CN112533944A - 多特异性结合蛋白及其改进 - Google Patents
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Abstract
本发明提供了对单链可变片段(scFv)抗体的改进、多特异性结合蛋白、包含此类蛋白质的药物组合物,以及使用此类蛋白质和药物组合物的治疗方法,包括用于治疗癌症。
Description
相关申请的交叉引用
本申请要求2018年5月28日提交的美国临时专利申请62/677,137的权益和优先权,所述申请的公开内容出于所有目的据此以引用方式整体并入。
序列表
本申请含有已经以ASCII格式电子递交的序列表,并且该序列表据此以引用方式整体并入。所述ASCII副本创建于2019年5月28日,名称为DFY-049WO_SL_ST25.txt并且大小为340,101字节。
技术领域
本发明提供了对单链可变片段(scFv)抗体的改进和多特异性结合蛋白、包含此类蛋白质的药物组合物,以及使用此类蛋白质和药物组合物的治疗方法,包括用于治疗癌症。
背景技术
尽管在文献中报道了治疗癌症的大量研究尝试和科学进展,但这种疾病依然是重大的健康问题。一些最经常诊断到的癌症包括前列腺癌、乳腺癌和肺癌。前列腺癌是男性中最常见的癌症形式。乳腺癌仍然是女性死亡的主要原因。当前用于这些癌症的治疗选项不是对于所有患者都有效的和/或可能具有大量的不良副作用。其他类型的癌症对于使用现有治疗选项治疗来说也仍然具有挑战性。
癌症免疫疗法是理想的,因为它们是高度特异性的并且可以使用患者自身的免疫系统促进癌细胞的破坏。融合蛋白诸如双特异性T细胞衔接器是文献中描述的与肿瘤细胞和T细胞结合以促进肿瘤细胞破坏的癌症免疫疗法。与某些肿瘤相关抗原和某些免疫细胞结合的抗体在文献中已有描述。参见,例如WO 2016/134371和WO 2015/095412。
自然杀伤(NK)细胞是先天免疫系统的组成部分并占循环淋巴细胞的大约15%。NK细胞几乎浸润所有组织,并且最初因其不需前期致敏即可有效杀伤肿瘤细胞的能力而被表征。激活的NK细胞通过与细胞毒性T细胞相似的手段杀伤靶细胞-即,通过含有穿孔素和颗粒酶的细胞溶解颗粒以及通过死亡受体途径。激活的NK细胞还分泌炎性细胞因子诸如IFNγ和促进其他白细胞向靶组织的募集的趋化因子。
NK细胞通过其表面上的多种激活和抑制受体对信号做出响应。例如,当NK细胞遇到健康的自体细胞时,其活性通过杀伤细胞免疫球蛋白样受体(KIR)的激活而被抑制。可替代地,当NK细胞遇到外来细胞或癌细胞时,则通过其激活受体(例如,NKG2D、NCR、DNAM1)被激活。NK细胞还通过其表面上的CD16受体被一些免疫球蛋白的恒定区激活。NK细胞对激活的总体敏感度取决于刺激性和抑制性信号的总和。NKG2D是基本上由所有自然杀伤细胞表达的II型跨膜蛋白,在其中NKG2D用作激活受体。NKG2D也存在于T细胞上,在其中它充当共刺激受体。通过NKG2D调节NK细胞功能的能力在包括恶性肿瘤的各种治疗背景中是有用的。
发明内容
在一个方面,本发明提供对通过铰链序列与抗体恒定结构域连接的单链可变片段(scFv)的改进。在一些实施方案中,铰链包含氨基酸Ala-Ser。在一些其他实施方案中,铰链包含氨基酸Ala-Ser和Thr-Lys-Gly。scFv可包括重链可变结构域和轻链可变结构域。在一些实施方案中,scFv结合NKG2D或肿瘤相关抗原。铰链序列提供与靶抗原结合的灵活性。
在scFv的一些实施方案中,重链可变结构域与轻链可变结构域形成二硫桥。例如,可以在重链可变结构域的C44残基与轻链可变结构域的C100残基之间形成二硫桥。在一些实施方案中,重链可变结构域通过柔性接头诸如(G4S)4(SEQ ID NO:427)与轻链可变结构域连接。在scFv的一些实施方案中,重链可变结构域位于轻链可变结构域的N端。在scFv的一些实施方案中,重链可变结构域位于轻链可变结构域的C端。
在一些实施方案中,与scFv连接的抗体恒定结构域能够与CD16结合。在一些实施方案中,抗体恒定结构域包含IgG抗体例如人IgG1抗体的CH2结构域和CH3结构域。在一些实施方案中,将突变引入抗体恒定结构域中,使其能够与另一抗体恒定结构域异二聚化。例如,如果抗体恒定结构域衍生自人IgG1的恒定结构域,那么所述抗体恒定结构域可以包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列,并且在选自由以下组成的组的一个或多个位置上有所不同:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和K439。在一些实施方案中,抗体恒定结构域可以包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列,并且不同之处在于选自由以下组成的组的一个或多个取代:Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、T411D、T411E、K439D和K439E。
在另一方面,本发明提供了一种蛋白质,其包含上述与抗体恒定区连接的scFv。在一些实施方案中,所述蛋白质包括第一抗原结合位点,其包含与抗体恒定结构域连接的scFv;第二抗原结合位点,其可采取Fab或此处所述的scFv形式;以及与第二抗原结合位点连接的第二抗体恒定结构域。在一些实施方案中,所述蛋白质是多特异性的,其中第一抗原结合位点结合NKG2D,第二抗原结合位点结合肿瘤相关抗原,并且抗体恒定区结合CD16。
在一些其他实施方案中,所述蛋白质是多特异性的,其中第一抗原结合位点结合肿瘤相关抗原,第二抗原结合位点结合NKG2D,并且抗体恒定区结合CD16。与scFv连接的抗体恒定区可以与第二抗体恒定区异二聚化。这些实施方案中的多特异性结合蛋白与自然杀伤细胞上的NKG2D受体和CD16受体结合,并且与癌细胞上的肿瘤相关抗原结合。此类蛋白质可以衔接多于一种NK激活受体,并且可阻断天然配体与NKG2D的结合。在某些实施方案中,所述蛋白质可以在人中激动NK细胞。在一些实施方案中,所述蛋白质可以在人,和/或其他物种诸如啮齿动物和/或食蟹猴中激动NK细胞。
在另一方面,本发明提供了一种多特异性结合蛋白,并且所述蛋白质包含结合肿瘤相关抗原的第一抗原结合位点;与第一抗原结合位点结合相同的肿瘤相关抗原的第二抗原结合位点;结合NKG2D的第三抗原结合位点;以及抗体恒定区或其足以结合CD16的部分,或结合CD16的第四抗原结合位点。抗原结合位点中的任一个可以采取Fab或scFv的形式,诸如上文描述的那些。此处提供的多特异性结合蛋白提供肿瘤相关抗原的二价衔接,从而稳定癌细胞表面上的肿瘤相关抗原,并增强NK细胞对癌细胞的细胞毒性。
在一些实施方案中,多特异性结合蛋白对肿瘤相关抗原的二价衔接赋予多特异性结合蛋白对癌细胞的更强结合,从而促进NK细胞对癌细胞,尤其是对表达低水平的肿瘤相关抗原的癌细胞的更强的细胞毒性反应。
在一些实施方案中,多特异性结合蛋白掺入抗体Fc结构域的足以结合CD16的部分,其中抗体Fc结构域包含人IgG抗体的铰链和CH2结构域和/或与其氨基酸序列234-332具有至少90%同一性的氨基酸序列。可以将突变引入抗体恒定结构域中,以使其能够与另一抗体恒定结构域异二聚化。例如,如果抗体恒定结构域衍生自人IgG1的恒定结构域,那么所述抗体恒定结构域可以包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列,并且在选自由以下组成的组的一个或多个位置上有所不同:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和K439。
在一些实施方案中,抗体恒定结构域可以包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列,并且不同之处在于选自由以下组成的组的一个或多个取代:Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、T411D、T411E、K439D和K439E。
上述肿瘤相关抗原结合位点可以是与任何肿瘤相关抗原结合的位点,所述肿瘤相关抗原例如,ANO1、BCMA、EpCAM、CAIX、CEA、CCR4、CD2、CD123、CD133、CD19、CD20、CD22、CD25、CD30、CD33、CD37、CD38、CD40、CD52、CD70、CLAUDIN-18.2、DLL3、EGFR/ERBB1、GD2、IGF1R、HER2、HER3/ERBB3、HER4/ERBB4、MUC1、cMET、SLAMF7、PSMA、间皮素、MICA、MICB、TRAILR1、TRAILR2、TROP2、MAGE-A3、B7.1、B7.2、CTLA4、PD1、5T4、GPNMB、FR-α、PAPP-A、FLT3、GPC3、CXCR4、ROR1、ROR2、HLA-E、PD-L1、VLA4、CD44、CD13、CD15、CD47、CLL1、CD81、CD23、CD79a、CD79b、CD80、CRLF2、SLAMF7、CD138、CA125、NaPi2b、结合素4(Nectin4)、ADAM8、ADAM9、SLC44A4、CA19-9、LILRBl、LILRB2、LILRB3、LILRB4、LILRB5、ULRA 1、LILRA2、LILRA3、ULRA4、LILRA5和ULRA6、CCR8、CD7、CTLA4、CX3CR1、ENTPD1、HAVCR2、IL-1R2、PDCD1LG2、TIGIT、TNFRSF4、TNFRSF8、TNFRSF9、GEM、NT5E、TNFRSFI8、MUC1、P-钙粘素、丛状蛋白-A1(Plexin-A1)、TNFRSF10B、STEAP1、CDCP1、PTK7、Ax1、erbB-3、EDNRB、Tyrp1、CD14、CD163、CSF3R、Siglec-9、ITGAM、VISTA、B7-H4(VTCN1)、CCR1、LRRC25、PTAFR、SIRPB1、TLR2、TLR4、CD300LB、ATP1A3、CCR5、MUC1(或MUC1-C)、丛状蛋白-A1、TNFRSFl0B、STEAP1、CDCP1、PTK7、AXL、EDNRB、OLR1和TYRP1。
在另一方面,本发明提供—种蛋白质,其包含:(a)结合NKG2D的抗原结合位点;(b)抗原结合性T细胞受体(TCR)片段;以及(c)抗体恒定区或其足以结合CD16的部分,或结合CD16的另外的抗原结合位点。在某些实施方案中,所述蛋白质是多特异性结合蛋白,其包含结合肿瘤相关抗原(TAA)的抗原结合性TCR片段。
在某些实施方案中,抗原结合位点是Fab片段,并且抗原结合性TCR片段是单链TCR(scTCR)片段。在某些实施方案中,scTCR片段通过包含Ala-Ser的铰链与抗体恒定区的多肽链连接。在某些实施方案中,铰链还包含氨基酸序列Thr-Lys-Gly。
在某些实施方案中,抗原结合位点是scFv,并且抗原结合性TCR片段是细胞外TCR片段。在某些实施方案中,scFv通过包含Ala-Ser的铰链与抗体恒定区的多肽链连接。在某些实施方案中,铰链还包含氨基酸序列Thr-Lys-Gly。
在某些实施方案中,抗原结合位点是Fab片段,并且抗原结合性TCR片段是细胞外TCR片段。
在某些实施方案中,多特异性结合蛋白还包含与抗原结合性TCR片段结合相同抗原的另外的抗原结合性TCR片段。在某些实施方案中,抗原结合位点是scFv,并且抗原结合性TCR片段和另外的抗原结合性TCR片段是细胞外TCR片段。在某些实施方案中,抗原结合位点是scFv,并且抗原结合性TCR片段和另外的抗原结合性TCR片段是scTCR片段。
在包含scFv的多特异性结合蛋白的某些实施方案中,scFv包含通过柔性接头与轻链可变结构域连接的重链可变结构域。在某些实施方案中,柔性接头包含(G4S)4。在某些实施方案中,scFv包含位于轻链可变结构域的N端或C端的重链可变结构域。
在某些实施方案中,抗原结合位点包含重链可变结构域和轻链可变结构域,并且其中重链可变结构域与轻链可变结构域形成二硫桥。在某些实施方案中,二硫桥在重链可变结构域的位置44处的Cys与轻链可变结构域的位置100处的Cys之间形成,所述位置根据Kabat编号定义。在某些实施方案中,包含这样的二硫桥的抗原结合位点是scFv。
在某些实施方案中,抗原结合位点在人中与NKG2D结合。
在某些实施方案中,抗原结合性TCR片段结合由主要组织相容性复合物(MHC)呈递的来自肿瘤相关抗原的肽。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A*02:01:48呈递的具有SEQID NO:425的氨基酸序列的ELAVL4肽。在某些实施方案中,抗原结合性TCR片段包含与SEQID NO:351相关的α链可变结构域和与SEQ ID NO:352相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:351具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:353)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:352具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:354)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:349所示的α链氨基酸序列和SEQ ID NO:350所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A*02:01:48呈递的具有SEQID NO:426的氨基酸序列的胰岛素肽。在某些实施方案中,抗原结合性TCR片段包含与SEQID NO:357相关的α链可变结构域和与SEQ ID NO:358相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:357具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:359)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:358具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:360)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:355所示的α链氨基酸序列和SEQ ID NO:356所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A*02:01:48呈递的具有SEQID NO:340的氨基酸序列的TERT肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ IDNO:363相关的α链可变结构域和与SEQ ID NO:364相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:363具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:365)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:364具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:366)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:361所示的α链氨基酸序列和SEQ ID NO:362所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A*02呈递的具有SEQ ID NO:341的氨基酸序列的ERBB2肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:430相关的α链可变结构域和与SEQ ID NO:431相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:430具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:367)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:431具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:368)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:428所示的α链氨基酸序列和SEQ ID NO:429所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A*02呈递的具有SEQ ID NO:342的氨基酸序列的WT1肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:434相关的α链可变结构域和与SEQ ID NO:435相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:434具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:369)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:435具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:370)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:432所示的α链氨基酸序列和SEQ ID NO:433所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A*02呈递的具有SEQ ID NO:342的氨基酸序列的WT1肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:438相关的α链可变结构域和与SEQ ID NO:439相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:438具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:371)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:439具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:372)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:436所示的α链氨基酸序列和SEQ ID NO:437所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A1呈递的具有SEQ ID NO:343的氨基酸序列的MAGE-A3肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:375相关的α链可变结构域和与SEQ ID NO:376相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:375具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:377)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:376具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:378)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:373所示的α链氨基酸序列和SEQ ID NO:374所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:344的氨基酸序列的MART1肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:381相关的α链可变结构域和与SEQ ID NO:382相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:381具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:383)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:382具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:384)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:379所示的α链氨基酸序列和SEQ ID NO:380所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:346的氨基酸序列的BIRC5肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:442相关的α链可变结构域和与SEQ ID NO:443相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:442具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:389)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:443具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:390)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:440所示的α链氨基酸序列和SEQ ID NO:441所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:346的氨基酸序列的BIRC5肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:444相关的α链可变结构域和与SEQ ID NO:445相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:444具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:391)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:445具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:392)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:385所示的α链氨基酸序列和SEQ ID NO:386所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:347的氨基酸序列的PRAME肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:395相关的α链可变结构域和与SEQ ID NO:396相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:395具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:397)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:396具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:398)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:393所示的α链氨基酸序列和SEQ ID NO:394所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:347的氨基酸序列的PRAME肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:401相关的α链可变结构域和与SEQ ID NO:402相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:401具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:403)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:402具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:404)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:399所示的α链氨基酸序列和SEQ ID NO:400所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:347的氨基酸序列的PRAME肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:407相关的α链可变结构域和与SEQ ID NO:408相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:407具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:409)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:408具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:410)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:405所示的α链氨基酸序列和SEQ ID NO:406所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:348的氨基酸序列的NY-ESO-1肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:413相关的α链可变结构域和与SEQ ID NO:414相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:413具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:415)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:414具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:416)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:411所示的α链氨基酸序列和SEQ ID NO:412所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:348的氨基酸序列的NY-ESO-1肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:418相关的α链可变结构域和与SEQ ID NO:414相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:418具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:415)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:414具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:416)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:417所示的α链氨基酸序列和SEQ ID NO:412所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:348的氨基酸序列的NY-ESO-1肽。在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:421相关的α链可变结构域和与SEQ ID NO:422相关的β链可变结构域。例如,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:421具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的α链可变结构域,和/或掺入与α链可变结构域的CDR3α序列(SEQ ID NO:423)相同的氨基酸序列。类似地,在某些实施方案中,抗原结合性TCR片段包含与SEQ ID NO:422具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的β链可变结构域,和/或掺入与β链可变结构域的CDR3β序列(SEQ ID NO:424)相同的氨基酸序列。在某些实施方案中,抗原结合性TCR片段包含SEQ ID NO:419所示的α链氨基酸序列和SEQ ID NO:420所示的β链氨基酸序列。
在某些实施方案中,抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:345的氨基酸序列的SSX2肽。在某些实施方案中,抗原结合性TCR片段包含掺入SEQ ID NO:387所示的CDR3α序列的α链可变结构域。在某些实施方案中,抗原结合性TCR片段包含掺入SEQID NO:388所示的CDR3β序列的β链可变结构域。
在某些实施方案中,多特异性结合蛋白包含抗体恒定区或其足以结合CD16的部分,其中抗体恒定区或其足以结合CD16的部分包含人IgG1抗体的铰链和CH2结构域。在某些实施方案中,抗体恒定区或其足以结合CD16的部分包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列。可以将突变引入抗体恒定结构域中,以使其能够与另一抗体恒定结构域异二聚化。例如,如果抗体恒定结构域衍生自人IgG1的恒定结构域,那么所述抗体恒定结构域可以包含与人IgG 1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列,并且在选自由以下组成的组的一个或多个位置上有所不同:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和K439。在一些实施方案中,抗体恒定结构域可以包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列,并且不同之处在于选自由以下组成的组的一个或多个取代:Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、T411D、T411E、K439D和K439E。
在包含结合NKG2D的抗原结合位点(也称为“NKG2D结合位点”)的前述多肽或蛋白质中的任一种的某些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:1相关的重链可变结构域,诸如通过具有与SEQ ID NO:1具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的氨基酸序列,和/或掺入与SEQ ID NO:1的CDR1(SEQ ID NO:3或SEQ ID NO:307)、CDR2(SEQ ID NO:4)和CDR3(SEQ ID NO:5或SEQ IDNO:308)序列相同的氨基酸序列。与SEQ ID NO:1相关的重链可变结构域可以与多种轻链可变结构域偶联,以形成NKG2D结合位点。例如,掺入与SEQ ID NO:1相关的重链可变结构域的NKG2D结合位点可以进一步掺入选自与SEQ ID NO:2、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41和43相关的任一序列的轻链可变结构域。例如,NKG2D结合位点掺入具有与SEQ ID NO:1具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的氨基酸序列的重链可变结构域和具有与选自SEQ ID NO:2、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41和43的任一序列具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的氨基酸序列的轻链可变结构域。
可替代地,NKG2D结合位点可以掺入与SEQ ID NO:44相关的重链可变结构域和与SEQ ID NO:48相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQID NO:44具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:44的CDR1(SEQ ID NO:45或SEQ ID NO:309)、CDR2(SEQ ID NO:46)和CDR3(SEQ ID NO:47或SEQ ID NO:310)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:48具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:48的CDR1(SEQ ID NO:49)、CDR2(SEQ ID NO:50)和CDR3(SEQ ID NO:51)序列相同的氨基酸序列。
在其他实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:52相关的重链可变结构域和与SEQ ID NO:56相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:52具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:52的CDR1(SEQ ID NO:53或SEQ IDNO:311)、CDR2(SEQ ID NO:54)和CDR3(SEQ ID NO:55或SEQ ID NO:312)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:56具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:56的CDR1(SEQ ID NO:57)、CDR2(SEQ ID NO:58)和CDR3(SEQ ID NO:59)序列相同的氨基酸序列。
可替代地,NKG2D结合位点可以掺入与SEQ ID NO:60相关的重链可变结构域和与SEQ ID NO:61相关的轻链可变结构域,诸如通过具有分别与SEQ ID NO:60具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性以及与SEQ ID NO:61具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的氨基酸序列。
在另一个实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:62相关的重链可变结构域和与SEQ ID NO:66相关的轻链可变结构域,例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:62具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:62的CDR1(SEQ ID NO:63)、CDR2(SEQ ID NO:64)和CDR3(SEQ ID NO:65)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:66具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:66的CDR1(SEQ IDNO:67)、CDR2(SEQ ID NO:68)和CDR3(SEQ ID NO:69)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:70相关的重链可变结构域和与SEQ ID NO:74相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:70具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:70的CDR1(SEQ ID NO:71或SEQ IDNO:313)、CDR2(SEQ ID NO:72)和CDR3(SEQ ID NO:73或SEQ ID NO:314)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:74具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:74的CDR1(SEQ ID NO:75)、CDR2(SEQ ID NO:76)和CDR3(SEQ ID NO:77)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:78相关的重链可变结构域和与SEQ ID NO:82相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:78具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:78的CDR1(SEQ ID NO:79或SEQ IDNO:315)、CDR2(SEQ ID NO:80)和CDR3(SEQ ID NO:81或SEQ ID NO:316)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:82具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:82的CDR1(SEQ ID NO:83)、CDR2(SEQ ID NO:84)和CDR3(SEQ ID NO:85)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:86相关的重链可变结构域和与SEQ ID NO:90相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:86具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:86的CDR1(SEQ ID NO:87或SEQ IDNO:317)、CDR2(SEQ ID NO:88)和CDR3(SEQ ID NO:89或SEQ ID NO:318)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:90具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:90的CDR1(SEQ ID NO:91)、CDR2(SEQ ID NO:92)和CDR3(SEQ ID NO:93)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:94相关的重链可变结构域和与SEQ ID NO:98相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:94具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:94的CDR1(SEQ ID NO:95或SEQ IDNO:319)、CDR2(SEQ ID NO:96)和CDR3(SEQ ID NO:97或SEQ ID NO:320)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:98具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:98的CDR1(SEQ ID NO:99)、CDR2(SEQ ID NO:100)和CDR3(SEQ ID NO:101)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:102相关的重链可变结构域和与SEQ ID NO:106相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:102具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:102的CDR1(SEQ ID NO:103或SEQID NO:313)、CDR2(SEQ ID NO:104)和CDR3(SEQ ID NO:105或SEQ ID NO:321)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:106具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:106的CDR1(SEQ ID NO:107)、CDR2(SEQ ID NO:108)和CDR3(SEQID NO:109)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:322相关的重链可变结构域和与SEQ ID NO:98相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:322具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:322的CDR1(SEQ ID NO:95或SEQ IDNO:319)、CDR2(SEQ ID NO:96)和CDR3(SEQ ID NO:323或SEQ ID NO:324)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:98具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:98的CDR1(SEQ ID NO:99)、CDR2(SEQ ID NO:100)和CDR3(SEQ ID NO:101)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:325相关的重链可变结构域和与SEQ ID NO:98相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:325具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:325的CDR1(SEQ ID NO:95或SEQ IDNO:319)、CDR2(SEQ ID NO:96)和CDR3(SEQ ID NO:326或SEQ ID NO:327)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:98具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:98的CDR1(SEQ ID NO:99)、CDR2(SEQ ID NO:100)和CDR3(SEQ ID NO:101)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:328相关的重链可变结构域和与SEQ ID NO:98相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:328具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:328的CDR1(SEQ ID NO:95或SEQ IDNO:319)、CDR2(SEQ ID NO:96)和CDR3(SEQ ID NO:329或SEQ ID NO:330)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:98具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:98的CDR1(SEQ ID NO:99)、CDR2(SEQ ID NO:100)和CDR3(SEQ ID NO:101)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:331相关的重链可变结构域和与SEQ ID NO:98相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:331具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:331的CDR1(SEQ ID NO:95或SEQ IDNO:319)、CDR2(SEQ ID NO:96)和CDR3(SEQ ID NO:332或SEQ ID NO:333)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:98具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:98的CDR1(SEQ ID NO:99)、CDR2(SEQ ID NO:100)和CDR3(SEQ ID NO:101)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:334相关的重链可变结构域和与SEQ ID NO:98相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:334具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:334的CDR1(SEQ ID NO:95或SEQ IDNO:319)、CDR2(SEQ ID NO:96)和CDR3(SEQ ID NO:335或SEQ ID NO:336)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:98具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:98的CDR1(SEQ ID NO:99)、CDR2(SEQ ID NO:100)和CDR3(SEQ ID NO:101)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:337相关的重链可变结构域和与SEQ ID NO:98相关的轻链可变结构域。例如,NKG2D结合位点的重链可变结构域可以与SEQ ID NO:337具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:337的CDR1(SEQ ID NO:95或SEQ IDNO:319)、CDR2(SEQ ID NO:96)和CDR3(SEQ ID NO:338或SEQ ID NO:339)序列相同的氨基酸序列。类似地,NKG2D结合位点的轻链可变结构域可以与SEQ ID NO:98具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)的同一性,和/或掺入与SEQ ID NO:98的CDR1(SEQ ID NO:99)、CDR2(SEQ ID NO:100)和CDR3(SEQ ID NO:101)序列相同的氨基酸序列。
在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:110相关的重链可变结构域和与SEQ ID NO:111相关的轻链可变结构域,诸如通过具有分别与SEQ ID NO:110具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性以及与SEQ ID NO:111具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的氨基酸序列。在一些实施方案中,NKG2D结合位点可以掺入与SEQ ID NO:112相关的重链可变结构域和与SEQ ID NO:113相关的轻链可变结构域,诸如通过具有分别与SEQ ID NO:112具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性以及与SEQ ID NO:113具有至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性的氨基酸序列。
还提供了包含本文所述的任一蛋白质的制剂;包含表达所述蛋白质的一种或多种核酸的细胞,以及使用所述蛋白质增强肿瘤细胞死亡的方法。
本发明的另一方面提供一种治疗患者癌症的方法。所述方法包括向有需要的患者施用治疗有效量的本文所述的多特异性结合蛋白。待治疗的癌症可包括急性骨髓性白血病、急性粒单核细胞白血病、B细胞淋巴瘤、膀胱癌、乳腺癌、结肠直肠癌、弥漫性大B细胞淋巴瘤、食道癌、尤文氏肉瘤(Ewing’s sarcoma)、滤泡性淋巴瘤、胃癌、胃肠道癌、胃肠道间质肿瘤、胶质母细胞瘤、头颈癌、黑素瘤、间皮瘤、多发性骨髓瘤、骨髓增生异常综合征、肾细胞癌、神经母细胞瘤、非小细胞肺癌、神经内分泌肿瘤、卵巢癌和胰腺癌、前列腺癌、肉瘤、小细胞肺癌、T细胞淋巴瘤、睾丸癌、胸腺癌、甲状腺癌、尿路上皮癌、髓源性抑制细胞浸润的癌症、调节性T细胞浸润的癌症、具有细胞外基质沉积的癌症、具有高水平反应性基质的癌症,以及具有新生血管形成(neoangiogenesis)的癌症。
附图说明
图1A-1C示出多特异性结合蛋白的三种示例性形式,其包括通过铰链与抗体恒定区/结构域连接的scFv。图1A表示三特异性抗体(TriNKET),其包含靶向肿瘤的scFv或单链TCR(scTCR)片段、靶向NKG2D的Fab,以及结合CD16的异二聚化的抗体恒定区/结构域(“CD结构域”)。所述抗体形式在本文称为F3’-TriNKET。图1B表示包含靶向NKG2D的scFv、靶向肿瘤的Fab或细胞外TCR片段,以及异二聚化的抗体恒定区的抗体。所述抗体形式在本文称为F3-TriNKET。图1C表示包含靶向NKG2D的scFv、靶向肿瘤的scFv或scTCR片段,以及异二聚化的抗体恒定区的抗体。在某些示例性TriNKET中,与结合NKG2D的抗原结合位点连接的CD结构域上的异二聚化突变包括K360E和K409W;相反CD上的异二聚化突变包括Q347R、D399V和F405T。
图2A示出三特异性抗体(TriNKET),其中第一抗原结合位点或抗原结合性TCR片段结合由主要组织相容性复合物(MHC)呈递的肿瘤相关抗原(诸如此处所示的BCMA)或其肽;第二抗原结合位点结合NKG2D;并且异二聚化的抗体恒定区结合CD16。在某些示例性TriNKET中,与结合NKG2D的抗原结合位点连接的CD结构域上的异二聚化突变包括K360E和K409W;相反CD上的异二聚化突变包括Q347R、D399V和F405T。
图2B-2C示出三特异性抗体(TriNKET),其中第一抗原结合位点和第二抗原结合位点,或第一抗原结合性TCR片段和第二抗原结合性TCR片段,结合由相同MHC呈递的相同肿瘤相关抗原(诸如此处所示的BCMA)或来自肿瘤相关抗原的相同肽;第三抗原结合位点结合NKG2D;并且异二聚化的抗体恒定区结合CD16。这些抗体形式在本文称为F4-TriNKET。在某些示例性TriNKET中,与结合NKG2D的抗原结合位点连接的CD结构域上的异二聚化突变包括K360E和K409W;相反CD上的异二聚化突变包括Q347R、D399V和F405T。图2B示出呈Fab形式的前两个抗原结合位点。图2C示出呈scFv形式的前两个抗原结合位点。
图3A-3C示出在37℃下进行的加速稳定性研究的结果,其中发现F3’-TriNKET在4周内是稳定的。
图4示出纯化的F3’-TriNKET在低pH保持期间是稳定的。
图5A和图5B示出无论pH如何,纯化的F3’-TriNKET在5个冻-融循环后都是稳定的(图5A示出在PBS中的冻-融循环,并且图5B示出在pH 5.5的柠檬酸盐中的冻-融循环)。
图6示出其中F3’-TriNKET保持稳定的强制降解条件的条形图。
图7示出F3’-TriNKET-HER2或曲妥珠单抗(Trastuzumab)与HER2+Colo-201细胞的结合。
图8示出F3’-TriNKET-CD33或CD33单克隆抗体与在Molm-13细胞上表达的CD33的结合。
图9和图10分别示出F3’-TriNKET-HER2介导的对HER2低表达细胞系(HER2-lowcell line)786-O和HER2高表达细胞系(HER2-high cell line)SkBr-3的细胞毒性。
图11和图12分别示出F3’-TriNKET-CD33介导的对两种CD33阳性人细胞系EOL-1和THP-1的细胞毒性。
图13A示出与FcγRIa结合的F3’-TriNKET-HER2类似于赫赛汀(Herceptin)。
图13B示出与FcγRIIa结合的F3’-TriNKET-HER2类似于赫赛汀。图13C示出与FcγRIIIa 158V结合的F3’-TriNKET-HER2类似于赫赛汀。
图14A示出与人HER2结合的F3’-TriNKET-HER2(其中HER2结合子(binder)是scFv)类似于赫赛汀(其中HER2结合子是Fab)。图14B示出与人CD33结合的F3’TriNKET-CD33(其中CD33结合子是scFv)类似于CD33单克隆抗体(其中CD33结合子是Fab)。
图15示出F3-TriNKET-BCMA的两步纯化实现99%的纯度。
图16示出F3-TriNKET-CD33同时高效衔接NKG2D和CD33靶标。
图17示出F3-TriNKET-BCMA同时高效衔接NKG2D和BCMA靶标。
图18A示出F3-TriNKET形式持续至少长达14天是稳定的。图18B示出F3-TriNKET形式在低pH保持后是稳定的。图18C示出F3-TriNKET形式在至少多达5个冻-融循环之后是稳定的。
图19是示出具有不同的NKG2D结合结构域的靶向BCMA的F4-TriNKET增强KMS12-PE骨髓瘤细胞的人NK细胞裂解的线图。
图20是示出具有不同的NKG2D结合结构域的靶向BCMA的F4-TriNKET增强MM.1R骨髓瘤细胞的人NK细胞裂解的线图。
图21是示出F4-TriNKET、duobody-TriNKET和BCMA单克隆抗体与MM.1R骨髓瘤细胞的结合的线图。
图22是示出与F4-TriNKET一起孵育随时间推移增加表面BCMA表达的FACS。
图23是示出F4-TriNKET使表面BCMA稳定的线图。
图24是示出在不同浓度下,经30小时,具有A49结合子的靶向BCMA的F4-TriNKET介导比Duobody-TriNKET更有效的KMS12-PE骨髓瘤细胞的杀伤的条形图。
图25是示出在不同浓度下,经30小时,具有A49结合子的靶向BCMA的F4-TriNKET介导比Duobody-TriNKET更有效的MM.1S骨髓瘤细胞的杀伤的条形图。
