JP WO2006/046661 A1 2006.5.4 (57)【要約】 本発明により、scFvとFc
Contents
1. Medi at ech2. HHHHHHHHHHHHH HHHHHHHHHHHH 0000000000 0000 000000000000 H N COOH 0 H L
3. 0000000 0000000 Od 11 1 1 1 ex vi 4 945 0500 HI lH o ul 0 oo 1 1000000000000 HM HHH uu pAdexl cw uu OH
4. 50 0000000 55 1 CN m O O gt im 7 oo 22 ooo 3 r3 E m 1 ooo 3 E 3 EET s un 2 m m 3 I ono O mm r3 oO 3 Oo Eu 0 3 ES gt O 3 din m M OR 2 e nig Ez MES E 3 a ae 3 L3 M dm m 2 TTE
5. D pij 15 210 1 2 2005 4 29 JP VO2006 046661 Al 2006 5 4 1000000000 51 Int d 1000000000 0000 3939 200601 0000 39395 ooog 0000 4800 2006 01 0000 4900 10000 0000 4300 2006 01 43 00 JUD 0000 3
6. 3 SV40 late poly A signal 00000 00 pShutthle QOO00 0000000 D 114961 pBluescript 110 1L 6 HHHHHHHHHH IL 6H 0000000000106 D DU Bi 10 10 61 000000000 I gG 1 600000 0 HHHHHHHHHHH 11 6 000000000060 11 0 0 0 KT 3 00000 10 60 00000000000 edi 0000 00000 00000 IL 6 0 O 511 6600 0 0 VEGF VEGF 0 0 LH 00000 el ement s elements scFv D 000 00000 IL 6 0 0000 1 6
7. 00000 IL 680 0 000000000 000 00000000 WC2 HHHHHHHHHHHHHHIL 6RHHH HHHHHHH D wo2005 061000 0 0 IL 6 IL 6 IHLHHHHHHHHHHHHHHHHHHHHHHHHHH 2 4 0 EP HET ICE 0000000 IL 6 IHHHIL eHHHHHHHHHHHHHHHHHHHH IHHHHHHHHHHHHHHHHHHHHHHHHH IL 6 IHHHHHHHHHHHHHHHHHHHHHHHHH IIL 6HHHHHHHHHHHHHHHHHHHHHHHHHHH IHHHH MIHHHHLMHHHHHHHHHHHHH IlgGFcHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH u 1 ggg 0 0000 u u IHHHHHHHHHHHHHHHH 10000 19 Fco H H HJ CDR10 SDHAV5H HJ CDR2 YI SYSGI TTYNPSLKS HJ CDR3 SLARTTAMDY CDR1 RASQDI SSYLNH CDR2 EE CDR3 QOGNTLPYTH
8. 0000 000 0 Ad easyp 00 000000000600 St rat agene 1000 IL 6H pA dEasy 1H HHHHHHHHHHBE5183HHHHHHHHHHHHHHHH 000 Un IlHHHHIL 6HHHDNAHHHHHHHHHHHHHH 0 PCRH HHHHHHHHHHHAdHHHHHHHH 29300 Ad5 1L 6 rescuell rn 0000000 Mizel et al 260 1 1 1x epa 000000 m Ad5 IL 6H 10 T75H il 100 0 Ad5 1L HOO 100000000600 0000000000060 1720H 0 PBS 11 Si St Louis A Protein A Anti body Purifi cati on Kit 1000000000000 10 0000000000 0000000000000 OIL
9. N Taa 3 gt 2 3 E 3 gt O 23 C 3 a 3 mm r 3 oO 3 E r3 3 3 3 3 3 E 2 3 3 Ooo Ba 5 2 coc Zo 3 a LL gt 3 3 r3 3 3 E 3 L3 2B mE 29 r7 oO 2 3 3 S m nana ET 2 m gt EA 2 amp E e i m 3 3 2 3 3 3 7 S 3 3 gt r3 r3 gt 3 2 m lt 3 i lt 2 Oa e 3 _ a ow E 5 5 ux cog a E LL gt gt a N 322 22 3 O I 4
10. 0 LH 0 Hut 000 hydrophobi c i nterac scFv 000 000 HHHHHH D U 000 scFv ug audmgmumuuHH ummguutudzgsttet t 1000000000000 CR V UU uu go g CDR J HH LO CDR H Hd B D D n V PM 1 CDR1 CDR2 CDR3H 00 0 WPM 10 O CDR2 CDR3H compl ementari t y det er m ni ng region CDR H HHHHHHHHHHHCDPRHHHHHHHHHHHHHH PM 1 0000000000000 0000000000000
11. Y 1 O Pj 22 06 12 2005 1 S AZ J P 5100 8915 436 3 E 03 3581 1101 3488 FC ISA 210 2 2005 4 27 JP VO2006 046661 Al 2006 5 4 PC JP2005 019820 C
12. CIO CO LJ PBS
