CN113004391A - 结合nkg2d、cd16和egfr、ccr4或pd-l1的蛋白质 - Google Patents
结合nkg2d、cd16和egfr、ccr4或pd-l1的蛋白质 Download PDFInfo
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- CN113004391A CN113004391A CN202110256674.8A CN202110256674A CN113004391A CN 113004391 A CN113004391 A CN 113004391A CN 202110256674 A CN202110256674 A CN 202110256674A CN 113004391 A CN113004391 A CN 113004391A
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Abstract
描述了结合NKG2D受体、CD16和选自EGFR、HLA‑E、CCR4和PD‑L1的肿瘤相关抗原的多特异性结合蛋白,以及可用于治疗癌症的药物组合物和治疗方法。
Description
与相关申请的交叉引用
本申请要求2017年8月16日提交的美国临时专利申请号62/546,300、2017年8月16日提交的美国临时专利申请号62/546,297、2017年8月30日提交的美国临时专利申请号62/552,152和2017年9月7日提交的美国临时专利申请号62/555,114的利益和优先权,所述每个申请的内容为所有目的整体通过引用并入本文。
序列表
本申请含有以ASCII格式电子提交并整体通过引用并入本文的序列表。所述在2018年8月15日生成的ASCII拷贝被命名为DFY-033WO_SL.txt,大小为214,413字节。
技术领域
本发明涉及结合到NKG2D、CD16和选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的多特异性结合蛋白。
背景技术
尽管在文献中已报道了治疗癌症的大量研究尝试和科学进展,但这种疾病依然是显著的健康问题。血液和骨髓癌症、包括多发性骨髓瘤、白血病和淋巴瘤是频繁被诊断到的癌症类型。当前用于这些癌症的治疗选项不对所有患者有效和/或可能具有实质性严重副作用。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己的免疫系统来促进癌细胞的破坏。融合蛋白例如双特异性T-细胞衔接器是文献中描述的结合到肿瘤细胞和T-细胞以促进肿瘤细胞破坏的癌症免疫疗法。结合到某些肿瘤相关抗原和结合到某些免疫细胞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)细胞是先天性免疫系统的组成部分,占循环淋巴细胞的大约15%。NK细胞事实上浸润所有组织,并且最初因它们不需前期致敏即可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例如IFN-γ和促进其他白细胞向靶组织的召集的趋化因子。
NK细胞通过它们表面上的各种不同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,它们的活性通过杀伤细胞免疫球蛋白样受体(KIR)的激活而被抑制。或者,当NK细胞遇到外来细胞或癌细胞时,它们通过它们的激活受体(例如NKG2D、NCR、DNAM1)而被激活。NK细胞也通过它们表面上的CD16受体被某些免疫球蛋白的恒定区激活。NK细胞对激活的总体灵敏度取决于刺激性和抑制性信号的总和。
表皮生长因子受体(EGFR、ErbB-1、HER1)是作为细胞外蛋白配体的表皮生长因子家族(EGF家族)的成员的受体的跨膜蛋白。在与其特异性配体包括表皮生长因子和转化生长因子α(TGFα)结合后,EGFR经历从无活性单体形式向有活性的同二聚体或与其他ErbB家族受体的异二聚体的转变。所述二聚化刺激它的固有的细胞内蛋白酪氨酸激酶活性,并引发下游信号传导级联,引起DNA合成和细胞增殖。EGFR参与表型例如细胞迁移、粘附和增殖的调节。
已将引起EGFR过表达或活性过高的突变与大量癌症包括非小细胞肺癌、肛门癌、成胶质细胞瘤和头颈部的上皮肿瘤相关联。这些涉及EGFR的体细胞突变导致它持续激活,这产生不受控制的细胞分裂。在成胶质细胞瘤中,常常观察到被称为EGFRvIII的EGFR的或多或少的特异性突变。EGFR或家族成员的突变、扩增或错误调控与其他实体肿瘤包括结肠直肠癌、肾细胞癌、膀胱癌、宫颈癌、卵巢癌、胰腺癌和肝癌相关。
免疫系统在肿瘤发生中发挥重要作用,逃避免疫监督已成为癌症的重要标志之一。HLA-E是一种非经典的主要组织相容性复合物(MHC)分子。它属于非经典的Ib类HLA家族,该家族还包括HLA-G、HLA-F和HLA-H。HLA-E的功能是结合源自于I类HLA分子(HLA-A、-B、-C和-G)的前导序列的肽,并通过与抑制性受体CD94/NKG2A的相互作用将它们呈递给NK细胞,从而抑制NK细胞对表达正常水平的I类HLA分子的细胞的裂解。这种机制已被许多癌症用于逃避免疫监督,包括淋巴瘤、头颈部癌、膀胱癌、宫颈癌、肺癌、肾癌、黑素瘤、结肠直肠癌、卵巢癌、成胶质细胞瘤和肉瘤。
CCR4是一种用于CC趋化因子的C-C型趋化因子受体,所述C-C型趋化因子受体包括CCL2、CCL4、CCL5、CCL17和CCL22。趋化因子是一类小的结构相关的蛋白质,其调控各种不同类型的白细胞的细胞转运,并在免疫系统的发育、内稳态和功能中发挥基础作用。此外,已显示CCR4在几种类型的恶性肿瘤中表达,包括成年人T-细胞淋巴瘤/白血病(ATLL)、外周T细胞淋巴瘤、皮肤T细胞淋巴瘤、慢性淋巴细胞性白血病、B细胞恶性肿瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性大细胞淋巴瘤、成熟T/自然杀伤(NK)细胞肿瘤、胸腺瘤、胃癌和肾细胞癌。
程序化死亡配体1(PD-L1)在维持免疫内稳态中发挥重要作用。它结合到T细胞上的PD-1受体并下调细胞毒性T-细胞,从而保护正常细胞免于附带损伤。肿瘤的发生和发展伴有特殊免疫微环境的形成。肿瘤细胞可以通过过表达PD-L1而避开免疫监督并破坏宿主的免疫检查点。当PD-L1结合到PD-1时,抑制性信号被传递到T细胞中,这减少细胞因子生产并抑制T-细胞增殖。肿瘤细胞利用这种免疫检查点途径作为逃避检测和抑制免疫应答的机制。PD-L1在各种不同类型的癌症中,特别是在淋巴瘤、白血病、多发性骨髓瘤、头颈部癌、膀胱癌、宫颈癌、肺癌、肾癌、黑素瘤、结肠直肠癌、卵巢癌、成胶质细胞瘤、肉瘤和胃癌中过表达。
发明内容
本发明提供了结合到自然杀伤细胞上的NKG2D受体和CD16受体和选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的多特异性结合蛋白。这些蛋白质可以结合超过一种NK激活受体,并且可以阻断天然配体与NKG2D的结合。在某些实施方式中,所述蛋白质可以在人类中激动NK细胞。在某些实施方式中,所述蛋白质可以在人类和其他物种例如啮齿动物和食蟹猴中激动NK细胞。本发明的各个不同方面和实施方式将在下文中更详细描述。
因此,本发明的一个方面提供了一种蛋白质,其包含:结合NKG2D的第一抗原结合位点;结合选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的第二抗原结合位点;和抗体可结晶片段(Fc)结构域、其足以结合CD16的部分或结合CD16的第三抗原结合位点。在某些实施方式中,所述第一抗原结合位点结合到人类中的NKG2D。
所述抗原结合位点可以各自包含抗体重链可变结构域和抗体轻链可变结构域(例如像在抗体中那样排列或融合在一起以形成单链可变片段(scFv)),或者一个或多个所述抗原结合位点可以是单域抗体,例如VHH抗体如骆驼抗体或VNAR抗体如在软骨鱼中发现的。例如,所述结合NKG2D的第一抗原结合位点包括抗体重链可变结构域和抗体轻链可变结构域。在某些实施方式中,所述结合选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的第二抗原结合位点包括抗体重链可变结构域和抗体轻链可变结构域。在某些实施方式中,所述结合CD16的第三抗原结合位点包括抗体重链可变结构域和抗体轻链可变结构域。在某些实施方式中,所述第一抗原结合位点、第二抗原结合位点和第三抗原结合位点中的两者或更多者包括抗体重链可变结构域和抗体轻链可变结构域。
在某些实施方式中,所述结合NKG2D的第一抗原结合位点是单域抗体例如VHH片段或VNAR片段。在某些实施方式中,所述结合选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的第二抗原结合位点是单域抗体,例如VHH片段或VNAR片段。在某些实施方式中,所述结合CD16的第三抗原结合位点是单域抗体,例如VHH片段或VNAR片段。在某些实施方式中,所述第一抗原结合位点、第二抗原结合位点和第三抗原结合位点中的两者或更多者是单域抗体,例如VHH片段或VNAR片段。
在某些实施方式中,抗体重链可变结构域和抗体轻链可变结构域存在于同一多肽上。例如,在某些实施方式中,所述结合NKG2D的第一抗原结合位点包括存在于同一多肽上的抗体重链可变结构域和抗体轻链可变结构域。在某些实施方式中,所述结合选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的第二抗原结合位点包括存在于同一多肽上的抗体重链可变结构域和抗体轻链可变结构域。在某些实施方式中,所述结合CD16的第三抗原结合位点包括存在于同一多肽上的抗体重链可变结构域和抗体轻链可变结构域。在某些实施方式中,所述第一抗原结合位点、第二抗原结合位点和第三抗原结合位点中的两者或更多者包括存在于同一多肽上的抗体重链可变结构域和抗体轻链可变结构域。
一方面,本发明提供了一种蛋白质,其包含:(a)包含结合NKG2D的Fab片段的第一抗原结合位点;(b)包含结合EGFR的单链可变片段(scFv)的第二抗原结合位点;和(c)抗体Fc结构域或其足以结合CD16的部分或结合CD16的第三抗原结合位点。本发明提供了一种蛋白质,其中所述结合NKG2D的第一抗原结合位点是Fab片段,并且所述结合肿瘤相关抗原EGFR的第二抗原结合位点是scFv。
本公开中描述的某些蛋白质包括scFv,其包含重链可变结构域和轻链可变结构域,通过包含Ala-Ser的铰链连接到抗体Fc结构域或其足以结合CD16的部分或结合CD16的第三抗原结合位点。本公开的某些蛋白质包括连接到抗体Fc结构域的scFv。本公开的某些蛋白质包括scFv的重链可变结构域,其与所述scFv的轻链可变结构域形成二硫桥。
本公开的某些蛋白质包括scFv片段,其中二硫桥在来自于所述重链可变结构域的C44与来自于所述轻链可变结构域的C100之间形成。
本公开的某些蛋白质包括连接到抗体Fc结构域的scFv,其中所述scFv的轻链可变结构域位于所述scFv的重链可变结构域的N-端处,并通过柔性连接物(GlyGlyGlyGlySer)4((G4S)4)(SEQ ID NO:263)连接到所述scFv的重链可变结构域,并且所述Fab连接到所述抗体Fc结构域。
本公开的某些蛋白质包括scFv的重链可变结构域,其通过柔性连接物例如(GlyGlyGlyGlySer)4((G4S)4)连接物连接到所述scFv的轻链可变结构域。
本公开的某些蛋白质包括scFv,其中所述重链可变结构域位于所述scFv的轻链可变结构域的N-端或C-端处。
本公开的某些蛋白质包括scFv,其中所述轻链可变结构域位于所述scFv的重链可变结构域的N-端处。
本公开的某些蛋白质包括Fab片段,其连接到所述抗体Fc结构域或其足以结合CD16的部分或所述结合CD16的第三抗原结合位点。
本公开的某些蛋白质包括Fab片段,其中所述Fab片段的重链部分包含重链可变结构域和CH1结构域,并且其中所述重链可变结构域连接到所述CH1结构域。
本公开的某些蛋白质包括连接到所述抗体Fc结构域的Fab。
本公开的某些蛋白质包括选自SEQ ID NO:264、SEQ ID NO:265和SEQ ID NO:266的序列。
本公开的某些蛋白质包括连接到抗体Fc结构域的scFv,其中所述连接到抗体Fc结构域的scFv由选自SEQ ID NO:267、SEQ ID NO:268和SEQ ID NO:269的序列表示。
本公开的某些蛋白质包括SEQ ID NO:270和SEQ ID NO:271的序列。
本公开的某些蛋白质包括与选自SEQ ID NO:264、SEQ ID NO:265和SEQ ID NO:266的氨基酸序列至少90%同一性的序列。
本公开的某些蛋白质包括与选自SEQ ID NO:264、SEQ ID NO:265和SEQ ID NO:266的氨基酸序列至少95%同一性的序列。
本公开的某些蛋白质包括与选自SEQ ID NO:264、SEQ ID NO:265和SEQ ID NO:266的氨基酸序列至少99%同一性的序列。
本公开的某些蛋白质包括与选自SEQ ID NO:267、SEQ ID NO:268和SEQ ID NO:269的氨基酸序列至少90%同一性的序列。
本公开的某些蛋白质包括与选自SEQ ID NO:267、SEQ ID NO:268和SEQ ID NO:269的氨基酸序列至少95%同一性的序列。
本公开的某些蛋白质包括与选自SEQ ID NO:267、SEQ ID NO:268和SEQ ID NO:269的氨基酸序列至少99%同一性的序列。
一方面,本发明提供了结合到自然杀伤细胞上的NKG2D受体和CD16受体和选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的多特异性结合蛋白。所述结合到NKG2D的第一抗原结合位点包括与选自SEQ ID NO:1、SEQ ID NO:41、SEQ ID NO:49、SEQ ID NO:57、SEQID NO:59、SEQ ID NO:61、SEQ ID NO:69、SEQ ID NO:77、SEQ ID NO:85和SEQ ID NO:93的氨基酸序列的氨基酸序列至少90%同一性的重链可变结构域。
在某些实施方式中,所述结合到NKG2D的第一抗原结合位点可以包含与SEQ IDNO:1相关的重链可变结构域,例如通过具有与SEQ ID NO:1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/或包含与SEQ ID NO:1的CDR1(SEQ ID NO:105)、CDR2(SEQ ID NO:106)和CDR3(SEQ ID NO:107)序列相同的氨基酸序列。所述与SEQ ID NO:1相关的重链可变结构域可以与各种不同的轻链可变结构域偶联,以形成NKG2D结合位点。例如,所述包含与SEQ ID NO:1相关的重链可变结构域的第一抗原结合位点还可以包含选自与SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38和40相关的序列中的任一者的轻链可变结构域。例如,所述第一抗原结合位点包含具有与SEQ ID NO:1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SEQID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38和40的序列中的任一者至少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。
可选地,所述第一抗原结合位点可以包含与SEQ ID NO:41相关的重链可变结构域和与SEQ ID NO:42相关的轻链可变结构域。例如,所述第一抗原结合位点的重链可变结构域可以与SEQ ID NO:41至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:41的CDR1(SEQ ID NO:43)、CDR2(SEQID NO:44)和CDR3(SEQ ID NO:45)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:42至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:42的CDR1(SEQ ID NO:46)、CDR2(SEQ ID NO:47)和CDR3(SEQ ID NO:48)序列相同的氨基酸序列。
在其他实施方式中,所述第一抗原结合位点可以包含与SEQ ID NO:49相关的重链可变结构域和与SEQ ID NO:50相关的轻链可变结构域。例如,所述第一抗原结合位点的重链可变结构域可以与SEQ ID NO:49至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:49的CDR1(SEQ ID NO:51)、CDR2(SEQ ID NO:52)和CDR3(SEQ ID NO:53)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:50至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:50的CDR1(SEQ ID NO:54)、CDR2(SEQ ID NO:55)和CDR3(SEQ ID NO:56)序列相同的氨基酸序列。
可选地,所述第一抗原结合位点可以包含与SEQ ID NO:57相关的重链可变结构域和与SEQ ID NO:58相关的轻链可变结构域,例如通过具有分别与SEQ ID NO:57至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性和与SEQID NO:58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。
在另一个实施方式中,所述第一抗原结合位点可以包含与SEQ ID NO:59相关的重链可变结构域和与SEQ ID NO:60相关的轻链可变结构域。例如,所述第一抗原结合位点的重链可变结构域可以与SEQ ID NO:59至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:59的CDR1(SEQ ID NO:134)、CDR2(SEQ ID NO:135)和CDR3(SEQ ID NO:136)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:60至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:60的CDR1(SEQ ID NO:137)、CDR2(SEQ ID NO:138)和CDR3(SEQ ID NO:139)序列相同的氨基酸序列。
