JP 5285437 B2 2013.9.11 10 20 (57)【特許請求の範囲】 【請求項1】 抗
Contents
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4. 100000000000000 310 10000 w0 1000000 H 0 0 U 0 0 50 50000 I II i I i Ii I I O 500 2000m UUUDUUDUUD puggggggumggugupg
5. ID I Uuuuuuunuu AIUUHUHUUDUUGI LIDO OO DO 00 O LH DD MB 11 0 0O Ll UE SAT FH DO DO OO HVG 10 IDDUUUUU HMB 31000000000000000000000000000000 D DOO0O000000000000000000
6. DOVOOGOGOO0O000000000000000000 VV0 HU Hut 30000000000 conplemntarity determ ni ng region CDRI 0O I V Muuggauauguuguuguguuudlgutdr 60 0 COR LU D ID UUUuUuuuU DOli0000000000 Ius ugemuuaguuraummuamuggugauguuguuusuuddctdstdtyt
7. 21 S194 Trowbri doe J Exp Med 1978 148 313 23 R210 Gal fre et al Nature 1979 277 31 301 00000000000 U 0000 OOOD 000000 Bu 0 0 0 M p OO O0 UDO EL SA U LH I EH LI EH LI HMB 0O0000000000000000 D 0000 UUUD Bt DB HMGB
8. 1989 341 544 6 0000000araB0000000000000000 Better I Bette Met al Science 1988 240 1041 331 00000000000000 000000000000000000000000 sese BI IDOL Lei SP et al J Bacteriol 1987 169 4379 83 0000000000000 ut O00000000000000000000000000000 MO 96 30394 0 IN 0 DOO0O00000000000000000 40 SV4O 0O00000
9. 0 0 0000000 0 0Ilgg ioy I I I I I i iiu HMG 20 0 O0 HMGB 1 DO000000000 o uut D00000 HMB 20000 HM 1 D U U U 0 0 HMSB 20 HM 1 HMGB 1 HM 21 00000 IOD uuum HMB 10 HMGB 2 I DUUDUUD HMB 1 0 dd HMGB 20 0 200 000000 0000 0 0 0 M 10 000000 0 0 HMB 20000000 DOO0S5000000000000000 MB U DD DD DD DD HMB 2D DO DO IOO 100 000000 0 HMGB 10 HM 2 Hut D DO ELI SAI BI ACORED O O O0 000 U Uu U Uu ELI SA BI ACORE I O
10. HM 1 16 0 O0 00 000 00000 00 0 O0 18000 0000 000000 OD DO DD I HM amp 10 00 0000000000 ELISAO DL LU ULDIUUubu ul l ii i NI DU IUIUUHUDUDUUUDU 0 0000000 KHO0000000 ID 0 BAO0 UDO 000 U DEUISAD DD DD OD DO HMB 1000000000000000 EU SAQ DO DD DD DIDI DD DD DO HMB 10000000000000 POT 000000019000 IOO DO OD Ll U IUIUUHUDUUUDUDIUDUU IUUULU HNGB 1 I UIUUHUUUUDUIUDULU IUUULU 8r H D HNGBE 10 1670 0 0 IT UUDUDUUDUUDU D 180 u t ul
11. 77 810 0 D 10 Fa i 00 0000000000000000 000000000000000000 1 0 Fab o PDM ort ho phenyl enedi ral ei de i I EH i D DO UU ul U LU 0000000000 Fa O000000000000000000 Fab U Da 000 Fab 2000000000000Keler T et al 1997 C ancer Res 57 4008 141 0 DD O Fb 00000000 0 180 0 0 0O Fa 000 SH IOoD DD 0000 0 DO O0 00000000 Brennan Met al 1985 Science 229 81 30 0 n o DOUDFosOJun000000000000000000000000ro sl Tut i i
12. Ll O0000000000000000000000 HMB8 100000000 LUUD UL QO00000000000000000000 HM8 10000000000000 HMB 1 200000000000000000000000000000000000000 UL IUHUHUUUUUDUDDUDUUUUUL UI mut O000000000010000000000000000000 200000000 HMGB 1 IODOOODOO0OHMB200000000000000000000000 e000OO0000000000000004 0 0 HMGB 2 DU H 0 8 20 000000000000 ugue 1 Hl B 4l UU HMGB 24ng O0 O0 O 290 CNBr IUUUU UU UU DDUUUUUUUI HMGB 20 0 0 HM 2 Ll UuBagmJud O00000000000000000000000000000006 DU UU IUUUUOUO OO00000000
13. 0000 Ll HM p DO O0 B UO B UO U U U UUUD Bm 0 0 0 0 0 O0 HM amp 10 HMGB 1 GenBank Accessi on No 00 DD 00 00 00 00 DO 0 0 O0 O0 GenBank Accessi on No NM 0021280 0 00000 o0 HMG 1 OD OO U d HMGB HMB 1 HMB 1 HMB 1 E cn da a Unn E T P Hopp et al Proc Natl Acad Sci USA 1981 78 3824 8500000 Parker et al Bi ochem stry 1986 25 5425 32 II DUUDUUODUUODUUDUUDUUDUUD HM 1 HM 2 O000000000000 HMB 10000000 u 0 0 0 M 10 MB 20 0000002000000 HMB 1 Hu IUDOODOO0O0O0O000000000000000 BU TT HMSB 2 DUOOOO0OO0OO0O0000000D0HMc IDDOOO0OOOO0OO0OO0
14. D BALB cO OD i10000 00 00000 2 IU 100 g0 000000 10000 o 0000000000000020 000 DDU Unn D D p ELISA EL AG D D 000 EIS 0000000000000001 U DU 0000000 0 000 800u ymI 00000000 1003 i10000 10 I0Ooo0 0009000000009 00 000000 100 LO 0000 37 C0O 2000000000 0 M 1 ID DO 000 050 000 g 200 Tween20 D D nM IDODOO00031 47nMOOOOOOO0OODO ID02 68nM0OOO0OO0O00000000pH7 2000000000 00000000000000pH 2001 C0200000000000000000000000 00000000000031oouLO0000 1000 1000000000 1000001 D 20 0031oouLO0OO0O0037c0 200000000 0000 00000000000 0 1M 100u L LH SCH 2 0000 pPonnuggmumnunt oegin
15. 1 202008 2005 0262000 000000 BAN D O Shapiro AM et al 2003 Immnol ogi cal Reviews 196 219 36 Wang H et al 1999 Science 285 9 248 51 B geut DOO000000000000000000000000000U00 II DUUDUUDUUODUUDUUDUUuuUuUuUuU DUUDUUugDUuUugnUuuUugUuuUuguUuuuuUuuU D DUOOUOO0OO0O0O0000000000000000000000 HMGB 1 J ELI SAT O0 H O 0O O Yanada et al 2 003 Clin Chem9 1535 7 00 Uu Ll 000000 0 HMB 1 HMGB 1 HD O HMB 1 LH D 2003 96099 0 UDO UDO UOO HM p 0 DB d Uu UUUDUUDUUD 1 H4x8 1 DO 0000001 Ll ul Jguguguggogugugdaud IHDEUU 22000000010 HMGB 1 OU00 2 HMGB 2 ID HMB 1 1 0 0 3 I