13. 6 00 JU JD I 0 Bradfordd OOH 000000 0 Bio Ra OH YHHHHHHHHHHHHHHHHHH 00 IL 69 0000 L000 0 single chain f ragment variant G DOQ0 Il 6 scFv 5 I gG Fc E Hu New receptor inhibitor for IL 6 Uu utluttkuiukili liiuLkY lU DU lU Ad CM 11111111 0 HHHHHHHHHH 00 IL 6 96 ELISAI L er 0000000 18 00000 M 180 IL 6 00000 00 00 0 IL 6 1L 6 00000 18 1 HHHHHHHH5hg7mHHHHHwellHH100uIHHHHHH TES 00000 bovine serum al bum nH nnnnnnn 0 60 000 51 668 00 00 0 0 0 11 511 68 100 ng m well 100u ID OD L 6H 0 19 G HRP conj ugated anti Fc fragment F ab 2 Dako OPD peroxi dase substrat e Si gma IL 6H 1L 6 HHHHHHHHHHH LU UU 1 61
14. 000 HHHHHH HHHHHHH 111 1 1 1 LU HHHHHHHHH HHHHHHH MIHHHHLHHMHHHHHHHHHHHH 0 1965 FcH OOO U H SDHAV5 H CDR2 SYSGI TTYNPSLKS H CDR3 SLARTTAMDY L CDR1 RASQD SSYLNH L CDR2H YTSRLHSH 00000 0 L CDR3 QOGNTLPYTH HI 00 QVQLQESGPGLVRPSQTLSLTCTVSGYSI SDHAV5 W ROPPGRGLEW YI 5 YSGI TTYNPSLKS RVTM RDTSKNQFSLRLSSVTAADTAVYYCAR SLARTTAMDY WGOGSLVTVS HHHHHHH LO DI QMTQSPSSLSASVGDRVTI TC RASQDI SSYLN WYQQKPGKAPKLLI Y YTSR LHS GVPSRFSGSGSGTDFTFTI 551 ATYYC QQGNTLPYT FGQGTKVEI KRO scFv LO HHHHHHHHHHHHHHIgGFcHHHHHHHHHH nn Ny ugagaumvuuaugauauuviuuuuuuaauaudadcueddlu GGGGSGGRASGGGGSGGGGS HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHIH Seley 111 11 0 11011011001111010101101010101 00000 HHHHHHHHHHH HHHHHHHHHHHHHHH 1MHIHHHHLHHMHHHHHHHHHHH 19G Fc 111 1 10101 01 luu H CDR1 SDHAVWS H CDR2 YI SYSGI TTYNPSLKS H CDR3 SLARTTAMDY LO CDR1 RASQDI SSYLN
15. PCT 17 2 a 1 PCT 39 113 2 td C C P C THAIS 4 2 2 8 1 3 KERAS K 2 iC EO389 234 2 k co RSS sp 752
16. 13 JP VO2006 046661 Al 2006 5 4 1000 000 HHHHHH 0000 00000000 00000 0000000000 PEG Tween EDTA ood 0 0 D D D 00000 000000 0000 PEG 0000000 800 50 1000000000000 00000 000000000 10 000000000 000 000 000000000000000000 Remngton s Pharnaceutic al Science 16th edition Oslo Ed 198001 08 0 0 000000 100000000 0 0 0 Langer et al J Biomed Mater
17. reshaped 0 0 E A Kabat O 1987 Sequences of Proteins of Immunol cal Interest Forth Ed ti on U S Department of Health and Human Servi ces 5 Government Pri nti ng Office U JU D I 111 11 1 1 0000100011090 CRO D FRI reshaped 1 0 humani zed antibody reshaped CDR HHH CDRI 0 111 1 CRT 0 8 8 3 franework region
18. Res 15 167 277 1981 Langer chem Tech 12 98 105 1982 3 773 9 197 0 0000 0 0 0 58 4811 Sidnan et al Biopol 5 22 547 556 198 3 133 9880 UU 1000000000160 00 UU 11000 0 0 10 2000ng 1 00010 100000 00000000000 500 500ngH 0 10
19. DNAD Molecular Cl oni ng 5 61 5 63 0 1000000000000 serotype 50 0 serotype 2 00000 EI regi on 1000000000000 10 20 30 40 50 15 JP WO2006 046661 1 2006 5 4 293 HHHHHHHHHHHHHH36KbHHHHHIlin ear D HHHHHHHHHHHHHHHHHHH AdEasy Adenoviral Vector System Stratagene 0 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
20. Y LIU J et al pPIC9 Fc a vector system for the production of 1 22 26 single chain Fv Fc fusions in Pichia pastoris as detection reagents in vitro 1 Biochem Tokyo 2003 Vol 134 No 6 p 911 7 Y ONO K et al Production of anti prion scFv Fc fusion proteins by recombinant animal cells J Biosci Bioeng 2003 Vol 95 Np 3 p 231 8 Y WU AM et al Multimerization of a chimeric anti CD20 single chain Fv Fe fusion protein is mediated through variable domain exchange Protein Eng 2001 Vol 14 No 12 p 1025 33 PC ISA 210 2 2005 4 28 JP WO2006 046661 1 2006 5 4 PCT JP2005 019820 SUM 1 2 8 3 PCT17 2 a 1 23 25 2 3 2 5 6
