CN 104479018 B (19) PEAR MEA RAR (21) AIS 201410743500.4 (22) 81% 2009.12.08 (65) BATE AAAI SCRRS BAAS CN 104479018 A (43) RIB A4HA) 2015.04.01 (30) RABE 61/121 ,092 2008.12.09 US (2D PRR ABA 200980149532.9 2009.12.08 (732) SULA ERG AMP AR A) Hh LEA (72) BABA AiG + WE SBME « a BAe RE + Me RMB R FEM RA LEI RE (74) SABA bee Ai CE EE. i] 1021 RBA RW EI (12) RASA a (10) BRAGS CN 104479018 B (45) #86 AL 2018. 09. 21 (51)Int.c1 CO7K 16/26 2005.01) C12N 15/13 2008.01) 12N 15/70(2006.01) G12N 15/85( 2006.01) 12N 1/21(2006.01) G12N 5/10(2006.01) AS1K 45/06 2008.01) ASIK 39/395 2008.01) AIP 31/0K 2008.01) AIP 35/0K 2008.01) A61P 33/0K 2008.01) (56) 7b Se WO 2008071447 A2, 2008.06.19, US 2008039653 AL,2003.02.27, Blockade of B7-HI and PD-1 by Monoclonal Antibodies Potentiates Hirano et al. Cancer Therapeutic Immunity. . 90% FTAA — He FAL (d) PARE RET AE (BEAR F-GSEQ LD NO: 21 AFR ARERT EDK BULA BL 4B > 90% RIFF —-te 2 ABA BEAR LH SA AS BRR 25 AB BH IT A ET 2S OX HY SE FF -GSEQ ID NO 21 RE 2 Dx SALEBY FA AY 2B 2b 95 96 YP PUTA] HE. SAA BEAR LY SAB BRT BR 25 HB TE ET EFF SEQ ID NO: 21 Me) 8 De SEF FAL 28 “9996 HF UTA TE AA ANBER 1 SLA BR SL BRAG Po HY Be TE PIR EE KH EB FFF SEQ TD NO: 21 HSE ERT AE EAR TA. 5 LAN BER LAS Hi A RTL DR A So HB SE TAS EET 2 DK AY EM PAG SEQ: ID NO: 20K HCE n] ED SA ERR FEB FLAT 35 295 96 19 FPF — HE» 6 ALA BEAR LH AB BRR 25 AH BR 5 a RE a) EX EPG SEQ ID NO: QO BE FY ED 4 SE FPP FLAY 3 299% FFF AT) — HE 7 ABA BEAR A SAAS BATT BR 28 OH BH IT RT 2S OY AE RFF -GSEQ: ID NO: 2OH HERE HY 2S Dx SAL HEIR FA AY 22 29996 YAP PUTAl HE. BAER ITH LE TARTAR A BL ae ME 9 AB AA BEAR SH Hi A rR 2 eH PARAL we DK DAF A HYP: Tee, 1gG2, e631 e640 10. AL AUER ARRAS A TR SE TELE DX AE TG Lo LL RAY BEAR 17 HP EE Sa PD Sr PS RSH PB LA AR a eB FD fe. 12. BRAUER 1 At AAS RT RA Po HB 5 TE PAAR AY SEF ES Pode 13 AOALSER 1200 RIAU AH BL, TC I EOL FIRB IENDOTA 14 BALERS BEA A Pr BL SE SA SE WF ERE DOHA N297A, 15 BAUER LADERA RT REE FYB SG PI eS SEP SE AP 16. 2599, SEL A AA BEAR 1-15 AE SSE HL PD-L Lt (BRAT A HBA PAGE LEAR.CN 101479018 B Rl BR BP 2/3 17. TSE A, HMA ABER 15 Hak TS 18. BRB SLED EER 1 TAY AER 19. Fei EAM» HL AAR 1 SHAE 20. ALALSER 19H Hei EAM FEE IC BEA 21 AUAER 20615 181 EAA SCL AL OH « 22, ALA BEOR 21 9 185 EAM» HL FL ak LSS (CHO) STH 23. Hl He A—-PD-L 1A AS BRIE Hi BRE HY BREA a TE: TELA EI RIA HS -PD-L GL ARBRE RA EH BS BU 1S AR EB SRA AU BER 19-22 1 HY TE A EL PTET A HT Le 