在某些实施方式中,所述结合到NKG2D的第一抗原结合位点可以包含与SEQ IDNO:61相关的重链可变结构域和与SEQ ID NO:62相关的轻链可变结构域。例如,所述第一抗原结合位点的重链可变结构域可以与SEQ ID NO:61至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:61的CDR1(SEQID NO:63)、CDR2(SEQ ID NO:64)和CDR3(SEQ ID NO:65)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:62至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:62的CDR1(SEQ ID NO:66)、CDR2(SEQ ID NO:67)和CDR3(SEQ ID NO:68)序列相同的氨基酸序列。
在某些实施方式中,所述第一抗原结合位点可以包含与SEQ ID NO:69相关的重链可变结构域和与SEQ ID NO:70相关的轻链可变结构域。例如,所述第一抗原结合位点的重链可变结构域可以与SEQ ID NO:69至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:69的CDR1(SEQ ID NO:71)、CDR2(SEQ ID NO:72)和CDR3(SEQ ID NO:73)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:70至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:70的CDR1(SEQ ID NO:74)、CDR2(SEQ ID NO:75)和CDR3(SEQ ID NO:76)序列相同的氨基酸序列。
在某些实施方式中,所述第一抗原结合位点可以包含与SEQ ID NO:77相关的重链可变结构域和与SEQ ID NO:78相关的轻链可变结构域。例如,所述第一抗原结合位点的重链可变结构域可以与SEQ ID NO:77至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:77的CDR1(SEQ ID NO:79)、CDR2(SEQ ID NO:80)和CDR3(SEQ ID NO:81)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:78至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:78的CDR1(SEQ ID NO:82)、CDR2(SEQ ID NO:83)和CDR3(SEQ ID NO:84)序列相同的氨基酸序列。
在某些实施方式中,所述第一抗原结合位点可以包含与SEQ ID NO:85相关的重链可变结构域和与SEQ ID NO:86相关的轻链可变结构域。例如,所述第一抗原结合位点的重链可变结构域可以与SEQ ID NO:85至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:85的CDR1(SEQ ID NO:87)、CDR2(SEQ ID NO:88)和CDR3(SEQ ID NO:89)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:86至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:86的CDR1(SEQ ID NO:90)、CDR2(SEQ ID NO:91)和CDR3(SEQ ID NO:92)序列相同的氨基酸序列。
在某些实施方式中,所述第一抗原结合位点可以包含与SEQ ID NO:93相关的重链可变结构域和与SEQ ID NO:94相关的轻链可变结构域。例如,所述第一抗原结合位点的重链可变结构域可以与SEQ ID NO:93至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:93的CDR1(SEQ ID NO:95)、CDR2(SEQ ID NO:96)和CDR3(SEQ ID NO:97)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:94至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:94的CDR1(SEQ ID NO:98)、CDR2(SEQ ID NO:99)和CDR3(SEQ ID NO:100)序列相同的氨基酸序列。
在某些实施方式中,所述第一抗原结合位点可以包含与SEQ ID NO:101相关的重链可变结构域和与SEQ ID NO:102相关的轻链可变结构域,例如通过具有分别与SEQ IDNO:101至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性和与SEQ ID NO:102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。
在某些实施方式中,所述第一抗原结合位点可以包含与SEQ ID NO:103相关的重链可变结构域和与SEQ ID NO:104相关的轻链可变结构域,例如通过具有分别与SEQ IDNO:103至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性和与SEQ ID NO:104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。
在某些实施方式中,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQID NO:217相关的重链可变结构域和与SEQ ID NO:109相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:217至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:217的CDR1(SEQ ID NO:218)、CDR2(SEQ ID NO:219)和CDR3(SEQ ID NO:220)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:109至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:109的CDR1(SEQ ID NO:110)、CDR2(SEQ ID NO:111)和CDR3(SEQ IDNO:112)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:113相关的重链可变结构域和与SEQ ID NO:117相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:113至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:113的CDR1(SEQ ID NO:114)、CDR2(SEQ ID NO:115)和CDR3(SEQ ID NO:116)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:117至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:117的CDR1(SEQ ID NO:118)、CDR2(SEQ ID NO:119)和CDR3(SEQ ID NO:120)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:121相关的重链可变结构域和与SEQ ID NO:125相关的轻链可变结构域。例如,所述第二抗原结合位点得重链可变结构域可以与SEQ ID NO:121至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:121的CDR1(SEQ ID NO:122)、CDR2(SEQ ID NO:123)和CDR3(SEQ ID NO:124)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:125至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:125的CDR1(SEQ ID NO:126)、CDR2(SEQ ID NO:127)和CDR3(SEQ ID NO:128)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:129相关的重链可变结构域和与SEQ ID NO:133相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:129至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:129的CDR1(SEQ ID NO:130)、CDR2(SEQ ID NO:131)和CDR3(SEQ ID NO:132)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:133至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:133的CDR1(SEQ ID NO:140)、CDR2(SEQ ID NO:141)和CDR3(SEQ ID NO:142)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:143相关的重链可变结构域和与SEQ ID NO:147相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:143至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:143的CDR1(SEQ ID NO:144)、CDR2(SEQ ID NO:145)和CDR3(SEQ ID NO:146)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:147至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:147的CDR1(SEQ ID NO:148)、CDR2(SEQ ID NO:149)和CDR3(SEQ ID NO:150)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:151相关的重链可变结构域和与SEQ ID NO:152相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:151至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,并且所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:152至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:153相关的重链可变结构域和与SEQ ID NO:154相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:153至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:153的CDR1(SEQ ID NO:227)、CDR2(SEQ ID NO:228)和CDR3(SEQ ID NO:229)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:154至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:154的CDR1(SEQ ID NO:230)、CDR2(SEQ ID NO:231)和CDR3(SEQ ID NO:232)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:155相关的重链可变结构域和与SEQ ID NO:156相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:155至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:155的CDR1(SEQ ID NO:233)、CDR2(SEQ ID NO:234)和CDR3(SEQ ID NO:235)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:156至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:156的CDR1(SEQ ID NO:236)、CDR2(SEQ ID NO:237)和CDR3(SEQ ID NO:238)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:157相关的重链可变结构域和与SEQ ID NO:158相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:157至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:157的CDR1(SEQ ID NO:239)、CDR2(SEQ ID NO:240)和CDR3(SEQ ID NO:241)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:158至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:158的CDR1(SEQ ID NO:242)、CDR2(SEQ ID NO:243)和CDR3(SEQ ID NO:244)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:159相关的重链可变结构域和与SEQ ID NO:160相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:159至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:159的CDR1(SEQ ID NO:245)、CDR2(SEQ ID NO:246)和CDR3(SEQ ID NO:247)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:160至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:160的CDR1(SEQ ID NO:248)、CDR2(SEQ ID NO:249)和CDR3(SEQ ID NO:250)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:161相关的重链可变结构域和与SEQ ID NO:162相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:161至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:161的CDR1(SEQ ID NO:251)、CDR2(SEQ ID NO:252)和CDR3(SEQ ID NO:253)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:162至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:162的CDR1(SEQ ID NO:254)、CDR2(SEQ ID NO:255)和CDR3(SEQ ID NO:256)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到EGFR,并且可以包含与SEQ ID NO:163相关的重链可变结构域和与SEQ ID NO:164相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:163至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:163的CDR1(SEQ ID NO:257)、CDR2(SEQ ID NO:258)和CDR3(SEQ ID NO:259)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:164至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:164的CDR1(SEQ ID NO:260)、CDR2(SEQ ID NO:261)和CDR3(SEQ ID NO:262)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到PD-L1,并且可以包含与SEQ ID NO:167相关的重链可变结构域和与SEQ ID NO:171相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:167至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:167的CDR1(SEQ ID NO:168)、CDR2(SEQ ID NO:169)和CDR3(SEQ ID NO:170)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:171至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:171的CDR1(SEQ ID NO:172)、CDR2(SEQ ID NO:173)和CDR3(SEQ ID NO:174)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到PD-L1,并且可以包含与SEQ ID NO:175相关的重链可变结构域和与SEQ ID NO:179相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:175至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:175的CDR1(SEQ ID NO:176)、CDR2(SEQ ID NO:177)和CDR3(SEQ ID NO:178)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:179至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:179的CDR1(SEQ ID NO:180)、CDR2(SEQ ID NO:181)和CDR3(SEQ ID NO:182)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到PD-L1,并且可以包含与SEQ ID NO:183相关的重链可变结构域和与SEQ ID NO:187相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:183至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:183的CDR1(SEQ ID NO:184)、CDR2(SEQ ID NO:185)和CDR3(SEQ ID NO:186)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:187至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:187的CDR1(SEQ ID NO:188)、CDR2(SEQ ID NO:189)和CDR3(SEQ ID NO:190)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到CCR4,并且可以包含与SEQ ID NO:192相关的重链可变结构域和与SEQ ID NO:196相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:192至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:192的CDR1(SEQ ID NO:193)、CDR2(SEQ ID NO:194)和CDR3(SEQ ID NO:195)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:196至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:196的CDR1(SEQ ID NO:197)、CDR2(SEQ ID NO:198)和CDR3(SEQ ID NO:199)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到CCR4,并且可以包含与SEQ ID NO:200相关的重链可变结构域和与SEQ ID NO:204相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:200至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:200的CDR1(SEQ ID NO:201)、CDR2(SEQ ID NO:202)和CDR3(SEQ ID NO:203)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:204至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:204的CDR1(SEQ ID NO:205)、CDR2(SEQ ID NO:206)和CDR3(SEQ ID NO:207)序列相同的氨基酸序列。
可选地,所述第二抗原结合位点可以结合到CCR4,并且可以包含与SEQ ID NO:208相关的重链可变结构域和与SEQ ID NO:212相关的轻链可变结构域。例如,所述第二抗原结合位点的重链可变结构域可以与SEQ ID NO:208至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:208的CDR1(SEQ ID NO:209)、CDR2(SEQ ID NO:210)和CDR3(SEQ ID NO:211)序列相同的氨基酸序列。同样地,所述第二抗原结合位点的轻链可变结构域可以与SEQ ID NO:212至少90%(例如90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同一性,和/或包含与SEQ ID NO:212的CDR1(SEQ ID NO:213)、CDR2(SEQ ID NO:214)和CDR3(SEQ ID NO:215)序列相同的氨基酸序列。
在某些实施方式中,所述第一抗原结合位点的轻链可变结构域包括与所述第二抗原结合位点的轻链可变结构域的氨基酸序列相同的氨基酸序列。例如,在某些实施方式中,所述结合NKGD2的第一抗原结合位点的轻链可变结构域包括与所述结合选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的第二抗原结合位点的轻链可变结构域的氨基酸序列相同的氨基酸序列。
在某些实施方式中,所述蛋白质包含抗体Fc结构域的足以结合CD16的部分,其中所述抗体Fc结构域包含铰链和CH2结构域,例如人类IgG抗体的铰链和CH2结构域。在某些实施方式中,所述抗体Fc结构域包括与人类IgG抗体的第234-332位氨基酸序列至少90%同一性的氨基酸序列。在某些实施方式中,所述抗体Fc结构域包含与人类IgG1的Fc结构域至少90%同一性的氨基酸序列,并且所述抗体Fc结构域的氨基酸序列在选自Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411、K439的一个或多个位置处有差异。
还提供了含有本文中描述的任一蛋白质的剂型、含有表达所述蛋白质的一个或多个核酸的细胞和使用所述蛋白质增加肿瘤细胞死亡的方法。在某些实施方式中,本发明提供了包括本文中描述的蛋白质和可药用载体的剂型。例如,在某些实施方式中,所述剂型包括蛋白质和可药用载体,所述蛋白质包含结合NKG2D的第一抗原结合位点,结合选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的第二抗原结合位点,和抗体Fc结构域、其足以结合CD16的部分或结合CD16的第三抗原结合位点。在某些实施方式中,本发明提供了含有表达蛋白质的一个或多个核酸的细胞,所述蛋白质包含结合NKG2D的第一抗原结合位点,结合选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的第二抗原结合位点和抗体Fc结构域、其足以结合CD16的部分或结合CD16的第三抗原结合位点。在某些实施方式中,本发明提供了一种增加肿瘤细胞死亡的方法,所述方法包括将肿瘤细胞和自然杀伤细胞暴露于有效量的本文中描述的蛋白质,其中所述肿瘤细胞表达EGFR、HLA-E、CCR4或PD-L1。例如,本文中提供了一种增加肿瘤细胞死亡的方法,所述方法包括将肿瘤细胞和自然杀伤细胞暴露于有效量的蛋白质,所述蛋白质包含结合NKG2D的第一抗原结合位点,结合选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的第二抗原结合位点和抗体Fc结构域、其足以结合CD16的部分或结合CD16的第三抗原结合位点,其中所述肿瘤细胞表达所述蛋白质的第二抗原结合位点结合到的肿瘤相关抗原(例如EGFR、HLA-E、CCR4或PD-L1)。
本发明的另一方面提供了一种在患者中治疗癌症的方法。所述方法包括向患者例如需要的患者施用治疗有效量的本文中描述的多特异性结合蛋白或包括治疗有效量的本文中描述的多特异性结合蛋白的剂型。例如,在某些实施方式中,所述治疗癌症的方法包括向患者例如需要治疗的患者施用包括治疗有效量的本文中描述的多特异性结合蛋白和可药用载体的剂型。
在某些实施方式中,所述治疗癌症的方法包括向患者例如需要治疗的患者施用治疗有效量的蛋白质,所述蛋白质包含结合NKG2D的第一抗原结合位点,结合选自EGFR、HLA-E、CCR4和PD-L1的肿瘤相关抗原的第二抗原结合位点和抗体Fc结构域、其足以结合CD16的部分或结合CD16的第三抗原结合位点。
使用所述多特异性结合蛋白治疗的示例性癌症包括成年人T-细胞淋巴瘤/白血病、间变性大细胞淋巴瘤、B细胞恶性肿瘤、膀胱癌、慢性淋巴细胞性白血病、宫颈癌、结肠直肠癌、皮肤T细胞淋巴瘤、胃癌、成胶质细胞瘤、神经胶质瘤、头颈部癌、霍奇金淋巴瘤、白血病、肝癌、肺癌、淋巴瘤、成熟T/自然杀伤(NK)细胞肿瘤、黑素瘤、多发性骨髓瘤、非霍奇金淋巴瘤、非小细胞肺癌、卵巢癌、胰腺癌、外周T细胞淋巴瘤、肾癌、肾细胞癌、肉瘤和胸腺瘤。在某些实施方式中,所述蛋白质的第二抗原结合位点结合EGFR,并且所述待治疗的癌症是头颈部癌、结肠直肠癌、非小细胞肺癌、神经胶质瘤、肾细胞癌、膀胱癌、宫颈癌、卵巢癌、胰腺癌或肝癌。在某些实施方式中,所述蛋白质的第二抗原结合位点结合HLA-E,并且所述待治疗的癌症是淋巴瘤、头颈部癌、膀胱癌、宫颈癌、肺癌、肾癌、黑素瘤、结肠直肠癌、卵巢癌、成胶质细胞瘤或肉瘤。在某些实施方式中,所述蛋白质的第二抗原结合位点结合PD-L1,并且所述待治疗的癌症是淋巴瘤、白血病、多发性骨髓瘤、头颈部癌、膀胱癌、宫颈癌、肺癌、肾癌、黑素瘤、结肠直肠癌、卵巢癌、成胶质细胞瘤、肉瘤或胃癌。在某些实施方式中,所述蛋白质的第二抗原结合位点结合CCR4,并且所述待治疗的癌症是成年人T-细胞淋巴瘤/白血病、白血病、外周T细胞淋巴瘤、皮肤T细胞淋巴瘤、慢性淋巴细胞性白血病、B细胞恶性肿瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性大细胞淋巴瘤、成熟T/自然杀伤(NK)细胞肿瘤、胸腺瘤、胃癌或肾细胞癌。
附图说明
图1是一种异二聚体多特异性抗体的图示。每个臂可以代表NKG2D结合结构域或EGFR、HLA-E、CCR4或PD-L1结合结构域。在某些实施方式中,所述NKG2D和所述EGFR、HLA-E、CCR4或PD-L1-结合结构域可以享有共同轻链。
图2A是一种异二聚体多特异性抗体的图示。所述NKG2D结合结构域或所述EGFR、HLA-E、CCR4或PD-L1结合结构域中的任一者可以采取scFv格式(右臂)。
图2B示出了一种三特异性抗体(TriNKET),其含有结合EGFR的scFv、靶向NKG2D的Fab和结合CD16的异二聚化抗体恒定区/结构域(“CD结构域”)(scFv-Fab格式)。在示例性实施方式中,所述连接到Fab片段的Fc结构域包含K360E、K409W突变,并且所述连接到scFv的Fc结构域包含用于形成Fc异二聚体的匹配的突变Q347R、D399V、F405T。所述抗体格式在本文中被称为F3’-TriNKET。在另一个示例性实施方式中,所述连接到的Fab片段的Fc结构域包含突变Q347R、D399V和F405T,并且所述连接到scFv的Fc结构域包含用于形成异二聚体的匹配的突变K360E和K409W。
图3是通过ELISA测定显示的NKG2D结合结构域(作为克隆列出)对人类重组NKG2D的结合亲和力的线图。
图4是通过ELISA测定显示的NKG2D结合结构域(作为克隆列出)对食蟹猴重组NKG2D的结合亲和力的线图。
图5是通过ELISA测定显示的NKG2D结合结构域(作为克隆列出)对小鼠重组NKG2D的结合亲和力的线图。
图6是通过流式细胞术显示的NKG2D结合结构域(作为克隆列出)与表达人类NKG2D的EL4细胞的结合的柱状图,示出了平均荧光强度(MFI)与背景相比的倍数(FOB)。
图7是通过流式细胞术显示的NKG2D结合结构域(作为克隆列出)与表达小鼠NKG2D的EL4细胞的结合的柱状图,示出了平均荧光强度(MFI)与背景相比的倍数(FOB)。
图8是通过与天然配体ULBP-6的竞争显示的NKG2D结合结构域(作为克隆列出)对重组人类NKG2D-Fc的特异性结合亲和力的线图。
图9是通过与天然配体MICA的竞争显示的NKG2D结合结构域(作为克隆列出)对重组人类NKG2D-Fc的特异性结合亲和力的线图。
图10是通过与天然配体Rae-1δ的竞争显示的NKG2D结合结构域(作为克隆列出)对重组小鼠NKG2D-Fc的特异性结合亲和力的线图。
图11是通过对表达人类NKG2D-CD3ζ融合蛋白的TNF-α阳性细胞百分率的定量测定显示的人类NKG2D被NKG2D结合结构域(作为克隆列出)激活的柱状图。
图12是通过对表达小鼠NKG2D-CD3ζ融合蛋白的TNF-α阳性细胞百分率的定量测定显示的小鼠NKG2D被NKG2D结合结构域(作为克隆列出)激活的柱状图。
图13是显示出人类NK细胞被NKG2D结合结构域(作为克隆列出)激活的柱状图。
图14是显示出人类NK细胞被NKG2D结合结构域(作为克隆列出)激活的柱状图。
图15是显示出小鼠NK细胞被NKG2D结合结构域(作为克隆列出)激活的柱状图。
图16是显示出小鼠NK细胞被NKG2D结合结构域(作为克隆列出)激活的柱状图。
图17是显示了NKG2D结合结构域(作为克隆列出)对肿瘤细胞的细胞毒性效应的柱状图。
图18是显示了通过差示扫描荧光测定法测量的NKG2D结合结构域(作为克隆列出)的熔解温度的柱状图。
图19A-19C是NK细胞使用CD16和NKG2D结合的协同激活的条形图。图19A显示了CD107a的水平;图19B显示了IFNγ的水平;图19C显示了CD107a和IFNγ的水平。图指示了平均值(n=2)±SD。数据代表了使用5位不同健康供体的5个独立实验。
图20是采取双特异性抗体(Triomab)形式的TriNKET的图示,其是一种维持IgG样形状的三功能、双特异性抗体。该嵌合体由源自于两个亲本抗体的两个半抗体构成,各自具有一条轻链和一条重链。Triomab型可以是含有1/2的大鼠抗体和1/2的小鼠抗体的异二聚体构建体。
图21是采取KiH共同轻链形式的TriNKET的图示,其包含杵臼结构(knobs-into-holes)(KIH)技术。KiH是含有结合到靶1和2的2个Fab片段和通过异二聚化突变稳定化的Fc的异二聚体。采取KiH格式的TriNKET可以是具有结合到靶1和靶2的2个Fab片段,含有2个不同重链和与两个重链配对的共同轻链的异二聚体构建体。
图22是采取双可变结构域免疫球蛋白(DVD-IgTM)形式的TriNKET的图示,其将两个单克隆抗体的靶结合结构域通过柔性的天然存在的连接物结合,并产生四价IgG样分子。DVD-IgTM是同二聚体构建体,其中靶向抗原2的可变结构域被融合到靶向抗原1的Fab片段的可变结构域的N端。DVD-IgTM形式含有正常的Fc。
图23是采取正交Fab界面(Ortho-Fab)形式的TriNKET的图示,其是含有结合到融合到Fc的靶1和靶2的2个Fab片段的异二聚体构建体。轻链(LC)-重链(HC)配对通过正交界面来确保。异二聚化通过Fc中的突变来确保。
图24是采取二合一Ig格式的TriNKET的图示。
图25是采取ES形式的TriNKET的图示,其是含有结合到融合到Fc的靶1和靶2的2个不同Fab片段的异二聚体构建体。异二聚化通过Fc中的静电操控突变来确保。
图26是采取Fab片段臂交换形式的TriNKET的图示:通过将重链和附连的轻链(半分子)与来自于另一个分子的重链-轻链对交换来交换Fab臂以产生双特异性抗体的抗体。Fab臂交换形式(cFae)是含有结合到靶1和2的2个Fab片段和通过异二聚化突变稳定化的Fc的异二聚体。
图27是采取SEED体形式的TriNKET的图示,其是含有结合到靶1和2的2个Fab片段和通过异二聚化突变稳定化的Fc的异二聚体。
图28是采取LuZ-Y形式的TriNKET的图示,其中使用亮氨酸拉链来诱导两个不同HC的异二聚化。所述LuZ-Y形式是含有融合到Fc的结合到靶1和2的两个不同scFab的异二聚体。异二聚化通过融合到Fc的C-端的亮氨酸拉链基序来确保。
图29是采取Cov-X体形式的TriNKET的图示。
图30A和30B是采取Kλ体形式的TriNKET的图示,其是具有融合到通过异二聚化突变稳定化的Fc的2个不同Fab片段的异二聚体构建体:靶向抗原1的一个Fab片段含有κLC,并且靶向抗原2的第二个Fab片段含有λLC。图30A是Kλ体的一种形式的示例性图示;图30B是另一种Kλ体的示例性图示。
图31是Oasc-Fab异二聚体构建体,其包括结合到靶1的Fab片段和结合到靶2的scFab,两者均融合到Fc结构域。异二聚化通过Fc结构域中的突变来确保。
图32是DuetMab,其是含有结合到抗原1和2的2个不同Fab片段和通过异二聚化突变稳定化的FC的异二聚体构建体。Fab片段1和2含有不同的S-S桥,其确保正确的轻链和重链配对。
图33是CrossmAb,其是具有结合到靶1和2的2个不同Fab片段和通过异二聚化突变稳定化的Fc的异二聚体构建体。CL和CH1结构域与VH和VL结构域被调换,例如CH1与VL内联融合,而CL与VH内联融合。
图34是Fit-Ig,其是一种同二聚体构建体,其中结合到抗原2的Fab片段被融合到结合到抗原1的Fab片段的HC的N端。所述构建体含有野生型Fc。
图35是示出了TriNKET和单克隆抗体(“mAb”)结合到表达在NCI-H2172人类肺癌细胞上的EGFR的线图。
图36是示出了TriNKET和mAb结合到表达在HCC827人类肺癌细胞上的EGFR的线图。
图37是示出了TriNKET和mAb结合到表达在NCI-H747人类结肠癌细胞上的EGFR的线图。
图38是示出了NCI-H2172细胞(肺,EGFR L858R T790M)被静息人类NK细胞的TriNKET介导的杀伤的线图。
图39是示出了NCI-H2172细胞(肺,EGFR L858R T790M)被静息人类NK细胞的TriNKET介导的杀伤的线图。
图40是示出了NCI-H747细胞(结肠,KRAS G13D)被静息人类NK细胞的TriNKET介导的杀伤的线图。
图41是示出了NCI-H747细胞(结肠,KRAS G13D)被静息人类NK细胞的TriNKET介导的杀伤的线图。
图42是示出了NCI-H2172细胞(肺,EGFR L858R T790M)被KHYG1-CD16V细胞的TriNKET介导的杀伤的线图。
图43是示出了NCI-H2172细胞(肺,EGFR L858R)被KHYG1-CD16V细胞的TriNKET介导的杀伤的线图。
