases of nasal. Thus, it can be a condition 0 certain such Zrm lymphoblastic Burkitt and Alatan Alber's 0 me that we do filter Agheirosh infections before these complications occur 'Li -212- ΜΑ 32948Β1.;; 0 Haile Evh 0 can be combined with antibodies PD for-L1 contained in the invention 0 p Tidho &amp; gt; Wineskin Aslidla treatment of cases of HIV infection, Epstein-Barr to achieve a therapeutic advantage. 8) ^ o 1 0 herpes to Boil ^ o Aaat herpes (HSV) has direct contact 0 p shame infected. Can be by me | skin without land, but they typically lead to blisters containing particles

S T_dh. Â A; Z in the form of courses of active disease Algtrut, which Cleanse Y guardian Alagat Hst 0 virus Ahbb potentially-ganglion to Aqirs spreads in a 0 Aadq walked that there are lesions on the face and interpreted by the genitals and interpreted by the eyes and interpreted by Aloala 0 In Bamad 'cases, can cause infection in infection AAC 0 Ag. Z 0 hope parchment Elaj infection herpes mainly with ease situations propagation Aqirs H'mmh Aloaad, Watch 0 t this race on a systemic antiviral drugs 0 such as: acyclovir (mesh; ®Zovirax) and Valasakulovar, and Vasesklovir, and Bnseclovir, and Alodola convergence 0 such as Doku 0 Adhul (®Abreva), and considerate 0 Aztadin and Zeladhan 0 and stillness Soha &amp; lt; machines a ^ Wei 1 Kamzh virus 1 herpes y 1 t benefit Secret &amp; quot; de Ezimh 0 and-possible Table 0 g because objects Lhasa g 15 PD.L1 Ashe 1 rose in .lachteraa 0 p ways' traditional cure for infections loose any p.

Therapeutic advantage. 9) virus HTLV 0 Il Aaaaus Lucky is not a one-Egawh A'brah τ (1-HTLV; 2-HTLV) p no 'for A_l. , Or RSS, Maeh 1 Ki, 1 or bad blood to DD. A 1 ml 0 j b {20 "τ ^ b j Th 'Z hoody to Rt Hri Dzt; ivory know -213- -213-ΜΑ 32948Β1 Atalqh d Thl (eg, Tiaj IFN-γ). This leads in turn to suppress lymphocytes Th2 and reduces Z production of cytokine I (such as 4-IL and 5-IL and 10-ÎL and 13-IL), I - in a reduced capacity of the infected host to achieve adequate immune response to invading organisms and thus there needed to achieve Astahabh dependent on Τ2 (for example, Alttme parasitic and production Alodjaam anti mucosal and humoral). Lead HTLV virus infection cases to the possibility of infection, which produce μ] 0 expanded bronchitis, inflammation of the skin and cases Addoy Algaiqh b .Staphylococcus spp and

Strongyloides spp. Leading to death due to multiple microbes Suppurations. Can Woody infection directly HTLV Oevia injury Blukemiaralorm lymphoblastic cell T seemed Mine 1 n 0 as well as advanced motor nerves upper-causing disease demyelination known D HAM / TSP · It will be the liquidation of cases of latent infection with HTLV Nat Wald 0 Mystery, Doria Ezimh 0 can combine objects l anti-PD-L1 contained in the invention 0 p 1 wineskin to Ylaj Asli 5 cases of virus infection HTL to achieve a therapeutic advantage. 10) Fros HPV Yu; Aaros tumor neighborhood 0 J human (HPV) mainly on the keratinocytes, which Atakn Sourin: Leather; E F-to Oalhh. Believed that HIV transmission is through direct contact with Rao activity \ λ: It can lead both the cases of infection Vnros HPV dermatologists to injury Pal 0 milk and cases of 1 de underlying cases of recurrent infection, which can be controlled from 0 intercourse host 1 t Ttak in symptoms and hinder Zarr warts, but leave host led us to transfer the infection to another den -214- μα 32948Β1 0 Ekn less friendly to the HPV virus infection developing certain cancerous cases, such as the neck will Mrtan and ERG and penile and oral pharyngeal Alrtan. There are no treatments Mrovh Ddoy HPV virus, but the current method of treatment is the use of topical Emekuemud, take 0 boggles my immune system to attack the infected area. Mchkun and liquidation cases of latent infection 5 Maiors HPV Nat clinical benefit is great. It can be combined Glades anti-PD-L1 for 1 to incoming to the invention with conventional methods of treatment for cases of virus infection HPV - a therapeutic advantage. C. fungus 1020 Amac that Woody cases of fungal infection, or disease 1 to Guetrah, AHA to ob infection or to the possibility of Asar families and that the weakness Afh devices by internal Albkipria AKA 0 and be .lthchin against the order 1 z 1 Guetrah &amp; lt; O u 0 per Ade, Od Allaaa 1 Vadlh 1 white and 1 cells 'charge of 1 large and 1 to 9 Hlaya insisted Gaoih cells August August (NK). And typically can not be one to spend on Alomrad.laftrah by r or I was 0 mm. 0 included land one of Guetrah enemy one Veh 1 for systemic 1 Btjh Saadoy up E 4 Z land one libel convergence and land Alguetrah spherical Odh Aldhev diseases Alguetr 0 of counterpart Awolo 'Z of infections 0 to Mzdh Aptjh Z 6 Alttm &amp; gt machines; Alguetrah, walked Atae fallow 0 delegation's PD-L1 Ashe (Rose; invention PR Epeshkd Metz 0 of 0 p or after any p ZF therapy S Almrovh FH The land | Z Nrih Hamah 0.0 Btjh reason 0 to Gdhat August Q 0, Barr &amp; quot; e Z lands &amp; quot; books b 1 Astzhak produces Rardh infection Aube or trauma of blood in the blood Weid 0 n skin -215- -215-ΜΑ 32948Β1 Wall 0 Zam and Agah aKA 0 even 1 de Avklr. k- that Akdn AAC 0 initial 'd' RIP RIP d can F Anh land b Basad Aloiora 0.0 Ekn! n  except land in p Zlo Z d. jj 0 love a; z shortage j S 1 Z 6 aluminum h RIP 'Laden 2 of 0 Laage S 0 friendly ^ Wei dermatitis .5 Z ;; Aalazdl ed' Idalozdl ed 5 intravenous injection Bomvunbarasnn of 0 the land of; Atril, for spherical, trafficking 0 Sep Coccidioides immitis' Eoal 0 z satisfied with the type Bala.tial and-Tj ^ Wei Lord AOP or supply and Levi blood ed RIP Hir in the father and Itags Bikd] DDS Aljk and one father Aljsa 0 and Adam and my pain 0 for Wuyi 0. to Be ed 1 ύΑ. Krd initial without incite (60%) or Weihai land to land Aloidro Here E0 Ekn the second leg Μ occur, pulmonary and inflaming Aai and Aksif Araoa. -, μ Aloerad God -bn altruism disease Ouay but-with Algeldah.i the F-Ed; Dade Aawat uh 0 r not 0 Rey Ps snitch 0 m b Sah Dloal and outgrow and Avhl; and his delegation R-R and j Alfdaaa.i deletion of inflammation 1 F 0 none. Z Z Amahb land in Ala 0 0 d a Yale 0 0 p / x 'for AIDS. Pray a positive treatment of land Alghleral Kru-H z ô) j ¥ jrf 15 and Adhakrz 1 Zeul Rvlokonzul, and Khahah Dllenbh viscous Alolana &amp; lt; Yale machines to land z pain 1 Bast. CM treatment Accor Aadsbh usually give Omgutteresf B Dar F 'that land flour Altzh, resulting BP Histoplasma capsulatum, a righteous p land. Balastfshaq infect thrusting 1 g .lthbki endothelial where yeasts accuracy lies in the Khala &amp; quot; not one of the big Almaghmh. This can result Almrdha! Hyman 1 pulmonary infection ops or Rara Hh disease destroyed or disease spread in one blood mainly includes Abe Abani and Alod device

CY -216- -216-μα 32948Β1 mucous glands Alodregalah. The languages ​​are activated aunts attic 0 Wei cam in the land of impaired Haaz immune to happen, as is the case in the RIP AIDS 0 0 Bmcn be Akaard .loola without Oer 1 or z Yin love Oars Hbbhh land one of Ozglora; 0 as upper in reminded Alakouab pneumonia and pleurisy and cavity pulmonary'zkhm SS . Tch 0 for Moaha 1 Zthar 5 disease on the reticulo-endothelial system (enlarged liver and spleen, including Allimgaoih glands, Y blood, lack of balls 1 blood-white, low blood Sfaj), Father membranes (Rah one and struck mine) E gut (one absorption), and not as an end Alodr. ha. In Z that the initial infections automatically turn off, when accompanied by Ngs in S. Kitt is the case 0 OpenID AIDS, the setback be nailed and dearly attendant 1 Khab pneumonia in one blood, ARDSj 10 and clot diffuse intravascular (DIC) and the spread of pimples papular in the blood and'khab August '0 have been treated using the exact Akh Omgooterresan B (and in particular trauma r S Almassabzn infected deployed heavily in the blood) and Alontrakunzul and ketoconazole. The disease Algarah counterpart spherical, resulting BPB Paracoccidioides brasiliensis', Ouarh for fungal diseases written by inhalation can produce R'doah infection Aube or trauma 0 raised in 15 one blood and includes mainly the skin and Alogshh mucous and 1 for your Akkh 0 of Albe 7 Ni'vd Alkglerah 0 can be &amp; quot; universe 1 infection without land initially land and Y are then rebound. These infections are treated using ketoconazole and Aztrakuzzul Slgoma 0 and j. Aggressive systemic fungal diseases that had the drivers of land Achhanla include, Laura occur in Alao 1 Il shortages that Amos is aware, the candidiasis, and diabetes mellitus and Almtkhvaate 20 Archathiat, and Alomr'd Algarah mucosal disease Almtxiat Araunh. Will by increasing Λ; -217- -217-ΜΑ 32948Β1 immune Alastahabh in a weak immune system 0.0 Bmcn to 0 that the original 0 or oxidation for PD-L1 Ashe 1 rose in only 0 Hraa Z't b 0 of therapeutic in the treatment of these Almrdh cases, especially when combined with treatments traditional. .ash Alakh &amp; lt ;; \ E \ Q 1 v (1 \ u 1 c .sp Candida albicans .; C. glabrata, c. Tropicalis) and cryptococcosis (output due to Cryptococcus neoformans) and diabetes 0 Rthat (1 Btj because iA. Tereus iA. Fumigatus, Aspergillus flavus and A. niger) and food-land &amp; lt; Yeh granted \ 0 g 1 Dagh some .spb Rhizomuco. Absidia, Rbizopns arlis a Cwnningbawella 00 Saksenaea spp. , Mortierella) Bastkhadd'm and 1 extent or \ / I Z: E 0 0 J Azrl Lurker / Mazul and Antrakounasul and fluconazole and Omvutteresan B using Alglosatosen or without. Are treated Almtxiat pulmonary disease (caused due to Almteixeih 1 pulmonary Prow 0 Ye) who cJ Aouadh -ma &amp; lt; a Z firsts ornament to Algeryat using Tri Masoubram- Slwamytotxol (-ΤΜΡ SMZ) and pentamidine Aazecionat intravenous as well as Aldapsov and? 7 A-dapsone, and Trimitrik 0 data and clindamycin Premakowin and Otovajnon . ci Makhana re-bashing disease spores per- minute due to a small parasite spores of the first ornament to Algeryat. It is a single-cell organisms lobby antibodies fillet instead z mitochondrion. Live Alkabat to include may Hbb injury Osher land contract 1 Lee \ Enterocytozoon bieneasi d Encephaiitozoon helleni Encepbalitozoon intestinalis d d d Encepbalitozoon canicwii to applicat Pleistopbora d Trachipleistophora Trachipleistopbora anthropopbtheray hotninis d Nosewa c5nn53i A Nosewa ocnlarnm -218- -218-ΜΑ 32948Β1

Brachiola vesicularumj and Vittaforma corneae and Microsporidium ceylonemis and Microsporidium africain d .Brachiola algerae Aafd that cases of infection transmitted to humans by direct Alatmal with animals, or water, or as upper Allut, for Mmap RSS. After the injury of host cells, proto-soul with a bond grows Altoaldeh cells divided or many -rh nucleus can have complex life cycles include sexual and asexual reproduction. The Gat what Q 1 cm infection Akash 0 n generations Amkaaakih and land Azt and Hafh cases of infection Dlqh Alorag '0 Bmcn that #NAME land Rirah of the disease based on the species and the situation immune to shame an asset Z 1 for inflammation conjunctiva (such as corneae Z chronic diarrhea and one absorption and wasting (such intestinalis £,. Bieneusi · £) 0 -asd baste Elaj disease spores kind minute. In the intestine and Abtcherh to give Aloligdasul. _memkn also use topical application of Gomajipn effectively to treat inflammation of Zen and conjunctivitis whistling Alorag 0 include Alakagahr Alokhrtma medicines anthelminthic (such as albendazole) and newcomer 1 T. vital (such as fumagillin) and immune rates (eg, thalidomide) and anti-firsts ornament (such as Brobbasul) a D_ priorities Alkhalig lends a; Z output Sep parasitic disorders such as malaria and schistosomiasis and diabetes Lesche 0 Maveat Z among the important health problems and tableware in developing countries. imposes this land one Z limit; t certain Nzna any invading immunity shame across many Allosar, including: 1) 1 Lsh inside Ath cells (such as leishmaniasis), and 2) Altefinr rents generators antibody Altahih -219- -219-ΜΑ 32948Β1 Aiab 0 s) and 3) «V b Kkhala, the I p Dalal RIP 0 o Z edit your b 0 such as diabetes, but 0 Harsat), can Ave. Amtt made using Alqoqr Alkepplo Lai; Lugg's 00 Rtan and 0 p Zri 0 to Oeghae and CNF Alahar global RIP 1 to AIDS z cases Leonine Elka 0 No ed vji \ Hcderda Z, Plasmodium spp a .Toxoplasma spp a .Lelshwania spp d .Cryptosporidium spp for. Trypanosoma spp and parasitic worms. , _aa -...; Mussels 2 1 0 lattes the DWI chronic infections resulting from the first Sat of cells 0 0.0 0 possible combination between 1 to 1 Osam delegation's PD-L1 contained in Alachter'a p through &amp; gt; Repair systems for Ikl 1 0 entangled with or before or after the standard treatment modalities anti priorities cells. .lmlria, Which are produced due to the type of parasites Plasmodium began (like malariae &amp; lt; -Ρ. Ovale 't, P vivax iP. Falciparum) infectious session Kkash Moshe neighborhood grows in Ate Ash Ba 6 Z 1 Odhuvh. Once the transition to humans, the 5 these organisms Albounmyh invade liver cells-e Tghaev me without any urge 0 Gael Anthabiy. Badeb Drew and show him this Alcaqat Keh, resorted to  Almnrozoat, red blood cells and then phase begins password cons of the disease, which including fever and feeling Bakcharirh. In areas of the world where the infection is and in what, ^ n all the, Touggourt was suffering from chronic infection continuous low level ranging Q rate - the average, with increased levels of IgG antibodies to provide protection Q Ayrosoat enter red blood cells. Tech 0 tire 1 Ayqr anti available for malaria Halia for the clinical treatment of the disease and prevention of the following: Orbmther- to Omegantren (treatment, such as Coartem® and ®Riamet) and Ortsunat- Omodako (treatment), and Orvakowin- Broujoazhl, (1 for the treatment and Aloia; of 0 such as ®Malarone) and Einf (S. ) 4 -220 -220ΜΑ 32948Β1 and chloro / yen (one for treatment and prevention) and Kotrigazer (treatment and prevention) and Doxycycline (treatment and prevention) Rmeglukwiyn (treatment and prevention, such as ®Lariam) and Bakowin (treatment at P vivax and Pi ovale I lobby for prevention), and Brojoinel ( prevention), and Silvadoudi- Peremithas (and prevention) and hydroxy Krukos therapy (treatment and prevention, such as ®. (Plaquenil will Khamlal Tntat T cells is active, it can be antibodies PD-L1 August 1 rose to the invention, a therapeutic to help filter parasites that cause malaria. be disease ingredient, Nah BPB by parasites of the species Toxoplasma, in one VLP asymptomatic, but can lead part Formulate 9 t t injury / z S.ra 0.0 possible that -raouh of inflation lymph nodes Hamid to ^ d r; to Alla tract infection 0 my Muay deadly . sacs infection sources in the mussels include a 0 1 0 Khazer mussels or lamb for August or kj.Ull Jzeta pain: and cells which graduated 0 p feces of infected cats. Infections occur in grape humans through one of Qmah one in it, and can penetrate Oopt cells and &amp; quot; Tikka; (&amp; lt; &amp; gt; Ka) with '.. b 1 Båge 1 Wurayah) in every cell of Raaham. 0 possible that this Alkatat Ij pressed for Alra 0 0 0 Wurayah of the vesicles filled with the bodies of infected Tnao slow (1 Alcaimat Beard 1 Dgah Taiih) 0 &amp; lt; Live for long periods of time, leading to slaves infection 0 Zmzh Kamzh 0 and-kun families y 0 v 1 for your Almghaei 'to weak Khola tucking Sorn Alaaahdhir Ace 7 ce or Z 0 Trn Q HIV specifically susceptible to toxoplasmosis nation 0 x 0 for .lodoah' for the employer to treat d; E curved 1 T. The initial Z follows: Peremithas 0.0 G and without anti 1 T. lively with 0 love it (such as Scadazs; Klindaamasinn, Rabin; Od-) '-221- -221-ΜΑ 32948Β1 can treat toxoplasmosis inherent with antibiotics such as Otuvakon disease 0.0 G and without Klindamahbn 0 infect leishmaniasis, caused BPB Tg; DAT 0 n Ra iLeishmania cells Almke 0 of pronation 1 Rh