16. DD DD 0003 O0 Cys Lys Pro Asp Ala Al a Lys Lys Gy Val Val Lys A la Gu Lys 3 0 0 BA0 DD 0000 0 100u g m0 IOO DO OD 0 9000000000000000000000000000 Il UD U IIIluununnnuuuuuuuuununoD Il D U 0 5mq DD UU 20000002 100 oi I Ii i i DD ii nu ui u uu Il D U U I UuUUUIDU IO0O0O00000D0 o SAID UDDDDUDDUUUUUU jiggudduddeueauyulu IDDU 300000000000000 O0000000000000000U000 ELSA EI AD IOD DO DO D60 OU 10 DO DO OLD DO ELI SA I I I Ui U 3 DI DD 3 DD OD DOO 0 KH OoODo DD DD Wgym UU IOO DO O0 U Ill 96 ID U UI DO I UIUUUDU l 100p LIDO OLD 37 CU 20 0000000000 KLH BH B D U EH H ll 3 2 0 000000000000 0 050 I 200 Tw
17. 20m 198SA 1 1 00000 O OOO 80u ol i i I i i iu i nu uu utu 2000000 iugm BatgaOomrp 0 DO O0 00 100 0 3l uu UU 0o H IgG O O 0 30 BAD DD 00 00 u t 5000 0 0 0 0 0 0 200 IUuuuuunnnuuuuuuuuu IDDU O0 0 O 20m 0 ll OO OD 100 0 u t ut ut HT 30 0 025 3 3 000000000000 0 01 IDDU 20m0 000000000000 15 Hug 110 00000 iniuuunuuuuuuuuununo 10 RO6GEIOI OC IUiunuuuuuuuunuuuunua4 0000 iiuguguguuuuuuululurttesqd AajgRoecEiogjnguguignuuguugsuuguuguuuuuucdtcetuttl 3000006000 0 0 HVGB 1I D DI D00000 D0000000 4000030000 lg Gi D ugggumgggugagauuuuguuuacdzrtutustcdstut Hcr t 00 HVGB 2 0000000000 nu 0 U UUUDU D 2000003100000000000000000D0 H B
18. I UUUUUUUUUUUUUUUUDUUDUUDUUOUI DQGOO0000000000000000000000000000 HMB8 100000 HMB 1 U DO HMB 20 0000000 UI U DO UUUO UU DO ULLD u t 0 IN E IDDU uglutld u y UH HMGB 1 0 M 20 DO H D Hl o 9g000000000000000000000 HMB 1 2000000000 U U U O UULD 0 D 900000000000000000000009 D1005 DO HM 1 m I HMB 2 1ng m 0 1 100 0000000 1 1000000 2000000015 SD 000000000000000000000000000 O00000000 pH8 8 00000000 2040 1800 00000 3 0 0 2 UUUO UUUDUUD UDULD U UL U U D UU U UU DU ULU U LUD l H uu UDO UU U OD UL U UL OD UL UU LUD U E U Ee E LUD u t 0 u y DOODOO0OO0O000 2000000000000000000000
19. Ll Ll DUOOO0OO0O0O00000000000000000000000000 0o Ll DOOUOO0O00000000 DUOUO0OO0O00000000000000000000000000000000000 u Ll IOD OO D00000 uH 1jyggmuguagauguguauaductlctselatluet IUINUNUUDUDUDDUDUDUUUUUUUUNUUDDUDDUDUUDUUUULD IUIUNUIDUDUDUDDUDUDUDUUUUUUUUUDDUDDUDUDUDUDUUULD O000000000HWMIi0000000000000000 1 0o 001h g m 1000ng m 0 0 0 0 0O 0 1 g m 0 100n gm0 00000000000 DU LU UU UU UUUUUDU UDD UUUHUULU 0000 OOD DU LU UU UU Ll UB Ll Ll Ll UDDUDD IDDU UUDDU UUUHUHUDU Ll UDDUDD 000000 0000 pj HMcB I000000090 DO000000000000 DUO0OO0O00D0 Ll Ll Ll Ll uuu IDDU a DHMB 1000000000000000 b a IOD DO OU0O HMGB 1 HMSB 100000000000000000000000 u Ll Ll Ll IOOOO000000000000000000 Ll DUO
20. 6 0 O 0 75m Cad am 00000000 IOAWWOIOD DO OO OD DinTB S 300000000000000000000000000000000 U TBSI 0 0O O000000000000000000000000000 1BS 100m LO O 20 Mal O00000 2090 rrt 300 nr iuuuulululu U 0 D 10m TBSI OD PBS 0 0 0 0 0 PBS IOOO0OO0O00000000 S0000000002 Ll OO0D000000000000000000 0000000 Ll IO0000000 8 0002 lOng O0 290 CNBr 0O000000000000 0000 I UO B DB iuugmagmumuadui Ll 000000 Ll IO0000D0 8 20000000000000000000000000000000 700000 8 400000000000000000000000000000000000050
21. 44000000000HMB 10000000000000000000000 DOO0OO00004000000000 HMB 10 100u oinmflDDUDDUDDDUDUDDUOo on DU IUUUUUULLUULL I UNUUUUDUDUUUL Ll ID000000000 0 gosmituu uluelu 2u0ggadgdgauuguagaauumunuuiougmpynggaadaadauuuuuuul IUUDDDUUUI ID00000000000 smlJ ou 0o Do 00 00000000002 OO0000000000000000000000000000000000 ELISA El A I000000600000100 ELI sag O000000 l 3 DD 0 HMB 10 iy g mt D D DO D D U 0 O 96 0 H B LI OO ODO DD DO OO OD WLUOD LOL 100p LI 0 0 U O 37ct 20 D000000 HM GB 1000000000 3 2 000000000000000 0 050000 0 200 Tween20 Iu uultu 2 59nM DO0000000001 4M000000 137mM I 0 ID 2 68M O0 000 00 000000 0 pHr 2 U DO 1j BSAU I onMJOO00000000 0000000000000 pH 2 01 300n LU 37 C0 20 0000000000000000 Ll u UU 3 3 000000000000000000D0310ohL 900p LI DL 0 O0 O 10000 O 100000 O0 O O O 100000 UU U utu DOD 100u Ll n I 37 C 20 000 DUOUO0O0O00
22. 24 LU UU IODOOOO0O20000 DI U1 2 N a co A Ll L3 L3 O Ll L3 L3 L3 D L3 L3 L3 28 JP 5285437 B2 2013 9 11
23. SS uuugunnnu O 00 DO0OO0OO000000000000000000031 HMs I DOOOOOOO0000 D0000000HMB 10000000 1000000000000000000000 ID D 0000 0000000000000i000000000000U00 LH UunuuugnuguuguuguuuuuguuguuuuugnuguuguauuuuuUuuuuou 10 ID Uu DHMB 100000000000000000000000002 HMB 2 000 HMB 1 ID 000000000000100000000000000000000 DUDDD HMGB 1 IOHMB 20000000000000000001i0000000000 J000000000 000000 0 HMsB 10000000000000000HMc I0000000 1000000000 ugugaugaddriululitlttl 20 2 JP 5285437 B2 2013 9 11 00000000000000000000 HMB 10000000 10 000000000000000000001 High Mobility Group Box HMB 1000HMDOO00000000000000