具体实施方式
本发明提供对通过铰链序列与抗体恒定结构域连接的单链可变片段(scFv)的改进。铰链序列提供scFv与抗原结合的灵活性。本发明还提供了包括一个或多个scFv的多特异性结合蛋白,其中多特异性结合蛋白结合自然杀伤细胞上的NKG2D受体和CD16受体,以及肿瘤相关抗原。本发明还提供了多特异性结合蛋白,其包含与相同肿瘤相关抗原结合的两个肿瘤相关抗原结合位点,并结合自然杀伤细胞上的NKG2D受体和CD16受体。还提供了包含此类多特异性结合蛋白的药物组合物,以及使用此类多特异性结合蛋白和药物组合物的治疗方法,出于诸如治疗癌症的目的。本发明的各个方面在以下部分中阐述;然而,在一个特定部分中描述的本发明的方面不限于任何特定部分。
为了有助于理解本发明,在下文定义多个术语和短语。
除非上下文不合适,否则如本文所用的术语“一个/种(a和an)”意指“一个/种或多个/种”并且包括复数个/种。
如本文所用,术语“受试者”和“患者”是指待通过本文所述的方法和组合物治疗的生物体。此类生物体优选包括但不限于哺乳动物(例如,鼠、猿、马、牛、猪、犬、猫等),并且更优选包括人。
如本文所用,术语“抗原结合位点”是指免疫球蛋白分子中参与抗原结合的部分。在人抗体中,抗原结合位点由重链(“H”)和轻链(“L”)的N端可变(“V”)区的氨基酸残基形成。重链和轻链的V区内的三个高度差异链段(highly divergent stretches)称为“高变区”,其插置在被称为“框架区”或“FR”的更为保守的侧翼链段之间。因此,术语“FR”是指天然存在于免疫球蛋白中的高变区之间且与其邻近的氨基酸序列。在人抗体分子中,轻链的三个高变区和重链的三个高变区在三维空间中相对于彼此设置以形成抗原结合表面。抗原结合表面与所结合抗原的三维表面互补,并且重链和轻链中的每一个的三个高变区被称为“互补决定区”或“CDR”。在某些动物,诸如骆驼和软骨鱼中,抗原结合位点由单个抗体链形成,从而提供“单结构域抗体”。抗原结合位点可以存在于完整抗体中,存在于抗体的保留抗原结合表面的抗原结合片段中,或存在于在单个多肽中使用肽接头将重链可变结构域与轻链可变结构域连接的重组多肽诸如scFv中。
如本文所用,术语“抗原结合性T细胞受体片段”和“抗原结合性TCR片段”可互换使用,并且是指结合同源抗原的T细胞受体(TCR)的部分。在人αβTCR中,抗原结合性TCR片段包含α链可变结构域(Vα)和β链可变结构域(Vβ),其各自包含三个互补决定区(CDR)。被称为CDR3α和CDR3β的高变环占据了用于结合抗原肽的中心位置;种系编码的CDR1α、CDR2α、CDR1β和CDR2β环与呈递抗原肽的MHC接触最多。在人γδTCR中,抗原结合性TCR片段包含γ链可变结构域(Vγ)和δ链可变结构域(Vδ),其各自包含三个CDR。人γδ TCR识别由MHC或MHC相关分子(例如,CD1、内皮蛋白C受体(EPCR)或MHCI类多肽相关序列A(MICA))呈递的抗原(例如,肽或脂质)。应当理解,其他蛋白质,诸如F1-ATP酶,也可向γδ TCR呈递抗原。抗原结合性TCR片段可以存在于完整TCR中,存在于具有通过二硫键连接的TCR链的工程改造的TCR中,存在于完整或工程改造的TCR的保留抗原结合表面的抗原结合片段中,或存在于具有在单个多肽中通过肽接头连接的TCR的可变结构域(例如,Vα和Vβ)的重组多肽中。抗原结合性TCR片段的非限制性实例包括这样的TCR片段,其包含TCR的可变结构域(例如,Vα和Vβ)和恒定结构域(例如,Cα和Cβ),但是缺乏其连接区、跨膜区和细胞质区,在本文称为“细胞外TCR片段”,以及通过肽接头连接的TCR的可变区(例如,Vα和Vβ),在本文称为“单链TCR(scTCR)片段”。
如本文所用,术语“有效量”是指足以实现有益或期望结果的化合物(例如,本发明的化合物)的量。有效量可以一次或多次施用、施加或给药来施用,并且不意图限于具体制剂或施用途径。如本文所用,术语“治疗”包括导致病状、疾病、病症等的改善或缓解其症状的任何效应,例如减轻、减少、调节、缓解或消除。
如本文所用,术语“药物组合物”是指活性剂与惰性或活性载剂的组合,其使组合物尤其适于体内或离体的诊断或治疗用途。
如本文所用,术语“药学上可接受的载剂”是指任何标准的药物载剂,诸如磷酸盐缓冲盐水溶液、水、乳液(例如像水包油或油包水型乳液)以及各种类型的润湿剂。组合物还可以包含稳定剂和防腐剂。关于载剂、稳定剂和佐剂的实例,参见例如Martin,Remington′sPharmaceutical Sciences,第15版,Mack Publ.Co.,Easton,PA[1975]。
贯穿本说明书,在组合物被描述为具有、包括或包含特定组分的情况下,或在工艺和方法被描述为具有、包括或包含具体步骤的情况下,设想到,另外,还存在基本由或由列举出的组分组成的本发明的组合物,并且还存在基本由或由列举出的加工步骤组成的根据本发明的工艺和方法。
一般情况下,除非另有说明,否则指定百分比的组合物以重量计。此外,如果变量没有定义,则以变量的先前定义为准。
I.蛋白质
本发明提供对通过铰链序列与抗体恒定结构域连接的单链可变片段(scFv)的改进。在一些实施方案中,铰链包含氨基酸Ala-Ser。在一些其他实施方案中,铰链包含氨基酸Ala-Ser和Thr-Lys-Gly。scFv可包括重链可变结构域和轻链可变结构域。在一些实施方案中,scFv结合NKG2D或肿瘤相关抗原。铰链序列提供scFv与靶抗原结合的灵活性。
在scFv的一些实施方案中,重链可变结构域与轻链可变结构域形成二硫桥,以提高scFv的稳定性。例如,可以在重链可变结构域的C44残基与轻链可变结构域的C100残基之间形成二硫桥。在一些实施方案中,重链可变结构域通过柔性接头与轻链可变结构域连接。可以使用任何合适的接头,例如,(G4S)4接头。在scFv的一些实施方案中,重链可变结构域位于轻链可变结构域的N端。在scFv的一些实施方案中,重链可变结构域位于轻链可变结构域的C端。
在一些实施方案中,与scFv连接的抗体恒定结构域可以衍生自与CD16结合的任何物种的抗体的恒定区。在一些实施方案中,恒定区的氨基酸序列与人抗体恒定区具有至少90%的同一性,所述人抗体恒定区诸如人IgG1恒定区、IgG2恒定区、IgG3恒定区或IgG4恒定区。在一些其他实施方案中,恒定区的氨基酸序列与来自另一哺乳动物(诸如兔、狗、猫、小鼠或马)的抗体恒定区具有至少90%的同一性。在一些实施方案中,抗体恒定区包括铰链、CH2结构域、CH3结构域和任选的CH1结构域。在一些实施方案中,包括铰链、CH2结构域、CH3结构域和任选的CH1结构域的抗体恒定区衍生自人IgG1抗体。在一些实施方案中,抗体恒定区包括与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列。
在Fc结构域内,CD16结合由铰链区和CH2结构域介导。例如,在人IgG1内,与CD16的相互作用主要集中在CH2结构域中的氨基酸残基Asp 265-Glu 269、Asn 297-Thr 299、Ala327-Ile 332、Leu 234-Ser 239和碳水化合物残基N-乙酰基-D-葡糖胺处(参见,Sondermann等,Nature,406(6793):267-273)。基于已知结构域,可以选择突变来增强或降低与CD16的结合亲和力,诸如通过使用噬菌体展示文库或酵母表面展示cDNA文库,或可以基于相互作用的已知三维结构进行设计。
在一些实施方案中,抗体恒定结构域包含IgG抗体例如人IgG1抗体的CH2结构域和CH3结构域。在一些实施方案中,将突变引入抗体恒定结构域中,使其能够与另一抗体恒定结构域异二聚化。例如,如果抗体恒定结构域衍生自人IgG1的恒定结构域,那么所述抗体恒定结构域可以包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列,并且在选自由以下组成的组的一个或多个位置上有所不同:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和K439。在一些实施方案中,抗体恒定结构域可以包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列,并且不同之处在于选自由以下组成的组的一个或多个取代:Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、T411D、T411E、K439D和K439E。
下面列出与抗体恒定区连接的scFv的实例,所述抗体恒定区也包括能够使两条多肽链异二聚化的突变。使用来自曲妥珠单抗的含有重链可变结构域(VH)和轻链可变结构域(VL)的scFv作为实例。每个序列表示含有异二聚化突变(加有下划线)的VL-(G4S)4-VH-铰链(AS)-Fc。VL和VH包含44VH-100VL S-S桥(加有下划线),并且可以来自任何靶向肿瘤的抗体或NKG2D结合抗体。肘关节铰链(elbow hinge)区域序列包括Ala-Ser(AS,加有下划线),以在柔韧性与最佳几何形状之间取得平衡。在某些实施方案中,可以在铰链处将附加序列Thr-Lys-Gly添加至AS序列。(G4S)4接头在以下段落列出的序列中加有下划线。
曲妥珠单抗-scFv-Fc A1和曲妥珠单抗-scFv-Fc B1可以优先配对并形成异二聚体。曲妥珠单抗-scFv-Fc A2和曲妥珠单抗-scFv-Fc B2可以优先配对并形成异二聚体。
曲妥珠单抗-scFv-Fc A1
曲妥珠单抗-scFv-Fc B1
曲妥珠单抗-scFv-Fc A2
曲妥珠单抗-scFv-Fc B2
在另一方面,本发明提供了一种蛋白质,其包含上述与抗体恒定区连接的scFv。在一些实施方案中,所述蛋白质包括第一抗原结合位点,其包含与抗体恒定结构域连接的scFv;第二抗原结合位点,其可采取Fab或scFv形式;以及与第二抗原结合位点连接的第二抗体恒定结构域。在一些实施方案中,所述蛋白质是多特异性的,其中第一抗原结合位点结合NKG2D,呈Fab形式的第二抗原结合位点结合肿瘤相关抗原,并且抗体恒定区结合CD16(在本文称为F3-TriNKET,如图1B所示)。在一些其他实施方案中,所述蛋白质是多特异性的,其中第一抗原结合位点结合肿瘤相关抗原,呈Fab形式的第二抗原结合位点结合NKG2D,并且抗体恒定区结合CD16(在本文称为F3’-TriNKET,如图1A所示)。与scFv连接的抗体恒定区与本文所述的蛋白质的第二抗原结合位点的抗体恒定区异二聚化。本文所述的包括scFv的多特异性结合蛋白可以采取如图1A-1C所示的若干形式。
多特异性结合蛋白可以结合表达NKG2D受体的细胞,其可以包括但不限于NK细胞、γδT细胞和CD8+αβT细胞。在NKG2D结合后,多特异性结合蛋白可阻断天然配体,诸如ULBP6和MICA,与NKG2D的结合并激活NKG2D受体。
多特异性结合蛋白结合表达CD16的细胞,CD16是白细胞表面上的Fc受体,所述白细胞包括自然杀伤细胞、巨噬细胞、嗜中性粒细胞、嗜酸性粒细胞、肥大细胞和滤泡树突状细胞。
在与自然杀伤细胞上的NKG2D受体和CD16受体以及癌细胞上的肿瘤相关抗原结合后,多特异性结合蛋白可以衔接多于一种NK激活受体,并可阻断天然配体与NKG2D的结合。在某些实施方案中,所述蛋白质可以在人中激动NK细胞。在一些实施方案中,所述蛋白质可以在人和其他物种诸如啮齿动物和食蟹猴中激动NK细胞。
在本发明的某些实施方案中,多特异性结合蛋白包含结合肿瘤相关抗原的第一抗原结合位点;与第一抗原结合位点结合相同的肿瘤相关抗原的第二抗原结合位点;结合NKG2D的第三抗原结合位点;以及抗体恒定区或其足以结合CD16的部分,或结合CD16的第四抗原结合位点。抗原结合位点中的任一个可以采取Fab或scFv的形式。示例性形式在图2B-2C中示出。scFv的VH-VL和VL-VH取向都是本公开的实施方案。
在某些实施方案中,与相同的肿瘤相关抗原结合的第一抗原结合位点或第二抗原结合位点是scFv,并且结合NKG2D的第三抗原结合位点是scFv。在某些实施方案中,与相同的肿瘤相关抗原结合的第一抗原结合位点和第二抗原结合位点各自是scFv,并且结合NKG2D的第三抗原结合位点是scFv。在某些实施方案中,与相同的肿瘤相关抗原结合的第一抗原结合位点或第二抗原结合位点是Fab,并且结合NKG2D的第三抗原结合位点是scFv。在某些实施方案中,与相同的肿瘤相关抗原结合的第一抗原结合位点和第二抗原结合位点各自是Fab,并且结合NKG2D的第三抗原结合位点是scFv。在某些实施方案中,本公开的F4-TriNKET的第一抗原结合位点和第二抗原结合位点具有相同的氨基酸序列。
在其他实施方案中,本文公开的多特异性结合蛋白包含结合肿瘤相关抗原的第一抗原结合位点;结合不同抗原的第二抗原结合位点;结合NKG2D的第三抗原结合位点;以及抗体恒定区或其足以结合CD16的部分,或结合CD16的第四抗原结合位点。抗原结合位点中的任一个可以采取Fab或scFv的形式(以VH-VL或VL-VH取向)。在某些实施方案中,与两种不同抗原结合的第一抗原结合位点或第二抗原结合位点是scFv,并且结合NKG2D的第三抗原结合位点是scFv。在某些实施方案中,与两种不同抗原结合的第一抗原结合位点和第二抗原结合位点各自是scFv,并且结合NKG2D的第三抗原结合位点是scFv。在某些实施方案中,与两种不同抗原结合的第一抗原结合位点或第二抗原结合位点是Fab,并且结合NKG2D的第三抗原结合位点是scFv。在某些实施方案中,与两种不同抗原结合的第一抗原结合位点和第二抗原结合位点各自是Fab,并且结合NKG2D的第三抗原结合位点是scFv。
在某些实施方案中,此处提供的多特异性结合蛋白(在本文称为F4-TriNKET)提供肿瘤相关抗原的二价衔接,从而稳定并维持癌细胞表面上的肿瘤相关抗原,并增强NK细胞对癌细胞的细胞毒性。在一些实施方案中,多特异性结合蛋白对肿瘤相关抗原的二价衔接赋予多特异性结合蛋白对癌细胞更高的亲合力,从而促进NK细胞对癌细胞,尤其是对表达低水平的肿瘤相关抗原的癌细胞的更强的细胞毒性反应。
本发明还提供一种多特异性结合蛋白,其包含(a)结合NKG2D的抗原结合位点;(b)抗原结合性TCR片段;以及(c)抗体恒定区或其足以结合CD16的部分,或结合CD16的另外的抗原结合位点。在某些实施方案中,抗原结合性TCR片段结合由MHC呈递的来自肿瘤相关抗原(TAA)的肽,例如,由人白细胞抗原(HLA)呈递的来自人肿瘤相关抗原的肽。元件(b)可以各种形式(例如,可溶形式)存在,诸如细胞外TCR片段或scTCR片段。元件(a)和(c)可以各种形式存在和/或包含以上公开的各种突变。例如,在某些实施方案中,元件(c)是抗体恒定区或其足以结合CD16的部分,所述抗体恒定区或其部分包含(i)与结合NKG2D的抗原结合位点连接的第一抗体恒定结构域,以及(ii)与抗原结合性TCR片段连接的第二抗体恒定结构域,其中第一和第二抗体恒定结构域可以异二聚化。
在某些实施方案中,抗原结合位点是Fab片段,并且抗原结合性TCR片段是scTCR片段。考虑到其NKG2D结合部分是Fab并且其TAA结合部分包含在单链中通过肽接头连接的可变结构域(类似于多特异性结合蛋白,所述多特异性结合蛋白包含第一抗原结合位点,其包含与抗体恒定结构域连接的scFv;第二抗原结合位点,其采取Fab的形式;以及与第二抗原结合位点连接的第二抗体恒定结构域,其中第一抗原结合位点结合肿瘤相关抗原,第二抗原结合位点结合NKG2D,并且抗体恒定区结合CD16),此多特异性结合蛋白的形式在本文也称为F3’-TriNKET,如图1A所示。
在某些实施方案中,抗原结合位点是scFv,并且抗原结合性TCR片段是细胞外TCR片段。考虑到其NKG2D结合部分是scFv并且其TAA结合部分包含可变结构域和恒定结构域(类似于多特异性结合蛋白,所述多特异性结合蛋白包含第一抗原结合位点,其包含与抗体恒定结构域连接的scFv;第二抗原结合位点,其采取Fab的形式;以及与第二抗原结合位点连接的第二抗体恒定结构域,其中第一抗原结合位点结合NKG2D,第二抗原结合位点结合肿瘤相关抗原,并且抗体恒定区结合CD16),此多特异性结合蛋白的形式在本文也称为F3-TriNKET,如图1B所示。
在某些实施方案中,抗原结合位点是scFv,并且抗原结合性TCR片段是scTCR片段。这种形式在图1C中示出。在某些实施方案中,抗原结合位点是Fab,并且抗原结合性TCR片段是细胞外TCR片段。这种形式在图2A中示出。
在某些实施方案中,多特异性结合蛋白包含结合抗原(例如,由MHC呈递的TAA肽)的第一抗原结合性TCR片段;与第一抗原结合性TCR片段结合相同抗原的第二抗原结合性TCR片段;结合NKG2D的抗原结合位点;以及抗体恒定区或其足以结合CD16的部分,或结合CD16的第四抗原结合位点。可替代地,预期第一抗原结合性TCR片段和第二抗原结合性TCR片段可以结合由相同或不同MHC呈递的两种不同的TAA肽。抗原结合位点中的任一个可以采取Fab或scFv的形式。第一和第二抗原结合性TCR片段可以采取细胞外TCR片段或scTCR片段的形式。提供抗原(例如,由MHC呈递的TAA肽)的二价衔接的示例性形式在本文称为F4-TriNKET,并且在图2B-2C中示出。
在某些实施方案中,本公开的F4-TriNKET的第一抗原结合性TCR片段和第二抗原结合性TCR片段结合由相同MHC呈递的相同TAA肽。在某些实施方案中,第一抗原结合性TCR片段或第二抗原结合性TCR片段是scFv。在某些实施方案中,第一抗原结合性TCR片段和第二抗原结合性TCR片段各自是scFv。在某些实施方案中,第一抗原结合性TCR片段或第二抗原结合性TCR片段是Fab。在某些实施方案中,第一抗原结合性TCR片段和第二抗原结合性TCR片段各自是Fab。
此处提供的具有抗原结合性TCR片段的F4-TriNKET提供抗原(例如,由MHC呈递的TAA肽)的二价衔接,从而稳定并维持癌细胞表面上的TAA肽,并增强NK细胞对癌细胞的细胞毒性。在一些实施方案中,多特异性结合蛋白对TAA肽的二价衔接赋予多特异性结合蛋白对癌细胞更高的亲合力,从而促进NK细胞对癌细胞,尤其是对呈递低水平的TAA肽的癌细胞的更强的细胞毒性反应。
应当理解,在本发明的蛋白质包含scFv的情况下,VH可以位于VL的C端或N端。类似地,在本发明的蛋白质包含scTCR片段的情况下,Vα可以位于Vβ的C端或N端。
本文列出可以掺入F3/F3’和F4-TriNKET中的NKG2D结合位点和肿瘤相关抗原结合位点或抗原结合性TCR片段的示例性序列。
NKG2D结合位点
表1列出可以组合地结合NKG2D的重链可变结构域和轻链可变结构域的肽序列。除非另外指明,否则表1提供的CDR序列是根据Kabat确定的。在一些实施方案中,重链可变结构域和轻链可变结构域被布置成Fab形式。在一些实施方案中,重链可变结构域和轻链可变结构域融合在一起形成scFv。
NKG2D结合结构域在其与NKG2D的结合亲和力方面可以变化,尽管如此,它们全部激活人NKG2D和NK细胞。
可替代地,通过SEQ ID NO:110表示的重链可变结构域可以与通过SEQ ID NO:111表示的轻链可变结构域配对,以形成可以结合NKG2D的抗原结合位点,如US 9,273,136中所示。
SEQ ID NO:110
SEQ ID NO:111
可替代地,通过SEQ ID NO:112表示的重链可变结构域可以与通过SEQ ID NO:113表示的轻链可变结构域配对,以形成可以结合NKG2D的抗原结合位点,如US 7,879,985中所示。
SEQ ID NO:112
SEQ ID NO:113
肿瘤相关抗原结合位点
本文所用的肿瘤相关抗原是指与癌症相关的任何抗原,包括但不限于蛋白质、糖蛋白、神经节苷脂、碳水化合物、脂质。这样的抗原可以在恶性细胞上或在肿瘤微环境中表达,诸如在肿瘤相关的血管、细胞外基质、间充质基质(mesenchymal stroma)或免疫浸润物上表达。例如,肿瘤相关抗原可以包括在癌细胞上表达的ANO1、BCMA、EpCAM、CAIX、CEA、CCR4、CD2、CD123、CD133、CD19、CD20、CD22、CD25、CD30、CD33、CD37、CD38、CD40、CD52、CD70、CLAUDIN-18.2、DLL3、EGFR/ERBB1、GD2、IGF1R、HER2、HER3/ERBB3、HER4/ERBB4、MUC1、cMET、SLAMF7、PSMA、间皮素、MICA、MICB、TRAILR1、TRAILR2、TROP2、MAGE-A3、B7.1、B7.2、CTLA4、PD1、5T4、GPNMB、FR-α、PAPP-A、FLT3、GPC3、CXCR4、ROR1、ROR2、HLA-E、PD-L1、VLA4、CD44、CD13、CD15、CD47、CLL1、CD81、CD23、CD79a、CD79b、CD80、CRLF2、SLAMF7、CD138、CA125、NaPi2b、结合素4、ADAM8、ADAM9、SLC44A4、CA19-9、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、ULRA 1、LILRA2、LILRA3、ULRA4、LILRA5和ULRA6、CCR8、CD7、CTLA4、CX3CR1、ENTPD1、HAVCR2、IL-1R2、PDCD1LG2、TIGIT、TNFRSF4、TNFRSF8、TNFRSF9、GEM、NT5E、TNFRSF18、MUC1、P-钙粘素、丛状蛋白-A1、TNFRSF10B、STEAP1、CDCP1、PTK7、Ax1、erbB-3、EDNRB、Tyrp1、CD14、CD163、CSF3R、Siglec-9、ITGAM、VISTA、B7-H4(VTCN1)、CCR1、LRRC25、PTAFR、SIRPB1、TLR2、TLR4、CD300LB、ATP1A3、CCR5、MUC1(或MUC1-C)、丛状蛋白-A1、TNFRSF10B、STEAP1、CDCP1、PTK7、AXL、EDNRB、OLR1和TYRP1。
可以开发肿瘤相关抗原结合位点以结合任何肿瘤相关抗原。在一些实施方案中,肿瘤相关抗原结合位点包括重链可变结构域和轻链可变结构域,它们可以配对以结合肿瘤相关抗原。在一些实施方案中,重链可变结构域和轻链可变结构域被布置成Fab形式。在一些实施方案中,重链可变结构域和轻链可变结构域融合在一起形成scFv。示例性的肿瘤相关抗原结合位点在下面列出。
表2列出可以组合地结合BCMA的重链可变结构域和轻链可变结构域的肽序列。
可替代地,BCMA结合结构域可以包括如下在EM-801和EM-901中列出的重链可变结构域和轻链可变结构域。
EM-801重链可变结构域(SEQ ID NO:157):
EM-801轻链可变结构域(SEQ ID NO:158):
EM-901重链可变结构域(SEQ ID NO:159):
EM-901轻链可变结构域(SEQ ID NO:160)
可替代地,可以通过针对与通过SEQ ID NO:156限定的氨基酸序列的结合进行筛选来鉴定可以结合BCMA的新型抗原结合位点。
SEQ ID NO:156
表3列出可以组合地结合CD33的重链可变结构域和轻链可变结构域的肽序列。CD33结合结构域在其与CD33的结合亲和力方面可以有所变化。
可替代地,可以通过针对与通过SEQ ID NO:273限定的氨基酸序列的结合进行筛选来鉴定可以结合CD33的新型抗原结合位点。
SEQ ID NO:273
表4列出可以组合地结合HER2的重链可变结构域和轻链可变结构域的肽序列。
可替代地,可以通过针对与通过SEQ ID NO:298限定的氨基酸序列的结合进行筛选来鉴定可以结合HER2的新型抗原结合位点。
可以开发抗原结合性TCR片段以结合由MHC呈递的肿瘤相关抗原肽。在一些实施方案中,抗原结合性TCR片段包括α链可变结构域和β链可变结构域,它们可以配对以结合由MHC呈递的TAA肽。在一些实施方案中,α链可变结构域和β链可变结构域被布置成细胞外TCR片段的形式。在一些实施方案中,α链可变结构域和β链可变结构域融合在一起形成scTCR片段。
可以加工成TCR可靶向的TAA肽的蛋白质的非限制性实例包括组织分化抗原(例如,MART-1、gp100、CEA、CD19和酪氨酸酶)、肿瘤种系抗原(例如,NY-ESO-1、MAGE-A1、MAGE-A3、MAGE-A4、MAGE-A12、MAGE-C2、BAGE1、GAGE1、CTAG1、CTAG2、XAGE-1B和SSX2)、癌细胞过表达的正常蛋白(例如,hTERT、EGFR、ERBB2、WT1、MUC1和间皮素)、病毒蛋白(例如,HPV、EBV和MCC)以及肿瘤特异性突变抗原。示例性的肿瘤相关抗原结合位点在下面列出。
表5列出TCR靶标的肽序列以及相应的TCRα链和β链序列。
抗体恒定区和异二聚化
本发明中描述的抗体恒定区(Fc结构域)可以衍生自与CD16结合的任何物种的抗体的恒定区。在一些实施方案中,恒定区的氨基酸序列与人抗体恒定区具有至少90%的同一性,所述人抗体恒定区诸如人IgG1恒定区、IgG2恒定区、IgG3恒定区或IgG4恒定区。在一些其他实施方案中,恒定区的氨基酸序列与来自另一哺乳动物(诸如兔、狗、猫、小鼠或马)的抗体恒定区具有至少90%的同一性。在一些实施方案中,抗体恒定区包括铰链、CH2结构域、CH3结构域和任选的CH1结构域。在一些实施方案中,包括铰链、CH2结构域、CH3结构域和任选的CH1结构域的抗体恒定区衍生自人IgG1抗体。在一些实施方案中,抗体恒定区包括与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列。
在Fc结构域内,CD16结合由铰链区和CH2结构域介导。例如,在人IgG1内,与CD16的相互作用主要集中在CH2结构域中的氨基酸残基Asp 265-Glu 269、Asn 297-Thr 299、Ala327-Ile 332、Leu 234-Ser 239和碳水化合物残基N-乙酰基-D-葡糖胺处(参见,Sondermann等,Nature,406(6793):267-273)。基于已知结构域,可以选择突变来增强或降低与CD16的结合亲和力,诸如通过使用噬菌体展示文库或酵母表面展示cDNA文库,或可以基于相互作用的已知三维结构进行设计。
在某些实施方案中,可以掺入人IgG1恒定区的CH1中的突变可位于氨基酸V125、F126、P127、T135、T139、A140、F170、P171和/或V173处。在某些实施方案中,可以掺入人IgG1恒定区的Cκ中的突变可处于氨基酸E123、F116、S176、V163、S174和/或T164处。
异二聚体抗体重链的组装可以通过在同一细胞中表达两种不同的抗体重链序列来完成,这可能导致每种抗体重链的同二聚体的组装以及异二聚体的组装。可以通过在每个抗体恒定区的CH3结构域中掺入不同的突变来促进异二聚体的优先组装,如US13/494870、US16/028850、US11/533709、US12/875015、US13/289934、US14/773418、US12/811207、US13/866756、US14/647480和US14/830336中所示。例如,可以基于人IgG1并且在第一多肽和第二多肽内掺入使这两条链选择性地彼此异二聚化的不同氨基酸取代对来在CH3结构域中进行突变。下文所示的氨基酸取代的位置均如在Kabat中一样按照EU索引进行编号。
在一种情况下,第一多肽中的氨基酸取代将原始氨基酸替换为较大氨基酸,所述较大氨基酸选自精氨酸(R)、苯丙氨酸(F)、酪氨酸(Y)或色氨酸(W),并且第二多肽中的至少一个氨基酸取代将原始氨基酸替换为较小氨基酸,所述较小氨基酸选自丙氨酸(A)、丝氨酸(S)、苏氨酸(T)或缬氨酸(V),使得较大氨基酸取代(隆凸)配合到较小氨基酸取代的表面(腔体)中。例如,一个多肽可以掺入T366W取代,并且另一个多肽可以掺入三个取代,包括T366S、L368A和Y407V。
与人IgG1恒定区相比,可以将一个或多个突变掺入恒定区中,例如在Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和/或K439处。示例性取代包括,例如,Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、T350V、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、T394W、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、T411D、T411E、K439D和K439E。
可替代地,氨基酸取代可以选自表6所示的以下各组取代。
可替代地,氨基酸取代可以选自表7所示的以下各组取代。
表7 | ||
第一多肽 | 第二多肽 | |
组1 | K409W | D399V/F405T |
组2 | Y349S | E357W |
组3 | K360E | Q347R |
组4 | K360E/K409W | Q347R/D399V/F405T |
组5 | Q347E/K360E/K409W | Q347R/D399V/F405T |
组6 | Y349S/K409W | E357W/D399V/F405T |
可替代地,氨基酸取代可以选自表8所示的以下各组取代。
表8 | ||
第一多肽 | 第二多肽 | |
组1 | T366K/L351K | L351D/L368E |
组2 | T366K/L351K | L351D/Y349E |
组3 | T366K/L351K | L351D/Y349D |
组4 | T366K/L351K | L351D/Y349E/L368E |
组5 | T366K/L351K | L351D/Y349D/L368E |
组6 | E356K/D399K | K392D/K409D |
可替代地,每个多肽链中的至少一个氨基酸取代可选自表9。
可替代地,至少一个氨基酸取代可以选自表10中的以下组的取代,其中第一多肽列中所示的一个或多个位置被任何已知的带负电荷的氨基酸替换,并且第二多肽列中所示的一个或多个位置被任何已知的带正电荷的氨基酸替换。
表10 | |
第一多肽 | 第二多肽 |
K392、K370、K409或K439 | D399、E356或E357 |
可替代地,至少一个氨基酸取代可以选自表11中的以下组,其中第一多肽列中所示的一个或多个位置被任何已知的带正电荷的氨基酸替换,并且第二多肽列中所示的一个或多个位置被任何已知的带负电荷的氨基酸替换。
表11 | |
第一多肽 | 第二多肽 |
D399、E356或E357 | K409、K439、K370或K392 |
可替代地,氨基酸取代可以选自表12中的以下组。
可替代地,或另外地,可通过在第一或第二多肽链中的任一个上引入S354C并且在相反多肽链上引入Y349C(它们在两个多肽的界面内形成人工二硫桥)来增加异源多聚体蛋白的结构稳定性。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在位置T366上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由T366、L368和Y407组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由T366、L368和Y407组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在位置T366上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由E357、K360、Q362、S364、L368、K370、T394、D401、F405和T411组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由Y349、E357、S364、L368、K370、T394、D401、F405和T411组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由Y349、E357、S364、L368、K370、T394、D401、F405和T411组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由E357、K360、Q362、S364、L368、K370、T394、D401、F405和T411组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由L351、D399、S400和Y407组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由T366、N390、K392、K409和T411组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由T366、N390、K392、K409和T411组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由L351、D399、S400和Y407组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由Q347、Y349、K360和K409组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由Q347、E357、D399和F405组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由Q347、E357、D399和F405组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由Y349、K360、Q347和K409组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由K370、K392、K409和K439组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由D356、E357和D399组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由D356、E357和D399组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由K370、K392、K409和K439组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由L351、E356、T366和D399组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由Y349、L351、L368、K392和K409组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列在选自由Y349、L351、L368、K392和K409组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一条多肽链的氨基酸序列在选自由L351、E356、T366和D399组成的组的一个或多个位置上与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是S354C取代,并且其中抗体恒定区的另一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是Y349C取代。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是Y349C取代,并且其中抗体恒定区的另一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是S354C取代。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是K360E和K409W取代,并且其中抗体恒定区的另一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是O347R、D399V和F405T取代。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是O347R、D399V和F405T取代,并且其中抗体恒定区的另一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是K360E和K409W取代。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是T366W取代,并且其中抗体恒定区的另一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是T366S、T368A和Y407V取代。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是T366S、T368A和Y407V取代,并且其中抗体恒定区的另一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是T366W取代。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是T350V、L351Y、F405A和Y407V取代,并且其中抗体恒定区的另一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是T350V、T366L、K392L和T394W取代。
在一些实施方案中,抗体恒定区的一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是T350V、T366L、K392L和T394W取代,并且其中抗体恒定区的另一条多肽链的氨基酸序列与IgG1恒定区的氨基酸序列的不同之处是T350V、L351Y、F405A和Y407V取代。
下面列出恒定区中能够使两条多肽链异二聚化的突变的实例。曲妥珠单抗重链A1、A2、B1和B2各自包括曲妥珠单抗的重链可变结构域(粗体序列)和衍生自人IgG1的具有呈加下划线的氨基酸形式的突变的恒定区。曲妥珠单抗重链A1和曲妥珠单抗重链B1可以优先配对并形成异二聚体。曲妥珠单抗重链A2和曲妥珠单抗重链B2可以优先配对并形成异二聚体。
曲妥珠单抗重链A
曲妥珠单抗重链B
曲妥珠单抗重链A1
曲妥珠单抗重链B1
可以使用本领域技术人员众所周知的重组DNA技术制备上述蛋白质。例如,可以将编码包含scFv、铰链和抗体恒定区的第一免疫球蛋白链的第一核酸序列克隆到第一表达载体中;可以将编码例如包含另一scFv、铰链和抗体恒定区或包含抗体重链的第二免疫球蛋白链的第二核酸序列克隆到第二表达载体中;并且可以将编码抗体轻链的第三核酸序列克隆到第三表达载体中。可以将第一、第二和任选的第三表达载体一起稳定地转染到宿主细胞中,以产生本文所述的多聚体蛋白。
为了实现多特异性结合蛋白的最高收率,可以对第一、第二和第三表达载体的不同比率进行探究,以确定用于转染到宿主细胞中的最佳比率。转染后,可以使用本领域已知的方法,诸如有限稀释、ELISA、FACS、显微镜检查或Clonepix分离单个克隆以用于产生细胞库。
克隆可以在适于生物反应器放大和多特异性结合蛋白的表达维持的条件下培养。可以使用本领域已知的方法分离和纯化多特异性结合蛋白,包括离心、深度过滤、细胞裂解、匀化、冻-融、亲和纯化、凝胶过滤、离子交换色谱、疏水相互作用交换色谱和混合模式色谱。
II.治疗应用
本发明提供了用于使用本文所述的多特异性结合蛋白和/或本文所述的药物组合物治疗癌症的方法。所述方法可用于治疗多种癌症,包括实体肿瘤、淋巴瘤和白血病。期望待治疗的癌症类型与蛋白质结合的癌细胞的类型相匹配。例如,表达HER2的癌症,诸如表达HER2的乳腺癌的治疗期望使用与蛋白质结合的本文所述的蛋白质进行治疗。在某些实施方案中,本发明提供了用于治疗多种表达BCMA的癌症的方法,其通过向有需要的患者施用治疗有效量的本文所述的多特异性结合蛋白来实现。在某些实施方案中,本发明提供了用于治疗多种表达CD33的癌症的方法,其通过向有需要的患者施用治疗有效量的本文所述的多特异性结合蛋白来实现。
因此,本发明的一个方面提供了一种治疗患者癌症的方法,其中所述方法包括向有需要的患者施用治疗有效量的本文所述的蛋白质,以治疗癌症。治疗方法的另外的方面和实施方案描述如下。
可以根据待治疗的癌症表征治疗方法。例如,在某些实施方案中,癌症是实体肿瘤。在某些其他实施方案中,癌症是脑癌、膀胱癌、乳腺癌、宫颈癌、结肠癌、结肠直肠癌、子宫内膜癌、食道癌、白血病、肺癌、肝癌、黑素瘤、卵巢癌、胰腺癌、前列腺癌、直肠癌、肾癌、胃癌、睾丸癌或子宫癌。在其他实施方案中,癌症是血管化肿瘤(vascularized tumor)、鳞状细胞癌、腺癌、小细胞癌、黑素瘤、成神经细胞瘤、肉瘤(例如,血管肉瘤或软骨肉瘤)、喉癌、腮腺癌、胆道癌、甲状腺癌、肢端雀斑样黑素瘤、光化性角化病、急性淋巴细胞性白血病、急性骨髓性白血病、腺样囊性癌、腺瘤、腺肉瘤、腺鳞癌、肛管癌、肛门癌、肛门直肠癌(anorectum cancer)、星形细胞肿瘤、前庭大腺癌(bartholin gland carcinoma)、基底细胞癌、胆管癌、骨癌、骨髓癌、支气管癌、支气管腺体癌、类癌、胆管癌、软骨肉瘤、脉络丛乳头状瘤/癌、慢性淋巴细胞性白血病、慢性骨髓性白血病、透明细胞癌、结缔组织癌、囊腺瘤、消化系统癌、十二指肠癌、内分泌系统癌、内胚窦瘤、子宫内膜增生、子宫内膜间质肉瘤、子宫内膜样腺癌、内皮细胞癌、室管膜癌、上皮细胞癌、尤文氏肉瘤、眼和眼眶癌、女性生殖器癌、局灶性结节性增生、胆囊癌、胃窦癌、胃底癌、胃泌素瘤、成胶质细胞瘤、胰高血糖素瘤、心脏癌、成血管细胞瘤、血管内皮瘤、血管瘤、肝腺瘤、肝腺瘤病、肝胆管癌、肝细胞癌、霍奇金病、回肠癌、胰岛瘤、上皮内瘤变、上皮间鳞状细胞瘤变(interepithelial squamous cellneoplasia)、肝内胆管癌、浸润性鳞状细胞癌、空肠癌、关节癌、卡波西肉瘤、盆腔癌、大细胞癌、大肠癌、平滑肌肉瘤、雀斑型恶性黑素瘤、淋巴瘤、男性生殖器癌、恶性黑素瘤、恶性间皮肿瘤、成神经管细胞瘤、髓上皮瘤、脑膜癌、间皮癌、转移癌、口腔癌、粘液表皮样癌、多发性骨髓瘤、肌肉癌、鼻道癌、神经系统癌、神经上皮腺癌结节性黑素瘤、非上皮性皮肤癌、燕麦细胞癌、少突胶质细胞癌(oligodendroglial cancer)、口腔癌、骨肉瘤、乳头状浆液性腺癌(papillary serous adenocarcinoma)、阴茎癌、咽癌、垂体肿瘤、浆细胞瘤、假性肉瘤、肺母细胞瘤、直肠癌、肾细胞癌、呼吸系统癌、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、浆液性癌、鼻窦癌(sinuscancer)、皮肤癌、小细胞癌、小肠癌、平滑肌癌、软组织癌、生长抑素分泌型肿瘤(somatostatin-secreting tumor)、脊柱癌、鳞状细胞癌、横纹肌癌、间皮下癌(submesothelial cancer)、浅表扩散性黑素瘤、T细胞白血病、舌癌、未分化癌、输尿管癌、尿道癌、膀胱癌、泌尿系统癌、子宫颈癌、子宫体癌、葡萄膜黑素瘤、阴道癌、疣状癌、血管活性肠肽瘤(VIPoma)、外阴癌、高分化癌或肾母细胞瘤(Wilms tumor)。
在某些其他实施方案中,待治疗的癌症是非霍奇金淋巴瘤,诸如B细胞淋巴瘤或T细胞淋巴瘤。在某些实施方案中,非霍奇金淋巴瘤是B细胞淋巴瘤,诸如弥漫性大B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤、滤泡性淋巴瘤、小淋巴细胞淋巴瘤、套细胞淋巴瘤、边缘区B细胞淋巴瘤、结外边缘区B细胞淋巴瘤、结边缘区B细胞淋巴瘤、脾边缘区B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞性淋巴瘤、毛细胞白血病,或原发性中枢神经系统(CNS)淋巴瘤。在某些其他实施方案中,非霍奇金淋巴瘤是T细胞淋巴瘤,诸如前体T淋巴母细胞性淋巴瘤、外周T细胞淋巴瘤、皮肤T细胞淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、结外自然杀伤/T细胞淋巴瘤、肠病型T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤、间变性大细胞淋巴瘤或外周T细胞淋巴瘤。
在某些实施方案中,癌症是AML、骨髓增生异常综合征、慢性骨髓单核细胞性白血病、慢性骨髓性白血病的骨髓母细胞急变期(myeloid blast crisis)和ALL。
在某些实施方案中,可以根据在癌细胞表面上表达的特定抗原的存在来表征待治疗的癌症。在某些实施方案中,除BCMA之外,癌细胞可以表达以下中的一种或多种:CD2、CD19、CD20、CD30、CD38、CD40、CD52、CD70、EGFR/ERBB1、IGF1R、HER3/ERBB3、HER4/ERBB4、MUC1、cMET、SLAMF7、PSCA、MICA、MICB、TRAILR1、TRAILR2、MAGE-A3、B7.1、B7.2、CTLA4和PD1。
在某些实施方案中,除CD33之外,癌细胞可以表达以下中的一种或多种:CD2、CD19、CD20、CD30、CD38、CD40、CD52、CD70、EGFR/ERBB 1、IGF 1R、HER3/ERBB3、HER4/ERBB4、MUC1、TROP2、cMET、SLAMF7、PSCA、MICA、MICB、TRAILR1、TRAILR2、MAGE-A3、B7.1、B7.2、CTLA4和PD1。
在某些实施方案中,除HER2之外,癌细胞可以表达以下中的一种或多种:CD2、CD19、CD20、CD30、CD38、CD40、CD52、CD70、EGFR/ERBB 1、IGF 1R、HER3/ERBB3、HER4/ERBB4、MUC1、cMET、SLAMF7、PSCA、MICA、MICB、TRAILR1、TRAILR2、MAGE-A3、B7.1、B7.2、CTLA4和PD1。
在某些实施方案中,可以根据癌细胞表面上MHC对特定TAA肽的呈递来表征待治疗的癌症。可以加工成TCR可靶向的TAA肽的蛋白质的非限制性实例包括组织分化抗原(例如,MART-1、gp100、CEA、CD19和酪氨酸酶)、肿瘤种系抗原(例如,NY-ESO-1、MAGE-A1、MAGE-A3、MAGE-A4、MAGE-A 12、MAGE-C2、BAGE1、GAGE1、CTAG1、CTAG2、XAGE-1B和SSX2)、癌细胞过表达的正常蛋白(例如,hTERT、EGFR、ERBB2、WT1、MUC1和间皮素)、病毒蛋白(例如,HPV、EBV和MCC)以及肿瘤特异性突变抗原。在某些实施方案中,癌细胞包含由HLA-A*02:01:48呈递的具有SEQ ID NO:425的氨基酸序列的ELAVL4肽。在某些实施方案中,癌细胞包含由HLA-A*02:01:48呈递的具有SEQ ID NO:426的氨基酸序列的胰岛素肽。在某些实施方案中,癌细胞包含由HLA-A*02:01:48呈递的具有SEQ ID NO:340的氨基酸序列的hTERT肽。在某些实施方案中,癌细胞包含由HLA-A*02呈递的具有SEQ ID NO:341的氨基酸序列的ERBB2肽。在某些实施方案中,癌细胞包含由HLA-A*02呈递的具有SEQ ID NO:342的氨基酸序列的WT1肽。在某些实施方案中,癌细胞包含由HLA-A1呈递的具有SEQ ID NO:343的氨基酸序列的MAGE-A3肽。在某些实施方案中,癌细胞包含由HLA-A2呈递的具有SEQ ID NO:344的氨基酸序列的MART1肽。在某些实施方案中,癌细胞包含由HLA-A2呈递的具有SEQ ID NO:346的氨基酸序列的BIRC5肽。在某些实施方案中,癌细胞包含由HLA-A2呈递的具有SEQ ID NO:347的氨基酸序列的PRAME肽。在某些实施方案中,癌细胞包含由HLA-A2呈递的具有SEQ ID NO:348的氨基酸序列的NY-ESO-1肽。在某些实施方案中,癌细胞包含由HLA-A2呈递的具有SEQ IDNO:345的氨基酸序列的SSX2肽。
III.组合疗法
本发明的另一方面提供组合疗法。本文所述的多特异性结合蛋白可以与另外的治疗剂组合使用来治疗癌症。
可作为组合疗法的一部分用于治疗癌症的示例性治疗剂包括,例如,辐射、丝裂霉素、维甲酸、苯达莫司汀(ribomustin)、吉西他滨(gemcitabine)、长春新碱(vincristine)、依托泊苷(etoposide)、克拉屈滨(cladribine)、二溴甘露醇(mitobronitol)、甲氨蝶呤(methotrexate)、多柔比星(doxorubicin)、卡波醌(carboquone)、喷司他丁(pentostatin)、硝氨吖啶(nitracrine)、净司他丁(zinostatin)、西曲瑞克(cetrorelix)、来曲唑(letrozole)、雷替曲塞(raltitrexed)、道诺霉素(daunorubicin)、法屈唑(fadrozole)、福莫司汀(fotemustine)、胸腺法新(thymalfasin)、索布佐生(sobuzoxane)、奈达铂(nedaplatin)、阿糖胞苷、比卡鲁胺(bicalutamide)、长春瑞滨(vinorelbine)、维司力农(vesnarinone)、氨鲁米特(aminoglutethimide)、安吖啶(amsacrine)、丙谷胺(proglumide)、依利醋铵(elliptinium acetate)、酮舍林(ketanserin)、去氧氟尿苷(doxifluridine)、依曲替酯(etretinate)、异维甲酸(isotretinoin)、链脲菌素(streptozocin)、尼莫司汀(nimustine)、长春地辛(vindesine)、氟他米特(flutamide)、氟他胺(drogenil)、布缩宫素(butocin)、卡莫氟(carmofur)、雷佐生(razoxane)、裂皱菌素(sizofilan)、卡铂(carboplatin)、二溴卫矛醇(mitolactol)、替加氟(tegafur)、异环磷酰胺(ifosfamide)、泼尼莫司汀(prednimustine)、必医你舒(picibanil)、左旋咪唑(levamisole)、替尼泊苷(teniposide)、英丙舒凡(improsulfan)、依诺他滨(enocitabine)、麦角乙脲(lisuride)、羟甲烯龙(oxymetholone)、他莫昔芬(tamoxifen)、黄体酮、美雄烷(mepitiostane)、环硫雄醇(epitiostanol)、福美司坦(formestane)、干扰素α、干扰素2α、干扰素β、干扰素γ、集落刺激因子1、集落刺激因子2、地尼白介素-白喉毒素连接物(denileukin diftitox)、白介素2、促黄体激素释放因子以及可表现出与其同源受体的不同结合和增加或减少的血清半衰期的上述药剂的变型。
可作为组合疗法的一部分用于治疗癌症的另一类药剂是免疫检查点抑制剂。示例性免疫检查点抑制剂包括抑制以下中的一种或多种的药剂:(i)细胞毒性T淋巴细胞相关抗原4(CTLA4),(ii)程序性细胞死亡蛋白1(PD1),(iii)PDL1,(iv)LAG3,(v)B7-H3,(vi)B7-H4和(vii)TIM3。CTLA4抑制剂伊匹木单抗(ipilimumab)已被美国食品和药物管理局批准用于治疗黑素瘤。
可作为组合疗法的一部分用于治疗癌症的其他药剂是靶向非检查点靶标的单克隆抗体药剂(例如,赫赛汀(herceptin))和非细胞毒性剂(例如,酪氨酸激酶抑制剂)。
其他类别的抗癌剂包括,例如:(i)选自ALK抑制剂、ATR抑制剂、A2A拮抗剂、碱基切除修复抑制剂、Bcr-Abl酪氨酸激酶抑制剂、布鲁顿(Bruton′s)酪氨酸激酶抑制剂、CDC7抑制剂、CHK1抑制剂、细胞周期蛋白依赖性激酶抑制剂、DNA-PK抑制剂、DNA-PK和mTOR两者的抑制剂、DNMT1抑制剂、DNMT1抑制剂加2-氯-脱氧腺苷、HDAC抑制剂、刺猬信号传导通路抑制剂、IDO抑制剂、JAK抑制剂、mTOR抑制剂、MEK抑制剂、MELK抑制剂、MTH1抑制剂、PARP抑制剂、磷酸肌醇3-激酶抑制剂、PARP1和DHODH两者的抑制剂、蛋白酶体抑制剂、拓扑异构酶II抑制剂、酪氨酸激酶抑制剂、VEGFR抑制剂以及WEE1抑制剂的抑制剂;(ii)OX40、CD137、CD40、GITR、CD27、HVEM、TNFRSF25或ICOS的激动剂;以及(iii)选自IL-12、IL-15、GM-CSF和G-CSF的细胞因子。
本发明的蛋白质也可以用作手术切除原发病灶的助剂。
可选择多特异性结合蛋白和另外的治疗剂的量以及施用的相对定时,以便实现期望的组合治疗效果。例如,当向需要这种施用的患者施用组合疗法时,组合中的治疗剂或包含治疗剂的一种或多种药物组合物可以任何顺序,例如依序、共同、一起、同时等施用。此外,例如,多特异性结合蛋白可在一种或多种另外的治疗剂发挥其预防或治疗作用的时间期间施用,或反之亦然。
IV.药物组合物
本公开的特征还在于包含治疗有效量的本文所述的多特异性结合蛋白的药物组合物/制剂。
所述组合物可以被配制用于多种药物递送体系。一种或多种生理上可接受的赋形剂或载剂也可以包括在组合物中以用于适当配制。用于本公开的合适制剂见于Remington′s Pharmaceutical Sciences,Mack Publishing Company,Philadelphia,Pa.,第17版,1985。关于药物递送方法的简要综述,参见,例如,Langer(Science 249:1527-1533,1990)。
本公开的静脉内药物递送制剂可包含在袋、笔或注射器中。在某些实施方案中,袋可连接至包括管和/或针头的通道。在某些实施方案中,制剂可以是冻干制剂或液体制剂。在某些实施方案中,制剂可冷冻干燥(冻干)并包含在约12-60个小瓶中。在某些实施方案中,可将制剂冷冻干燥,并且45mg冷冻干燥的制剂可包含在一个小瓶中。在某些实施方案中,约40mg-约100mg的冷冻干燥的制剂可包含在一个小瓶中。在某些实施方案中,将来自12、27或45个小瓶的冷冻干燥的制剂组合以获得治疗剂量的呈静脉内药物制剂形式的蛋白质。在某些实施方案中,制剂可以是液体制剂并且以约250mg/小瓶至约1000mg/小瓶储存。在某些实施方案中,制剂可以是液体制剂并且以约600mg/小瓶储存。在某些实施方案中,制剂可以是液体制剂并且以约250mg/小瓶储存。
本公开的蛋白质可以液体含水药物制剂的形式存在,其在缓冲溶液中包括治疗有效量的蛋白质,从而形成制剂。
这些组合物可通过常规灭菌技术来灭菌,或可进行无菌过滤。可将所得水溶液包装以用于原样使用,或冻干,在施用之前,将冻干的制剂与无菌含水载剂组合。制剂的pH通常将在3与11之间,更优选在5与9之间或在6与8之间,并且最优选在7与8之间,诸如7至7.5。可将固体形式的所得组合物以多个单剂量单位包装,每个单位包含固定量的一种或多种上述药剂。固体形式的组合物也可以包装在容器中以灵活取量。
在某些实施方案中,本公开提供了一种具有延长保质期的制剂,其包括与甘露糖醇、柠檬酸一水合物、柠檬酸钠、磷酸二钠二水合物、磷酸二氢钠二水合物、氯化钠、聚山梨酸酯80、水和氢氧化钠组合的本公开的蛋白质。
在某些实施方案中,制备在pH缓冲溶液中包括本公开的蛋白质的含水制剂。本发明的缓冲液可具有在约4至约8,例如,约4.5至约6.0,或约4.8至约5.5范围内的pH,或可具有约5.0至约5.2的pH。上述pH值中间的范围也旨在成为本公开的一部分。例如,旨在包括使用任何上述值的组合作为上限和/或下限的值的范围。将把pH控制在此范围内的缓冲液的实例包括乙酸盐(例如,乙酸钠)、琥珀酸盐(诸如琥珀酸钠)、葡糖酸盐、组氨酸、柠檬酸盐以及其他有机酸缓冲液。
在某些实施方案中,制剂包括包含柠檬酸盐和磷酸盐的缓冲体系,以将pH维持在约4至约8的范围内。在某些实施方案中,pH范围可为约4.5至约6.0,或约pH 4.8至约5.5,或在约5.0至约5.2的pH范围内。在某些实施方案中,缓冲体系包括柠檬酸一水合物、柠檬酸钠、磷酸二钠二水合物和/或磷酸二氢钠二水合物。在某些实施方案中,缓冲体系包括约1.3mg/ml的柠檬酸(例如,1.305mg/m1)、约0.3mg/ml的柠檬酸钠(例如,0.305mg/ml)、约1.5mg/ml的磷酸二钠二水合物(例如,1.53mg/m1)、约0.9mg/ml的磷酸二氢钠二水合物(例如,0.86)以及约6.2mg/ml的氯化钠(例如,6.165mg/m1)。在某些实施方案中,缓冲体系包括1-1.5mg/ml的柠檬酸、0.25至0.5mg/ml的柠檬酸钠、1.25至1.75mg/ml的磷酸二钠二水合物、0.7至1.1mg/ml的磷酸二氢钠二水合物,以及6.0至6.4mg/ml的氯化钠。在某些实施方案中,用氢氧化钠调节制剂的pH。