Almugodn in the skin and viscera and transmitted to humans through flies Widowed. Of that there is little 5 a refugee 0 or anti quality cauterizing or .mma but not Rjd at all, the fortified who "contributed to the occurrence ornament E 1 t of active T cells is the only way through which the biting 1 E Elj 0 of infection 0 survey injury disease to Bhmanaat A not old by called Oevia UN d E 1 1 0 Q Thet skin by several Oraa of leishmaniasis are: L. tropica and L major and L aelhiopica. Uaj injury disease Pmanat world Alhdbt BP Edh Oraa FRP z 10 »Mexican and braziliensis! V 0 v 0 Q Alabt 1UJ 0 Zelo Hoya Z 0 in m &amp; lt; for * \ cells, but reaped disease Rra -oda u 6 a, T. loyal to the ABS. In I p 1 Ala.l lattes) in a -mm Mootha Allaaa Tkdn Mkrta or non Kai ', the b Ik 00 N. Aagar cutaneous leishmaniasis Lars' h r all in the Y-Z vomiting NVH (strain L. aethiopka E L. Mexicana} In Lala Ml a land . 0 Zi -bm 5A in &amp; lt; guardian Knleia, a; n except 0 Touaba scrn disease for young women Nii Akkl or Wax '0 p 1 1 t Z 1 Q .lsgarh Aachaouil is Primers &amp; lt ;, Lala , but &amp; quot; Yt ops &amp; lt; t L, can Sat pixels not z first uh 'no; ranged p I diabetes shows; 0.10 z, t and Emak Y-FM. of the disease, to the valley and'tefi' r additional; Labs-H j t; fetch Jack 1 Bjb T. Afhi 1 the one who Bim in Adla love any z ed 20 to the ground and in the images; Alot.be be Althamin Olney nations of the Hddla trotting Ge -222- -222-ΜΑ 32948Β1 f or Ge 0 and the Aud, shows Murr 0 u are / Ήβ in p; &amp; lt; i uu El0- is entering the mother of cytopenia coming, Ao spleen and Alaeltag Akzaid d. &amp; quot; .TNF longer Aptlgr 0 1 yen Il ®Impavido) and age Z IRRI Lalai Adodhir; gu's 0 Laage cutaneous leishmaniasis and visceral disease. It produces d 0 E Khga 1 T. Alobo 1 g, but 0 0 loomed because of cases of acne Wei 0 0 n Oopt Allaaa Z Ra iCrytosporidia Z , but &amp; quot; human capital of one of the direct feces of infected hosts. -s That we do Edoy 'of tissue . Mokha 0 t in the intestines to diarrhea · The Ahher land of Bach 0 per typical ^ Wei 0 sharp, but it can be true Mzmian not 0 Q A in Alorad 1 Fein Iern XY AST 0 and be baste 1 for the treatment of analgesic typically not b Aba 0 and y found 0 to 1 Brorsin and Alozatrome 0 age c 1 deadlines (such as ®Lactobin-R) Q Aquar 0 Alajehh in Aie E 4 Z infection. Calls Almtkabaat disease, caused due to parasites 0 n Ra Trypanosoma &amp; lt; like 1 Brucei subsp. gambiensej and rodesiense) humans and 1 for 1 as a show of cattle to one bites TS Zlola 1 Ne. The problem posed by the pathogen Almz / l in camels 0 Ieqh Ten to the back of generators against superficial Mokhtlgh that. Qmaz 0 ravages of a ^ Wei 0 Ymtoyat 0 Rngah 0 n immunoglobulins of serum non - specific and non - flimsy 0 include methods of treating disease Almtkabaat to give 0 a DVI intravenous 0: Bzta 0 condemns (August's · lb gambiense) and Aloramin intravenous (clothing for Tb. Rhodesiense) and bilge and melarsoprol 0 p Without Alnegortimoks . -223- -223-ΜΑ 32948Β1 share .lty) to worm a 7 Tjh of worms 1 to Mtillh (0 such as .Schistomsoma spp) and Alded 0 tape 0 of confirmed 1 n 1 Beard in Alitzhabat 1 general Dap cells Aloizinofelih and bridles anti resistor, which Alastahabat that rely on cell T. 0 without Albulharsat (aka bilharzia ); Avatjh BPB Shistosoma mansoni and! s. japonic and Haem 5. Atobium and S. mekongi Dorz Haava as 8 per Alaa, will then Aahs land and turns to Tgellat, violating the snails and-Sthae several generations of Houselat spores. This in turn produces vesicles Khalaiv animals Nat female humiliation and that b 0 righteousness of blood in X'lepeshra in the form of worms Blharsa move initially to land balances and then to 0 females gather these flukes then mated and &amp; quot; Dbed in mesenteric veins. While many Dzvl the eggs into the intestines and come out with Adraz; FBM Ahthaz Z eggs in the veins of 1:00 a 7 endodontic TeX 0 T. mucous BAS Q veins of other members of the body. And be one of the Albb Alor 0 1 J particleboard Kahb eggs Alchtdz is Anhdd trauma to chronic disease schistosomiasis. Party treat schistosomiasis on Aeala Praziquantel® and include; Laboon and; and Yzloan (s. Mansoni) and ®Mirazid. Can be classified as cases of infection worms Aharitdh to Mjmut; N, Ahd'hma accompanied 0 1 Abalgh that the striping that the intestines , such as housing iTaenia saginataj Diphyllobothrium latum and'lta I Tathber 0 Mas is humoral. Ahamuah Acanih 1 describes Kdan tapeworm 0 for larval atopic u Father &amp; lt ;, Hymenolepis nana and Echinococcus granulosus and Taenia solium to Ih 0 w occurrence is 0 responses of Ki Anel Z is deafen the stomach and intestines and protective antibodies to the vaccine. 0 E 1 is d Ducat for brother &amp; lt; Infections Alharialah worms that Thib humans who -224- -224-ΜΑ 32948Β1 when grown in the liver, lungs , or brain or kidneys or other 0 n Oedhae other body μ lead to Zqan Gdari bags. Pray treatments echinococcosis to give syrup 0 0 F Azul Azul and Aschl such as surgical removal. Or pressure or Altokhaev or Chet greater 0 are worms funicular 0 n more than 1 Kdan Ashthaz 1 1 t Tahjb humans, and B in injury disorders such as diabetes Target and diabetes Agheilarriet and diabetes Alostoaveat 0 0 Ekn trichinosis that Anth D 1 E 1 to Charimat, Almath because iTrichinella spiralis 0 n z) lived up 1 T. Τ spiralis in meat | for uncooked or cooked meat b? O &amp; lt;) Kerdr · In humans, raises this one Frei termination ^ by humoral strong 0 p high IgM, Mtboia Baztaj IgG, then S totally unknown Sedan 1 t name ΨΪ antibody by Alrovh way Adlaj only T Allimgaoih cells 0 Chl to kill the adult worms in the intestine in thiabendazole, while there is no way Mrolo treatment Elkez 0 Alerhat 0 v 0 I 1 t DD 1 P Alomakaris, Almrovh Oehta as the circular worms giant (Ascaris iQumbricoides p common Alotfilat that infect humans and that results from digesting contaminated with materials 1 Raz. while the hero S. long Fsat time without they show any symptoms of the disease, neighborhood 0 w j 0 Shell Arahal telegram through the body, it may Hbb in the viscera damage and inflammation of the peritoneal otherwise 0 SAP and enlarged liver or spleen, mechanism and pneumonia. Pray parchment Hlaj disease zero to give mebendazole (such ®Vermox) and Arazs and pyrantel pamoate (such ®Pin -Rid®, Antiminth; ®Ρίη-Χ) and Ornasul and Abd'zul p 0 and 1 without Lafer , Zain and the tendency Rsorcol and Santonin oil Chenopodium. You can give objects -225- -225-ΜΑ 32948Β1 'to counter for PD-L1 in conjunction .lachteraa 0 Aoohbloobad E ^ E wineskin Almnkurh therapy for the treatment of diabetes Flee. Alassane Agheilarriet catch a disease, because worms Naih funicular Alguilarlo 'Bois 0 0 cough insects move Onchocerca volvulus who reviled the injury or disease Onchocerca defending one of the barn blindness, Boamth black fly bites. Inhabiting the infective larvae themselves under the skin and develop into a very Ddeddan, and Terre Astahabh shame - generating fibers and Tf large amount of Almikrogelarah to Q 0 t ci skin bumpy Ann raises inflammation of the cornea or retina BBC inflammation - is 0 deletion in Aetam Alqrveh 0 produces d 1 E Alguilar.dat 0 Foy Q infection. 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5 Oehta Allaa yaws 0 Study in the blood. And, making that! Permanent infection for less Strongyloides x J; V Elegrah! Faithful, it is the Thaeh 0 1 1 .mamrd injury to the bitterness and Crohn's disease Ora A-. Z This infection problem in Alawal Almassabzn with HIV. Methods 1 for the treatment of Alambrovh's Strongyloidiosis {Aafenrmkzn or Atzul or Habandasul include but this treatment kills only adult worms 0.0 p necessity &amp; quot; Karrar bold 0 10 H0- Altgheih Gan used Altqah or giving material generated for and against - against the disease for Ohaah Q your responsibilities to ease contagion effects by BP the disease. It can use &amp; lt; nature of the Open 0 0 Preheat intercourse host on generators antibody is Argob which are not only on the causes of infectious Alomr'd but Oifta Alencih on the infected host disease (such as cancerous tissue). Ai Z funky; 15 are derived vaccines Mbbat Alfievh or Alambth diseases, but they can Oas \ a peptides represent Fmm adhesive BP land of the sea and started cm an administrative Bo't complex molecules compatible Inihta Rasah (MHC) as Category I or Category 11 . considered 0 and authorities F peptide of interest are those that are recognized by T. cells of an event, it became clear that the combination of therapeutic vaccine and give factor hampering PD-L1 on CD8 cells + T 20 Almstzvh led to improved Alozigh and control viral in Nmong mouse infected infection Ps 0 Study

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-227- -227-ΜΑ 32948Β1 up a 0.0 Ekn 1 to collect bin 1 of Assam · Ha et al, j.Exp.Med. 205 (3): 543-555 (2008) described in this Aloqh vaccine generated antibody (such as administration before or a PD-L1 Alamada 0 for concurrently with or after) for the treatment of infection (such as acute infection and Elms 0 cent) Adabi of Adro Alheirosa or bacterial or Algara or run correctly rudiments ornament as well as in August against the ashram 0 g pharmaceutical Dosage: Amemkn doses vary the concentration of the drug required SAT accompanied 0 No Rardh in the present invention based on the desired use. The owners aware of ordinary skill in the JAL Peggy determine Aharah Almnash or Mar Algasp administration. Animal Altharb provide credible evidence to determine which Aara 1 T. effective for the treatment of humans. They can identify effective doses to follow the principles endorsed by all &amp; quot; The Use of Interspecies Scaling in the Chappell, w. And Mordenti, j. From Toxicokinetics, &amp; quot; In Toxicokinetics and New Drug Development, Yacobi et al, Eds .Pergamon Press, New York 1989, pp.42.4g g 0 made using the method of giving the urinary peptides or antibodies described in this document ^ En neighborhood, can range quantities of natural dose of about 10 Madhugram / km until ho me 1 100 mg / kg gm Idna or more object weight per day, preferably ranging Z about 1 mg / LMO / day to 10 mg / kg / day, us; the Saar administration. It can be found Ouay 0 doses Guide Trth Delivery Anhddh in the literature; see, for example torrent, Br'ouat equ p 1 US 4657760 or 5206344 or 5225212 numbers. Located Z 0 n ^ for 0 to Akhcaa formulas Almokhtlgh will be effective 0 p ways Almokhtlgh treatment and disorders Almokhtlgh,? N desired administration for the treatment of Edo 0 or tissue. Maan may have to plug it means rejecting; Meh not different Q Em 0 t -228 -228ΜΑ 32948Β1 or tissue to another. Moreover, it can Aea 7 E Jerouat Brasit 1 Atae Way. Or eat Z civilian side separate Aeala, or by Walter-b Eduasal 0 WAP operations Alatae Alkrrh 1 Lenny are several nest mother or longer, Builders &amp; lt ;, Adla enshrined, all Alat'r in treatment?, Repression required to land surface-5 0 p happen, Hkd Taku 0 there Onglmh other doses Mvidh- will ease monitoring Ngdm this treatment Balolhrq traditional tests. H. Give sorry 0 no framework 1 E Eselj present invention, the torrent but not limited to, Asg 1 Mead composition and Adaila Is to 0 breast object in need of treatment antibody to PD-L1, preferably A.sano Tabga roads Almrovh, such as the administration of intravenous Kplah or infusion meter &amp; lt ;, over a period of Htrh, or intramuscular, or within the membrane proton, or within Amaj and'lhabl Shu / a, or, under the skin, or inside Manhal, or within the synovium, or within Kl'b; or r &amp; lt; Coordination Nations, or topically, or by Alamschavy. ;. A 0 0 pw Hmang a favorite, they are given the formulas for Cash mammal Balaatta under the skin. And Lzv 4 15 0 E 00 possible exhorted formula using a syringe. However, there is another slant to give August &amp; lt; &amp; gt; Ial 0 .lhakn (eg ™ GENJECT ™ j INJECT-EASE); Pens 1 for injection (Mesh ™ GENPEN); 0 (-229- -229-ΜΑ 32948Β1 and Adu 1 T. injection 1 Klhaia, and medicines 1 T. useless needles (such ™ mediector and BIOJECTOR'M); and Ozz 0 of recommendation 0 a's; repast cJ slob 0 in a 0 extent Alazj the ring, the present invention crews unit giving a single dose. and include Tllt 0 only 0 bits Z container Nat Sgh dire of a therapeutic protein or body Advantaged, includes both 5 Z Amehoguen Anouhadh or multiple closets Saabakh refill. the Amhakn Mabakh refill provided, for example, the company GmbH, Raensburg Germany. it will depend appropriate dose) &amp; quot; effective amount therapeutically) for Pro &amp; quot; between, Z 0 cell 1 for money; z case to be Alab; and Ndz situation and extent; and 0 A. If the blood Aea 7 E PRO 0 Tzn to land and Iena or therapeutic; and Allaj Ababak, and Date is clinical response to the disease and Ap antibody 10 PD-Llj; Almamdmh formula and shape, and the experience of the doctor will Atelj 0 0 AFP Aeala palpation for

