CN112969719B - 双功能融合蛋白及其医药用途 - Google Patents

双功能融合蛋白及其医药用途 Download PDF

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CN112969719B
CN112969719B CN202080005976.1A CN202080005976A CN112969719B CN 112969719 B CN112969719 B CN 112969719B CN 202080005976 A CN202080005976 A CN 202080005976A CN 112969719 B CN112969719 B CN 112969719B
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顾晓玲
叶鑫
胡兵
葛虎
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Abstract

涉及双功能融合蛋白及其医药用途。具体地，涉及一种包含SIRPγ肽变体和抗人PD‑L1抗体的双功能融合蛋白、SIRPγ肽变体以及其医药用途。根据双功能融合蛋白能够特异性结合PD‑L1和CD47，来阻断PD‑L1或CD47与其受体或配体的结合。同时，还提供所述双功能融合蛋白的制备、应用及癌症和免疫相关疾病的治疗。

Description

双功能融合蛋白及其医药用途
技术领域
本公开涉及一种特异性结合PD-L1和CD47的双功能融合蛋白、包含所述双功能融合蛋白的药物组合物，以及其作为抗癌药物的用途。
背景技术
这里的陈述仅提供与本公开有关的背景信息，而不必然地构成现有技术。
程序性死亡分子1(programmed death-l，PD-l)是1992年发现的表达在T细胞表面的一个蛋白受体，参与细胞的凋亡过程。PD-l属于CD28家族，与细胞毒性T淋巴细胞抗原4(cytotoxic T Iymphocyte antigen 4，CTLA-4)具有23％的氨基酸同源性，但其表达却与CTLA-4不同，主要表达在活化的T细胞、B细胞和髓系细胞上。PD-1有两个配体，分别为PD-L1和PD-L2。PD-L1的主要表达于T细胞、B细胞、巨噬细胞和树突状细胞(dendritic cell，DC)上，在活化后细胞上的表达能够进行上调。而PD-L2的表达相对较局限，主要表达在抗原呈递细胞上，如活化的巨噬细胞和树突状细胞。
新的研究发现乳腺癌、肺癌、胃癌、肠癌、肾癌、黑素瘤等人类肿瘤组织中检测到高PD-L1蛋白的表达，且PD-L1的表达水平和患者的临床及预后紧密相关。由于PD-L1起到着第二信号通路抑制T细胞增殖的作用，所以阻断PD-L1/PD-1之间结合成为了肿瘤免疫治疗领域一个非常有潜力的新兴靶点。
细胞表面蛋白CD47在许多肿瘤类型上表达或过度表达，包括急性骨髓性白血病，B细胞非霍奇金淋巴瘤的多种亚型，以及许多人类实体瘤细胞。CD47与巨噬细胞上的信号调节蛋白α(SIRPα)结合，是肿瘤细胞表面的“不吃我”信号。最近的数据表明抗CD47抗体也有助于提高免疫耐受性小鼠中有效的抗肿瘤T细胞应答。因此，抗CD47抗体是调节先天免疫***和适应性免疫***的新一类免疫检查点抑制剂。
目前已有相关的CD47专利，如WO2016065329、WO2016109415、WO2014087248、WO2014093678、CN107849143A、CN108350048、CN106535914、WO2016023001A、CN107459578A、CN2017110167989等。例如，WO2016023001A中描述了包含高亲和性PD-1模拟肽和特异性结合CD47的高亲和性SIRP-α的多特异性PD-1模拟肽及其用途；CN107459578A中描述了一种包含SIRPα突变体和抗PD-L1抗体的靶向CD47分子与PD-L1分子的重组融合蛋白；CN201711016798.9公开了包含SIRPα的胞外部分和PD-1的胞外部分的多功能融合蛋白。
然而，目前临床前和临床研究许多疗法是针对CD47/SIRPα相互作用的，包括抗CD47抗体、SIRPα受体蛋白和工程SIRPα受体蛋白、抗SIRPα抗体和双特异性抗体等，并没有关于包含SIRPγ肽的多特异性融合蛋白的相关报道。
SIRPγ在T细胞和活化的NK细胞上表达，并且与SIRPα相比，SIRPγ以低10倍的亲和力结合CD47。CD47-SIRPγ相互作用参与抗原呈递细胞与T细胞之间的接触，共刺激T细胞活化并促进T细胞增殖(Piccio等人，Blood 2005，105，2421-2427)。此外，CD47-SIRPγ相互作用在T细胞的跨内皮迁移中发挥作用(Stefanisakis等人，Blood 2008，112，1280-1289)。
发明内容
本公开提供了包含SIRPγ肽变体的双功能融合蛋白。其中SIRPγ肽变体相较于野生型SIRPγ肽具有显著大幅提高的CD47亲和活性。
在一些实施方案中，提供一种双功能融合蛋白，所述双功能融合蛋白包含SIRPγ肽变体和抗人PD-L1抗体，所述SIRPγ肽变体连接至所述抗人PD-L1抗体的多肽链，
所述SIRPγ肽变体是在相当于如SEQ ID NO：20所示的野生型SIRPγ肽的N51位具有替代突变的SIRPγ肽变体。在一些实施方案中，如前所述的SIRPγ肽变体具有结合肿瘤细胞表面CD47的活性，优选地，所述SIRPγ肽变体具有较野生型SIRPγ肽增强地结合肿瘤细胞表面CD47的活性。
在一些实施方案中，提供一种双功能融合蛋白，所述双功能融合蛋白包含人SIRPγ肽变体和抗人PD-L1抗体，所述SIRPγ肽变体连接至所述抗人PD-L1抗体的多肽链，
所述SIRPγ肽变体是在如SEQ ID NO：20所示的野生型SIRPγ肽的N51位具有替代突变的SIRPγ肽变体。在一些实施方案中，如前所述SIRPγ肽变体具有结合肿瘤细胞表面CD47的活性，优选地，所述SIRPγ肽变体具有较野生型SIRPγ肽增强地结合肿瘤细胞表面CD47的活性。在一些实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体与所述抗人PD-L1抗体的多肽链之间由肽键直接连接或通过连接子共价连接。优选地连接子可选自SEQ ID NO：89-96和(GGGGS)n、(GGGES)n和(GKPGS)n，其中n＝2-7的整数中任一所示的连接子。
在一些实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体的羧基端与所述抗人PD-L1抗体的重链可变区的氨基端连接，
或所述SIRPγ肽变体的羧基端与所述抗人PD-L1抗体的轻链可变区的氨基端连接，
或所述抗人PD-L1抗体的重链的羧基端与所述SIRPγ肽变体的氨基端连接，
或所述抗人PD-L1抗体的轻链的羧基端与所述SIRPγ肽变体的氨基端连接。
在一些优选的实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体是相对于所述野生型SIRPγ肽进一步地在K19、K53、N101、L31、Q52、E54、H56、N70、M72和M112中的一个或更多个位点具有氨基酸替代的SIRPγ肽变体。
在一些优选的实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体是相对于所述野生型SIRPγ肽进一步地在K19、K53和N101中的一个或更多个位点具有氨基酸替代的SIRPγ肽变体。
在一些优选的实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体是相对于如SEQ ID NO：20所示的野生型SIRPγ肽具有N51R替代突变的SIRPγ肽变体。
在一些优选的实施方案中，如前所述双功能融合蛋白，其中所述N51位具有替代突变的SIRPγ肽变体基本不结合红细胞表面的CD47，优选地，所述N51位具有替代突变的SIRPγ肽变体是具有N51F、N51I、N51L、N51M或N51V替代突变的SIRPγ肽变体。
在一些优选的实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体相对于如SEQ ID NO：20所示的野生型SIRPγ肽是进一步地具有K19E、K53G和N101D替代突变的SIRPγ肽变体。
在一些优选的实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体相对于如SEQ ID NO：20所示的野生型SIRPγ肽具有K19E、N51V、Q52S、K53G、E54R、M72K和N101D突变。
在一些优选的实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体相对于如SEQ ID NO：20所示的野生型SIRPγ肽具有K19E、N51M、Q52S、K53G、E54R、M72K和N101D突变。
在一些优选的实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体是进一步地在M6、V27、L30、V33、V36、L37、V42、E47、L66、T67、V92或S98的一个或更多个位点具有氨基酸替代的SIRPγ肽变体。
在一些优选的实施方案中，如前所述的双功能融合蛋白，其中所述SIRPγ肽变体的氨基酸序列(通式I)如SEQ ID NO：1所示：
EEELQMIQPE KLLLVTVGET ATLHCTVTSL X1PVGPVLWFR GVGPGRELIY X2X3GX4GX5FPRVTTVSDLTKRX6 NX7DFSIRISS ITPADVGTYY CVKFRKGSPE DVEFKSGPGT EX8ALGAKPS(SEQ ID NO：1)
其中，X1选自L或W，X2选自M、V、F、I或L，X3选自Q、S或T，X4选自E、T或R，X5选自H或R，X6选自D、N或E，X7选自I、V、M、R或K，和X8选自M或V。
在一些实施方案中，如前所述双功能融合蛋白，所述SIRPγ肽变体的氨基酸序列(通式II)如SEQ ID NO：2所示：
EEELQMIQPE KLLLVTVGET ATLHCTVTSL X1PVGPVLWFR GVGPGRELIY RX3GX4GX5FPRVTTVSDLTKRX6 NX7DFSIRISS ITPADVGTYY CVKFRKGSPE DVEFKSGPGT EX8ALGAKPS(SEQ ID NO：2)
其中，X1选自L或W，X3选自Q、S或T，X4选自E、T或R，X5选自H或R，X6选自D、N或E，X7选自I、V、M、R或K，和X8选自M或V。
在进一步优选的实施方案中，如前所述双功能融合蛋白，其中所述SIRPγ肽变体如SEQ ID NO：21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40所示，优选如26或27所示。
在一些实施方案中，如前所述双功能融合蛋白，其中所述抗人PD-L1抗体选自Avelumab、Atezolizumab、Durvalumab、JS-003、CS-1001、LY-3300054、KD-033、CK-301、CCX-4503、CX-072、KN-035、HRP00052、HRP00049、FAZ-053、GR-1405、KD-005、HLX-20、KL-A167、CBT-502、STI-A1014、REMD-290、BGB-A333、BCD-135和MCLA-145。
在一些实施方案中，如前所述双功能融合蛋白，其中所述抗人PD-L1抗体包含重链可变区和轻链可变区，其中：
所述重链可变区包含与SEQ ID NO：6所示重链可变区具有相同序列的HCDR1、HCDR2和HCDR3区，和所述轻链可变区包含与SEQ ID NO：7所示轻链可变区具有相同序列的LCDR1、LCDR2和LCDR3区；或
所述重链可变区包含与SEQ ID NO：8所示重链可变区具有相同序列的HCDR1、HCDR2和HCDR3区，和所述轻链可变区包含与SEQ ID NO：9所示轻链可变区具有相同序列的LCDR1、LCDR2和LCDR3区；或
所述重链可变区包含与SEQ ID NO：8所示重链可变区具有相同序列的HCDR1、HCDR2和HCDR3区，和所述轻链可变区包含与SEQ ID NO：113所示轻链可变区具有相同序列的LCDR1、LCDR2和LCDR3区。更进一步地，在一些实施方案中，所述HCDR1、HCDR2和HCDR3区和LCDR1、LCDR2和LCDR3区是kabat编号规则定义的。
在一些实施方案中，如前所述双功能融合蛋白，所述抗人PD-L1抗体重链可变区分别包含如SEQ ID NO：97、98和99所示的HCDR1、HCDR2和HCDR3区和所述抗人PD-L1抗体轻链可变区分别包含如SEQ ID NO：100、101和102所示的LCDR1、LCDR2和LCDR3区，或
所述抗人PD-L1抗体重链可变区分别包含如SEQ ID NO：103、104和105所示的HCDR1、HCDR2和HCDR3区和所述抗人PD-L1抗体轻链可变区分别包含如SEQ ID NO：106、107和108所示的LCDR1、LCDR2和LCDR3区；
或所述抗人PD-L1抗体重链可变区分别包含如SEQ ID NO：103、104和105所示的HCDR1、HCDR2和HCDR3区和所述抗人PD-L1抗体轻链可变区分别包含如SEQ ID NO：106、112和108所示的LCDR1、LCDR2和LCDR3区。
在一些实施方案中，如前所述双功能融合蛋白，所述的抗人PD-L1抗体包含重链可变区和轻链可变区，其中：
所述重链可变区为SEQ ID NO：6所示，和所述轻链可变区为SEQ ID NO：7所示；或
所述重链可变区为SEQ ID NO：8所示，和所述轻链可变区为SEQ ID NO：113所示；
或
所述重链可变区为SEQ ID NO：8所示，和所述轻链可变区为SEQ ID NO：9所示。
在一些实施方案中，如前所述双功能融合蛋白，其中所述抗人PD-L1抗体还包括重链恒定区和轻链恒定区，优选地，所述重链恒定区如SEQ ID NO：10或11所示，所述轻链恒定区如SEQ ID NO：12所示。
在一些实施方案中，如前所述双功能融合蛋白，其中所述抗人PD-L1抗体包含重链和轻链，其中：所述重链如SEQ ID NO：13或15所示，所述轻链如SEQ ID NO：14所示；或
所述重链如SEQ ID NO：16或18所示，所述轻链如SEQ ID NO：17所示；或
所述重链如SEQ ID NO：16或18所示，所述轻链如SEQ ID NO：111所示。
在一些实施方案中，如前所述双功能融合蛋白，其中所述双功能融合蛋白具有第一多肽和第二多肽，其中：
所述第一多肽选自如SEQ ID NO：41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61和62任一所示的多肽，和所述第二多肽选自如SEQ ID NO：14所示的多肽；或
所述第一多肽选自如SEQ ID NO：63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82和109任一所示的多肽，和所述第二多肽选自如SEQ ID NO：17所示的多肽；或
所述第一多肽选自如SEQ ID NO：63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82和109中任一所示的多肽，和所述第二多肽选自如SEQ ID NO：111所示的多肽。