21. QVQLQESGPGLVRPSQTLSLTCTVSGYSI T SDHAV5 WROPPGRGLEW TTYNPSLKS RVTMLRDTSKNOFSLRLSSVTAADTAVYYCAR SLARTTAMDY VWGOGSLVTVS DI QMTQSPSSLSASVGDRVTI RASQDI SSYLN W QOKPGKAPKLLI GVPSRFSGSGSGTDFTFTI SSLQPEDI ATYYC QQGNTLPYT FGOGTKVEI KRO n gG Fc Fv MMHHHHHHHHLHMIHHHHHHHHHHHHH 6 JP 02006 046661 1 2006 5 4 HHHHHHHHH HHHHHHHHHH 1211 0 0 Hg lg9G Fc
22. 10 JP WO2006 046661 1 2006 5 4 COR 0 FR HHHHHHHHHHHHHHHHHHHHHHHH PCR 00000 CORI O O 000 FRI DNA
23. 0 000 0000 5 S e dpi nn 2 ME RENE a E 00000 m 1 2 0 0 0 0 0 000 1 10 20 30 40 50 7 JP VO2006 046661 Al 2006 5 4
24. IL 6 0 000 0 IL 6 H L V 11 0 11 gG 0 0 H CDR1 SDHAVS H CDR2 Yl SYSGI TTYNPSLKS CDR3 SLARTTAMDY L CDR1 RASQDI SSYLN L YTSRLHSH L CDR3 QOGNTLPYTH 00 LO I gG Fc Od scFv 10 000 single chain variable fragnents scFvl scFvll V VLH U Huston J S et al Proc Natl Acad Sci U S A 1988 85 5879 5883 SCFv 1000 Vu scFv scFv uckt hun The Pharmacol ogy of Monoclonal Anti bodi es Vol 1130 R osenburg and Moore ed Springer Verlag New York 269 315 1994 10 20 30 40 50 JP WO2006 046661 1 2006 5 4 8
25. r3 E LE 9 Ld EJ EJ 1 LL LL 3 O O C Ld 3 3 O LL 3 E EE r3 22023 C C 5 Om oo m ow To 3 a o _ oO _ n ow oO m r ES e o L3 Sa in gt LJ Ez r O mrt _ 2 n 1 st 3 Cl Y CI Lr oo ow 3 3 o m mw gt L3 3 3 o 3 a 0 ri 2 wO gt m nm 2 3 E 3 1 3 e ac e m I ZG E i PC ccm LL 3 DA N EJ E ys U l c 22 3 E LL ES gt ii gt I x
26. L CDR2H YTSRLHSH L CDR3 QOGNTLPYTH H VO D O0 QVQLQESGPGLVRPSQTLSLTCTVSGYSI T SDHAV5 W ROPPGRGLEW G YI 5 YSGI TTYNPSLKS RVTM RDTSKNQFSLRLSSVTAADTAVYYCAR SLARTTAMDY WGOGSLVTVS 11111111 1 1 1 JP WO2006 046661 1 2006 5 4 3
27. 2 3 Invitrogen ill ill 10 ill 111 CD34 0 2930 0 Type Culture Manassas VAI OOOO 2937 00 0 1091 0000 DEM KT 3 ShhimzuSet al Blood 1988 7 2 1826 18280 1096 5 0 4 ng m IL 6 Ajinomoto Co Inc Kawasak i Japan 0 U 16400 00 0000000000 01 680 siL 60 0000 Chugai Pharmaceutical Co LTD Roche Group Shizuoka Japan 16 JP WO2006 046661 1 2006 5 4
28. Kansas City New Engl and Biolabs Beverly T4 DO D Promega Madison WO 000 000000 0 0 PCRO Q AGENG Valencia Bg 00000000000 11 60 0000000000000 0000000000000 cDNA VI 1 DU Fv canoni cal Fv boundary definition 00000 10 2 VI O VII 1 2000 0000000 0 0 5 5 5 D DNA 000 0 1 scFvl DNAH5 3 No Not 100 1L 6H 0 00 00 0 0 O pOPE101 scFv NI 1 RU ED scFv 1000000 0 5 DNA 1 0 0 c 64 000000 J PCR 00000 sna 5 Avr 1 3 pPI C9H 100000 Invitrogen Carls 20 bad 60000000000 1060 00000 5 O0 d IL 6 D y 1 CH2 O CH30 O O Feco O O O fragment constan 0000000000 000000 0 cDNA PCR i 10000 0 0 Fc O0 1ok 0 2 pSecTag2a O
29. 5 Y ac gt m _ 1 z O I x c T G 9 JP WO2006 046661 1 2006 5 4