24. Hills AD AeA BER 1-151 EA AS HB 25. filth HOS AER MAA 26. BUA BEAR 2425 9 filth» HEH Ih LE BLT 27 BAY BER 26 FITTS il » HEH PIT CE FAA a De 28. LASER 26 PITA til th » Sh Ta LAT AL VEGP HE. 29. SAVER 28105 fil» SEE PR SL -VEGE DE AE UTR AUT. 30. ALAN BEAR 24 25 (tlh «He A Yh ae AE A TEES I} PE A. SL BOAR 2425 i til th FE i Yb BT PEI ALLA. 32. AER 24 R25 (1 tl th SE IL ED PBT RID F 33. BOY EER 2425 (05 flit» He Yh ay EE BAA MRR ABER 1-154 FE Sak — SOUS AASB BRA AY AE ee DE AMSA. 35. AF PRC LAA BER LORD AA FN FE Hh FLT aT PRES 2 36. ALA) BER 3.4 BRI YE FAD SE POTS REE a IH DAS 20 WR SEL PL 5 2 HE» OB SEGRE» CE, BAT GI» HAR IPP ELAR» PT PSI LI 5 PCR DR E28 » Sk USSR FA ARR 37. BONER 343519 NL SEH TR 2a PST URS BA 38. BAU SEAR STAY BE FY, SOS BISA AGT HDA PE HO 2d PLR 5 28» SHOVE» ESS «ICA Tk» HE HER» FE PS He A PPAR ea I 5 Be ‘EE Sh AULA» A. 39. BUABER 37 BEAL, Sec aR Her AALS -VECP DUE. 40. BAIR 39 1 FAL, Se VEGI DE DURE A. 41 BAY EER S7HA IL AL SE UP ALI FALAEPOLPOX. 42. ALBERT, SEH POLPOX 4 SUD AHH 5-PUAI Leucovovinit4 43. AUER STi BAL SE SR ATT FAL UD A A. 44. BUA EER 37 BEAL HEH RR AGI ALAERAP AA 45 FA SCR LAUER 11549 FE Sak — SOUT AAR BRE PHY BE PF AMPH. 16. AF RCE ATL AA BE OR LOBED AL 2D EH FLT aT RRS 2 47 SABER ASRS HY NEA So AZ AP SSE IA A 3CN 101479018 B Rl BR BP 3/3 48. ALA SE RAT WE AL, SEP PTR A ETL AT A 49 BAER ASI LF SU FF A EHH A A. 50 ALAA BER A911) WEF, HCH Fae AO J A RE SF. BL BR AAYSE AR ASH) MF SPT AU A SA 52. BUAISE RAS BAGH NLA JL IRB 20) ADT 5 28 — Pi A UR A AAG NE A HH IR EE = OF PEPE 6 of) WE PAL» SO PTA A PE A TA OE 8) RSG PAL 5 CT PAS PE BE A fi) RLF» Sof PS ea oi ST A» CTE BL, LET wR SS SC BS. BUA BERS TA WN PAL SF a DO a LH 2 PT SR 59 ALA BE AR 57 HS OME AD BC A A A HE 2 DT SS a Fie 60 BCA BE AR 7S ONE FS» SE AR A DV AR ELT 28 FT So RB PUB Ai. 61 BCAU SEARS 7H OE SE A A AE a RT SE UK ARF.CN 104479018 B hh A 1/106 Fi HPO-L 1A EA BF GT HT BE AY (0001) ASHUEEAL Ha 920094612 H8A RN BPI “HL-PD-L 1A BE AL PT AUDI EH FEL” SP Fal Ae AAS GENO . 200980149532. 9/5 Hi. (0002) ISG Hi [0003] ASHHGFHLYE35 USC 119 (0) 22008412 HOH HEC AN FIM MIT HH S61 /121092 FOR Fe LMA a8 TEAS FPN Ae SCHL S| LE AARC 8 RAS (ood) Ax AR HH ARTA Be $e He A ANE Be SRG AIM» LAE TALS SY SH Se BE FUG TAN REE ETT 0 (ooos] ee HSE Coos) Hal ec BK uy TSIM LB ES PS Ab AS Tl fs SA SL AR SST A (APCs) ARE 2 RQ SARA HR Lg PE ESE BEY Lafferty Aust. J.Exp.Biol.Med.Sci. QRAAIIE SEM AE nF ABR FBLA