在本公开的另一些实施方案，提供一种SIRPγ肽变体，所述SIRPγ肽变体是在相当于如SEQ ID NO：20所示的野生型SIRPγ肽的N51位具有替代突变的SIRPγ肽变体。在一些实施方案中，如前所述SIRPγ肽变体具有结合肿瘤细胞表面CD47的活性，优选地，所述SIRPγ肽变体具有较野生型SIRPγ肽增强地结合肿瘤细胞表面CD47的活性。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述SIRPγ肽变体是相对于所述野生型SIRPγ肽在K19、K53、N101、L31、Q52、E54、H56、N70、M72和M112中的一个或多个位点具有氨基酸替代的SIRPγ肽变体。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述SIRPγ肽变体是相对于所述野生型SIRPγ肽在K19、K53和N101中的一个或多个位点具有氨基酸替代的SIRPγ肽变体。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述SIRPγ肽变体是相对于如SEQ ID NO：20所示的野生型SIRPγ肽具有N51R替代突变的SIRPγ肽变体。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述N51位替代突变的SIRPγ肽变体基本不结合红细胞表面的CD47，优选地，所述具有N51位替代突变的SIRPγ肽变体是具有N51F、N51I、N51L、N51M或N51V替代突变的SIRPγ肽变体。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述SIRPγ肽变体是相对于如SEQ ID NO：20所示的野生型SIRPγ具有K19E、K53G和N101D替代突变的SIRPγ肽变体。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述SIRPγ肽相对于如SEQ ID NO：20所示的野生型SIRPγ肽具有K19E、N51V、Q52S、K53G、E54R、M72K和N101D突变。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述SIRPγ肽相对于如SEQ ID NO：20所示的野生型SIRPγ肽具有K19E、N51M、Q52S、K53G、E54R、M72K和N101D突变。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述SIRPγ肽变体是进一步地在M6、V27、L30、V33、V36、L37、V42、E47、L66、T67、V92或S98的一个或更多个位点具有氨基酸替代的SIRPγ肽变体。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述SIRPγ肽变体如SEQ ID NO：1所示，
EEELQMIQPE KLLLVTVGET ATLHCTVTSL X1PVGPVLWFR GVGPGRELIY X2X3GX4GX5FPRVTTVSDLTKRX6 NX7DFSIRISS ITPADVGTYY CVKFRKGSPE DVEFKSGPGT EX8ALGAKPS(SEQ ID NO：1)
其中，X1选自L或W，X2选自M、V、F、I或L，X3选自Q、S或T，X4选自E、T或R，X5选自H或R，X6选自D、N或E，X7选自I、V、M、R或K，和X8选自M或V。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，所述SIRPγ肽变体如SEQID NO：2所示：
EEELQMIQPE KLLLVTVGET ATLHCTVTSL X1PVGPVLWFR GVGPGRELIY RX3GX4GX5FPRVTTVSDLTKRX6 NX7DFSIRISS ITPADVGTYY CVKFRKGSPE DVEFKSGPGT EX8ALGAKPS(SEQ ID NO：2)
其中，X1选自L或W，X3选自Q、S或T，X4选自E、T或R，X5选自H或R，X6选自D、N或E，X7选自I、V、M、R或K，和X8选自M或V。
在一些优选的实施方案中，如前所述的SIRPγ肽变体，其中所述SIRPγ肽变体如SEQ ID NO：21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40所示。
本公开另一些方面还提供一种融合蛋白，包含SIRPγ肽变体和抗体Fc片段，所述SIRPγ肽变体为前述任一项所述的SIRPγ肽变体；在一些实施方案中，所述抗体Fc片段为人抗体Fc片段；在一些优选的实施方案中，所述抗体Fc片段序列与SEQ ID NO：10或11所示的重链恒定区中的Fc片段序列相同；在一些优选的实施方案中，所述融合蛋白的氨基酸序列如SEQ ID NO：86、110、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130或131所示。
本公开另一些方面还提供一种抗人PD-L1抗体，其包含抗体的轻链可变区和重链可变区，所述重链可变区包含序列分别如SEQ ID NO：103、104和105所示的HCDR1、HCDR2和HCDR3区，和所述轻链可变区包含序列分别如SEQ ID NO：106、112和108所示的LCDR1、LCDR2和LCDR3区。
在一些实施方案中，如前所述的抗人PD-L1抗体，所述重链可变区为SEQ ID NO：8所示，和所述轻链可变区为SEQ ID NO：113所示。
在一些实施方案中，如前所述的抗人PD-L1抗体，所述抗人PD-L1抗体为全长抗体，进一步包括抗体恒定区，优选地，所述抗体的重链恒定区选自人IgG1、IgG2、IgG3和IgG4恒定区，所述抗体的轻链恒定区选自人抗体κ和λ链恒定区，更优选所述全长抗体包含SEQ IDNO：10或11所示的重链恒定区和SEQ ID NO：12所示的轻链恒定区。
在一些优选的实施方案中，如前所述的抗人PD-L1抗体，所述抗体包含如SEQ IDNO：16或18所示的重链，和如SEQ ID NO：111所示的轻链。
在另一些方面，本公开还提供一种药物组合物，其含有治疗有效量的根据如前所述的双功能融合蛋白，或如前所述的SIRPγ肽变体，或如前所述的融合蛋白，或如前所述的抗人PD-L1抗体，以及一种或多种药学上可接受的载体、稀释剂、缓冲剂或赋形剂。在一些实施方案中，所述治疗有效量为单位剂量的组合物中含有0.1-3000mg的如前所述的双功能融合蛋白，或根据如前所述的SIRPγ肽变体，或根据如前所述的融合蛋白，或根据如前所述的抗人PD-L1抗体。
在另一些方面，本公开还提供一种分离的核酸分子，其编码如前所述的双功能融合蛋白，或编码如前所述的SIRPγ肽变体。
在另一些方面，本公开还提供一种分离的核酸分子，其编码如前所述的抗人PD-L1抗体。
在另一些方面，本公开还提供一种重组载体，其包含如前所述的分离的核酸分子。
在另一些方面，本公开还提供一种用根据如前所述的重组载体转化的宿主细胞，所述宿主细胞选自原核细胞和真核细胞，优选为真核细胞，更优选哺乳动物细胞或昆虫细胞。
在另一些方面，本公开还提供用于生产如前所述的双功能融合蛋白，或生产根据如前所述的SIRPγ肽变体的方法，或生产根据如前所述的融合蛋白，或生产根据如前所述的抗人PD-L1抗体的方法，所述方法包括将如前所述的宿主细胞在培养基中进行培养以形成并积累如前所述的双功能融合蛋白，或根据如前所述的SIRPγ肽变体，以及从培养物回收所述双功能融合蛋白或SIRPγ肽变体，或根据如前所述的融合蛋白，或根据如前所述的抗人PD-L1抗体。
在另一些方面，本公开还提供一种消除受试者免疫抑制相关疾病的方法，所述方法包括向受试者施用治疗有效量的如前所述的双功能融合蛋白，或根据如前所述的SIRPγ肽变体，或根据如前所述的融合蛋白，或根据如前所述的抗人PD-L1抗体，或如前所述的药物组合物，或如前所述的分离的核酸分子，优选地，所述治疗有效量为单位剂量的组合物中含有0.1-3000mg的如前所述的双功能融合蛋白，或根据如前所述的SIRPγ肽变体，或根据如前所述的抗人PD-L1抗体。
在一些实施方案中，在单次或累积的施加中向个体施用约10μg/kg、约50μg/kg、约100μg/kg、约200μg/kg、约300μg/kg、约400μg/kg、约500μg/kg、约600μg/kg、约700μg/kg、约800μg/kg、约900μg/kg、约1000g/kg、约1100g/kg、1200g/kg、1300g/kg、1400g/kg、1500g/kg、1600g/kg、1700g/kg、1800g/kg、1900g/kg、约2000g/kg、约3000g/kg、约4000g/kg、约5000g/kg、约6000g/kg、约7000g/kg、约8000g/kg、约9000g/kg、约10mg/kg、约20mg/kg、约30mg/kg、约40mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约200mg/kg、约300mg/kg、约400mg/kg、约500mg/kg、约600mg/kg、约700mg/kg、约800mg/kg、约900mg/kg或约1000mg/kg剂量的本公开所述的PD-L1-CD47双功能融合蛋白、SIRPγ变体肽、或根据如前所述的融合蛋白，或根据如前所述的抗人PD-L1抗体。
在另一些方面，本公开还提供利用如前所述的双功能融合蛋白，或根据如前所述的SIRPγ肽变体，或根据如前所述的融合蛋白，或根据如前所述的抗人PD-L1抗体，或如前所述的药物组合物，或如前所述的分离的核酸分子制备消除受试者免疫抑制相关疾病的药物中的用途，优选地，所述药物的单位剂量的组合物中含有0.1-3000mg的如前所述的双功能融合蛋白，或如前所述的SIRPγ肽变体，或如前所述的抗人PD-L1抗体。
在另一些方面，本公开还提供一种用作消除受试者免疫抑制相关疾病的药物的如前所述的双功能融合蛋白，或如前所述的SIRPγ肽变体，或根据如前所述的融合蛋白，或根据如前所述的抗人PD-L1抗体，或如前所述的药物组合物，或如前所述的分离的核酸分子，优选地，所述药物单位剂量的组合物中含有0.1-3000mg的如前所述的双功能融合蛋白，或如前所述的SIRPγ肽变体，或如前所述的抗人PD-L1抗体。
在另一方面，本公开还提供一种用作药物的如前所述的双功能融合蛋白，或如前所述的SIRPγ肽变体，或根据如前所述的融合蛋白，或根据如前所述的抗人PD-L1抗体，或如前所述的药物组合物，或如前所述的分离的核酸分子，优选地，所述药物单位剂量的组合物中含有0.1-3000mg的如前所述的双功能融合蛋白，或如前所述的SIRPγ肽变体，或如前所述的抗人PD-L1抗体。
在一些实施方案中，如前所述的消除受试者免疫抑制相关疾病包括癌症、细菌或病毒感染。所述癌症包括但不限于癌瘤，淋巴瘤，胚细胞瘤(blastoma)，肉瘤，和白血病或淋巴样恶性。这种癌症的更具体的例子包括鳞状细胞癌、骨髓瘤、小细胞肺癌、非小细胞肺癌(NSCLC)、头和颈鳞状细胞癌(HNSCC)、神经胶质瘤、何杰金淋巴瘤、非何杰金淋巴瘤、弥漫性大B-细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤、急性成淋巴细胞性白血病(ALL)、急性髓细胞样白血病(AML)、慢性淋巴细胞性白血病(CLL)、慢性髓细胞样白血病(CML)、原发性纵隔大B-细胞淋巴瘤、套细胞淋巴瘤(MCL)、小淋巴细胞性淋巴瘤(SLL)、富含T-细胞/组织细胞的大B-细胞淋巴瘤、多发性骨髓瘤、髓样细胞白血病-1蛋白(Mcl-1)、骨髓异常增生综合征(MDS)、胃肠(道)癌、肾癌、卵巢癌、肝癌、成淋巴细胞性白血病、淋巴细胞白血病、结肠直肠癌、子宫内膜癌、***癌、甲状腺癌、黑素瘤、软骨肉瘤、神经母细胞瘤、胰腺癌、多形性成胶质细胞瘤、胃癌、骨癌、尤因氏肉瘤、子***、脑癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、肝细胞癌(HCC)、透明细胞肾细胞癌(RCC)、头和颈癌、咽喉癌、肝胆癌(hepatobiliary cancer)、中枢神经***癌、食管癌、恶性胸膜间皮瘤、全身性轻链淀粉样变性、淋巴浆细胞性淋巴瘤(lymphoplasmacytic lymphoma)、骨髓异常增生综合征、骨髓增生性肿瘤、神经内分泌肿瘤、梅克尔细胞癌、睾丸癌和皮肤癌。
附图说明
图1：部分实施方案中的PD-L1-CD47双功能融合蛋白结构示意图。
图2A-图2C：PD-L1-CD47双功能融合蛋白与人红细胞表面CD47的结合能力测试，最右侧阴性对照(control)均为细胞+二抗。图2A和图2B为不同PD-L1-CD47双功能融合蛋白(10μg/ml)与红细胞表面CD47的结合能力测试；图2C为不同PD-L1-CD47双功能融合蛋白(10μg/ml和1μg/ml)与红细胞表面CD47的结合能力测试。
图3：PD-L1-CD47双功能融合蛋白与Raji细胞表面CD47的结合能力测试，最右侧阴性对照为细胞+二抗。
图4：PD-L1-CD47双功能融合蛋白介导的红细胞吞噬作用。
图5A-图5B：PD-L1-CD47双功能融合蛋白介导的肿瘤细胞(Molp-8细胞)的吞噬作用。图5A和图5B为不同批次试验检测的不同PD-L1-CD47双功能融合蛋白介导的肿瘤细胞的吞噬作用。
图6：PD-L1-CD47双功能融合蛋白介导的红细胞凝结作用。
图7A-图7E：PD-L1-CD47双功能融合蛋白介导的IFN-γ的分泌作用。图7A、图7B、图7C、图7D和图7E为不同PD-L1-CD47双功能融合蛋白在介导IFN-γ的分泌作用的结果。
图8：不同PD-L1-CD47双功能融合蛋白对B-hCD274/hCD47/hSIRPα小鼠移植瘤MC38/H-11-hCD47(#5-4)模型肿瘤体积的影响。
图9：不同PD-L1-CD47双功能融合蛋白对C57/BL-6小鼠移植瘤MC38-hPD-L1-hCD47模型肿瘤体积的影响。
图10：不同PD-L1-CD47双功能融合蛋白对C57/BL-6小鼠移植瘤MC38-hPD-L1模型肿瘤体积的影响。
图11：不同PD-L1-CD47双功能融合蛋白对Molp-8荷瘤裸鼠体内模型肿瘤体积的影响。该模型重点考察双功能融合蛋白中CD47靶点通路的抑瘤作用。
具体实施方式
术语
本公开所用氨基酸三字母代码和单字母代码如J.biol.chem，243，p3558(1968)中所述。
术语“双功能融合蛋白”指能够与两个目标蛋白或目标抗原结合的蛋白分子，在本公开双功能融合蛋白主要包含能够结合细胞表面的PD-L1和CD47，其由抗PD-L1抗体和SIRPγ多肽变体连接融合后形成的蛋白。
术语“PD-L1”是指程序性死亡配体1，也称为CD274或B7H1。人全长PD-L1的氨基酸序列在GenBank中以登录号NP_054862.1提供。除非指定来自非人物种，否则术语“PD-L1”意指人PD-L1。
抗人PD-L1抗体指能够结合人PD-L1，并且能够阻断PD-1与PD-L1的结合的抗体。抗人PD-L1抗体可选自Avelumab、Atezolizumab、Durvalumab、JS-003、CS-1001、LY-3300054、KD-033、CK-301、CCX-4503、CX-072、KN-035、HRP00052、HRP00049、FAZ-053、GR-1405、KD-005、HLX-20、KL-A167、CBT-502、STI-A1014、REMD-290、BGB-A333、BCD-135、MCLA-145等。除此之外，本公开中的抗人PD-L1抗体还可选自全长抗体h1830、h1831或分别与h1830、h1831抗体具有相同CDR组合的抗PD-L1抗体或其抗原结合片段。
“SIRPγ肽”指人SIRPγ-D1结构域肽(其野生型SIRPγ肽的氨基酸序列如SEQ IDNO：20所示)，其具有结合人CD47的活性。SIRPγ肽还可以包括人SIRPγ-D1结构域肽突变体，或称“SIRPγ肽变体”，所述SIRPγ肽变体在相当于野生型SIRPγ肽的一个或更多个位点具有氨基酸替代，所述氨基酸替代突变数量至多不超过20个、19个、18个、17个、16个、15个、14个、13个、12个、11个、10个、9个、8个、7个、6个、5个、4个、3个，2个，所述SIRPγ肽变体相对于野生型SIRPγ肽具有增强的结合肿瘤细胞表面CD47的活性(野生型SIRPγ结合CD47的亲和活性为微摩尔级)。进一步地，在一些具体实施方案中，所述SIRPγ肽变体获得不结合或(相对于肿瘤细胞表面CD47结合活性)降低结合人红细胞表面CD47的特性。如下表1所示，如S58肽是在相当于SEQ ID NO：20所示的野生型SIRPγ肽的K19位进行K19E，N51位进行N51M，Q52位进行Q52S，K53位进行K53G，E54位进行E54R，N101位进行N101D的替代突变体。