图44是示出了NCI-N87细胞(胃)被KHYG1-CD16V细胞的TriNKET介导的杀伤的线图。
图45是示出了HCT116细胞(结肠,KRAS G13D)被KHYG1-CD16V细胞的TriNKET介导的杀伤的线图。
图46是示出了A549细胞(肺,KRAS G12S)被KHYG1-CD16V细胞的TriNKET介导的杀伤的线图。
详细描述
本发明提供了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EGFR、HLA-E、CCR4或PD-L1的多特异性结合蛋白。在某些实施方式中,所述多特异性蛋白还包括结合EGFR、HLA-E、CCR4或PD-L1或另一种肿瘤相关抗原的另外的抗原结合位点。本发明还提供了包含这些多特异性结合蛋白的药物组合物,以及使用这些多特异性蛋白和药物组合物用于例如治疗癌症目的的治疗方法。本发明的各个不同方面在下文分章节阐述;然而,在一个特定章节中描述的本发明的方面不应限于任何特定章节。
为了便于本发明的理解,下文定义了许多术语和短语。
当在本文中使用时,没有具体数目的指称意味着“一个或多个”,并包括复数指称物,除非上下文不适合。
当在本文中使用时,术语“抗原结合位点”是指免疫球蛋白分子的参与抗原结合的部分。在人类抗体中,抗原结合位点由重(“H”)链和轻(“L”)链的N-端可变(“V”)区的氨基酸残基形成。所述重链和轻链的V区内的三个高度趋异的区段被称为“高变区”,它们插入在被称为“构架区”或“FR”的更保守的侧翼区段之间。因此,术语“FR”是指天然存在于免疫球蛋白中的高变区之间并与其相邻的氨基酸序列。在人类抗体分子中,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配置,以形成抗原结合表面。所述抗原结合表面与被结合的抗原的三维表面互补,并且每个重链和轻链的三个高变区被称为“互补决定区”或“CDR”。在某些动物例如骆驼和软骨鱼中,抗原结合位点由单一抗体链形成,提供了“单域抗体”。抗原结合位点可以存在于完整抗体中、抗体的保留了抗原结合表面的抗原结合片段中或重组多肽例如scFv中,所述scFv在单一多肽中使用肽连接物将重链可变结构域连接到轻链可变结构域。
当在本文中使用时,术语“肿瘤相关抗原”意味着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、糖类、脂类。这些抗原可以表达在恶性细胞上或肿瘤微环境中,例如与肿瘤相关的血管、细胞外基质、间充质基质或免疫浸润物上。
当在本文中使用时,“EGFR”(表皮生长因子受体,也被称为ERBB、ERBB1和HER1)是指Uniprot登记号P00533的蛋白质和相关亚型。
当在本文中使用时,“HLA-E“(I类HLA组织相容性抗原α链E,也被称为I类MHC抗原E、HLA-6.2和HLAE)是指Uniprot登记号P13747的蛋白质和相关亚型。
当在本文中使用时,“CCR4”(C-C趋化因子受体4型,也被称为C-C CKR-4、CC-CKR-4、CCR-4、K5-5和CMKBR4)是指Uniprot登记号P51679的蛋白质和相关亚型。
当在本文中使用时,“PD-L1”(程序化细胞死亡1配体1,也被称为PDCD1配体1、程序化死亡配体1、B7同系物1、B7-H1、CD274、B7H1、PDCD1L1、PDCD1LG1和PDL1)是指Uniprot登记号Q9NZQ7的蛋白质和相关亚型。
当在本文中使用时,术语“受试者”和“患者”是指将要通过本文描述的方法和组合物治疗的生物体。这些生物体优选地包括但不限于哺乳动物(例如鼠科、猿猴、马科、牛科、猪科、犬科、猫科动物等),更优选地包括人类。
当在本文中使用时,术语“有效量”是指化合物(例如本发明的化合物)的足以实现有益或所需结果的量。有效量可以在一次或多次施用、应用或剂量中施用,并且不打算限于特定剂型或施用途径。当在本文中使用时,术语“治疗”包括导致病症、疾病、障碍等的改善的任何效应例如减轻、降低、调节、改善或消除或改善其症状。
当在本文中使用时,术语“药物组合物”是指活性药剂与惰性或有活性的载体的组合,使得所述组合物特别适合于体内或离体诊断或治疗用途。
当在本文中使用时,术语“可药用载体”是指任何标准的制药载体,例如磷酸盐缓冲盐水溶液、水、乳液(例如油/水或水/油乳液)和各种不同类型的润湿剂。所述组合物也可以包括稳定剂和防腐剂。对于载体、稳定剂和佐剂的实例,参见例如Martin,《Remington's制药学》(Remington's Pharmaceutical Sciences),第15版,Mack Publ.Co.,Easton,PA[1975]。
当在本文中使用时,术语“可药用盐”是指本发明的化合物的任何制药上可接受的盐(例如酸或碱式盐),其在施用到受试者后,能够提供本发明的化合物或其有活性的代谢物或残留物。正如本领域技术人员所知,本发明的化合物的“盐”可以源自于无机或有机酸和碱。示例性的酸包括但不限于盐酸、氢溴酸、硫酸、硝酸、高氯酸、延胡索酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、乙磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸等。其他酸例如草酸,尽管本身不是可药用的,但可用于制备在获得本发明的化合物及其可药用酸加成盐中可用作中间体的盐。
示例性的碱包括但不限于碱金属(例如钠)氢氧化物、碱土金属(例如镁)氢氧化物、氨和式NW4 +的化合物(其中W是C1-4烷基)等。
示例性的盐包括但不限于:乙酸盐,己二酸盐,藻酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,柠檬酸盐,樟脑酸盐,樟脑磺酸盐,环戊烷丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,延胡索酸盐,氟代庚酸盐,甘油磷酸盐,半硫酸盐,庚酸盐,己酸盐,盐酸盐,氢溴酸盐,氢碘酸盐,2-羟基乙磺酸盐,乳酸盐,马来酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,草酸盐,棕榈酸盐,果胶酸盐,过硫酸盐,苯基丙酸盐,苦味酸盐,新戊酸盐,丙酸盐,琥珀酸盐,酒石酸盐,硫氰酸盐,甲苯磺酸盐,十一烷酸盐等。盐的其他实例包括与适合的阳离子例如Na+、NH4 +和NW4 +(其中W是C1-4烷基)等化合的本发明的化合物的阴离子。
对治疗应用来说,设想的本发明的化合物的盐是可药用的。然而,不可药用的酸和碱的盐也可以在例如可药用化合物的制备或纯化中发现用途。
在整个本描述中,在组合物被描述为具有、包括或包含特定组分时,或在过程和方法被描述为具有、包括或包含特定步骤时,设想了另外还存在基本上由所叙述的组分构成或由所叙述的组分构成的本发明的组合物,并且还存在基本上由所叙述的过程步骤构成或由所叙述的过程步骤构成的符合本发明的过程和方法。
一般来说,除非另有规定,否则规定百分率的组成是以重量计的。此外,如果变量不伴有定义,则以所述变量的以前的定义为准。
I.蛋白质
本发明提供了结合到自然杀伤细胞上的NKG2D受体和CD16受体以及肿瘤相关抗原EGFR、HLA-E、CCR4或PD-L1的多特异性结合蛋白。所述多特异性结合蛋白在本文描述的药物组合物和治疗方法中有用。所述多特异性结合蛋白与自然杀伤细胞上的NKG2D受体和CD16受体的结合增强了所述自然杀伤细胞对表达EGFR、HLA-E、CCR4或PD-L1的肿瘤细胞的破坏的活性。所述多特异性结合蛋白与表达EGFR、HLA-E、CCR4或PD-L1的细胞的结合将所述癌细胞带到所述自然杀伤细胞附近,促进了所述癌细胞被所述自然杀伤细胞的直接和间接破坏。一些示例性的多特异性结合蛋白的进一步描述在下文中提供。
所述多特异性结合蛋白的第一组分结合到表达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。在结合NKG2D后,所述多特异性结合蛋白可以阻断天然配体例如ULBP6(UL16结合蛋白6)和MICA(I类主要组织相容性复合物链相关蛋白A)结合到NKG2D并激活NKG2D受体。
所述多特异性结合蛋白的第二组分结合EGFR、HLA-E、CCR4或PD-L1。表达EGFR、HLA-E、CCR4或PD-L1的细胞可以在白血病例如急性髓系白血病和T-细胞白血病中发现。
所述多特异性结合蛋白的第三组分结合到表达CD16的细胞,所述CD16是白细胞包括自然杀伤细胞、巨噬细胞、嗜中性粒细胞、嗜曙红细胞、肥大细胞和滤泡树突细胞的表面上的Fc受体。
本文中描述的多特异性结合蛋白可以采取各种不同的格式。例如,一种格式是异二聚体多特异性抗体,其包括第一免疫球蛋白重链、第一免疫球蛋白轻链、第二免疫球蛋白重链和第二免疫球蛋白轻链(图1)。所述第一免疫球蛋白重链包括第一Fc(铰链-CH2-CH3)结构域、第一重链可变结构域和任选的第一CH1重链结构域。所述第一免疫球蛋白轻链包括第一轻链可变结构域和第一轻链恒定结构域。所述第一免疫球蛋白轻链与所述第一免疫球蛋白重链一起,形成结合NKG2D的抗原结合位点。所述第二免疫球蛋白重链包含第二Fc(铰链-CH2-CH3)结构域、第二重链可变结构域和任选的第二CH1重链结构域。所述第二免疫球蛋白轻链包括第二轻链可变结构域和第二轻链恒定结构域。所述第二免疫球蛋白轻链与所述第二免疫球蛋白重链一起,形成结合EGFR、HLA-E、CCR4或PD-L1的抗原结合位点。所述第一Fc结构域和第二Fc结构域一起能够结合到CD16(图1)。在某些实施方式中,所述第一免疫球蛋白轻链与所述第二免疫球蛋白轻链相同。
另一种示例性格式涉及一种异二聚体多特异性抗体,其包括第一免疫球蛋白重链、第二免疫球蛋白重链和免疫球蛋白轻链(图2)。所述第一免疫球蛋白重链包括通过连接物或抗体铰链融合到单链可变片段(scFv)的第一Fc(铰链-CH2-CH3)结构域,所述scFv由配对并结合NKG2D或结合EGFR、HLA-E、CCR4或PD-L1抗原的重链可变结构域和轻链可变结构域构成。所述第二免疫球蛋白重链包括第二Fc(铰链-CH2-CH3)结构域、第二重链可变结构域和任选的CH1重链结构域。所述免疫球蛋白轻链包括轻链可变结构域和轻链恒定结构域。所述第二免疫球蛋白重链与所述免疫球蛋白轻链配对并结合到NKG2D或结合肿瘤相关抗原EGFR、HLA-E、CCR4或PD-L1。所述第一Fc结构域和所述第二Fc结构域一起能够结合到CD16(图2)。
一个或多个另外的结合基序,可以任选地通过连接物序列融合到所述恒定区CH3结构域的C-端。在某些实施方式中,所述抗原结合基序是单链或二硫键稳定的可变区(scFv),形成四价或三价分子。
在某些实施方式中,所述多特异性结合蛋白采取三功能抗体形式,其是维持IgG样形状的三功能、双特异性抗体。这种嵌合体由源自于两个亲本抗体的两个半抗体构成,各自具有一条轻链和一条重链。
在某些实施方式中,所述多特异性结合蛋白是KiH共同轻链(LC)形式,其涉及杵臼结构(KIH)技术。所述KIH包括工程化的CH3结构域,以在每条重链中产生“杵”或“臼”来促进异二聚化。在“杵臼结构(KiH)”Fc技术背后的概念是通过将小残基用大体积的残基替换而在一个CH3结构域(CH3A)中引入“杵”(例如采取EU编号的T366WCH3A)。为了容纳所述“杵”,通过将最邻近所述球的残基用较小的残基代替,在另一个CH3结构域(CH3B)上产生互补的“臼”表面(例如T366S/L368A/Y407VCH3B)。所述“臼”突变通过结构化指导的噬菌体筛选进行优化(Atwell S,Ridgway JB,Wells JA,Carter P.,使用噬菌体展示文库从同二聚体的结构域界面的重塑得到的稳定的异二聚体(Stable heterodimers from remodeling thedomain interface of a homodimer using a phage display library),J Mol Biol(1997)270(1):26–35)。KiH Fc变体的X-射线晶体结构(Elliott JM,Ultsch M,Lee J,TongR,Takeda K,Spiess C等,杵和臼非糖基化半抗体同二聚体的反平行构象由CH2-CH3疏水相互作用介导(Antiparallel conformation of knob and hole aglycosylated half-antibody homodimers is mediated by a CH2-CH3 hydrophobic interaction),J MolBiol(2014)426(9):1947–57;Mimoto F,Kadono S,Katada H,Igawa T,Kamikawa T,Hattori K等,对FcγR具有提高的亲和力的新的不对称工程化Fc变体的晶体结构(Crystalstructure of a novel asymmetrically engineered Fc variant with improvedaffinity for FcgammaRs),Mol Immunol(2014)58(1):132–8)证实了由CH3结构域间核心界面处的空间互补性驱动的疏水相互作用使异二聚化在热力学上有利,而杵-杵和臼-臼界面分别由于空间位阻和有利相互作用的破坏而不利于同二聚作用。
在某些实施方式中,所述多特异性结合蛋白采取双可变结构域免疫球蛋白(DVD-IgTM)形成,其通过柔性的天然存在的连接物将两个单克隆抗体的靶结合结构域合并,并得到四价IgG样分子。
在某些实施方式中,所述多特异性结合蛋白采取正交Fab界面(Ortho-Fab)形式。在ortho-Fab IgG方法中(Lewis SM,Wu X,Pustilnik A,Sereno A,Huang F,Rick HL等,通过正交Fab界面的基于结构的设计产生双特异性IgG抗体(Generation of bispecific IgGantibodies by structure-based design of an orthogonal Fab interface),Nat.Biotechnol.(2014)32(2):191–8),基于结构的区域性设计在仅仅一个Fab片段中的LC和HCVH-CH1界面处引入互补突变,对另一个Fab片段没有做出任何改变。
在某些实施方式中,所述多特异性结合蛋白采取二合一Ig格式。在某些实施方式中,所述多特异性结合蛋白采取ES形式,其是含有结合到融合到Fc的靶1和靶2的2个不同Fab片段的异二聚体构建体。异二聚化通过所述Fc中的静电操控突变来确保。
在某些实施方式中,所述多特异性结合蛋白采取Kλ体形式,其是具有融合到通过异二聚化突变稳定化的Fc的2个不同Fab片段的异二聚体构建体:靶向抗原1的Fab片段1含有κLC,而靶向抗原2的第二个Fab片段含有λLC。图30A是一种形式的Kλ体的示例性图示;图30B是另一种Kλ体的示例性图示。
在某些实施方式中,所述多特异性结合蛋白采取Fab臂交换形式(通过将重链和附连的轻链(半分子)与来自于另一个分子的重链-轻链对交换来交换Fab臂以产生双特异性抗体的抗体)。
在某些实施方式中,所述多特异性结合蛋白采取SEED体形式。所述链交换工程化结构域(SEED)平台被设计成产生不对称且双特异性的抗体样分子,这种能力扩展了天然抗体的治疗性应用。这种蛋白质工程化平台是基于保守的CH3结构域内免疫球蛋白的结构相关的序列的交换。所述SEED设计允许高效产生AG/GA异二聚体,而不利于AG和GA SEED CH3结构域的同二聚作用。(Muda M.等,Protein Eng.Des.Sel.,2011,24(5):447-54)。
在某些实施方式中,所述多特异性结合蛋白采取LuZ-Y形式,其中使用亮氨酸拉链来诱导两个不同HC的异二聚化(Wranik,BJ.等,J.Biol.Chem.(2012),287:43331-9)。
在某些实施方式中,所述多特异性结合蛋白采取Cov-X体形式。在双特异性CovX体中,两个不同的肽使用支链氮杂环丁酮连接物联结在一起,并在温和条件下以位点特异性方式融合到支架抗体。所述抗体支架提供长的半衰期和Ig样分布,而所述药效团负责功能活性。所述药效团可以被化学优化或用其他药效团代替,以产生优化的或独特的双特异性抗体(Doppalapudi VR等,PNAS(2010),107(52);22611-22616)。
在某些实施方式中,所述多特异性结合蛋白采取Oasc-Fab异二聚体形式,其包括结合到融合到Fc的靶1的Fab片段和结合到靶2的scFab。异二聚化通过所述Fc中的突变来确保。
在某些实施方式中,所述多特异性结合蛋白采取DuetMab形式,其是含有结合到抗原1和2的2个不同Fab片段和通过异二聚化突变稳定化的FC的异二聚体构建体。Fab片段1和2含有不同的S-S桥,其确保正确的LC和HC配对。
在某些实施方式中,所述多特异性结合蛋白采取CrossmAb形式,其是具有融合到通过异二聚化稳定化的Fc的结合到靶1和2的2个不同Fab片段的异二聚体构建体。CL和CH1结构域与VH和VL结构域被调换,例如CH1与VL内联融合,而CL与VH内联融合。
在某些实施方式中,所述多特异性结合蛋白采取Fit-Ig形式,其是一种同二聚体构建体,其中结合到抗原2的Fab片段被融合到结合到抗原1的Fab片段的HC的N端。所述构建体含有野生型Fc。
表1列出了相组合可以结合到NKG2D的重链可变结构域和轻链可变结构域的肽序列。所述NKG2D结合结构域在它们对NKG2D的结合亲和力方面可以不同,然而它们都激活人类NKG2D和NK细胞。
可选地,由SEQ ID NO:101所表示的重链可变结构域可以与由SEQ ID NO:102所表示的轻链可变结构域配对,以形成如US 9,273,136中所示的可以结合到NKG2D的抗原结合位点。
SEQ ID NO:101
QVQLVESGGGLVKPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRGLGDGTYFDYWGQGTTVTVSS
SEQ ID NO:102
QSALTQPASVSGSPGQSITISCSGSSSNIGNNAVNWYQQLPGKAPKLLIYYDDLLPSGVSDRFSGSKSGTSAFLAISGLQSEDEADYYCAAWDDSLNGPVFGGGTKLTVL
可选地,由SEQ ID NO:103表示的重链可变结构域可以与由SEQ ID NO:104所表示的轻链可变结构域配对,以形成如US 7,879,985中所示的可以结合到NKG2D的抗原结合位点。
SEQ ID NO:103
QVHLQESGPGLVKPSETLSLTCTVSDDSISSYYWSWIRQPPGKGLEWIGHISYSGSANYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCANWDDAFNIWGQGTMVTVSS
SEQ ID NO:104
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK
本公开的蛋白质以10nM的KD或更弱的亲和力结合到NKG2D。
一方面,本公开提供了结合到自然杀伤细胞上的NKG2D受体和CD16受体以及抗原EGFR的多特异性结合蛋白。表2列出了相组合可以结合到EGFR的重链可变结构域和轻链可变结构域的一些示例性序列。
相组合可以结合到EGFR的重链可变结构域和轻链可变结构域的另外的示例性序列在下文提供(CDR被下划线)
P1X
>Gm_CA17P1X_HC(SEQ ID NO:151)
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGSIIPIFGTVNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDPSVNLYWYFDLWGRGTLVTVSS
CDR1(SEQ ID NO:221):SYAIS
CDR2(SEQ ID NO:222):SIIPIFGTVNYAQKFQG
CDR3(SEQ ID NO:223):DPSVNLYWYFDL
>Gm_CA17P1X_LC(SEQ ID NO:152)
DIQMTQSPSTLSASVGDRVTITCRASQSISSWWAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYHAHPTTFGGGTKVEIK
CDR1(SEQ ID NO:224):RASQSISSWWA
CDR2(SEQ ID NO:225):DASSLES
CDR3(SEQ ID NO:226):QQYHAHPTT
P2X
>Gm_CA17P2X_HC(SEQ ID NO:153)
QVQLVQSGAEVKKPGSSVKVSCKASGGTFGSYAISWVRQAPGQGLEWMGSIIPIFGAANPAQKSQGRVTITADESTSTAYMELSSLRSEDTAVYYCAKMGRGKVAFDIWGQGTMVTVSS
CDR1(SEQ ID NO:227):SYAIS
CDR2(SEQ ID NO:228):SIIPIFGAANPAQKSQG
CDR3(SEQ ID NO:229):MGRGKVAFDI
>Gm_CA17P2X_LC(SEQ ID NO:154)
DIVMTQSPDSLAVSLGERATINCKSSQSVLYSPNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYGSPITFGGGTKVEIK
CDR1(SEQ ID NO:230):KSSQSVLYSPNNKNYLA
CDR2(SEQ ID NO:231):WASTRES
CDR3(SEQ ID NO:232):QQYYGSPIT
帕尼单抗
>WT_CA17Pan_HC(SEQ ID NO:155)
QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS
CDR1(SEQ ID NO:233):SGDYYWT
CDR2(SEQ ID NO:234):HIYYSGNTNYNPSLKS
CDR3(SEQ ID NO:235):DRVTGAFDI
>WT_CA17Pan_LC(SEQ ID NO:156)
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIK
CDR1(SEQ ID NO:236):QASQDISNYLN
CDR2(SEQ ID NO:237):DASNLET
CDR3(SEQ ID NO:238):QHFDHLPLA
AdiCLC2
>WT_CA17AdiCLC2_HC(SEQ ID NO:157)
QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARTNLYSTPFDIWGQGTMVTVSS
CDR1(SEQ ID NO:239):SGSYYWS
CDR2(SEQ ID NO:240):YIYYSGSTNYNPSLKS
CDR3(SEQ ID NO:241):TNLYSTPFDI
>WT_CA17AdiCLC2_LC(SEQ ID NO:158)
DIQLTQSPSSVSASVGDRVTITCRASQDISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQEHDFPWTFGGGTKVEIK
CDR1(SEQ ID NO:242):RASQDISSWLA
CDR2(SEQ ID NO:243):AASSLQS
CDR3(SEQ ID NO:244):QQEHDFPWT
耐昔妥珠单抗
>耐昔妥珠单抗_HC(SEQ ID NO:159)
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGDYYWSWIRQPPGKGLEWIGYIYYSGSTDYNPSLKSRVTMSVDTSKNQFSLKVNSVTAADTAVYYCARVSIFGVGTFDYWGQGTLVTVSS
CDR1(SEQ ID NO:245):SGDYYWS
CDR2(SEQ ID NO:246):YIYYSGSTDYNPSLKS
CDR3(SEQ ID NO:247):VSIFGVGTFDY
>耐昔妥珠单抗_LC(SEQ ID NO:160)
EIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQYGSTPLTFGGGTKAEIK
CDR1(SEQ ID NO:248):RASQSVSSYLA
CDR2(SEQ ID NO:249):DASNRAT
CDR3(SEQ ID NO:250):HQYGSTPLT
西妥昔单抗
>西妥昔单抗_HC(SEQ ID NO:161)
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA
CDR1(SEQ ID NO:251):NYGVH
CDR2(SEQ ID NO:252):IWSGGNTDYN
CDR3(SEQ ID NO:253):ALTYYDYEFAY
>西妥昔单抗_LC(SEQ ID NO:162)
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGGGTKLELK
CDR1(SEQ ID NO:254):RASQSIGTNIH
CDR2(SEQ ID NO:255):YASESIS
CDR3(SEQ ID NO:256):QQNNNWPTT
AdiCLC3
>WT_CA17AdiCLC3_HC(SEQ ID NO:163)
QVQLQESGPGLVKPSETLSLTCTVSGGSVNSGDYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARTNLYSTPFDIWGQGTMVTVSS
CDR1(SEQ ID NO:257):SGDYYWS
CDR2(SEQ ID NO:258):YIYYSGSTNYNPSLKS
CDR3(SEQ ID NO:259):TNLYSTPFDI
>WT_CA17AdiCLC3_LC(SEQ ID NO:164)
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCHQYQSYSWTFGGGTKVEIK
CDR1(SEQ ID NO:260):RASQSISSWLA
CDR2(SEQ ID NO:261):DASSLES
CDR3(SEQ ID NO:262):HQYQSYSWT
本公开的一些TriNKET采取A49-F3’-TriNKET-EGFR的形式,其序列在下文提供(CDR(Kabat编号)被下划线)。
A49-F3’-TriNKET-EGFR包括:结合EGFR的单链可变片段(scFv)(SEQ ID NO:264、272、265、273、274和266是这些结合EGFR的scFv多肽的示例性序列),其通过包含Ala-Ser的铰链连接到Fc结构域(例如SEQ ID NO:267);和结合NKG2D的Fab片段(“A49”),其包括包含重链可变结构域(SEQ ID NO:85)和CH1结构域的重链部分和包含轻链可变结构域(SEQ IDNO:86)和轻链恒定结构域的轻链部分,其中所述重链可变结构域连接到所述CH1结构域,并且所述CH1结构域连接到所述Fc结构域。
本公开的结合EGFR的scFv可以包括使用(G4S)4连接物连接到耐昔妥珠单抗、帕尼单抗或AdiCLC2的轻链可变结构域的耐昔妥珠单抗、帕尼单抗或AdiCLC2的重链可变结构域(被表示为VL(G4S)4VH或LH,其中VL在VH的N-端,和被表示为VH(G4S)4VL或HL,其中VH在VL的N-端)。SEQ ID NO:264、272、265、273、274和266是这些结合EGFR的scFv多肽的示例性序列。所述耐昔妥珠单抗scFv的VL和VH(SEQ ID NO:264或272)含有100VL-105VH S-S桥(分别由G100C和Q105C替换产生)(在下面的序列中半胱氨酸残基采用粗体-斜体-下划线)。所述帕尼单抗scFv的VL和VH(SEQ ID NO:265或273)含有100VL-44VH S-S桥(分别由G100C和G44C替换产生)(在下面的序列中半胱氨酸残基采用粗体-斜体-下划线)。(G4S)4是例如SEQ IDNO:264中的粗体-下划线序列GGGGSGGGGSGGGGSGGGGS(SEQ ID NO:263)。
EGFR(neciLH)scFv(源自于耐昔妥珠单抗的可变结构域)
EGFR(neciHL)scFv(源自于耐昔妥珠单抗的可变结构域)
EGFR(panLH)scFv(源自于帕尼单抗的可变结构域)
EGFR(panHL)scFv(源自于帕尼单抗的可变结构域)
EGFR(adiCLC2LH)scFv(源自于AdiCLC2的可变结构域)
EGFR(adiCLC2HL)scFv(源自于AdiCLC2的可变结构域)
SEQ ID NO:267、SEQ ID NO:275、SEQ ID NO:268、SEQ ID NO:276、SEQ ID NO:269和SEQ ID NO:277代表了通过包含Ala-Ser的铰链连接到Fc结构域的结合EGFR的scFv(scFv-Fc)的6个序列。所述连接到scFv的Fc结构域包括Q347R、D399V和F405T替换。
EGFR(neciLH)scFv-Fc
EGFR(neciHL)scFv-Fc
EGFR(panLH)scFv-Fc
EGFR(panHL)scFv-Fc
EGFR(adiCLC2LH)scFv(源自于AdiCLC2的可变结构域)
EGFR(adiCLC2HL)scFv-Fc
SEQ ID NO:270代表了连接到Fc结构域的Fab片段的重链部分,所述重链部分包含NKG2D结合位点的重链可变结构域(SEQ ID NO:85)和CH1结构域。SEQ ID NO:270中的Fc结构域在CH3结构域中包括Y349C替换,其与连接到结合EGFR的scFv(例如SEQ ID NO:264、SEQID NO:265和SEQ ID NO:266)的Fc上的S354C替换形成二硫键。在SEQ ID NO:270中,Fc结构域也包括K360E和K409W替换。
A49-VH
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGAPMGAAAGWFDPWGQGTLVTVSS(SEQ ID NO:85)
A49 VH-CH1-Fc
SEQ ID NO:271代表了Fab片段的轻链部分,其包含NKG2D结合位点的轻链可变结构域(SEQ ID NO:86)和轻链恒定结构域。
A49–VL
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVSFPRTFGGGTKVEIK(SEQ ID NO:86)
A49 LC VL-恒定结构域
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGVSFPRTFGGGTKVEIK
RTVAAPSPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:271)
在示例性实施方式中,所述连接到结合NKG2D的Fab片段的Fc结构域包括Q347R、D399V和F405T突变,并且所述连接到EGFR scFv的Fc结构域包含用于形成异二聚体的匹配的突变K360E和K409W。在示例性实施方式中,所述连接到结合NKG2D的Fab片段的Fc结构域在CH3结构域中包括S354C替换,其与所述连接到结合EGFR的scFv的Fc上的Y349C替换形成二硫键。
可选地,可以通过筛选与由SEQ ID NO:165所定义的氨基酸序列的结合,来确定可以结合到EGFR的新的抗原结合位点。
SEQ ID NO:165
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVVLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRVAPQSSEFIGA
可以通过筛选与由SEQ ID NO:166所定义的氨基酸序列的结合,来确定可以结合到HLA-E的抗原结合位点。
SEQ ID NO:166
MVDGTLLLLLSEALALTQTWAGSHSLKYFHTSVSRPGRGEPRFISVGYVDDTQFVRFDNDAASPRMVPRAPWMEQEGSEYWDRETRSARDTAQIFRVNLRTLRGYYNQSEAGSHTLQWMHGCELGPDRRFLRGYEQFAYDGKDYLTLNEDLRSWTAVDTAAQISEQKSNDASEAEHQRAYLEDTCVEWLHKYLEKGKETLLHLEPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQQDGEGHTQDTELVETRPAGDGTFQKWAAVVVPSGEEQRYTCHVQHEGLPEPVTLRWKPASQPTIPIVGIIAGLVLLGSVVSGAVVAAVIWRKKSSGGKGGSYSKAEWSDSAQGSESHSL
表3列出了相组合可以结合到PD-L1的重链可变结构域和轻链可变结构域的肽序列。
可选地,可以通过筛选与SEQ ID NO:191所定义的氨基酸序列的结合,来确定可以结合到PD-L1的新的抗原结合位点。
SEQ ID NO:191
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET
表4列出了相组合可以结合到CCR4的重链可变结构域和轻链可变结构域的肽序列。
可选地,可以通过筛选与SEQ ID NO:216所定义的氨基酸序列的结合,来确定可以结合到CCR4的新的抗原结合位点。
SEQ ID NO:216
MNPTDIADTTLDESIYSNYYLYESIPKPCTKEGIKAFGELFLPPLYSLVFVFGLLGNSVVVLVLFKYKRLRSMTDVYLLNLAISDLLFVFSLPFWGYYAADQWVFGLGLCKMISWMYLVGFYSGIFFVMLMSIDRYLAIVHAVFSLRARTLTYGVITSLATWSVAVFASLPGFLFSTCYTERNHTYCKTKYSLNSTTWKVLSSLEINILGLVIPLGIMLFCYSMIIRTLQHCKNEKKNKAVKMIFAVVVLFLGFWTPYNIVLFLETLVELEVLQDCTFERYLDYAIQATETLAFVHCCLNPIIYFFLGEKFRKYILQLFKTCRGLFVLCQYCGLLQIYSADTPSSSYTQSTMDHDLHDAL
在所述Fc结构域内,CD16结合由所述铰链区和CH2结构域介导。例如,在人类IgG1内,与CD16的相互作用主要聚焦于氨基酸残基Asp 265-Glu 269、Asn 297-Thr 299、Ala327-Ile 332、Leu 234-Ser 239和CH2结构域中的糖残基N-乙酰基-D-葡萄糖胺(参见Sondermann等,Nature,406(6793):267-273)。在所述已知结构域的基础上,可以选择突变以提高或降低与CD16的结合亲和力,例如通过使用噬菌体展示文库或酵母表面展示cDNA文库,或者可以在相互作用的已知三维结构的基础上设计突变。
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抗体重链序列来实现,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。促进异二聚体的偏好性组装可以通过在每种抗体重链恒定区的CH3结构域中并入不同的突变来实现,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,可以在人类IgG1的基础上在CH3结构域中制造突变,并在第一多肽和第二多肽内并入不同对的氨基酸替换,以允许这两条链选择性地彼此异二聚化。下面示出的氨基酸替换的位置都按照Kabat中的EU指数来编号。
在一种情形中,所述第一多肽中的氨基酸替换将原始氨基酸用选自精氨酸(R)、苯丙氨酸(F)、酪氨酸(Y)或色氨酸(W)的较大氨基酸代替,并且所述第二多肽中的至少一个氨基酸替换将原始氨基酸用选自丙氨酸(A)、丝氨酸(S)、苏氨酸(T)或缬氨酸(V)的较小氨基酸代替,使得所述较大氨基酸替换(突起)契合到所述较小氨基酸替换(孔穴)的表面中。例如,一个多肽可以包含T366W替换,并且另一个多肽可以包含三个替换,包括T366S、L368A和Y407V。
本发明的抗体重链可变结构域可以被任选地偶联到与抗体恒定区,例如包括铰链、CH2和CH3结构域并含有或不含CH1结构域的IgG恒定区至少90%同一性的氨基酸序列。在某些实施方式中,所述恒定区的氨基酸序列与人类抗体恒定区例如人类IgG1恒定区、IgG2恒定区、IgG3恒定区或IgG4恒定区至少90%同一性。在某些其他实施方式中,所述恒定区的氨基酸序列与来自于另一种哺乳动物例如兔、狗、猫、小鼠或马的抗体恒定区至少90%同一性。与人类IgG1恒定区相比可以在所述恒定区内并入一个或多个突变,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。示例性的替换包括例如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。
在某些实施方式中,可以并入到人类IgG1恒定区的CH1中的突变可以在氨基酸V125、F126、P127、T135、T139、A140、F170、P171和/或V173处。在某些实施方式中,可以并入到人类IgG1恒定区的Cκ中的突变可以在氨基酸E123、F116、S176、V163、S174和/或T164处。