30. INTERNATIONAL SEARCH REPORT International application No PCT JP2005 019820 Continuation DOCUMENTS CONSIDERED RELEVANT Continuation DOCUMENTS CONSIDERED RELEVANT DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document with indication where appropriate of the relevant passages Relevant to claim No ONO K et al Production of anti prion 1 22 26 ScFv Fc fusion proteins by recombinant animal cells J Biosci Bioeng 2003 Vol 95 No 3 p 231 8 WU AM et al Multimerization of chimeric anti CD20 single chain Fv Fe fusion protein is mediated through variable domain exhange Protein Eng 2001 Vol 14 12 p 1025 33 Form PCT ISA 210 continuation of second sheet April 2005 24 JP VO2006 046661 Al 2006 5 4 INTERNATIONAL SEARCH REPORT International application No PCT JP2005 019820 Box No II Observations where certain claims were found unsearchable Continuation of item 2 of first sheet This international search report has not been established in respect of certain claims under Article 17 2 a for the following reasons l Claims Nos 23 25 because they relate to subject matter not required to be searched by this Authority namely Claims 23 25 relate to a method of treating diseases caused by the action of interleukin 6 so that they pertain to methods for treatment of a human body by surgery or therapy and relevant diagnostic met
31. 4 JP VO2006 046661 Al 2006 5 4 000 2 HHHHHHHHHHH 3 10000000000 1000900000010 00 I nterl euki n 6 L 6 B 2 BSF2 1000 0 8 2 0 O0 IL 6 B
32. 0 0 0 00 0000 010 60 00000 scFv PERI DI D 30 IL 6 5 BGH pShuttlell 0 0 O Stratagen e La Jola CA HHHHHHHHHHIL 6HHHHHHHHH pShuttl CW Fc scFv 1000 00 elenentso 0 0 0 0 elements 60000200 i pShuttl e O0 Stratagene La CA log multi ple cloning site pGL3basi c Vector SV40 late po y A si gnal Od A 1 0 1950 HI OO000000 pBluescript 110 Barni 40 o UU HU NJ Spel B 00000 pBluescript 110 Xhol U U UU CM U U A 00 0 0 CW nultiple cloning site BO KpnlH EcoRV Spel 0 Fc IL 6 0 000 0 0 pShuttl e CM Fc scFv scFv 00 0 0 EcoRM Spel 1L 6 O00 p Eo ES EET D D 50 17 JP WO2006 046661 1 2006 5 4
33. L1 1 L1 L1 eo L1 Oo Sees g OOOO L1 L3 L3 Oo a 2 JP VO2006 046661 Al 2006 5 4
34. a i IIT EIS 5 i E id 108143 AO 5 2 1985 a H lt amp G r Pacl 47 s Ses wood AMNOod THIPUIHTUO Judy e ss NIIT N Sa i I N Y E 5 3 S R d MM 7 94 153 43 AWO lt d v 6L9 JP VO2006 046661 Al 2006 5 4 20 OD OD 0 05 0 04 0 03 0 nM 0 4 10 50 1 4 12 0 8 0 6 0 4 0 2 ug ml 1 0 0 2 0 04 i 45 TN pA 6 aR 1 a n i 4 gt 2052 pg ml w o IL 6 sIL 6R with IL 6 sIL 6R 800 600 21 JP VO2006 046661 Al 2006 5 4 E 8 2 22271 E gt n gt amp Arg Gln ao 4 zt 5 40 e 5 l 2 AS 2 m 8 agt gga G 2 TK ar 2 2 Tyr Ser Gly 5 g 55 M a in gt Tie E S t atg ctg pl iL e o Lys Met Leu Arg Asp EN eg 6 10 B 6 oR E ctg agc gtg aca gcc gcc gt Leu Arg Ser Val Thr Ala Ala ES SR x Ts gca cta gct cgg act acg gct AR alr Ala Arg Leu Arg Thr Thr Ala lt 100 105 thi mR gga