在制剂中还可包括多元醇,其用作张力调节剂(tonicifier)并可使抗体稳定。多元醇以相对于制剂的期望等张性可变化的量添加到制剂中。在某些实施方案中,含水制剂可以是等张的。还可相对于多元醇的分子量改变多元醇的添加量。例如,与二糖(诸如海藻糖)相比,可添加较少量的单糖(例如,甘露糖醇)。在某些实施方案中,可在制剂中用作张度剂的多元醇是甘露糖醇。在某些实施方案中,甘露糖醇浓度可为约5至约20mg/ml。在某些实施方案中,甘露糖醇的浓度可为约7.5至15mg/ml。在某些实施方案中,甘露糖醇的浓度可为约10-14mg/ml。在某些实施方案中,甘露糖醇的浓度可为约12mg/ml。在某些实施方案中,多元醇山梨糖醇可包括在制剂中。
也可将去污剂或表面活性剂添加到制剂中。示例性去污剂包括非离子型去污剂,诸如聚山梨酸酯(例如,聚山梨酸酯20、80等)或泊洛沙姆(例如,泊洛沙姆188)。去污剂的添加量使得其减少所配制抗体的聚集和/或最小化制剂中的颗粒形成和/或减少吸附。在某些实施方案中,制剂可包括为聚山梨酸酯的表面活性剂。在某些实施方案中,制剂可包含去污剂聚山梨酸酯80或吐温80。吐温80是用于描述聚氧乙烯(20)脱水山梨糖醇单油酸酯的术语(参见Fiedler,Lexikon der Hifsstoffe,Editio Cantor Verlag Aulendorf,第4版,1996)。在某些实施方案中,制剂可包含在约0.1mg/mL与约10mg/mL之间,或在约0.5mg/mL与约5mg/mL之间的聚山梨酸酯80。在某些实施方案中,可在制剂中添加约0.1%的聚山梨酸酯80。
在实施方案中,本公开的蛋白质产物被配制为液体制剂。液体制剂可以10mg/mL的浓度存在于USP/Ph Eur I型50R小瓶中,所述小瓶用橡胶塞封闭并用铝卷边密封盖(crimpseal closure)密封。塞子可由符合USP和Ph Eur的弹性体制成。在某些实施方案中,小瓶可填充有61.2mL的蛋白质产品溶液,以允许60mL的可提取体积。在某些实施方案中,液体制剂可用0.9%盐水溶液稀释。
在某些实施方案中,本公开的蛋白质的液体制剂可与稳定水平的糖组合制备成10mg/mL浓度的溶液。在某些实施方案中,液体制剂可在含水载剂中制备。在某些实施方案中,可以不大于可能导致对于静脉内施用不期望或不适合的粘度的量添加稳定剂。在某些实施方案中,糖可以是二糖,例如蔗糖。在某些实施方案中,液体制剂还可包括缓冲剂、表面活性剂和防腐剂中的一种或多种。
在某些实施方案中,液体制剂的pH可通过添加药学上可接受的酸和/或碱来设定。在某些实施方案中,药学上可接受的酸可以是盐酸。在某些实施方案中,碱可以是氢氧化钠。
除聚集之外,脱氨基(deamidation)是肽和蛋白质的常见产物变化,其可发生在发酵、收获/细胞澄清、纯化、药物物质/药物产品储存期间以及样品分析期间。脱氨基是蛋白质损失NH3,形成可以进行水解的琥珀酰亚胺中间体。琥珀酰亚胺中间体导致亲本肽的质量降低17道尔顿。随后的水解导致质量增加18道尔顿。琥珀酰亚胺中间体由于在含水条件下的不稳定性而难以分离。因此,脱氨基通常可检测为质量增加1道尔顿。天冬酰胺的脱氨基产生天冬氨酸或异天冬氨酸。影响脱氨基的速率的参数包括pH、温度、溶剂介电常数、离子强度、一级序列、局部多肽构象和三级结构。肽链中与Asn相邻的氨基酸残基影响脱氨基速率。蛋白质序列中Asn之后的Gly和Ser导致对脱氨基具有更高敏感性。
在某些实施方案中,本公开的蛋白质的液体制剂可在防止蛋白质产物脱氨基的pH和湿度条件下保存。
本文感兴趣的含水载剂是药学上可接受的载剂(对人施用安全且无毒)并且对液体制剂的制备有用。例示性载剂包括无菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH缓冲溶液(例如,磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液或右旋糖溶液。
可将防腐剂任选地添加到本文的制剂中以减少细菌作用。防腐剂的添加可以例如促进多用途(多剂量)制剂的生产。
在特定情况下,诸如当患者在移植后在医院中通过IV途径接受所有药物时,静脉内(IV)制剂可以是优选的施用途径。在某些实施方案中,液体制剂在施用前用0.9%氯化钠溶液稀释。在某些实施方案中,用于注射的稀释药物产品是等张的并且适于通过静脉内输注进行施用。
在某些实施方案中,可以10mM-200mM的量添加盐或缓冲液组分。盐和/或缓冲液是药学上可接受的,并且衍生自具有“碱形成”金属或胺的各种已知酸(无机和有机)。在某些实施方案中,缓冲液可以是磷酸盐缓冲液。在某些实施方案中,缓冲液可以是甘氨酸盐、碳酸盐、柠檬酸盐缓冲液,在这种情况下,钠、钾或铵离子可以充当抗衡离子。
可将防腐剂任选地添加到本文的制剂中以减少细菌作用。防腐剂的添加可以例如促进多用途(多剂量)制剂的生产。
本文感兴趣的含水载剂是药学上可接受的载剂(对人施用安全且无毒)并且对液体制剂的制备有用。例示性载剂包括无菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH缓冲溶液(例如,磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液或右旋糖溶液。
本公开的蛋白质可以包括蛋白质和冻干保护剂的冻干制剂的形式存在。冻干保护剂可以是糖,例如二糖。在某些实施方案中,冻干保护剂可以是蔗糖或麦芽糖。冻干制剂还可包括缓冲剂、表面活性剂、填充剂和/或防腐剂中的一种或多种。
可用于稳定冻干药物产品的蔗糖或麦芽糖的量可以是至少1∶2的蛋白质与蔗糖或麦芽糖的重量比。在某些实施方案中,蛋白质与蔗糖或麦芽糖的重量比可为1∶2至1∶5。
在某些实施方案中,可通过添加药学上可接受的酸和/或碱来设定冻干之前制剂的pH。在某些实施方案中,药学上可接受的酸可以是盐酸。在某些实施方案中,药学上可接受的碱可以是氢氧化钠。
在冻干之前,可将包含本公开的蛋白质的溶液的pH调节在6至8之间。在某些实施方案中,冻干药物产品的pH范围可以是7至8。
在某些实施方案中,可以10mM-200mM的量添加盐或缓冲液组分。盐和/或缓冲液是药学上可接受的,并且衍生自具有“碱形成”金属或胺的各种已知酸(无机和有机)。在某些实施方案中,缓冲液可以是磷酸盐缓冲液。在某些实施方案中,缓冲液可以是甘氨酸盐、碳酸盐、柠檬酸盐缓冲液,在这种情况下,钠、钾或铵离子可以充当抗衡离子。
在某些实施方案中,可添加“填充剂”。“填充剂(bulking agent)”是这样的化合物,其增加冻干混合物的质量并且有助于冻干饼的物理结构(例如,促进产生基本上均匀的冻干饼,以维持开孔结构)。例示性填充剂包括甘露糖醇、甘氨酸、聚乙二醇和山梨糖醇。本发明的冻干制剂可包含此类填充剂。
可将防腐剂任选地添加到本文的制剂中以减少细菌作用。防腐剂的添加可以例如促进多用途(多剂量)制剂的生产。
在某些实施方案中,冻干药物产品可以用含水载剂构制。本文感兴趣的含水载剂是药学上可接受的载剂(例如,对人施用安全且无毒)并且可用于在冻干后制备液体制剂。例示性稀释剂包括无菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH缓冲溶液(例如,磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液或右旋糖溶液。
在某些实施方案中,将本公开的冻干药物产品用无菌注射用水,USP(SWFI)或0.9%氯化钠注射液,USP重构。在重构期间,冻干粉末溶解成溶液。
在某些实施方案中,将本公开的冻干蛋白产物构制到约4.5mL注射用水中,并用0.9%盐水溶液(氯化钠溶液)稀释。
本发明的药物组合物中活性成分的实际剂量水平可有所变化,以便获得对于特定患者、组合物和施用模式有效实现期望治疗反应而对患者无毒的活性成分的量。
对于各个患者,特定剂量可以是统一剂量,例如50-5000mg蛋白质。可替代地,患者的剂量可以根据患者的近似体重或表面积进行调整。确定适当剂量的其他因素可以包括待治疗或预防的疾病或病状、疾病的严重程度、施用途径,以及患者的年龄、性别和医疗状况。确定适当的治疗剂量所必需的计算的进一步精细改进是本领域技术人员常规进行的,尤其是根据本文公开的剂量信息和测定。剂量也可以通过使用与适当的剂量-反应数据结合使用的用于确定剂量的已知测定来确定。可以在监测疾病进展时调节个体患者的剂量。可以测量患者的可靶向构建体或复合物的血液水平,以查看是否需要调节剂量以达到或维持有效浓度。药物基因组学可用于确定哪种可靶向构建体和/或复合物及其剂量对于给定个体最可能有效(Schmitz等.,Clinica Chimica Acta 308:43-53,2001;Steimer等.,ClinicaChimica Acta 308:33-41,2001)。
一般来讲,基于体重的剂量为约0.01μg至约100mg/kg体重,诸如约0.01μg至约100mg/kg体重、约0.01μg至约50mg/kg体重、约0.01μg至约10mg/kg体重、约0.01μg至约1mg/kg体重、约0.01μg至约100μg/kg体重、约0.01μg至约50μg/kg体重、约0.01μg至约10μg/kg体重、约0.01μg至约1μg/kg体重、约0.01μg至约0.1μg/kg体重、约0.1μg至约100mg/kg体重、约0.1μg至约50mg/kg体重、约0.1μg至约10mg/kg体重、约0.1μg至约1mg/kg体重、约0.1μg至约100μg/kg体重、约0.1μg至约10μg/kg体重、约0.1μg至约1μg/kg体重、约1μg至约100mg/kg体重、约1μg至约50mg/kg体重、约1μg至约10mg/kg体重、约1μg至约1mg/kg体重、约1μg至约100μg/kg体重、约1μg至约50μg/kg体重、约1μg至约10μg/kg体重、约10μg至约100mg/kg体重、约10μg至约50mg/kg体重、约10μg至约10mg/kg体重、约10μg至约1mg/kg体重、约10μg至约100μg/kg体重、约10μg至约50μg/kg体重、约50μg至约100mg/kg体重、约50μg至约50mg/kg体重、约50μg至约10mg/kg体重、约50μg至约1mg/kg体重、约50μg至约100μg/kg体重、约100μg至约100mg/kg体重、约100μg至约50mg/kg体重、约100μg至约10mg/kg体重、约100μg至约1mg/kg体重、约1mg至约100mg/kg体重、约1mg至约50mg/kg体重、约1mg至约10mg/kg体重、约10mg至约100mg/kg体重、约10mg至约50mg/kg体重、约50mg至约100mg/kg体重。
剂量可每天、每周、每月或每年给予一次或多次,或甚至每2至20年给予一次。本领域的普通技术人员可以基于所测得的可靶向构建体或复合物在体液或组织中的滞留时间和浓度容易地估算出给药的重复率。本发明的施用可以是静脉内、动脉内、腹膜内、肌内、皮下、胸膜内、鞘内、腔内、通过导管灌注或通过病灶内直接注射。可每天施用一次或多次、每周施用一次或多次、每月施用一次或多次,以及每年施用一次或多次。
以上说明描述了本发明的多个方面和实施方案。本专利申请具体涵盖所述方面和实施方案的所有组合和排列。
实施例
现已大体上描述本发明,参考以下实施例将更容易理解本发明,所述实施例仅出于说明本发明的某些方面和实施方案的目的被包括在内并且不旨在限制本发明。
实施例1-F3-TriNKET和F3’-TriNKET的纯化
按照用于纯化治疗性单克隆抗体的步骤纯化F3-TriNKET和F3’-TriNKET蛋白。简单来说,纯化方法包括蛋白A纯化(实现约80-90%单体),以及随后的Poros HS CIEX盐步骤洗脱(实现约97-99%单体)。对于临床制造过程,可以添加使用Q Cepharose或Q Mustang(流通模式)(以实现约99%单体)的附加纯化步骤,以进一步减少全细胞蛋白(WCP)和CHODNA。
纯化的F3’-TriNKET具有高热稳定性(DSC),类似于治疗性单克隆抗体。并且含有突变Fc的F3’-TrinKET的稳定性接近于IgG1 Fc。参见以下表13。
表13
实施例2-F3’-TriNKET持续至少4周是稳定的
在37℃下进行的加速稳定性研究中,发现F3’-TriNKET经4周保持稳定。参见图3A-3C。
纯化的F3’-TriNKET在低pH保持期间是稳定的。将20mg/mL的纯化蛋白在甘氨酸中于pH 3.0下孵育2小时。图4示出纯化的F3’-TriNKET在低pH保持期间是稳定的。
纯化的F3’-TriNKET在5个冻-融循环后是稳定的。图5A和图5B示出无论pH如何,纯化的F3’-TriNKET在5个冻-融循环后都是稳定的(图5A示出在PBS中的冻-融循环,并且图5B示出在pH 5.5的柠檬酸盐中的冻-融循环)。
纯化的F3’-TriNKET在强制降解研究中是稳定的。图6示出其中F3’-TriNKET保持稳定的强制降解条件的条形图。
实施例3-评估TriNKET与表达人癌抗原的细胞的结合
使用表达目标癌抗原的人癌细胞系评估TriNKET的肿瘤抗原结合。使用人AML细胞系Molm-13评估F3’-TriNKET-CD33与CD33表达细胞的结合。使用HER2+Colo-201细胞系评估F3’-TriNKET-HER2与HER2表达细胞的结合。将F3’-TriNKET-HER2和F3’-TriNKET-CD33稀释,并与相应细胞一起孵育。使用荧光团缀合的抗人IgG二抗分别检测F3’-TriNKET-HER2与HER2表达细胞以及F3’-TriNKET-CD33与CD33表达细胞的结合。通过流式细胞术分析细胞,分别将对HER2和CD33表达细胞的结合MFI针对二抗对照归一化,以获得相对于背景的倍数(fold over background)值。
实施例4-原代人NK细胞的细胞毒性测定
使用密度梯度离心从人外周血血沉棕黄层中分离出外周血单核细胞(PBMC)。将分离的PBMC洗涤并制备以用于NK细胞分离。使用负选择技术,用磁珠分离NK细胞,分离的NK细胞的纯度通常>90%CD3-CD56+。使分离的NK细胞静息(rest)过夜,并且第二天用于细胞毒性测定。
DELFIA组胞毒性测定:
从培养物中收获表达目标靶标的人癌细胞系,用PBS洗涤细胞,并以106/mL重悬于生长培养基中,以用BATDA试剂(Perkin Elmer AD0116)进行标记。按照制造商的说明标记靶细胞。标记后,将细胞用PBS洗涤3x,并以0.5-1.0x105/mL重悬于培养基中。为了制备背景孔,将标记细胞的等分试样暂放一边,并将细胞从培养基中离心出来。小心地将100μl培养基一式三份添加到孔中,以免干扰沉淀的细胞。将100μl BATDA标记的细胞添加到96孔板的每个孔中。保存孔以用于从靶细胞的自发释放,并通过添加1%Triton-X制备孔以用于靶细胞的最大裂解。将针对目标肿瘤靶标的单克隆抗体或TriNKET在培养基中稀释,向每个孔中添加50μl稀释的mAb或TriNKET。从培养物中收获静息和/或激活的NK细胞,洗涤细胞,并根据期望的E∶T比以105-2.0x106/mL重悬于培养基中。将50μl NK细胞添加到板的每个孔中,以得到200μl的总培养体积。将板在37℃与5%CO2下孵育2-3小时,然后对测定显影。
培养2-3小时后,将板从培养箱中移出,并通过以200g离心5分钟沉淀细胞。将20μl培养上清液转移至制造商提供的干净微板中,并向每个孔中添加200μl室温铕溶液。使板避光,并在板振荡器上以250rpm孵育15分钟。使用Victor 3或SpectraMax i3X仪器读板。特异性裂解%计算如下:特异性裂解%=((实验释放-自发释放)/(最大释放-自发释放))*100%。
流式细胞术细胞毒性测定
从培养物中收获嘌呤霉素选择后的表达BCMA并被转导以稳定表达NucLightGreen(Essen BioScience 4475)的人癌细胞系,离心,并以105/mL重悬于培养基中。将100μl靶细胞添加到96孔板的每个孔中。将针对BCMA的TriNKET在培养基中稀释,并且将各50μl添加到重复孔中。从培养物中收获静息过夜的纯化的人NK,洗涤,并以4×105/mL重悬于培养基中。对于2∶1的E∶T比,将50μl NK细胞添加到所有孔中,仅靶标的对照除外,所述对照接受100μl培养基。将板在37℃与5%CO2下孵育30小时。
共培养后,将细胞染色、固定并通过流式细胞术进行分析。检测到在FITC通道中具有强烈偏移的其余靶细胞,其中通过活力染色排除死细胞。输出绿色事件的数量,并通过与仅靶标的对照样品进行比较来计算杀伤%。计数珠粒被包括在内,以确保记录的体积相当。
实施例5-F3’TriNKET与表达肿瘤抗原的细胞的结合
图7示出F3’-TriNKET-HER2或曲妥珠单抗与HER2+Colo-201细胞的结合。F3’-TriNKET-HER2以更高的最大相对于背景的倍数结合Colo-201细胞,但具有略微降低的EC50结合值。
图8示出F3’-TriNKET-CD33或CD33单克隆抗体与在Molm-13细胞上表达的CD33的结合。与CD33 mAb相比,F3’-TriNKET以类似的最大相对于背景的倍数和EC50结合值结合Molm-13细胞。
实施例6-F3’-TriNKET介导针对HER2+和CD33+靶细胞的NK细胞毒性:
图9和图10分别示出F3’-TriNKET-HER2介导的针对HER2低表达细胞系786-O和HER2高表达细胞系SkBr-3的细胞毒性。F3’-TriNKET-HER2为诱导NK介导的针对HER2低表达和HER2高表达细胞系的细胞毒性均提供了有效的EC50值。对于HER2高表达和低表达细胞,与曲妥珠单抗相比,F3’-TriNKET-HER2提供了更大的最大特异性裂解和更有效的EC50值。
图11和图12分别示出F3’-TriNKET-CD33介导的针对两种CD33阳性人细胞系EOL-1和THP-1的细胞毒性。CD33单克隆抗体能够增加EOL-1靶细胞的NK细胞裂解(图11),但是发现它对高FcR的THP-1细胞系无效(图12)。F3’-TriNKET-CD33为诱导NK介导的针对THP-1和EOL-1靶细胞的细胞毒性提供了次纳摩尔EC50值。
实施例7-F4-TriNKET介导NK细胞毒性
本实施例描述了靶标癌细胞的NK细胞杀伤的二价F4形式TriNKET介导的增强的效力。本实施例描述了二价F4形式TriNKET与靶细胞的结合。本实施例描述了二价F4形式TriNKET在稳定和维持BCMA在细胞表面上的高细胞表面表达中的作用。本实施例描述了二价F4形式TriNKET与其靶标的亲合力改善了TriNKET与靶抗原结合的亲和力,这实际上稳定了高水平的靶抗原在细胞表面上的表达和维持。
通过F4-TriNKET实现的BCMA表面稳定
将BCMA阳性的KMS12-PE骨髓瘤细胞与10μg/mL F4-TriNKET或单克隆抗体(EM-901)一起孵育,将样品分成三份,将每份样品等分试样在冰上放置20分钟、在37℃下放置2小时或在37℃下放置24小时。孵育期后,洗涤细胞并使用抗人IgG二抗检测结合的F4-TriNKET。染色后,将细胞固定并储存在4℃,在研究结束时分析所有样品。
评估F4-TriNKET与表达人癌抗原的细胞的结合
使用表达BCMA的人癌细胞系评估F4-TriNKET的肿瘤抗原结合(例如,A49-F4-TriNKET-BCMA,来自克隆ADI-27749的NKG2D结合结构域和衍生自EM-901的BCMA结合结构域)。使用以比KMS12-PE骨髓瘤细胞更高的水平表达BCMA的人多发性骨髓瘤细胞系MM.1R评估TriNKET与表达高水平BCMA的细胞的结合。将F4-TriNKET稀释,并与MM.1R细胞一起孵育。使用荧光团缀合的抗人IgG二抗检测F4-TriNKET的结合。通过流式细胞术分析细胞,将对表达BCMA的细胞的结合MFI针对二抗对照归一化,以获得相对于背景的倍数值。
原代人NK细胞的细胞毒性测定
使用密度梯度离心从人外周血血沉棕黄层中分离出外周血单核细胞(PBMC)。将分离的PBMC洗涤并制备以用于NK细胞分离。使用负选择技术,用磁珠分离NK细胞,分离的NK细胞的纯度通常>90%CD3-CD56+。将分离的NK细胞静息过夜,并且第二天用于细胞毒性测定。
DELFIA细胞毒性测定:从培养物中收获表达目标靶标的人癌细胞系,用PBS洗涤细胞,并以106/mL重悬于生长培养基中,以用BATDA试剂(Perkin Elmer AD0116)进行标记。按照制造商的说明标记靶细胞。标记后,将细胞用PBS洗涤3x,并以0.5-1.0x105/mL重悬于培养基中。为了制备背景孔,将标记细胞的等分试样暂放一边,并将细胞从培养基中离心出来。小心地将100μl培养基一式三份添加到孔中,以免干扰沉淀的细胞。将100μl BATDA标记的细胞添加到96孔板的每个孔中。保存孔以用于从靶细胞的自发释放,并通过添加1%Triton-X制备孔以用于靶细胞的最大裂解。将针对目标肿瘤靶标的单克隆抗体或TriNKET在培养基中稀释,向每个孔中添加50μl稀释的mAb或TriNKET。从培养物中收获静息和/或激活的NK细胞,洗涤细胞,并根据期望的E∶T比以105-2.0x106/mL重悬于培养基中。将50μl NK细胞添加到板的每个孔中,以得到200μl的总培养体积。将板在37℃与5%CO2下孵育2-3小时,然后对测定显影。培养2-3小时后,将板从培养箱中移出,并通过以200g离心5分钟沉淀细胞。将20μl培养上清液转移至制造商提供的干净微板中,并向每个孔中添加200μl室温铕溶液。使板避光,并在板振荡器上以250rpm孵育15分钟。使用Victor 3或SpectraMax i3X仪器读板。特异性裂解%计算如下:特异性裂解%=((实验释放-自发释放)/(最大释放-自发释放))*100%。
F4-TriNKET介导的NK细胞毒性
对F4-TriNKET介导的BCMA阳性骨髓瘤细胞的裂解进行测定。图19示出F4-TriNKET介导的静息的人NK效应细胞对BCMA阳性KMS 12-PE骨髓瘤细胞的裂解。图20示出F4-TriNKET介导的静息的人NK效应细胞对BCMA阳性MM.1R骨髓瘤细胞的裂解。EM-901单克隆抗体在两个实验中均用作对照。在图19中,使用KMS12-PE细胞(低BCMA表达)作为靶细胞;在图20中,使用MM.1R(高BCMA表达)作为靶细胞。对于相应的高表达和低表达BCMA的细胞MM.1R和KMS12-PE,F4-TriNKET具有次纳摩尔EC50值。与BCMA单克隆抗体EM-901相比,F4-TriNKET提供了针对两种细胞系的更大的最大特异性裂解和效力。
图21示出F4-TriNKET(A49-F4-TriNKET-BCMA)、duobody-TriNKET(A49-DB-TriNKET-BCMA)或BCMA单克隆抗体(EM-901)与MM.1R骨髓瘤细胞的结合。所有这三种蛋白质都能够以剂量反应方式与MM.1R细胞上表达的BCMA结合。与一价结合子相比,亲合(avid)结合子能够以略微降低的最大相对于背景的倍数结合,但是亲合结合提供了提高的EC50结合值。
F4-TriNKET稳定表面BCMA
图22示出在持续指示时间的孵育后,用F4-TriNKET或BCMA单克隆抗体(EM-901)对表面BCMA的染色。孵育后,BCMA mAb(EM-901)和F4-TriNKET都能快速稳定表面BCMA。BCMAmAb(EM-901)和F4-TriNKET能够在24小时的时期内维持增加的BCMA表面表达。
图23示出在与F4-TriNKET或BCMA单克隆抗体(EM-901)一起孵育后,KMS12-PE细胞上的表面BCMA的稳定。在暴露于F4-TriNKET或mAb(EM-901)之后,细胞表面上BCMA的初始稳定迅速发生。由F4-TriNKET和单克隆抗体(EM-901)提供的亲和结合维持比一价BCMA结合持续更长时间的高表面BCMA,如通过使用duobody-TriNKET的情况下在24小时处表面BCMA表达的下降所表明。
F4-TriNKET介导大量的长期细胞毒性
流式细胞术细胞毒性测定:从培养物中收获嘌呤霉素选择后的表达BCMA并被转导以稳定表达NucLight Green(Essen BioScience 4475)的人癌细胞系,离心,并以105/mL重悬于培养基中。将100μl靶细胞添加到96孔板的每个孔中。将针对BCMA的TriNKET在培养基中稀释,并且将各50μl添加到重复孔中。从培养物中收获静息过夜的纯化的人NK,洗涤,并以4×105/mL重悬于培养基中。对于2∶1的E∶T比,将50μl NK细胞添加到所有孔中,仅靶标的对照除外,所述对照接受100μl培养基。将板在37℃与5%CO2下孵育30小时。
共培养后,将细胞染色、固定并通过流式细胞术进行分析。检测到在FITC通道中具有强烈偏移的其余靶细胞,其中通过活力染色排除死细胞。输出绿色事件的数量,并通过与仅靶标的对照样品进行比较来计算杀伤%。计数珠粒被包括在内,以确保记录的体积相当。
F4-TriNKET介导大量的长期细胞毒性
图24和图25示出在30小时后,在F4-或DB-TriNKET的存在下,利用2∶1的E∶T比时BCMA阳性靶细胞系的人NK细胞裂解。图24示出KMS12-PE细胞(低BCMA表达)的杀伤高于无蛋白对照的杀伤,而在图25中,使用MM.1S细胞(更高的BCMA表达)作为靶细胞。与一价duobody-TriNKET相比,F4-TriNKET在所有测试浓度下均表现出BCMA高表达和低表达细胞系的杀伤增加。
以引用的方式并入
本文引用的每一个专利文献和科技文章的全部公开内容出于全部目的以引用的方式并入。
等效方案
在不脱离本发明的精神或基本特征的情况下,本发明可以其他具体形式来实施。因此,前述实施方案在所有方面都应被视为说明性的,而非是对本文描述的本发明的限制。因此,本发明的范围是由随附权利要求而非由上述描述所指示,并且属于权利要求的等效性含义和范围内的所有变化都意图包括在本文中。
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100 105
<210> 12
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 12
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 13
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 13
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 14
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 14
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Gly Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 15
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 15
Glu Leu Gln Met 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 Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp 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 Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asp Ile Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 16
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 16
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 17
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 17
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gly Ser Phe Pro Ile
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 18
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 18
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 19
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 19
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu 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
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Lys Glu Val Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 20
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 20
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 21
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 21
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Phe Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 22
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 22
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 23
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 23
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ile Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 24
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 24
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 25
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 25
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 26
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 26
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 27
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 27
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gly Ser Phe Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 28
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 28
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 29
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 29
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Ser Phe Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 30
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 30
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 31
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 31
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Phe Ser Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 32
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 32
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 33
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 33
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Glu Ser Tyr Ser Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 34
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 34
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 35
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 35
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Phe Ile Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 36
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 36
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 37
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 37
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 38
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 38
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 39
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 39
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Phe Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 40
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 40
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 41
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 41
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Glu Leu Tyr Ser Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 42
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 43
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 43
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Thr Phe Ile Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 44
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 44
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr 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 Asp Ser Ser Ile Arg His Ala Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 45
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 45
Gly Thr Phe Ser Ser Tyr Ala Ile Ser
1 5
<210> 46
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 46
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 47
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 47
Ala Arg Gly Asp Ser Ser Ile Arg His Ala Tyr Tyr Tyr Tyr Gly Met
1 5 10 15
Asp Val
<210> 48
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 48
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 Val Leu Tyr Ser
20 25 30
Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp 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 Ser Thr Pro Ile Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 49
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 49
Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 50
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 50
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 51
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 51
Gln Gln Tyr Tyr Ser Thr Pro Ile Thr
1 5
<210> 52
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 52
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val 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 Gly Ser Asp Arg Phe His Pro Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 53
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 53
Gly Ser Ile Ser Ser Ser Ser Tyr Tyr Trp Gly
1 5 10
<210> 54
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 54
Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 55
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 55
Ala Arg Gly Ser Asp Arg Phe His Pro Tyr Phe Asp Tyr
1 5 10
<210> 56
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 56
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Asp Thr Trp Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 57
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 57
Arg Ala Ser Gln Ser Val Ser Arg Tyr Leu Ala
1 5 10
<210> 58
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 58
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 59
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 59
Gln Gln Phe Asp Thr Trp Pro Pro Thr
1 5
<210> 60
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 60
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 61
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 61
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Glu Gln Tyr Asp Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 62
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 62
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr 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 Arg Gly Arg Lys Ala Ser Gly Ser Phe Tyr Tyr Tyr Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 63
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 63
Gly Thr Phe Ser Ser Tyr Ala Ile Ser
1 5
<210> 64
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 64
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 65
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 65
Ala Arg Arg Gly Arg Lys Ala Ser Gly Ser Phe Tyr Tyr Tyr Tyr Gly
1 5 10 15
Met Asp Val
<210> 66
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 66
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 Glu Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Pro Leu Ile Tyr Trp 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 Asn
85 90 95
Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 67
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 67
Glu Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 68
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 68
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 69
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 69
Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr
1 5
<210> 70
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<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
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly 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 Ala Pro Asn Tyr Gly Asp Thr Thr His Asp Tyr Tyr Tyr
100 105 110
Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 71
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 71
Tyr Thr Phe Thr Ser Tyr Tyr Met His
1 5
<210> 72
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 72
Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 73
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 73
Ala Arg Gly Ala Pro Asn Tyr Gly Asp Thr Thr His Asp Tyr Tyr Tyr
1 5 10 15
Met Asp Val
<210> 74
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 74
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asp Trp Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 75
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 75
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 76
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 76
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 77
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 77
Gln Gln Tyr Asp Asp Trp Pro Phe Thr
1 5
<210> 78
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<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 Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly 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 Asp Thr Gly Glu Tyr Tyr Asp Thr Asp Asp His Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 79
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 79
Tyr Thr Phe Thr Gly Tyr Tyr Met His
1 5
<210> 80
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 80
Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 81
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 81
Ala Arg Asp Thr Gly Glu Tyr Tyr Asp Thr Asp Asp His Gly Met Asp
1 5 10 15
Val
<210> 82
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 82
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Asp Asp Tyr Trp Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 83
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 83
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 84
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 84
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 85
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 85
Gln Gln Asp Asp Tyr Trp Pro Pro Thr
1 5
<210> 86
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 86
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Gly Tyr Tyr Asp Ser Gly Ala Gly Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 87
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 87
Phe Thr Phe Ser Ser Tyr Ala Met Ser
1 5
<210> 88
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 88
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 89
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 89
Ala Lys Asp Gly Gly Tyr Tyr Asp Ser Gly Ala Gly Asp Tyr
1 5 10
<210> 90
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 90
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asp Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser 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 Gly Val Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 91
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 91
Arg Ala Ser Gln Gly Ile Asp Ser Trp Leu Ala
1 5 10
<210> 92
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 92
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 93
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 93
Gln Gln Gly Val Ser Tyr Pro Arg Thr
1 5
<210> 94
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 94
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 95
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 95
Phe Thr Phe Ser Ser Tyr Ser Met Asn
1 5
<210> 96
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 96
Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 97
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 97
Ala Arg Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 98
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 98
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser 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 Gly Val Ser Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 99