Anti PDLlJ of the disease once and one unit or over Drlo Z 1 Alajat u Abeh of the disease at a time when it seemed diagnosis onwards. Luohe Aehlae Lean 1 FD and PD-L1J monotherapy or in combination Aakkakar p 0 or 1 Elaj other T. Moghaidh in Elaj pressed him 1 0 quality of AAC. For .lamadadh antibodies for PD-L1, you can Hraouh 1 Jrah ops 1 educator Z 6 15 0.1 20 mg / LMO loyalty 4 Adha disease. However, p Htk be Jrouat see useful. It is easy to monitor the progress of therapy using the Blue Aohleydah. I. Altsaa Tools

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Ahng 0 for F-1 is accused of curbing anti-p 0 0 bugs only Adzhlah Mmuk Aq 0 to 2 ^ 3 and has increased the intensity of washing dishes. Gradually. After four role 1 v 1 to Gail, it was observed enrichment of SPS. Were collected 96 Zselh of &amp; lt; g b VH a and VIWL to determine whether they are related to a qualitatively 0 every x PD.L1.Fc Labrie and Afoura &amp; lt ;, alike, was the work sequences PCR areas changing as Dave 1 Vil s-d a) for 1 Doapt Ahlgredh. Has been re-Tzquil original clones to IgGs Backh 0 Ttq a 7 and 7Η Western media in y) Say LPG3 and (LPG4 (Lee et al, supra; Z acknowledged &amp; quot; B 1; t &amp; quot; f Bach 0 per Zazl in cells CHO Cdaah, and Aknqah pole Protein A. the Tviem antibodies omnivorous 13 to see ^ Ri to impede interaction between the integration of PD-1-Fc Akabl soluble ^ L-human P5 or 1 Ira, which is expressed in the cells of 293 routine (iCso values ​​flash in table 1. the upper half) 0 has been selected YW243.55, Lean Otml counter with a value of 50 a solution to impede Artat PD-L1 -233- -233-ΜΑ 32948Β1

All my b 0 1-PD Neveh p less gc Ken both Z PD-L1 Valley Dalara '(LDL [). Of | rein | Q | the one who's 0 Iad led Mnaren FD both p Larry types Dalolo (Onv Please choose a Lanz of humanity) will Lehrer 0 for Ats L b 'n z dream Assad, but-I was E 0 g 0 in August; c S 0 can Amedf my bear Ala- Z Ed. And it kills it to avoid confusion caused by the use of Del specified Mozj 0 create groups to improve Please choose a seedlings derived Z S-1 I Vh 1 business for Gajmad pW0703 ( 'to is derived from one of Gajmad pV0350-2b (claimed Lee et al, j. Mol. Biol (2004) 1073-1093: 1 t (34Q shame Z Raz Alaie (TAA) in Gmeha Moo 1 x CDR-L3 and display Fab and single parity on the surface - Alkraa Μ13) CQ 1 core of 0 Hmuh for i 0 Bam Madalat Almng 1 Rh Thala Vh) lu) for Nael concerned group 7Η to maturity of familiarity. It was a bad 13:00 0 both Adharasat 1 Hawwaebh rigid and soft in Ndg familiarity. For random rigid, it was one of Achar Ahawaia Ndjemuah Khgegh series Nat placement areas CDRs Althelat trot 4 of Mother 3 P using the amino acids designed to reduce the antibody 1 Jharih 1 Study of the realistic limit was 1 Nhlal DNA Almsam 1a Tqa 1 was Wad in .Mol RO) ((2004) 1073 -1,093.340, 0; 0. The door to the nest 0 Aiah imams, were Add'v August 0 s B Dmo 1 x 91 of 94 and 96 for CDR.L3, and 28-31 and 34-35 for CDR-H1, and 50; 52; and 53-58, and CDR-H2; and 95-99 and 00 of A's CDR-H3; was chosen -234- ΜΑ 32948Β1 Mjmuabn Mokhtlgtin of CDR loops, and L3 / H1I and L3 / H3 for Ashraiah. in order to achieve the conditions soft Grill, which is the maturity of the rate entered almost 50% when inhibitions selected, DNA synthesis was Amualld alloy 70. 10-10-10 rules that Ngdil nucleotides from wild-type ((1994) 1251-37: 1233, .Gallop et al). Do not sort the macrophages to produce improved familiarity were exposed Nael Almmelthmat previously determined to &amp; lt ; g dishes first Adorh 'drawstring 1:00 or six cycles Z rice Anhlol. Andjemoat been stored against PD-Ll-Fc human and Larry on the grass

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-235- -235-ΜΑ 32948Β1 Z must be generous (5 de Jama 0 l) for 15 HD Der p 0 ^ August heat 1 to t 0 Alhgev b connects tambourine processor biotin macrophages. Wash and sleep assets 10 times d% 0.05 -PBS Tween 20. To determine connecting Alhgheih, was a 0 Thaz b Mgarzh containing Z Almakemh 0 EF ^ F-AA Bam Maljtha biotin on Maftah Bgiotraviden dishes. The elution of the Almke 0; furnace 0.1 p HCl for 20 minutes, and the equation d pain 10 Hjmmnamular 11_ρΗ, and Alamaa_rh, and Alhl to 1 Korh Azib. B 0 d it was Eger 4 1 E Z Dor't others Q of the solution with Ziqtin to increase the strength of selection. The first is the absence of rate Alusil p &amp; lt; Coordination Z RC 0 g a ^ Wayne Almtahedv processor Balbaos of 4 nano Molar to s 00 Nano 0 and Lahr and the 0 Subject to 1 THB ci, for the selection of waffle adding excessive amounts Q Arrutin 1 rate objective of z processor Balbers (100 ~ 200 times) for Mnavh active links weaker So'e score a free one or Rh Id 37 m. Well, it was Khgd Almmelthmat income (0.1 ~ 0.5 H.h 0.0 l) to the amount of less than Z linking Mmelthat background. For the goal PD.L1 Fc gari, it was a way sort Almmelthmat similar to the previous method described for antigen PD-Ll Fc Alepesh 0 Rey 0.0 p some minor modifications. In particular, the use of PD-Ll-Fc Murine processor Balbewtonn a concentration of 100 nano Molar Ldhar Aglul after the first Aldroh directly from the wash Alotaq 0 at the fourth session in a row of washing Aglul, was Khgd wizard goal biotin of 10 s 1 t '236-' 236-ΜΑ 32948Β1 Molar 1 Li 1 nano Molar, and has added an excessive amount of 200-500 twice Q target Z target processor biotin counting degree room temperature and then were examined 0 Bel Madjh familiarity Rh see Baskhadd 13:00 &amp; lt; Aiqa ELISA clove Z high Azj described in automated example. ELISA Vsolgh output high (competing single Stain) growth taking Stahran of Raz 1 Korh Daphne and Alahdesh J 0 P PD-L1 Lasry and Aqera 'E. Wacker-Sep 0 were planted Aqmrat all night at 37 pm in the 150 mezzo reiterated 7 weak and i 2ΥΤ with 50 curlers m / ml / Haas ΐΕΐ.Αηΐ K07J in Z 96 Z (Falcon) p z S 'then p Mzra 0 0 n Mkea 0 pour 0 Mape easly' &amp; quot; XL Z Mei X (Z p 0 No ;, Nunc Mais .. *, jut Nat 96 b 0 d 100 curlers seen ZZ Ross PD.L1.FC .pfera Sri (2 Λ (Mar) d 0 Dal in PBS P 16:00 pal Alllad der 0 of the 0 Rh Aagri LED; Latin. P obstruction Alogaq; _ 65 LAPD 0 m y g a% BSA d; 30 minutes and 40 Auns 1 ./. &amp; quot; Rs 20 to extend; 30 days Ri j r Ako.r 0 0 Lalla called the news of 1:10 j ELISA (News Alamas Walles Artt Alaram) and TAWD Tm (PBS with 0.5% 0-05 'BSA./. -rn 'e 2) h. without 10:00 6 of Lahr! protein Adedv in Ham Total 50; Bd'r β eyes of Ed; 0.0 termination Z deer count Drjm Algrlo heat in bugs (F (NUNC Al was 75 -237- -237-ΜΑ 32948Β1 Dodd Wu Dnaaysdy; Lev! to Yalobag only; Hds'tm shake format glaze I 15 friendly Uah,; &amp; lt; &amp; lt; b z Aq; 0 Bartend equ 0 goal. Tmels 0 Fbtd only; l b p5s - Ge -0% -rs 0.2 'name Yasin a; i Fill the 1 Qalz Ed 2 1 FD d ύ ^ Ι Μ13 RIM Up'z Ed-Geller Ashe 1 Eelaa 5 Mahaouomtm 5000: 1) ELISA) and Alaaan i 30 at 5 Drgel decision; August nm E 00 only 0 bugs to 0.05% - PBS Zen 20 days for Qualities z 'Lash' b 0 d Zq 's Attalla 100 Skrodr / Eanaa: Lasry 1 Zvem Ikd'z 3' 3'5'5-Z 0.0 Gul Aoadn (TMB) and Mahrl Edb'z b ^ E? -hleehs) (l 0 to aa laboratories (Gaithersburg , MD)) to F and'lapf category 0 5 &amp; quot; &amp; quot; for I &amp; quot; Which

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-238- -238-ΜΑ 32948Β1 and, Ira and Y 7th to analyze sequences. Unique Nassar was chosen to prepare the macrophages to measure Please choose a Alar'bt (phage IC50) against both the PD-L-Fc human and murine by comparison 0 p original Ahail. 5 materials were purchased mPDLl-Fc, mPD-1-Fc, hB7.1-Fc, hPD-Ll-Fc, hPD-1-Fc, and mB7.1 from RD Systems &amp; amp; . It was the generation of 293 cells expressing hPD-Ll at Genentech using traditional methods. The purchase of anti-IgG Fc Alpmthrey Alokhoun goats 2 ( 'F (ab z Jackson

Immuno Research Laboratories. Comparing proteins 10 proteins were treated PD-1-Fc and B7.1-FC Balbewtonn Association EZ Slfo- 1S-LC-LC -biontn (Pierce) for 30 minutes at room temperature Tabga to the specifications of Mahna. Biotin has been removed excess unreacted using G50- columns, Quick spin High Capacity Columns Sephadex (Roche) according to the manufacturer's specifications. The anti numbering IgG Fc urticaria Almokhoun Z goats 2 ( 'F (ab Balrotheiom b -Sulfo-Tag NHS 15 (Ester (Meso Scale Discovery, according to the specifications of Akaa and has Azak Sulfo-Tag unreacted using Quick Spin High Capacity Column G50-Sephadex. linking test cell ECL to test the antibodies macrophages

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-239- -239-ΜΑ 32948Β1 was measured pylons palpation 0) counter, which leads to the Zs 0 inhibition of 50% (50 h 1) in Ardat -hPD Fc- and meanest; a 293 expressive hPD-Ll. Using the experience of connecting cells look Luminosity! To Kahroaeliaiah (ECL). The wash-cell 2930 lesson Z hPD-LJ using: · ôjL 0 neighborhood phosphate regulator (PBS), agriculture, Mmadl 25000 cell in all of 25 your responsibilities der PBS 5 on High dish Bind 96 eyes (Mes. ScaJe Discovery). S has been embracing when Drt weddings temperature to allow the cells to communicate the carbon surface of the dish. And added 25 micro liter Z 30% FBS for each eye and embrace the dish for 30 minutes, 0 p flipping light to obstruct Muah Link is Alkhadddh. Wim Gul dish three times in PBS d washing dishes minute ELISA (ELx405 Select, Bio-Tek Instruments) with 1 to distribute the A- and Zouk clouds 0 0 sniff have removed 10 Araidh quantity of PBS in the eyes using a dish staining the tissue paper. Tbm additional 1 FH 12.5 micro liters of R'Kiz Mud 1 Escherichia of Agam 1 to counter each eye in 3% FBS in PBS (unregulated experiment) and 12.5 micro liter of 4 micro g / ml solution (kicking the multiplier) Q hPD-Ι- U Tin in Althrbh organizer solution and incubate the dish for hours 0 p Alnglab mild dish washing · Bam χ3 d PBS on the washer-minute dishes, Ttikh S-Ted's Lori -15 then added 25 micro liter of 2 ml of Mkrojmr Srepettavides- Rordom Mes. Scale) (Discovery and incubation in the formal test solution at a temperature of temperatures in August for 30 Dhthh 0 p! To lose! To light. Bam 1 legal χ3 B. PBS in 0 Oyak Dehigh and smudging Las Z

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-240- -240-ΜΑ 32948Β1 0 Tdel Lord. Chem adding 150 micro liter of solution xl Mazm MSD Read Buffer without antipyretic 0 to 0; 0 Zha (Meso Scale Discovery). Are read light Almenbmt of Luminosity at 620 r meters on the reader (Sector Imager 6000 (Meso Scale Discovery. It was Ohh with concentrations of antibodies for the test used in the experiment values ​​analysis, using the least square non-linear agree, for pregnancies {vilified J5Ü IC50 has since 1 vs. the Akhrbh 0 Results The debate has been chosen Scher of antibodies Ahlgred for Mmelthmat of YW243.55 that connect each Q PD-L1 August 0 Rey and murine and reshaped by antibodies full-length IgGl to remover 0 of Aks 0 The Benin Eyes 11 a and B sequences region changing Khgegh and heavy chain to those of the anti-radiation countermeasures. The 71 th Abs test reconfigured to luxuriantly Kdrq impede link 1-PD-cell 2931 b r a r PD-human L1 or murine about deafness linking cells x 0 or the appearance of one of the luminescence 1 Zkahrodua experience (ECL). (Jdula- Brighten 1 T: ^ well 1 Aahalo 1 describes r-Bhatt PD-1-Fc 1 to Shri 1 Negotiable Vauban 00 &amp; lt; a 293 Zal 0 Edoy PD-L1 1 to a human need; and describes one as a body 2 &amp; quot; Arrt PD-1-Fc Aqera d exception; a 293 pp Edoy PD-L1 .lvora Nlleha; describes Hih 3 Artat 1-PD Asri.l exception-da 293 ran out of Z 0 Wei PD-L1 1 Foura it. although the collection of antibodies Ahamsh E 1 evil b -241- -241-ΜΑ 32948Β1 familiarity might type interactive mutual Dr. PD-L1 murine, but it has been chosen as the main YW243.55S70 transpire based on its ability to impede connect both PD-L1 human and murine! - 1-PD (Jdoda: iCso values ​​for 49 and 22 Molar Pico Pico Molar, the Altertb). 1 states