ak) 53: 27-42 (1975) i BPA ME — ABE PEE See ALK SIS Bretscher Science (FH) 169: 1042-1049 (1970) ;Bretscher,P.A., P.N.A.S.USA 96: 185-190 (1999) ; Jenkins ,J.Exp.Med. (S2gmbK 2k a) L 02-319 (1987) ET) Sia EE BANA FE 5S A) (MIC) SRG HY FR KZ IC LIGNE SME Ses 5 i TA MLS AS (TCR) BG SP ERI SIL Zea ATR Sa (APCs) ASSES SS iB TEM MG SPT ZA DA Ee APS 2A RG PB A AEF fig Lenschow% ,Ann.Rev. Immunol. (Si He*#4F HESRiR) 14 : 233 (1996) BATE aT TAA FRBRAZ A RUG AP Fh BA IE LS FETT SEBS FL BERRI (exhaustion or tolerance) o [ooo] fa ML AYTA—fes SUG PL REALL Tf TS TCR eee me AUD FAT EBL . Viola , Science (F}#) 273: : Nature (4 #8) 16-159 (1993) 0 DEH 5 HU RTCR (4 I A MB IAD ae A TRG A 0 BE LA A» TEMA AE TE HEY ALA HENY (positive and negative) ik BS SAU RB ek SLD «CAS TE EI AAPL 425 AN AT EBACE EY CRAP HE ES PAID) SHE 5 FE SEH AE ah SE A HE UNE ik EAT SP TA SE AOL AD GME At SARE HET SN A 0 ISP) A SDA SI 9 BR i ES AE AT SCRE AE » TEED Pa JEE WSLS HB AS HL AD HG Hd BRS HEE RE TO (ooos) i sa) CART HL tL AT AIT PIE RSE CAS ER EB ET RAR FEF ANE HE 2 AS FB HCH ER ELT A LT EP BR FE: BEE: (anergy) Si SF A EPEAT ZEA LESSEE EEL & Ik (PD-1) ALI Be» ADE TER EAE Ta PD 1 AE Ei iS PD-1 AEE A fe Sat SF RL PEE RAL (PD-L 1) AULA ABE fie 62 (PD- 12) ) AB UAB MS SHU 5 EH HH PDL 1 ed 4 SE SRP DT a CPS GFE) AUR: LEG AE ARE (Bou UES SEE) RBI) AY THA a GE FI FB A TT» LPR ER BERE FE HEI APL EO BE TH Bek VT TAT MAL, AP CE ARG AE BIT TRCN 104479018 B hh A 2/106 Fe [0009] 425) fi Coote] ACHR OEA-PD-L LTA, THE MIPS ILI ABN ERAN AE LSI A Oo VA BRE SRE AT ASP 288 S12 AD AA lL 2 SS i EF SURED AEE» PITA Hae CLA (Bil HAY TEE A) ATT SE C0011) EASIER AT SEM, ASB UIE DE AP AA ED EX & FE, EVAL HVR-H2 A TVRIP FAL, Heep [0012] (a) fIFIASHIVR-HLF-FJEGPTPSKSWTH (SEQ. 1D NO=1) + [0013] (b) FFLRHVR-H2/F°Fi] SZ AWIXePYGGSXSYYADSVKG (SEQ ID NO:2) ; [0014] (c) /IFSASHVR-H3/F-Z1)AERHWPGGPDY (SEQ ID NO (0015) if ELIE tH + Xi SEDBRG ; NoASERL : XoKE TAKS. (0016) E-BAY Xi ED No ESIF ELNSALT. 7 SMD HE Bat FEHVR fe FF A AT AS XB HAR FAA: (HC-FR1) — (HVR-HL) - (HC-FR2) ~ (HVR-H2) - (HC PR3) ~ CHYR-H3) ~ (HC-PR4) 0 E75 Td PR ARF UA PASE Ar BR SF SAR FA EVES IY LSA IR Fa IPR A 2 A A [0017] HC-FRIALEVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 4) [0018] HC-FR2JEWVR@APGKGLEWV (SEQ ID NO:5) [0019] HC-FR3JERPTISADTSKNTAYLQVNSLRAEDTAVYYCAR (SEQ ID NO:6) [0020] HC-FR44EWGQGTLVTVSA (SEQ ID NO:7) 5 (oozt] SQ Py il, Fr we & 5 € AP HVR-L1 