24. o o o o o Ki N m Es A E r3 Too E ES zm Zee ES m c qup E EJ E A Ll lt O E L CC CC LE N LJ CH u e ee oO L3 r3 jo oO B EJ E3 ET Er ei E SS ro m oo DC L3 T CO CC IF ynu _ N Ed 9 3 or L 5S EN e El CC o EC z mE 8 oO m zu m o o en Er Ed ET ELE ES N E3 I oO oO i CC Sei ES CH 3 m m PIA UNUS o _ LO S i 4 CS ES oO ss Lr ELE TE oem E O m Fel EJCEJE ESSET E S E o o Er Er CC T o 1 Soon go EE ge E S L3 CDI x 1 E3 I Er Tr CC L3 r3 o EC AN AT E b Pu oO o 3 cd GNIS ONE oO C CL C N N KS ono A x S Soon L3 r3 Cv TOUSE T CC L3 r3 N CN CO Fi i SN I Soon CC F ee EZ EZ rd St i rr nm EE H CN Er E oO CC CC S Effet E E3 I i ET IE Er m CC L3 r3 og S CC CC T a ad Eu a N El CC L3 r3 m o ES S L3 r3 N IL L3 Lj i E Er S CO CO L3 r3 T I N 1 Te E Er
25. M 1640 0 DO DD DD DD 0 Im 0 00 Ap 10 14 00000 BAB CJ UI 0 iu au au nu uu ugn uuguunaudu UUUDUUUUUUDUUUDUUUDUUUDUI o0 000000000000002000050000000 nn U iuuuuuuuuuunnnnuuuuuuuunnunnunoD 6 1 1gqJ DU 5 0 I ll Hl 10m 22 C 1 8g U 0 O 22 C 700090 150 DO H B 30nM 40nM pH8 O 2n 30nM 40nM pH8 0 0 I 100090 20 U 30nM U 40nM pH8 oi DEAE 1x 10cm O Ant Hu 0 O 2m IN Illai ioa iuunuuunuunonu ut 0 280nnh 0 IT 0 000 2mM0 000 ul AD DO OD 0O CL 4B IDOD DO 00000 0 IU Hutt o0 0 E GAOT E E EES E E 2000000000 0 9M00 5 IIUluuununnuuuuuuuuuununnnuuuuuuuuunnoD 1lOm 20M 0 0 0 0 0 O pH7 5 0 8MO0O0000000000000000000 0 d 20 MI 000 pH7 5 0 8M0 000000000000000 Hi Trap I gM purification HP 1m O00000 00000000 20nM pH7 5 O 8M000 1000 20nMDOOOODO pH7 5 0 U DD DO DO IgM IDDU Lu IDDU D ULILULL HNGP 1 2 LU LI 50 00000 0 HG 1 2 UULU I UuUUUUUUDU o0 uggamggduaagaamgmgguadagdrmhReecimgnuuugsguuudgtctlut LI D UU LLL 1 U0LD0D1000000000000000000000000000000 50 0 0 0 0 0 0 M 1 1mw m 0 O0 HNGBE 2 1ng mb 1 1 00000000 1 1 ID DD DO OO OD DI 23 SDS DD 0000000
26. EE EFE Ll L3 EU Ll LU Ll L3 Oo L3 O EE EILER E Ll L3 EU L3 LU Ll L3 Oo L3 O CLC EZ EST E Ll L3 Oo Ll O High Mbbility Group Box Protein H Mobility Group Protein HMGJII I UI uu I uu Ilu I u U i un iu uu ui au I HMGBD UU IOO OD uU l uU Ll GENETYXI SOFTWARE DEVELOPME IU DU UU HNCE 1 E D HMB 1 I 98 6 HMGB 1 99 1 U UU HMGB 1 UU 81 20000000HMs20000072 3 0 0 0 0 HMB 2
27. YIHM YUDUIUuUguuuuuuuuuUgugUUU UU YDD Henn YD U nn 00 D qpHG I g 0 1999 HMB 10000000 in D DE 00000000000HM81090000 HVGB 1 000000000000000000 HMcB 10 00000000 HMGB 1 0 HMGB 1 0000000000000000 0 HMGB 1 HMB 10 NOO0000000000000000 00001002 Dung HMGB 10 D D 0000 00000000 HMGB 1 HMB 1000000 0000 000 00 DS 0000000000000000 HVGB 1 0 HMS 10 900000000000000000000000000 Iluuuunuuuuuuuunuuuuu 0 9000000000000000HM810000000000 H4 10 000000000000000 a FO AU RE Tn EE 0 0000000Hvss1I000 00 HMGB 1 HMGB 1 0 HMB 10 00000 000203 0 HMGB 1 0 JIDHM8 1000000000000000 0 o 6 468 5330 0 0 0 6 448 2230 0 0 2005 5125070 D D 2005 5089130 0 0 0 0 0 0 O 2004 0440010 0 0 0000 4 JP 5285437 B2 2013 9 11
28. ult utt 2 0 0 0 0 O EP 239400 VO 96 025761 0 II CD DOO0O000000000FR0000000000000000000U0 ORTH IOFROO0OO0000000000000000 cR utt O000000000000000FRI00000 I Sato K et al 1993 Cancer Res 53 851 600000000000 FRI WD 99 517430 000 0000009 D00000000000000000000000000000000 DOo D0o 0012 oO DO I 1000050 100075 I 0200 85 uat 95 W I bur Li pnan Proc Natl Acad Sci USA 1983 80 726 300 Hu D00000000000000000000000 U ugggPgainuugguguugausuuuuluctutleu u t MO DO DD DO DD DO OO DM 40 O0000000000000000000000000000000000 SV40 Mllingg I 0 Milling R al Nature 1979 277 108 14 I o ia 00000000D Mzushi ma M zu Nucl eic Aci ds Res 1990 18 5322 Wu ID Dl 0 utt 0 Hut DI U DNA ODOO000000000000 ID U Lac ar ab 15 JP 5285437 B2 2013 9 11 I UH B LL Lacs 0000000000000000 0 Wrd D OD Wrd ES et al Nature
29. S qiuugggagggaudul D l l IGIIUUUDUDDUDUDD n n HMGB 11 HMB 20 0 0 HMGB 1 0 0 60 0 O0 HMB 2U DO 00 70 0 P Cabart et al Cell B i ochen stry and Function 13 125 133 1995 eog UI UU UU IIu I I U I 1 HL60 cell 1096 U FCS DU L 20 DU RPM 1640 D O 300 ni O LU UO LI 2D 0 0 Uu HL6OI D 0 00O RPM 16400 0 0 000 3L0 PHMII OO000000 00 MEME LU UL 300000000 PBS Hl HU Uu Hepari n Sephar ose 4 PBS ll 0 00 5 Mi UULU ll 280nM O00000 LOU H DB UO UB LZB GL I UU pH9 0 O 2M IUUUDUUUDUU DJ ut DO OD 000 7 5nM pHO O UU IPS 000000000000 I00000000000 SM LU UU UB DI 1