在一些具体实施方案中，所述氨基酸替代突变的可选位点可以包括K19、K53、N101、L31、N51、Q52、E54、H56、N70、M72、M112、M6、V27、L30、V33、V36、L37、V42、E47、L66、T67、V92或S98中的一个或更多个进行氨基酸替代突变。
在一些具体实施方案中，SIRPγ肽变体如SEQ ID NO：1所示：
EEELQMIQPE KLLLVTVGET ATLHCTVTSL X1PVGPVLWFR GVGPGRELIY X2X3GX4GX5FPRVTTVSDLTKRX6 NX7DFSIRISS ITPADVGTYY CVKFRKGSPE DVEFKSGPGT EX8ALGAKPS(SEQ ID NO：1)
其中，X1选自L或W，X2选自M、V、F、I或L，X3选自Q、S或T，X4选自E、T或R，X5选自H或R，X6选自D、N或E，X7选自I、V、M、R或K，和X8选自M或V。
在一些具体实施方案中，SIRPγ肽变体如SEQ ID NO：2所示：
EEELQMIQPE KLLLVTVGET ATLHCTVTSL X1PVGPVLWFR GVGPGRELIY RX3GX4GX5FPRVTTVSDLTKRX6 NX7DFSIRISS ITPADVGTYY CVKFRKGSPE DVEFKSGPGT EX8ALGAKPS(SEQ ID NO：2)
其中，X1选自L或W，X3选自Q、S或T，X4选自E、T或R，X5选自H或R，X6选自D、N或E，X7选自I、V、M、R或K，和X8选自M或V。
下表显示了不同SIRPγ肽变体相对于野生型SIRPγ肽的氨基酸替代突变位点及示例性替代氨基酸残基。
表1
Figure GPA0000304234790000121
Figure GPA0000304234790000131
术语“抗体(antibody，Ab)”包含任何包括至少一个与具体抗原(或其表位，例如PD-L1抗原或其表位)特异性结合或相互作用的互补决定区(CDR)的抗原结合分子或分子复合物。术语“抗体”包含：包括通过双硫键相互连接的四条多肽链，两条重(H)链和两条轻(L)链的免疫球蛋白分子以及其多聚体(例如IgM)。各重链包含重链可变区(文中缩写为HCVR或VH)和重链恒定区(CH)。这一重链恒定区包含三个区(结构域)，CH1、CH2和CH3。各轻链包含轻链可变区(文中缩写为LCVR或VL)和轻链恒定区(CL)。轻链恒定区包含一个区(结构域，CL)。VH和VL区可进一步细分为高变区，称为互补决定区(CDR)，其间散布着较保守性区域，称为框架区(framework region，FR，也称骨架区、构架区)。各VH和VL是由三个CDR和四个FR所组成，以下列顺序由氨基端排列到羧基端：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在本公开的不同实施例中，抗PD-L1抗体(或其抗原结合片段)的FR可与人种系序列相同，或可经自然或人工修饰。抗体可以是不同亚类(subclass)的抗体，例如，IgG(例如：IgG1、IgG2、IgG3、或IgG4亚类)、IgA1、IgA2、IgD、IgE或IgM抗体。
术语“全长抗体”、“完整抗体”、“完全抗体”和“全抗体”在本文中可互换使用，指基本上完整形式的抗体，与下文定义的抗原结合片段相区分。该术语特别指重链由氨基端至羧基端依次包含VH区、CH1区、铰链区和Fc区，轻链由氨基端至羧基端依次包含VL区和CL区的抗体。
抗原结合片段的非限定示例包含：(i)Fab片段；(ii)F(ab′)2片段；(iii)Fd片段；(iv)Fv片段；(v)单链Fv(scFv)分子；(vi)dAb片段；和(vii)由模拟抗体高变区的氨基酸残基所组成的最小识别单位(例如分离的互补决定区(CDR)，例如CDR3肽)或限制性FR3-CDR3-FR4肽。其它工程改造分子，例如区域特异性抗体、单域抗体、区域删除抗体、嵌合抗体、CDR-植入抗体、双抗体、三抗体、四抗体、微抗体、纳米抗体(例如单价纳米抗体、双价纳米抗体等)、小模块免疫医药(SMIP)和鲨可变IgNAR区，也涵盖在文中所用的“抗原结合片段”的词语内。
抗体的抗原结合片段典型地将包含至少一个可变区。可变区可以是任何大小或氨基酸组成的区域，且一般将包含与一个或多个框架序列相邻或在其框架内的CDR。在具有VH区与VL区的抗原结合片段中，VH和VL区可以任何适合的排列位于彼此相对处。例如可变区可为二聚化并含有VH-VL或VL-VH二聚体。
在某些实施例中，抗原结合片段在任何可变区和恒定区的配置中，可变区和恒定区可直接彼此相连接或可通过完整或部分的绞链或连接子区相连接。绞链区可由至少2个(例如5、10、15、20、40、60或更多个)氨基酸所组成，使得其在单一多肽分子中在相邻的可变和/或恒定区之间产生柔性和半柔性连结。再者，在本公开抗原结合片段可包含以非共价彼此相互连结和/或与一个或多个单体VH或VL区相连结(例如以双硫键)的具有可变区和恒定区的同源二聚体或异源二聚体(或其它多聚体)。
“鼠源抗体”在本公开中为根据本领域知识和技能制备的来源于小鼠或大鼠的单克隆抗体。制备时用抗原注射试验对象，然后分离表达具有所需序列或功能特性的抗体的杂交瘤，当所注射的试验对象为小鼠时，所产生的抗体为小鼠来源抗体，当所注射的试验对象为大鼠时，所产生的抗体为大鼠来源抗体。
“嵌合抗体(chimeric antibody)”，是将第一物种(如：鼠)抗体的可变区与第二物种(如：人)抗体的恒定区融合而成的抗体。建立嵌合抗体，要先建立分泌第一物种单抗的杂交瘤，然后从杂交瘤细胞中克隆可变区基因，再根据需要克隆第二物种抗体的恒定区基因，将第一物种可变区基因与第二物种恒定区基因连接成嵌合基因后***表达载体中，最后在真核***或原核***中表达嵌合抗体分子。在本公开一个优选的实施方案中，所述的嵌合抗体的抗体轻链进一步包含人源κ、λ链或其变体的轻链恒定区。所述的嵌合抗体的抗体重链进一步包含人源IgG1、IgG2、IgG3、IgG4或其变体的重链恒定区，优选包含人源IgG1、IgG2或IgG4重链恒定区，或者使用氨基酸突变(如YTE突变，回复突变，L234A和/或L235A突变，或S228P突变)的IgG1、IgG2或IgG4重链恒定区变体。
术语“人源化抗体(humanized antibody)”，包括CDR移植抗体(CDR-graftedantibody)，是指将动物来源抗体，例如鼠源抗体的CDR序列移植到人的抗体可变区框架区(或构架区，framework region)中产生的抗体。人源化抗体可以克服嵌合抗体由于携带大量异源蛋白成分，从而诱导的异源性反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(在因特网http：//www.vbase2.org/获得)，以及在Kabat，EA.等人，1991 Sequences of Proteins of Immunological Interest，第5版中找到。为避免免疫原性下降引起活性的下降，可对所述的人抗体可变区框架序列进行量少的回复突变，以保持活性。本公开的人源化抗体也包括进一步由噬菌体展示对CDR进行亲和力成熟后的人源化抗体。
由于抗原的接触残基，CDR的移植可由于与抗原接触的构架残基而导致产生的抗体或其抗原结合片段对抗原的亲和力减弱。此类相互作用可以可能是体细胞高度突变的结果。因此，可能仍然需要将此类供体构架氨基酸移植至人源化抗体的构架。来自非人抗体或其抗原结合片段的参与抗原结合的氨基酸残基可通过检查动物单克隆抗体可变区序列和结构来鉴定。CDR供体构架中与种系不同的各残基可被认为是相关的。如果不能确定最接近的种系，那么可将序列与亚类共有序列或具有高相似性百分数的动物抗体序列的共有序列相比较。稀有构架残基被认为可能是体细胞高度突变的结果，从而在结合中起着重要作用。
在本公开一个的实施方案中，所述的抗体或其抗原结合片段，可进一步包含人源或鼠源κ、λ链或其变体的轻链恒定区，或进一步包含人源或鼠源IgG1、IgG2、IgG3、IgG4或其变体的重链恒定区。
人抗体重链恒定区和人抗体轻链恒定区的“常规变体”是指现有技术已公开的来源于人的不改变抗体可变区结构和功能的重链恒定区或轻链恒定区的变体，示例性变体包括对重链恒定区进行定点改造和氨基酸替换的IgG1、IgG2、IgG3或IgG4重链恒定区变体，具体替换如现有技术已知的YTE突变，L234A和/或L235A突变，或S228P突变，或获得knob-into-hole结构的突变(使得抗体重链具有knob-Fc和hole-Fc组合)，这些突变已被证实使得抗体具有新的性能，但不改变抗体可变区的功能。
“人抗体”与“人源抗体”可以互换使用，可以是源于人的抗体或者是从一种转基因生物体中获得的抗体，该转基因生物体经“改造”以响应于抗原刺激而产生特异性人抗体并且可以通过本领域已知的任何方法产生。在某些技术中，将人重链和轻链基因座的元件引入到细胞株中，这些细胞株中的内源性重链和轻链基因座被靶向破坏。转基因生物可以合成对抗原特异的人抗体，并且该生物可以用于产生人抗体-分泌杂交瘤。人抗体还可以是一种抗体，其中重链和轻链是由源于一个或多个人DNA来源的核苷酸序列编码的。完全人抗体还可以通过基因或染色体转染方法以及噬菌体展示技术来构建，或者由体外活化的B细胞构建，所有的这些都是本领域已知的。
“单克隆抗体”是指从基本上均质抗体的群体获得的抗体，即除可能的变体抗体(例如含有天然存在的突变或在制造单克隆抗体制剂的期间产生的突变，这些变体通常以少量存在)之外，构成所述群体的个别抗体识别相同和/或结合相同表位。单克隆抗体制备物(制剂)的每个单克隆抗体针对抗原上的单一决定簇。因此，修饰语“单克隆”指示如从基本上均质抗体群体获得的抗体的特性，且不应解释为需要通过任何特定方法来制造抗体。例如，根据本公开使用的单克隆抗体可通过各种技术制备，所述技术包括但不限于杂交瘤方法、重组DNA方法、噬菌体展示方法以及利用含有全部或部分人免疫球蛋白基因座的转基因动物的方法，此类方法以及用于制备单克隆抗体的其他示例性方法在本文中进行描述。
此外，虽然Fv片段的两个结构域VL和VH由分开的基因编码，但可使用重组方法，通过合成的接头连接它们，从而使得其能够产生为其中VL和VH区配对形成单价分子的单个蛋白质链(称为单链Fv(scFv)；参见，例如，Bird等人(1988)Science242：423-426；和Huston等人(1988)Proc.Natl.Acad.Sci USA85：5879-5883)。此类单链抗体也意欲包括在术语抗体的“抗原结合片段”中。使用本领域技术人员已知的常规技术获得此类抗体片段，并且以与对于完整抗体的方式相同的方式就功用性筛选的片段。可通过重组DNA技术或通过酶促或化学断裂完整免疫球蛋白来产生抗原结合部分。
抗原结合片段还可并入至包含一对串联Fv片段(VH-CH1-VH-CH1)的单链分子中，该对串联Fv片段连同互补轻链多肽一起形成一对抗原结合区(Zapata等人，1995 ProteinEng.8(10)：1057-1062；及美国专利US5641870)。
Fab是通过用蛋白酶木瓜蛋白酶(切割H链的224位的氨基酸残基)处理IgG抗体所获得的具有约50,000Da的分子量并具有抗原结合活性的抗体片段，其中H链N端侧的约一半和整个L链通过二硫键结合在一起。
F(ab′)2是通过用胃蛋白酶消化IgG铰链区中两个二硫键的下方部分而获得的分子量为约100,000Da并具有抗原结合活性，并包含在铰链位置相连的两个Fab区的抗体片段。
Fab′是通过切割上述F(ab′)2的铰链区的二硫键而获得的分子量为约50,000Da并具有抗原结合活性的抗体片段。Fab′可以通过用还原剂例如二硫苏糖醇处理特异性识别并结合抗原的F(ab′)2来生产。
此外，可以通过将编码抗体的Fab′片段的DNA***到原核生物表达载体或真核生物表达载体中，并将载体导入到原核生物或真核生物中以表达Fab′。
术语“单链抗体”、“单链Fv”或“scFv”意指包含通过接头连接的抗体重链可变结构域(或区域；VH)和抗体轻链可变结构域(或区域；VL)的分子。此类scFv分子可具有一般通式：NH2-VL-接头-VH-COOH或NH2-VH-接头-VL-COOH。合适的现有技术接头由重复的GGGGS氨基酸序列或其变体组成，例如使用1-4个(包括1个、2个、3个或4个)重复的变体(Holliger等人(1993)，Proc Natl Acad Sci USA.90：6444-6448)。可用于本公开的其他接头由Alfthan等人(1995)，Protein Eng.8：725-731，Choi等人(2001)，Eur J Immuno.31：94-106，Hu等人(1996)，Cancer Res.56：3055-3061，Kipriyanov等人(1999)，J Mol Biol.293：41-56和Roovers等人(2001)，Cancer Immunol Immunother.50：51-59.描述。
“抗人PD-L1抗体”包括能够特异性结合人PD-L1的全长抗体，也包括包含该全长抗体的轻链可变区和重链可变区的抗原结合片段，包括但不限于包含该全长抗体的轻链可变区和重链可变区的单链抗体(scFv)、Fab片段或包含scFv或Fab的其他抗原结合片段。
SIRPγ肽连接至所述抗人PD-L1抗体的多肽链中的“连接”指多肽之间的有效连接，包括例如经过肽键连接，或使用连接子连接。所述连接不会使SIRPγ肽和抗人PD-L1抗体各自的功能丧失。
“Linker”或“接头”或“连接子”指用于连接蛋白质结构域或不同蛋白或不同多肽的连接性多肽序列，通常具有一定的柔性，连接子的使用不会使蛋白质结构域原有的功能丧失。示例性的连接子如下表所示。
表2.示例性连接子序列
Figure GPA0000304234790000171
在一些实施方案中，抗PD-L1抗体可以与SIRPγ肽变体使用接头连接起来，一些示例性的双功能融合蛋白包括以下所示的融合蛋白：
表3.PD-L1-CD47双功能融合蛋白
Figure GPA0000304234790000172
Figure GPA0000304234790000181
双抗体(diabody)是指scFv被二聚体化的抗体片段，是具有二价抗原结合活性的抗体片段。在二价抗原结合活性中，两个抗原可以是相同或不同的。
dsFv是通过将其中每个VH和VL中的一个氨基酸残基被半胱氨酸残基取代的多肽经由半胱氨酸残基之间的二硫键相连而获得的。可以按照已知方法(ProteinEngineering.7：697(1994))基于抗体的三维结构预测来选择被半胱氨酸残基取代的氨基酸残基。
本公开一些实施例中抗原结合片段可以通过以下步骤来生产：获得本公开的特异性识别并结合抗原的单克隆抗体的VH和/或VL及所需的其他结构域的编码cDNA，构建编码抗原结合片段的DNA，将所述DNA***到原核生物表达载体或真核生物表达载体中，然后将所述表达载体导入到原核生物或真核生物中以表达抗原结合片段。
″Fc区″可以是天然序列Fc区或变体Fc区。虽然免疫球蛋白重链的Fc区的边界可能变化，但人IgG重链Fc区通常被定义成从位置Cys226上的氨基酸残基或从Pro230延伸至其羧基端。Fc区中的残基的编号为如Kabat中的EU索引的编号。Kabat等，Sequences ofProteins of Immunological Interest，第5版Public Health Service，NationalInstitutes of Health，Bethesda，Md.，1991。免疫球蛋白的Fc区通常具有两个恒定区结构域CH2和CH3。
术语“氨基酸差异”或“氨基酸突变”是指相较于原蛋白质或多肽，变体蛋白质或多肽存在氨基酸的改变或突变，包括在原蛋白质或多肽的基础上发生1个或更多个氨基酸的***、缺失或替代。
抗体的“可变区”是指单独的或组合的抗体轻链的可变区(VL)或抗体重链的可变区(VH)。如在本领域中已知的，重链和轻链的可变区各自由通过3个互补决定区(CDR)(也称为高变区)连接的4个框架区(FR)组成。每一条链中的CDR通过FR紧密地保持在一起并且与来自另一条链的CDR一起促成抗体的抗原结合部位的形成。存在至少2个用于确定CDR的技术：(1)基于跨种序列变异性的方法(即，Kabat等Sequences of Proteins ofImmunological Interest，(第5版，1991，National Institutes of Health，BethesdaMD))；和(2)基于抗原-抗体复合物的晶体学研究的方法(Al-Lazikani等，J.Molec.Biol.273：927-948(1997))。如本文中所用，CDR可指由任一方法或由两种方法的组合确定的CDR。