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Clone Format 1 Format 2 Format 3 hPDl- / Fc- butene hPDLl- 293 55IC nano Molar mPDl- / Fc- Biodan mPDLl- 293 5.IC nano Molar hPDl- / Fc- butene mPDLl- 293 55IC nano Molar YW251.ll 8.6 YW 243.1 0.234 YW243.55 0.099 100 &amp; lt; YW254.1 100 &amp; lt; 0.795 YW254.2 100 &amp; lt; 3.76 YW254.3 100 &amp; lt; 100 &amp; lt; YW254.4 1.73 15.6 YW254.9 100 &amp; lt; 0.224 YW254.33 2.2 100 &amp; lt; YW262.4 50 1.42 YW2S2.5 90 25 YW2S2.16 7.5 0.626 YW2S2.64 0.256 100 YW243.55.5 0.104 0.141 YW243.55.8 0.061 0.063 YW243.55.30 0.108 0.1 YW243.55.34 0.084 0.049 YW243.55.49 0.08 0.032 YW243.55.51 0.078 0.031 YW243.55.62 0.096 0.066 YW243.55.84 0.124 0.051 YW243.55.89 0.066 0.13 YW243.55.H12 0.103 0.156 YW243.55.H37 0.109 0.163 YW243.55.H70 0.084 0.042 YW243.55.Sl 0.114 0.074 YW243.55.S37 0.1 0.024 Μα 32948Β1 -242- I YW243.55.S7Q 1 0.049 II 0.022 1 eg 1 for 2 pbrSl JLi's (PD-L1 (BIAcore were measured for 0.1 strap 'to Agam 1 to counter anti .llthmh PD.L1 YW243.55J and 5 YW243.55S70 weathered PD-L1 human and murine through land Albulasmony Ed Dahi SRP)) using Haaz 3000-BIAcoreTM. The packaging Trah - 0 vital CM5's ~ .PD Ll-Fc 1 to Shri Nah about the return of genetic Alarabat (R &amp; amp; D Systems, cat # Ι56-Β7) and -PD-L1 Fc 1 Foura one of the consortium p return of genetic correlation (R &amp; amp; D Systems, cat # 1019-Β7) to achieve approximately 500 units Asthah (RU). To measure Aharakiat, serial dilutions were injected Mphaafh 10 (3.9 To meters to 500 nm) in Mazm PBS solution) PBT with 0.055 Tweinl 20) 25 Je; M Bmadd flow of 30 micro liters a minute. The SAP Sdlat a land. &amp; Quot; Duck ( «ko) and the rate of separation (koff) b 1 Stehaddam Nmong link Languir veterinary and 1 extent R'hd (BIAcore (3.2 Evaluation Software version. Then a fixed separation SAP (kD) O.dha Z Azh August kon / koff · in and d ^ 2 automated Please choose a Nael El Jem counter link devouring counter for PD-L1 YW243.55 and YW243.55.S70 Almqa 0 of 15 -243- ΜΑ 32948Β1 two countries Please choose a BIAcore an active fixed link rhPD-Ll Fc hard rmPD-Ll Fc l) / k0n hope Vlj / koff -;,!) a kilo Balnon (Molar) hope l) / kon kofT / (! / ';') Balnon kilometers (Molar) (Fab) YW243.55 5) 0x5.80 7.30 10 X's 10x1 0.26 does not 510χ1 &amp; lt; (IgG) YW243.55 510χ2.70 610χ2.60 Όχ9.63 0 10 X 5.80 1.Χ9.20 'ΊΟ X 1.59 (Fab) YW243.55.S70 5 10 X 5.30 * 10 X 1.00 - - 1,40 10 x e * Ί0χ2.92 (IgG) YW243.55.S7Q 10x3.90; 10 X 30.a 62.10χ1 not - Οχ 1.80 'U &amp; quot; 10x6.43_ 3 a Noi Abs Aldhadh PD-L1J own &amp; lt; - | 7_ahari, and Arse and Afoura 5 and the experience of the cell linking molecule response r) this one shows such as quality LED 0 cm counter d private PD.L1 invention relating to PD-L1 1 to pustular, and 1 layer and gari, Alad 0 spyware, it Hazh opportunities p PD-LlJ Ab Aqera and 0 for a human tastiest 0 j is one of expression than in the membrane 1 Ornament &amp; lt ;; Khala.da 293 Ibb infection 0 Tkd infection steadily PD-L1J .lepeshra and Afoura in the cells 293 'has been encouraged cells bear 10 Z a 0 to staying Bmadd 150000 cell in each Z in Z 9 96 I t 1 at Ward. Blood was obtained z z 0 Ras Southwest Foundation for Biomedical Research (San (Antonio, T0xa5. It was blood thinning Amisam PBS Odi 0 Wii 96% -Κ..Ι1 (Paque (GE Healthcare to separate Allaoa Olz hurt him 0 ex '244-' 244-ΜΑ 32948Β1 the single-cell analysis of the nucleus of Alhabra blood cells Bachkd'm solution 0 Talm Q-fighting cells (Qiagen) and grown throughout the night when 1.5 10 X c cell / &amp; lt ;, d 5 Madhu g / {, PMA plus 1 micro Molar Air Nomsn in Obag 4 0 n 6 b. and ^ q central Orai a 1640 RPMI 0 p 10./. serum Hafni Larry, 20 your responsibilities Rlar HEPES; 5 and Takgegat 1: 100 of the Almkmla 0 T. Alabh of Gluta-ΜΑΧ: Gibco; ^ and lattes sodium, penicillin / streptomycin, and amino acids is essential. the 1 Ha Khala 0 a in the 0 Om robot up on a platter 96 kind of Dramat linkage (almost 120,000 cell in Celle.) has antibody PD calibration-L1 YW243.55.S70 or b 1 Qrla 0 n palpation 0 m Khal ®Herceptin starting d 10 Mkrojm / ml, the dilutions - eg, de-fold War -10 cells in 50 micro-liter sizes for 25 minutes folding Ashe. the Z 1 cells then Rbahlha using IgG PE anti-human (Caltag) concentration of 20 0 Kroj 0 a / 0 for extension 0 25 minutes &amp; lt; a Althelh. The Conley joint smudging to Hlaya monitoring CD3 FITC and CD4 APC (BD (Biosciences to distinguish Allaa CD4 + Tcells. Then run the samples on a Beckman Dickinson FACSCalibur was pannier stretched Alaic Alglori 15 oug 1 linking PD.L1 as a function of the concentration of antibody PDLlJ using Tree ® program Star, Inc. FlowJo; T-0 was not seen ECso &amp; lt ;; / 1 for almost a body 1; St d Us link) using Kaleidagraph. in addition, the views were Dr'at 1 Rlat

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-245- -245-ΜΑ 32948Β1 balance to determine the exact familiarity (Kds) of the Arbat YW24355S70 J PD-L1 Lasry and Afoura expressed on the cells 293 (Example 3 b). These values ​​are summarized in Table 3 below: Table 3 Summary ECso kind ECso (Na Nu meters) FACS Kd (nano Molar) Arbat linkage portion irradiated balance .dra 0.4 0.4 Opportunities 0.3 Vary 0.3 0:30:13 Rve 0.8 0 Thal 3b measure Please choose a antibodies d PD-L1 balance PD-human L1 and murine linking boat mooring irradiated cells experience of the link has cell culture 293 transferred to infection d PD-human L1 or murine in the center of growth, where they are from the middle 1640 RPMI signal d 10% fetal bovine serum (FBS) and 2 Micro Molar L - glutamine, and 1 ^ Pencill- Stervtomiszn, at 32 ° C in 5 ^ -246 ΜΑ 32948Β1

2.C. Alkhalaaapmhlol regulator was Gul correlation (50: 50 F12 / DMEM Ha 2% FBS and 50 micro Molar Hepes, pH 7.2) was placed in a 0 bugs Z't 96 b .mmadd 0 approximately 230,000 cell in the 0.2 t p 1 Iol regulator wanted. ci m 0 thrusting additional counter for YW243.55.S70.hIgG, PD-L1; Adud Q 0 M &amp; lt; Aiqa Iodogen. Wu Φ '1 to 1 antibodies to counter for PD.LJ 1 paper radioactively 0 n Ι-ΝΑ ​​&amp; quot;' A &amp; lt; R &amp; lt; Levi; u h 0 Ashe a-intentional or 5-ΝΑΡ; has a sufficient specific activity to resolve the anti Almnd your responsibilities 17.41 inches of semi Mkrojm. Was developed mixer competition Nat reaction volume of 50 MPC; and Lear August Z; kHz Aatt of the body, the Anti Altod processor and concentrations Alkhvdh p Ashe 1 FD lighter non-Arz cells strains 0 Adegv d 0 Tll in a 0 bugs Z't 6 and B s tops 293 d Easyway agents Adberh p PD-L1 and AA-Alpfera He murine in and i y, z and i Lalai En 50: 50 DMEM F12 I provide the E 00 to E p (FBS, Are% '2

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BFH, a Mali 150 Lecco 0 Rlad to 120000 cpms each 25-0 ml) Taven with -247 -247ΜΑ 32948Β1 and; Ikirkiz the 0 Haia to rein counter is No. j wi 0 p interaction of cells ranged; starting 0 n 5007 with a Molar then decline .mmkdar doubled to 10 concentrations. And sleep embrace AAC 0 Aks interactions with cells for two hours at a temperature of reindeer heat. The reactions Akovs 0 p 1 cells Qkl concentration of anti Jem is No. test three times. Dimension move worsened 1 n z 5 Alassane; angle reactions have been competing to dish Millipore MuJtiscreen candidate and aluminum 4 0 0 Rat Mmahlol, structured link to separate free from Jem counter associated with iodized. Filters were counted on a 1470 Wallac Wizard gamma counter PerkinElmer Life and Analytical)

(Sciences Inc. Wellesley, MA. The link data using NewLigand Genentech Assessment Programme)), IP uses an algorithm Compatibility Munson and Robard to Tahdid Please choose a link 10 antibody (1980) 39-220: .Musson et al., Anal. Biochem. O has strengthened the Kd values ​​were measured using Scatchard EC50 values ​​to link the antibody to PD-L1 and PD-L1 human and murine analysis as shown in Table 3. shawl 4 \ φ ~ and uH \ g? Alamada: T's (PD-L1 (iCso 15 opportunities in one example the experience Please choose a selective link (in Horh iCjo) Altkhaddmh in assessing the ability of Glades l Anti-PD-L1 full-length Alopecia present invention to impede -PD if LI link 0 n 1-PD and Β7.1. 01 -248- -248-ΜΑ 32948Β1 1 of ways: Akhcar 1 ELISA (for the financial framework üÿjti - hB7.1-Fc and hPD-1-Fc- Biottn hPD-Ll-Fç --j (* marginalized 4): the Packaging Nunc dish Maxisorp its 284 kind .25 -J micro liter of 250 hPD-Ll-Fç 5 a 3 and c 0 m / 0's in PBS overnight. dishes three times d is washed 0.05% Tween in PBS (buffer solution vessel) in Galh minute dishes and impeding the eye and 0.05% BSA in PBS. u 0 AAA 0 spyware 12.5 microseconds Qr of χ2 concentration of antibodies for each eye in 0.05% &amp; quot; Rennes, and 0.5% BSA in PBS (diluted August) and 12.5 your responsibilities β Z 2507 with a JAMA D (χ2 see Z hB7, l-Fc - Buyten in dilute Althrbh and embrace the dish for an hour here and Nhv stirring. the Gal eyes six times 0 lysosome entrepreneur 1 TB wa 0 spyware 25 your responsibilities loan of Mds- 40000: 1) agitation in dilute soil Assay diluent 4 GE Healthcare) . Wim pain 01 births 30 clingy 1 0 p less &amp; lt; - sales b 0 Lt. Aat'slll j as 0's. -tm;, 25 iiL curlers j z Rey TMB Kirkegaard and Perry (Laboratories Linda i and A.agaf Aqgael 25 Skdd poison 0 Es Addz 15 / β . -tm Leah Asas x 450 Odhu Barr, .nhll been vilified .Ur JC and 0 beam s shield Arbat ECL cells in Example 1.1 Ready for 5, 6 and 7: -249- -249-ΜΑ 32948Β1 to link -hPD-1-Fc- butene b hPD-Ll-Fc (body 5), Cat August Mchavh h.jJ least Ba_i_a use -hPD-1-Fc- butene instead of hB7.1-Fc - Bewtonn the Arbat was 0 Zs TMB substrate 17 min reaction. Linking mB7.1-Fc - butene d mPD-Ll-Fc (form 6), August was Mcha 4 of the body 5 'with the exception of the use of mPD.LI.Fc cover the dish instead of hPD-Ll-Fc and use mB7.1-Fc - butene in connecting instead of hB7.1-Fc - butene. The reaction time p.7 Diiq 0 and linking -mPD-ï-Fc - butene b mPD-Ll-Fc (form 7), the August g in Tell ELISA Ababak hate Basze use mPD-1-Fc - butene in Alarabat instead Q .mB7. 1 Fc - butene. It was time Arkizh TMB reaction is 5 minutes. Results: reported in Table 3 to estimate the ICso for curbing anti-PD-LI YW243.55.S70 values ​​-nadjh familiarity to hinder the interactions between Alarabat designed pairs. Market Asitaa YW243.55.S70 disability Arbat human PD-L1 d hB7.1 Fc half Ogahy; / I of 38 Bekomolar, a Zkiz 0 relatively similar value iCjo not Ouaqh 0 0 Rgael PD-L1 a 1-.Ρ (42 Pico Molar). Biacore studies to measure the ability è \ YW243.55S70 &amp; quot was; Both Tvaafee PD.L1 0 p 1.PD and Β7.1 compatible 0 p Ntah ELISA (data not shown) 0 grandparents 3 -25.- -25.-ΜΑ 32948Β1 antibody 4 body body body 5 6 6 _hB7.1-'s body ICj. hPD- d 1 lCso -mB7.1 ICs for. mPD-'s ICso-yos a \ 1-ϋ butene a hPD-L1 butene / mPD-Ll -1- Aaos a Ballbeckomolar Ballbeckomolar Ballbeckomolar mPDLl Ballbeckomolar YW243.55.S70 38 42 29 48 0 Hull 5 jdjtf of \ i + and CD4 + sU \ YW243.55.S7Q S \ J \ çJrW CD4 for PD-L1 experience Β16 / PMEL in S illustrates this one for example Taeir antibodies PDLlJ own invention to activate the CD8 + T cells Amehorh and Raba for the acceptor cell PMEL T, as measured by the enhanced production of γ-IFN Ascabh Lapid ornament Almilanettih, gpioo. In this consensus; been pregnancies Z Khala-a CD8 + T o mice PMEL TCR .nhorh and heal one told permeated 0 cells, CD8 + T 1 alfalfa U r TCR Khahy Balbbb; d ..gpl, and after -i | to Khalaa CD8.T, are conducted several sessions of Essen Ataj Dr. Elaha -CDS. I eat 1, .j- to 0 of -iom Bdwoha upwardly Aigm guardian large z 1-PD- u Akoizi,. 0 returned 0 Ola, a Β16 Elaia; _ IFN-γ for rad; prisoner p PD-L1 his club cm where 0, reminded, Z a 7 Z August j Rard pain newcomer PD-L 'WPM -251- -251-μα 32948Β1 Ngder Altaiar to produce IFN- γ. Β16 cells were selected for Nhvez triple 0 o any expression of an internal Almonto for low levels of peptides gpioo (0 Garzh use Wagners Almz 0 tha peptide). Elaoh on it, as 0 of those Alkhala.da lattes 0 Bran PD-L2, or 70 c or Β7.2, tie the effect of additional signals is one of the Mrsth b 0 PD-L1 (&amp; lt ;, Aral departments ÜS the 5 CD28 or 4-CTLA or send signals through PD -L2). 1 experience as evidenced by my Figure 3, the antibody to PD-L1 Tazz'los b PMEL CDS T cells Aptjh -IFN-γ's average level -IFN-γ which DONC cm and Ahabh 7 Amehddh amounts Q peptide .gpioo 10 011.10.Ρ in Tjobh Silaya experience z u 0 Ahh -m solution, a TCR Tg CD4 + T own eggs increased T cell proliferation in the presence of the antibody PD-LlJ after the previous stimulus polypeptide oval to bring about 0:00 Z 1-.Ρ (Figure 4). In the stimulus congratulations, was used Α20 cells B 1 for me &amp; quot; f r PD-L1 in Tqa 0 Yum Anikiz 0 T. Anhddh late 0 d Otway cells Α20 B. will Aljdd to note, that the contribution of Anhol 15 1-PD-L1 / pD more pronounced at least scores of stimulating Z Mo 0 LED Equal will Aktoyat that reflect as much as the largest amount of stimulus physiology Cleat · materials and methods: 51 -252- -252-ΜΑ 32948Β1