HIVR-L2AMVR-L Bf ABB EEE J op: £0022] (a) /FASHVR-L1 FFF) AERASQKUNSXeTXiXaA (SEQ ID NOS:8) 5 [0023] (b) fFBHVR-LZFFUAESASKALNi0S (SEQ ID NOs=9) [0024] (c) /UPIASHVR~L3FFSALQANuXraXssXsPNis? (SEQ ID NOs: 10) + [0025] if LSE: XAEDBRV; XoALVBRT ; NoALSBRN: XPAEABKE ; NoALVBRL ; NoALPFBRT ; X10 YER AsXiEY,G,F,, BES:XoKEL., ¥,PARW: XioALY,N,A,1,G, PORT XioAEH,V,P, TBRL sXioAEA,WLR,P BT. [0026] Py ll XeAED s Xo ALV s NALS sXTAEA a NoALV s NAEP s Nao s NALY s Nua HEL s Ni3ALY s Xu AEH XasAEA. 75 UBL » OF EAS EE £0 ARAB SC EHV RZ DF A A EH Bll: (LC-PRI) ~ (WVR-L1) ~ (LC-PR2) ~ (HVR-L2) ~ (LC-PR3) ~ (HVR-L3) ~ (LO-PRA) «XTi RARER TADS RE A iT IT PR ARV Le LR. QT, PRAIA FES E> MF Ba [0027] LC-FRIJEDIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 11) + [0028] 1.C-FR2JEWYQQKPGKAPKLLTY (SE@ 1D NO:12) + [0029] LC-FR342GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 13) ; [0030] 1,C-FR4JLFGQGTKVETKR (SEQ ID NO:14) « (0031) EA SETT EH, ARAB OEP NDE -PD-L LUA RRS Po A REALE HEMT AEX FF FAL Se 0032] (a) FA ee APHVR-HL HVR-H2ANHVR-H3, ii LSE: [0033] (i) /IPIASHVR-HI FFIJEGPTPSKSWTH (SEQ. 1D NOz1) +CN 104479018 B hh A 3/106 [0034] (ii) FIFYBHIVR-H2 P53 AEAWIX2PYG (0035) (i ii) FARHVR-HSFFIALRUMPGGFDY (SEQ 1D NO:3) (0036) (b) /iriA FE HED ATHIVR-L1 HIVR-L2AUHVR-L3, Tig es [0037] (i) PIFSASHIVR-L1 FF FUAERASQNANSXTXiXsA (SEQ ID NOs:8) + [0038] (ii) FFHBHVR-L2FFFI AESASNoL XwwS (SEQ ID NOs:9) ; A (0039) (iii) PIFSABHVR-L3FFAIJEQAKNieXtsXisPXil (SEQ 1D NOs: 10) s (0040) if FLFE4! s Xs AEDERG ; XofZ SARL s Xa TARS s XAEDERV : Xs AEVBRT ; NoAESERN : Xr EAB PF XsA&VBRL s XofZ FART: Nios YBRA: XALY GF, BES: XiodEL. VY, PBRWs NagdzY,N,A,T,G, PERT XiEH,V,P, TART XiskEA,W,R, PRET. (0041) fe AEA TT» Xi RED: Nok SIE ALNOAET . Ty UD» NHED s XoHEV s NoAES s NEA XoABV s NosEPsXioAEY :XALY s Kio Ls NioKEY sXuGEH: XioALA MH Ul NED NAESIP ANE 1, XoED; XoAEV s NOSES: NrAEA sNoABV sXoABEs Xo MEY s Xi SEY NrsdELs NroABY sXr ABH LNs HEA (0042) TG » PTR AL RET 8K oe AO EHV RZ Ul FA — RS PRs CHC FRL) ~ (HVR-HL) ~ (HC-FR2) ~ (HVR-H2) ~ (HC-FR3) ~ (HVR-H3) ~ (HC-FR4) , PTR BEAT EX A UR EWVRZ IAL SF AAS aR AR Es (LC-FRL) ~ (HVR-LL) ~ (LC-FR2) ~ (HVR-L2) - (LC-PR3) ~ (HVR-L3) - (LO-FR4) «Jy TH» IER RFU TA SEAT ERIE MH TL, Firs RE RF A A T Kabat Me YT LTBI TLRS oy Ud» re REP AVE MELTS A HER. FG UD, SE RS PRS FG [0043] HC-FRI EVQLVESGGGLVQPGGSLRLSCAAS {SEQ ID NO:4) HC-FR2 WVRQAPGKGLEWV {SEQ ID