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 99
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 100
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 100
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 101
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 101
Gln Gln Gly Val Ser Phe Pro Arg Thr
1 5
<210> 102
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 102
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
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly 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 Glu Gly Ala Gly Phe Ala Tyr Gly Met Asp Tyr Tyr Tyr Met
100 105 110
Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 103
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 103
Tyr Thr Phe Thr Ser Tyr Tyr Met His
1 5
<210> 104
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 104
Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 105
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 105
Ala Arg Glu Gly Ala Gly Phe Ala Tyr Gly Met Asp Tyr Tyr Tyr Met
1 5 10 15
Asp Val
<210> 106
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 106
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Asp Asn Trp Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 107
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 107
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 108
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 108
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 109
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 109
Gln Gln Ser Asp Asn Trp Pro Phe Thr
1 5
<210> 110
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 110
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Gly Leu Gly Asp Gly Thr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 111
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 111
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Phe Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 112
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 112
Gln Val His Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Asp Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Ser Tyr Ser Gly Ser Ala Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Asn Trp Asp Asp Ala Phe Asn Ile Trp Gly Gln Gly Thr Met Val Thr
100 105 110
Val Ser Ser
115
<210> 113
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 113
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 114
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 114
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 Ser Phe Pro Asp Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 115
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 115
Asp Tyr Tyr Ile Asn
1 5
<210> 116
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 116
Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe Thr
1 5 10 15
Gly
<210> 117
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 117
Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val
1 5 10
<210> 118
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 118
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His 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 Ala Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Glu Thr
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 119
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 119
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His 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 Ile Tyr Tyr Cys Ser Gln Ser
85 90 95
Ser Ile Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 120
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 120
Lys Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 121
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 121
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 122
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 122
Ala Glu Thr Ser His Val Pro Trp Thr
1 5
<210> 123
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 123
Ser Gln Ser Ser Ile Tyr Pro Trp Thr
1 5
<210> 124
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 124
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe
50 55 60
Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 125
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 125
Asp Tyr Ser Ile Asn
1 5
<210> 126
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 126
Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe Arg
1 5 10 15
<210> 127
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 127
Asp Tyr Ser Tyr Ala Met Asp Tyr
1 5
<210> 128
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 128
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 129
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 129
Arg Ala Ser Glu Ser Val Thr Ile Leu Gly Ser His Leu Ile His
1 5 10 15
<210> 130
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 130
Leu Ala Ser Asn Val Gln Thr
1 5
<210> 131
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 131
Leu Gln Ser Arg Thr Ile Pro Arg Thr
1 5
<210> 132
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 132
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr 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 Ala Ile Tyr Asn Gly Tyr Asp Val Leu Asp Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 133
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 133
Asn Tyr Trp Met His
1 5
<210> 134
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 134
Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 135
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 135
Gly Ala Ile Tyr Asn Gly Tyr Asp Val Leu Asp Asn
1 5 10
<210> 136
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 136
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu His 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 Tyr Arg Lys Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 137
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 137
Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 138
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 138
Tyr Thr Ser Asn Leu His Ser
1 5
<210> 139
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 139
Gln Gln Tyr Arg Lys Leu Pro Trp Thr
1 5
<210> 140
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 140
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ser Tyr Phe Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ile Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val 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 His Asp Gly Ala Thr Ala Gly Leu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 141
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 141
Ser Ser Ser Tyr Phe Trp Gly
1 5
<210> 142
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 142
Ser Ile Tyr Tyr Ser Gly Ile Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 143
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 143
His Asp Gly Ala Thr Ala Gly Leu Phe Asp Tyr
1 5 10
<210> 144
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 144
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val
20 25 30
His Trp Tyr Gln Gln Pro Pro Gly Gln Ala Pro Val Val Val Val Tyr
35 40 45
Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
Asp Glu Ala Val Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 145
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 145
Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His
1 5 10
<210> 146
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 146
Asp Asp Ser Asp Arg Pro Ser
1 5
<210> 147
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 147
Gln Val Trp Asp Ser Ser Ser Asp His Val Val
1 5 10
<210> 148
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 148
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Asn
20 25 30
Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Pro Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 149
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 149
Arg Ala Ser Gln Ser Val Ser Asp Glu Tyr Leu Ser
1 5 10
<210> 150
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 150
Ser Ala Ser Thr Arg Ala Thr
1 5
<210> 151
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 151
Gln Gln Tyr Gly Tyr Pro Pro Asp Phe Thr
1 5 10
<210> 152
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 152
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asp Glu
20 25 30
Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile His Ser Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro
85 90 95
Asp Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 153
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 153
Arg Ala Ser Gln Ser Val Ser Asp Glu Tyr Leu Ser
1 5 10
<210> 154
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 154
Ser Ala Ser Thr Arg Ala Thr
1 5
<210> 155
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 155
Gln Gln Tyr Gly Tyr Pro Pro Asp Phe Thr
1 5 10
<210> 156
<211> 184
<212> PRT
<213> 智人(Homo sapiens)
<400> 156
Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser
1 5 10 15
Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr
20 25 30
Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser
35 40 45
Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu
50 55 60
Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile
65 70 75 80
Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu
85 90 95
Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu
100 105 110
Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys
115 120 125
Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe
130 135 140
Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys
145 150 155 160
Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu
165 170 175
Ile Glu Lys Ser Ile Ser Ala Arg
180
<210> 157
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 157
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 158
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 158
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro
85 90 95
Asp Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 159
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 159
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Asn
20 25 30
Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Pro Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 160
<211> 109
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 160
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asp Glu
20 25 30
Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile His Ser Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro
85 90 95
Asp Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 161
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 161
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Gly Pro Tyr Tyr Asp Ser Ser Gly Tyr Phe Val Tyr
100 105 110
Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 162
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 162
Phe Thr Phe Ser Ser Tyr Gly Met Ser
1 5
<210> 163
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 163
Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 164
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 164
Ala Arg Glu Gly Gly Pro Tyr Tyr Asp Ser Ser Gly Tyr Phe Val Tyr
1 5 10 15
Tyr Gly Met Asp Val
20
<210> 165
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 165
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Glu Ser Phe Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 166
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 166
Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 167
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 167
Asp Ala Ser Ser Leu Glu Ser
1 5
<210> 168
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 168
Gln Gln Tyr Glu Ser Phe Pro Thr
1 5
<210> 169
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 169
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Leu Asn Ala Gly Glu Leu Asp Val Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser
115
<210> 170
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 170
Phe Thr Phe Ser Ser Tyr Trp Met Ser
1 5
<210> 171
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 171
Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 172
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 172
Ala Arg Pro Leu Asn Ala Gly Glu Leu Asp Val
1 5 10
<210> 173
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 173
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Glu Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 174
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 174
Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 175
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 175
Glu Ala Ser Ser Leu Glu Ser
1 5
<210> 176
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 176
Gln Gln Leu Glu Ser Tyr Pro Leu Thr
1 5
<210> 177
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 177
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Tyr
20 25 30
Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Val Gly Ser Gly Glu Ser Thr Tyr Phe Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Gly Pro Tyr Tyr Asp Ser Ser Gly Tyr Phe Val Tyr
100 105 110
Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 178
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 178
Phe Thr Phe Ser Lys Tyr Thr Met Ser
1 5
<210> 179
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 179
Ala Ile Val Gly Ser Gly Glu Ser Thr Tyr Phe Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 180
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 180
Ala Arg Glu Gly Gly Pro Tyr Tyr Asp Ser Ser Gly Tyr Phe Val Tyr
1 5 10 15
Tyr Gly Met Asp Val
20
<210> 181
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 181
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 182
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 182
Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 183
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 183
Lys Ala Ser Ser Leu Glu Ser
1 5
<210> 184
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 184
Gln Gln Tyr Asp Asp Leu Pro Thr
1 5
<210> 185
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 185
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 Ser Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Met Ile Asn Pro Ser Trp Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly 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 Glu Ala Ala Asp Gly Phe Val Gly Glu Arg Tyr Phe Asp Leu
100 105 110
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 186
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 186
Tyr Thr Phe Ser Asp Tyr Tyr Met His
1 5
<210> 187
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 187
Met Ile Asn Pro Ser Trp Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 188
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 188
Ala Arg Glu Ala Ala Asp Gly Phe Val Gly Glu Arg Tyr Phe Asp Leu
1 5 10 15
<210> 189
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 189
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 Leu Leu Tyr Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala 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 Met Gln Asp
85 90 95
Val Ala Leu Pro Ile Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 190
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 190
Arg Ser Ser Gln Ser Leu Leu Tyr Ser Asn Gly Tyr Asn Tyr Leu Asp
1 5 10 15
<210> 191
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 191
Leu Gly Ser Asn Arg Ala Ser
1 5
<210> 192
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 192
Met Gln Asp Val Ala Leu Pro Ile Thr
1 5
<210> 193
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 193
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Lys Gln Asp Gly Ser Glu Lys Ser Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Leu Asn Ala Gly Glu Leu Asp Val Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser
115
<210> 194
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 194
Phe Thr Phe Gly Ser Tyr Trp Met Ser
1 5
<210> 195
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 195
Thr Ile Lys Gln Asp Gly Ser Glu Lys Ser Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 196
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 196
Ala Arg Pro Leu Asn Ala Gly Glu Leu Asp Val
1 5 10
<210> 197
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 197
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Gln Ser Tyr Pro Pro
85 90 95
Ile Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 198
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 198
Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 199
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 199
Glu Ala Ser Ser Leu Glu Ser
1 5
<210> 200
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 200
Gln Gln Ser Gln Ser Tyr Pro Pro Ile Thr
1 5 10
<210> 201
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 201
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Pro Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Lys Arg Asp Gly Ser Glu Lys Gly Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Leu Asn Ala Gly Glu Leu Asp Val Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser
115
<210> 202
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 202
Phe Thr Phe Pro Ser Tyr Trp Met Ser
1 5
<210> 203
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 203
Thr Ile Lys Arg Asp Gly Ser Glu Lys Gly Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 204
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 204
Ala Arg Pro Leu Asn Ala Gly Glu Leu Asp Val
1 5 10
<210> 205
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 205
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Gln Ser Tyr Pro Pro
85 90 95
Ile Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 206
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 206
Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 207
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 207
Glu Ala Ser Ser Leu Glu Ser
1 5
<210> 208
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 208
Gln Gln Ser Gln Ser Tyr Pro Pro Ile Thr
1 5 10
<210> 209
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 209
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 Gly Thr Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Arg Gly Ser Thr Val Tyr Ala Gln Lys Phe
50 55 60
Gln Gly 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 Ala Gly Tyr Asp Asp Glu Asp Met Asp Val Trp Gly Lys
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 210
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 210
Tyr Thr Phe Gly Thr Tyr Tyr Met His
1 5
<210> 211
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 211
Ile Ile Asn Pro Ser Arg Gly Ser Thr Val Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 212
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 212
Ala Arg Gly Ala Gly Tyr Asp Asp Glu Asp Met Asp Val
1 5 10
<210> 213
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 213
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asp Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser 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 Ala His Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 214
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 214
Arg Ala Ser Gln Gly Ile Asp Ser Trp Leu Ala
1 5 10
<210> 215
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 215
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 216
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 216
Gln Gln Ala His Ser Tyr Pro Leu Thr
1 5
<210> 217
<211> 128
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 217
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Glu Gly Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Gly Pro Tyr Tyr Asp Ser Ser Gly Tyr Phe Val Tyr
100 105 110
Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 218
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 218
Phe Thr Phe Ser Ser Tyr Ala Met Ser
1 5
<210> 219
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 219
Ser Ile Ser Ser Ser Ser Glu Gly Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 220
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 220
Ala Arg Glu Gly Gly Pro Tyr Tyr Asp Ser Ser Gly Tyr Phe Val Tyr
1 5 10 15
Tyr Gly Met Asp Val
20
<210> 221
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 221
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Asn Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Ser Thr Lys Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 222
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 222
Arg Ala Ser Asn Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 223
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 223
Glu Ala Ser Ser Thr Lys Ser
1 5
<210> 224
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 224
Gln Gln Tyr Asp Asp Leu Pro Thr
1 5
<210> 225
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 225
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asn Thr Asp Gly Ser Glu Val Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Gly Pro Gly Ile Ala Tyr Gln Gly His Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 226
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 226
Phe Thr Phe Ser Ser Tyr Trp Met Ser
1 5
<210> 227
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 227
Asn Ile Asn Thr Asp Gly Ser Glu Val Tyr Tyr Val Asp Ser Val Lys
1 5 10 15
Gly
<210> 228
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 228
Ala Arg Asp Val Gly Pro Gly Ile Ala Tyr Gln Gly His Phe Asp Tyr
1 5 10 15
<210> 229
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 229
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Tyr Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Lys 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 Val Tyr Asp Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 230
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 230
Arg Ala Ser Gln Val Ile Tyr Ser Tyr Leu Asn
1 5 10
<210> 231
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 231
Ala Ala Ser Ser Leu Lys Ser
1 5
<210> 232
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 232
Gln Gln Val Tyr Asp Thr Pro Leu Thr
1 5
<210> 233
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 233
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Thr
20 25 30
Asp Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser Ile Gly Tyr Ser Gly Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Thr Ala His Asp Val His Gly Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 234
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 234
Gly Ser Ile Ser Ser Thr Asp Tyr Tyr Trp Gly
1 5 10
<210> 235
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 235
Ser Ile Gly Tyr Ser Gly Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 236
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 236
Ala Arg Glu Thr Ala His Asp Val His Gly Met Asp Val
1 5 10
<210> 237
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 237
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser His Ser Val Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 238
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 238
Arg Ala Ser His Ser Val Tyr Ser Tyr Leu Ala
1 5 10
<210> 239
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 239
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 240
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 240
Gln Gln Tyr Asp Asn Leu Pro Thr
1 5
<210> 241
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 241
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Ser Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn 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 Arg Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 242
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 242
Gly Tyr Thr Phe Thr Asp Tyr
1 5
<210> 243
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 243
Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly
1 5 10
<210> 244
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 244
Gly Arg Pro Ala Met Asp Tyr
1 5
<210> 245
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 245
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 246
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 246
Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn
1 5 10
<210> 247
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 247
Ala Ala Ser Asn Gln Gly Ser
1 5
<210> 248
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 248
Gln Gln Ser Lys Glu Val Pro Trp Thr
1 5
<210> 249
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 249
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Ile Thr Asp Ser
20 25 30
Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Asn Arg Ala Thr Leu Thr Val Asp Asn Pro Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Tyr Cys
85 90 95
Val Asn Gly Asn Pro Trp Leu Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 250
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 250
Gly Tyr Thr Ile Thr Asp Ser
1 5
<210> 251
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 251
Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Asp
1 5 10
<210> 252
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 252
Gly Asn Pro Trp Leu Ala Tyr
1 5
<210> 253
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 253
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Leu Asp Asn Tyr
20 25 30
Gly Ile Arg Phe Leu Thr Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Met Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Lys
85 90 95
Glu Val Pro Trp Ser Phe Gly Gln Gly Thr Lys Val Glu Val Lys
100 105 110
<210> 254
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 254
Glu Ser Leu Asp Asn Tyr Gly Ile Arg Phe Leu Thr
1 5 10
<210> 255
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 255
Ala Ala Ser Asn Gln Gly Ser
1 5
<210> 256
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 256
Gln Gln Thr Lys Glu Val Pro Trp Ser
1 5
<210> 257
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 257
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Ile His Trp Ile Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
Gly Val Ile Tyr Pro Gly Asn Asp Asp Ile Ser Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Arg Leu Arg Tyr Phe Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 258
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 258
Gly Tyr Thr Phe Thr Ser Tyr
1 5
<210> 259
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 259
Tyr Pro Gly Asn Asp Asp
1 5
<210> 260
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 260
Glu Val Arg Leu Arg Tyr Phe Asp Val
1 5
<210> 261
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 261
Glu Ile Val Leu Thr Gln Ser Pro Gly Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Phe Phe Ser
20 25 30
Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln
35 40 45
Ser Pro Arg Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Pro Glu Asp Leu Ala Ile Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 262
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 262
Gln Ser Val Phe Phe Ser Ser Ser Gln Lys Asn Tyr Leu Ala
1 5 10
<210> 263
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 263
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 264
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 264
His Gln Tyr Leu Ser Ser Arg Thr
1 5
<210> 265
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 265
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
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Ala Lys Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Tyr Glu Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala
115
<210> 266
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 266
Gly Tyr Thr Phe Thr Asn Tyr
1 5
<210> 267
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 267
Tyr Pro Gly Asp Gly Ser
1 5
<210> 268
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 268
Gly Tyr Glu Asp Ala Met Asp Tyr
1 5
<210> 269
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 269
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Asn Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
20 25 30
Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile
35 40 45
Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Gln Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 270
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 270
Gln Asp Ile Asn Ser Tyr Leu Ser
1 5
<210> 271
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 271
Arg Ala Asn Arg Leu Val Asp
1 5
<210> 272
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 272
Leu Gln Tyr Asp Glu Phe Pro Leu Thr
1 5
<210> 273
<211> 364
<212> PRT
<213> 智人(Homo sapiens)
<400> 273
Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala
1 5 10 15
Met Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln
20 25 30
Glu Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro
35 40 45
Tyr Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly
50 55 60
Ala Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln
65 70 75 80
Glu Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro
85 90 95
Ser Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp
100 105 110
Asn Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser
115 120 125
Tyr Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg
130 135 140
Pro Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn
145 150 155 160
Leu Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile
165 170 175
Phe Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr
180 185 190
His Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr
195 200 205
Asn Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu
210 215 220
Arg Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr
225 230 235 240
Gly Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly
245 250 255
Val Val His Gly Ala Ile Gly Gly Ala Gly Val Thr Ala Leu Leu Ala
260 265 270
Leu Cys Leu Cys Leu Ile Phe Phe Ile Val Lys Thr His Arg Arg Lys
275 280 285
Ala Ala Arg Thr Ala Val Gly Arg Asn Asp Thr His Pro Thr Thr Gly
290 295 300
Ser Ala Ser Pro Lys His Gln Lys Lys Ser Lys Leu His Gly Pro Thr
305 310 315 320
Glu Thr Ser Ser Cys Ser Gly Ala Ala Pro Thr Val Glu Met Asp Glu
325 330 335
Glu Leu His Tyr Ala Ser Leu Asn Phe His Gly Met Asn Pro Ser Lys
340 345 350
Asp Thr Ser Thr Glu Tyr Ser Glu Val Arg Thr Gln
355 360
<210> 274
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 274
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 275
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 275
Gly Phe Asn Ile Lys Asp Thr
1 5
<210> 276
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 276
Tyr Pro Thr Asn Gly Tyr
1 5
<210> 277
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 277
Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
1 5 10
<210> 278
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 278
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg 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 Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 279
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 279
Gln Asp Val Asn Thr Ala Val Ala
1 5
<210> 280
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 280
Ser Ala Ser Phe Leu Tyr Ser
1 5
<210> 281
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 281
Gln Gln His Tyr Thr Thr Pro Pro Thr
1 5
<210> 282
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 282
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala
115 120
<210> 283
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 283
Gly Phe Thr Phe Thr Asp Tyr
1 5
<210> 284
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 284
Asn Pro Asn Ser Gly Gly
1 5
<210> 285
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 285
Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr
1 5 10
<210> 286
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 286
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr 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 Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 287
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 287
Gln Asp Val Ser Ile Gly Val Ala
1 5
<210> 288
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 288
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 289
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 289
Gln Gln Tyr Tyr Ile Tyr Pro Tyr Thr
1 5
<210> 290
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 290
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Val Ser Arg Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Ala Ser Val Thr Val Ser Ser Ala
115 120
<210> 291
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 291
Gly Phe Asn Ile Lys Asp Thr
1 5
<210> 292
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 292
Tyr Pro Thr Asn Gly Tyr
1 5
<210> 293
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 293
Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
1 5 10
<210> 294
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 294
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly His Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 295
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 295
Gln Asp Val Asn Thr Ala Val Ala
1 5
<210> 296
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 296
Ser Ala Ser Phe Arg Tyr Thr
1 5
<210> 297
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 297
Gln Gln His Tyr Thr Thr Pro Pro Thr
1 5
<210> 298
<211> 1255
<212> PRT
<213> 智人(Homo sapiens)
<400> 298
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys
625 630 635 640
Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser
645 650 655
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
660 665 670
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
675 680 685
Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
690 695 700
Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
705 710 715 720
Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
725 730 735
Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
740 745 750
Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
755 760 765
Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
770 775 780
Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
785 790 795 800
Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
805 810 815
Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
820 825 830
Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
835 840 845
Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
850 855 860
Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
865 870 875 880
Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
885 890 895
Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
900 905 910
Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
915 920 925
Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
930 935 940
Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
945 950 955 960
Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
965 970 975
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
980 985 990
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
995 1000 1005
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr
1010 1015 1020
Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly
1025 1030 1035
Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg
1040 1045 1050
Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu
1055 1060 1065
Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser
1070 1075 1080
Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu
1085 1090 1095
Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser
1100 1105 1110
Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val
1115 1120 1125
Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro
1130 1135 1140
Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro
1145 1150 1155
Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu
1160 1165 1170
Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly
1175 1180 1185
Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala
1190 1195 1200
Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp
1205 1210 1215
Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro
1220 1225 1230
Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
1235 1240 1245
Leu Gly Leu Asp Val Pro Val
1250 1255
<210> 299
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 299
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
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 Cys
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Glu 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 Trp 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
<210> 300
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 300
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
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 Arg Val Tyr
340 345 350
Thr Leu Pro Pro Cys 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 Val Ser Asp Gly Ser Phe Thr 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
<210> 301
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 301
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
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 Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp 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
<210> 302
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 302
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
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 Cys
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Ser Cys Ala 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 Val 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
<210> 303
<211> 475
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 303
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg 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 Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr
145 150 155 160
Ile His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala
165 170 175
Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser
210 215 220
Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser Ala Ser Asp Lys Thr His Thr Cys Pro
245 250 255
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
260 265 270
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
275 280 285
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
290 295 300
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
305 310 315 320
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
325 330 335
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
340 345 350
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
355 360 365
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg
370 375 380
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly
385 390 395 400
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
405 410 415
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
420 425 430
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
435 440 445
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
450 455 460
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 304
<211> 475
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 304
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg 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 Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr
145 150 155 160
Ile His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala
165 170 175
Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser
210 215 220
Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser Ala Ser Asp Lys Thr His Thr Cys Pro
245 250 255
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
260 265 270
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
275 280 285
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
290 295 300
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
305 310 315 320
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
325 330 335
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
340 345 350
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
355 360 365
Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg
370 375 380
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly
385 390 395 400
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
405 410 415
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
420 425 430
Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
435 440 445
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
450 455 460
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 305
<211> 475
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 305
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg 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 Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr
145 150 155 160
Ile His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala
165 170 175
Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser
210 215 220
Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser Ala Ser Asp Lys Thr His Thr Cys Pro
245 250 255
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
260 265 270
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
275 280 285
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
290 295 300
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
305 310 315 320
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
325 330 335
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
340 345 350
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
355 360 365
Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg
370 375 380
Asp Glu Leu Thr Glu Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
385 390 395 400
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
405 410 415
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
420 425 430
Phe Phe Leu Tyr Ser Trp Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
435 440 445
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
450 455 460
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 306
<211> 475
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 306
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg 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 Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr
145 150 155 160
Ile His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala
165 170 175
Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser
210 215 220
Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser Ala Ser Asp Lys Thr His Thr Cys Pro
245 250 255
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
260 265 270
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
275 280 285
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
290 295 300
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
305 310 315 320
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
325 330 335
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
340 345 350
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
355 360 365
Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro Cys Arg
370 375 380
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
385 390 395 400
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
405 410 415
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp Gly Ser
420 425 430
Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
435 440 445
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
450 455 460
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 307
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 307
Gly Tyr Tyr Trp Ser
1 5
<210> 308
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 308
Ala Arg Gly Pro Trp Ser Phe Asp Pro
1 5
<210> 309
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 309
Ser Tyr Ala Ile Ser
1 5
<210> 310
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 310
Gly Asp Ser Ser Ile Arg His Ala Tyr Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 311
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 311
Ser Ser Ser Tyr Tyr Trp Gly
1 5
<210> 312
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 312
Gly Ser Asp Arg Phe His Pro Tyr Phe Asp Tyr
1 5 10
<210> 313
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 313
Ser Tyr Tyr Met His
1 5
<210> 314
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 314
Gly Ala Pro Asn Tyr Gly Asp Thr Thr His Asp Tyr Tyr Tyr Met Asp
1 5 10 15
Val
<210> 315
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 315
Gly Tyr Tyr Met His
1 5
<210> 316
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 316
Asp Thr Gly Glu Tyr Tyr Asp Thr Asp Asp His Gly Met Asp Val
1 5 10 15
<210> 317
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 317
Ser Tyr Ala Met Ser
1 5
<210> 318
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 318
Asp Gly Gly Tyr Tyr Asp Ser Gly Ala Gly Asp Tyr
1 5 10
<210> 319
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 319
Ser Tyr Ser Met Asn
1 5
<210> 320
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 320
Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 321
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 321
Glu Gly Ala Gly Phe Ala Tyr Gly Met Asp Tyr Tyr Tyr Met Asp Val
1 5 10 15
<210> 322
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 322
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 323
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 323
Ala Arg Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 324
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 324
Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 325
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 325
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Gln Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 326
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 326
Ala Arg Gly Ala Pro Gln Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 327
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 327
Gly Ala Pro Gln Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 328
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 328
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Leu Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 329
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 329
Ala Arg Gly Ala Pro Leu Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 330
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 330
Gly Ala Pro Leu Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 331
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 331
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Phe Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 332
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 332
Ala Arg Gly Ala Pro Phe Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 333
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 333
Gly Ala Pro Phe Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 334
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 334
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Val Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 335
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 335
Ala Arg Gly Ala Pro Val Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 336
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 336
Gly Ala Pro Val Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 337
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<220>
<221> 变体
<222> (102)..(102)
<223> X为Met、Leu、Ile、Val、Gln或Phe
<400> 337
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Xaa Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 338
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<220>
<221> 变体
<222> (6)..(6)
<223> X为Met、Leu、Ile、Val、Gln或Phe
<400> 338
Ala Arg Gly Ala Pro Xaa Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 339
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<220>
<221> 变体
<222> (4)..(4)
<223> X为Met、Leu、Ile、Val、Gln或Phe
<400> 339
Gly Ala Pro Xaa Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 340
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 340
Ile Leu Ala Lys Phe Leu His Trp Leu
1 5
<210> 341
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 341
Lys Ile Phe Gly Ser Leu Ala Phe Leu
1 5
<210> 342
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 342
Arg Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210> 343
<211> 13
<212> PRT
<213> 智人(Homo sapiens)
<400> 343
Cys Ala Ser Ser Phe Asn Met Ala Thr Gly Gln Tyr Phe
1 5 10
<210> 344
<211> 10
<212> PRT
<213> 智人(Homo sapiens)
<400> 344
Glu Ala Ala Gly Ile Gly Ile Leu Thr Val
1 5 10
<210> 345
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 345
Lys Ala Ser Glu Lys Ile Phe Tyr Val
1 5
<210> 346
<211> 10
<212> PRT
<213> 智人(Homo sapiens)
<400> 346
Glu Leu Thr Leu Gly Glu Phe Leu Lys Leu
1 5 10
<210> 347
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 347
Gln Leu Leu Ala Leu Leu Pro Ser Leu
1 5
<210> 348
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 348
Ser Leu Leu Met Trp Ile Thr Gln Cys
1 5
<210> 349
<211> 200
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 349
Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly Ala
1 5 10 15
Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser Phe