35. IL 60 0 L 6 TL 60 80kD 000 IL 6 L 6H HHHHHHHHHHHHHHHHHHHH 1L 6 0 IL 6RIH 1L 6R IL 6 1 6 1L 6 E nnm 0 000 11 11 11 61 1 1 0 0 0 0 IL 6R 00000000000 O 2 MEE 2 nn EE 11 68 11 0 00 0111010101100 00101011 tl 1 11 111111 68 00 IL 6RHHHHHHHHHHHHHHHHHHHHH 0 6 0000000000000 0000000000 0 0 0 11 68 6000000000000 00000000000 00 WO92 19759 WO96 11020 WO96 12503 WO98 42377 WO99 47170 WO00 10607 WO02 34292 WO02 080969 T et al Nature 1986 324 73 76 0 Akira S et al Adv in Immunol 1993 54 1 78 Lotz M et al J Exp Med 1988 167 1253 1258 Taga T et al J Exp Med 1987 166 967 981 0 Yamasaki et al Science 1988 241 825 828 10 20 30 40 50 5 WO2006 046661 1 2006 5 4
36. 1994 20054 F FA AOA 5 BIOSIS MEDLINE WPIDS STN CAplus STM SwissProt PIR Geneseq JSTPlus JOIS C Y WO 92 19759 A1 1992 11 12 5 4 5 7 amp JP 05 227970 amp US 5795965 Al amp EP 628639 Al Y WO 2003 072134 A 2003 09 04 amp EP 1491209 A1 amp US 2005 095242 A1 CHE Dj T HELTE Ta bO T lt X IL
37. 25 24012433 249 2313 206 40085 BB36 C22 1 40087 AAO1 BC83 M4 201 ZA33 ZA89 2313 216 44045 ANI A0 BAl4 BAIS BAU BA41 1 1
38. 20525 6000000000000 1 60 0000 IHHHHHHHH PC052H 50 000 wellHHHHHHHHH IHHH5nMMHHHHHHHHHHH iL 60g 0000000 199 01000 HHHHHHHHHHHHHHHIL 6 20 plate ng m 51 L 6R 100ng m tripli cate 30 0 00000000 0000 VEGF ipggagaggummuuuaglsbuett HHHHHHHHHHHHH IL 6 20 JP WO2006 046661 1 2006 5 4 19 Sav d wane eS 4A Wo W Gn AWD 49 i 91 4633 EI Su G eee ra ft C 2 TA HA GAA s 5 SYO 4 E 3 HUE MAS LISPZIBE SENE V I duong YZE 0 9 11 ZHON OYYE E C3 Es 3 amp 9 11 142 A u W 22 amp zh x
39. CDR 00 00 00 111111 0000000000000 0 PCR 000 000000000 CDRH HHHHHHHHHHHHHHHHHHHHHHHHHH 1000000 239400 WO 96 02576 CDR FRHHCDRHHHHHHHHHHHHHHHHHHHHH 00000 11111 11 1010101011010101101010101100110101010101010110011101011011 00000 0 0000000000000 000 000000000 REIQ 0 O FR1Q FR2 FR3 j H MEUM FR HHHHH NEW NEVHHHHHHHHHHHHHHHHHHHHH NEW FR1 2 FRA il uUugcemnuuuusuuguuuvwiuuslgerRi 0 0 0 HHHHHHHHHHHHHHHHHH 000 i Sato Ket al Cancer Res 1993 5 3 851 856 00 0000000000000 000 RV a RV f HHHHHHHHHHHHHHH 000 0 000000 00000 0000000000 RV f qesgpgl vrpsqtl 51 tctvsgysi t SDHAV5 ew g YI S YSG TTYNPSLKS rvtm rdtskngfsl ssvtaadtavyycar SLARTTA
40. HHHHHHHHHHHHH 0 H SDHAV5 u H CDR2 YI SYSGI TTYNPSLKS H CDR3 SLARTTAMDY 000 L CDR1 RASQDI SSYLNH L CDR2H YTSRLHSH L CDR3 QOGNTLPYTH HI QVQLQESGPGLVRPSQTLSLTCTVSGYSI T SDHAV5 VWROPPGRGL EW G YI S YSGI TTYNPSLKS RVTM RDTSKNQFSLRLSSVTAADTAVYYCAR SLARTTANDY WGQGSLVTVS 111 1 1 1 1 LO DI QMTQSPSSLSASVGDRVTI TC RASQDI SSYLN WYQQKPGKAPKL LI Y YTSRLHS GVPSRFSGSGSGTDFTFTI SSLQPEDI ATYYC QQGNTLPYT FGQGTKVEI 0 scFv LO M 19G FcH scFv NI 1005000000 00000 GGGGSGGRASGGGGSGGGGS
41. HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 0 scFv 0000 0 0 0 0 10 0000000000000 0 0 00000000000 co isdem 2 M E nnnnmn Og HHHHHHH 000 HHHHHHHHHHHHH HHHHHHH 11 11 11 1 11 1 lgGk HHHHHHHHHHHHHHHHHHHHHHHHHHH HHHHHHHHHHHHHHHHHHHHHHHHHHH 000 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Expressi on of engi neered antibodi es and anti body fragments in sns Methods Enzymol 1989 178 476 96 Single chai n anti bod y variable regions Trends Biotechnol 1991 9 4 132 7 ERI Og 000 Od Hog human cytonegal ovi rus i medi ate earl y HC HC HCW VH HCy HCW VL HCW 12h 0 HOW 12k 0 k pSV2neoH 0V 000000000000000 1111 000000000 0000000000 11 OHOOO0000000000000 0 O HEF 12h gy HEF 12k gk HEF HEF VL gk 10 20 30 40 50 WO2006 0466
42. 19 JP 20 5 22 2008 5 22 51 Int Cl C12N 15 09 CO7K 16 46 CO7K 16 28 C12N 5 10 C12P 21 08 2006 01 2006 01 2006 01 2006 01 2006 01 882006 543262 P2006 543262 PCT JP2005 019820 17 10 27 2005 10 27 60 623 018 16 10 28 2004 10 28 US FI C12N 15 00 CO7K 16 46 CO7K 16 28 C12N 5 00 C12P 21 08 JP WO2006 046661 Al 2006 5 4 A1 1 WO2006 046661 43 18 5 4 2006 5 4 ZNAA 4BO24 48064 48065 B 40084 40085 BARR RAR 20 ED 71 11 54 6891 57 D D 71 504176911 1 1 594067748 ay UAB RESEARCH FOUNDA T ION 35294 0111 20 701 000003311 5 5 1 L1
43. 00 300ng 00 naked 11 JU BU BU BU HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH AdolphH CRC Press Florid 1996 WO 93 17706 0000000000000 JP 02006 046661 1 2006 5 4
44. 10 60 000 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 00 0 t sl L 6R ELI sag 10 U D IL 60 18 JP WO2006 046661 1 2006 5 4 11 6 HHHHHIL 6HHHHHHHHHHHHHH L 6HHHHHHHHHHHHH HHHHH IL 6HHHHHHHHHHHHKT 3HHHHHHHHHHHHHHHHHH 10 66 00000000000 0000 K 30000 0 0 10 000 1 1 0 0 9 wellO 0000500 pg7mHIL 6HHHHHHHHHKT 3HHHHHHHHH IHHHHHH IL eHHHHHHHHHHHHHHH 199 000000 0 30 5080000000 og 11 600 0 0 0 0 0 0 D 10 IHHHHHH H20520 11 6 511 6 0 OOOO 0 0 0 00 0
45. 61 1 2006 5 4 12 dhfr DHFR A AE DHFR 10 U 20 U U 0 dhfr 30 40 50 RVh PML
46. HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 100000000000 000000000 0000000080 111 1 1 01 11 909100 10 0110010001010 01004 HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 000 Od 1
47. MDY wgqgsl vt vs LQ RVial 2 di qntqspssl sasvgdrvtitc RASQDI SSYLN wyqqkpgkapkl liy YTSRLHS gvpsrfsgsgsgtdft fti ssl qpedi atyyc QQGNTLPYT f gqgt kvei kr oa EJ EJ iL oa L3 oa 5 CDR2 SYSGI TTYNPSLKS CDR3 SLARTTAMDY CDR1 RASQDI SSYL 0 CDR2 YTSRLHSH CDR3 QOGNTLPYT aaa ES Eat 111 11 1 1 1 10 1010111010101011011101010101101011010110101010 11 JP VO2006 046661 Al 2006 5 4
48. assification symbols CO7K16 28 2006 01 12 15 00 2006 01 C12P21 08 2006 01 A61K39 395 2006 01 A61P29 00 2006 01 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Jitsuyo Shinan Koho 1922 1996 Jitsuyo Shinan Toroku Koho 1996 2005 Kokai Jitsuyo Shinan Kcho 1971 2005 Torcku Jitsuyo Shinan Koho 1994 2005 Electronic data base consulted during the international search name of data base and where practicable search terms used BIOSIS MEDLINE WPIDS STN CAplus STN SwissProt PIR Geneseq JSTPlus JOIS C DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document with indication where appropriate of the relevant passages Relevant to claim No WO 92 19759 Al Chugai Pharmaceutical Co Ltd 12 