Proven PMEL initial stimulus (today Sgr- 4) has been encouraged Afd lymph Misargueh and splenic of mice modified Ratha PMEL - 7 T. cell was grinding members of the suspensions individual cell has been resolved cells 1 km Alyra 0 the cells 5 CD8 + T Dam 13:00 isolating trotting CD8 crew) T and the unity of the separation AutoMACS cells (Miltenyi (Biotec according to the manufacturer's instructions. was isolated spleen of the mouse is genetically modified compatible sexually and grinding in 0 commented disband the vinegary 0 red blood decadent. the Tenbagy cells d 0.1 microseconds JAMA ml of Sir gpioo for a period of players at 37 m and Glha 0 10 grown common cultivation of cells in a flat bottom with a dish 96 Ah h 200,000 cells PMEL CD8 + T and 75000-cell spleen Menbdh d gpioo for 4 days. Lund Lj button; cent is the center of% 10 + Modified Dulbecco bovine serum - + 20 HEPES, and dilutions of 1: 100 from Akalih supplements Gluta-ΜΑΧ: Gibco; Byoronat sodium, and penicillin / Stervtubmsn, and Ohmahny amino non-core 0.15 second stimulus (day 4-7) was spin PMEL farms were withdrawn center using multiple Alfouat absorbent · The Tmt Ahavh amid fresh mixed to wash one of Hlaya , and then followed by another spin. has 0 Tm have removed the center does not 2 -253- -253-ΜΑ 32948Β1 and add exponent 13:00, the counter (®YW243.55.S70, Herceptin, or nothing) Dkhz 4 of 10 Kro 0 g / ml. It was created conditions so that in the eyes of Zdugh · 0 0 are possible Tq Hist Anaj IFN-γ at the terminal point. Tnwhit cells were 1-DC d 12:10 Jkro g / 0 for 0 n strain 0 0 gpioo to extend its humanitarian partners sa 6 37 m and Eadslha 0 ci add 1 cell-DC Almenbdh d gpioo to planter PMEL Almgsolh.mmadl 40,000 cells / eye. And has agriculture Almczkh d PMEL and 1-DC + antibody for 3 days 0 stimulus Althak (twisting 7-8) Gazz Althver Althak one day in Day 6, Sleep embrace melanocytes Β16 with 20 nano grams of ml Z IFN-γ murine (R &amp; amp ; D Systems) throughout the night to increase the clapper 1 r PD-L1 increase controlled. In the required 7, it has been recycling Rreet PMEL and the withdrawal of the national using a multichannel pipette. Wen added amid fresh mixed to wash the cells, and then followed by another spin. It has been removed most of Alloa and add antibody concentration Nhaia of 10 micro g / ml. After .lthvez throughout the night to IFN-γ, were washing Β16 cells and separated into three groups of Ahtephan for two hours 0 p absence gpioo, and gpioo at 1 Madhuhama 0's (gplOO Ash) E -254- -254-ΜΑ 32948Β1 and gpioo at 10 Madhu JAMA ml (gplOO higher). The wash Khala-A then Adagha to PMEL laundered PMEL planter Ab .mmadl 40000 cell Klaan otherwise 0 Anadan m 0 of Loral Allahl 0 Day 8 staining inside the ornament IFN-γ has been added (Golgi-Plug (BD Biosciences for 5 hours z persons z Alr'i b Help factory. The staining and IFN-γ within the cell using a crew BD Biosciences Cytofix / Cytoperm Fixation / Permeabilization Solution according C4 died Akaa 0 as all antibodies alopecia Baltlatikh from BD Biosciences. The surface staining of cells d CD8aPE and Thyl.1 FITC and Smudge inside ornament d IFN -γ APC concentrations Z was all samples run on a Beckman Dickinson FACSCalibur and circumvent Ba-M program ™ Tree Star data, Inc. FLOWJO. experience DOlllO entertaining were collected lymph nodes Misariqih and splenic of mice modified Ratha 11.10 DO. It was Tkhha in suspensions rosy cell, it was resolved the red blood cells. has cell cultivation for 72 hours density 1 x 10 5 cells per ml in six dishes Nat Aaov 0 p peptide oval at 0.3 Molar. it was the center of agriculture is central 1640% 10 + RPMI fetal bovine serum +20 Micro HEPES, and dilutions of 1: 100 Z supplements mechanism Gluta-ΜΑΧ: Gibco; Boroffat sodium, and Ptsill / streptomycin, and acids Omatah is Omasah. -255- -255-ΜΑ 32948Β1 after Seas 1 to an initial, one was encouraged to Lusa cells to Khalada T CD40 B'm Bam at any CD4 T Alga'rah Tabga for instructions F (Miltenyi Biotec). Then Zla Khala_da C.4 T delivered throughout the night. The next day, the collection has been one of the cells, washed, jointly cultivated p 0 Khalada Α20 trauma Radiation (10000.1 d). It was created farm Iturkh at the bottom dishes shaped 7 96 U b in Thelabh eyes, 50,000 cell CD4.T to 40,000 cell 20 ^, peptide oval and bridles daad concentration ^ ne of 20 0 Kro g / &amp; lt;, · After 0 48 abuse, has been 0 Ad farms throughout the night L_ 1 cubic inch Micro / weakness was 3 H - thymidine WAP on day 1 ble. Then d freezes only 0 bugs later, and encourages cells collected on the tool, and the reading on the meter Example 6 0 0 marginalized Azzh to Khalaa 1 CD8 + T j Afawi reaction scheme Bassadam counter to PD-L1

Figure 5 illustrates the ability of Jem's anti-PD-L1 (such as YW243.55.Sl) to promote the proliferation of human CD8 T-cell response to cells from an incompatible donor MHC. Been enriched CD8 cells in response + T from each blood donor a first cell using CD8 + T RosetteSep® (StemCeJJ

Technologies), according to T. less tiring. Then eased equal size of the phosphate solution cells

Organizer (PBS) and centrifugal separation gradual coverage on Ficoll-Paque Plus (GE -256- -256-ΜΑ 32948Β1 (Healthcare. S 0 to 0.5 -sch Aaela, August &amp; lt; CDS APC (BD Bi, éK0s and 0 Ed p instrument to 78 % of Delaiah CDS + T- been 0.0 m S Aalolq Aladora Adam 2.5 screw Molar from Formulate CFSE confirmed (MolecularProbes). The Laa 0 for Kkhalaa one donor 1 1 and Dasesay du (APC) 'was Adla Erl &amp; lt; a and b; harming p ace blood ALMA 0 Hoz Z survey by then Ujbl Z S-CD3 + T · nm Z mother Mex size of PBS and then isolating the cells RCA; let it b 0 d Earl of; no AAC 0 shake Z

Rc.il. Eli was Tlhlkh 0 CD3 FITC (BD Biosciences) _ί, and Ouaoua, then not. Colleges Dnich Dd 1 Ende and (FITC (Millenyi Biotec., And then I; FITC W5U T. 0 E Almlhab 0 z JH) g Act 1 cells (AutoMACS (Mlltenyi Blotec. Then the T / juicy 1 cells loyalty 2500 R'd in the unit Cs rays' s Adhirah Akr- i Kleio in Tpf surface Altoa a 96 b h 50000; 0 Z the cells 1 T APCs CD80 births 5! j 13:00 with one welding 0 Tadh Barakaz 0 e z what t 'Dec. 1 t i Alrrao Ib 1 Rh from 1.40 RPMI 0 0 [% 0 Pray cheesy non + 20 * A and Rlao HEPES, any 0 lattes 1:00 for 1 to Kmlat only-by 0 n Oluta-ΜΑΧ lOibco 'Sete sodium; Ssll / Lester Btobin, and amino acids non-core' -257- -257-ΜΑ 32948Β1 day 5, was encouraged cells, washed and tarnishing CD8 -I- butene after Srepettavides- PerCp BD Biosciences)). been running cells on Beckman Dickinson FACSCalibur and analysis &amp; gt; data using .Tree Star program, Inc. FIowJo observed proportion promote about 45% in -cather CD8 T cells and Ahabh cells 1 to Okhozh Q 0 Azh is .tuaq MHC in the presence of the antibody PD-LlJ. w 7 obstruction PD-LI effects on LCMV in Nmong Dakhaml body organism may 7: 2-1 Oie constant stimulation conditions of the T cells to increase the expression of the future inhibitor 1-PD and keep it . And it contributes to link the 1-PD either by Turabaalih vehicles PD-L1 and PD-L2 in the case of activated T bossing resistance continuously, thus weakening their response to the recent birth of her antibody. In Algiran always infected with HIV infection Mahaya and placentas lymphoblastic (LCMV), palm loyal; of 1.PD or vehicle Alrabotta PD-L1 to revive the resistance Dalmh T cells, thus enhancing the amount of functional and quantity of the T cell response to anti-virus. Well, humans have shown age is 0 0 0 g n with HIV or HCV T cells resistant to stimulate activity can be enhanced in the lab Z deafness a disability PD-L1 or PD-L1. Therefore, the inhibition in PD-L1 ^ Zj LCMV Del strength therapeutic liters immunity against viruses and against tumors. -258- -258-ΜΑ 32948Β1 Mieh late ^ Lord LCMV d 1 Vinegar James 2 1 object one neighborhood in Acar 4 0 Mga B 1 de Z Adam 1 FD and PDLl Alravq with one evil (YW243.55S70), Bantak sequences region Almtaarh Khgegh and heavy chain-derived Z August Is Alieh I Aoi Agalat Kappa 1 Fourah weight and the chain's Ig52a Murine. Let the toxicity of one of the cells into Dodd Adam, one of Mad y. August for PD.L1, from 0 saliva inhibition of linking the future of Fey, has been Demir Modann 265 (0 Levy needles-Dat) and 297 (Apr 1 Mud) to alanine (Biol Chem. (DANA SAL Shields, RL et al 6591-6604: (9) 276 2001. Ader ^ Rh 1 rein AAC 1 d PD-L1J Z to Arden Almmaeh strayed 0 Algirolla 0 data in one DWI Elms 0 No; the angle Bedouin Giran day small units configured to Oih 1 t (6 10 x2 (pfu of 1 to 13 LCMV or Armstrong Q LCMV b compared to a reference. shows the design of the experiment scheme 6. in Dekel and Woody Adoy obsolete 13 to chronic infection, characterized by T cells that span z and y Dadrh against a (Gbros Psahlah while 4 have been exempt Armstrong LCMV within 8-10 Momma Z Adoy. in Edom 14; began processing Algiran Ama.mamadad PD-L1 or Baevh compared mlgG are like DAT 10 b LMO three times a week. in two days, 21 and 28, have been conducting functions Ashe T analysis and viral assays in the blood and tissues.