术语“抗体框架”或“FR区”，是指可变结构域VL或VH的一部分，其用作该可变结构域的抗原结合环(CDR)的支架。从本质上讲，其是不具有CDR的可变结构域。
术语“互补决定区”和“CDR”是指抗体的可变结构域内主要促成抗原结合的6个高变区之一。通常，每个重链可变区中存在三个CDR(HCDR1、HCDR2、HCDR3)和每个轻链可变区中存在三个CDR(LCDR1、LCDR2、LCDR3)。可以使用各种公知方案中的任何一种来确定CDR的氨基酸序列边界，包括“Kabat”编号规则(参见Kabat等(1991)，“Sequences of Proteinsof Immunological Interest”，第5版，Public Health Service，National Institutes ofHealth，Bethesda，MD)、“Chothia”编号规则(Al-Lazikani等人，(1997)JMB 273：927-948)和ImMunoGenTics(IMGT)编号规则(LefrancM.P.，Immunologist，7，132-136(1999)；Lefranc，M.P.等，Dev.Comp.Immunol.，27，55-77(2003))等。例如，对于经典格式，遵循Kabat规则，所述重链可变域(VH)中的CDR氨基酸残基编号为31-35(HCDR1)、50-65(HCDR2)和95-102(HCDR3)；轻链可变域(VL)中的CDR氨基酸残基编号为24-34(LCDR1)、50-56(LCDR2)和89-97(LCDR3)。遵循Chothia规则，VH中的CDR氨基酸编号为26-32(HCDR1)、52-56(HCDR2)和95-102(HCDR3)；并且VL中的氨基酸残基编号为26-32(LCDR1)、50-52(LCDR2)和91-96(LCDR3)。通过组合Kabat和Chothia两者的CDR定义，CDR由人VH中的氨基酸残基26-35(HCDR1)、50-65(HCDR2)和95-102(HCDR3)和人VL中的氨基酸残基24-34(LCDR1)、50-56(LCDR2)和89-97(LCDR3)构成。遵循IMGT规则，VH中的CDR氨基酸残基编号大致为26-35(CDR1)、51-57(CDR2)和93-102(CDR3)，VL中的CDR氨基酸残基编号大致为27-32(CDR1)、50-52(CDR2)和89-97(CDR3)。遵循IMGT规则，抗体的CDR区可以使用程序IMGT/DomainGapAlign确定。
“抗体恒定区结构域”指来源于抗体的轻链和重链的恒定区的结构域，包括CL和来源于不同类抗体的CH1、CH2、CH3和CH4结构域。
“表位”或“抗原决定簇”是指抗原上免疫球蛋白或抗体特异性结合的部位。表位通常以独特的空间构象包括至少3、4、5、6、7、8、9、10、11、12、13、14或15个连续或非连续的氨基酸。参见，例如，Epitope Mapping Protocols in Methods in Molecular Biology，第66卷，G.E.Morris，Ed.(1996)。
术语“特异性结合”、“选择性结合”、“选择性地结合”和“特异性地结合”是指抗体对预先确定的抗原上的表位的结合。
术语“亲和力”是指在单一表位处，抗体与抗原之间相互作用的强度。在各抗原位点内，抗体“臂”的可变区通过弱非共价力与抗原在多个氨基酸位点处相互作用；相互作用愈大，亲和力愈强。如本文所用，抗体或其抗原结合片段(例如Fab片段)的术语“高亲和力”通常是指具有1E-9M或更小的KD(例如1E-10M或更小的KD、1E-11M或更小的KD、1E-12M或更小的KD、1E-13M或更小的KD、1E-14M或更小的KD等)的抗体或抗原结合片段。
术语″KD″或“KD”是指特定抗体-抗原相互作用的解离平衡常数。通常，抗体以小于大约1E-8M，例如小于大约1E-9M、1E-10M或1E-11M或更小的解离平衡常数(KD)结合抗原，例如，如使用表面等离子体共振(SPR)技术在BIACORE仪中测定的。KD值越小，亲和力越大。
术语“核酸分子”是指DNA分子和RNA分子。核酸分子可以是单链或双链的DNA分子或RNA分子，例如是双链DNA或mRNA。当将核酸与另一个核酸序列置于功能关系中时，核酸是“有效连接的”。例如，如果启动子或增强子影响编码序列的转录，那么启动子或增强子有效地连接至所述编码序列。
术语″载体″意指能够递送一个或多个目标基因或序列并且优选地在宿主细胞中表达其的构建体。载体的示例包括，但不限于，病毒载体、裸露DNA或RNA表达载体、质粒、粘粒或噬菌体载体、与阳离子凝聚剂缔合的DNA或RNA表达载体、包封在脂质体中的DNA或RNA表达载体和某些真核生物细胞诸如生产细胞。
现有技术中熟知生产和纯化抗体和抗原结合片段的方法，如冷泉港的抗体实验技术指南，5-8章和15章。例如，鼠可以用抗原或其片段免疫，所得到的抗体能被复性、纯化，并且可以用常规的方法进行氨基酸测序。抗原结合片段同样可以用常规方法制备。本公开所述的抗体或抗原结合片段用基因工程方法在非人源的CDR区加上一个或多个人源FR区。人FR种系序列可以通过比对IMGT人类抗体可变区种系基因数据库和MOE软件，从网站http：// www.imgt.org/得到，或者从免疫球蛋白杂志，2001ISBN012441351上获得。
术语“宿主细胞”是指已向其中引入了表达载体的细胞。宿主细胞可包括细菌、微生物、植物或动物细胞。易于转化的细菌包括肠杆菌科(enterobacteriaceae)的成员，例如大肠杆菌(Escherichia coli)或沙门氏菌(Salmonella)的菌株；芽孢杆菌科(Bacillaceae)例如枯草芽孢杆菌(Bacillus subtilis)；肺炎球菌(Pneumococcus)；链球菌(Streptococcus)和流感嗜血菌(Haemophilus influenzae)。适当的微生物包括酿酒酵母(Saccharomyces cerevisiae)和毕赤酵母(Pichia pastoris)。适当的动物宿主细胞系包括CHO(中国仓鼠卵巢细胞系)、HEK293细胞(非限制性实施例如HEK293E细胞)和NS0细胞。
工程化的抗体或抗原结合片段可用常规方法制备和纯化。比如，编码重链和轻链的cDNA序列，可以克隆并重组至GS表达载体。重组的免疫球蛋白表达载体可以稳定地转染CHO细胞。作为一种可选的现有技术，哺乳动物类表达***会导致抗体的糖基化，特别是在Fc区的高度保守N端位点。通过表达与抗原特异性结合的抗体得到稳定的克隆。阳性的克隆在生物反应器的无血清培养基中扩大培养以生产抗体。分泌了抗体的培养液可以用常规技术纯化。比如，用含调整过的缓冲液的蛋白A或蛋白G Sepharose FF柱进行纯化。洗去非特异性结合的组分。再用pH梯度法洗脱结合的抗体，用SDS-PAGE检测抗体片段，收集。抗体可用常规方法进行过滤浓缩。可溶的混合物和多聚体，也可以用常规方法去除，比如分子筛、离子交换。得到的产物需立即冷冻，如-70℃，或者冻干。
“施用”、“给药”、“给予”和“处理”当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时，是指将外源性药物、治疗剂、诊断剂、组合物或者人为操作(比如实施例中的“安乐死”)提供给动物、人、受试者、细胞、组织、器官或生物流体的接触。“给予”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触，以及试剂与流体的接触，其中所述流体与细胞接触。“给予”和“处理”还意指通过试剂、诊断、结合组合物或通过另一种细胞体外和离体处理例如细胞。“处理”当应用于人、兽医学或研究受试者时，是指治疗处理、预防或预防性措施，研究和诊断应用。
“治疗”意指给予患者(或受试者)内用或外用治疗剂，例如包含本公开实施例的任一种化合物的组合物，所述患者(或受试者)具有(或疑似患有、或易感于)一种或多种疾病症状，而已知所述治疗剂对这些症状具有治疗作用。通常，在受治疗患者(或受试者)或群体中以有效缓解一种或多种疾病症状的量给予治疗剂，以诱导这类症状退化或抑制这类症状发展到任何临床有测量的程度。有效缓解任何具体疾病症状的治疗剂的量(也称作“治疗有效量”)可根据多种因素变化，例如患者(或受试者)的疾病状态、年龄和体重，以及药物在患者(或受试者)产生需要疗效的能力。通过医生或其它专业卫生保健人士通常用于评价该症状的严重性或进展状况的任何临床检测方法，可评价疾病症状是否已被减轻。尽管本公开的实施方案(例如治疗方法或制品)可能无法在缓解每个目标疾病症状方面都有效，但是根据本领域已知的任何统计学检验方法如Student t检验、卡方检验、依据Mann和Whitney的U检验、Kruskal-Wallis检验(H检验)、Jonckheere-Terpstra检验和Wilcoxon检验确定，其在统计学显著数目的患者(或受试者)中应当减轻目标疾病症状。
“氨基酸保守修饰”或“氨基酸保守取代”指蛋白质或多肽中的氨基酸被具有相似特征(例如电荷、侧链大小、疏水性/亲水性、主链构象和刚性等)的其他氨基酸取代，从而使得在不改变蛋白质或多肽的生物活性或其他所需特性(例如抗原亲和力和/或特异性)的情况下，可以经常进行改变。本领域技术人员认识到，通常，多肽的非必需区域中的单个氨基酸取代基本上不改变生物活性(参见，例如，Watson等人，(1987)Molecular Biology ofthe Gene，The Benjamin/Cummings Pub.Co.，第224页(第4版))。此外，结构上或功能上相似的氨基酸的取代不太可能破坏生物活性。示例性保守取代于下表“示例性氨基酸保守取代”中陈述。
表4.示例性氨基酸保守取代
Figure GPA0000304234790000211
Figure GPA0000304234790000221
“有效量”、“有效剂量”是指获得任一种或多种有益的或所需的治疗结果所必需的药物、化合物或药物组合物的量。对于预防用途，有益的或所需的结果包括消除或降低风险、减轻严重性或延迟病症的发作，包括病症、其并发症和在病症的发展过程中呈现的中间病理表型的生物化学、组织学和/或行为症状。对于治疗应用，有益的或所需的结果包括临床结果，诸如减少各种本公开靶抗原相关病症的发病率或改善所述病症的一个或多个症状，减少治疗病症所需的其它药剂的剂量，增强另一种药剂的疗效，和/或延缓患者(或受试者)的本公开靶抗原相关病症的进展。
“外源性”指根据情况在生物、细胞或人体外产生的物质。
“内源性”指根据情况在细胞、生物或人体内产生的物质。
“分离的”指纯化状态，并且在这种情况下意味着在指定的分子基本上不含其他生物分子，例如核酸、蛋白质、脂质、碳水化合物或其他材料，例如细胞碎片和生长培养基。通常，术语“分离的”并不意图指完全不存在这些材料或不存在水、缓冲液或盐，除非它们以显著干扰如本文所述的化合物的实验或治疗用途的量存在。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。
“药物组合物”表示含有一种或多种本公开所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，所述其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
术语“药学上可接受的载体”指适合用于制剂中用于递送抗体或抗原结合片段的任何无活性物质。载体可以是抗粘附剂、粘合剂、包衣、崩解剂、充填剂或稀释剂、防腐剂(如抗氧化剂、抗菌剂或抗真菌剂)、增甜剂、吸收延迟剂、润湿剂、乳化剂、缓冲剂等。合适的药学上可接受的载体的示例包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等)右旋糖、植物油(例如橄榄油)、盐水、缓冲液、缓冲的盐水和等渗剂例如糖、多元醇、山梨糖醇和氯化钠。
此外，本公开另一方面涉及用于免疫检测或测定目标抗原的方法、用于免疫检测或测定目标抗原的试剂、用于免疫检测或测定表达目标抗原的细胞的方法和用于诊断与目标抗原阳性细胞相关的疾病的诊断剂，其包含本公开的特异性识别并结合目标抗原的单克隆抗体或抗体片段、或融合蛋白、或双功能融合蛋白作为活性成分。
术语“癌症”、“癌的”或“恶性肿瘤”指或描述哺乳动物中一般以不受调节的细胞生长为特征的生理状况，在本公开中可以互换使用。癌症或恶性肿瘤的例子包括但不限于癌瘤，淋巴瘤，胚细胞瘤(blastoma)，肉瘤，和白血病或淋巴样恶性。这种癌症的更具体的例子包括鳞状细胞癌、骨髓瘤、小细胞肺癌、非小细胞肺癌(NSCLC)、头和颈鳞状细胞癌(HNSCC)、神经胶质瘤、何杰金淋巴瘤、非何杰金淋巴瘤、弥漫性大B-细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤、急性成淋巴细胞性白血病(ALL)、急性髓细胞样白血病(AML)、慢性淋巴细胞性白血病(CLL)、慢性髓细胞样白血病(CML)、原发性纵隔大B-细胞淋巴瘤、套细胞淋巴瘤(MCL)、小淋巴细胞性淋巴瘤(SLL)、富含T-细胞/组织细胞的大B-细胞淋巴瘤、多发性骨髓瘤、髓样细胞白血病-1蛋白(Mcl-1)、骨髓异常增生综合征(MDS)、胃肠(道)癌、肾癌、卵巢癌、肝癌、成淋巴细胞性白血病、淋巴细胞白血病、结肠直肠癌、子宫内膜癌、肾癌、***癌、甲状腺癌、黑素瘤、软骨肉瘤、神经母细胞瘤、胰腺癌、多形性成胶质细胞瘤、胃癌、骨癌、尤因氏肉瘤、子***、脑癌、胃癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、肝细胞癌(HCC)、透明细胞肾细胞癌(RCC)、头和颈癌、咽喉癌、肝胆癌(hepatobiliary cancer)、中枢神经***癌、食管癌、恶性胸膜间皮瘤、全身性轻链淀粉样变性、淋巴浆细胞性淋巴瘤(lymphoplasmacyticlymphoma)、骨髓异常增生综合征、骨髓增生性肿瘤、神经内分泌肿瘤、梅克尔细胞癌、睾丸癌和皮肤癌。
“炎性病症”是指其中过度或不受调节的炎症反应导致过度炎性症状、宿主组织损伤或组织功能丧失的任何疾病、病症或综合征。“炎性疾病”也是指由白细胞或嗜中性粒细胞趋化性的汇集而介导的病理状态。
“炎症”是指由于组织损伤或破坏而引起的局部保护性反应，其用来破坏、削弱或杜绝(隔离)有害物质和受伤组织。炎症与白细胞或中性粒细胞趋化性的汇集显著相关。炎症可以由病原生物体和病毒以及非感染性原因引起，所述非感染性原因如创伤或心肌梗塞后的再灌注或中风、对外源性抗原的免疫应答和自身免疫应答。
上述与目标抗原阳性细胞相关的疾病可以通过用本公开的单克隆抗体或抗体片段检测或测定表达目标抗原的细胞来诊断。
为了检测表达多肽的细胞，可以使用已知的免疫检测方法，并优选使用免疫沉淀法、荧光细胞染色法、免疫组织染色法等。此外，可以使用利用FMAT8100HTS***(AppliedBiosystem)的荧光抗体染色法等。
在本公开中，对用于检测或测定目标抗原的活体样品没有特别限制，只要它具有包含表达目标抗原的细胞的可能性即可，例如组织细胞、血液、血浆、血清、胰液、尿液、粪便、组织液或培养液。
根据所需的诊断方法，含有本公开的单克隆抗体或其抗体片段的诊断剂还可以含有用于执行抗原-抗体反应的试剂或用于检测反应的试剂。用于执行抗原-抗体反应的试剂包括缓冲剂、盐等。用于检测的试剂包括通常用于免疫检测或测定方法的试剂，例如识别所述单克隆抗体、其抗体片段或其结合物的标记的第二抗体和与所述标记对应的底物等。
在以上说明书中提出了本发明一种或多种实施方式的细节。虽然可使用与本文所述类似或相同的任何方法和材料来实施或测试本公开，但是以下描述优选的方法和材料。通过说明书和权利要求书，本公开的其他特点、目的和优点将是显而易见的。在说明书和权利要求书中，除非上下文中有清楚的另外指明，单数形式包括复数指代物的情况。除非另有定义，本文使用的所有技术和科学术语都具有本发明所属领域普通技术人员所理解的一般含义。说明书中引用的所有专利和出版物都通过引用纳入。提出以下实施例是为了更全面地说明本发明公开的优选实施方式。这些实施例不应以任何方式理解为限制本公开的范围，本公开的范围由权利要求书限定。