30. HVGB 10 0000000000 A000000 00000000000000000 0 0 0 0 0 HMB 10 16700000 101800000000000000000000Lys Pro Asp Ala A la Lys Lys Gy Val Val Lys Aa duLlyli ID 00 0 1 0 DD DO DD 02 0 000 MB 1 Lys Pro Asp Ala Ala Lys Lys Gy Val Val Lys Ala Gu Lys ll i oD l 0 00000 W8 21 0000000 Lys Ser Gu Ala Gy Lys Ly s Gy Pro Gy Arg Pro Thr Gy00000 20090000000000000000 0 IIIluunnnuuuuuuuuuunnnnnnunonu Cys Lys Pro Asp Ala Ala Lys Lys Gy Val Val Lys Ala Gu Lys000000 3000000000000000 0 Appl i ed Bi osystens I O O 430A0000 Model 430A peptide synthesizerD D OOO000000000000t 000 Cys Lys Pro Asp Ala Ala Lys Lys G y Va Val Lys Aa GuLysDO00000 30000000000000000000000 p m U nn U B I ll 0000 0000 U 0000 2NI 00 I 1 X2 DOVEX 1 X2 ut o u t ut ODS I UD U DO HPLG Ll U UDO I HPLO O O OO0O000000000000 PLOJ IT u I ODS YMC D ODS 50 20rmx 300nmf 0 TWNCLEI DO DO O0 O0 GP A40 U 0o 10000000000TFA InULU og 0o 0O 7000000000000 7 0m ID UVI DEC 100v 210nmj 1 28AUFSU BL Ui I I I I D U IIIlunnnnuuuuuuuuuunnnuuuuuuuuuununnuounnonu 000000H9000000000000000000000000 o YMC R ODS 5 4 9mx 300nm0000000000007TWNCEODODODOOOODOODODOOO CP A400 0 00 000 0000 0 10 00 000 200 0 00 0 To O00000 000O 70 IO000000001 0m0002500000000000000 UVIDC10 OM 210nmj 1 28AUFSSI ID I iu ui i i
31. HMBID OO0O00000000000000000000000000000 1 10HMB 1000HMIO000000000000000000000 IOHWM0000000000000000000 30HM300000 000000 800 HM80000000000000000000 170 OOOO00000000000 I10HWMI0000000000000 3 JP 5285437 B2 2013 9 11
32. Ke E4 s HM LT f ei Io Ui e e T e DI L 00000000000000000000000005 00 IU IU Uu HM 1 IDD DOD00000000000 OOOD HMcB 10 00000000 000 IU IU Uu nts I 0000 000 0 D00000000 000 00 0000 000 0000002000000 20 DUDU IEN 0 0 0 HM amp 1 000 14 IU ID 6000000000 1000 0 amp 10 CDI1b OIFNyYO0000000000 FACSCAI i b Becton Decki nson all
33. 25 JP 5285437 B2 2013 9 11 IDDU 9cmx 9cnh DI 1 DI IU OO DD 0 1 BSA C C C u r3 r3 u u 3 n SES I 0 200 V V 1 47nM iUug ugddagzrgse uaiaznMirtgdrtetut NU o 0 O pH A0 O 20m0 4 co 1000000000000000 O 05 200 Tween20 00000000000300000 IUUUUUL 80u gr 20m0 IWSAI TODD OD OU U1 l I00000000000002 N o R m o e c F z Ft o L1 30 BSAI El 20m0000000000000 700000 DI 1 HM e Ll DI L1 DI 1 uana
34. o o HM II uuunuuuunun L r3 r3 Ej r3 r3 u 1500000000000 Inu 10000000000 30000000000 0000000000009 0000000 0 2000000000000000001ogY Up Data I 3000006 HMGB 1 00000 Hs 1 2 000000 000 I0000000000000000000000HM8100000 MGB 2 0000000000000000 0 U 100000900 00000 0 EEUU 000000 HMG 20 0 o onnuuuuuuununu HMcsB 1000000000Hvs200000000000000
35. CM SehadexC25 Phar m Ez 21 JP 5285437 B2 2013 9 11 DI 1 N o E DI 1 aci a 7 5mMj 00000000 IOD DO DUOUO o o e 1 Ll I I gt Sal
36. o 100u oi nm IOOO0OO0O0OO000000000000000000000000 26 JP 5285437 B2 2013 9 11
37. HMGB 1 HMGB 1 10 O UU O ll B HMGBI HMGB2 oorNuoO Oooo HMHL Uug KLH AZ FF a BSA AZ E 0 202 50 EX 0 6 o5 Ne 0 4 iQ 0 3 t 15 20 10 TURIS EC u g ml JP 5285437 B2 2013 9 11 32 0000 60 40 20 E is KR 200 HMGB 1 400 re me i idr DIO Xv CORE laid DE EHE Bae RR IS Bl Hi lu HER EO 4 RHOWN L M i sd Heizen Yr UE erziehen 327 1U 8 H L E Leena tt Pr DI WE S z X 09 or 07 0 E gt 2 i Y is 3 S sT EN T do M 5 So O qe N gt eie 3 o T pOLeOLzOL Lef vOL sOLzOL Loft is t o e o pr amp TA e A Sa zv jo O oz 2 y0 ek zOL OL o0 vOL et z0L LOL 0017 ke oo Ie S ud s 2 o e NS X i o o E E eo A A GEN sObLgOLzOL OL 09017 vil cOL zOL LOL o0 HU 1 33 JP 5285437 B2 201
38. P o N Ui LA o o P 1 000m 000000 00004000 Iz L1 LI w U1 o o S NJ HM 3 E Unuuuuuunuunun Ll IOO DOD Unuuuuuunuu 7 000000000000000000000 HM 10 HM 2 O LU UU 3 80 0 0 WB O0 HMcB 200000000000020orM0OOO0OO0OO00 0 0 0 bm pH9 OD 10m0 000000 0 0 200nMj O0 O p9 OD DO DO DO LDDODOO Bn O00 000000 N S o g Q 8 o 2 r3 r3 r3 r3 r3 r3
39. HMGB 1 HM CB 2 U IE 00 00 Hce 1 HMGB 2 U UUUD 00000 HM 2 HMGB 1 HMGB 2 I HU U HMGB 10 HMGB 2 uggumgsrtmetseE LsA D put DU ut DOO0000000000000U0U00 HMB 1 utt I 0 HMG 1j DO D Ll 0 HMS 10 III Hut I 020029 ELI SA BI ACORE 000 I HMGB 1 IUnluUunu D UUUDUUD 000000 000 0 HMB 1 0 0 HMB 1 Ll 000000000 HMGB 1 UU Hut I HMD 10 0 0000 H D UUUD U UUUD H D UU UU TU 0000 UUUD 0000 UUUDUUD HD HNGB 1 DUOOUOOO0O0O0000000000000000000000 HMGB 1 000000000000000000H 60000000 Goodw n H et al Bi ochem Bi ophy Acta 1975 405 280 91 Yoshida Met al J Bi ochem 1980 95 117 24 Adachi Y et al J Chromatogr 1992 530 39 46 0 0 HM 10 0 0 0 M 20 0000000000000 IOO OO UUOO 0 0 0 W810 DO DO DD DDODODDUODOO ud 7 JP 5285437 B2 2013 9 11
40. DI L1 0 L I DI DI 1 DI 1 22 JP 5285437 B2 2013 9 11 O0000000040000000HMB 1000000000000000 u IUUUUUUL 8 1 00040000 HMS 14ngD 0 0 O 290 CNBr 000000000000 Ll IO000000000000000 Ll LU UU 8 2 0000000000000000000000000000000 470050 P o HM pH3 O