20 25 30
Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met Ser
35 40 45
Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln Leu
50 55 60
Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp Ser Gln Pro
65 70 75 80
Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Thr Thr Asp Ser Trp Gly
85 90 95
Lys Leu Gln Phe Gly Ala Gly Thr Gln Val Val Val Thr Pro Asp Ile
100 105 110
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
115 120 125
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
130 135 140
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu
145 150 155 160
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
165 170 175
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
180 185 190
Pro Glu Asp Thr Phe Phe Pro Ser
195 200
<210> 350
<211> 245
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 350
Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly
1 5 10 15
Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His Glu Tyr Met
20 25 30
Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr
35 40 45
Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro Asn Gly Tyr
50 55 60
Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg Leu Leu Ser
65 70 75 80
Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Arg Pro Gly
85 90 95
Leu Ala Gly Gly Arg Pro Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
100 105 110
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
115 120 125
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
130 135 140
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
145 150 155 160
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
165 170 175
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser
180 185 190
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His
195 200 205
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
210 215 220
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
225 230 235 240
Trp Gly Arg Ala Asp
245
<210> 351
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 351
Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly Ala
1 5 10 15
Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser Phe
20 25 30
Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met Ser
35 40 45
Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln Leu
50 55 60
Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp Ser Gln Pro
65 70 75 80
Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Thr Thr Asp Ser Trp Gly
85 90 95
Lys Leu Gln Phe Gly Ala Gly Thr Gln Val Val Val Thr Pro Asp Ile
100 105 110
Gln Asn Pro
115
<210> 352
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 352
Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly
1 5 10 15
Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His Glu Tyr Met
20 25 30
Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr
35 40 45
Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro Asn Gly Tyr
50 55 60
Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg Leu Leu Ser
65 70 75 80
Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Arg Pro Gly
85 90 95
Leu Ala Gly Gly Arg Pro Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
100 105 110
Thr Val Thr Glu Asp Leu Lys Asn Val Phe
115 120
<210> 353
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 353
Cys Ala Val Thr Thr Asp Ser Trp Gly Lys Leu Gln Phe
1 5 10
<210> 354
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 354
Cys Ala Ser Arg Pro Gly Leu Ala Gly Gly Arg Pro Glu Gln Tyr Phe
1 5 10 15
<210> 355
<211> 199
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 355
Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu Gly Ala Ile
1 5 10 15
Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln Tyr Phe Met
20 25 30
Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu Met Tyr Thr
35 40 45
Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala Gln Val Asp
50 55 60
Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser Gln Pro Ser
65 70 75 80
Asp Ser Ala Thr Tyr Leu Cys Ala Met Arg Gly Asp Ser Ser Tyr Lys
85 90 95
Leu Ile Phe Gly Ser Gly Thr Arg Leu Leu Val Arg Pro Asp Ile Gln
100 105 110
Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp
115 120 125
Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser
130 135 140
Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp
145 150 155 160
Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn
165 170 175
Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro
180 185 190
Glu Asp Thr Phe Phe Pro Ser
195
<210> 356
<211> 245
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 356
Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln
1 5 10 15
Gln Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asp Tyr Leu Phe
20 25 30
Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu Leu Ile Tyr Phe
35 40 45
Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe
50 55 60
Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro
65 70 75 80
Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Leu Trp
85 90 95
Glu Lys Leu Ala Lys Asn Ile Gln Tyr Phe Gly Ala Gly Thr Arg Leu
100 105 110
Ser Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
115 120 125
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
130 135 140
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
145 150 155 160
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
165 170 175
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser
180 185 190
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His
195 200 205
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
210 215 220
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
225 230 235 240
Trp Gly Arg Ala Asp
245
<210> 357
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 357
Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu Gly Ala Ile
1 5 10 15
Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln Tyr Phe Met
20 25 30
Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu Met Tyr Thr
35 40 45
Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala Gln Val Asp
50 55 60
Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser Gln Pro Ser
65 70 75 80
Asp Ser Ala Thr Tyr Leu Cys Ala Met Arg Gly Asp Ser Ser Tyr Lys
85 90 95
Leu Ile Phe Gly Ser Gly Thr Arg Leu Leu Val Arg Pro Asp Ile Gln
100 105 110
Asn Pro
<210> 358
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 358
Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr Glu Met Gly Gln
1 5 10 15
Gln Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His Asp Tyr Leu Phe
20 25 30
Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu Leu Ile Tyr Phe
35 40 45
Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe
50 55 60
Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro
65 70 75 80
Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Leu Trp
85 90 95
Glu Lys Leu Ala Lys Asn Ile Gln Tyr Phe Gly Ala Gly Thr Arg Leu
100 105 110
Ser Val Leu Glu Asp Leu Lys Asn Val Phe
115 120
<210> 359
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 359
Cys Ala Met Arg Gly Asp Ser Ser Tyr Lys Leu Ile Phe
1 5 10
<210> 360
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 360
Cys Ala Ser Ser Leu Trp Glu Lys Leu Ala Lys Asn Ile Gln Tyr Phe
1 5 10 15
<210> 361
<211> 200
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 361
Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile Leu Gln Glu Gly Ala
1 5 10 15
Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser Val Asn Asn Leu Trp
20 25 30
Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile Asn Leu Phe Tyr Ile
35 40 45
Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser Ala Thr Thr Val Ala
50 55 60
Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser Ser Gln Thr Thr Asp
65 70 75 80
Ser Gly Val Tyr Phe Cys Ala Val Asp Ser Ala Thr Ala Leu Pro Tyr
85 90 95
Gly Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys Val Leu Ala Asn Ile
100 105 110
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
115 120 125
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
130 135 140
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu
145 150 155 160
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
165 170 175
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
180 185 190
Pro Glu Asp Thr Phe Phe Pro Ser
195 200
<210> 362
<211> 240
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 362
Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly Gln
1 5 10 15
Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His Glu Tyr Met Ser
20 25 30
Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr Ser
35 40 45
Ile His Pro Glu Tyr Thr Asp Gln Gly Glu Val Pro Asn Gly Tyr Asn
50 55 60
Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg Leu Leu Ser Ala
65 70 75 80
Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Tyr Gln Gly
85 90 95
Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu Asp
100 105 110
Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser Glu
115 120 125
Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala Thr
130 135 140
Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys
145 150 155 160
Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys Glu Gln
165 170 175
Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser Ser Arg Leu Arg Val
180 185 190
Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His Phe Arg Cys Gln Val
195 200 205
Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg Ala
210 215 220
Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala Asp
225 230 235 240
<210> 363
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 363
Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile Leu Gln Glu Gly Ala
1 5 10 15
Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser Val Asn Asn Leu Trp
20 25 30
Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile Asn Leu Phe Tyr Ile
35 40 45
Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser Ala Thr Thr Val Ala
50 55 60
Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser Ser Gln Thr Thr Asp
65 70 75 80
Ser Gly Val Tyr Phe Cys Ala Val Asp Ser Ala Thr Ala Leu Pro Tyr
85 90 95
Gly Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys Val Leu Ala Asn Ile
100 105 110
Gln Asn Pro
115
<210> 364
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 364
Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly Gln
1 5 10 15
Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His Glu Tyr Met Ser
20 25 30
Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr Ser
35 40 45
Ile His Pro Glu Tyr Thr Asp Gln Gly Glu Val Pro Asn Gly Tyr Asn
50 55 60
Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg Leu Leu Ser Ala
65 70 75 80
Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Tyr Gln Gly
85 90 95
Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu Asp
100 105 110
Leu Asn Lys Val Phe
115
<210> 365
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 365
Cys Ala Val Asp Ser Ala Thr Ala Leu Pro Tyr Gly Tyr Ile Phe
1 5 10 15
<210> 366
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 366
Cys Ala Ser Ser Tyr Gln Gly Thr Glu Ala Phe Phe
1 5 10
<210> 367
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 367
Cys Ala Met Ser Leu Tyr Tyr Gly Gly Ser Gln Gly Asn Leu Ile Phe
1 5 10 15
<210> 368
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 368
Cys Ala Ser Ser Leu Glu Ile Phe Gly Gly Ile Ala Asp Thr Asp Thr
1 5 10 15
Gln Tyr Phe
<210> 369
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 369
Cys Ala Val Asn Asp Gln Gly Gly Gly Ala Asp Gly Leu Thr Phe
1 5 10 15
<210> 370
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 370
Cys Ala Ser Ser Trp Trp Asp Thr Gly Glu Leu Phe Phe
1 5 10
<210> 371
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 371
Cys Ala Val Ser Glu Gly Gly Asp Tyr Lys Leu Ser Phe
1 5 10
<210> 372
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 372
Cys Ala Trp Gly Thr Leu Ala Thr Glu Gln Tyr Phe
1 5 10
<210> 373
<211> 197
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 373
Ala Gln Glu Val Thr Gln Ile Pro Ala Ala Leu Ser Val Pro Glu Gly
1 5 10 15
Glu Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala Ile Tyr Asn
20 25 30
Leu Gln Trp Phe Arg Gln Asp Pro Gly Lys Gly Leu Thr Ser Leu Leu
35 40 45
Tyr Val Arg Pro Tyr Gln Arg Glu Gln Thr Ser Gly Arg Leu Asn Ala
50 55 60
Ser Leu Asp Lys Ser Ser Gly Arg Ser Thr Leu Tyr Ile Ala Ala Ser
65 70 75 80
Gln Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Pro Gly Gly
85 90 95
Ala Gly Pro Phe Phe Val Val Phe Gly Lys Gly Thr Lys Leu Ser Val
100 105 110
Ile Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
115 120 125
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
130 135 140
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
145 150 155 160
Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
165 170 175
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
180 185 190
Asn Ser Ile Ile Pro
195
<210> 374
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 374
Ala Gly Val Thr Gln Thr Pro Arg Tyr Leu Ile Lys Thr Arg Gly Gln
1 5 10 15
Gln Val Thr Leu Ser Cys Ser Pro Ile Ser Gly His Arg Ser Val Ser
20 25 30
Trp Tyr Gln Gln Thr Pro Gly Gln Gly Leu Gln Phe Leu Phe Glu Tyr
35 40 45
Phe Ser Glu Thr Gln Arg Asn Lys Gly Asn Phe Pro Gly Arg Phe Ser
50 55 60
Gly Arg Gln Phe Ser Asn Ser Arg Ser Glu Met Asn Val Ser Thr Leu
65 70 75 80
Glu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Phe Asn Met
85 90 95
Ala Thr Gly Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu
100 105 110
Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser
115 120 125
Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala
130 135 140
Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
145 150 155 160
Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys Glu
165 170 175
Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser Ser Arg Leu Arg
180 185 190
Val Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His Phe Arg Cys Gln
195 200 205
Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg
210 215 220
Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala
225 230 235 240
Asp
<210> 375
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 375
Ala Gln Glu Val Thr Gln Ile Pro Ala Ala Leu Ser Val Pro Glu Gly
1 5 10 15
Glu Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala Ile Tyr Asn
20 25 30
Leu Gln Trp Phe Arg Gln Asp Pro Gly Lys Gly Leu Thr Ser Leu Leu
35 40 45
Tyr Val Arg Pro Tyr Gln Arg Glu Gln Thr Ser Gly Arg Leu Asn Ala
50 55 60
Ser Leu Asp Lys Ser Ser Gly Arg Ser Thr Leu Tyr Ile Ala Ala Ser
65 70 75 80
Gln Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Pro Gly Gly
85 90 95
Ala Gly Pro Phe Phe Val Val Phe Gly Lys Gly Thr Lys Leu Ser Val
100 105 110
Ile Pro Asn Ile Gln Asn Pro
115
<210> 376
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 376
Ala Gly Val Thr Gln Thr Pro Arg Tyr Leu Ile Lys Thr Arg Gly Gln
1 5 10 15
Gln Val Thr Leu Ser Cys Ser Pro Ile Ser Gly His Arg Ser Val Ser
20 25 30
Trp Tyr Gln Gln Thr Pro Gly Gln Gly Leu Gln Phe Leu Phe Glu Tyr
35 40 45
Phe Ser Glu Thr Gln Arg Asn Lys Gly Asn Phe Pro Gly Arg Phe Ser
50 55 60
Gly Arg Gln Phe Ser Asn Ser Arg Ser Glu Met Asn Val Ser Thr Leu
65 70 75 80
Glu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Phe Asn Met
85 90 95
Ala Thr Gly Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu
100 105 110
Asp Leu Lys Asn Val Phe
115
<210> 377
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 377
Cys Ala Val Arg Pro Gly Gly Ala Gly Pro Phe Phe
1 5 10
<210> 378
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 378
Cys Ala Ser Ser Phe Asn Met Ala Thr Gly Gln Tyr Phe
1 5 10
<210> 379
<211> 199
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 379
Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu Gly Ala Ile
1 5 10 15
Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln Tyr Phe Met
20 25 30
Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu Met Tyr Thr
35 40 45
Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala Gln Val Asp
50 55 60
Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser Gln Pro Ser
65 70 75 80
Asp Ser Ala Thr Tyr Leu Cys Ala Met Ser Glu Thr Gly Gly Phe Lys
85 90 95
Thr Ile Phe Gly Ala Gly Thr Arg Leu Phe Val Lys Ala Asn Ile Gln
100 105 110
Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp
115 120 125
Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser
130 135 140
Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu Asp
145 150 155 160
Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn
165 170 175
Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro
180 185 190
Glu Asp Thr Phe Phe Pro Ser
195
<210> 380
<211> 244
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 380
Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr Val Thr Gly
1 5 10 15
Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His Glu Tyr Met
20 25 30
Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln Ile Tyr Tyr
35 40 45
Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro Glu Gly Tyr
50 55 60
Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile Leu Glu Ser
65 70 75 80
Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser Ser Leu Val
85 90 95
Gly Thr Ala Gly Ser Pro Leu His Phe Gly Asn Gly Thr Arg Leu Thr
100 105 110
Val Thr Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe
115 120 125
Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val
130 135 140
Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
145 150 155 160
Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro
165 170 175
Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser
180 185 190
Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe
195 200 205
Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr
210 215 220
Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp
225 230 235 240
Gly Arg Ala Asp
<210> 381
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 381
Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu Gly Ala Ile
1 5 10 15
Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln Tyr Phe Met
20 25 30
Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu Met Tyr Thr
35 40 45
Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala Gln Val Asp
50 55 60
Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser Gln Pro Ser
65 70 75 80
Asp Ser Ala Thr Tyr Leu Cys Ala Met Ser Glu Thr Gly Gly Phe Lys
85 90 95
Thr Ile Phe Gly Ala Gly Thr Arg Leu Phe Val Lys Ala Asn Ile Gln
100 105 110
Asn Pro
<210> 382
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 382
Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr Val Thr Gly
1 5 10 15
Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His Glu Tyr Met
20 25 30
Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln Ile Tyr Tyr
35 40 45
Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro Glu Gly Tyr
50 55 60
Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile Leu Glu Ser
65 70 75 80
Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser Ser Leu Val
85 90 95
Gly Thr Ala Gly Ser Pro Leu His Phe Gly Asn Gly Thr Arg Leu Thr
100 105 110
Val Thr Glu Asp Leu Asn Lys Val Phe
115 120
<210> 383
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 383
Cys Ala Met Ser Glu Thr Gly Gly Phe Lys Thr Ile Phe
1 5 10
<210> 384
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 384
Cys Ala Ser Ser Leu Val Gly Thr Ala Gly Ser Pro Leu His Phe
1 5 10 15
<210> 385
<211> 200
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 385
Ala Gln Lys Ile Thr Gln Thr Gln Pro Gly Met Phe Val Gln Glu Lys
1 5 10 15
Glu Ala Val Thr Leu Asp Cys Thr Tyr Asp Thr Ser Asp Gln Ser Tyr
20 25 30
Gly Leu Phe Trp Tyr Lys Gln Pro Ser Ser Gly Glu Met Ile Phe Leu
35 40 45
Ile Tyr Gln Gly Ser Tyr Asp Glu Gln Asn Ala Thr Glu Gly Arg Tyr
50 55 60
Ser Leu Asn Phe Gln Lys Ala Arg Lys Ser Ala Asn Leu Val Ile Ser
65 70 75 80
Ala Ser Gln Leu Gly Asp Ser Ala Met Tyr Phe Cys Ala Met Arg Glu
85 90 95
Gly Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly Thr Arg Leu Ala
100 105 110
Val His Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
115 120 125
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
130 135 140
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu
145 150 155 160
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
165 170 175
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
180 185 190
Pro Glu Asp Thr Phe Phe Pro Ser
195 200
<210> 386
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 386
Ser Gln Thr Ile His Gln Trp Pro Ala Thr Leu Val Gln Pro Val Gly
1 5 10 15
Ser Pro Leu Ser Leu Glu Cys Thr Val Glu Gly Thr Ser Asn Pro Asn
20 25 30
Leu Tyr Trp Tyr Arg Gln Ala Ala Gly Arg Gly Leu Gln Leu Leu Phe
35 40 45
Tyr Ser Val Gly Ile Gly Gln Ile Ser Ser Glu Val Pro Gln Asn Leu
50 55 60
Ser Ala Ser Arg Pro Gln Asp Arg Gln Phe Ile Leu Ser Ser Lys Lys
65 70 75 80
Leu Leu Leu Ser Asp Ser Gly Phe Tyr Leu Cys Ala Gly Gln Asp Leu
85 90 95
Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu
100 105 110
Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser
115 120 125
Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala
130 135 140
Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
145 150 155 160
Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys Glu
165 170 175
Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser Ser Arg Leu Arg
180 185 190
Val Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His Phe Arg Cys Gln
195 200 205
Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg
210 215 220
Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala
225 230 235 240
Asp
<210> 387
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 387
Cys Ala Met Thr Ser Gly Phe Gly Asn Glu Lys Leu Thr Phe
1 5 10
<210> 388
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 388
Cys Ala Thr Ser Arg Gly Gln Gly Gly Gln Pro Gln His Phe
1 5 10
<210> 389
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 389
Cys Ala Glu Thr Val Thr Asp Ser Trp Gly Lys Leu Gln Phe
1 5 10
<210> 390
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 390
Cys Ala Thr Ser Arg Gly Asp Ser Thr Ala Glu Pro Gln His Phe
1 5 10 15
<210> 391
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 391
Cys Ala Met Arg Glu Gly Gly Gly Tyr Asn Lys Leu Ile Phe
1 5 10
<210> 392
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 392
Cys Ala Gly Gln Asp Leu Asn Thr Glu Ala Phe Phe
1 5 10
<210> 393
<211> 204
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 393
Ala Gln Ser Val Thr Gln Leu Gly Ser His Val Ser Val Ser Glu Arg
1 5 10 15
Ala Leu Val Leu Leu Arg Cys Asn Tyr Ser Ser Ser Val Pro Pro Tyr
20 25 30
Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln Leu Leu Leu
35 40 45
Lys Tyr Thr Ser Ala Ala Thr Leu Val Lys Gly Ile Asn Gly Phe Glu
50 55 60
Ala Glu Phe Lys Lys Ser Glu Thr Ser Phe His Leu Thr Lys Pro Ser
65 70 75 80
Ala His Met Ser Asp Ala Ala Glu Tyr Phe Cys Ala Val Ser Gly Gln
85 90 95
Thr Gly Ala Asn Asn Leu Phe Phe Gly Thr Gly Thr Arg Leu Thr Val
100 105 110
Ile Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
115 120 125
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
130 135 140
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
145 150 155 160
Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
165 170 175
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
180 185 190
Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser
195 200
<210> 394
<211> 243
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 394
Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr Ala Thr Gly
1 5 10 15
Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp Leu Ser Val
20 25 30
Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe Leu Ile Gln
35 40 45
Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu Glu Arg Phe
50 55 60
Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn Leu Ser Ser
65 70 75 80
Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ala Arg Trp
85 90 95
Asp Arg Gly Gly Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val
100 105 110
Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu
115 120 125
Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys
130 135 140
Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val
145 150 155 160
Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu
165 170 175
Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg
180 185 190
Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg
195 200 205
Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln
210 215 220
Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly
225 230 235 240
Arg Ala Asp
<210> 395