实施例
实施例1.CD47抗原及检测用蛋白的制备
以UniProt白细胞表面抗原CD47(人CD47蛋白，Uniprot号：Q08722)作为CD47的模板，设计本公开涉及的抗原及检测用蛋白的氨基酸序列，可选的在CD47蛋白基础上融合不同的标签如his标签或Fc等。
1.带His标签的CD47蛋白胞外域(CD47-ECD-His)：(SEQ ID NO：3)
Figure GPA0000304234790000241
注释：划线部分为6×his标签。
2.CD47胞外域与人IgG1Fc融合蛋白(CD47-ECD-Fc)作为检测试剂：(SEQ ID NO：4)
Figure GPA0000304234790000251
注释：划线部分为人IgG1-Fc部分。
3.人SIRPα与人IgG1Fc融合蛋白(SIRPα-Fc)作为结合及阻断检测试剂：(SEQ IDNO：5)
Figure GPA0000304234790000252
注释：划线部分为人IgG1-Fc部分。
4.带His标签的SIRPα蛋白胞外域(SIRPα-His)
Figure GPA0000304234790000253
实施例2.CD47、SIRPα相关重组蛋白的纯化
1.带His标签的重组蛋白的纯化步骤：
将细胞表达上清高速离心去除杂质，并将缓冲液置换为PBS，加入咪唑至终浓度为5mM。用含有5mM咪唑的PBS溶液平衡镍柱，冲洗2-5倍柱体积。将置换后的上清样品上IMAC柱。用含有5mM咪唑的PBS溶液冲洗柱子，至A280读数降至基线。后用PBS+10mM咪唑冲洗层析柱，除去非特异结合的杂蛋白，并收集流出液。再用含有300mM咪唑的PBS溶液洗脱目的蛋白，并收集洗脱峰。收集的洗脱液浓缩后用凝胶层析Superdex200(GE，28-9893-35)进一步纯化，流动相为PBS。去除聚体峰，收集洗脱峰。所得到的蛋白经电泳、肽图、LC-MS鉴定为正确后，分装备用。
得到带His标签的CD47-ECD-His(SEQ ID NO：3)用于本公开抗体的免疫原或检测试剂。CD47-ECD-His也可以通过体外化学法与KLH蛋白进行偶联反应后作为免疫原刺激小鼠免疫。
2.CD47-ECD-Fc及SIRPα-Fc融合蛋白的纯化步骤：
将细胞表达上清高速离心去除杂质，上清进行MabSelect Sure(GE，17-5438-01)亲和层析。MabSelect Sure层析柱先用0.1M NaOH再生，利用纯水冲洗后用PBS平衡柱子，将上清结合后，利用PBS进行洗涤至A280读数降至基线。用0.1M醋酸缓冲液在pH3.5条件下洗脱目的蛋白，用1M Tris-HCl中和。洗脱样品适当浓缩后利用PBS平衡好的凝胶层析Superdex200(GE，28-9893-35)进一步纯化，合并收集目的蛋白所在接收管浓缩至适当浓度。
此方法用来纯化CD47-ECD-Fc(SEQ ID NO：4)及SIRPα-Fc(SEQ ID NO：5)融合蛋白，该方法也可以用来纯化本公开中涉及的人源化抗体蛋白。
实施例3.构建和表达抗PD-L1人源化抗体(IgG4-S228P形式)
抗PD-L1抗体的轻重链可变区改造自WO2017084495A1的抗PD-L1抗体，其序列和相关性能记载在申请号为PCT/CN2019/070982的PCT申请中，该PCT申请中的全部内容引用至本申请。
抗PD-L1抗体9-2H5L11：
9-2 H5重链可变区(SEQ ID NO：6)
Figure GPA0000304234790000261
9-2 L11轻链可变区(SEQ ID NO：7)
Figure GPA0000304234790000262
抗PD-L1抗体24D5H12L61：
24D5 H12重链可变区(SEQ ID NO：8)
Figure GPA0000304234790000263
24D5 L61轻链可变区(SEQ ID NO：9)
Figure GPA0000304234790000264
注释：上述抗体9-2和24D5来源的轻重链可变区中下划线所示CDR为Kabat编号规则所定义的CDR。
表5.Kabat编号规则定义的抗体CDR
Figure GPA0000304234790000265
Figure GPA0000304234790000271
设计引物，PCR搭建各人源化抗体VH/VK基因片段，再与表达载体pHr(带信号肽及恒定区基因(CH1-FC/CL)片段)进行同源重组，构建抗体全长表达载体VH-CH1-FC-pHr/VK-CL-pHr。
IgG4-S228P的重链恒定区序列如下：(SEQ ID NO：10)
Figure GPA0000304234790000272
IgG1的重链恒定区序列如下：(SEQ ID NO：11)
Figure GPA0000304234790000273
抗体的轻链(Kappa链)恒定区序列如下：(SEQ ID NO：12)
Figure GPA0000304234790000274
构建的全长抗体如下：
抗PD-L1 IgG4抗体h1830
h1830重链(SEQ ID NO：13)
Figure GPA0000304234790000275
Figure GPA0000304234790000281
h1830轻链(SEQ ID NO：14)
Figure GPA0000304234790000282
抗PD-L1 IgG1抗体h1830G1
h1830G1重链：(SEQ ID NO：15)
Figure GPA0000304234790000283
h1830G1轻链(同h1830轻链，SEQ ID NO：14)：
Figure GPA0000304234790000284
PD-L1抗体h1831：
h1831重链(SEQ ID NO：16)
Figure GPA0000304234790000285
Figure GPA0000304234790000291
h1831轻链(SEQ ID NO：17)
Figure GPA0000304234790000292
抗PD-L1 IgG1抗体h1831G1
h1830G1重链：(SEQ ID NO：18)
Figure GPA0000304234790000293
h1831G1轻链(同h1831轻链，SEQ ID NO：17)
Figure GPA0000304234790000294
实施例4.SIRPγ突变体筛选和制备
4.1 SIRPγ的亲和力成熟噬菌体文库的构建以及文库的筛选
为获得高亲和力的CD47受体，通过噬菌体展示平台技术对CD47的受体SIRPγD1结构域进行亲和力成熟，在野生型SIRPγ的基础上设计并制备针对CD47结合结构域的亲和力成熟噬菌体文库，并从中筛选新的SIRPγ突变体。野生型SIRPγD1结构域具体序列如下：
野生型SIRPγ肽的DNA编码序列：(SEQ ID NO：19)
Figure GPA0000304234790000295
Figure GPA0000304234790000301
野生型SIRPγ肽：(SEQ ID NO：20)
Figure GPA0000304234790000302
噬菌体文库的构建：设计简并引物，通过PCR的方法将设计的突变氨基酸引入到SIRPγ噬菌体突变体文库中，每个文库的大小在109左右。
SIRPγ噬菌体突变体文库的筛选：将包装好的SIRPγ噬菌体突变体文库(1×1012-1×1013)与100μl链菌素微珠(Milenvi Biotec，Auburn，CA)加入1m1含2％脱脂牛奶-磷酸盐缓冲液(缩写MPBS)中于室温下孵育1小时，放置在磁力架上，取上清。上清加10μg/ml生物素化的人CD47-ECD-his蛋白(购自Sino Biological)，于室温下孵育1小时，再加入100μl链霉亲和素包被的磁珠(1ml MPBS预孵育)于室温下孵育1小时。并使其负载于磁力架***上用于分选，吸去上清。加入1ml PBST(含0.1％Tween-20的磷酸盐缓冲液)，翻转多次，吸尽后再加入新鲜洗液，重复11次，以去除未结合的突变体，加入0.5ml洗脱液(50μl 10mg/mltrypsin stock solution(存储液)加入450μl PBS中)。室温下摇晃15min。放置在磁力架上，吸出上清至一新EP管中。TG1接入2YT培养基中，扩增至细菌密度OD600＝0.4时。每管加入1.75ml TG1(OD600＝0.4)，并加入250μl洗脱后phage(噬菌体)，37℃水浴中静置孵育30min，梯度稀释涂板，用于测试滴度。其余TG1溶液离心，涂板，37℃过夜孵育。
SIRPγ噬菌体突变体文库利用生物素化的人CD47-ECD-his蛋白抗原，经过2-3轮MACS筛选(链霉素磁珠，Invitrogen)，最终获得比野生型SIRPγ亲和力高的噬菌体突变体单克隆进行测序验证。对测序克隆进行比对分析，去除冗余序列之后，将非冗余序列转换成PDL1-CD47双功能融合蛋白后进行哺乳动物细胞表达。
4.2 SIRPγ的亲和力成熟酵母文库的构建以及文库的筛选
为获得更高亲和力的CD47受体，通过酵母展示平台技术对CD47的受体SIRPγ-D1domain进行亲和力成熟，在SIRPγ-D1的基础上设计并制备针对CD47结合的domain的亲和力成熟酵母文库，并从中筛选新的SIRPγ突变体。
酵母文库的构建：设计简并引物，通过PCR的方法将设计的突变氨基酸引入到SIRPγ突变体文库中，每个文库的大小在109左右，构建好的酵母菌文库通过二代测序的方法验证文库的多样性。
在第一轮筛选中，将来自SIRPγ突变体文库的约5×1010个细胞与10μg/ml生物素化的人CD47-Fc蛋白在50ml含0.1％牛血清白蛋白(BSA)-磷酸盐缓冲液(称为PBSA)中于室温下孵育1小时。然后，混合物用0.1％PBSA洗涤三次，以去除未结合的抗体片段。然后往结合生物素化人CD47-Fc蛋白的SIRPγ突变体文库中加入100μl链菌素微珠(MilenviBiotec，Auburn，CA)，并使其负载于AutoMACS***上用于分选。收集具有对CD47-Fc的高亲和力的文库的细胞，然后在SDCAA培养基(20g右旋糖，6.7g Difco酵母菌氮源-无氨基酸，5gBacto酪蛋白氨基酸，5.4gNa2HPO4和8.56g NaH2PO4·H2O，溶解于1L蒸榴水中)中于250rpm和30℃下扩增24小时。然后，将培养物在SGCAA培养基(20g半乳糖，6.7g Difco酵母菌氮源-无氨基酸，5g Bacto酪蛋白氨基酸，5.4g Na2HPO4和8.56g NaH2PO4·H2O，溶解于1L蒸榴水中)中，于250rpm和20℃下诱导18个小时。将所得到的富集文库进行针对与生物素化的重组人CD47-Fc的结合的第二轮筛选。为了确保用于第二和/或第三轮筛选的抗体文库的充分多样性，将来自前一轮的文库大小的100倍用作输入的细胞数量。
对于第三轮和第四轮的筛选，将来自前一轮的文库细胞与1μg/ml生物素化的人CD47-Fc蛋白和10μg/ml Mouse Anti-cMyc(9E10，sigma)抗体在0.1％PB SA中于室温下孵育1小时，混合物用0.1％PBSA洗涤三次，以去除未结合的抗体片段。加入Goat anti-mouse-Alexa488(A-11001，life technologies)和Strepavidin-PE(S-866，Life technologies)于4℃下孵育1小时，混合物用0.1％PBSA洗涤三次，以去除未结合的抗体片段。最后，通过FACS筛选(BD FACSAriaTM FUSION)出亲和力高的SIRPγ突变体。
SIRPγ突变体文库利用生物素化的人CD47-Fc抗原，经过2-3轮MACS筛选(链霉素磁珠，Invitrogen)和2-3轮FACS筛选(BD FACSAriaTM FUSION)。再挑选400个左右的酵母单克隆培养和诱导表达，使用FACS(BD FACSCanto II)检测酵母单克隆对人CD47-Fc抗原的结合，挑选出比野生型SIRPγ亲和力高的酵母单克隆进行测序验证，对测序克隆进行比对分析，去除冗余序列之后，将非冗余序列转换成PDL 1-CD47双功能融合蛋白后进行哺乳动物细胞表达。
经过筛选，最终获得SIRPγ肽变体如下：
S58(SEQ ID NO：21)
Figure GPA0000304234790000311
S79(SEQ ID NO：22)
Figure GPA0000304234790000312
Figure GPA0000304234790000321
S15(SEQ ID NO：23)
Figure GPA0000304234790000322
S12(SEQ ID NO：24)
Figure GPA0000304234790000323
S19(SEQ ID NO：25)
Figure GPA0000304234790000324
S85(SEQ ID NO：26)
Figure GPA0000304234790000325
S37(SEQ ID NO：27)
Figure GPA0000304234790000326
S38(SEQ ID NO：28)
Figure GPA0000304234790000327
S22(SEQ ID NO：29)
Figure GPA0000304234790000328
S29(SEQ ID NO：30)
Figure GPA0000304234790000331
S34(SEQ ID NO：31)
Figure GPA0000304234790000332
S41(SEQ ID NO：32)
Figure GPA0000304234790000333
S42(SEQ ID NO：33)
Figure GPA0000304234790000334
S43(SEQ ID NO：34)
Figure GPA0000304234790000335
S44(SEQ ID NO：35)
Figure GPA0000304234790000336
S45(SEQ ID NO：36)
Figure GPA0000304234790000337
S46(SEQ ID NO：37)
Figure GPA0000304234790000341
S47(SEQ ID NO：38)
Figure GPA0000304234790000342
S48(SEQ ID NO：39)
Figure GPA0000304234790000343
S49(SEQ ID NO：40)
Figure GPA0000304234790000344
实施例5.构建和表达PD-L1-CD47双功能融合蛋白
将所获得的抗PD-L1抗体与SIRPγ连接，形成融合蛋白，经常规方法表达和纯化，获得PD-L1-CD47双功能融合蛋白。
表6.PD-L1-CD47双功能融合蛋白及序列
Figure GPA0000304234790000345
Figure GPA0000304234790000351
Figure GPA0000304234790000361
Figure GPA0000304234790000371
Figure GPA0000304234790000381
Figure GPA0000304234790000391
Figure GPA0000304234790000401
Figure GPA0000304234790000411
Figure GPA0000304234790000421
Figure GPA0000304234790000431
Figure GPA0000304234790000441
Figure GPA0000304234790000451
Figure GPA0000304234790000461
Figure GPA0000304234790000471
Figure GPA0000304234790000481
Figure GPA0000304234790000491
Figure GPA0000304234790000501
Figure GPA0000304234790000511