41. u 0000 III IDU3I000000 CDRU DU utu 30 0 CDRE O O O 0O FV 0 HMB 100000000000000000 III O0 000 0 Fab 0 F ab 0000 LOOODOOO0D0 9 DOCH 10 10 0000 Fab D DO F ab I0000 Hg CH1 Fa bjO00000000Fab SHU F ab SH UUUDUUD 1100 Fab F ab ID UI I 2 Fab SH O0O0 000 C00000 000000000000000 0000 U U BU UUUDU H HHN EL H D DO ut uu Co M et al J Immunol 19941 152 2968 76 0 000000000000 D 20 U Uu 0 O O bi val ent Holliger P et al 1993 Proc Natl Acad Sci USA 1993 90 6444 8 EP404 097 W93 11161 uuiuuunuununoas2 IIUUUuguuUuuauuU I LE DB HO EU CM U 0 OO M4 BU I DU ut sD000000000000000000 VO Va I Iuuunnnu l l H EE E Enu E E 20 n m inmmmmtH 30 scFv iuVwMgIgUMBaugagggaugaududuagudgtd 02000 0 0 uugurvaiuuuuuguunvuuvnuunu IDUUscvinuiuuuuuuuunuunanu IU O Huston JS et al Proc Natl Acad Sci USA 1988 85 5879 8 30 scFvi 0000000 0 Pl uckthun The Pharmacol ogy of Mbnocl onal Anti bodi es V ol 113 Rosenburg and Moore ed Springer Verl ag New York pp 269 315 19940 I IOOo OOUUUOUOO 000000000000U000000000 D gumgggmumgpgBugBuggdeszziustytl I 40 scFV 0 DA Ui i i uu DUO uiuguununuu 1 DOHHOODOOODOHVOOODOOODOOODODNAOOODOODODLIOOOOODOLOOODOODO PNAU DUODODOODOOODOOODOOOOODOOODOODOOO0ODO 0 0 DNAD O UUUDUUD UPRIUUUDUUUDOUD 2 0 0 0 DNAD O IDHIDL IOO OUUUUOOUOO scFVYJDOO0O0000MW000000000000000000000000 I IUlnDDDDDUUgugu
42. 11 0 VI 0 0 cDNAT o cDNA 0 0 OD O AW Reverse Transcriptase First strand cDNA Synthesis Kt O0000 000000000 00000 0 0 0 0 c DNA Uu 2 U 5 Anpli FINDER RACE Kit Cl ontech PCRU O0 0 0 O 5 RACEI Fro hnan et al Proc Natl Acad Sci USA 1988 85 8998 9002 Bel yavsky et al Nucl eic Aci ds Res 1989 17 2919 320 UU J ID lU RT PCRO O0 LO I HO VLO WD 0 cDNA cRiIHuumguuuuulut cmi tu t CHI IDOL E E z IUUnbe UUUUuuunuunuuuuunuuuguuguunuunuuou O I U U u u UL Ll O Inu UU l Ll UL WD
43. DUUDUUD HMGB 1 HMGB 2 E UU 0 30000 O HMB 1 LH 000 1 uu IOUOD OUO00 IO0 DD 000 1 J O 0 S0 00 000 0 HMB 1 LH LH 0 00 0 HMB 1000 Ll UDO UO0O HMGB 1 IDUUD 0 0 HMSB 10 0 uu iggggggmamuid a OHMB 10000000000000000 b a TU D 00000 D U UDO 0000000 a DO HMB 1000000000000000 b a UUUDUUD UDO UO0O HD HU D UUUD Ll HMG 10 O0 HMB 20000000000000000000000 HD iugguggagauduasguudse utlsa2asonmi 0000000 UD igugugguguguguuuuutultsaz5ysbps PAGEH I 0 OO DO Ad uBiIWuugHeeijnpgmguuggusuugHce2a2gnmnguuuuturutlutl JP 5285437 B2 2013 9 11
44. ophycocyani n O IFN y 0O O O SEROTECI O O Per C D amp ip 0 0 SEROTEGI FI TC 0 0 CD11b I O SEROTEG IDDU Inga G I OOllibulnuuuuuuuuuuuuuuuuanw naiveD islet txXxJ Il 0000000 0 Gr 1 7 CD11Lb DDHDIFNYDD D OD 000 D0 DO O naive islet tx IH T 0 0 HMGB 1 I000001slet tx anti HMBl ahp Jl UI DI U D T 9Y ID Hisle tx0 0 000 a 1 cpib nu 000000 IU 30 Gr 1 CD11b IOIFyYyYDO00000000000006 IUD H ID 0 D0 DD DD D0O0 DD O0 0 0 0 G TR CDllb 7 IFNy DU Ll Ll Ll Ll DDO00000 0 0 0 0 0 DDDUDHMBIlIDD lu g m Ilu ont D J 40 0 596 24 unu 0 I0000000000 0 0 0 0 Inu 0 0000 D 0 2000 0 000000 0 D 0300000000000000000000000000000 90000000000000000000000000 JP 5285437 B2 2013 9 11 31 HMGB 1 24
45. u uu uuuguuuguuuguuunuu 1000 00000000000 0 0000000 UDUuguuunuuugugunu enpndfnnuuuunuuu uuuunuununn 0 BSA 0 00O O Omg 10M I 000000 000 00000000000 pH7 O 0 U NN OODo DO DD OD DO 00 0002350 00000 N U 0 0 0 BS ID DD OD JE 0 1450 O00000 300 000 U 4 C 10nM DOO0G00 0000000000000 pH7 o 0 UU 0 0 O G25 Sephadex G25 0 000000 000 U Z nn I ll Ii I Il i i i ui 00 0 0 MS I 00 nn H MBS OO DD DD DD OU pH7 00000000 20 0 Cys Lys Pro Asp Ala Ala Lys Lys Gy Val Val Lys Ala Gu Lys 30 0 150 DD DD DO DD DD DODODOUD 300 D 0000 nn II DUUDUUODUUDUUDUUD 10 20 30 40 50 20 JP 5285437 B2 2013 9 11 0000 0 HM 10 HM 2 ID 0 0 HMB 1 ID I C Sanders et al BBR 3 000 0 0 50090 0 140nM 0 40 OO OO HMB 200000 5000000 1034 42 00000000 0 5nM PMSF O L3 LJ HM LO N N N co o o o P DI 2 3 DI Oo L S i i z N
46. ul D 0 HMGB 2 III U HMGB 1 00 ELISAIOO000000000000000 HMB 100000000000000 DD LU D U 0 0 C7BL 6 0 O O 23 25 g IN IIIlunnnnunnu IUIUULU H DUUUDUUUUUUUUU 180 ng Kg 300000000000 U Du Du LU UU Du 0 ID UUDUUUUuUuNU 40 ng d00000000000000000000000 Hu 0 U OOOD C57BL 60 0 OD 23 25 g 0 000 000000 00000000 000000 DOLL iuumg aumJ utdricoli corayjgugumadaumgadauaeuectteu ut iguggaadadgauuuuguuguuuuseuuaajyumguuuldldtll u iiuiniuuuuuuuuuuuuuuununuuuuuunuuununo 0 O O Sutton R Peters M McShane P Gray DW Morris PJ Isol ation of rat pancreatic islets by ductal injection of collagenase Transpl antat ion 1986 Dec 42 6 689 91 Erratumin Transplantation 1987 Apr 43 4 608 O htsuka K Yasunam Y Ikehara Y Nagai T Kodama S Maki T Tomta A Abo T Ike da S Expansi on of internediate T cell receptor cells expressi ng i nterl euki n 2 receptor al pha beta CD8al phar beta and ynphocyte functi on associ ated anti g en I in the liver in association wth intrahepatic islet xenograft rejection fr omrat to mouse prevention of rejection wth anti interl euki n 2 receptor beta m onocl onal anti body treatment Transpl antati on 1997 Aug 27 64 4 633 9 30 JP 5285437 B2 2013 9 11 200 HM Les IN I U tduucttu