November 1992 12 11 92 Claims sequence 54 57 amp JP 05 227970 amp US 5795965 A1 amp EP 628639 A1 WO 2003 072134 A Kyowa Hakko Kogyo Co Ltd 04 September 2003 04 09 03 Claims amp EP 1491209 A1 amp US 2005 095242 A1 LIU J et al pPIC9 Fc a vector system for the production of single chain Fv Fc fusions in Pichia pastoris as detection reagents in vitro J Biochem Tokyo 2003 Vo1 134 No 6 p 911 7 Further documents are listed in the continuation of Box C L See patent family annex Special categories of cited documents T later document published after the international filing date
49. gee get Ser Leu Thr Ser 120 get EEC gga 881 Gly Gly Gly Gly Gly Gly Gly Gly 130 135 age cca agc agc gcc gtg Ser Pro Ser Ser Ser Ala Ser Val 145 150 geg gcc cag gte ptc geg gcc geg ctc gag atc aaa get CMV atg gag aca aca ctc ctg cta tgg gta ctg ctg ctc gtt cca get tcc act gt q tgt aga gcc agc gac atc agc agt Arg Ala Ser Asp Ser Ser e x 4236 aag cca gga aag cca aag ctg ctg up Lys Pro Lys Pro Lys Leu Leu E VE 180 185 TENE NN tet t tt t 1 cac tc gtg aga ttc gg K N His Ser Val Ser Arg Phe Ser Gly 1 200 ttc acc agc agc ctc cag Phe Thr Ser Ser Leu Gin Pro 210 215 tac tgo t aac acg ctt cca tac Tyr Cys Thr Leu Pro Tyr 225 230 aag gtg SEQ ID NO 10 al Lys V Arg SEQ ID NO 1 HHH 2006046661000001 app 22 JP WO2006 046661 1 2006 5 4 HHHHHHHH INTERNATIONAL SEARCH REPORT International application No PCT JP2005 019820 A CLASSIFICATION OF SUBJECT MATTER CO7K16 28 2006 01 12 15 00 2006 01 12 21 08 2006 01 A61K39 395 2006 01 A61P29 00 2006 01 According to International Patent Classification IPC or to both national classification and IPC B FIELDS SEARCHED Minimum documentation searched classification system followed by cl
50. hods and thus relate to a subject matter which this International continued to extra sheet 2 O Claims Nos because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out specifically 3 Claims Nos because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6 4 a Box No Observations where unity of invention is lacking Continuation of item 3 of first sheet This International Searching Authority found multiple inventions in this international application as follows 1 0 As all required additional search fees were timely paid by the applicant this international search report covers all searchable claims 2 As all searchable claims could be searched without effort justifying an additional fee this Authority did not invite payment of any additional fee 3 As only some of the required additional search fees were timely paid by the applicant this international search report covers only those claims for which fees were paid specifically claims Nos No required additional search fees were timely paid by the applicant Consequently this intemational search report is restricted to the invention first mentioned in the claims it is covered by claims Nos Remark on Protest The additional search fees were accompanied by the applicant s