Figure GPA0000304234790000521
Figure GPA0000304234790000531
同样经常规方法制备纯化下列蛋白作为阳性或阴性对照。抗CD47抗体hu5F9(序列来自US09017675B)
Hu5F9重链(SEQ ID NO：83)
Figure GPA0000304234790000541
Hu5F9轻链(SEQ ID NO：84)
Figure GPA0000304234790000542
SIRPα-CV(参照Engineered SIRPα Variants as Immunotherapeutic Adjuvantsto Anticancer Antibodies合成，Science.2013 Jul 5；341(6141)：88-91，SEQ ID NO：85)
Figure GPA0000304234790000543
TTI-621：(序列来自WO2014094122A1，SEQ ID NO：133)
Figure GPA0000304234790000544
S58-Fc(SEQ ID NO：86)
Figure GPA0000304234790000551
抗CD47抗体Hu167-IgG4 AA(按照WO2018095428A1专利申请中公开的方法制备)
Hu167-IgG4 AA重链(SEQ ID NO：87)
Figure GPA0000304234790000552
Hu167-IgG4 AA轻链(SEQ ID NO：88)
Figure GPA0000304234790000553
S37-Fc(SEQ ID NO：110)
Figure GPA0000304234790000554
抗体h1831K
对h1831抗体进行CDR突变改造，获得36个突变体，最终筛选到N53K(位置根据Kabat编号规则确定)突变体h1831K。即将h1831轻链LCDR2由AASNLES突变为AASKLES，获得新的抗体h1831K。
h1831K轻链：(SEQ ID NO：111)
Figure GPA0000304234790000561
其中LCDR1为RASESVSIHGTHLMH(SEQ ID NO：106)，LCDR2为AASKLES(SEQ ID NO：112)，LCDR3为QQSFEDPLT(SEQ ID NO：108)。
h1831K轻链可变区(SEQ ID NO：113)
Figure GPA0000304234790000562
h1831K重链(与h1831重链序列相同，SEQ ID NO：16)
Figure GPA0000304234790000563
＞h1831K-19-S37重链(与h1831-19-S37重链序列相同，SEQ ID NO：109)
Figure GPA0000304234790000564
＞h1831K-19-S37轻链(与h1831K轻链序列相同，SEQ ID NO：111)
Figure GPA0000304234790000571
S79-Fc(SEQ ID NO：114)
Figure GPA0000304234790000572
S15-Fc(SEQ ID NO：115)
Figure GPA0000304234790000573
S12-Fc(SEQ ID NO：116)
Figure GPA0000304234790000574
S19-Fc(SEQ ID NO：117)
Figure GPA0000304234790000575
Figure GPA0000304234790000581
S85-Fc(SEQ ID NO：118)
Figure GPA0000304234790000582
S38-Fc(SEQ ID NO：119)
Figure GPA0000304234790000583
S22-Fc(SEQ ID NO：120)
Figure GPA0000304234790000584
S29-Fc(SEQ ID NO：121)
Figure GPA0000304234790000585
S34-Fc(SEQ ID NO：122)
Figure GPA0000304234790000591
S41-Fc(SEQ ID NO：123)
Figure GPA0000304234790000592
S42-Fc(SEQ ID NO：124)
Figure GPA0000304234790000593
S43-Fc(SEQ ID NO：125)
Figure GPA0000304234790000594
S44-Fc(SEQ ID NO：126)
Figure GPA0000304234790000595
Figure GPA0000304234790000601
S45-Fc(SEQ ID NO：127)
Figure GPA0000304234790000602
S46-Fc(SEQ ID NO：128)
Figure GPA0000304234790000603
S47-Fc(SEQ ID NO：129)
Figure GPA0000304234790000604
S48-Fc(SEQ ID NO：130)
Figure GPA0000304234790000605
S49-Fc(SEQ ID NO：131)
Figure GPA0000304234790000611
作为阴性对照的IgG4对照为与PD-L1和CD47均无关的靶点的抗体，IgG4-Fc和IgG1-Fc为分别仅含Fc区段，不含针对任何抗原的可变区区段。
测试例
测试例1.PD-L1-CD47双功能融合蛋白结合CD47-his蛋白的ELISA实验
PD-L1-CD47双功能融合蛋白的结合力通过双功能融合蛋白与固定在ELISA板上人CD47或cyno CD47的结合的量来检测。用PBS稀释CD47-ECD-His(见表7)至1μg/ml包被在96孔ELISA板上，洗板封闭后，加入不同浓度的双功能融合蛋白样品，再洗板后加入辣根过氧化物酶-羊抗人(H+L)抗体(Jackson，CAT#109-035-088)，再洗板，加入四甲基联苯胺溶液显色，最后加入终止液，在酶标仪上测量OD450并计算其EC50值，结果见表8-1和表8-2。
表7.不同种系的CD47来源
CD47类型 MW/kDa Cat.No. Lot.No. 生产商
人CD47 15.2 12283-H08H N/A S.B
Cyno CD47 15.8 CD7-C52H1 2171b-76VF1-K9 ACROBiosystems
表8-1.PD-L1-CD47双功能融合蛋白和人CD47及cyno CD47结合ELISA
Figure GPA0000304234790000612
Figure GPA0000304234790000621
表8-2.PD-L1-CD47双功能融合蛋白和人CD47及cyno CD47结合ELISA
Figure GPA0000304234790000622
结果显示，各PD-L1-CD47双功能融合蛋白与游离的人CD47蛋白具有很强的亲和力，同时，与猴CD47也有很强的交叉亲和活力。
测试例2.PD-L1-CD47双功能融合蛋白结合PD-L1-his蛋白的ELISA
PD-L1-CD47双功能融合蛋白的结合力通过抗体与固定在ELISA板上不同种属PD-L1结合的量来检测。用PBS稀释不同种系PD-L1-his抗原(见表9)至1μg/ml包被在96孔ELISA板(Costar，CAT#3590)上，洗板封闭后，加入不同浓度的PD-L1-CD47双功能融合蛋白样品，洗板后加入辣根过氧化物酶-羊抗人(H+L)抗体(Jackson，CAT#109-035-088)，再洗板，加入四甲基联苯胺溶液显色，最后加入终止液，在酶标仪上测量OD450并计算其EC50值，结果见表10。
表9.不同种系的PD-L1来源
PD-L1类型 MW/kDa Cat.No. Lot.No. 生产商
hPD-L1-His 26.8 10084-H08H LC11SE1203 S.B
Cyno PD-L1-His 26.7 90251-C08H LC1ODE1308 S.B
mPD-L1 26.3 50010-M08H LC10N00102 S.B
表10.PD-L1-CD47双功能融合蛋白和不同种属PD-L1结合ELISA
Figure GPA0000304234790000631
结果显示，各PD-L1-CD47双功能融合蛋白与游离的人PD-L1蛋白具有很强的亲和力，同时，与猴PD-L1也有很强的交叉亲和活力。包含h1830抗体的PD-L1-CD47双功能融合蛋白与小鼠PD-L1也有很强的交叉亲和活力。
测试例3.PD-L1-CD47双功能融合蛋白对PD-L1/PD1，PD-L1/B7.1结合的阻断
用PBS将PD-L1-Fc(内部制备)稀释至1μg/ml，以100μl/孔的体积加于96孔板中，于4℃放置16h-20h。将96孔板中PBS缓冲液吸掉，用PBST(pH7.4 PBS含0.05％tween20)缓冲液洗板1次后，加入120μl/孔PBST/1％milk，室温孵育1h进行封闭。移去封闭液，用PBST缓冲液洗板1次后，加入90μl用样品稀释液(pH7.4 PBS含5％BSA，0.05％Tween20)稀释至合适浓度的待测PD-L1-CD47双功能融合蛋白，置4℃预孵育1h。以10μl/孔的体积加入10×浓度的生物素标记PD-1(北京义翘神州生物技术有限公司，10μg/ml)或B7-1(北京义翘神州生物技术有限公司10μg/ml)，在振荡器上振荡、混匀后，置37℃孵育1h。移去反应体系，用PBST洗板6次后，加入100μl/孔用PBST缓冲液1∶400稀释的Streptavidin-Peroxidase Polymer，室温振荡孵育50分钟。用PBST洗板6次后，加入100μl/孔TMB，于室温孵育5-10min。加入100μl/孔1M H2SO4终止反应。用NOVOStar在酶标仪上测量OD450并计算其IC50值，结果见表11。
表11.PD-L1-CD47双功能融合蛋白的阻断ELISA
Figure GPA0000304234790000641
试验结果显示所有双功能融合蛋白也均能有效的对PD-L1/PD-1和PD-L1/B7.1通路产生阻断双功能融合蛋白。
测试例4.PD-L1-CD47双功能融合蛋白结合人的红细胞的实验
新鲜健康人血与PBS等体积混合后，300g离心5min得到细胞团，用PBS洗涤3-5次后，得到红细胞。用FACS buffer(PBS+5％BSA)重悬，调整细胞密度为2×106个/ml，按照100μl/well，种到96孔圆底板(3795#，corning)，然后加入不同浓度的抗体及双功能融合蛋白，4℃孵育1小时。然后用FACS buffer(PBS+2％FBS)洗涤2次后，加入二抗(Alexa 488 goatanti-human IgG antibody(Invitrogen，CAT#A11013)，冰上避光孵育30min。最后用FACSbuffer洗涤2次后再重悬细胞。FACS Cantoll中读板。
FACS检测结果显示，对照抗体hu5F9和Hu167 IgG4AA对人的红细胞表面的天然CD47有较强的结合能力，涉及的双功能融合蛋白中，除含S79，S34和S49的双功能融合蛋白能结合人红细胞表面CD47外，其他双功能融合蛋白对人的红细胞表面的天然CD47几乎没有结合能力，提示上述双功能融合蛋白在安全性方面的优势，结果见图2A、图2B和图2C(其中图2A、图2B和图2C所做实验是三批次实验，所使用供体细胞不同)。
测试例5.PD-L1-CD47双功能融合蛋白结合肿瘤细胞的实验
Raji细胞培养在RPMI培养基中(Hyclone，CAT#SH30809.01B)(含10％胎牛血清)，1×106细胞/ml Raji细胞用5％BSA封闭后，加入双功能融合蛋白样品至10μg/ml，洗两次后，再加入Alexa Fluor 488-羊抗人(H+L)抗体(Invitrogen，CAT#A11013)，洗两次后，流式细胞仪读取荧光信号值。
FACS检测结果显示，涉及的PD-L1-CD47双功能融合蛋白对Raji细胞表面的天然CD47具有很强的结合能力，和对照抗体Hu5F9的结合能力相当，结果见图3。
测试例6.PD-L1-CD47双功能融合蛋白在体外细胞介导的细胞吞噬作用(ADCP)的实验
PBMC分离自新鲜人血，然后利用Human CD14 MicroBeads(130-050-201#，Miltenyi Biotec)分选CD14+单核细胞。这些CD14+单核细胞通过在巨噬细胞分化培养基(1640+10％FBS+50ng/ml M-CSF)中培养9天分化成为巨噬细胞。这些单核细胞来源的巨噬细胞(MDM)变得具有粘附力，长有触角。实验当天，将巨噬细胞用胰酶消化5min，刮刀轻轻刮下，铺在96孔圆底板(3795#)。用0.5μM CFSE(BD，货号565082#)在37℃水浴锅标记人RBC细胞(血红细胞)13分钟，随后PBS清洗2次后，并将其以每个巨噬细胞给予5个RBC细胞的比例添加至巨噬细胞中，并以多种浓度加入PD-L1-CD47双功能融合蛋白。对靶细胞进行2.5小时的吞噬作用。吞噬结束后，用PBS清洗两次，然后按照一定的比例加入人抗体Fc封闭试剂(Human Fc blocker，564219#，BD)，室温放置10分钟，以排除非特异性结合。随后加入标记了APC的CD14抗体(17-0149-42#，Ebioscience)。冰上孵育30分钟。最后清洗2次后通过流式细胞术进行分析。通过在APC+阳性活细胞门选CFSE+阳性细胞，随后评估CSFE+阳性细胞百分比的方式测量吞噬作用(见图4)。
测试例7.PD-L1-CD47双功能融合蛋白在体外细胞介导的细胞吞噬作用(ADCP)的实验
PBMC分离自新鲜人血，然后利用Human CD14 MicroBeads(130-050-201#，Miltenyi Biotec)分选CD14+单核细胞。这些CD14+单核细胞通过在巨噬细胞分化培养基(1640+10％FBS+50ng/ml M-CSF)中培养9天分化成为巨噬细胞。这些单核细胞来源的巨噬细胞(MDM)变得具有粘附力，长有触角。实验当天，将巨噬细胞用胰酶消化5min，刮刀轻轻刮下，铺在96孔圆底板(3795#)。用0.1μM CFSE在37℃水浴锅标记Molp-8细胞(南京科佰)13分钟，随后PBS清洗2次后，并将其以每个巨噬细胞给予5个Molp-8肿瘤细胞的比例添加至巨噬细胞中，并以加入多种浓度的PD-L1-CD47抗体。对靶细胞进行2.5小时的吞噬作用。吞噬结束后，用PBS清洗两次，然后按照一定的比例加入人抗体Fc封闭试剂(Human Fc blocker)，室温放置10分钟，以排除非特异性结合。随后加入标记了APC的CD14抗体。冰上孵育30分钟。最后清洗2次后通过流式细胞术进行分析。通过在APC+阳性活细胞门选，随后评估CSFE+阳性细胞百分比的方式测量吞噬作用(见图5A和图5B)。
测试例6和7的结果见图4和图5A-图5B，显示加入的双功能融合蛋白可以有效促进对肿瘤细胞的吞噬作用。但是双功能融合蛋白对红细胞没有吞噬作用，提示本公开的双功能融合蛋白抗体在安全性方面的潜在优势。而对照抗体hu5F9可以有效的吞噬红细胞。
测试例8.PD-L1-CD47双功能融合蛋白的红细胞凝集实验
新鲜健康人血用PBS(B320#，上海源培生物科技股份有限公司)稀释100倍。稀释后的全血铺到96孔圆底板(3795#，corning)，30μl/well。然后等体积加入不同浓度梯度的抗体或双功能融合蛋白。混匀后，放在37℃静置4-6h。用高内涵显微镜观察红细胞沉降情况。未发生血凝为清晰红点，发生血凝为弥散样。
每个样品从第一列(0.5mg/ml)往后，稀释到第11列，1∶3稀释。第12列是不加抗体的PBS空白孔。
结果显示(见图6)，同样条件下双功能融合蛋白h1830-S37、h1830-S19、h1830-S12、h1830-S15、h1831-19-S58、h1831-19-S79，在测试的不同浓度下均不会引起红细胞凝集，提示本公开的双功能融合蛋白在安全性方面的优势。
测试例9.BIAcore检测PD-L1-CD47双功能融合蛋白的亲和力实验