可选地,氨基酸替换可以选自下面表5中示出的成组替换。
表5 | ||
第一多肽 | 第二多肽 | |
组1 | S364E/F405A | Y349K/T394F |
组2 | S364H/D401K | Y349T/T411E |
组3 | S364H/T394F | Y349T/F405A |
组4 | S364E/T394F | Y349K/F405A |
组5 | S364E/T411E | Y349K/D401K |
组6 | S364D/T394F | Y349K/F405A |
组7 | S364H/F405A | Y349T/T394F |
组8 | S364K/E357Q | L368D/K370S |
组9 | L368D/K370S | S364K |
组10 | L368E/K370S | S364K |
组11 | K360E/Q362E | D401K |
组12 | L368D/K370S | S364K/E357L |
组13 | K370S | S364K/E357Q |
组14 | F405L | K409R |
组15 | K409R | F405L |
可选地,氨基酸替换可以选自下面表6中示出的成组替换。
可选地,氨基酸替换可以选自下面表7中示出的成组替换。
表7 | ||
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 |
可选地,每条多肽链中的至少一个氨基酸替换可以选自表8。
可选地,至少一个氨基酸替换可以选自下面表9中的成组替换,其中在所述第一多肽列中标注的位置被任何已知的带负电荷的氨基酸代替,并且在所述第二多肽列中标注的位置被任何已知的带正电荷的氨基酸代替。
表9 | |
第一多肽 | 第二多肽 |
K392,K370,K409或K439 | D399,E356或E357 |
可选地,至少一个氨基酸替换可以选自下面表10中的成组替换,其中在所述第一多肽列中标注的位置被任何已知的带正电荷的氨基酸代替,并且在所述第二多肽列中标注的位置被任何已知的带负电荷的氨基酸代替。
表10 | |
第一多肽 | 第二多肽 |
D399,E356或E357 | K409,K439,K370或K392 |
可选地,氨基酸替换可以选自下面表11中的成组替换。
表11 | |
第一多肽 | 第二多肽 |
T350V,L351Y,F405A和Y407V | T350V,T366L,K392L和T394W |
可选地或另外地,异多聚体蛋白的结构稳定性可以通过在所述第一或第二多肽链任一者上引入S354C并在相对的多肽链上引入Y349C来提高,所述突变在所述两个多肽的界面内形成人造二硫桥。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在T366位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自T366、L368和Y407的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自T366、L368和Y407的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在T366位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自E357、K360、Q362、S364、L368、K370、T394、D401、F405和T411的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自Y349、E357、S364、L368、K370、T394、D401、F405和T411的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自Y349、E357、S364、L368、K370、T394、D401、F405和T411的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自E357、K360、Q362、S364、L368、K370、T394、D401、F405和T411的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自L351、D399、S400和Y407的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自T366、N390、K392、K409和T411的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自T366、N390、K392、K409和T411的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自L351、D399、S400和Y407的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自Q347、Y349、K360和K409的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自Q347、E357、D399和F405的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自Q347、E357、D399和F405的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自Y349、K360、Q347和K409的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自K370、K392、K409和K439的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自D356、E357和D399的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自D356、E357和D399的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自K370、K392、K409和K439的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自L351、E356、T366和D399的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自Y349、L351、L368、K392和K409的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述抗体恒定区的一条多肽链的氨基酸序列在选自Y349、L351、L368、K392和K409的一个或多个位置处不同于IgG1恒定区的氨基酸序列,并且其中所述抗体恒定区的另一条多肽链的氨基酸序列在选自L351、E356、T366和D399的一个或多个位置处不同于IgG1恒定区的氨基酸序列。
在某些实施方式中,所述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差异在于S354C替换,并且其中所述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差异在于Y349C替换。
在某些实施方式中,所述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差异在于Y349C替换,并且其中所述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差异在于S354C替换。
在某些实施方式中,所述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差异在于K360E和K409W替换,并且其中所述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差异在于O347R、D399V和F405T替换。
在某些实施方式中,所述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差异在于O347R、D399V和F405T替换,并且其中所述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差异在于K360E和K409W替换。
在某些实施方式中,所述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差异在于T366W替换,并且其中所述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差异在于T366S、T368A和Y407V替换。
在某些实施方式中,所述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差异在于T366S、T368A和Y407V替换,并且其中所述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差异在于T366W替换。
在某些实施方式中,所述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差异在于T350V、L351Y、F405A和Y407V替换,并且其中所述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差异在于T350V、T366L、K392L和T394W替换。
在某些实施方式中,所述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差异在于T350V、T366L、K392L和T394W替换,并且其中所述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差异在于T350V、L351Y、F405A和Y407V替换。
上述的多特异性蛋白可以使用本领域技术人员公知的重组DNA技术来制造。例如,可以将编码所述第一免疫球蛋白重链的第一核酸序列克隆到第一表达载体中;可以将编码所述第二免疫球蛋白重链的第二核酸序列克隆到第二表达载体中;可以将编码所述免疫球蛋白轻链的第三核酸序列克隆到第三表达载体中;并且可以将所述第一、第二和第三表达载体一起稳定转染到宿主细胞中,以产生所述多聚体蛋白。
为了获得所述多特异性蛋白的最高产量,可以探索所述第一、第二和第三表达载体的不同比率,以确定用于转染到所述宿主细胞中的最佳比率。在转染后,可以使用本领域中已知的方法例如有限稀释法、ELISA、FACS、显微术或Clonepix来分离单一克隆,用于细胞库产生。
可以将克隆在适合于生物反应器规模放大的条件下培养,并维持所述多特异性蛋白的表达。所述多特异性蛋白可以使用本领域中已知的方法包括离心、深度过滤、细胞裂解、匀浆、冻融、亲和纯化、凝胶过滤、离子交换层析、疏水相互作用交换层析和混合模式层析来分离和纯化。
II.多特异性蛋白的特征
本文描述的多特异性蛋白包括NKG2D结合位点、CD16结合位点和EGFR、HLA-E、CCR4或PD-L1结合位点。在某些实施方式中,所述多特异性蛋白同时结合到表达NKG2D和/或CD16的细胞例如NK细胞并结合到表达EGFR、HLA-E、CCR4或PD-L1的肿瘤细胞。所述多特异性蛋白与NK细胞的结合能够提高所述NK细胞对所述癌细胞的破坏的活性。
在某些实施方式中,所述多特异性蛋白以与相应的EGFR、HLA-E、CCR4或PD-L1单克隆抗体(即含有与所述多特异性蛋白中所包含的相同的EGFR、HLA-E、CCR4或PD-L1结合位点的单克隆抗体)相近的亲和力结合到EGFR、HLA-E、CCR4或PD-L1。在某些实施方式中,所述多特异性蛋白与相应的EGFR、HLA-E、CCR4或PD-L1单克隆抗体相比在杀伤表达EGFR、HLA-E、CCR4或PD-L1的肿瘤细胞中更加有效。
在某些实施方式中,本文中描述的包括NKG2D结合位点和用于EGFR、HLA-E、CCR4或PD-L1的结合位点的多特异性蛋白,当与表达EGFR、HLA-E、CCR4或PD-L1的细胞共培养时激活原代人类NK细胞。NK细胞激活以CD107a脱颗粒和IFN-γ细胞因子生产的增加为特征。此外,与相应的EGFR、HLA-E、CCR4或PD-L1单克隆抗体相比,在表达EGFR、HLA-E、CCR4或PD-L1的细胞存在下,所述多特异性蛋白可能显示出人类NK细胞的更高的激活。
在某些实施方式中,本文中描述的包括NKG2D结合位点和用于EGFR、HLA-E、CCR4或PD-L1的结合位点的多特异性蛋白,提高与表达EGFR、HLA-E、CCR4或PD-L1的细胞共培养的静息和IL-2激活的人类NK细胞的活性。
在某些实施方式中,与结合到EGFR、HLA-E、CCR4或PD-L1的相应单克隆抗体相比,所述多特异性蛋白在靶向表达中和低水平的EGFR、HLA-E、CCR4或PD-L1的肿瘤细胞中提供优势。本文中描述的多特异性结合蛋白在降低肿瘤生长和杀伤癌细胞中更加有效。例如,本公开的靶向表达EGFR的肿瘤/癌细胞的多特异性结合蛋白比帕尼单抗或耐昔妥珠单抗更加有效。本公开的一种TriNKET即A49-F3’-TriNKET-EGFR(其包含:通过包含Ala-Ser的铰链连接到Fc结构域的结合EGFR的scFv(例如SEQ ID NO:264)(由SEQ ID NO:267表示的scFv-Fc);和结合NKG2D的Fab片段,其包括包含ADI-27749(A49)的重链可变结构域(SEQ ID NO:85)和CH1结构域的重链部分,以及包含轻链可变结构域(SEQ ID NO:86)和轻链恒定结构域的轻链部分,其中所述重链可变结构域连接到所述CH1,并且所述CH1结构域连接到所述Fc结构域(重链部分被表示为VH-CH1-Fc,氨基酸序列阐述在SEQ ID NO:270中)),在促进表达EGFR的人类癌细胞系的NK介导的细胞裂解中有效。
III.治疗性应用
本发明提供了使用本文中描述的多特异性结合蛋白和/或本文中描述的药物组合物治疗癌症的方法。所述方法可用于治疗表达EGFR、HLA-E、CCR4或PD-L1的各种不同的癌症。在某些实施方式中,所述癌症是白血病例如急性髓系白血病、T-细胞白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性髓系白血病或毛细胞白血病。
在某些其他实施方式中,所述癌症是乳腺癌、卵巢癌、食管癌、膀胱癌或胃癌、涎腺导管癌、肺的腺癌或子宫癌的侵袭性形式例如浆液性子宫内膜癌。在某些其他实施方式中,所述癌症是脑癌、乳腺癌、宫颈癌、结肠癌、结肠直肠癌、子宫内膜癌、食管癌、白血病、肺癌、肝癌、黑素瘤、卵巢癌、胰腺癌、直肠癌、肾癌、胃癌、睾丸癌或子宫癌。在其他实施方式中,所述癌症是鳞状细胞癌、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、胆管癌、甲状腺癌、肢端雀斑痣样黑素瘤、光化性角化病、急性淋巴细胞性白血病、急性髓性白血病、腺样囊性癌、腺瘤、腺肉瘤、腺鳞癌、肛管癌、肛门癌、肛门直肠癌、星形胶质细胞瘤、巴氏腺癌、基底细胞癌、胆管癌、骨癌、骨髓癌、支气管癌、支气管腺体癌、类癌瘤、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、慢性髓系白血病、透明细胞癌、结缔组织癌、囊腺瘤、消化系统癌症、十二指肠癌、内分泌系统癌症、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、心脏癌症、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、霍奇金氏病、回肠癌、胰岛细胞瘤、上皮内瘤变、上皮内鳞状细胞瘤变、肝内胆管癌、侵入性鳞状细胞癌、空肠癌、关节癌、卡波斯肉瘤、盆腔癌、大细胞癌、大肠癌、平滑肌肉瘤、恶性雀斑样痣黑素瘤、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、转移性癌、口腔癌、粘液表皮样癌、多发性骨髓瘤、肌肉癌、鼻道癌、神经系统癌症、神经上皮腺癌、结节性黑素瘤、非上皮性皮肤癌、非霍奇金氏淋巴瘤、燕麦细胞癌、少突神经胶质癌、口腔癌、骨肉瘤、浆液性乳头状腺癌、阴茎癌、舌咽癌、垂体肿瘤、浆细胞瘤、假性肉瘤、肺母细胞瘤、直肠癌、肾细胞癌、呼吸系统癌症、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、浆液性癌、窦癌、皮肤癌、小细胞癌、小肠癌、平滑肌癌、软组织癌、分泌生长抑素的肿瘤、脊椎癌、鳞状细胞癌、横纹肌癌、间皮下癌、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、尿道膀胱癌、泌尿系统癌症、宫颈癌、宫体癌、葡萄膜黑素瘤、阴道癌、疣状癌、血管活性肠肽瘤、外阴癌、高分化癌或肾母细胞瘤。
在某些其他实施方式中,所述待治疗的癌症是非霍奇金氏淋巴瘤例如B-细胞淋巴瘤或T-细胞淋巴瘤。在某些实施方式中,所述非霍奇金氏淋巴瘤是B-细胞淋巴瘤,例如弥漫性大B-细胞淋巴瘤、原发性纵隔B-细胞淋巴瘤、滤泡性淋巴瘤、小淋巴细胞性淋巴瘤、套细胞淋巴瘤、边缘区B-细胞淋巴瘤、淋巴结外边缘区B-细胞淋巴瘤、淋巴结边缘区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。在某些其他实施方式中,所述非霍奇金氏淋巴瘤是T-细胞淋巴瘤,例如前T淋巴母细胞淋巴瘤、外周T-细胞淋巴瘤、皮肤T-细胞淋巴瘤、血管免疫母细胞T-细胞淋巴瘤、淋巴结外自然杀伤细胞/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。
在某些其他实施方式中,所述待治疗的癌症选自头颈部癌、结肠直肠癌、非小细胞肺癌、神经胶质瘤、肾细胞癌、膀胱癌、宫颈癌、卵巢癌、胰腺癌和肝癌。
在某些其他实施方式中,所述待治疗的癌症选自淋巴瘤、头颈部癌、膀胱癌、宫颈癌、肺癌、肾癌、黑素瘤、结肠直肠癌、卵巢癌、成胶质细胞瘤和肉瘤。
在某些其他实施方式中,所述待治疗的癌症选自淋巴瘤、白血病、多发性骨髓瘤、头颈部癌、膀胱癌、宫颈癌、肺癌、肾癌、黑素瘤、结肠直肠癌、卵巢癌、成胶质细胞瘤、肉瘤和胃癌。
在某些其他实施方式中,所述待治疗的癌症选自成年人T-细胞淋巴瘤/白血病、外周T细胞淋巴瘤、皮肤T细胞淋巴瘤、慢性淋巴细胞性白血病、B细胞恶性肿瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性大细胞淋巴瘤、成熟T/自然杀伤(NK)细胞肿瘤、胸腺瘤、胃癌和肾细胞癌。