Barber et, al Nature.: 682.7 (2006) Ibex towards compatible 0 p published data from the saliva on improving Amtahabh toxic cellular cells 1 Foe PD-L1 Ab This example shows the ability of ΜΑ 32948Β1 --- LCMV and Nlun after two weeks of treatment using a processing system in infection chronic LCMV. 0 age form Rim 7a that the percentage of cells CD8 T to express CD107a on the surface Gas is in response to poly private peptide b - 0gp33 LCMV plasma membrane expression of CD107a normally works within cells, and includes a process of removing Althab and thus are Astkhadda 0 e Kmno. alternative to the process of removing Althab. As for the response of cells in infection Armstrong LCMV sharp, they are contaminating cells Z infected animals z severe strain, and is again 0 At monoclonal 13 in the process of removing anticipate (comparison sample group Ig), while the PD-be L1 1's ability to peer able to restore disarmament graininess + CD8 levels Mshamh to those observed in Olney ci infection Armstrong. Similarly, 7Β explained that the increase in the percentage of -IFN-γ, which not had Ascabh CD8 T cells for LCMV gp33 in Anhmuah Altalqh _ PD-L1 for sample comparison Ig. WebMD, it was Jem counter the impact of PD-L1 Ab to minimize or eradicate Vnros LCMV in the blood and tissue testing. In Figure 8a, the charts show log virus Alench shown in comparison Ig and PD-L1, which has been addressed in animals at Allum sample of 21 measurements, twisting 28 after the LED Balblh 13 LCMV. The start of the antibody treatment at day 14 after 0 to infection. As a result, Z disability PD-L1 Alkhvvy dramatically standards virus in the blood, liver, brain, lung and kidney. As 0 thier surprising the 3 out of 5 Fber'n as 1 Zt have together; they saw blood incomplete d α-PD-Ll Ab door LCMV -I, and under discovery (&amp; lt; 1 5 ΙΟχ) - In the following Althrbh of similar design, has Mad 0 moment hopes to Gerus in 1 km and 1 liver in 5/5 Z 1 that one Lenny ci Dljtha for two weeks using the PD-L1 at doses of either 10 -260- -260-ΜΑ 32948Β1 mg / LMO or 2 mg / LMO 0.3 times / Ombua (no cm data shows) . Showed planned A- kinetics reduce Almainr Agheirosh in the blood and shows Mtot reduction of up to 96.8% in Jem's anti-PD-L1 at 28 days for the Ephah comparison. Supports those 1 to Bamat importance walked PD-1 / PD-Ll in the Shatt live to Ahabh T in types 1 infection Almzmzh The fact compatible 0 p Altotnrat to work raw blocking PD-L1 on T cells that have been obtained her knowledge of humans 0 p types of chronic infection such as hepatitis C and HIV. MATERIALS AND METHODS: August August to Alta ^ JP IFN uv ^ i (Coordination CD8 cells Τ for \ λ) \ * ϋ for peptide LCMVgp33 been isolated spleen cells from Algiran infected were not hanging single cells fire grinding members among full: Invitrogen Inc., Carlsbad, CA) IMDM) and'ti j 1 SHTML to 0% of a cow serum brow is Algsht 0.2 ml Molar of glutamine and 00 and a Hdnaml Z penicillin and Alsrepettomaysan and 10 ml of 2 Molar Mrkapto ethanol. It was analyzed 1 M red Bashaddam Anhlol systematic analysis 0.15) ACK Molar from ICI, and 10 ml of Molar KHC03 and 0.1 ml of Molar EDTA). In order to measure the Yum own cell response by CD8 T cells were washed spleen in the entire community and are re-alarm in the lab for 4 hours using a peptide KAVYNFATC, Prolmmune Inc., Bradenton,) LCMV GP33 FL). And; Zt button 1 cent 1 10 X X in the flat bottom 96 dishes U consciousness using 100 nano-g / ml 0 n effort GP33 in the presence of 100 units / Mejlis of interleukin -2 (-Sigma 1, (Aldrich, St, Louis, MO du u / 0 for 0 n Barr 0 Saladin a and 1 (1000: 1 Takhelv) 0 n -261- -261-ΜΑ 32948Β1 BD, ID4B monoclonal) CD107a FITC and 1 for the antibody's (BD pharmingen) -r, which includes PBS and after incubation, was washing the cells in the (Biosciences, San Jose, CA 2% of Jenin Alpfer serum and No.at cell surface that is contaminated using Floro Chrome (53.67, BD Biosciences, San Jose, CA monoclonal antibody) CD8 APC utilities 0 G antibodies (BD Biosciences, San Jose, CA, RM4-5 monoclonal ) CD4PerCp-Cy5.5 and the antibody's been conducted. (J43, BD Biosciences, San Jose, CA monoclonal antibody) PD-1 PE and antibody for BD Biosciences, San) Cytofix Cytoperm Plus inside cells using IFN-γ staining kit XMG1.2 , monoclonal antibody) IFN-yPE-Cy7 in accordance with the instructions made by using the Anti (Jose, CA private GP33 in order to detect a certain number of cells. (eBioscience Inc. San Diego, CA H2-Db) GP33 has added a new spleen cells were kept using Bntamerat CD8 T _l according to the manufacturer's instructions. Been compiled (APC, Prolmmune Inc., Bradenton, FL Almertbaalh b were analyzed using BD FACSAria (BD Biosciences, San Jose, CA) 77 T. using | .FlowJo (Tree Star Inc. Ashland OR) Rnameh determine viral standards Q7 Lgel already 0 of exception 0 of 1 Sharm 1 brown prostitute, using 10-fold dilutions of blood CJ Alcaml- has IMDM or one father 0 t have been processed Bahermonat in LCMV 1 each pearl 0 of 1 Tagael then, for Mn2-6 hydroxide in 37 m in affection Akhaddan Zri 1 Vij, who shower Elyl% from 0 Schell Cellulose 0 u so , DMEM and after deletion -sm covered d 1 to the son specified 3-5 days, after Zlktaat 0 m Az'lh s Shboz p &amp; lt; Yi literature 'has been 4 percent are Bararmaladhead and &amp; quot; the fact that Dr. Zq to Dgaz PBS to Hlaya using (-262- -262-ΜΑ 32948Β1 using 0.5% of Trretn- X for 20 minutes, and the chapter Bashaddam PBS and is close it after that in 10% of FCS for one hour using arrogance average. are made Altbga LCMV Bamthaddam's Jem daad VL4 (one hour) WPM rancor twice and after the deletion, Bam optimization using anti-murine 400: 1) HRP) in a buffer solution of the closure. U That chapter three times and then adding a pillar of 0 - Phenylenediamine Dai Secretary (SIGMA 3 Ρ8806.50ΤΑΒ Bhm CD / CD) in the eyes wanted to improve it. Almhal 8 obstruction PD.L1 my Almrtan will be inserter now that many tumors can be used in one Rhett relational's 1-PD average for traumatized Ascabh cells T 1 delegation of the tumor 0 Ot 1 Mr Q Human Alrtanat to be Altabar for high Vnuyat of PD-L1 on each of the tumors and white cells Alambrahh of tumors associated prisoner of Artha r PD-LI in 1 FB b-1 Ka weak 0 illustrate models 0 tumor Afoura 1 Mshamh to express growing 1 Wallachia ^ r PD-L1 must 0 breached the Euro-13:00 and recommended role in 0 marched PD-1 / PD-L1 in Tbit immunity Athrtan. In this Aluthhh cm Presentation | experiments that illustrate the impact of termination 1 Ge PD-LI folding Mamo oncologist Dr. position of Oorh. MC38 in the exception, da Arrm SPS in the colon in mice C57B6 (RFM Figure 9a). Reflect fulfilled one of Hlaya for misery oval through Least Alalakh Alexei who crosses p PD-L1 But Bs PD-L2 Ouaytah'db to be 0 p Ka name of Zq d 0 S flow Allaa 0 (striped 'to form modulate 10;) • was Ttabm antibiotic P Waddle nebulae 0.5 mm a a | ™ MC38.0 in Adam wasting · In one Adam! Adam and 14 -263- -263-ΜΑ 32948Β1 (Ed a Tslaloor 0 0 4 m Li .tot Ehlaly 250 mm 3) 0.1 mice in August and has de Sdam 10 Bhm / k 0 m from the S YW243.55S70- mouse IgG2a-DANA) PD-L1) up 1 Qrzh of Ig and take a hamper 0 Gadd (and i-3 CTLA4 Ab, (UC10-4Fi5 times Ralosbua for Durr 1 Study. can shut PD-L1 E0 of a e or 0 infants 0 Zekhr 0 n 1 Schl lowest 5 that the soles a little as 0 hope Mld special S p prevention 0 n z tumors' u 1 to reflect the deletion, working Aouaqh CTLA4 in E0 to Har Akaaber 0 to a special section F r u 1 Hlaya T of CTLA4 molecule 1 inhibitor only / z T cells and Oni not  any particular indications by inhibiting tumor growth. explained those Algoij to 0 core Ahlgred Creek PD-1 / PD-Ll &amp; lt ;, CTLA4 / B7 in 1 hanging from one of the causes of the disease .lamadadh core 1 Rum are supported 0 n in 0 treatment plant cancer 10 using an antibody to PD-L1 0 your p interaction d 1-PD and Β7. 1 · Nmang tumor .MC38 oval synergistic: the roads. in today's small four were Iabn 70 animal I 1-to-skin? 0.5 Tion Bh Whitao 4 of MC38 in 100 microseconds Barr Z HBSS + matrigel · and starting with 1 to day 1, was divided 20 Vara 1 Li Ohdmjmootain Ela.hhn (Anzfimadna : F &amp; quot; of your responsibilities Alkhmuah 2). It was Almah Bgmo tumor in Algiran Bahia 40 guestrooms Ir 1 and y 7 w z 15-day 14. from these .lorbaan a fugitive, was the inclusion of 30 Va'ra mm tumors any Alhhm in Ahdtm 4 three treatment groups (Ahamoat 3_ 5). Tumors were measured and the weight of the largest 1 0 n Rtzn

CK -264- -264-ΜΑ 32948Β1 week. Were killed Ghabran is falling in the following treatment groups, because of the similarity of size Alrrm: Anhmuah 1: antibody for 10, gpi20 Mjma LMO, inside the membrane proton 0.100 micro liters, 'the day 1.3 * A Week 5 Agmoah 2: Antibody for 10, PD-L1 mg / LMO, inside the membrane proton 0.100 micro-liter 0.1-day 1.3 * a week Atjmuah 3: antibody for 10, gpi20 Mjma LMO, inside the membrane proton 0.100 micro-liter 0.1-day 14, χ3 a Anhmuah week 4: antibody d 10, PD-L1 mg / LMO, inside the membrane proton, 10 010 micro liters, today 14, χ3 a week Andjemuah 5: 4-10 for the antibody, CTLA mg / LMO, inside the membrane proton, 100 micro liter 0.1-day 14, χ3 / Osus assemblies 1 and 2 doses starting on day 1; and Aljmrat 3, 4, 5 per day 14. eg \ 9 15 combinations add my hypothalamus pdlJ and other factors to provide Tire anti-tumor or treatment enhanced Mnaah- Nmong MC38 Oval

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265- 265-ΜΑ 32948Β1 in one blame Wigger, the age of 150 p 1 P d subcutaneously 0.5 million oval cell MC38 My 100 microseconds z oo HBSS + matrigel. Almah the growth of the tumor and sleep in Algiran. Measuring growth of tumors and Osv Algiran twice weekly until Edom 11 &amp; lt; Ezdma hovered r 1 tumor z 100-200 t then. 1 Rom 11; Algiran been staying at one of the 12 groups therapeutic next. Say then Alhiran is a, to the point in the following treatment groups, because of the lack of similarity of tumor size. Began treatment Gemcitabine (Atjmuah 4) at day 12, while treating the rest of the antibody groups began the day 14 were all sizes p 1000 Kro der 6 inert, the following are some additional Alngesel: Atjmuah 1: antibody for 10, gpi20 mg / LMO, inside the membrane Albroorna 0.100 micro liters, day 1, Χ3 R. week 5 X, p = 10 1 Deh 2: antibody for 10, PDLI mg / LMO, inside the membrane proton 0.100 microseconds der, one day χ3,1 / Acts 5 X; p = 10 Atjmuah 3: antibody for 7EGF, 5 mg / kg, within the membrane proton, 1000 Kro liter, day 1, Χ3 a week 5 X, p = 10 1 Deh 4: 40, Gemcitabine Mahm / LMO, within the membrane Albroorna 0.100 micro layer, Name of 2A, 16.20, p = 10 Agmo.eh 5: antibody for + rJr.PD-Ll counter for 20! ρ, p = 10 -266- ΜΑ 32948Β1 Atjmuah 6: Jem's anti + + Jem anti-VEGF's, p = 10 Atjmuah 7: antibody for PD-L1 + Gemcitabine, p = 10 Akhmuah 8: antibody for Gemcitabine + gpl20, p = 10 Aljmuah 9: Jem counter for 20! gp + anti-VEGF, GS = 1051 for day 12: blood was taken from the &amp; lt; from that, Ndjemuah 1 (100 Hkro lar) i 1 to Hhaj a drug to analyze the CBC. The 0 Om'boum 14 and 22: Then he took blood from Fran p August 4 (100 Ed y) d pilgrims under anesthetic for the analysis of CBC &amp; quot; 1 to Day 19: Take 2 has been collecting blood p 1 Ghassan Anh Med 1 0 Uh 4 (100 microseconds cr) d 1 Yj 10 under anesthetic for the analysis of CBC.

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Somparyrac et «no., Proc. Natl. Acad. Sci. Dextran sulfate described in 7575: Qa 1 (1981). And it is grown to 293 cell Oqskthavh in Drouk role and added 700 micro grams of DNA encoded to curb anti -0pRK5 and is first &amp; quot; R'Kiz cells from the flask dizziness -269- -269-ΜΑ 32948Β1 Zed 1 Focus and washed with PBS d. This is one Anadan arap DNA - Dicksr 1 n z b Rest specified hours. Z Azlaa 1 Bjeerod 20% Linda 90, a father, has 0 d Rrai August 'Iouadh Adz 0 Alhafedorv Hawar contain folding Rt Dri'lobau 5 Skll over the 0 to Dhirlin Da, Wa curlers 0.0 m / Mmeltrazdhan Pfera. D 4 to 6 Oame m Ra'ldd but Lara landfill 0 F and ascending still 0 1 Aglaa and As.la for-Ek 0 d Zq Ra August August Nest II of 0 to Z, crossing senile b 0 Tvha any way 0.0 Il dialysis Wa or vertical Aloratderav. In a Alazj, Imknadsaljm Akadvijlaya (! 0 and Amkinsledoy DNA encoded to curb anti-related d pRK5 into CHO cells using 0 Wade Mzonh 0 such as CaP54 or DEAE - Dicksran. As described above, it can be 'Htephan planter cells, Adal 1 Lrt Boumt 1 Mrzeh (alone) or and i contain Mrim radiant Shell S &amp; quot; - the age of 0 and hubby 0 solved 0 hands of the existence of Table 0 cm daad, can be replaced amid Azraah central p o 0 each. Wavel 4A-n 1 to farms for about six days, then was encouraged middle-conditioned. it can R'Kiz 1 Lot Anhtoa E 0 Li Lean counter the expressed and purified in a certain way . K. walked, for you to express images of antibody numbered lenses and peaks in CHO cells 0 and family, possible sub-transcription g DNA encoded antibody associated _l ~ PRK5 of a 0-for -270- -270-ΜΑ 32948Β1

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Alaztak Secret 0 j d DNA code Yoo-B-A; t to 1 Ooi did equ! Li Lash b

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5 &amp; ​​lt; da CHO (Z Seve described) 0 0 d Amaqlloj SV40. It can Ajaddae Ahrime Z Z SSH, Sekd p health. Then spray area and i Arry evacuated Z μι a newcomer; then b Rla_ 0 m 0 0 Et Alambr not covet a way to, like chromatograph Please choose a Ni S-Ju. Mmaimkzmes the reported pregnancies in Hlaya Wa CHO or COS conduct health Arar d CHO cells any remuneration 0 E 0 Deir lattes R 0 10 wpm Eger 1 E Almestbr expression in CHO cells using the following procedure. The one functioning Z Albrooaat in the form of Mfeto IgG (Paste immunotherapy), where Bam Hamad sequences coding for photos Aq ^ for Azun (such Akhalat extracellular), relevant proteins with sequence fixed area for IgGJ Bang &amp; lt ;, aunts lobar, and CH2 and CH2, War or image coded Bbola- Hesse.