51. or priority document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention earlier application or patent but published on or after the international X document of particular relevance the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim s or which is step when the document is taken alone cited to establish the publication date of another citation or other document of particular relevance the claimed invention cannot be special reason as specified considered to involve an inventive step when the document is document referring to an oral disclosure use exhibition or other means combined with one or more other such documents such combination document published prior to the international filing date but later than being obvious to a person skilled in the art the priority date claimed document member of same patent family Date of the actual completion of the international search Date of mailing of the international search report 22 November 2005 22 11 05 06 December 2005 06 12 05 Name and mailing address of the ISA Authorized officer Japanese Patent Office Facsimile No Telephone No Form PCT ISA 210 second sheet April 2005 23 JP WO2006 046661 1 2006 5 4
52. protest and where applicable the payment of a protest fee The additional search fees were accompanied by the applicant s protest but the applicable protest fee was not paid within the time limit specified in the invitation No protest accompanied the payment of additional search fees Form PCT ISA 210 continuation of first sheet 2 April 2005 25 JP WO2006 046661 1 2006 5 4 INTERNATIONAL SEARCH REPORT International application No PCT JP2005 019820 Continuation of Box 11 1 of continuation of first sheet 2 Searching Authority is not required to search under the provisions of PCT Article 17 2 1 and Rule 39 1 iv Form PCT ISA 210 extra sheet April 2005 26 JP VO2006 046661 Al 2006 5 4 PCT P2005 019820 A 1 PC Int Cl on 2006 01 12NI16 00 2006 01 CZ2P21 08 2006 01 461 39 395 2006 01 A61P29 00 B I P C Int Cl Bony 2006 01 CIZN15 00 2006 01 CIZPZ1 08 2006 01 A61K39 396 2006 01 20 00 2006 01 1922 19964 1971 2005 1996 20054 Hz
53. y76 2006 01 35 76 0000 2700 2006 01 25 00 0000 2702 2006 01 27 02 514 2006 01 5 14 0000 3708 2006 01 37 08 ooog 1700 2006 01 17 00 89000 AP BWdH GM KE LS NA SD SL SZ TZ UG ZM ZW EA AM AZ BY KZ MD RU TJ EP AT BE BG CH CY CZ DK ES Fl FR GR HJ I E IS I T LT LU LV PL SE 9 SK TR OX BF B QN GYM SN TG AE AG AL AM AT AZ BA BB BG BWBY CA CH CN CR QJ CZ LE K EM EZ EG EG ES G OE TL IN TS J P KE KG KM KN KP KR KZ LG LK L R LS LT LU LV LY M M M5 K W WK NA NG NZ PG PH PL PT RU SG SD SE SG SK SL SM SY 1 TN TR TT TZ UA UG L5 UZ G W YU ZA 74 100102978 74 100128048 72 72 1000 72 72 72 O 00 48024 BA44 BA63 QO7 DO2 DW EAO2 FAI5 HN2 HAL7 48064 07 CA9 G24 DOL 4B065 26 AA93Y ABOl 2
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