47. 0000 u ut pH8 80 0070 IT 20nA 1800 I I I iu iU i in iu iu uu u uu u uni uu uu uu uu nuu uu LU CUu 0 Hu LU ULL o o o DD 9cnx 9cM 48nM LU UL Hg Zon 0 0357 m M 0 SDS 200 0 M V 60nN 2 10 BSA 0 0 0 El 5 59nM I 1 47nM 137nM d DO 2 68nM pH7 2 0 20m 4P C 10000 IDDU 0 050 0 0 0 0 200 Tween20 O0000000000 0 20nt 10 0 000000003000000001100 IN IDDU 29 JP 5285437 B2 2013 9 11
48. 0000 oO 3408008088080 H080 3 2 IDoD DO Do OD Do O0 0 00 WM BSA O EH 0 1MIJ 0 0000 100p LI O0 O 37 C0 20 0 00000000 IUUUUUUL 3 0 DO DO DID POOL DO 19YO O Uc Data I 0 O 30 BAD DON 50000 1 1 1 ID 3 300 3 4 000000000030000 100p LI O U 37 C 20000 IIUDUUUDD 3 6 00000000000000000000000003nM 2 2 000 00 3 u Ll 6 0 0 0 0 O ABTS O O O0 Som DD OD DO OD DD DO 24nM 0000p 0 01m0 0002y LO 1 70 0 00000000000000000001 100u L I0000000000150001i00000150H10 6NI ID 3 2000 ELA O0000000000000000415n000000000 40 11220000000000000000000000000000000 Ll IOOo DD DD DO DD IWOODDO 5 0 0 1Onb TBS 0 14M Nad 0 01M Tri s HCl pH7 4 0 01 NaN 40n IUUUUUUUULLL 3 Q Q d 104 W V S 3000000000000000000000000000000000000 TBSI 0 0O O000000000000000000000000000 TBSO D 100m 2 UJ 20 u LU UU 10r TBS O0 O O PBSI N o Q LA o
49. 000000000000 0O00000000000000000 ut 0 ut ut DOO0O00000000000000000 DOO00000000000000000 HH 0 uin vitro in vivol l Jlll I UUDUinvitro d d t etlut a DODO 0 0 Ha Co b O00000000000000000000 O DO DD DO DD sf90 sf21 020000 a Uu o0 b 0000 UnuuuuUnnu UI 15920 0 in vitroDOO0000000000000000000000 DMEM MEM RPM 16400 000 00000000099 0 uagagmmaudddtdl 0 IT O0000000000inviv oO000000000000in vivo OO UDO DO OUOUDD 000000090099 00000000 IN UDO DO DD DOO000000000000000 B DODNWNIOOOOOOOO0O00000000000000000000000U0U0 ut I I Maeda S et al Nature 1 985 315 592 4 O000000000000000000000000000 IUUUDUUUUIUUUU I PMON5300 DT i i i i DD uu ui ui ui uanuuuuuuuunu AgrobacteriumtunefacienD O00000000000000000 I10000000 Ncotianatabacunmf 0000000000 Io 2000820 D 02 022 M et al Eur J Immunol 1994 24 131 8 16 JP 5285437 B2 2013 9 11 L3 E ELE n oa Oo L3 n n n oaa L3 n DO000000000 SDSOOOO00000000000000000000000 Antibodies A Laboratory Manual Ed Harl ow and David Lane Cold Spring Harbor Laboratory 1988 0000
50. 00000000000000000000000000000 000000000000000000000 HMB8 100000000 HMG 2 IDOOOOOO0O000000000000000000000000 HMSB 10000000000000 HMB 100000000 HMB 200000 UDDUDD 0o HMGB 1 LII TL GU LU UO UOLUIT HI IE 300000000000000000006000000000HMc U 000 20 003 lu gm O0 000000000000000 0 960 0000000000000000 10 000 0 iu Lr 37 CU 20 000 DO UUUUUUDU 2000000000000000 0 050000 0 200 Tween20 IU UO U ULutl 5 59nM ID 0 0000147 M 000000 uU gis7mMj Dn 0 0 1 2 68nM 1 000 CpH7 2 10 BSA O0 0 10m MI H E E TEE JH Hs IDD0000000 pH 2 01 ID 300p LO O O 37 C0 20 0000000000000000 Ll u UU 3 000000000000000000D0 100p L 900u LO I O UU ID 0 0 0 0 D 1000 O0 100000 UD O O 100000 ID I UU DOOOO0O0O0031IoonLI0OO0O0037CcO200000 DUOUO0O000000 UU 23 JP 5285437 B2 2013 9 11 ID002 AN D 200000000000000030BsA00D00 IMODOD IO0O0O0O000D031oouLO0O0O0037cOz2z00000000000000
51. 00000000U00 DOO000000000000000000000000000000000000U00 D HMB 10000000000000000000000000000000 IUUUDDDIUUUUUUUUI I UUUUuUDo UUUD DOOG00000000000000 00000000 0000 Ll Ll DO DO DD 00 00 PEQ Twen ll 00000 ED TAI gt uiuunuuuuuuuuunuuugnuuuuguuuuugnunuuuununu U DJ ut U UUUDUUDU ID UUD IUUD IUUD U UUUD D000D000000 D D I IUOUUD 000000 OO DD DD DO DO DPEIW O B H Ll 0 0 0 0 D 0 0 800 HCO 50 00000 0 0 HMGB 1 Ll Ll Ll IUDOO0ODOO0O0O000 UU U U IIUUUUUUUU HEH D ut D Io 0000000 II DO D 000000 UU 0000 UUUD 0000 UUUD BH UUUD U But 000000 DO OD DO 0 000 Rem ngton s Pharnaceutical Science 16th edition Oslo E d 1980 00 ID 0 00 Langer et al 1981 J Bi oned Mater Res 15 267 77 Langer 1982 Chentech 12 98 105 0 0 0 0 0O 3 773 9190 EP58 4810 Sidnan et al 1983 Bio pol ymers 22 547 56 EP133 988 I00000 I0OS0 000000000000 00000000000000000000000 DE00000000000000000000000000000000000000 17 JP 5285437 B2 2013 9 11
52. 000050 5 0 0 0 0 POQ 0000000 g9Y0 0 0 W Batall O0 0 O 30 BADO DO IO00O00000050oo00000000 300 4000000000030000011 00H L 37 C0 20 0000000 IU 6 0 o OOOO 00 00 00 DD 000 3m 2 2 0 00 00 3 00 0 6 0 0 0 0 O ABTS 50nM 000000 24nM 0 imp ng au td 1 7000 00000000000001000 DD 10H L0000000000000015 1000005ouLO6NNOOOODOD e N I m gt 415nn I I 00000000