IV.组合疗法
本发明的另一方面提供了组合疗法。本文描述的多特异性结合蛋白可以与其他治疗剂组合使用以治疗癌症。
可以在治疗癌症中用作组合疗法的一部分的示例性治疗剂包括例如放射线、丝裂霉素、维甲酸、盐酸苯达莫司汀(ribomustin)、吉西他滨、长春新碱、依托泊苷、克拉屈滨、二溴甘露醇、甲氨蝶呤、多柔比星、卡波醌、喷司他丁、硝基可润、净司他丁、西曲瑞克、来曲唑、雷替曲塞、柔红霉素、法倔唑、福莫司汀、胸腺法新、索布佐生、奈达铂、阿糖胞苷、比卡鲁胺、长春瑞滨、维司力农、氨鲁米特、安吖啶、丙谷胺、依利醋铵、酮色林、去氧氟尿苷、依曲替酯、异维甲酸、链脲佐菌素、尼莫司汀、长春地辛、氟他胺(flutamide)、氟他胺(drogenil)、布缩宫素、卡莫氟、雷佐生、西佐喃、卡铂、二溴卫矛醇、替加氟、异环磷酰胺、泼尼莫司汀、毕西巴尼、左旋咪唑、替尼泊苷、英丙舒凡、依诺他滨、麦角乙脲、羟甲烯龙、他莫昔芬、孕酮、美雄烷、环硫雄醇、福美司坦、干扰素-α、干扰素-2α、干扰素-β、干扰素-γ(IFN-γ)、集落刺激因子-1、集落刺激因子-2、地尼白介素、白介素-2、黄体生成激素释放因子和上述药剂的可能表现出对同源受体的差异结合和增加或减少的血清半衰期的变化形式。
可以在治疗癌症中用作组合疗法的一部分的另一类药剂是免疫检查点抑制剂。示例性的免疫检查点抑制剂包括抑制下述一者或多者的药剂:(i)细胞毒性T-淋巴细胞相关抗原4(CTLA4),(ii)程序化细胞死亡蛋白1(PD1),(iii)PDL1,(iv)LAG3,(v)B7-H3,(vi)B7-H4,和(vii)TIM3。CTLA4抑制剂伊匹单抗已被美国食品和药品监督管理局(United StatesFood and Drug Administration)批准用于治疗黑素瘤。
可以在治疗癌症中用作组合疗法的一部分的另一类药剂是靶向非检查点靶的单克隆抗体(例如赫赛汀)和非细胞毒性药剂(例如酪氨酸激酶抑制剂)。
另一类抗癌药剂包括例如:(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、Bruton's酪氨酸激酶抑制剂、CDC7抑制剂、CHK1抑制剂、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、Hedgehog信号传导途径抑制剂、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、磷脂酰肌醇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抑制剂和WEE1抑制剂的抑制剂;(ii)OX40、CD137、CD40、GITR、CD27、HVEM、TNFRSF25或ICOS的激动剂;和(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用作原发性病灶的手术去除的辅助物。
为了实现所需的组合治疗效果,可以选择多特异性结合蛋白和其他治疗剂的量和施用的相对时间安排。例如,当向需要这种施用的患者施用组合疗法时,所述组合的治疗剂或包含所述治疗剂的一种或多种药物组合物可以以任何顺序施用,例如顺序、并行、一起、同时施用等。此外,例如,多特异性结合蛋白可以在所述其他治疗剂发挥其预防或治疗效果的时间内施用,或与之相反。
V.药物组合物
本发明还描述了含有治疗有效量的本文中描述的蛋白质的药物组合物。所述组合物可以被配制成用于各种不同的药物递送系统。对于适合的剂型来说,一种或多种生理上可接受的赋形剂或载体也可以包含在所述组合物中。适合在本公开中使用的剂型参见《Remington's制药学》(Remington's Pharmaceutical Sciences,Mack PublishingCompany,Philadelphia,Pa.,17th ed.,1985)。对于用于药物递送的方法的简要综述,参见例如Langer(Science 249:1527-1533,1990)。
本公开的静脉内药物递送剂型可以包含在袋子、笔或注射器中。在某些实施方式中,所述袋子可以被连接到包含管和/或针头的通道。在某些实施方式中,所述剂型可以是冷冻干燥剂型或液体剂型。在某些实施方式中,所述剂型可以被冷冻干燥(冻干)并包含在约12-60个小瓶中。在某些实施方式中,所述剂型可以被冷冻干燥,并且可以将45mg所述冷冻干燥的剂型包含在一个小瓶中。在某些实施方式中,可以将约40mg-约100mg所述冷冻干燥的剂型包含在一个小瓶中。在某些实施方式中,将来自于12、27或45个小瓶的冷冻干燥的剂型合并,以获得所述蛋白质在静脉内药物剂型中的治疗剂量。在某些实施方式中,所述剂型可以是液体剂型,并以约250mg/小瓶至约1000mg/小瓶储存。在某些实施方式中,所述剂型可以是液体剂型并以约600mg/小瓶储存。在某些实施方式中,所述剂型可以是液体剂型并以约250mg/小瓶储存。
所述蛋白质可以以水性液体药物剂型的形式存在,其在形成剂型的缓冲溶液中包括治疗有效量的所述蛋白质。
这些组合物可以通过常规的灭菌技术灭菌,或者可以除菌过滤。得到的水性溶液可以原样包装以备使用,或者可以被冷冻干燥,所述冷冻干燥的制剂在施用之前与无菌水性载体合并。所述制剂的pH通常在3至11之间,更优选地在5至9之间或6至8之间,最优选地在7至8之间,例如7至7.5。所述得到的固体形式的组合物可以被包装在多个单一剂量单元中,各自含有固定量的上述一种或多种药剂。所述固体形式的组合物也可以以灵活的量包装在容器中。
在某些实施方式中,本公开提供了具有延长的储存期限的剂型,其包含本公开的蛋白质与甘露糖醇、单水柠檬酸、柠檬酸钠、二水磷酸氢二钠、二水磷酸二氢钠、氯化钠、聚山梨醇酯80、水和氢氧化钠的组合。
在某些实施方式中,制备了一种水性剂型,其在pH缓冲的溶液中包含本公开的蛋白质。本发明的缓冲液可以具有约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,或者可以具有约5.0至约5.2的pH。在上述pH之间的范围也打算作为本公开的一部分。例如,打算包括使用任何上述值的组合作为上限和/或下限的值范围。将pH控制在这个范围之内的缓冲剂的实例包括乙酸盐(例如乙酸钠)、琥珀酸盐(例如琥珀酸钠)、葡萄糖酸盐、组氨酸、柠檬酸盐和其他有机酸缓冲剂。
在某些实施方式中,所述剂型包括含有柠檬酸盐和磷酸盐的缓冲系统,以将pH维持在约4至约8的范围内。在某些实施方式中,所述pH范围可以是约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。在某些实施方式中,所述缓冲系统包括单水柠檬酸、柠檬酸钠、二水磷酸氢二钠和/或二水磷酸二氢钠。在某些实施方式中,所述缓冲系统包括约1.3mg/mL柠檬酸(例如1.305mg/mL)、约0.3mg/mL柠檬酸钠(例如0.305mg/mL)、约1.5mg/mL二水磷酸氢二钠(例如1.53mg/mL)、约0.9mg/mL二水磷酸二氢钠(例如0.86)和约6.2mg/mL氯化钠(例如6.165mg/mL)。在某些实施方式中,所述缓冲系统包括1-1.5mg/mL柠檬酸、0.25至0.5mg/mL柠檬酸钠、1.25至1.75mg/mL二水磷酸氢二钠、0.7至1.1mg/mL二水磷酸二氢钠和6.0至6.4mg/mL氯化钠。在某些实施方式中,所述剂型的pH用氢氧化钠调节。
充当等渗剂并且可以使抗体稳定的多元醇,也可以包含在所述剂型中。所述多元醇以可能根据剂型的所需等渗性而变的量添加到所述剂型。在某些实施方式中,所述水性剂型可以是等渗的。添加的多元醇的量也可能根据所述多元醇的分子量而变。例如,与二糖(例如海藻糖)相比,可以添加较低量的单糖(例如甘露糖醇)。在某些实施方式中,可以在所述剂型中用作等渗剂的多元醇是甘露糖醇。在某些实施方式中,甘露糖醇的浓度可以是约5至约20mg/mL。在某些实施方式中,甘露糖醇的浓度可以是约7.5至15mg/mL。在某些实施方式中,甘露糖醇的浓度可以是约10-14mg/mL。在某些实施方式中,甘露糖醇的浓度可以是约12mg/mL。在某些实施方式中,多元醇山梨糖醇可以包含在所述剂型中。
也可以向所述剂型添加去污剂或表面活性剂。示例性的去污剂包括非离子型去污剂例如聚山梨醇酯(例如聚山梨醇酯20、80等)或泊洛沙姆(例如泊洛沙姆188)。添加的去污剂的量使得它减少所述配制的抗体的聚集和/或将所述剂型中颗粒物的形成降至最低和/或减少吸附。在某些实施方式中,所述剂型可以包含作为表面活性剂的聚山梨醇酯。在某些实施方式中,所述剂型可以含有去污剂聚山梨醇酯80或吐温80。吐温80是用于描述聚氧乙烯(20)失水山梨糖醇单油酸酯的术语(参见Fiedler,Lexikon der Hifsstoffe,EditioCantor Verlag Aulendorf,4th ed.,1996)。在某些实施方式中,所述剂型可以含有约0.1mg/mL至约10mg/mL之间或约0.5mg/mL至约5mg/mL之间的聚山梨醇酯80。在某些实施方式中,可以在所述剂型中添加约0.1%聚山梨醇酯80。
在实施方式中,本公开的蛋白质产品被配制成液体剂型。所述液体剂型可以以10mg/mL的浓度存在于USP/Ph Eur I型50R小瓶中,用橡胶塞封闭并用铝制压合密封盖密封。所述橡胶塞可以由符合USP和Ph Eur的弹性体制成。在某些实施方式中,小瓶可以装填有61.2mL所述蛋白质产品溶液,以便允许可抽出体积为60mL。在某些实施方式中,可以将所述液体剂型用0.9%盐水溶液稀释。
在某些实施方式中,本公开的液体剂型可以被制备成浓度为10mg/mL的溶液,并与稳定剂水平的糖相组合。在某些实施方式中,所述液体剂型可以在水性载体中制备。在某些实施方式中,稳定剂可以以不超过可能产生对静脉内施用来说不理想或不适合的黏度的量添加。在某些实施方式中,所述糖可以是二糖例如蔗糖。在某些实施方式中,所述液体剂型也可以包括一种或多种缓冲剂、表面活性剂和防腐剂。
在某些实施方式中,所述液体剂型的pH可以通过添加可药用酸和/或碱来设定。在某些实施方式中,所述可药用酸可以是盐酸。在某些实施方式中,所述碱可以是氢氧化钠。
除了聚集之外,脱酰胺是肽和蛋白质在发酵、收获/细胞澄清、纯化、药物物质/药物制品储存期间和样品分析期间可能发生的常见产品变异。脱酰胺是从蛋白质失去NH3,形成琥珀酰亚胺中间体,其可能经历水解。所述琥珀酰亚胺中间体引起母体肽的质量减少17道尔顿。随后的水解导致质量增加18道尔顿。由于在水性条件下不稳定,所述琥珀酰亚胺中间体的分离是困难的。因此,脱酰胺通常可检测为质量增加1道尔顿。天冬酰胺的脱酰胺产生天冬氨酸或异天冬氨酸。影响脱酰胺速率的参数包括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。在肽链中与Asn相邻的氨基酸残基影响脱酰胺速率。蛋白质序列中Asn之后的Gly和Ser导致对脱酰胺更高的敏感性。
在某些实施方式中,本公开的液体剂型可以在防止所述蛋白质产品脱酰胺的pH和湿度条件下保存。
本文中感兴趣的水性载体是可药用(对于向人类施用来说安全且无毒)并且可用于制备液体剂型的水性载体。说明性载体包括无菌注射用水(SWFI)、抑菌性注射用水(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。
防腐剂可以任选地添加到本发明的剂型以减少细菌作用。防腐剂的添加可以例如便于生产多次使用(多剂)剂型。
在特定情况下,例如当患者在医院中在移植后通过IV途径接受所有药物时,静脉内(IV)剂型可能是优选的施用途径。在某些实施方式中,在施用前将所述液体剂型用0.9%氯化钠溶液稀释。在某些实施方式中,所述稀释的注射用药物产品是等渗的,并适合于通过静脉内输注施用。
在某些实施方式中,盐或缓冲剂组分可以以10mM-200mM的量添加。所述盐和/或缓冲剂是可药用的,并源自于各种不同的已知酸(无机和有机酸)和“成碱”金属或胺。在某些实施方式中,所述缓冲剂可以是磷酸盐缓冲剂。在某些实施方式中,所述缓冲剂可以是甘氨酸盐、碳酸盐、柠檬酸盐缓冲剂,在所述情况下,钠、钾或铵离子可以充当平衡离子。
防腐剂可以任选地添加到本发明的剂型以减少细菌作用。防腐剂的添加可以例如便于生产多次使用(多剂)剂型。
本文中感兴趣的水性载体是可药用(对于向人类施用来说安全且无毒)并且可用于制备液体剂型的水性载体。说明性载体包括无菌注射用水(SWFI)、抑菌性注射用水(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以冷冻干燥剂型的形式存在,其包括所述蛋白质和冻干保护剂。所述冻干保护剂可以是糖例如二糖。在某些实施方式中,所述冻干保护剂可以是蔗糖或麦芽糖。所述冷冻干燥剂型也可以包括一种或多种缓冲剂、表面活性剂、增量剂和/或防腐剂。
可用于使所述冷冻干燥的药物制品稳定的蔗糖或麦芽糖的量可以是蛋白质与蔗糖或麦芽糖至少1:2的重量比。在某些实施方式中,所述蛋白质与蔗糖或麦芽糖的重量比可以为1:2至1:5。
在某些实施方式中,在冷冻干燥之前,所述剂型的pH可以通过添加可药用酸和/或碱来设定。在某些实施方式中,所述可药用酸可以是盐酸。在某些实施方式中,所述可药用碱可以是氢氧化钠。
在冷冻干燥之前,含有本公开的蛋白质的溶液的pH可以被调整到6至8之间。在某些实施方式中,用于所述冷冻干燥的药物制品的pH范围可以是7至8。
在某些实施方式中,盐或缓冲剂组分可以以10mM-200mM的量添加。所述盐和/或缓冲剂是可药用的,并源自于各种不同的已知酸(无机和有机酸)和“成碱”金属或胺。在某些实施方式中,所述缓冲剂可以是磷酸盐缓冲剂。在某些实施方式中,所述缓冲剂可以是甘氨酸盐、碳酸盐、柠檬酸盐缓冲剂,在所述情况下,钠、钾或铵离子可以充当平衡离子。
在某些实施方式中,可以添加“增量剂”。“增量剂”是为冻干混合物增添质量并对冻干饼的物理结构有贡献(例如便于生产维持开放孔隙结构的基本上均匀的冻干饼)的化合物。说明性的增量剂包括甘露糖醇、甘氨酸、聚乙二醇和山梨糖醇。本发明的冷冻干燥剂型可以含有这些增量剂。
防腐剂可以任选地添加到本发明的剂型以减少细菌作用。防腐剂的添加可以例如便于生产多次使用(多剂)剂型。
在某些实施方式中,所述冷冻干燥的药物制品可以用水性载体构造。本文中感兴趣的水性载体是可药用(例如对于向人类施用来说安全且无毒)并且可用于在冷冻干燥后制备液体剂型的水性载体。说明性稀释剂包括无菌注射用水(SWFI)、抑菌性注射用水(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。
在某些实施方式中,本公开的冷冻干燥的药物制品用USP级无菌注射用水(SWFI)或USP级0.9%氯化钠注射液重构。在重构期间,将所述冷冻干燥的粉剂溶解在溶液中。
在某些实施方式中,本公开的冷冻干燥的蛋白质产品构造到约4.5mL注射用水,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以改变,以便获得对特定患者、组合物和施用方式来说有效实现所需治疗响应并且对所述患者无毒的活性成分的量。
具体剂量可以是对每位患者来说均一的剂量,例如50-5000mg蛋白质。或者,患者的剂量可以根据所述患者的大致的体重或表面积定制。确定适合剂量的其他因素可以包括待治疗或预防的疾病或病症、疾病的严重性、施用途径和患者的年龄、性别和医疗状况。确定用于治疗的适合剂量所必需的计算的进一步精化由本领域技术人员按常规进行,特别是根据本文中公开的剂量信息和测定法。所述剂量也可以通过使用用于确定使用剂量的已知测定法并联合适合的剂量响应数据来确定。当监测到疾病进展时,个体患者的剂量可以进行调整。可以测量患者中可靶向构建体或复合物的血液水平,以观察是否需要调整剂量来达到或维持有效浓度。可以使用药物基因组学来确定哪些可靶向构建体和/或复合物及其剂量最可能对给定个体有效(Schmitz等,Clinica Chimica Acta 308:43-53,2001;Steimer等,Clinica Chimica Acta 308:33-41,2001)。
一般来说,基于体重的剂量是每kg体重约0.01μg至约100mg,例如约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。
药剂可以每日、每周、每月或每年施用一次或多次,或甚至每2至20年施用一次,本领域普通技术人员可以根据体液或组织中可靶向构建物或复合物的测量到的停留时间和浓度,容易地估算施用的重复率。本发明的施用可以是静脉内、动脉内、腹膜内、肌肉内、皮下、胸膜内、鞘内、腔内、通过导管灌注或通过直接病灶内注射。这可以施用每日一次或多次、每周一次或多次、每月一次或多次或每年一次或多次。
上面的描述描述了本发明的多个方面和实施方式。本申请具体来说设想了所述方面和实施方式的所有组合和排列。
实施例
现在正一般性描述的本发明,通过参考下面的实施例将更容易被理解,包括所述实施例仅仅是出于说明本发明的某些方面和实施方式的目的,并且不打算限制本发明。
实施例1–NKG2D结合结构域结合到NKG2D
NKG2D结合结构域结合到纯化的重组NKG2D
将人类、小鼠或食蟹猴NKG2D胞外结构域(ectodomains)的核酸序列与编码人类IgG1 Fc结构域的核酸序列融合,并引入到哺乳动物细胞中进行表达。在纯化后,将NKG2D-Fc融合蛋白吸附到微孔板的孔。在用牛血清白蛋白阻断所述孔以防止非特异性结合后,对NKG2D结合结构域进行滴定并将其添加到预先吸附有NKG2D-Fc融合蛋白的孔。第一抗体结合使用偶联到辣根过氧化物酶并特异性识别人类κ轻链以避免Fc交叉反应性的第二抗体来检测。向所述孔添加辣根过氧化物酶的底物3,3',5,5'-四甲基联苯胺(TMB)以可视化结合信号,所述信号在450nm处测量并在540nm处校正。向每个孔添加NKG2D结合结构域克隆、同种型对照或阳性对照(包含选自SEQ ID NO:101-104的重链和轻链可变结构域,或可以在eBioscience获得的抗小鼠NKG2D抗体克隆MI-6和CX-5)。
所述同种型对照显示出与重组NKG2D-Fc蛋白极小的结合,而所述阳性对照最强结合到所述重组抗原。由所有克隆产生的NKG2D结合结构域都表现出跨人类、小鼠和食蟹猴重组NKG2D-Fc蛋白的结合,尽管在不同克隆之间具有不同的亲和力。总体来说,每种抗NKG2D克隆以相近的亲和力结合到人类(图3)和食蟹猴(图4)重组NKG2D-Fc,但结合到小鼠(图5)重组NKG2D-Fc的亲和力较低。
NKG2D结合结构域结合到表达NKG2D的细胞