用Protein A生物传感芯片(Cat.#29127556，GE)亲和捕获IgG，不同抗原(hCD47，cyno CD47，hPD-L1，cyno PD-L1，mPD-L1来源见测试例3，4)流过芯片表面，Biacore T200仪器实时检测双功能融合蛋白和不同抗原反应信号，获得结合和解离曲线。在每个实验循环解离完成后，用10mM Glycine-HCl pH1.5的缓冲液将生物传感芯片洗净再生。实验缓冲体系为1×HBS-EP缓冲溶液(Cat#BR-1001-88，GE)。实验结束后用GE Biacore T200Evaluation version 3.0软件以(1∶1)Langmuir模型拟合数据，得出亲和力数值，结果见表12-1和表12-2。结果显示，所有改造的SIRPγ肽变体与人CD47的亲和力均较野生型SIRPγ肽大幅度提高。
表12-1 抗体对不同抗原的Biacore亲和力(KD(M))
Figure GPA0000304234790000661
Figure GPA0000304234790000671
表12-2 双功能融合蛋白对人CD47的Biacore亲和力(KD(M))
Figure GPA0000304234790000672
测试例10.PD-L1-CD47双功能融合蛋白在PBMC-T淋巴细胞激活实验中对细胞IFNγ的分泌作用
为了研究PD-L1-CD47双功能融合蛋白对人原代T淋巴细胞功能的影响，收集和纯化人外周血单核细胞(PBMC)，采用结核菌素(TB)体外刺激5天后，检测细胞因子IFNγ分泌水平。实验过程简单描述如下：
新鲜血液利用Ficoll-Hypaque(17-5442-02，GE)，密度梯度离心(Stem CellTechnologies)得到PBMC，于RPMI 1640(SH30809.01，GE)培养基中培养，该培养基中添加10％(v/v)FBS(10099-141，Gibco)，37℃，5％CO2条件下培养。
新鲜分离纯化的PBMC以RPMI 1640培养基调整密度为2×106个/ml，20mL细胞悬液中加入40μl结核菌素(97-8800，Synbiotics)，37℃，5％CO2培养箱培养5天。第5天，收集上述培养的细胞离心，重悬至新鲜的RPMI 1640培养基中，调整密度为1.1×106个/ml，接种至96孔细胞培养板，每孔90μl。同时加入梯度稀释的抗体样品，用PBS(B320，上海源培生物科技股份有限公司)稀释，每孔10μl。细胞培养板置于37℃，5％CO2培养箱孵育3天。取出细胞培养板，离心(4000rpm，10min)收集细胞培养上清，采用ELISA的方法(人IFN-γ检测试剂盒：EHC102g.96，欣博盛)，检测IFN-γ的水平。具体操作参考试剂说明书。
结果(见图7A-图7E)显示，在所测试的分子中，所有双功能融合蛋白都可以激活IFN-γ的分泌，和对照抗体HRP00052相当。
测试例11.PD-L1-CD47双功能融合蛋白在小鼠结肠癌模型MC38/H-11-hCD47中的作用
本实验采用B-hCD274/hCD47/hSIRPα小鼠接种人为改造过的鼠结肠癌MC38细胞：MC38/H-11-hCD47(转入人PD-L1和人CD47，敲除鼠CD47和PDL1)，建立小鼠荷瘤模型，并评价不同剂量的PD-L1-CD47双功能融合蛋白h1830-S85，SIRPγ蛋白S58-Fc和PD-L1单抗h1830对鼠结肠癌移植瘤生长抑制的体内药效作用。B-hCD274/hCD47/hSIRPα小鼠购自百奥赛图实验动物，SPF级；体重：22.0±3.0g；性别：雌性。
将MC38/H-11-hCD47(#5-4)细胞以1×106个/100μl/只的接种量接种到B-hCD274/hCD47/hSIRPa小鼠皮下，荷瘤模型确立后，测量肿瘤体积，去除体重、肿瘤过大和过小的动物，按照肿瘤体积大小将荷瘤小鼠随机分为5组(n＝7)：PBS对照组、h1830-S85高剂量组实验组、h1830-S85低剂量组实验组、h1830实验组、S58-Fc实验组，以分组给药日期设定为D0。
1)使用测量瘤径的方法，观察并记录肿瘤的生长情况，同时观察并记录动物体重。
2)肿瘤瘤径和动物体重的测量周期为每周2次。
3)给药后第17天，PBS对照组动物瘤体积较大，遵循动物福利原则，处死PBS实验组动物；给药后第25天，处死剩余实验组动物。
4)肿瘤体积(tumor volume，TV)计算公式：TV＝1/2×a×b2，其中a，b分别代表测量肿瘤的长径和短径。
5)相对肿瘤增殖率T/C％＝(T-T0)/(C-C0)×100％
6)抑瘤率TGI％＝1-T/C％
应用Excel和GraphPad对实验数据进行统计分析，各组动物体重、肿瘤体积、瘤重均用平均值±标准差(Mean±SEM)表示，并用Graphpad Prism 6软件作图。
本实验旨在评价不同剂量的PD-L1-CD47双功能融合蛋白对B-hCD274/hCD47/hSIRPa小鼠鼠结肠癌移植瘤模型中肿瘤生长的抑制作用。本次实验在分组同时开始给予不同抗体或双功能融合蛋白。
如图8，表13的结果显示，不同剂量的双功能融合蛋白(h1830-S85)实验组、PD-L1单抗(h1830)实验组和SIRPγ蛋白S58-Fc实验组肿瘤体积均小于PBS对照组；PD-L1-CD47双功能融合蛋白高剂量实验组抑瘤效应优于同等剂量的PD-L1单抗实验组和SIRPγ蛋白实验组，并且不同剂量的h1830-S85实验组之间存在剂量依赖关系。
实验过程中，给药组与对照组动物体重未出现明显差异，小鼠对各给药抗体耐受良好。
表13.抗体或双功能融合蛋白对小鼠移植瘤的抑瘤作用(TGI％)
Figure GPA0000304234790000691
测试例12.PD-L1-CD47双功能融合蛋白在小鼠结肠癌模型MC38-hPD-L1-hCD47中的作用
将MC38-hPD-L1-hCD47细胞(向MC38细胞转入人PD-L1和人CD47，敲除小鼠CD47)以5.8×105个/100μl/只接种到C57/BL-6小鼠皮下，荷瘤模型确立后，测量肿瘤体积，去除体重、肿瘤过大和过小的动物，按照肿瘤体积大小将荷瘤小鼠随机分为5组(n＝7)：IgG4对照组、h1830-S58实验组、HRP00052实验组、h1830实验组和TTI-621实验组，以分组给药日期设定为D0。分组后腹腔给与各药物，每周三次，共10次，给药周期18天，停药后两天结束对荷瘤小鼠的监测。每周测2次瘤体积，称体重，记录数据。分组及给药情况见下表。本次实验在分组同时开始给予不同抗体，给药后第14天开始，所有实验组给药剂量减半；给药后第25天开始，所有实验组停止给药。
表14.实验分组及给药情况
Figure GPA0000304234790000692
注：i.p表示腹腔注射，q.o.d表示隔一天给药一次。
各组动物体重、肿瘤体积以及瘤重均用平均值±标准差(Mean±SEM)表示，并用Graphpad Prism 6和Excel软件作图，使用student t test统计分析。
肿瘤体积(TV)＝1/2×L长×L短 2
肿瘤增殖率T/C％＝(T-T0)/(C-C0)×100％
抑瘤率％TGI＝1-T/C％
如图9结果显示，与小鼠PD-L1存在交叉反应的PD-L1-CD47双功能融合蛋白h1830-S58实验组和PD-L1单抗(h1830)实验组肿瘤体积均小于对照组和TTI-621实验组，并且在给药后一周左右与对照组之间出现统计学差异；TTI-621实验组在本次实验中未表现出抑瘤效应。h1830-S58实验组在给药后7天抑瘤率达到128.51％，至实验结束，抑瘤率维持在较高的水平。
实验结束后对荷瘤小鼠进行安乐死并剥瘤称重，瘤重结果与瘤体积大小存在一定相似性。实验过程中，给药组与对照组动物体重未出现明显差异，小鼠对各给药抗体耐受良好。
测试例13.PD-L1-CD47双功能融合蛋白在小鼠结肠癌模型MC38-hPD-L1中的作用
将MC38-hPD-L1细胞(向MC38细胞转入人PD-L1)以3.5×105个/100μl/只接种到C57/BL-6小鼠皮下，荷瘤模型确立后，测量肿瘤体积，去除体重、肿瘤过大和过小的动物，按照肿瘤体积大小将荷瘤小鼠随机分为5组(n＝7)：IgG4对照组、h1830-19-S79实验组、h1830G1-19-S79实验组、SIRPα-CV实验组和h1830实验组，以分组给药日期设定为D0。分组后腹腔给与各药物，每周三次，共12次，给药周期28天，停药后两天结束对荷瘤小鼠的监测。每周测2次瘤体积，称体重，记录数据。分组及给药情况见下表。
表15.实验分组及给药情况
Figure GPA0000304234790000701
各组动物体重、肿瘤体积以及瘤重均用平均值±标准差(Mean±SEM)表示，并用Graphpad Prism 5和Excel软件作图，使用student t test统计分析。
肿瘤体积(TV)＝1/2×L长×L短 2
肿瘤增殖率T/C％＝(T-T0)/(C-C0)×100％
抑瘤率％TGI＝1-T/C％
本实验旨在检测不同IgG形式的PD-L1-CD47双功能融合蛋白对C57/BL-6小鼠结肠癌移植瘤模型中肿瘤生长的抑制作用。本次实验在分组同时开始给予不同抗体，给药后第14天开始，所有实验组给药剂量减半；给药后第25天开始，所有实验组停止给药。
如图10结果显示，截止至给药后第25天，所有双功能融合蛋白给药组和PD-L1单抗h1830给药组肿瘤体积均小于IgG4对照组和SIRPα-CV(TTI-621)实验组，并且与对照组之间存在统计学差异。
给药后第25天后，对照组和SIRPα-CV(TTI-621)实验组由于肿瘤体积较大，对小鼠进行安乐死处理，剩余实验组则停药继续观察。结果显示，PD-L1单抗h1830实验组肿瘤体积随着时间的推移呈现出快速回升的趋势，双功能融合蛋白h1830-19-S79和h1830G1-19-S79实验组肿瘤体积未发生明显变化，且这两种不同IgG形式的双抗之间也没有显著性差异。
实验结束后对荷瘤小鼠进行安乐死并剥瘤称重，瘤重结果与瘤体积大小存在一定相似性，给药组与对照组动物体重未出现明显差异，小鼠对各给药抗体耐受良好。
测试例14.PD-L1-CD47双功能融合蛋白对MOLP-8移植瘤裸鼠疗效
Balb/c裸鼠在右肋部皮下接种MOLP-8细胞(5×106+50％matrigel/只)，共120只。10d后，按照平均瘤体积约214.89±6.75mm3。将荷瘤小鼠随机分为7组(n＝8)：PBS对照组、h1830-S37实验组、h1830-S58实验组、h1831K-19-S37、h1830实验组、S37-Fc、和Hu167IgG4AA实验组，以分组给药日期设定为D0。分组后腹腔给与各药物，一周二次，连续给药3周。每周测2次瘤体积，称体重，记录数据。各组动物体重、肿瘤体积以及瘤重均用平均值±标准差(Mean±SEM)表示，并用Graphpad Prism 6和Excel软件作图，使用student t test统计分析。
肿瘤体积(V)计算公式为：V＝1/2×L长×L短 2
相对体积(RTV)＝VT/V0
抑瘤率(％)＝(CRTV-TRTV)/CRTV(％)
其中V0、VT分别为实验开始时及实验结束时的肿瘤体积。CRTV、TRTV分别为实验结束时的空白对照组(Blank)及实验组的相对肿瘤体积。
本次实验结果显示(见图11)，腹腔注射、隔天一次，连续给药10次。以实验进行到21天时的数据进行统计。PD-L1-CD47双功能融合蛋白h1830-S37(30mpk)抑瘤率达到34.98％(P＜0.05)；双功能融合蛋白h1831K-19-S37(30mpk)抑瘤率达到54.18％(P＜0.01)；h1830(25mpk)没有抑制该肿瘤生长的作用。
给药过程中各组动物体重正常，提示各双功能融合蛋白无明显毒副作用。
测试例15.PD-L1-CD47双功能融合蛋白对CD47/SIRPα结合的阻断
用PBS将CD47-Fc稀释至1μg/ml，以100μl/孔的体积加于96孔板中，于4℃放置16h-20h。将96孔板中PBS缓冲液吸掉，用PBST(pH7.4 PBS含0.05％tween20)缓冲液洗板1次后，加入120μl/孔PBST/1％milk，室温孵育1h进行封闭。移去封闭液，用PBST缓冲液洗板1次后，加入90μl用样品稀释液(pH7.4PBS含5％BSA，0.05％Tween20)稀释至合适浓度的待测PD-L1-CD47双功能融合蛋白，置4℃预孵育1h。以10μl/孔的体积加入10×浓度的生物素标记SIRPα-his(5μg/ml)，在振荡器上振荡、混匀后，置37℃孵育1h。移去反应体系，用PBST洗板6次后，加入100μl/孔用PBST缓冲液1∶400稀释的Streptavidin-Peroxidase Polymer，室温振荡孵育50分钟。用PBST洗板6次后，加入100μl/孔TMB，于室温孵育5-10min。加入100μl/孔1M H2SO4终止反应。用NOVOStar在酶标仪上测量OD450并计算其IC50值，结果见表16。
表16.双特异性抗体对CD47/SIRPα结合的阻断结果
样品 IC50(ng/ml)
h1831K-19-S37 251.7
S37-Fc 566
TTI-621 25985
Hu5F9 263.1
结果显示双功能融合蛋白能有效阻断CD47与SIRPα的通路。
测试例16.PD-L1-CD47双功能融合蛋白对人乳腺癌细胞MDA-MB-231移植瘤的疗效
将MDA-MB-231细胞(ATCC)3×106cells/200μl/mouse(含50％基质胶)接种于NOD/SCID小鼠右肋部皮下，当荷瘤小鼠平均肿瘤体积达到145mm3左右时将小鼠随机分为4组：PBS、h1831K-19-S37-30mpk、h1831K-19-S37-10mpk、h1831K-25mpk(与h1831K-19-S37高剂量保持等摩尔浓度)，每组8只，并将分组当天定义为该实验Day0。Day0时将经CD3抗体刺激3天的两名志愿者的PBMCs以1∶1比例混合，以5×105cells/100μl/mouse注射到小鼠肿瘤组织中，剩余的PBMCs停止刺激并继续培养，1周后以5×106cells/100μl/mouse腹腔注射到荷瘤鼠体内，视为第1轮注射，至实验结束共注射两轮轮PBMCs。Day0开始每周三次腹腔注射各待测抗体。每周2次监测肿瘤体积、动物重量并记录数据。当肿瘤体积超过1000mm3或多数肿瘤出现破溃或体重下降20％时，将荷瘤动物进行安乐死作为实验终点。
所有数据使用Excel和GraphPad Prism 5软件进行作图及统计分析。
肿瘤体积(V)计算公式为：V＝1/2×a×b2其中a、b分别表示长、宽。
相对肿瘤增殖率T/C(％)＝(T-T0)/(C-C0)×100其中T、C为实验结束时治疗组和对照组的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
抑瘤率TGI(％)＝1-T/C(％)。
实验结果显示，在人乳腺癌MDA-MB-231小鼠皮下移植瘤模型中，PDL1-CD47双特异性抗体h1831K-19-S37、及PDL1单抗h1831K均表现出良好的抑瘤效果(p＜0.001 vs PBS)。
PD-L1-CD47双特异性抗体h1831K-19-S37(30、10mg/kg)能显著抑制人乳腺癌MDA-MB-231小鼠皮下移植瘤的生长，且高低剂量间呈剂量依赖性。从给药后3天开始至实验结束(Day23)，无论是高剂量组还是低剂量组，h1831K-19-S37的抑瘤效果始终优于高剂量的PD-L1单抗对照h1831K(25mg/kg)(p＜0.001)，且高低剂量间也存在统计学差异(p＜0.01)(表17)。
实验终点将荷瘤小鼠安乐死，剥离肿瘤并测量瘤重，结果显示离体的肿瘤重量与肿瘤体积趋势相符，所有给药组均显著优于对照组(p＜0.001)，双特异性抗体h1831K-19-S37的高低剂量组均优于高剂量的PDL1单抗对照h1831K(25mg/kg，p＜0.001)，且h1831K-19-S37的高低剂量之间存在剂量效应。
荷瘤小鼠对PDL1-CD47双特异性抗体及其单抗均耐受良好，在整个给药过程中体重只有轻微波动，无明显药物致体重减轻等症状发生。
表17.双特异性抗体对小鼠皮下移植瘤的抑制效果
Figure GPA0000304234790000731
注：第0天：第一次给药时间。***表示p＜0.001 vs PBS通过student T test测定.