53. 2 ELISAIOOO0000000000000000000000000000 HMB 2 HMB 1 HM 1 HMGB 2 0000000 0 D00000 ud ug 000 0 000 Io 0 HMB 1 HM 2 UUUD U UUUDUUD Bu I UUUD DJ ut UUUDUUUDOU Uu I I I UUUDUUDUUD 00000 Bu DIVEM RPM 1640 ASF O 103 I ID D gd l l in vitro I0 000 IDDU D UUUD U 0 Bub IH D 00 1 598780 00 0000 000000000000000002000000000 LIO TD Dg WD94 25585 VD93 122270 W092 039180 WD94 026020 00000 IOUOO0ODODOHMB1I0O0OO0ODHM8B IDDOOOOOODOOODOODOODOODOODOODOOO0ODD0 ugggguggaggggauauguuuuuguuudutcdseiusedgerv y Fa b Fab I Fab l 000000 diabedy DDIDDDDDUDDDDUDDDDDD scFv IlIluugnuuunuurviunuunuunuunuunuuuuunauu ugugugguggugumgugurviunuguiuuuuHiumguauugdejdaulut LIDO 11 JP 5285437 B2 2013 9 11
54. 3 9 11 I UDD 0005285437000001 app 34 JP 5285437 B2 2013 9 11 L BUBBauut 74 100119507 74 O 100142929 74 3100148699 74 100128048 74 100129506 74 100130845 74 100114340 74 100121072 2000 0 I pad UI 2000 un un Du 1000 00 00 nnuuuuuuuununununu 72 000000000 00 00 0000000000 IOD 590 DU IU O DUOOUD O DD U ED L HELLE E 000000 NN T amp al Fol e of arti nuclear arti bodi es in egperinental and clinical liver tra nspl antati ori Tanspl at Prod XI 38 N 10 p 3605 6 5S9O0 00000 14 0 0000 1 E D OOOD 1 E D EL E 000000000000000000000000000U0U00 D00000000000000000000000000000UU000
55. 93 12227 W092 03918 WO94 02602 WD94 255850 WO96 3 Ll Ll Ll D L3 L3 L3 4096 WD96 33735 o0 U I Iuuunnnu 00 0 0 0 0 0 000000000 I 0 Du Du 0 DUOUOO0O0O000000 D o IHIDUDULDOUU o IN uHiguur muudelattldu DNA DO DO U D d Du DAiUUunuuunuuuuuuuuunuugnuunuunnununD 0 o0 reshaped IIUluunnnu IO OO 0 CDRU H 0 O0 O0 O O CDRI LU D UO DULL LED D UDO DO I UuuUuuUUUUU CDRI I 0000 Ll OD framework regi on FRI HD D D D DH U DNA O O D iUIUuuuunuunguunuunuuuuuuguuuguuununu ID0OO0O0O0000PcOODODOODOODOODOODOODODOONA UU UDO Hu 0 DAIUUDUunuuuuuuuguuuPNAuUunuunD IO OO 0 14 JP 5285437 B2 2013 9 11
56. JP 5285437 B2 2013 9 11 19 JP at EB 1 5285437 P5285437 45 25 9 11 2013 9 11 24 25 8 7 2013 6 7 51 Int Cl F1 A61K 39 39 X 2006 01 A61K 39 35 ZNAN A61P 37 06 206 01 A61P 37 06 AO1N 1 8 2006 01 AOIN 1 0 DD 7 EUR 21 2008 558147 P2008 558147 i 73 598015084 86 22 HER 20 2 15 2008 2 15 86 PCT JP2008 052520 TR S HR TR ARA CER S TH 1 9201 8 W02008 099917 87 20 8 21 2008 8 21 23 2 14 2011 2 14 31 2007 34280 P2007 34280 32 19 2 15 2007 2 15 33 f t f E SR ESI JP 73 504258527 BWEBAPE RUE REEUIETSBI IH21924 5 T3 000131474 gt 5 6 7 100102978 Et Ak ME TAREA 100102118 Fer BE NX 74 100160923 fT fax PRECES 64 DE SPLHMGB 1 Bus amp te cs EP ETE ET SUR
57. NI B LU d LU UUUDUUUUDLUL KL I UIUUHUDUDUDULU DAT LU DULL ul O HMB 1 HMB 2 OOOD IOO DO OD Hu ul Ill 1 IUuuuuuuuuununuo U IDDU 20000000000000000019 Up Dat al D0O00000000 3 0 iugdgdaduuuHceigrgdsl ulutl u HNGP 1 2 LU dl H D RO6G7E10 0 0 0 0 0 HMB 10 0 HMB 20 0 ll 0000 IOD 10 0 0 19G O DO000000000002 RO6G7E10 110 0 0000 3000006 HMB 1 HMB 1 2 ut 0 u t HMB 1 U U DU ut In Uu In Uu 0 U ll nun HMGB 1 naive I0O 000000 0islet tx 0 0 HMB I D DB I d 0 Islet tx anti HVGB1 ab UU UU G 1 IFNy D CD11b utu 200004 0 HMGB 10 D 0 0 0 HMB 1 1 u g nt LH 24 D HMGB H H H H H H H H Lu g m 24 HMB 1 IN UDO OD 0 0 0 HMcB 1I000D U D UU LU ULUUHBWuL Uu U UU HMB 1 HMGB 1 LU ULULUHBWUL LU UL UU IUIUUUU uuuuauuaugnuuuugdunnugad IOO DO OD 10 20 30 40 50 6 JP 5285437 B2 2013 9 11
58. O 37 C wv FCS 30 60 PEG 1000 6000 oO 10 JP 5285437 B2 2013 9 11 O00000000000000000000000000000000000U00 O00g000000000000000000000000000000000P3 P 3x 63Ag8 653 J Inmunol 1979 123 1548 500 O P3x 63Ag8U 1 Curr Topics M crobi ol Immo 1978 81 1 7 NS Kohl er MI stein Eur J Immunol 1976 6 511 9 0 MPC 11 Margulies et al Cell 1976 8 405 15 SP2 0 Shul nan et al Nat ure 1978 276 269 700 0 FO deSt Groth et al J Immunol Methods 1980 35 1
59. O HG 10 1670 D00000000000000 180 O Lys Pro Asp Ala Al a Lys Lys G y Val Val Ly LysD UL HH B Hl D U 0 IUDUUOO0OO0O000D0 000000 UDO OO OO DO OD DO 00 PB iuyuugBpBBbBnumumuyuuguulululluililirmniultntutututututkutlutltl 40 210000000 TU U BU UUUUDOU IIUUUuuuUuunuuU I UUuuuognonon U o IIUUuUuguuUuunuuU U IOD DO DO UOOD U U gumnggmugggggmgamgmgaesr tmscdsedgrtstldeudtl Ll Ll U U U U UUDUUUuunununuu U 00000000 DOO000000000 HMB8 100001000000 HMG i OD OO 00 HM B 11 0000 o0 0 0 HMG 1 H B D U U d HMB 1 DO DO 00 M amp 1 I UIUuuUuuonnon UUUDUUDDUUD BU 000000 0 0 HMBG 1j D U JP 5285437 B2 2013 9 11 8
60. OO0OO0O0O00000000000000000000000000 IUNUUUDUUUUUUUUUUUDUUUUL UUDUU Ll Ll Ll DUOUOO0O000000000000000000 DUU UUUOOUUUUUDUUUUUUUUUUIU DUOUO0OO0O0000000 0 0 HMB 10000 D00000000000000 HMB8 200000 DUU 0000 0 0 HMGB 20 DUOOOOOOO0OO0OO0000000HMc U DO00HMB 10000000 Fernp g D HRH H HIE LEI HE DEI ON VW al Nucleic Acids Res 1989 17 1197 214 0000HMB I100000000000000000000000000000 I00000 T P Hopp et al Proc Natl Acad Sci USA 1981 78 3824 8 ID utl 3000000 0 MB 0000000000000000 0 0 He A0 0 B O M Yoshida et al J Biol Chem 1992 267 6641 S I DO 00000 00000 000 000 0000 000 0000 00 0 0 HMB 1 0 0 M 20 00000000 10 20 30 40 50 19 JP 5285437 B2 2013 9 11