After PCR amplification, including transcription Borai acids DNA in an expression vector z CHO Basimhaddam 15 conventional methods as described in Ausubel et al, Current Protocols ofMolecular 1997) Biology, Unit 3.16, John Wiley and Sons. The expression vectors are generated Z CHO to contain restriction sites compatible 5 = 3 = L DNA of Oleihh to allow the composition Dhu'ql

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-271- -271-ΜΑ 32948Β1 shuttle suitable for cDNA = s. It was the carrier that was used expression in CHO Khala.a km 1 nm described in (1996) 1779-1774) 24: 9 .Lucas et al., Nucl. Acids Res, and m-Mazzata improvers initial SV40 to direct the expression of cDNA on the Oleihh and enzyme Reel 0 0 Carr Hill Dai Rowe folate (DHFR). Ash and the expression of DHFR choosing fixed maintain Albulaz 0 hands of Baal 0 0 Shell infection. Yum enter twelve micro grams of plasmid DNA required in about 10 0 ion CHO cell Bashaddam materials Zql infection available to traders (SUPERFECT® (Quiagen 'or ®DOSPER, or (FUGENE® (B0ehinger Mannheim uncle button; cent a 0 cells Z name Wad in Lucas et ai, supra., and is frozen ho 0 me 10 χ3 cell in Abol Z Q 0 fled and production as Pettm described later. the unfreezing .lompolat .nhtoah on DNA! to Blazmida placing them in the flesh 2 0 loyalty and Khalalha Baltdubm. WPM Sep 1 Tjtoyat Pipette to the tube centrifuges contain Z 0 to Mlmn 0 Lot and the deportation procedure one of the central abuse in 1000 the language per minute for 5 Dieads' and'hm Q 9 b 1 a substance Alhlavih and affirm 5 Tiq Allaava 010 for 0 Nalost 1 Aztghani (0.2 PS20 ΓΦ Rdlo 0 p 5% Ayumi Mamd villages Rev Zduga Φ0.2 m). Temtem &amp; quot; Hamalkhala-a in the basket. Doam 10 0 for financing 90 mL and i Antqash. after 1. a short, E 21:00 p S to injury &amp; quot; Doam 250 ml 0 p 150 ml and i growth of 1 ^ '^ and Near Ezd 0 37 m. -272- -272-ΜΑ 32948Β1 after Merv 2-3 days, I see, are button 1 cent 10/35 trot me and Adsdl Ddoam 250 ml, 500 ml and 2000 ml., and is replaced by the central cells new Butt for &amp; lt; Levi expulsion 1 to central and re Alttiq in the middle of production. in spite of the possibility of the use of any and i CHO Masp 0, 0, but it can already use the center described the production in reading Urdu Oam Patent 5,122,469, issued on June 16, 1992. it was Zrat 2.10 χΐ Jklah / my profile to spin the production of the 3-liter. In today's small, is measured in the number of cells and balances Alheidlogia 0 at 1 for 1 day, samples are taken from the injury and the spin begins Larch air filter. Day two, the frameworks aware T. from the basket spin, taking the temperature at which turn to 33 m, and 30 ml of glucose 500 g / l and 0.6 ml of the antagonist of the foam 10 Huh (for example, Sthalb 35% poly d 1 j methyl Saluxan, the Dow Corning 365 Medical Grade Emulsion). During Alaiaj process, pH is adjusted Arqam complex adaptive love to keep it in the range of 7.2. After 0.1 days, or until the viability dropped to less than 70%, the cells are collected farm Arabs Focus 1 and filtrate through the filter of 0.22 Φ meters. Filtrate was stored at 16 o'clock or downloaded Z hollow columns for purification. And M for Tkoaiat Ano.h Bbola- Hess, how proteins purified using Ni-NTA column (Qiagen). Before purification, imidazole was added to the center to focus adjuster 5 ml Molar. WPM center-pump air conditioner on the d E 0 6 Ni-NTA ml balanced d 16:00, in 20 ml Molar -273- -273-ΜΑ 32948Β1

Hepes, and modulate Mdrome 7.4, and 0 Iol systems; Miiay 0.3 Smlal 0 NaCI R. 5 &amp; lt ;, 6 Lahr never. And counting stretched shower generates. 4-5 Ra bear d in August; μ r, August .sauo Tmtoazina 0 cormorant and Aftvalas μ- Razin Ad Ih 6 0.25 4 Adasul. After reminded been Azall b Lardy, p less Viyolilmelzhn edematous Z 10.0 Rlar Hepes E and 0.14 Rlar NaCI and 4% Trilon, and Rzm Ddros 6.8 'Srdhdh 025 25 Phamacia) y) Dakchin p -80 m-and are purified Mkumat 1 Aagafy S (1 contain the Z fc) z the national 0 Aq as 0 the following 0 pump 1 to the center of one of the air eBay column Rowe 0 x 05 a's (Pharmacia) Ku 0 was not one Taza ^ 20 t Molar Mahvol Hosgat .oubeyom Mazm, drum Hydro-Haba 6.8 'and d 1 to Seltm E 1 TB 1 column strongly.;, Halolmt 0 m Lalla &amp; quot ; Ran D. del. ja Str'k 100 g 0 Rlar was meant Ghor Altro-Q bevelled pages 0 p equation 1 ml portions in Alonab Anhtoah on 275 Φ β 0 n 1 Molar real entrepreneur gear, and the number and pH. Then sniff remove salinity 1 for routine E 1 I 1 Cgqah in 0 Tm to Kkhoz.dn 0 and z d father of Bruyat 1 to Marie Bbola_ Hess Wim s 0 S Althad Bashaddam gel poly Acryl amide SDS and action sequences a! Acid only 0 Lenny &amp; lt; with N, O 0 Thilal Idman 0 Il 11 -274- -274- ΜΑ 32948Β1 hav a example prepare an image Z .aaljh Paljlakozl Q Table 13:00 Assad P.-L1-J z 1 illustrates saliva Kaaoar Nah r return Alarabat gene j Ahresaa E. coli. Lo amplified DNA sequence Cedar antibody PD-LlJ Q 0 M 0 as upper Adouat PCR; and must contain one Bdiat the claimed enzymes Tvazer Raca creams Alhied Z Lash Ace 1 Ayimar. And can be made using many of the expression vectors. Examples Showers Alash PBR322 (1 to 0 mAh of E. coli Dricia R'dja 4, (1977) 2:95, Bolivar et al., Gene) 1 t Ioa &amp; lt ;, Lmq 1 1 Mssll anybody as long pain and liters Assen. WPM digesting enzyme S j WPM Dzaa 8 of AAC. Then one of Mtoapt Akkh 0 of b PCR much less 0 .hdil that Ahabri 1 Lash Z 6 machines 00 0 Besmquaom of Anti 1 Vivid, and Mzz trp, and Iedh early Hesse (s z p 0 t t; Zat E: gone, and Mab 1 Boulez 0 Q, and 0 and Aalllar Ezim; against me 0, D 4 Shake Eha Y Antaka lambda and Jane argU. Kkhym, to Tarbts 1 Aadtha / for Arta; Athaddam 1 tactless Araodunfa

Sambrook aul, supra. Is determined 1 Aullac b Nadwa Z AAC 0 R &amp; lt; Then less and work sequences DNA. .memkn Button cent 0 1 Bil Aptqah 0 Lual 1 label in and i button cent 1 0 means 0 such as the Rzq LB provided counter-1 T. vital 0 can then reminded Assad 13:00 Arrah that d To'l SV overcharged 0 P -275- -275-ΜΑ 32948Β1 Zri; /. Then R ministers 1 1 Adlai density alienation Almtade 1 DVI Acae Zq Bam p Sz expression. After Button 1 cent 1 cells we consider a ^ t, Be b 0 p 1 cells expulsion of; Xie 0 can Dissolve B 1 B 1 t been one to get El 0 Behold the expulsion of one of the central Adam Aua &amp; lt ;, Z Q »in Anhal, and can d 0 that purify one's body 1 of the Anti Almz 1b Bastkhadd 13:00 E 0 replies b Ddn Z conditions 0 allowed lard Angm to curb counterattack. It can also express, antibody to PD-U-J in a Ahres 0 7 J in the picture No. 0 of Sola_ Hess, a land. Sdam 1 to E 1. Was first amplified DNA sequence encoded M anti-PD-L1J using selected PCR primers. Od Abdtat Z 0 wor It Ir-Ta &amp; lt; Jeremiah sites 0 Yt j z Ashe expression chosen, and other sequences useful in providing start-effective and reliable knuckle 0.0 p purification speed on chelation column of the metal, and have removed 1 Karim routine Aztroyz 0 and v 0 E. linking one Doualat numbered Bbola - Heye and huge d PCR mated Altaber, used in 4 Aual Ouail 0 A, ;,. Lira 7 j depends on the strain 52 W3110 fijhA (tonA) Ion galE) (rpoHts (htpRts) clpP (lacIq. and is first ministers 0 Dilat in LB Ahari z 50 mg / &amp; lt; a Asvan d 30 t C Balrj down to the light intensity 600 Kraouh 2-3. then u 1 4 mph Ra 50-100 once and i CRAP (protected the harm it by mixing 3.57 g 0.71, (NH4) 2S04 leave gm sodium Α2Η20, and 07.a g KC1 E and 5.36 g -276- -276- ΜΑ 32948Β1 - yeast Difco, and 5.36 grams of SheffieldhycaseSF in 500 ml of water, and enough 110 Hrlar MPOS; Rim pH 7.3, and 0.55% (Rzza size) Jlokon and 7 t Molar MPOS) and agriculture for about 20-30 hours at 30 m h shaking. The place have removed one of the Aivat to Kokamn expression by transmitting SDS-PAGE, Wim making centrifuge Q Almzra 0 of b cells. WPM Tjmaa cell granules until the purification and re-folding. sniff Aouadh tolerate paste point 0 Gha Kolays Nhrat ranged Z 0.5 to 1 liter (6 '10 granular) in 10 sizes (and influenza size) at 7 Molar flown ^ Ane and 20 t Rlar Rse liked regulator Brnm pH 8. added sulfite Akoderm August and Dara Theolot 1 Krdiom to form the focus 1 v 1 to Zharh of 0.1 Molar and 0002 Rlara Z Walker &amp; quot; burden then m dome Aglutaiw 1 for 1 night at 16:00. This leads one to Ahtoh to Aztoj Loral routine I Ashe; p 0 p natural impede the collection of the building blocks of the Sistine about deafness 0 Queen ¥ Kabrept 'Eger is 1 E 1 to flush out' for a central black when 40,000 Agh in Aldhhhh in Beckman

Ultracentifuge Idh 30 minutes. Marking ease 1 Article 1 of Tath b 0 Say humanitarian partners 0 Hham Mnmahlol 0 i 0 m column x \ core Fdn (6 Rlargeo 1 Vedan 0.20 ml Molarrs, and bridging Hmadrouhna 7.4) and filtration d Rcent 0.22 micron Study 0 ¥ case, the blood of μ, Laden professional for column x 1 core Fdn 5 Νΐ-ΝΤΑ Qiagen Mlmertvi Anhlol Zm to Aamod 0 0 chelator to the offerer and complements the juicy Alsod.mmtodniz agave Wei Z ^ 50 t Rlar ΜΑ 32948Β1 -in- Aead 1 Zeul CaJbiochem, utrol grade); No. 0 for 0 Ruginy 7.4 b. · JL to Pro &amp; quot; yen.: Entrepreneur tried to Ahari Z 250 D Molar Adasul 0 Om Z opinions intifada Aye Z &amp; quot; Q .lmzawb and Tkhoz_dtha at 16:00. This is a harsh kicked protein Aamassas. J. 280 lar t using Antghae coefficient Mhob Bghaeo Z Mtwarh \ ~ 2 Alomaa its own for 0 sniff re - folded proteins Ptkhvev'laanat slowly in solution 0 Tm to Aouadh S extent 0 At one component Thoudbr of: 20 ml Molar gear; Ord e; Drugiy 8.6; 0:30 and Lahr NaCi E and 2 0.5 Mulariuraa 4 and 5 ml Molar Sistn, 20 SAL .rlargelesnn 0 and 1's and 0 lar EDTA. Are selected Ohham Ali re - focus so that one Klia of protein Z 50 and a 00 microgram / ​​ml range. Om giving priority to re - folding solution gently at 4 ° C for 12-36 shiny. Wim extinguish the re - folding added TFA to a concentration Nmana 5 cr 0.4% interaction (RIP pH of about 3). Before further purification of the protein then purified Anhlol through over the p 0.22 micron tattoo added Acetonitrile Nitrile to R'Kiz teleological 2-0 a 0% WPM 1 Shaddam Chromatography of Brod re - attached to the reverse phase column Poros Rl / Η using buffer solution passed down from 0.1% TFA with rinsing steeply of acetonitrile from 10 to 80%. The bites are parts analysis absorbs Α280 on poly Acryl Forever Om SDS gel assembling parts that contain protein uniformly hostile Ta. In general, a Mnab are rinsed re - Z fold types most Alrotefat at lower concentrations of Acetonitrile Vetr; for because FH 1-278 species are most integrated with the internal aspects of the water is Alalgh a Nhjos of Z interaction with Ratinh Alalor reverse. Usually rinse stacked parts at the highest concentrations of aceto nitrile. In addition to solving the images that U defect in the folding of proteins from the desired image, step by reverse phase as well as working to remove Alandooudin of samples. Agtoah parts are assembled antibodies for PD-L1 and required removal Acetonitrile Nitrile Batshaddam thin stream of nitrogen directed at Atjlol. , And the formulation of proteins in 20 ml Molar Hepes, No. pH 6.8 0.0 G sodium chloride 0.14 Molar and 4% mannitol dialysis or filtration on gel using Ratinhat (G25 Superfine (Pharmacia balanced in a buffer solution to the formula and filtered sterilization. -279- 1 32948Β1 List 1 Tdlat &amp; lt; 110 &amp; gt; Genentech Inc..

&amp; Lt; 120 &amp; gt; Antibodies for PD-L1 and use it to improve the functions of the cell T 5 P4192R1 W0 &amp; lt; 130 &amp; gt; US 61 / 121,092 &amp; lt; 150 &amp; gt; 2008/12/9 &amp; lt; 151 &amp; gt; 10 40 &amp; lt; 160 &amp; gt; 1 &amp; lt; 210 &amp; gt; 10 &amp; lt; 211 &amp; gt; 15 prt &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 20 &amp; lt; 220 &amp; gt; variable residue &amp; lt; 221 &amp; gt; 6 &amp; lt; 222 &amp; gt;

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-280- 1 32948Β1 residue is Dor G &amp; lt; 223 &amp; gt; 1 &amp; lt; 400 &amp; gt; GJy Phe Thr Phe Ser Xaa Ser Trp IJe His 10 5 5 2 &amp; lt; 210 &amp; gt; 18 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificiaisequence &amp; lt; 2110 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; &amp; Lt; 220 &amp; gt; 15 variable resitJues &amp; lt; 221 &amp; gt; 4 &amp; lt; 222 &amp; gt; residue isSorL &amp; lt; 223 &amp; gt; &amp; Lt; 220 &amp; gt; 20 variable residue &amp; lt; 221 &amp; gt; 10 &amp; lt; 222 &amp; gt; residue is T or s &amp; lt; 223 &amp; gt; 2 &amp; lt; 400 &amp; gt; 25

Ala Trp lie Xaa Pro Tyr Gly Gly Ser Xaa Tyr Tyr Ala Asp Ser -281- 1 32948Β1 15 10 5 1

Val Lys Gly 3 &amp; lt; 210 &amp; gt; 9 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 3 &amp; lt; 400 &amp; gt;

Arg His Trp Pro GJy Gly Phe Asp Tyr 5 4 &amp; lt; 210 &amp; gt; 25 &amp; lt; 211 &amp; gt; PRT &amp; lt; 22 E &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 4 &amp; lt; 400 &amp; gt;

-282- MA 32948Β1

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 15 10 5 1

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser 5 25 20 5 &amp; lt; 210 &amp; gt; 13 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; 10 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 5 &amp; ​​lt; 400 &amp; gt; 15

Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 10 5 6 &amp; lt; 210 &amp; gt; 32 &amp; lt; 211 &amp; gt; 20 PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 25

<img img-format="tif" img-content="drawing" file="MA-32948-B1D02841.tif" id="idf0046" />

-283- 1 32948Β1 6 &amp; lt; 400 &amp; gt;

Arg Phe Thr IJe Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu 15 10 5 1

Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 5 30 25 20

Ala Arg 7 &amp; lt; 210 &amp; gt; 11 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; 15 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 7 &amp; lt; 400 &amp; gt;

Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala 20 10 5 8 &amp; lt; 210 &amp; gt; 11 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; 25

Artificial sequence &amp; lt; 213 &amp; gt; -284- 1 32948Β1 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; &amp; Lt; 220 &amp; gt; 5 variable residue &amp; lt; 22-1 &amp; gt; 5 &amp; ​​lt; 222 &amp; gt; residue is D or V &amp; lt; 2-2-9 &amp; gt; &amp; Lt; 220 &amp; gt; 10 variable residue &amp; lt; 221 &amp; gt; 6 &amp; lt; 222 &amp; gt; residue is V or I &amp; lt; 223 &amp; gt; &amp; Lt; 220 &amp; gt; 15 variable residue &amp; lt; 22 1 &amp; gt; 6 &amp; lt; m &amp; gt; residue is s or N &amp; lt; 223 &amp; gt; &amp; Lt; 220 &amp; gt; 20 variable residue &amp; lt; 221 &amp; gt; 9 &amp; lt; 222 &amp; gt; residue is A or F &amp; lt; 223 &amp; gt; &amp; Lt; 220 &amp; gt; 25 variable residue &amp; lt; 2-2.1 &amp; gt; 51