NO:5) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (SEQ ID NO:6) HC-FR4 WGQGTLVTVSA (SEQ ID NO:7) [0044] SQ Fy HT PRE REE IE A FKabated 11 TTT RIVE ER. My TBAB EMIS FP AEN T SEAS HS Te UB» SRE ER BE US — PRS TB TI = (004s) LO-FRE DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO:11) LO-FR2 WYQQKPGKAPRLLIY (SEQ 1D NO:12) LC-ER3 GVPSRFSGSGSGTDFTLTISSLOPEDFATYYC, (SEQ 1D NO:13) LC-FR4 FGQGTKVEIKR {SEQ ID NO:14) , (0046) 7E RANA TH» LA A RR HE EK.» TR He FH 1gG1. 1962, 1963. 1eG42EL RAY2HL EA EG TL TR MHL EK 38 LG» MF TEL PFS A AE RG A A Lg 1gG2A, 1gG2B, 19632 RUA. My FE ED A TgG2A5 28 AAS ELAS Aa OD» SAR SFL AC A Re WEF FE TEL , FIPS Sak 1 EA Re EF A He “BB 3 EW FHP HEAR (effector-less Fe mutation)” BK A BISE(L (aglycosy lation) PE FEMA SEMA SEP 5 FIR BFE FNP FOE FE ETL SDK 1 N29TARRD2GSA/N2OTABL BE. [0047] HE MASE EP AS AR HE PEST -PD-L GALA SEC A BEY KF, 7CN 104479018 B hh A 4/106 seh (0048) (a) fii HE PEI QHVR-H1 HVR-H2AIHVR-13/¢ 3), H¢4} HA]GGFTFSDSWIH (SEQ ID NO: 15) ,AWISPYGGSTYYADSVKG (SEQ ID NO: 16) #IRHWPGGFDY (SEQ ID NO:3) F415 28596 [Ny FEB Te BR [0049] (b) FABRE £2 APHVR-LA HVR-L2ANHVR-L3 4-3], FES} Fil -GRASQDYSTAVA (SEQ ID NOz17) ,SASFLYS (SEQ ID NO:18) AIQQYLYHPAT (SEQ ID NO: 19) £4728 >85% f/F3U Al — tee (0050) ZE—/ELABy THE PITA FY FATA] — PE AL86% , 87% ,88% ,8996 90% ,91% 92% , 93% ,94% ,95% ,96% ,9796 98% ,9996 2K 100% . 7} — Fr ll » WA HE ERT EK 12 BFE VR fil FF A — 4% RP Bs CHC-FRI) — (HVR-HL) ~ (HC-FR2) ~ (HYR-H2) ~ (HC-FR3) — (HYR=H3) ~ (HC-FRA) , PsA HE FY AE IX FH EHV RZ A) IF ARS PRB (LC-FRL) ~ (HVR-LL) ~ (LC-FR2) ~ (HYR-L2) ~ (LC-FR3) ~ (HVR-L3) ~ (LC-FR4) «77» HS MPR FF URE PASSA AR PHA 0 SOFT FT EAR FP PKatba tA 11 TELFF 5 SF » FIPGA8 FEARS BA VE 20) TAG PRS Sk PE PIAS PRS POF IE (0051. ae EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID N04) HC-FR2 WVRQAPGKGLEWV (SEQ ID NO:s) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR — (SEQIDNO:6) HC-FRA WGQGTLVIVSA (SEQ ID NO), [0052] Fy TH. PREETI FKabatel 11 TTR IVE ER. MA TBAB EIR E PAE VLR TSE AS HS Ty UB» SARE ER I — PRS ST Ta = [0053] LC-FRI DIQMTQSPSSLSASVGDRVTITC, (SEQ 1D NO: 11) LC-ER2 WYQQKPGKAPKLLIY (SEQ ID NO:12) LC-ER3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO:13) LO-FR4 FOQGTKVEIKR (SEQ ID NO:14), (0054) AEA ELA TH» TA AH A BR HK FIT He Ath IgG1,TeG2,1eG3, TeG42il AYE ZEA EAT TE» TG MASE DX 2 TG MA Gs Tas A ez RHE A G1, [eG2A, 1 eG 2B, eG 320 RRA AA. Qa Ted» POT HR He A TgG2A. 