61. UuuUuDo ScFM EH EH nnnn 50 12 JP 5285437 B2 2013 9 11 DOO000000000000000000000000000000000196 DO00000001g99000000U0U00O BU ut UUUDUUDUUD hybrid hybri dona quadr ona MI stein C et a 1983 Nature 305 537 400000000019q900000000L000HODO ID4uuuuuuuuuou DU ut UUUDUUDDUUD igugggugamgagaHiuges uaduguauguududcidcdsteltHelutcttHIi ugggumguuguuuuust seadi UD 0000 Uu Ri dgwey JB et al 1996 Protein Engineering 9 617 21 Merchant AM et al 1998 Nat Biotech 16 6
62. amgygpBugmputlsb ut Hu U 0 iniuuuiuuuuuuuununnnnunnonu DO ID naked O00000000000000000000000000000 LU dl HMODOOODOOD 0000 0 000000000 0 Adol ph 00000 CRC Pr ess Florid 1996 W093 17706 0000 00 O00000000000000 ex vivo ug 4 945 0500 OD 000 000 000000 0000 Du H Hu I Iulunnnnu 0 Du HMGB 1 iuggHMiggugguuguutdseurctstl ed t iiuuuuuuuuuuunnnuuguuuuuuuunnnnnnnonu Uu ulbuuttiuliltiiu iiutiuiulliuliuililiuiulkitl Ill Iiugnuuugnuuurmciuuiuuuuuunuunuunuunou o 001 u g m0 1000ng mi 0 0 I UU 9 11 mt 100 om U i ii i ii uu uu uu ui U UU o0 ininuuuuuuuuununwD In Lu LU ULULHBUYBULBtULHBLEUUL It Du 00000 Hu Du 0 iinuuuuuuuuununno U UDO OD o0 U iinuuuuuuuuununo In Lu HMGB 1 I UIUUHUUUUUDU In Lu UUUUO UUOUUOUULULUD u a OHMB 10000000000000000 b O000000000000000000000 DHMB 10000000000HMB100000000000000000000U00 18 JP 5285437 B2 2013 9 11
63. een20 ugamaudtldtl 5 59M O00 DD uu IIu Gi uu 00 1 47M 000000 137nM O0 0002 68M 00 00 00000 000 0 pH7 2 u t 10 BSAU 0 01 OM DODODODOOOODODODOOO0O 0OOOOOODOOODOO0OOOO0ODO0O CH203I0000D030oonL0D0 37 CU 20 0000000000000000 Uu U 3 30 DD DD DO DD DD DO DOO DO DD DD 100p L 900p LA 1 O IT I 0 0 DO 1000 0 100000 I O O O 100000 U Uu ll 1 O 100u Lr D fr 37CI 20 000 IUD U 3 ID DD OD OD 000 3 2 U DE 0 0 0 0 0 00 10 BSA i 0 0 1M I 1 O 100u Lr Dn fr 37 C0 20 000000000 I UuUuUuUUDU 3 50 000000 0 0 P 0 U 19YO O Up Deta I 30 BSA U UU 0 0 O 50000 Un U 3 30 0 3 4 H H H BH LU 0 0100 100u LO 0 O0 O O 37 C0 200000000000000 3 60 0000000000000000 00000 00 0 3 2 2 00 3 24 JP 5285437 B2 2013 9 11 8 2 u 3 IO00000 Z00O0000000000000090 24nM 100 LOO 00000000000 0 150 00 100 IO 1 150p LO 6N I EH EH DI 1 DI 415nn DI 40 0 220000000000000000000000000000000 O0000000000 Ig9 0000 5 0 0 1Onb TBS 0 14M Nad 0 01M Tri s HCl pH7 4 0 01 aN 40n IUUUUUUULLL
64. o E L e ES Cr Ne T oa i Er N m JP 5285437 B2 2013 9 11 9 10 O ngi 0 1u g0 O BALB c 5ng UU UU O O n oO UU ELI SA 20 30 5 20 6 O O 1981 73 3 460 Methods Enzynol MI stein 1 2 0 lu g PBS Kohl er 30 O RPM 1640 HOD 10 10 PE 40 O O HAT
65. t 50000 0 U LO O 0 0 0O 37 C02 ID 3nM 2 2 000 00 3 00000 ABTS 500 Mi DDDDDDD0D D 24M 1 100000000 100000 100 50 001 0 O 150 LO eNj 0000 0 30 IDO0O000000000000415nnmD0D 0 0 0 DU 00 X63 Ag8 UID I 0000000000000 90850000 RPM 16 0000 0000000000 U 002oom000000000000080 000 40 2000 0 0 RPM 16400 0 0 0 0000 ID DD 20 P3 X63 Ag8 U10 10000 000000000000000050000 RPM 1640 50000 10050 D 0 000000 00s 000000 00 50 27 JP 5285437 B2 2013 9 11 uu 000000000000000 800000000 37 co 0000 IA o L3 L3 O T 0 0O1nM 1 I L1 D 1 DU l 10 14 HMGB 1 O EIST UUUUDUUUUDDUDUDDD ELSA DO 1 1 O00000000000 HMB I000000000001 1 ELI SAT
66. uiuuuunuunuunguunguunuuunuuuuuuguuuou 20 Fos 000000000000 Far DJun0000000000000Fab gu ft DO U DE DD 00 DD Fab Fosl Fab jung O0000000000 F ab O0 00000 0 Kostelny SA et al 1992 J munol 148 1547 5350 0000000 Fa 000000000000 sco FvIDDUDUDUDODU OO0O000000000000000000000U0U0000U00 cross over scFv DOO0O0000000000000000000A BIUD VD VOSOGOO0000000000000000000000000V A V B V4CB vilggugaaguasuagagugugagaagagugaumuamuduatututeiutrteHelliger 30 P et al 1993 Proc Natl Acad Sci USA 90 6444 80 Uu t IOOODODOSscFvO 1500000000000000000000 0000000 Ki pri yanov SM et al 1999 J Mil Biol 293 41 56 0 000000000 kno bs i nto hol es Zhu Z et al 1997 Protein Sci 6 781988 I Ii IIu iU uu uu u IO00000000000 scFrvd 15000000000000000000 I000000scFv 00000000000000 Mllender VD et al 1994 J Biol Chem 269 199 2061 40 Du U U Hu U iinuuuuuuuuunno U 0 o0 ininuuuuuuuuununo Vandanme et al Eur J Bio chem 1990 192 767 750 000000000000000000000000000 NRNA 10 000 0 amp irgwn et al Biochemstry 1979 18 5294 90 0 AGPQ O Chonvzynski et al Anal Biochem 1987 162 156 9 RNAI O0 0 0 O O O mRNA Pu rification Kit Pharmacia nNnRNA 000000000 qi ckP rep mRNA Purification Kit Pharracia 0000000000 RI II I UU ui au Il mRNA UI UUDUDUUU DD UDDUnRAJDUUDUUDDUadD 50 13 JP 5285437 B2 2013 9
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