-285- MK 32948Β1 222 &amp; gt; 0 &amp; gt's; residue is 7 or L &amp; lt; 223 A 8 &amp; lt; 400 &amp; gt;

Arg AJa Ser GJn Xaa Xaa Xaa Thr Xaa Xaa AJa 5 10 5 9 &amp; lt; 210 &amp; gt; 7 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; 10

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; &amp; Lt; 220 &amp; gt; variable residue &amp; lt; 221 &amp; gt; 4 &amp; lt; 222 &amp; gt; residue isForT &amp; lt; 223 &amp; gt; 20 &amp; lt; 220 &amp; gt; variable residue &amp; lt; 221 &amp; gt; 6 &amp; lt; 222 &amp; gt; residue is Y or A &amp; lt; 223 &amp; gt; 25 9 &amp; lt; 400 &amp; gt; o1 -286- i 32948Β1

Ser Ala Ser Xaa Leu Xaa Ser 5 10 &amp; lt; 210 &amp; gt; 9 &amp; lt; 211 &amp; gt; 5 PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 10 &amp; lt; 220 &amp; gt; variable residue &amp; lt; 221 &amp; gt; 3 &amp; lt; 222 &amp; gt; residue is Y, G, ForS &amp; lt; 223 &amp; gt; 15 &amp; lt; 220 &amp; gt; variable residue &amp; lt; 221 &amp; gt; 9 &amp; lt; rn &amp; gt; residue is L, Y, F, or w &amp; lt; 223 &amp; gt; 20 &amp; lt; 220 &amp; gt; variable residue &amp; lt; 221 &amp; gt; 5 &amp; ​​lt; 222 &amp; gt; residue is Y, N, A, T, G, F or I &amp; lt; 223 &amp; gt; 25

<img img-format="tif" img-content="drawing" file="MA-32948-B1D02881.tif" id="idf0047" />

-287- -287-32948Β1 &amp; Lt; 220 &amp; gt; variable residue &amp; lt; 22 1 &amp; gt; 6 &amp; lt; 222 &amp; gt; residue is H, V, P, T or I &amp; lt; 223 &amp; gt; &amp; Lt; 220 &amp; gt; variable residue &amp; lt; 221 &amp; gt; 8 &amp; lt; 222 &amp; gt; residue is A, w, R, p or T &amp; lt; 223 &amp; gt; 10 10 &amp; lt; 400 &amp; gt; GJn Gin Xaa Xaa Xaa Xaa Pro Xaa Thr 5 11 &amp; lt; 210 &amp; gt; 15 23 &amp; lt; 211 &amp; gt; prt &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; 20 sequence is synthesized &amp; lt; 223 &amp; gt; 11 &amp; lt; 400 &amp; gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1 25 O) -288- i 32948Β1

Gly Asp Arg Val Thr lie Thr Cys 20 12 &amp; lt; 210 &amp; gt; 15 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 12 &amp; lt; 400 &amp; gt;

Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 15 10 5 1 13 &amp; lt; 210 &amp; gt; 32 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 13 &amp; lt; 400 &amp; gt;

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 15 10 5 1 -289- 1 32948Β1

Thr Leu Thr IJe Ser Ser Leu GJn Pro GJu Asp Pbe Ala Thr Tyr 30 25 20

TyrCys 5 14 &amp; lt; 210 &amp; gt; 11 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; 10

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 15 14 &amp; lt; 400 &amp; gt;

Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Arg 10 5 15 &amp; lt; 210 &amp; gt; 20 10 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; 25 sequence is synthesized &amp; lt; 223 &amp; gt; -29.- -29.-ΜΑ 32948Β1 15 &amp; lt; 400 &amp; gt;

Gly Phe Thr Phe Ser Asp Ser Trp IJe His 10 5 16 &amp; lt; 210 &amp; gt; 18 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 21 3 &amp; gt; 10 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 16 &amp; lt; 400 &amp; gt;

Ala Trp lie Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser 15 15 10 5 1

Val Lys Gly 20 17 &amp; lt; 210 &amp; gt; 11 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt;

<img img-format="tif" img-content="drawing" file="MA-32948-B1D02921.tif" id="idf0048" />

-291-! 32948Β1 sequence is synthesized &amp; lt; 223 &amp; gt; 17 &amp; lt; 400 &amp; gt;

Arg Ala Ser Gin Asp Val Ser Thr Ala Val Ala 10 5 5 &amp; lt; 210 &amp; gt; 18 &amp; lt; \\ 2 &amp; gt; 6 PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; 10 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 18 &amp; lt; 400 &amp; gt; 15

Ser Ala Ser Phe Leu Tyr Ser 5 19 &amp; lt; 210 &amp; gt; 9 &amp; lt; 211 &amp; gt; 20 PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 25 -292- 1 32948Β1 19 &amp; lt; 400 &amp; gt;

Gin Gin Tyr Leu Tyr His Pro Ala Thr 5 20 &amp; lt; 210 &amp; gt; 5 118 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; 10 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 20 &amp; lt; 400 &amp; gt;

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 15 10 5 1 15

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 30 25 20

Asp Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 20 45 40 35

Glu Trp Val Ala Trp lie Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr 60 55 50

Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 25 -293- -293-ΜΑ 32948Β1 75 70 65

Lys As. Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 90 85 80 5

Thr Ala Val Tyr Tyr Cys Ala Arg Arg His Trp Pro Gly Gly Phe 105 100 95

Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ala 115 110 10 21 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; 15 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 21 &amp; lt; 400 &amp; gt; 20

Asp Ile Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20 25 -294- ΜΑ 32948Β1

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35

Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 5 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 60; 6 es

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 10 90 85 80

Tyr Leu Tyr His Pro Ala Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95 5 A

Ile Lys Arg 22 &amp; lt; 210 &amp; gt; 113 &amp; lt; 211 &amp; gt; 20 prt &amp; lt; 212 &amp; gt;

Homo sapiens &amp; lt; 213 &amp; gt; 22 &amp; lt; 400 &amp; gt;

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 25 15 10 5 1 -295- ΜΑ 32948Β1

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 30 25 20 5

Ser Tyr Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 45 40 35

Glu Trp Val Ser Val Ile Ser Gly Asp Gly Gly Ser Thr Tyr Tyr 60 55 50 1.

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 75 70 65

Lys Asn Thr Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 15 90 85 80

Thr Ala Val Tyr Tyr Cys Ala Arg Gly Phe Asp Tyr Trp Gly Gin 105 100 95

Gly Thr Leu Val Thr Val Ser Ala 20 110 23 &amp; lt; 210 &amp; gt; 118 &amp; lt; 211 &amp; gt; prt &amp; lt; 212 &amp; gt; 25

Artificial sequence &amp; lt; 213 &amp; gt;

<img img-format="tif" img-content="drawing" file="MA-32948-B1D02971.tif" id="idf0049" />

-296- 1 32948Β1 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 23 &amp; lt; 400 &amp; gt; 5

Glu Va. Gin Leu Val Glu Ser GJy Gly Gly Leu VaJ Gin Pro Gly 15 10 5 1

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 30 25 20 10

Asp Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 45 40 35

Glu Trp Val Ala Trp lie Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr 15 60 55 50

Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 75 70 65 20

Lys Asn Thr Ala Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp 90 85 80

Thr Ala Val Tyr Tyr Cys Ala Arg Arg His Trp Pro Gly Gly Phe 105 100 95 25

<img img-format="tif" img-content="drawing" file="MA-32948-B1D02981.tif" id="idf0050" />

-291- 1 32948Β1

Asp Tyr Trp GJy Gin Gly Thr Leu Val Thr Val Ser Ala 115 110 24 &amp; lt; 210 &amp; gt; 118 &amp; lt; 211 &amp; gt; 5 PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 10 24 &amp; lt; 400 &amp; gt;

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly 15 10 5 1 15

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Plie Ser 30 25 20

Gly Ser Trp lie His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu 45 40 35 20

Glu Trp Val Ala Trp lie Leu Pro Tyr Gly Gly Ser Ser Tyr Tyr 60 55 50

Ala Asp Ser Val Lys Gly Arg Phe Thr lie Ser Ala Asp Thr Ser 25 75 70 65 -298- -298- 1 32948Β1

Lys Asn Thr Ala Tyr Leu G0 a Met As. Ser Leu Arg Ala Glu Asp 90 85 80

Thr AJa Va. Tyr Tyr Cys Ala Arg Arg His Trp Pro G0y G0y Phe 5 105 100 95

Asp Tyr Trp G0y Gin G0y Thr Leu Val Thr Val Ser Ala 115 110 10 25 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Homo sapiens &amp; lt; 213 &amp; gt; 25 &amp; lt; 400 &amp; gt;

Asp Ile Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1

Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gin Ser Ile Ser 20 30 25 20

Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35 25

Leu Leu Ile Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser ex -299- 1 32948Β1 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr IJe 75 70 65 5

Ser Ser Leu Gin Pro GIu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80

Tyr Asn Ser Leu Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95 10

Ile Lys Arg 26 &amp; lt; 210 &amp; gt; 15 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; 20 sequence is synthesized &amp; lt; 223 &amp; gt; 26 &amp; lt; 400 &amp; gt;

Asn lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1 25

MA 32948Β1 -3.0-

Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35 5

Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 10

; 6 IQ bS

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 S5 80 15

Tyr Tyr Asn Val Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95

Ile Lys Arg 20 27 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; prt &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; 25 51 -301- ΜΑ 32948Β1 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 27 &amp; lt; 400 &amp; gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 5 15 10 5 1

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20 10

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35

Leu Leu He Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 15 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He 75 70 65

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 20 90 85 80

Tyr Tyr Ala Pro Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95 25

He Lys Arg

<img img-format="tif" img-content="drawing" file="MA-32948-B1D03031.tif" id="idf0051" />

-302- 1 32948Β1 28 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; 5

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 10 28 &amp; lt; 400 &amp; gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 15 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35 20

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 75 70 65 25 -303- 1 32948Β1

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80

Tyr Tyr Tlir Val Fro Trp Tfcr Phe Gly Glo Gly Tfcr Lys Val Gla J05 100 95 5

Ile Lys Arg 29 &amp; lt; 210 &amp; gt; 10 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; 15 sequence is synthesized &amp; lt; 223 &amp; gt; 29 &amp; lt; 400 &amp; gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1 20

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Val lie Asn 30 25 20

Thr Phe Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 25 45 40 35 51 1 32948Β1 -3.4-

Leu Leu lie Tyr Ser Ala Ser Thr Leu Ala Ser Gly Val Pro Ser 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 5

IS 60 6S

Ser Ser Leu Gin Pro GIu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80 10

Tyr Tyr Thr Val Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95

Ile Lys Arg 15 30 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; 20 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 30 &amp; lt; 400 &amp; gt; 25

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 0 &amp; lt; -305- 1 32948Β1 15 10 5 1 GJy Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50 10

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 75 70 65

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 15 90 85 80

Gly Tyr Gly Val Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95 20 lie Lys Arg 31 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; 25 PRT &amp; lt; 212 &amp; gt;

<img img-format="tif" img-content="drawing" file="MA-32948-B1D03071.tif" id="idf0052" />

-306-MA 32948Β1

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 31 &amp; lt; 400 &amp; gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 10 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35 15

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 75 70 65 20

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80

Tyr Leu Phe Thr Pro Pro Tlir Phe Gly Gin Gly Thr Lys Val Glu 25 105 100 95

<img img-format="tif" img-content="drawing" file="MA-32948-B1D03081.tif" id="idf0053" />

1 32948Β1 -3.7-

Ile Lys Arg 32 &amp; lt; 210 &amp; gt; 5 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt;

&amp; Lt; 220 &amp; gt; JO sequence is synthesized &amp; lt; 223 &amp; gt; 32 &amp; lt; 400 &amp; gt;

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1 15

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 20 45 40 35

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50 25

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 51

-308-MA 32948Β1 15 IQ 5 of

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80 5

Tyr Phe lie Thr Pro Thr Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95

Ile Lys Arg 10 33 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; 15 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 33 &amp; lt; 400 &amp; gt; 20

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20 25 1 -.-

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50 5

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 75 70 65

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 10 90 85 80

Tyr Tyr Tyr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95 15 lie Lys Arg 34 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; 20 prt &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 25 -310- 1 32948Β1 34 &amp; lt; 400 &amp; gt;

Asp IJe Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 5 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35 10

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Jle 15

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80

Phe Phe Tyr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu 20 105 100 95 lie Lys Arg 35 &amp; lt; 210 &amp; gt;

<img img-format="tif" img-content="drawing" file="MA-32948-B1D03121.tif" id="idf0054" />

-311- -311-ΜΑ 32948Β1 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 35 &amp; lt; 400 &amp; gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1 10

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 15 45 40 35

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50 20

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 75 70 65

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80 25 -312- -312- 1 32948Β1

Ser Leu Phe Thr Pro Pro Thr Phe GJy GJn GJy Thr Lys Val GJu 105 100 95

Ile Lys Arg 5 36 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificia.sequence &amp; lt; 213 &amp; gt; 10 &amp; lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 36 &amp; lt; 400 &amp; gt; 15

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1

Gly Asp Arg Val Thr Jle Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 25 60 55 50

Cy -313- 1 32948Β1

Arg Phe Ser Gly Ser GJy Ser GJy Thr Asp Phe Thr Leu Thr lie 75 70 65

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 5 90 85 80

Ser Leu Tyr Thr Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95 10

Ile Lys Arg 37 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; 15 PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 20 37 &amp; lt; 400 &amp; gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1 25

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser

<img img-format="tif" img-content="drawing" file="MA-32948-B1D03151.tif" id="idf0055" />

-314-MA 32948Β1 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35

Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 75 70 65 10

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80

Ser Trp Tyr His Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu 15 105 100 95

Ile Lys Arg 38 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; &amp; Lt; 220 &amp; gt; 25

-315-MA 32948Β1 sequence is synthesized &amp; lt; 223 &amp; gt; 38 &amp; lt; 400 &amp; gt;

Asp JJe Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 15

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 10 45 40 35

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50 15

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 75 70 65

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80 20

Tyr Phe Tyr lie Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu 105 100 95 lie Lys Arg 25

Cv

-316- MK 32948Β1 39 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt;

Artificial sequence &amp; lt; 213 &amp; gt; 5 &amp; ​​lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 39 &amp; lt; 400 &amp; gt; 10

Asp Ile Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 15 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35

Leu Leu lie Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 20 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 75 70 65

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 25 -317- -317-ΜΑ 32948Β1 90 85 80

Tyr Trp Tyr Thr Pro Thr Thr Phe GJy Gin Gly Thr Lys Val Glu 105 100 95 5

Ile Lys Arg 40 &amp; lt; 210 &amp; gt; 108 &amp; lt; 211 &amp; gt; 10 PRT &amp; lt; 212 &amp; gt; Artificial sequence &amp; lt; 21 3 &amp; gt; &amp; Lt; 220 &amp; gt; sequence is synthesized &amp; lt; 223 &amp; gt; 15 40 &amp; lt; 400 &amp; gt;

Asp Ile Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val 15 10 5 1 20

Gly Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp Val Ser 30 25 20

Thr Ala Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys 45 40 35 25

<img img-format="tif" img-content="drawing" file="MA-32948-B1D03191.tif" id="idf0056" />

-318- 1 32948Β1

Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser 60 55 50

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie 75 70 65 5

Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin 90 85 80

Ser Tyr Phe lie Pro Pro Thr Phe Gly Gin Gly Thr Lys Val Glu 10 105 100 95

Ile Lys Arg

Cx