76-4 OB a 7S ATR Sk ASD 3 OE FDA 2 FE EDP, FIPS Sk 1 A FE FB HH “SE EEL Pe FER” BR ALPE ER SEAT SRA FIPS FE EL FP RARE (EAA EDX NZI TABRD2G5A/N297A FLAS» (0055) ESSER EH AS AAR OEY BS SE PD—L GLIA HS, RE ETE Berea, dtp [0056] (a) FFs REP SF 28 RE Ay 8 85% HB [0057] EVQLVESGGGLVQPGGSLRLSCAASGPTFSDSW1HWVRQAPGKGLEWV AWISPYGGSTYYADSVKGRPTISADTSKN 8CN 104479018 B hh A 5/106 Ti TAYLOMNSLRAEDTAVYYCARRINPGGEDYWGQGTLVTYSA (SEQ. 1D NOz20) ,3& [0058] (b) FAS PARERE TIS F AHS BEAD EL AY aE 85 96M FETA Hk (0059) DIQMTQSPSSLSASVGDRVTTTCRASQDYSTAVAWYQQKPGKAPKLLIYSASFI LQPEDFATYYCQQYLYHPATFGQGTKVETKR (SEQ TD NO:21) o (0060) fé— 4 LAB TT MH, BCARF FAIA] —HHEALB6%6 8726 , 886 899 90% ,91% 92% , 93% 194% 95% 962% 97% ,98% ,99% BR 100% o Fh Ay Ul» FTA a BE HY 28K Lo AE AE, TVR FE OR RFF «(HIC-FRI) ~ CHIVR-HIL) = (HIC-FR2) ~ (HIVR-H12) ~ (HE-FR3) ~ (HVR-H3) ~ (HC-FR4) , APS 48 EFT 2 K€ FHF EHV RZ TIE A NERY PRE (LC-PRI) ~ CHVR-L1) ~ (LC-PR2) ~ (HVR-L2) ~ (LC-PR3) ~ (HVR-L3) ~ (LO-FR4) © QF Td» PORE SUIT ASA HR FP a UL FT PAK Kabat MYT, TBR TILER Fy TL PTA AE PA AV TTS AR. Ms PU — PRS PE TE [0061] HCFRI EVQLVESGGGLVQPGGSLRLSCAAS. (SEQ ID NO:4) HC-FR2 WVRQAPGKGLEWV (SEQ ID NO:5) HC-FR3 RETISADTSKNTAYLQMNSLRAEDTAVYYCAR — (SEQ ID NO:6) HC-ER4 WGOQGTLVTVSA {SEQ ID NO:7) , (0062) Fy TH, PP AREF KA TKabate 111. TTERIVE MES. L—W, PRA EERE EVE SEAT RDI © 7 UO» FIR EPR FF A Re BB HB: 0063) LC-FRI DIQMTOSPSSLSASVGDRVTITC (SEQ ID NO:11) LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO:12) ERS GVPSRFSGSGSGTDETLTISSLQPEDFATY YC, (SEQ ID NO:13) LC-FR4 FGQGTKVEIKR: (SEQ ID NO:14) [0064] ER AAA ITH RSIS ABR HER. M7 RE FU G1. 1g62. 1963. 1gG-428l Rie 7 AE TE TR MH eK J LgG1 «MF TH, PPAR GR Lo Ke AH TeG@ 1. TeG2A Te 2B 1g RAI 2H « SQFT» POT BA DK TgG2No ZE SAS ELA Ay OD» PSR A LT AR 1 Be SA EF HE» LE TG TDP, PASS AY SEP RE FE SM Pe ET RR PSE DU HE “SE SIR EF AP EAS” A BE PH EA SERA SEP FTIR IR BF AYP eRe AL EHH FE EX PNZ97ABRD265A/N297A Bi Bl (0065) fi SERRATE 5 AS AC ERE Ca, SEA CHAS 9 FE APT — PSL PD-LL TATED MAE LARA. (0066) ZEA SHEA EF ASA OR CUR» SE i PDL 1S AAS He EB HL ERB FAL, Soop [0067] (a) JF RES ta PHVR-HI HVR-H2-RINVR-H3/F3), FL} Sh] SGPTPSDSWIH (SEQ ID 9CN 104479018 B hh A 6/106 Fi NO: 15) ,ANLSPYGGSTYYADSVKG (SEQ ID NO: 16) AIRHWPGGRDY (SEQ LD NOz3) }L47 28 485% 04) PPP“ Al (0068) (b) FIFA HES £2 APHVR-L 1 HVR-L2AIAVR-L3 FRI, HE4} Sl GRASQDVSTAVA (SEQ ID NO:17) ,SASFLYS (SEQ TD NO:18) AIQQYLYHPAT (SEQ ID NO: 19) FL47 28285 % EN FBI — tee (0069) fe EAST TL , BAR FAIA] —HHEML86%6 , 87 %6 , 882% ,89%6 , 9096 ,91% 92% , 93% ,94% ,95% ,9626 97% ,98% ,99% BR 100% «Fy Hi » PTA He A] EX 4 da FEHR ZAI BA — ARS HAR AEDs (HC-FRI) ~ (HVR-H1) ~ (HC-FR2) ~ (HVR-H2) ~ (HC-FR3) ~ (HVR-H3) ~ (HC-PRA) , JY 848 REPT AB EX £0 HOF AEHVRZ [A] FF LN — PRS PARE (LC-PR1) ~ CHVR-L1) ~ (LC-PR2) ~ (HVR-L2) ~ (LC-PRQ) ~ (HVR=L3) ~ (LO-PRA) «My ld IT HARPER TA SEAT ARE aL» FES HE ER FAIR AF Kabat Me YT, TBR LLLP BA Or TD» PUTAS SE FAI 2S A VE LASS RS PS PUL — ARS HO IR [0070] HC-FRI EVQLVESGGGLVQPGGSLRLSCAAS, (SEQ ID NO:4) HC-FR2 WVRQAPGKGLEWV (SEQ ID NO:5) HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR — (SEQ ID NO:6) HC-ER4 WGOQGTLVTVSA (SEQ ID NO:7), (0071) QT 8 RE PRP FAL K FP Kaba tx] TTT TBRIVIES EA. Me 5 SAE REAR FF Fa AVL TSE AG HR LO» PT A PEF — APRS OB PT [0072] LC-FRI DIQMTOSPSSLSASVGDRVTITC (SEQ ID NO:11) LC-FR2 WYQQKPGKAPKLLIY (SEQ ID NO;12) LE-ER3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC, (SEQ ID NO:13) LCERS FGQGTKVEIKR (SEQ ID NO:14) (0073) EAE Th, TRL AR HEE EK. MT, TRA He FIFE LeG1. 1962, 1963. 1eG-428L WRAY 2EL « ZA API TED FS HELE DX AE G1» MIG ET POTS RA BE HH LG 1. 1gG2A. IgG 2B. 196328 IN Al. Ie Ted OT BR A TgG2A0 ZL 4S ELA a TL» APSARA ASF A BR A EF LE EDP, FSA Hak AS SF EF SSSR FE LE te FUSE ED BH “SE ZEB EF AAI Pc REAR” BIE ALA AE ASE HAI SEP TIS BER BEF APR AE TEAH 5 EK 41N297 ABKD265A/N2O7A BEB. 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A ASEAN IRIS EO: LEELA) A AEDT EMAL A PEN FS HMR AR SK RG AOE As TURRET EA BS «SS ARE CR ARAN, ei bMolecular Cloning:A Laboratory Manual (}-F sift SPD — ii (Sambrook , 1989) ;Oligonucleotide Synthesis (HMMA) M.J.Gait, Hitt, 1984) ;Animal Cell Culture (ay 4ilwsi38) (R.1.Preshney , 44% ,1987) Methods in Enzymology (HE4#4 1H 7714) (Academic Press, Inc.) ;.Current Protocols in Molecular Biology (4B F 4M HS) (FM. Ausubel % , M43 1987 , AE IB) ;PCR: The Polymerase Chain Reaction (PCR: 28 AE RM) , Mullis, Hv, 1994) ;A Practical Guide to Molecular Cloning (473232 /14%AD (Perbal Bernard V. ,1988) ;Phage Display:A Laboratory Manual (RTE (hea: Sc36 3 Ff) Barbas #2001) » (0103) 1. y= ME (0104) A. HES Santa eACN 104479018 B hh A 10/106 i [0105] SSPE BES HET CRD) AUB CAPER SRE) an BE TRANG (fetal Liver) $12 26 5a fay yyhES Be Fade EY 3 a A 2 FA RIE AE AST 9 TH SL. 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