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 395
Ala Gln Ser Val Thr Gln Leu Gly Ser His Val Ser Val Ser Glu Arg
1 5 10 15
Ala Leu Val Leu Leu Arg Cys Asn Tyr Ser Ser Ser Val Pro Pro Tyr
20 25 30
Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln Leu Leu Leu
35 40 45
Lys Tyr Thr Ser Ala Ala Thr Leu Val Lys Gly Ile Asn Gly Phe Glu
50 55 60
Ala Glu Phe Lys Lys Ser Glu Thr Ser Phe His Leu Thr Lys Pro Ser
65 70 75 80
Ala His Met Ser Asp Ala Ala Glu Tyr Phe Cys Ala Val Ser Gly Gln
85 90 95
Thr Gly Ala Asn Asn Leu Phe Phe Gly Thr Gly Thr Arg Leu Thr Val
100 105 110
Ile Pro Tyr Ile Gln Asn Pro
115
<210> 396
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 396
Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr Ala Thr Gly
1 5 10 15
Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp Leu Ser Val
20 25 30
Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe Leu Ile Gln
35 40 45
Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu Glu Arg Phe
50 55 60
Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn Leu Ser Ser
65 70 75 80
Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ala Arg Trp
85 90 95
Asp Arg Gly Gly Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val
100 105 110
Thr Glu Asp Leu Lys Asn Val Phe
115 120
<210> 397
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 397
Cys Ala Val Ser Gly Gln Thr Gly Ala Asn Asn Leu Phe
1 5 10
<210> 398
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 398
Cys Ala Ser Ala Arg Trp Asp Arg Gly Gly Glu Gln Tyr Phe
1 5 10
<210> 399
<211> 203
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 399
Gly Gln Gln Leu Asn Gln Ser Pro Gln Ser Met Phe Ile Gln Glu Gly
1 5 10 15
Glu Asp Val Ser Met Asn Cys Thr Ser Ser Ser Ile Phe Asn Thr Trp
20 25 30
Leu Trp Tyr Lys Gln Asp Pro Gly Glu Gly Pro Val Leu Leu Ile Ala
35 40 45
Leu Tyr Lys Ala Gly Glu Leu Thr Ser Asn Gly Arg Leu Thr Ala Gln
50 55 60
Phe Gly Ile Thr Arg Lys Asp Ser Phe Leu Asn Ile Ser Ala Ser Ile
65 70 75 80
Pro Ser Asp Val Gly Ile Tyr Phe Cys Ala Gly Ile Pro Arg Asp Asn
85 90 95
Tyr Gly Gln Asn Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu
100 105 110
Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
115 120 125
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
130 135 140
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
145 150 155 160
Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
165 170 175
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
180 185 190
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser
195 200
<210> 400
<211> 244
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 400
Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys Arg Thr Gly
1 5 10 15
Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His Glu Asn Met
20 25 30
Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu Ile Tyr Phe
35 40 45
Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro Glu Gly Tyr
50 55 60
Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile Leu Glu Ser
65 70 75 80
Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Ser Thr Pro Trp
85 90 95
Leu Ala Gly Gly Asn Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu Thr
100 105 110
Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe
115 120 125
Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val
130 135 140
Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp
145 150 155 160
Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro
165 170 175
Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser
180 185 190
Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe
195 200 205
Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr
210 215 220
Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp
225 230 235 240
Gly Arg Ala Asp
<210> 401
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 401
Gly Gln Gln Leu Asn Gln Ser Pro Gln Ser Met Phe Ile Gln Glu Gly
1 5 10 15
Glu Asp Val Ser Met Asn Cys Thr Ser Ser Ser Ile Phe Asn Thr Trp
20 25 30
Leu Trp Tyr Lys Gln Asp Pro Gly Glu Gly Pro Val Leu Leu Ile Ala
35 40 45
Leu Tyr Lys Ala Gly Glu Leu Thr Ser Asn Gly Arg Leu Thr Ala Gln
50 55 60
Phe Gly Ile Thr Arg Lys Asp Ser Phe Leu Asn Ile Ser Ala Ser Ile
65 70 75 80
Pro Ser Asp Val Gly Ile Tyr Phe Cys Ala Gly Ile Pro Arg Asp Asn
85 90 95
Tyr Gly Gln Asn Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu
100 105 110
Pro Tyr Ile Gln Asn Pro
115
<210> 402
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 402
Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys Arg Thr Gly
1 5 10 15
Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His Glu Asn Met
20 25 30
Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu Ile Tyr Phe
35 40 45
Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro Glu Gly Tyr
50 55 60
Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile Leu Glu Ser
65 70 75 80
Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Ser Thr Pro Trp
85 90 95
Leu Ala Gly Gly Asn Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu Thr
100 105 110
Val Leu Glu Asp Leu Lys Asn Val Phe
115 120
<210> 403
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 403
Cys Ala Gly Ile Pro Arg Asp Asn Tyr Gly Gln Asn Phe Val Phe
1 5 10 15
<210> 404
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 404
Cys Ala Ser Thr Pro Trp Leu Ala Gly Gly Asn Glu Gln Phe Phe
1 5 10 15
<210> 405
<211> 201
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 405
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp Ser Gln
65 70 75 80
Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Lys Asp Asn Ala Gly
85 90 95
Asn Met Leu Thr Phe Gly Gly Gly Thr Arg Leu Met Val Lys Pro His
100 105 110
Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser
115 120 125
Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
130 135 140
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
145 150 155 160
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
165 170 175
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
180 185 190
Ile Pro Glu Asp Thr Phe Phe Pro Ser
195 200
<210> 406
<211> 243
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 406
Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr Ala Thr Gly
1 5 10 15
Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp Leu Ser Val
20 25 30
Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe Leu Ile Gln
35 40 45
Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu Glu Arg Phe
50 55 60
Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn Leu Ser Ser
65 70 75 80
Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ser Asp Gly
85 90 95
Gly Gly Val Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val
100 105 110
Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu
115 120 125
Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys
130 135 140
Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val
145 150 155 160
Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu
165 170 175
Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg
180 185 190
Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg
195 200 205
Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln
210 215 220
Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly
225 230 235 240
Arg Ala Asp
<210> 407
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 407
Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser
20 25 30
Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met
35 40 45
Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp Ser Gln
65 70 75 80
Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Lys Asp Asn Ala Gly
85 90 95
Asn Met Leu Thr Phe Gly Gly Gly Thr Arg Leu Met Val Lys Pro His
100 105 110
Ile Gln Asn Pro
115
<210> 408
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 408
Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr Ala Thr Gly
1 5 10 15
Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp Leu Ser Val
20 25 30
Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe Leu Ile Gln
35 40 45
Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu Glu Arg Phe
50 55 60
Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn Leu Ser Ser
65 70 75 80
Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ser Asp Gly
85 90 95
Gly Gly Val Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val
100 105 110
Thr Glu Asp Leu Lys Asn Val Phe
115 120
<210> 409
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 409
Cys Ala Val Lys Asp Asn Ala Gly Asn Met Leu Thr Phe
1 5 10
<210> 410
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 410
Cys Ala Ser Ser Asp Gly Gly Gly Val Tyr Glu Gln Tyr Phe
1 5 10
<210> 411
<211> 203
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 411
Gln Glu Val Thr Gln Ile Pro Ala Ala Leu Ser Val Pro Glu Gly Glu
1 5 10 15
Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala Ile Tyr Asn Leu
20 25 30
Gln Trp Phe Arg Gln Asp Pro Gly Lys Gly Leu Thr Ser Leu Leu Leu
35 40 45
Ile Gln Ser Ser Gln Arg Glu Gln Thr Ser Gly Arg Leu Asn Ala Ser
50 55 60
Leu Asp Lys Ser Ser Gly Arg Ser Thr Leu Tyr Ile Ala Ala Ser Gln
65 70 75 80
Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Pro Thr Ser Gly
85 90 95
Gly Ser Tyr Ile Pro Thr Phe Gly Arg Gly Thr Ser Leu Ile Val His
100 105 110
Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
115 120 125
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
130 135 140
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
145 150 155 160
Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
165 170 175
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
180 185 190
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser
195 200
<210> 412
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 412
Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly Gln Ser
1 5 10 15
Met Thr Leu Gln Cys Ala Gln Asp Met Asn His Glu Tyr Met Ser Trp
20 25 30
Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr Ser Val
35 40 45
Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro Asn Gly Tyr Asn Val
50 55 60
Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg Leu Leu Ser Ala Ala
65 70 75 80
Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Tyr Val Gly Asn
85 90 95
Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg Leu Thr Val Leu Glu
100 105 110
Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser
115 120 125
Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala
130 135 140
Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
145 150 155 160
Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys Glu
165 170 175
Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser Ser Arg Leu Arg
180 185 190
Val Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His Phe Arg Cys Gln
195 200 205
Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg
210 215 220
Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala
225 230 235 240
Asp
<210> 413
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 413
Gln Glu Val Thr Gln Ile Pro Ala Ala Leu Ser Val Pro Glu Gly Glu
1 5 10 15
Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala Ile Tyr Asn Leu
20 25 30
Gln Trp Phe Arg Gln Asp Pro Gly Lys Gly Leu Thr Ser Leu Leu Leu
35 40 45
Ile Gln Ser Ser Gln Arg Glu Gln Thr Ser Gly Arg Leu Asn Ala Ser
50 55 60
Leu Asp Lys Ser Ser Gly Arg Ser Thr Leu Tyr Ile Ala Ala Ser Gln
65 70 75 80
Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Pro Thr Ser Gly
85 90 95
Gly Ser Tyr Ile Pro Thr Phe Gly Arg Gly Thr Ser Leu Ile Val His
100 105 110
Pro Tyr Ile Gln Asn Pro
115
<210> 414
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 414
Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly Gln Ser
1 5 10 15
Met Thr Leu Gln Cys Ala Gln Asp Met Asn His Glu Tyr Met Ser Trp
20 25 30
Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr Ser Val
35 40 45
Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro Asn Gly Tyr Asn Val
50 55 60
Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg Leu Leu Ser Ala Ala
65 70 75 80
Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Tyr Val Gly Asn
85 90 95
Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg Leu Thr Val Leu Glu
100 105 110
Asp Leu Lys Asn Val Phe
115
<210> 415
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 415
Cys Ala Val Arg Pro Thr Ser Gly Gly Ser Tyr Ile Pro Thr Phe
1 5 10 15
<210> 416
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 416
Cys Ala Ser Ser Tyr Val Gly Asn Thr Gly Glu Leu Phe Phe
1 5 10
<210> 417
<211> 206
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 417
Lys Gln Gln Val Thr Gln Ile Pro Ala Ala Leu Ser Val Pro Glu Gly
1 5 10 15
Glu Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala Ile Tyr Asn
20 25 30
Leu Gln Trp Phe Arg Gln Asp Pro Gly Gly Lys Leu Thr Ser Leu Leu
35 40 45
Leu Ile Gln Ser Ser Gln Arg Glu Gln Thr Ser Gly Arg Leu Asn Ala
50 55 60
Ser Leu Asp Lys Ser Ala Gly Ser Ser Thr Leu Tyr Ile Ala Ala Ser
65 70 75 80
Gln Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Pro Thr Ser
85 90 95
Gly Gly Ser Tyr Ile Pro Thr Phe Gly Arg Gly Thr Ser Leu Ile Val
100 105 110
His Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
115 120 125
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
130 135 140
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
145 150 155 160
Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
165 170 175
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
180 185 190
Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu
195 200 205
<210> 418
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 418
Lys Gln Gln Val Thr Gln Ile Pro Ala Ala Leu Ser Val Pro Glu Gly
1 5 10 15
Glu Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala Ile Tyr Asn
20 25 30
Leu Gln Trp Phe Arg Gln Asp Pro Gly Gly Lys Leu Thr Ser Leu Leu
35 40 45
Leu Ile Gln Ser Ser Gln Arg Glu Gln Thr Ser Gly Arg Leu Asn Ala
50 55 60
Ser Leu Asp Lys Ser Ala Gly Ser Ser Thr Leu Tyr Ile Ala Ala Ser
65 70 75 80
Gln Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Pro Thr Ser
85 90 95
Gly Gly Ser Tyr Ile Pro Thr Phe Gly Arg Gly Thr Ser Leu Ile Val
100 105 110
His Pro Tyr Ile Gln Asn Pro
115
<210> 419
<211> 194
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 419
Lys Gln Glu Val Thr Gln Ile Pro Ala Ala Leu Ser Val Pro Glu Gly
1 5 10 15
Glu Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala Ile Tyr Asn
20 25 30
Leu Gln Trp Phe Arg Gln Asp Pro Gly Lys Gly Leu Thr Ser Leu Leu
35 40 45
Leu Ile Gln Ser Ser Gln Arg Glu Gln Thr Ser Gly Arg Leu Asn Ala
50 55 60
Ser Leu Asp Lys Ser Ser Gly Ser Ser Thr Leu Tyr Ile Ala Ala Ser
65 70 75 80
Gln Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Pro Leu Leu
85 90 95
Asp Gly Thr Tyr Ile Pro Thr Phe Gly Arg Gly Thr Ser Leu Ile Val
100 105 110
His Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
115 120 125
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
130 135 140
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
145 150 155 160
Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
165 170 175
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
180 185 190
Asn Ser
<210> 420
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 420
Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly Gln Ser
1 5 10 15
Met Thr Leu Gln Cys Ala Gln Asp Met Asn His Glu Tyr Met Ser Trp
20 25 30
Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr Ser Val
35 40 45
Gly Ala Gly Thr Thr Asp Gln Gly Glu Val Pro Asn Gly Tyr Asn Val
50 55 60
Ser Arg Ser Thr Ile Glu Asp Phe Pro Leu Arg Leu Leu Ser Ala Ala
65 70 75 80
Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Tyr Leu Gly Asn
85 90 95
Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg Leu Thr Val Leu Glu
100 105 110
Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser
115 120 125
Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala
130 135 140
Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
145 150 155 160
Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys Glu
165 170 175
Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser Ser Arg Leu Arg
180 185 190
Val Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His Phe Arg Cys Gln
195 200 205
Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg
210 215 220
Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala
225 230 235 240
Asp
<210> 421
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 421
Lys Gln Glu Val Thr Gln Ile Pro Ala Ala Leu Ser Val Pro Glu Gly
1 5 10 15
Glu Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala Ile Tyr Asn
20 25 30
Leu Gln Trp Phe Arg Gln Asp Pro Gly Lys Gly Leu Thr Ser Leu Leu
35 40 45
Leu Ile Gln Ser Ser Gln Arg Glu Gln Thr Ser Gly Arg Leu Asn Ala
50 55 60
Ser Leu Asp Lys Ser Ser Gly Ser Ser Thr Leu Tyr Ile Ala Ala Ser
65 70 75 80
Gln Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg Pro Leu Leu
85 90 95
Asp Gly Thr Tyr Ile Pro Thr Phe Gly Arg Gly Thr Ser Leu Ile Val
100 105 110
His Pro Tyr Ile Gln Asn Pro
115
<210> 422
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 422
Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly Gln Ser
1 5 10 15
Met Thr Leu Gln Cys Ala Gln Asp Met Asn His Glu Tyr Met Ser Trp
20 25 30
Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr Ser Val
35 40 45
Gly Ala Gly Thr Thr Asp Gln Gly Glu Val Pro Asn Gly Tyr Asn Val
50 55 60
Ser Arg Ser Thr Ile Glu Asp Phe Pro Leu Arg Leu Leu Ser Ala Ala
65 70 75 80
Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Tyr Leu Gly Asn
85 90 95
Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg Leu Thr Val Leu Glu
100 105 110
Asp Leu Lys Asn Val Phe
115
<210> 423
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 423
Cys Ala Val Arg Pro Leu Leu Asp Gly Thr Tyr Ile Pro Thr Phe
1 5 10 15
<210> 424
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 424
Cys Ala Ser Ser Tyr Leu Gly Asn Thr Gly Glu Leu Phe Phe
1 5 10
<210> 425
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 425
Leu Gly Tyr Gly Phe Val Asn Tyr Ile
1 5
<210> 426
<211> 10
<212> PRT
<213> 智人(Homo sapiens)
<400> 426
Ala Leu Trp Gly Pro Asp Pro Ala Ala Ala
1 5 10
<210> 427
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成肽
<400> 427
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 428
<211> 197
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 428
Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu Gly Ala Ile
1 5 10 15
Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln Tyr Phe Met
20 25 30
Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu Met Tyr Thr
35 40 45
Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala Gln Val Asp
50 55 60
Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser Gln Pro Ser
65 70 75 80
Asp Ser Ala Thr Tyr Leu Cys Ala Met Ser Leu Tyr Tyr Gly Gly Ser
85 90 95
Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys Pro
100 105 110
Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser
115 120 125
Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser
130 135 140
Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp Met Arg
145 150 155 160
Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser
165 170 175
Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp
180 185 190
Thr Phe Phe Pro Ser
195
<210> 429
<211> 248
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 429
Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile Glu Lys Arg Gln
1 5 10 15
Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His Ala Thr Leu Tyr
20 25 30
Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu Leu Ile Gln Phe
35 40 45
Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro Lys Asp Arg Phe
50 55 60
Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu Lys Ile Gln Pro
65 70 75 80
Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu Glu
85 90 95
Ile Phe Gly Gly Ile Ala Asp Thr Asp Thr Gln Tyr Phe Gly Pro Gly
100 105 110
Thr Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu
115 120 125
Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys
130 135 140
Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu
145 150 155 160
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
165 170 175
Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr
180 185 190
Ala Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asp Pro
195 200 205
Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn
210 215 220
Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser
225 230 235 240
Ala Glu Ala Trp Gly Arg Ala Asp
245
<210> 430
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 430
Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu Gly Ala Ile
1 5 10 15
Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln Tyr Phe Met
20 25 30
Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu Met Tyr Thr
35 40 45
Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala Gln Val Asp
50 55 60
Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser Gln Pro Ser
65 70 75 80
Asp Ser Ala Thr Tyr Leu Cys Ala Met Ser Leu Tyr Tyr Gly Gly Ser
85 90 95
Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys Pro
100 105 110
<210> 431
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 431
Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile Glu Lys Arg Gln
1 5 10 15
Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His Ala Thr Leu Tyr
20 25 30
Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu Leu Ile Gln Phe
35 40 45
Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro Lys Asp Arg Phe
50 55 60
Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu Lys Ile Gln Pro
65 70 75 80
Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu Glu
85 90 95
Ile Phe Gly Gly Ile Ala Asp Thr Asp Thr Gln Tyr Phe Gly Pro Gly
100 105 110
Thr Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe
115 120 125
<210> 432
<211> 196
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 432
Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly Ala Ile
1 5 10 15
Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser Phe Phe
20 25 30
Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met Phe Ile
35 40 45
Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln Leu Asn
50 55 60
Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp Ser Gln Pro Ser
65 70 75 80
Asp Ser Ala Thr Tyr Leu Cys Ala Val Asn Asp Gln Gly Gly Gly Ala
85 90 95
Asp Gly Leu Thr Phe Gly Lys Gly Thr His Leu Ile Ile Gln Pro Asp
100 105 110
Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val
115 120 125
Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys
130 135 140
Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp Met Arg Ser
145 150 155 160
Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp
165 170 175
Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr
180 185 190
Phe Phe Pro Ser
195
<210> 433
<211> 242
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 433
Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Arg Val Leu Lys Thr Gly
1 5 10 15
Gln Ser Met Thr Leu Leu Cys Ala Gln Asp Met Asn His Glu Tyr Met
20 25 30
Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr
35 40 45
Ser Val Gly Glu Gly Thr Thr Ala Lys Gly Glu Val Pro Asp Gly Tyr
50 55 60
Asn Val Ser Arg Leu Lys Lys Gln Asn Phe Leu Leu Gly Leu Glu Ser
65 70 75 80
Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Trp Trp
85 90 95
Asp Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg Leu Thr Val Leu
100 105 110
Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
115 120 125
Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu
130 135 140
Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
145 150 155 160
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys
165 170 175
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser Ser Arg Leu
180 185 190
Arg Val Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His Phe Arg Cys
195 200 205
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
210 215 220
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
225 230 235 240
Ala Asp
<210> 434
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 434
Glu Val Glu Gln Asn Ser Gly Pro Leu Ser Val Pro Glu Gly Ala Ile
1 5 10 15
Ala Ser Leu Asn Cys Thr Tyr Ser Asp Arg Gly Ser Gln Ser Phe Phe
20 25 30
Trp Tyr Arg Gln Tyr Ser Gly Lys Ser Pro Glu Leu Ile Met Phe Ile
35 40 45
Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr Ala Gln Leu Asn
50 55 60
Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp Ser Gln Pro Ser
65 70 75 80
Asp Ser Ala Thr Tyr Leu Cys Ala Val Asn Asp Gln Gly Gly Gly Ala
85 90 95
Asp Gly Leu Thr Phe Gly Lys Gly Thr His Leu Ile Ile Gln Pro
100 105 110
<210> 435
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 435
Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Arg Val Leu Lys Thr Gly
1 5 10 15
Gln Ser Met Thr Leu Leu Cys Ala Gln Asp Met Asn His Glu Tyr Met
20 25 30
Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr
35 40 45
Ser Val Gly Glu Gly Thr Thr Ala Lys Gly Glu Val Pro Asp Gly Tyr
50 55 60
Asn Val Ser Arg Leu Lys Lys Gln Asn Phe Leu Leu Gly Leu Glu Ser
65 70 75 80
Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Trp Trp
85 90 95
Asp Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg Leu Thr Val Leu
100 105 110
Glu Asp Leu Lys Asn Val Phe
115
<210> 436
<211> 197
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 436
Ala Gln Ser Val Thr Gln Leu Gly Ser His Val Ser Val Ser Glu Gly
1 5 10 15
Ala Leu Val Leu Leu Arg Cys Asn Tyr Ser Ser Ser Val Pro Pro Tyr
20 25 30
Leu Phe Trp Tyr Val Gln Tyr Pro Gln Gly Leu Gln Leu Leu Leu Lys
35 40 45
Tyr Thr Ser Ala Ala Thr Leu Val Lys Gly Ile Asn Gly Phe Glu Ala
50 55 60
Glu Phe Lys Lys Ser Glu Thr Ser Phe His Leu Thr Lys Pro Ser Ala
65 70 75 80
His Met Ser Asp Ala Ala Glu Tyr Phe Cys Ala Val Ser Glu Gly Gly
85 90 95
Asp Tyr Lys Leu Ser Phe Gly Ala Gly Thr Thr Val Thr Val Arg Ala
100 105 110
Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser
115 120 125
Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser
130 135 140
Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Cys Val Leu Asp Met Arg
145 150 155 160
Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser
165 170 175
Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp
180 185 190
Thr Phe Phe Pro Ser
195
<210> 437
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 437
Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys Arg Thr Gly
1 5 10 15
Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His Glu Asn Met
20 25 30
Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu Ile Tyr Phe
35 40 45
Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro Glu Gly Tyr
50 55 60
Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile Leu Glu Ser
65 70 75 80
Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Trp Gly Thr Leu
85 90 95
Ala Thr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu
100 105 110
Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser
115 120 125
Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala
130 135 140
Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
145 150 155 160
Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Pro Leu Lys Glu
165 170 175
Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser Ser Arg Leu Arg
180 185 190
Val Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His Phe Arg Cys Gln
195 200 205
Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg
210 215 220
Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala
225 230 235 240
Asp
<210> 438
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 438
Ala Gln Ser Val Thr Gln Leu Gly Ser His Val Ser Val Ser Glu Gly
1 5 10 15
Ala Leu Val Leu Leu Arg Cys Asn Tyr Ser Ser Ser Val Pro Pro Tyr
20 25 30
Leu Phe Trp Tyr Val Gln Tyr Pro Gln Gly Leu Gln Leu Leu Leu Lys
35 40 45
Tyr Thr Ser Ala Ala Thr Leu Val Lys Gly Ile Asn Gly Phe Glu Ala
50 55 60
Glu Phe Lys Lys Ser Glu Thr Ser Phe His Leu Thr Lys Pro Ser Ala
65 70 75 80
His Met Ser Asp Ala Ala Glu Tyr Phe Cys Ala Val Ser Glu Gly Gly
85 90 95
Asp Tyr Lys Leu Ser Phe Gly Ala Gly Thr Thr Val Thr Val Arg Ala
100 105 110
<210> 439
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 439
Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys Arg Thr Gly
1 5 10 15
Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His Glu Asn Met
20 25 30
Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu Ile Tyr Phe
35 40 45
Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro Glu Gly Tyr
50 55 60
Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile Leu Glu Ser
65 70 75 80
Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Trp Gly Thr Leu
85 90 95
Ala Thr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu
100 105 110
Asp Leu Lys Asn Val Phe
115
<210> 440
<211> 101
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 440
Trp Gly Lys Leu Gln Phe Gly Ala Gly Thr Gln Val Val Val Thr Pro
1 5 10 15
Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser
20 25 30
Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser
35 40 45
Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg
50 55 60
Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser
65 70 75 80
Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp
85 90 95
Thr Phe Phe Pro Ser
100
<210> 441
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 441
Ser Ile Leu Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val
1 5 10 15
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
20 25 30
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
35 40 45
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
50 55 60
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Ala Leu Ser
65 70 75 80
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asp Pro Arg Asn His
85 90 95
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
100 105 110
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
115 120 125
Trp Gly Arg Ala Asp
130
<210> 442
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 442
Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly
1 5 10 15
Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr
20 25 30
Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile
35 40 45
Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val
50 55 60
Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr
65 70 75 80
Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Asn Cys Ala Glu
85 90 95
Thr Val Thr Asp Ser Trp Gly Lys Leu Gln Phe Gly Ala Gly Thr Gln
100 105 110
Val Val Val Thr Pro
115
<210> 443
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 443
Asp Ala Met Val Ile Gln Asn Pro Arg Tyr Gln Val Thr Gln Phe Gly
1 5 10 15
Lys Pro Val Thr Leu Ser Cys Ser Gln Thr Leu Asn His Asn Val Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Ser Ser Gln Ala Pro Lys Leu Leu Phe His
35 40 45
Tyr Tyr Asp Lys Asp Phe Asn Asn Glu Ala Asp Thr Pro Asp Asn Phe
50 55 60
Gln Ser Arg Arg Pro Asn Thr Ser Phe Cys Phe Leu Asp Ile Arg Ser
65 70 75 80
Pro Gly Leu Gly Asp Ala Ala Met Tyr Leu Cys Ala Thr Ser Arg Gly
85 90 95
Asp Ser Thr Ala Glu Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser
100 105 110
Ile Leu Glu Asp Leu Asn Lys Val Phe
115 120
<210> 444
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 444
Ala Gln Lys Ile Thr Gln Thr Gln Pro Gly Met Phe Val Gln Glu Lys
1 5 10 15
Glu Ala Val Thr Leu Asp Cys Thr Tyr Asp Thr Ser Asp Gln Ser Tyr
20 25 30
Gly Leu Phe Trp Tyr Lys Gln Pro Ser Ser Gly Glu Met Ile Phe Leu
35 40 45
Ile Tyr Gln Gly Ser Tyr Asp Glu Gln Asn Ala Thr Glu Gly Arg Tyr
50 55 60
Ser Leu Asn Phe Gln Lys Ala Arg Lys Ser Ala Asn Leu Val Ile Ser
65 70 75 80
Ala Ser Gln Leu Gly Asp Ser Ala Met Tyr Phe Cys Ala Met Arg Glu
85 90 95
Gly Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly Thr Arg Leu Ala
100 105 110
Val His Pro
115
<210> 445
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列的描述:合成多肽
<400> 445
Ser Gln Thr Ile His Gln Trp Pro Ala Thr Leu Val Gln Pro Val Gly
1 5 10 15
Ser Pro Leu Ser Leu Glu Cys Thr Val Glu Gly Thr Ser Asn Pro Asn
20 25 30
Leu Tyr Trp Tyr Arg Gln Ala Ala Gly Arg Gly Leu Gln Leu Leu Phe
35 40 45
Tyr Ser Val Gly Ile Gly Gln Ile Ser Ser Glu Val Pro Gln Asn Leu
50 55 60
Ser Ala Ser Arg Pro Gln Asp Arg Gln Phe Ile Leu Ser Ser Lys Lys
65 70 75 80
Leu Leu Leu Ser Asp Ser Gly Phe Tyr Leu Cys Ala Gly Gln Asp Leu
85 90 95
Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu
100 105 110
Asp Leu Asn Lys Val Phe
115
Claims (126)
1.一种多肽,其包含通过包含Ala-Ser的铰链与抗体恒定结构域连接的单链可变片段(scFv),其中所述scFv包含重链可变结构域和轻链可变结构域。
2.根据权利要求1所述的多肽,其中所述重链可变结构域与所述轻链可变结构域形成二硫桥。
3.根据权利要求2所述的多肽,其中所述二硫桥在来自所述重链可变结构域的C44与来自所述轻链可变结构域的C100之间形成。
4.根据权利要求1-3中任一项所述的多肽,其中所述重链可变结构域通过柔性接头与所述轻链可变结构域连接。
5.根据权利要求4所述的多肽,其中所述柔性接头包含(G4S)4。
6.根据权利要求1-5中任一项所述的多肽,其中所述重链可变结构域位于所述轻链可变结构域的N端或C端。
7.根据权利要求1-6中任一项所述的多肽,其中所述铰链还包含氨基酸序列Thr-Lys-Gly。
8.根据权利要求1-7中任一项所述的多肽,其中所述抗体恒定结构域包含抗体Fc结构域或其足以结合CD16的部分。
9.根据权利要求8所述的多肽,其中所述抗体恒定结构域包含人IgG1抗体的CH2和CH3结构域。
10.根据权利要求9所述的多肽,其中所述抗体恒定结构域包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列。
11.根据权利要求10所述的多肽,其中所述抗体恒定结构域包含与人IgG1的Fc结构域具有至少90%同一性的氨基酸序列,并且在选自由以下组成的组的一个或多个位置上有所不同:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和K439。
12.根据权利要求11所述的多肽,其中所述抗体恒定结构域包含与人IgG1的Fc结构域具有至少90%同一性的氨基酸序列,并且不同之处在于选自由以下组成的组的一个或多个取代:Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、T411D、T411E、K439D和K439E。
13.根据权利要求1-12中任一项所述的多肽,其中所述scFv结合NKG2D或肿瘤相关抗原。
14.根据权利要求13所述的多肽,其中所述scFv结合NKG2D,并且所述scFv的所述重链可变结构域包含与选自SEQ ID NO:94、SEQ ID NO:1、SEQ ID NO:44、SEQ ID NO:52、SEQ IDNO:60、SEQ ID NO:62、SEQ ID NO:70、SEQ ID NO:78、SEQ ID NO:86、SEQ ID NO:102、SEQID NO:322、SEQ ID NO:325、SEQ ID NO:328、SEQ ID NO:331、SEQ ID NO:334和SEQ ID NO:337的氨基酸序列具有至少90%同一性的氨基酸序列。
15.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:94具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:98具有至少90%同一性的氨基酸序列。
16.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:322具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:98具有至少90%同一性的氨基酸序列。
17.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:325具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:98具有至少90%同一性的氨基酸序列。
18.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:328具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:98具有至少90%同一性的氨基酸序列。
19.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:331具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:98具有至少90%同一性的氨基酸序列。
20.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:334具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:98具有至少90%同一性的氨基酸序列。
21.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:337具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:98具有至少90%同一性的氨基酸序列。
22.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:44具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:48具有至少90%同一性的氨基酸序列。
23.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:52具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:56具有至少90%同一性的氨基酸序列。
24.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:60具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:61具有至少90%同一性的氨基酸序列。
25.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:62具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:66具有至少90%同一性的氨基酸序列。
26.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:70具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:74具有至少90%同一性的氨基酸序列。
27.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:78具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:82具有至少90%同一性的氨基酸序列。
28.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:86具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:90具有至少90%同一性的氨基酸序列。
29.根据权利要求14所述的多肽,其中所述重链可变结构域包含与SEQ ID NO:102具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:106具有至少90%同一性的氨基酸序列。
30.根据权利要求13所述的多肽,其中所述scFv结合NKG2D,并且其中所述重链可变结构域包含与SEQ ID NO:110具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:111具有至少90%同一性的氨基酸序列。
31.根据权利要求13所述的多肽,其中所述scFv结合NKG2D,并且其中所述重链可变结构域包含与SEQ ID NO:112具有至少90%同一性的氨基酸序列,并且所述轻链可变结构域包含与SEQ ID NO:113具有至少90%同一性的氨基酸序列。
32.根据权利要求13所述的多肽,其中所述scFv结合肿瘤相关抗原,所述肿瘤相关抗原选自由以下组成的组:ANO1、BCMA、EpCAM、CAIX、CEA、CCR4、CD2、CD123、CD133、CD19、CD20、CD22、CD25、CD30、CD33、CD37、CD38、CD40、CD52、CD70、CLAUDIN-18.2、DLL3、EGFR/ERBB1、GD2、IGF1R、HER2、HER3/ERBB3、HER4/ERBB4、MUC1、cMET、SLAMF7、PSMA、间皮素、MICA、MICB、TRAILR1、TRAILR2、TROP2、MAGE-A3、B7.1、B7.2、CTLA4、PD1、5T4、GPNMB、FR-α、PAPP-A、FLT3、GPC3、CXCR4、ROR1、ROR2、HLA-E、PD-L1、VLA4、CD44、CD13、CD15、CD47、CLL1、CD81、CD23、CD79a、CD79b、CD80、CRLF2、SLAMF7、CD138、CA125、NaPi2b、结合素4、ADAM8、ADAM9、SLC44A4、CA19-9、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、ULRA 1、LILRA2、LILRA3、ULRA4、LILRA5和ULRA6、CCR8、CD7、CTLA4、CX3CR1、ENTPD1、HAVCR2、IL-1R2、PDCD1LG2、TIGIT、TNFRSF4、TNFRSF8、TNFRSF9、GEM、NT5E、TNFRSF18、MUC1、P-钙粘素、丛状蛋白-A1、TNFRSF10B、STEAP1、CDCP1、PTK7、Ax1、erbB-3、EDNRB、Tyrp1、CD14、CD163、CSF3R、Siglec-9、ITGAM、VISTA、B7-H4(VTCN1)、CCR1、LRRC25、PTAFR、SIRPB1、TLR2、TLR4、CD300LB、ATP1A3、CCR5、MUC1(或MUC1-C)、丛状蛋白-A1、TNFRSF10B、STEAP1、CDCP1、PTK7、AXL、EDNRB、OLR1和TYRP1。
33.一种蛋白质,其包含根据前述权利要求中任一项所述的scFv。
34.一种蛋白质,其包含:
(a)第一抗原结合位点,其中所述第一抗原结合位点包含根据权利要求1-32中任一项所述的多肽;
(b)第二抗原结合位点;以及
(c)第二抗体恒定结构域。
35.根据权利要求34所述的蛋白质,其中所述第一抗原结合位点结合NKG2D,并且所述第二抗原结合位点结合肿瘤相关抗原。
36.根据权利要求34所述的蛋白质,其中所述第一抗原结合位点结合肿瘤相关抗原,并且所述第二抗原结合位点结合NKG2D。
37.根据权利要求34-36中任一项所述的蛋白质,其中所述第二抗原结合位点包含scFv或Fab。
38.根据权利要求34-37中任一项所述的蛋白质,其中所述第二抗体恒定结构域包含人IgG1抗体的铰链和CH2结构域。
39.根据权利要求34-38中任一项所述的蛋白质,其中所述第二抗体恒定结构域包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列。
40.根据权利要求39所述的蛋白质,其中所述第二抗体恒定结构域包含与人IgG1的Fc结构域具有至少90%同一性的氨基酸序列,并且在选自由以下组成的组的一个或多个位置上有所不同:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和K439。
41.一种蛋白质,其包含:
(a)结合肿瘤相关抗原的第一抗原结合位点;
(b)与所述第一抗原结合位点结合相同的肿瘤相关抗原的第二抗原结合位点;
(c)结合NKG2D的第三抗原结合位点;以及
(d)抗体恒定区或其足以结合CD16的部分,或结合CD16的第四抗原结合位点。
42.根据权利要求41所述的蛋白质,其中所述第一抗原结合位点包含scFv或Fab。
43.根据权利要求41或42所述的蛋白质,其中所述第二抗原结合位点包含scFv或Fab。
44.根据权利要求41-43中任一项所述的蛋白质,其中所述第三抗原结合位点包含scFv或Fab。
45.根据权利要求41-44中任一项所述的蛋白质,其中所述肿瘤相关抗原选自由以下组成的组:ANO1、BCMA、EpCAM、CAIX、CEA、CCR4、CD2、CD123、CD133、CD19、CD20、CD22、CD25、CD30、CD33、CD37、CD38、CD40、CD52、CD70、CLAUDIN-18.2、DLL3、EGFR/ERBB1、GD2、IGF1R、HER2、HER3/ERBB3、HER4/ERBB4、MUC1、cMET、SLAMF7、PSMA、间皮素、MICA、MICB、TRAILR1、TRAILR2、TROP2、MAGE-A3、B7.1、B7.2、CTLA4、PD1、5T4、GPNMB、FR-α、PAPP-A、FLT3、GPC3、CXCR4、ROR1、ROR2、HLA-E、PD-L1、VLA4、CD44、CD13、CD15、CD47、CLL1、CD81、CD23、CD79a、CD79b、CD80、CRLF2、SLAMF7、CD138、CA125、NaPi2b、结合素4、ADAM8、ADAM9、SLC44A4、CA19-9、LILRB1、LILRB2、LILRB3、LILRB4、LILRB5、ULRA1、LILRA2、LILRA3、ULRA4、LILRA5和ULRA6、CCR8、CD7、CTLA4、CX3CR1、ENTPD1、HAVCR2、IL-1R2、PDCD1LG2、TIGIT、TNFRSF4、TNFRSF8、TNFRSF9、GEM、NT5E、TNFRSF18、MUC1、P-钙粘素、丛状蛋白-A1、TNFRSF10B、STEAP1、CDCP1、PTK7、Axl、erbB-3、EDNRB、Tyrp1、CD14、CD163、CSF3R、Siglec-9、ITGAM、VISTA、B7-H4(VTCN1)、CCR1、LRRC25、PTAFR、SIRPB1、TLR2、TLR4、CD300LB、ATP1A3、CCR5、MUC1(或MUC1-C)、丛状蛋白-A1、TNFRSF10B、STEAP1、CDCP1、PTK7、AXL、EDNRB、OLR1和TYRP1。
46.根据权利要求41-45中任一项所述的蛋白质,其中所述第三抗原结合位点包含重链可变结构域,所述重链可变结构域包含与选自SEQ ID NO:94、SEQ ID NO:1、SEQ ID NO:44、SEQ ID NO:52、SEQ ID NO:60、SEQ ID NO:62、SEQ ID NO:70、SEQ ID NO:78、SEQ ID NO:86、SEQ ID NO:102、SEQ ID NO:322、SEQ ID NO:325、SEQ ID NO:328、SEQ ID NO:331、SEQID NO:334和SEQ ID NO:337的序列具有至少90%同一性的氨基酸序列。
47.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:94具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
48.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:322具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
49.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:325具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
50.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:328具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
51.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:331具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
52.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:334具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
53.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:337具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
54.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:44具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:48具有至少90%同一性的氨基酸序列的轻链可变结构域。
55.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:52具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:56具有至少90%同一性的氨基酸序列的轻链可变结构域。
56.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:60具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:61具有至少90%同一性的氨基酸序列的轻链可变结构域。
57.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:62具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:66具有至少90%同一性的氨基酸序列的轻链可变结构域。
58.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:70具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:74具有至少90%同一性的氨基酸序列的轻链可变结构域。
59.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:78具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:82具有至少90%同一性的氨基酸序列的轻链可变结构域。
60.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:86具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:90具有至少90%同一性的氨基酸序列的轻链可变结构域。
61.根据权利要求46所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ IDNO:102具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:106具有至少90%同一性的氨基酸序列的轻链可变结构域。
62.根据权利要求41-45中任一项所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ ID NO:110具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ IDNO:111具有至少90%同一性的氨基酸序列的轻链可变结构域。
63.根据权利要求41-45中任一项所述的蛋白质,其中所述第三抗原结合位点包含含有与SEQ ID NO:112具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ IDNO:113具有至少90%同一性的氨基酸序列的轻链可变结构域。
64.根据权利要求41-63中任一项所述的蛋白质,其中所述抗体恒定区或其足以结合CD16的所述部分包含人IgG1抗体的铰链和CH2结构域。
65.根据权利要求64所述的蛋白质,其中所述抗体恒定区或其足以结合CD16的所述部分包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列。
66.根据权利要求65所述的蛋白质,其中所述抗体恒定区或其足以结合CD16的所述部分包含与人IgG1的Fc结构域具有至少90%同一性的氨基酸序列,并且在选自由以下组成的组的一个或多个位置上有所不同:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和K439。
67.一种蛋白质,其包含:
(a)结合NKG2D的第一抗原结合位点;
(b)抗原结合性T细胞受体(TCR)片段;以及
(c)抗体恒定区或其足以结合CD16的部分,或结合CD16的另外的抗原结合位点。
68.根据权利要求67所述的蛋白质,其中所述抗原结合位点是Fab片段,并且所述抗原结合性TCR片段是单链TCR(scTCR)片段。
69.根据权利要求68所述的蛋白质,其中所述scTCR片段通过包含Ala-Ser的铰链与所述抗体恒定区的多肽链连接。
70.根据权利要求67所述的蛋白质,其中所述抗原结合位点是scFv,并且所述抗原结合性TCR片段是细胞外TCR片段。
71.根据权利要求70所述的蛋白质,其中所述scFv通过包含Ala-Ser的铰链与所述抗体恒定区的多肽链连接。
72.根据权利要求69或71所述的蛋白质,其中所述铰链还包含氨基酸序列Thr-Lys-Gly。
73.根据权利要求67所述的蛋白质,其中所述抗原结合位点是Fab片段,并且所述抗原结合性TCR片段是细胞外TCR片段。
74.根据权利要求67所述的蛋白质,其还包含与所述抗原结合性TCR片段结合相同抗原的另外的抗原结合性TCR片段。
75.根据权利要求74所述的蛋白质,其中所述抗原结合位点是scFv,并且所述抗原结合性TCR片段和所述另外的抗原结合性TCR片段是细胞外TCR片段。
76.根据权利要求74所述的蛋白质,其中所述抗原结合位点是scFv,并且所述抗原结合性TCR片段和所述另外的抗原结合性TCR片段是scTCR片段。
77.根据权利要求70-72和75-76中任一项所述的蛋白质,其中所述scFv包含通过柔性接头与轻链可变结构域连接的重链可变结构域。
78.根据权利要求77所述的蛋白质,其中所述柔性接头包含(G4S)4。
79.根据权利要求70-72和75-78中任一项所述的蛋白质,其中所述scFv包含位于轻链可变结构域的N端或C端的重链可变结构域。
80.根据权利要求67-79中任一项所述的蛋白质,其中所述抗原结合位点包含重链可变结构域和轻链可变结构域,并且其中所述重链可变结构域与所述轻链可变结构域形成二硫桥。
81.根据权利要求80所述的蛋白质,其中所述二硫桥在所述重链可变结构域的位置44处的Cys与所述轻链可变结构域的位置100处的Cys之间形成,所述位置根据Kabat编号定义。
82.根据权利要求67-81中任一项所述的蛋白质,其中所述抗原结合位点在人中与NKG2D结合。
83.根据权利要求67-82中任一项所述的蛋白质,其中所述抗原结合位点包含与选自以下的氨基酸序列具有至少90%同一性的重链可变结构域:SEQ ID NO:94、SEQ ID NO:1、SEQID NO:44、SEQ ID NO:52、SEQ ID NO:60、SEQ ID NO:62、SEQ ID NO:70、SEQ ID NO:78、SEQID NO:86、SEQ ID NO:102、SEQ iD NO:322、SEQ ID NO:325、SEQ ID NO:328、SEQ ID NO:331、SEQ ID NO:334和SEQ ID NO:337。
84.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:94具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
85.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:322具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
86.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:325具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
87.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:328具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
88.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:331具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
89.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:334具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
90.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:337具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:98具有至少90%同一性的氨基酸序列的轻链可变结构域。
91.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:44具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:48具有至少90%同一性的氨基酸序列的轻链可变结构域。
92.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:52具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:56具有至少90%同一性的氨基酸序列的轻链可变结构域。
93.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:60具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:61具有至少90%同一性的氨基酸序列的轻链可变结构域。
94.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:62具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:66具有至少90%同一性的氨基酸序列的轻链可变结构域。
95.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:70具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:74具有至少90%同一性的氨基酸序列的轻链可变结构域。
96.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:78具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:82具有至少90%同一性的氨基酸序列的轻链可变结构域。
97.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:86具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:90具有至少90%同一性的氨基酸序列的轻链可变结构域。
98.根据权利要求83所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:102具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:106具有至少90%同一性的氨基酸序列的轻链可变结构域。
99.根据权利要求67-82中任一项所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:110具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:111具有至少90%同一性的氨基酸序列的轻链可变结构域。
100.根据权利要求67-82中任一项所述的蛋白质,其中所述抗原结合位点包含含有与SEQ ID NO:112具有至少90%同一性的氨基酸序列的重链可变结构域和含有与SEQ ID NO:113具有至少90%同一性的氨基酸序列的轻链可变结构域。
101.根据权利要求67-100中任一项所述的蛋白质,其中所述抗原结合性TCR片段结合由主要组织相容性复合物(MHC)呈递的来自肿瘤相关抗原的肽。
102.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A*02:01:48呈递的具有SEQ ID NO:425的氨基酸序列的ELAVL4肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:351具有至少90%同一性的α链可变结构域和与SEQ ID NO:352具有至少90%同一性的β链可变结构域。
103.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A*02:01:48呈递的具有SEQ ID NO:426的氨基酸序列的胰岛素肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:357具有至少90%同一性的α链可变结构域和与SEQ ID NO:358具有至少90%同一性的β链可变结构域。
104.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A*02:01:48呈递的具有SEQ ID NO:340的氨基酸序列的TERT肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:363具有至少90%同一性的α链可变结构域和与SEQ ID NO:364具有至少90%同一性的β链可变结构域。
105.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A*02呈递的具有SEQ ID NO:341的氨基酸序列的ERBB2肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:430具有至少90%同一性的α链可变结构域和与SEQ ID NO:431具有至少90%同一性的β链可变结构域。
106.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A*02呈递的具有SEQ ID NO:342的氨基酸序列的WT1肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:434具有至少90%同一性的α链可变结构域和与SEQ ID NO:435具有至少90%同一性的β链可变结构域。
107.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A*02呈递的具有SEQ ID NO:342的氨基酸序列的WT1肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:438具有至少90%同一性的α链可变结构域和与SEQ ID NO:439具有至少90%同一性的β链可变结构域。
108.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A1呈递的具有SEQ ID NO:343的氨基酸序列的MAGE-A3肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:375具有至少90%同一性的α链可变结构域和与SEQ ID NO:376具有至少90%同一性的β链可变结构域。
109.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:344的氨基酸序列的MART1肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:381具有至少90%同一性的α链可变结构域和与SEQ ID NO:382具有至少90%同一性的β链可变结构域。
110.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:346的氨基酸序列的BIRC5肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:442具有至少90%同一性的α链可变结构域和与SEQ ID NO:443具有至少90%同一性的β链可变结构域。
111.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:346的氨基酸序列的BIRC5肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:444具有至少90%同一性的α链可变结构域和与SEQ ID NO:445具有至少90%同一性的β链可变结构域。
112.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:347的氨基酸序列的PRAME肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:395具有至少90%同一性的α链可变结构域和与SEQ ID NO:396具有至少90%同一性的β链可变结构域。
113.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:347的氨基酸序列的PRAME肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:401具有至少90%同一性的α链可变结构域和与SEQ ID NO:402具有至少90%同一性的β链可变结构域。
114.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:347的氨基酸序列的PRAME肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:407具有至少90%同一性的α链可变结构域和与SEQ ID NO:408具有至少90%同一性的β链可变结构域。
115.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:348的氨基酸序列的NY-ESO-1肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:413具有至少90%同一性的α链可变结构域和与SEQ ID NO:414具有至少90%同一性的β链可变结构域。
116.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:348的氨基酸序列的NY-ESO-1肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:418具有至少90%同一性的α链可变结构域和与SEQ ID NO:414具有至少90%同一性的β链可变结构域。
117.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:348的氨基酸序列的NY-ESO-1肽,并且其中所述抗原结合性TCR片段包含与SEQ ID NO:421具有至少90%同一性的α链可变结构域和与SEQ ID NO:422具有至少90%同一性的β链可变结构域。
118.根据权利要求101所述的蛋白质,其中所述抗原结合性TCR片段结合由HLA-A2呈递的具有SEQ ID NO:345的氨基酸序列的SSX2肽。
119.根据权利要求67-118中任一项所述的蛋白质,其中所述抗体恒定区或其足以结合CD16的所述部分包含人IgG1抗体的铰链和CH2结构域。
120.根据权利要求119所述的蛋白质,其中所述抗体恒定区或其足以结合CD16的所述部分包含与人IgG1抗体的氨基酸234-332具有至少90%同一性的氨基酸序列。
121.根据权利要求120所述的蛋白质,其中所述抗体恒定区或其足以结合CD16的所述部分包含与人IgG1的Fc结构域具有至少90%同一性的氨基酸序列,并且在选自由以下组成的组的一个或多个位置上有所不同:Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和K439。
122.一种制剂,其包含根据权利要求33-121中任一项所述的蛋白质和药学上可接受的载剂。
123.一种细胞,其包含编码根据权利要求33-121中任一项所述的蛋白质的一种或多种核酸。
124.一种增强肿瘤细胞死亡的方法,所述方法包括使肿瘤和自然杀伤细胞暴露于根据权利要求33-121中任一项所述的蛋白质。
125.一种治疗癌症的方法,其中所述方法包括向患者施用根据权利要求33-121中任一项所述的蛋白质或根据权利要求122所述的制剂。
126.根据权利要求125所述的方法,其中所述癌症选自由以下组成的组:急性骨髓性白血病、急性粒单核细胞白血病、B细胞淋巴瘤、膀胱癌、乳腺癌、结肠直肠癌、弥漫性大B细胞淋巴瘤、食道癌、尤文氏肉瘤、滤泡性淋巴瘤、胃癌、胃肠道癌、胃肠道间质瘤、胶质母细胞瘤、头颈癌、黑素瘤、间皮瘤、多发性骨髓瘤、骨髓增生异常综合征、肾细胞癌、神经母细胞瘤、非小细胞肺癌、神经内分泌肿瘤、卵巢癌和胰腺癌、前列腺癌、肉瘤、小细胞肺癌、T细胞淋巴瘤、睾丸癌、胸腺癌、甲状腺癌、尿路上皮癌、髓源性抑制细胞浸润的癌症、具有细胞外基质沉积的癌症、具有高水平反应性基质的癌症,以及具有新生血管形成的癌症。
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