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Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr
115 120 125
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
130 135 140
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
145 150 155 160
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
165 170 175
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
180 185 190
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
195 200 205
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
210 215 220
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
225 230 235 240
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
245 250 255
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
260 265 270
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
275 280 285
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
290 295 300
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
305 310 315 320
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
325 330 335
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 6
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 9-2 H5重链可变区
<400> 6
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 7
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 9-2 L11轻链可变区
<400> 7
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Tyr His
20 25 30
Ser Asn Gln Lys His Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Gly Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 8
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 24D5 H12重链可变区
<400> 8
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 9
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 24D5 L61轻链可变区
<400> 9
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ile His
20 25 30
Gly Thr His Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Phe
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 10
<211> 327
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> IgG4-S228P的重链恒定区
<400> 10
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 11
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> IgG1的重链恒定区
<400> 11
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 12
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 抗体的轻链（Kappa链）恒定区
<400> 12
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 13
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830重链
<400> 13
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 14
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830轻链
<400> 14
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Phe Tyr His
20 25 30
Ser Asn Gln Lys His Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Gly Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 15
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830G1重链
<400> 15
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 16
<211> 445
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831重链
<400> 16
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 17
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831轻链
<400> 17
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ile His
20 25 30
Gly Thr His Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Phe
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 18
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830G1重链
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 19
<211> 357
<212> DNA
<213> Homo sapiens
<220>
<221> gene
<223> 野生型SIRPγ肽的 DNA编码序列
<400> 19
gaggaggagc tacagatgat tcagcctgag aagctcctgt tggtcacagt tggaaagaca 60
gccactctgc actgcactgt gacctccctg cttcccgtgg gacccgtcct gtggttcaga 120
ggagttggac caggccggga attaatctac aatcaaaaag aaggccactt ccccagggta 180
acaacagttt cagacctcac aaagagaaac aacatggact tttccatccg catcagtagc 240
atcaccccag cagatgtcgg cacatactac tgtgtgaagt ttcgaaaagg gagccctgag 300
aacgtggagt ttaagtctgg accaggcact gagatggctt tgggtgccaa accctct 357
<210> 20
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 野生型SIRPγ肽
<400> 20
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Lys Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asn Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 21
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S58
<400> 21
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 22
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S79
<400> 22
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Trp Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Arg Thr Gly Thr Gly Arg Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Val
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 23
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S15
<400> 23
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 24
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S12
<400> 24
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 25
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S19
<400> 25
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 26
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S85
<400> 26
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 27
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S37
<400> 27
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 28
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S38
<400> 28
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Phe Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 29
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S22
<400> 29
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Ile Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 30
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S29
<400> 30
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Leu Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 31
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S34
<400> 31
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Arg Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 32
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S41
<400> 32
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 33
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S42
<400> 33
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Ile Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 34
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S43
<400> 34
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 35
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S44
<400> 35
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Val Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 36
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S45
<400> 36
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asp Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 37
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S46
<400> 37
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 38
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S47
<400> 38
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Val
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 39
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S48
<400> 39
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Arg Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 40
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S49
<400> 40
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Arg Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser
115
<210> 41
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S58含重链部分
<400> 41
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 42
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S15含重链部分
<400> 42
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Glu Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 43
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S12含重链部分
<400> 43
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 44
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S19含重链部分
<400> 44
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 45
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S85含重链部分
<400> 45
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 46
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S37含重链部分
<400> 46
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 47
<211> 584
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-19-S79含重链部分
<400> 47
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val
465 470 475 480
Thr Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Trp
485 490 495
Pro Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu
500 505 510
Leu Ile Tyr Arg Thr Gly Thr Gly Arg Phe Pro Arg Val Thr Thr Val
515 520 525
Ser Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser
530 535 540
Ser Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg
545 550 555 560
Lys Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu
565 570 575
Val Ala Leu Gly Ala Lys Pro Ser
580
<210> 48
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S79含重链部分
<400> 48
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Trp Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Arg Thr Gly Thr Gly Arg Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Val Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 49
<211> 589
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830G1-19-S79含重链部分
<400> 49
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Gly Gly Gly Gly Glu Glu Glu Leu Gln Met Ile Gln Pro Glu
465 470 475 480
Lys Leu Leu Leu Val Thr Val Gly Glu Thr Ala Thr Leu His Cys Thr
485 490 495
Val Thr Ser Leu Trp Pro Val Gly Pro Val Leu Trp Phe Arg Gly Val
500 505 510
Gly Pro Gly Arg Glu Leu Ile Tyr Arg Thr Gly Thr Gly Arg Phe Pro
515 520 525
Arg Val Thr Thr Val Ser Asp Leu Thr Lys Arg Asn Asn Met Asp Phe
530 535 540
Ser Ile Arg Ile Ser Ser Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr
545 550 555 560
Cys Val Lys Phe Arg Lys Gly Ser Pro Glu Asp Val Glu Phe Lys Ser
565 570 575
Gly Pro Gly Thr Glu Val Ala Leu Gly Ala Lys Pro Ser
580 585
<210> 50
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S38含重链部分
<400> 50
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Phe Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 51
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S22含重链部分
<400> 51
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Ile Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 52
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S29含重链部分
<400> 52
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Leu Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 53
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S34含重链部分
<400> 53
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Arg Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 54
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S41
<400> 54
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 55
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S42含重链部分
<400> 55
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Ile Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 56
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S43含重链部分
<400> 56
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 57
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S44含重链部分
<400> 57
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Val Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 58
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S45含重链部分
<400> 58
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asp Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 59
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S46含重链部分
<400> 59
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 60
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S47含重链部分
<400> 60
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Val Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 61
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S48含重链部分
<400> 61
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Arg Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 62
<211> 581
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1830-S49含重链部分
<400> 62
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asp Gly
20 25 30
Ser Ala Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Tyr Ile Gly Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser
50 55 60
Leu Lys Gly Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu
450 455 460
Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly
465 470 475 480
Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly
485 490 495
Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr
500 505 510
Arg Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu
515 520 525
Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr
530 535 540
Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser
545 550 555 560
Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu
565 570 575
Gly Ala Lys Pro Ser
580
<210> 63
<211> 583
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-19-S58含重链部分
<400> 63
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
465 470 475 480
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
485 490 495
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
500 505 510
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
515 520 525
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
530 535 540
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
545 550 555 560
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
565 570 575
Ala Leu Gly Ala Lys Pro Ser
580
<210> 64
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S15含重链部分
<400> 64
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Val
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Glu Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 65
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S12含重链部分
<400> 65
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Val
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 66
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S19含重链部分
<400> 66
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Val
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 67
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S85含重链部分
<400> 67
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Val
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 68
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S37含重链部分
<400> 68
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Met
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 69
<211> 583
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-19-S79含重链部分
<400> 69
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
465 470 475 480
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Trp Pro
485 490 495
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
500 505 510
Ile Tyr Arg Thr Gly Thr Gly Arg Phe Pro Arg Val Thr Thr Val Ser
515 520 525
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
530 535 540
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
545 550 555 560
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Val
565 570 575
Ala Leu Gly Ala Lys Pro Ser
580
<210> 70
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S38含重链部分
<400> 70
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Phe
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 71
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S22含重链部分
<400> 71
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Ile
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 72
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S29含重链部分
<400> 72
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Leu
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 73
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S34含重链部分
<400> 73
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Arg
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 74
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S41含重链部分
<400> 74
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Val
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 75
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S42含重链部分
<400> 75
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Met
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Ile Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 76
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S43含重链部分
<400> 76
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Met
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 77
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S44含重链部分
<400> 77
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Met
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Val Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 78
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S45含重链部分
<400> 78
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Met
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asp Asn Met Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 79
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S46含重链部分
<400> 79
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Met
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 80
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S47含重链部分
<400> 80
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Met
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Val Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 81
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S48含重链部分
<400> 81
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Arg
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 82
<211> 580
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1831-S49含重链部分
<400> 82
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Glu Glu Glu
450 455 460
Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr Val Gly Glu
465 470 475 480
Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro Val Gly Pro
485 490 495
Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu Ile Tyr Arg
500 505 510
Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser Asp Leu Thr
515 520 525
Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser Ile Thr Pro
530 535 540
Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro
545 550 555 560
Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met Ala Leu Gly
565 570 575
Ala Lys Pro Ser
580
<210> 83
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> Hu5F9重链
<400> 83
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 84
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> Hu5F9轻链
<400> 84
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val Tyr Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 85
<211> 351
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> SIRPα-CV
<400> 85
Glu Glu Glu Leu Gln Ile Ile Gln Pro Asp Lys Ser Val Leu Val Ala
1 5 10 15
Ala Gly Glu Thr Ala Thr Leu Arg Cys Thr Ile Thr Ser Leu Phe Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Gly Arg Val Leu
35 40 45
Ile Tyr Asn Gln Arg Gln Gly Pro Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Thr Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Gly Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Ile Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Asp Val Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu
100 105 110
Ser Val Arg Ala Lys Pro Ser Glu Pro Lys Ser Ser Asp Lys Thr His
115 120 125
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
130 135 140
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
145 150 155 160
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
165 170 175
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
180 185 190
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
195 200 205
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
210 215 220
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
225 230 235 240
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
245 250 255
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
260 265 270
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
275 280 285
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
290 295 300
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
305 310 315 320
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
325 330 335
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 86
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S58-Fc
<400> 86
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 87
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> Hu167-IgG4 AA重链
<400> 87
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Tyr Leu Gly Arg Ser Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 88
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> Hu167-IgG4 AA轻链
<400> 88
Asp Val Gln Ile Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Lys Ser Ile Ser Lys Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Asn Glu Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 89
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> GGGGS
<400> 89
Gly Gly Gly Gly Ser
1 5
<210> 90
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> GS16
<400> 90
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly
1 5 10 15
<210> 91
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> GS17
<400> 91
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly
<210> 92
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> GGGGSGGGGSGGGGSGGG
<400> 92
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly
<210> 93
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> GS19
<400> 93
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly
<210> 94
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 30AA-linker
<400> 94
Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Gly Gly Gly Gly
1 5 10 15
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
20 25 30
<210> 95
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> GKPGS
<400> 95
Gly Lys Pro Gly Ser
1 5
<210> 96
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> GGGES
<400> 96
Gly Gly Gly Glu Ser
1 5
<210> 97
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 9-2 H5L11 HCDR1
<400> 97
Asp Gly Ser Ala Tyr Trp Ser
1 5
<210> 98
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 9-2 H5L11 HCDR2
<400> 98
Phe Ile Ser Arg Ala Gly Ser Thr Tyr Asn Thr Pro Ser Leu Lys Gly
1 5 10 15
<210> 99
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 9-2 H5L11 HCDR3
<400> 99
Ser Gly Gly Trp Leu Ala Pro Phe Asp Tyr
1 5 10
<210> 100
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 9-2 H5L11 LCDR1
<400> 100
Lys Ser Ser Gln Ser Leu Phe Tyr His Ser Asn Gln Lys His Ser Leu
1 5 10 15
Ala
<210> 101
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 9-2 H5L11 LCDR2
<400> 101
Gly Ala Ser Thr Arg Glu Ser
1 5
<210> 102
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 9-2 H5L11 LCDR3
<400> 102
Gln Gln Tyr Tyr Gly Tyr Pro Tyr Thr
1 5
<210> 103
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 24D5 H12L61 HCDR1
<400> 103
Ser Tyr Trp Met His
1 5
<210> 104
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 24D5 H12L61 HCDR2
<400> 104
Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe Lys
1 5 10 15
Asn
<210> 105
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 24D5 H12L61 HCDR3
<400> 105
Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr
1 5 10
<210> 106
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 24D5 H12L61 LCDR1
<400> 106
Arg Ala Ser Glu Ser Val Ser Ile His Gly Thr His Leu Met His
1 5 10 15
<210> 107
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 24D5 H12L61 LCDR2
<400> 107
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 108
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 24D5 H12L61 LCDR3
<400> 108
Gln Gln Ser Phe Glu Asp Pro Leu Thr
1 5
<210> 109
<211> 583
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> h1831-19-S37重链
<400> 109
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Thr Pro Ser Ser Gly Phe Ala Met Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ser Ser Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
465 470 475 480
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
485 490 495
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
500 505 510
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
515 520 525
Asp Leu Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
530 535 540
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
545 550 555 560
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
565 570 575
Ala Leu Gly Ala Lys Pro Ser
580
<210> 110
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S37-Fc
<400> 110
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 111
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> h1831K轻链
<400> 111
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ile His
20 25 30
Gly Thr His Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Lys Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Phe
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 112
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> h1831K LCDR2
<400> 112
Ala Ala Ser Lys Leu Glu Ser
1 5
<210> 113
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> h1831K轻链可变区
<400> 113
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ile His
20 25 30
Gly Thr His Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Lys Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Phe
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 114
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S79-Fc
<400> 114
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Trp Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Arg Thr Gly Thr Gly Arg Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Val
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 115
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S15-Fc
<400> 115
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 116
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S12-Fc
<400> 116
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 117
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S19-Fc
<400> 117
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 118
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S85-Fc
<400> 118
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 119
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S38-Fc
<400> 119
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Phe Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 120
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S22-Fc
<400> 120
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Ile Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 121
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S29-Fc
<400> 121
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Leu Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 122
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S34-Fc
<400> 122
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Arg Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 123
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S41-Fc
<400> 123
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Val Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 124
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S42-Fc
<400> 124
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Ile Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 125
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S43-Fc
<400> 125
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Arg Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 126
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S44-Fc
<400> 126
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Val Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 127
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S45-Fc
<400> 127
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asp Asn Met Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 128
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S46-Fc
<400> 128
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 129
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S47-Fc
<400> 129
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Met Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Val
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 130
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S48-Fc
<400> 130
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Arg Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Asn Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 131
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> S49-Fc
<400> 131
Glu Glu Glu Leu Gln Met Ile Gln Pro Glu Lys Leu Leu Leu Val Thr
1 5 10 15
Val Gly Glu Thr Ala Thr Leu His Cys Thr Val Thr Ser Leu Leu Pro
20 25 30
Val Gly Pro Val Leu Trp Phe Arg Gly Val Gly Pro Gly Arg Glu Leu
35 40 45
Ile Tyr Arg Ser Gly Arg Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Asp Leu Thr Lys Arg Glu Asn Lys Asp Phe Ser Ile Arg Ile Ser Ser
65 70 75 80
Ile Thr Pro Ala Asp Val Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Glu Asp Val Glu Phe Lys Ser Gly Pro Gly Thr Glu Met
100 105 110
Ala Leu Gly Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
115 120 125
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
130 135 140
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
145 150 155 160
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
165 170 175
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
180 185 190
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
195 200 205
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
210 215 220
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
225 230 235 240
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
245 250 255
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
260 265 270
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
275 280 285
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
290 295 300
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
305 310 315 320
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
325 330 335
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
340 345
<210> 132
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<221> PEPTIDE
<223> 带His标签的SIRPα蛋白胞外域
<400> 132
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser His His His His His His
115 120
<210> 133
<211> 345
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> TTI-621
<400> 133
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
115 120 125
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
130 135 140
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
145 150 155 160
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
165 170 175
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
180 185 190
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
195 200 205
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
210 215 220
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
225 230 235 240
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
245 250 255
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
260 265 270
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
275 280 285
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
290 295 300
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
305 310 315 320
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
325 330 335
Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345

Claims (18)

1.一种双功能融合蛋白，所述双功能融合蛋白包含SIRPγ肽变体和抗人PD-L1抗体，所述SIRPγ肽变体通过连接子连接至所述抗人PD-L1抗体的多肽链，
所述SIRPγ肽变体如SEQ ID NO：21、22、23、24、25、26或27中的任一所示；所述连接子选自SEQ ID NO：89-96和（GGGGS）n、（GGGES）n和（GKPGS）n中的任一个，其中n=2-7的整数；其中所述抗人PD-L1抗体的重链的羧基端与所述SIRPγ肽变体的氨基端连接；
其中所述抗人PD-L1抗体包含重链可变区和轻链可变区，其中：
所述重链可变区包含分别如SEQ ID NO：97、98和99所示的HCDR1、HCDR2和HCDR3区，和所述轻链可变区包含分别如SEQ ID NO：100、101和102所示的LCDR1、LCDR2和LCDR3区；或
所述重链可变区包含分别如SEQ ID NO：103、104和105所示的HCDR1、HCDR2和HCDR3区，和所述轻链可变区包含分别如SEQ ID NO：106、107和108所示的LCDR1、LCDR2和LCDR3区；或
所述重链可变区包含分别如SEQ ID NO：103、104和105所示的HCDR1、HCDR2和HCDR3区，和所述轻链可变区包含分别如SEQ ID NO：106、112和108所示的LCDR1、LCDR2和LCDR3区。
2.根据权利要求1所述的双功能融合蛋白，其中所述的抗人PD-L1抗体包含重链可变区和轻链可变区，其中：
所述重链可变区为SEQ ID NO：6所示，和所述轻链可变区为SEQ ID NO：7所示；或
所述重链可变区为SEQ ID NO：8所示，和所述轻链可变区为SEQ ID NO：113所示；或
所述重链可变区为SEQ ID NO：8所示，和所述轻链可变区为SEQ ID NO：9所示。
3.根据权利要求1或2所述的双功能融合蛋白，其中所述抗人PD-L1抗体还包括重链恒定区和轻链恒定区。
4.根据权利要求3所述的双功能融合蛋白，所述重链恒定区如SEQ ID NO:10或11所示，所述轻链恒定区如SEQ ID NO:12所示。
5.根据权利要求4所述的双功能融合蛋白，其中所述抗人PD-L1抗体包含重链和轻链，其中所述重链如SEQ ID NO：13或15所示，所述轻链如SEQ ID NO：14所示；或
所述重链如SEQ ID NO：16或18所示，所述轻链如SEQ ID NO：17或111所示。
6.根据权利要求5所述的双功能融合蛋白，其中所述双功能融合蛋白具有第一多肽和第二多肽，其中：
所述第一多肽选自如SEQ ID NO：41、42、43、44、45、46、47、48和49中任一所示的多肽，和所述第二多肽选自如SEQ ID NO：14所示的多肽；或
所述第一多肽选自如SEQ ID NO：63、68、69和109中任一所示的多肽，和所述第二多肽选自如SEQ ID NO：17所示的多肽；或
所述第一多肽选自如SEQ ID NO：109所示的多肽，和所述第二多肽选自如SEQ ID NO：111所示的多肽。
7.一种SIRPγ肽变体，其中所述SIRPγ肽变体如SEQ ID NO：21、22、23、24、25、26或27所示。
8.一种融合蛋白，其包含SIRPγ肽变体和抗体Fc片段，所述SIRPγ肽变体为权利要求7所述SIRPγ肽变体。
9.根据权利要求8所述的融合蛋白，其中所述抗体Fc片段为人抗体Fc片段。
10.根据权利要求8或9所述的融合蛋白，其中所述抗体Fc片段序列与SEQ ID NO：10或11所述重链恒定区中的Fc片段序列相同。
11.根据权利要求10所述的融合蛋白，其中所述融合蛋白的氨基酸序列如SEQ ID NO：86、110、114、115、116、117或118所示。
12.一种药物组合物，其含有治疗有效量的根据权利要求1至6任一项所述的双功能融合蛋白，以及一种或多种药学上可接受的载体、稀释剂、缓冲剂或赋形剂。
13.一种分离的核酸分子，其编码权利要求1至6任一项所述的双功能融合蛋白。
14.一种重组载体，其包含权利要求13所述的分离的核酸分子。
15.权利要求1至6任一项所述的双功能融合蛋白在制备用于消除受试者免疫抑制相关疾病的药物中的用途，其中所述免疫抑制相关疾病为癌症。
16.根据权利要求15的用途，所述癌症选自癌瘤、淋巴瘤和白血病。
17.根据权利要求15的用途，所述癌症选自骨髓瘤、小细胞肺癌、非小细胞肺癌、头和颈鳞状细胞癌、神经胶质瘤、何杰金淋巴瘤、非何杰金淋巴瘤、弥漫性大B-细胞淋巴瘤、急性髓细胞样白血病、胃肠道癌、卵巢癌、肝癌、结肠直肠癌、子宫内膜癌、***癌、甲状腺癌、黑素瘤、胰腺癌、骨癌、尤因氏肉瘤、子***、脑癌、膀胱癌、乳腺癌、透明细胞肾细胞癌、咽喉癌、肝胆癌、中枢神经***癌、食管癌、恶性胸膜间皮瘤、神经内分泌肿瘤睾丸癌和皮肤癌。
18.根据权利要求15的用途，所述癌症选自鳞状细胞癌、多发性骨髓瘤、骨髓异常增生综合征、结肠癌、肝细胞癌、软骨肉瘤、神经母细胞瘤、多形性成胶质细胞瘤、头和颈癌和梅克尔细胞癌。
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