对EL4小鼠淋巴瘤细胞系进行工程化改造,以表达人类或小鼠NKG2D-CD3ζ信号传导结构域嵌合抗原受体。将NKG2D结合克隆、同种型对照或阳性对照以100nM的浓度用于染色在所述EL4细胞上表达的细胞外NKG2D。抗体结合使用荧光团偶联的抗人类IgG第二抗体来检测。细胞通过流式细胞术进行分析,并使用表达NKG2D的细胞与母体EL4细胞的平均荧光强度(MFI)的比较来计算高于背景的倍数(FOB)。
由所有克隆产生的NKG2D结合结构域都结合到表达人类和小鼠NKG2D的EL4细胞。阳性对照抗体(包含选自SEQ ID NO:101-104的重链和轻链可变结构域,或可以在eBioscience获得的抗小鼠NKG2D抗体克隆MI-6和CX-5)给出最好的FOB结合信号。在表达人类NKG2D(图6)和小鼠(图7)NKG2D的细胞之间,每种克隆的NKG2D结合亲和力相近。
实施例2–NKG2D结合结构域阻断天然配体结合到NKG2D
与ULBP-6的竞争
将重组人类NKG2D-Fc蛋白吸附到微孔板的孔,并将所述孔用牛血清白蛋白阻断以降低非特异性结合。向所述孔添加饱和浓度的ULBP-6-His-生物素,然后添加NKG2D结合结构域克隆。在温育2小时后,将孔清洗,并通过链亲合素偶联的辣根过氧化物酶和TMB底物检测仍结合于NKG2D-Fc包被的孔的ULBP-6-His-生物素。吸收值在450nM处测量并在540nM处校正。在减去背景后,从被阻断与孔中的NKG2D-Fc蛋白结合的ULBP-6-His-生物素的百分率,来计算NKG2D结合结构域与NKG2D-Fc蛋白的特异性结合。阳性对照抗体(包含选自SEQID NO:101-104的重链和轻链可变结构域)和各种不同的NKG2D结合结构域阻断ULBP-6结合到NKG2D,而同种型对照显示出很小的与ULBP-6的竞争(图8)。
ULBP-6序列由SEQ ID NO:108表示
MAAAAIPALLLCLPLLFLLFGWSRARRDDPHSLCYDITVIPKFRPGPRWCAVQGQVDEKTFLHYDCGNKTVTPVSPLGKKLNVTMAWKAQNPVLREVVDILTEQLLDIQLENYTPKEPLTLQARMSCEQKAEGHSSGSWQFSIDGQTFLLFDSEKRMWTTVHPGARKMKEKWENDKDVAMSFHYISMGDCIGWLEDFLMGMDSTLEPSAGAPLAMSSGTTQLRATATTLILCCLLIILPCFILPGI(SEQ ID NO:108)
与MICA的竞争
将重组人类MICA-Fc蛋白吸附到微孔板的孔,并将所述孔用牛血清白蛋白阻断以降低非特异性结合。向所述孔添加NKG2D-Fc-生物素,然后添加NKG2D结合结构域。在温育和清洗后,使用链亲合素-HRP和TMB底物检测仍结合于MICA-Fc包被的孔的NKG2D-Fc-生物素。吸收值在450nM处测量并在540nM处校正。在减去背景后,从被阻断与MICA-Fc包被的孔结合的NKG2D-Fc-生物素的百分率,来计算NKG2D结合结构域与NKG2D-Fc蛋白的特异性结合。阳性对照抗体(包含选自SEQ ID NO:101-104的重链和轻链可变结构域)和各种不同的NKG2D结合结构域阻断MICA结合到NKG2D,而同种型对照显示出很小的与MICA的竞争(图9)。
与Rae-1δ的竞争
将重组小鼠Rae-1δ-Fc(购自R&D Systems)吸附到微孔板的孔,并将所述孔用牛血清白蛋白阻断以降低非特异性结合。向所述孔添加小鼠NKG2D-Fc-生物素,然后添加NKG2D结合结构域。在温育和清洗后,使用链亲合素-HRP和TMB底物检测仍结合于Rae-1δ-Fc包被的孔的NKG2D-Fc-生物素。吸收值在450nM处测量并在540nM处校正。在减去背景后,从被阻断与Rae-1δ-Fc包被的孔结合的NKG2D-Fc-生物素的百分率,来计算NKG2D结合结构域与NKG2D-Fc蛋白的特异性结合。阳性对照(包含选自SEQ ID NO:101-104的重链和轻链可变结构域,或可以在eBioscience获得的抗小鼠NKG2D抗体克隆MI-6和CX-5)和各种不同的NKG2D结合结构域克隆阻断Rae-1δ结合到小鼠NKG2D,而同种型对照抗体显示出很小的与Rae-1δ的竞争(图10)。
实施例3–NKG2D结合结构域克隆激活NKG2D
将人类和小鼠NKG2D的核酸序列融合到编码CD3ζ信号传导结构域的核酸序列以获得嵌合抗原受体(CAR)构建体。然后将所述NKG2D-CAR构建体使用Gibson组装克隆到逆转录病毒载体中,并转染到expi293细胞中用于逆转录病毒生产。将EL4细胞用含有NKG2D-CAR的病毒与8μg/mL聚凝胺一起感染。感染后24小时,通过流式细胞术分析所述EL4细胞中NKG2D-CAR的表达水平,并选择在细胞表面上表达高水平NKG2D-CAR的克隆。
为了确定NKG2D结合结构域是否激活NKG2D,将它们吸附到微孔板的孔,并将NKG2D-CAR EL4细胞在布雷菲德菌素-A和莫能菌素存在下在抗体片段包被的孔上培养4小时。通过流式细胞术测定细胞内TNF-α生产这种NKG2D激活的指示。将TNF-α阳性细胞归一化到用阳性对照处理的细胞。所有NKG2D结合结构域激活人类NKG2D(图11)和小鼠NKG2D(图12)两者。
实施例4–NKG2D结合结构域激活NK细胞
原代人类NK细胞
使用密度梯度离心从人类外周血血沉棕黄层分离外周血单核细胞(PBMC)。使用磁珠负选择从PBMC分离NK细胞(CD3-CD56+),分离到的NK细胞的纯度通常>95%。然后将分离的NK细胞在含有100ng/mL IL-2的培养基中培养24-48小时,然后将它们转移到吸附有NKG2D结合结构域的微孔板孔,并在含有荧光团偶联的抗CD107a抗体、布雷菲德菌素-A和莫能菌素的培养基中培养。在培养后,使用荧光团偶联的针对CD3、CD56和IFN-γ的抗体通过流式细胞术测定NK细胞。在CD3-CD56+细胞中分析CD107a和IFN-γ染色,以评估NK细胞激活。CD107a/IFN-γ双阳性细胞的增加指示了通过接合两个激活受体而不是一个受体的更好的NK细胞激活。NKG2D结合结构域和阳性对照(例如由SEQ ID NO:101或SEQ ID NO:103表示的重链可变结构域,和由SEQ ID NO:102或SEQ ID NO:104表示的轻链可变结构域)与同种型对照相比显示出变成CD107a+和IFN-γ+的NK细胞的百分率更高(图13和图14代表了来自于两个独立实验的数据,其各自使用不同供体的PBMC用于NK细胞制备)。
原代小鼠NK细胞
从C57Bl/6小鼠获得脾脏并将其通过70μm细胞筛压碎,以获得单细胞悬液。将细胞离心沉淀并重悬浮在ACK裂解缓冲液(购自Thermo Fisher Scientific#A1049201;155mM氯化铵,10mM碳酸氢钾,0.01mM EDTA)中,以除去红细胞。将剩余的细胞用100ng/mL hIL-2培养72小时,然后收获并准备用于NK细胞分离。然后用磁珠使用反向贫化技术从脾细胞分离NK细胞(CD3-NK1.1+),通常纯度>90%。将纯化的NK细胞在含有100ng/mL mIL-15的培养基中培养48小时,然后将它们转移到吸附有NKG2D结合结构域的微孔板孔,并在含有荧光团偶联的抗CD107a抗体、布雷菲德菌素-A和莫能菌素的培养基中培养。在NKG2D结合结构域包被的孔中培养后,使用荧光团偶联的针对CD3、NK1.1和IFN-γ的抗体通过流式细胞术测定NK细胞。在CD3-NK1.1+细胞中分析CD107a和IFN-γ染色,以评估NK细胞激活。CD107a/IFN-γ双阳性细胞的增加指示了通过接合两个激活受体而不是一个受体的更好的NK细胞激活。NKG2D结合结构域和阳性对照(选自可以在eBioscience获得的抗小鼠NKG2D抗体克隆MI-6和CX-5)与同种型对照相比显示出变成CD107a+和IFN-γ+的NK细胞的百分率更高(图15和图16代表了来自于两个独立实验的数据,其各自使用不同小鼠用于NK细胞制备)。
实施例5–NKG2D结合结构域能够引起对靶肿瘤细胞的细胞毒性
人类和小鼠原代NK细胞激活测定法证实了在与NKG2D结合结构域温育后NK细胞上的细胞毒性标志物增加。为了研究这是否转变成肿瘤细胞裂解的增加,利用了基于细胞的测定法,其中将每个NKG2D结合结构域开发成单特异性抗体。将Fc区用作一个靶向臂,而Fab片段区(NKG2D结合结构域)充当另一个靶向臂,以激活NK细胞。将人类起源并表达高水平Fc受体的THP-1细胞用作肿瘤靶,并使用Perkin Elmer DELFIA细胞毒性试剂盒。将THP-1细胞用BATDA试剂标记,并以105/mL重悬浮在培养基中。然后将标记的THP-1细胞与NKG2D抗体和分离的小鼠NK细胞在微孔板的孔中合并,在37℃下温育3小时。在温育后,取出20μL培养上清液,与200μL铕溶液混合,并在暗处振摇温育15分钟。通过装备有时间分辨荧光模块(激发337nm,发射620nm)的PheraStar读板器随时间测量荧光,并按照试剂盒说明书计算特异性裂解。
阳性对照偶联到Fc的ULBP-6、即NKG2D的天然配体,显示出THP-1靶细胞被小鼠NK细胞的特异性裂解的增加。NKG2D抗体也增加了THP-1靶细胞的特异性裂解,而同种型对照抗体显示出特异性裂解的减少。虚线指示在不添加抗体的情况下THP-1细胞被小鼠NK细胞的特异性裂解(图17)。
实施例6–NKG2D抗体显示出高的热稳定性
使用差示扫描荧光测定法测定NKG2D结合结构域的熔解温度。外推的表观熔解温度相对于典型的IgG1抗体来说更高(图18)。
实施例7–人类NK细胞被交联的NKG2D和CD16的协同激活原代人类NK细胞激活测定法
使用密度梯度离心从人类外周血血沉棕黄层分离外周血单核细胞(PBMC)。使用负磁珠(StemCell#17955)从PBMC纯化NK细胞。通过流式细胞术确定NK细胞为>90%CD3-CD56+。然后将分离的NK细胞在含有100ng/mL hIL-2(Peprotech#200-02)的培养基中扩增48小时,然后用于激活测定法中。将抗体以2μg/mL(抗CD16抗体,Biolegend#302013)和5μg/mL(抗NKG2D抗体,R&D#MAB139)的浓度,在100μL无菌PBS中在96孔平底板上在4℃包被过夜,然后充分清洗所述孔以除去过量抗体。为了评估脱颗粒,将IL-2激活的NK细胞以5×105个细胞/mL重悬浮在增补有100ng/mL hIL2和1μg/mL APC偶联的抗CD107a mAb(Biolegend#328619)的培养基中。然后将1×105个细胞/孔添加到抗体包被的板上。分别以1:1000和1:270的最终稀释度添加蛋白质转运抑制剂布雷菲德菌素A(BFA,Biolegend#420601)和莫能菌素(Biolegend#420701)。将铺板的孔在5%CO2中在37℃下温育4小时。对于IFN-γ的细胞内染色来说,将NK细胞用抗CD3抗体(Biolegend#300452)和抗CD56 mAb(Biolegend#318328)标记,然后固定,通透化,并用抗IFN-γmAb(Biolegend#506507)标记。在对活的CD56+CD3-细胞进行门选后,通过流式细胞术分析NK细胞的CD107a和IFN-γ表达。
为了调查受体组合的相对效能,通过板结合刺激进行了NKG2D或CD16的交联和两种受体的共同交联。如图19(图19A-19C)中所示,CD16和NKG2D的组合刺激产生大大提高的CD107a水平(脱颗粒)(图19A)和/或IFN-γ生产(图19B)。虚线表示每种受体的单独刺激的累加效应。
在用抗CD16抗体、抗NKG2D抗体或两种单克隆抗体的组合进行4小时的板结合刺激后,分析IL-2激活的NK细胞的CD107a水平和细胞内IFN-γ生产。图指示了平均值(n=2)±Sd。图19A显示了CD107a的水平;图19B显示了IFNγ的水平;图19C显示了CD107a和IFNγ的水平。图19A-19C中示出的数据代表了使用5位不同健康供体的5个独立实验。
实施例8–TriNKET或mAb与细胞表达的人类癌抗原的结合的评估
使用表达EGFR的人类癌细胞系(例如H2172、H747、H1975、N87、HCT116和A549细胞系)来评估源自于不同EGFR靶向性单克隆抗体(mAb)的TriNKET的肿瘤抗原结合。测试的TriNKET包括A49-F3’-TriNKET-EGFR-帕尼单抗(来自于克隆ADI-27749的NKG2D结合结构域和源自于EGFR单克隆抗体帕尼单抗的靶向EGFR的scFv)、A49-F3’-TriNKET-EGFR-耐昔妥珠单抗(来自于克隆ADI-27749的NKG2D结合结构域和源自于单克隆抗体耐昔妥珠单抗的靶向EGFR的scFv)和A49-F3’-TriNKET-EGFR-AdiCLC3(来自于克隆ADI-27749的NKG2D结合结构域和源自于单克隆抗体AdiCLC2的靶向EGFR的scFv)。
将TriNKET或mAb稀释并与相应的细胞系温育。TriNKET或mAb的结合使用荧光团偶联的抗人类IgG第二抗体来检测。细胞通过流式细胞术来分析,并将TriNKET和mAb对表达EGFR的细胞的结合荧光强度中位数(MFI)针对最大信号进行归一化,以获得TriNKET和mAb的最大信号值的百分率。
原代人类NK细胞细胞毒性测定法
使用密度梯度离心从人类外周血血沉棕黄层分离PBMC。将分离的PBMC洗涤并准备用于NK细胞分离。使用磁珠通过负选择技术分离NK细胞。获得的分离的NK细胞的纯度通常高于90%CD3-CD56+。将分离的NK细胞在不含细胞因子的情况下温育过夜,并在第二天用于细胞毒性测定法中。
将被转导以表达CD16-F158V的KHYG-1细胞用于研究NKG2D和CD16双重刺激的贡献。KHYG-1CD16-F158V细胞被维持在含有10ng/mL IL-2的10%HI-FBS-RPMI-1640中。在杀伤测定法中用作效应细胞前一天,从培养物收获细胞并洗掉IL-2。将KHYG-1CD16-F158V细胞重悬浮在10%HI-FBS-RPMI-1640中,并在没有细胞因子的情况下温育过夜。
DELFIA细胞毒性测定法
从培养物收集表达感兴趣的靶的人类癌细胞系,用HBS清洗,并以106个细胞/mL的密度重悬浮在生长培养基中,以备使用BATDA试剂(Perkin Elmer,AD0116)进行标记。遵照制造商的说明书进行靶细胞的标记。在标记后,将细胞用HBS清洗三次并以0.5×105个细胞/mL的密度重悬浮在培养基中。为了制备背景孔,将标记的细胞的等分试样放在一边,然后将细胞从培养基中离心出来。向孔一式三份小心地添加100μL培养基,以避免扰动沉积的细胞。向96孔板的每个孔添加100μL BATDA标记的细胞。保留用于测量从靶细胞的自发释放的孔,并准备用于通过添加1%Triton-X来裂解靶细胞的孔。将针对感兴趣的肿瘤靶的单克隆抗体或TriNKET在培养基中稀释,并向每个孔添加50μL稀释的mAb或TriNKET。从培养基收获静息NK细胞,清洗,并根据所需的效应细胞与靶细胞比例以1.0×105-2.0×106个细胞/mL的密度重悬浮在培养基中。向所述板的每个孔添加50μL NK细胞,以提供总共200μL培养体积。在测定法显色之前,将所述板在37℃和5%CO2下温育2-4小时。
在培养2-4小时后,将板从温箱取出,并通过以200xg离心5分钟将细胞沉积。将20μL培养上清液转移到由制造商提供的干净的微孔板,并向每个孔添加200μL室温铕溶液。将板避光并在摇板器上以250rpm温育15分钟。使用i3X仪器(MolecularDevices)读板,并计算特异性裂解的%(特异性裂解的%=((实验释放–自发释放)/(最大释放–自发释放))x 100)。
细胞抗原结合
图35示出了TriNKET和mAb与在NCI-H2172人类肺癌细胞上表达的EGFR的结合。图36示出了TriNKET和mAb与在HCC827人类肺癌细胞上表达的EGFR的结合。图37示出了TriNKET和mAb与在NCI-H747人类结肠癌细胞上表达的EGFR的结合。细胞用图35-37的图中指示的浓度的TriNKET或单克隆抗体处理。
原代人类NK细胞毒性测定法
图38-46示出了静息人类NK细胞或KHYG1-CD16V细胞针对各种不同细胞类型的TriNKET介导的细胞毒性。与它们的亲代mAb相比,TriNKET更有效地杀伤靶细胞。
细胞用在每张图中指示的浓度的TriNKET或单克隆抗体处理。在每个实验中,效应细胞与靶细胞的比例为10:1。图38示出了NCI-H2172细胞(肺,EGFR L858R T790M)被静息人类NK细胞的TriNKET介导的(A49-F3’-TriNKET-EGFR-neciLH)和单克隆抗体介导的(耐昔妥珠单抗)杀伤(DELFIA测定法)。
图39示出了NCI-H2172细胞(肺,EGFR L858R T790M)被静息人类NK细胞的TriNKET介导的(A49-F3’-TriNKET-EGFR-panLH)和单克隆抗体介导的(帕尼单抗)杀伤(DELFIA测定法)。图40示出了NCI-H747细胞(结肠,KRAS G13D)被静息人类NK细胞的TriNKET介导的(A49-F3’-TriNKET-EGFR-帕尼单抗LH(panLH))和单克隆抗体介导的(帕尼单抗)杀伤(DELFIA测定法)。图41示出了NCI-H747细胞(结肠,KRAS G13D)被静息人类NK细胞的TriNKET介导的(A49-F3’-TriNKET-EGFR-耐昔妥珠单抗LH(neciLH))和单克隆抗体介导的(耐昔妥珠单抗)杀伤(DELFIA测定法)。图42示出了NCI-H2172细胞(肺,EGFR L858R T790M)被KHYG1-CD16V细胞的TriNKET介导的(A49-F3’-TriNKET-EGFR-耐昔妥珠单抗LH(neciLH))和单克隆抗体介导的(耐昔妥珠单抗)杀伤(DELFIA测定法)。图43示出了NCI-H1975细胞(肺,EGFR L858R)被KHYG1-CD16V细胞的TriNKET介导的(A49-F3’-TriNKET-EGFR-耐昔妥珠单抗LH(neciLH))和单克隆抗体介导的(耐昔妥珠单抗)杀伤(DELFIA测定法)。图44示出了NCI-N87细胞(胃)被KHYG1-CD16V细胞的TriNKET介导的(A49-F3’-TriNKET-EGFR-耐昔妥珠单抗LH(neciLH))和单克隆抗体介导的(耐昔妥珠单抗)杀伤(DELFIA测定法)。图45示出了HCT116细胞(结肠,KRAS G13D)被KHYG1-CD16V细胞的TriNKET介导的(A49-F3’-TriNKET-EGFR-耐昔妥珠单抗LH(neciLH))和单克隆抗体介导的(耐昔妥珠单抗)杀伤(DELFIA测定法)。图46示出了A549细胞(肺,KRAS G12S)被KHYG1-CD16V细胞的TriNKET介导的(A49-F3’-TriNKET-EGFR-耐昔妥珠单抗LH(neciLH))和单克隆抗体介导的(耐昔妥珠单抗)杀伤(DELFIA测定法)。
在所有实验中,TriNKET与它们的亲代mAb相比更有效地杀伤靶细胞。这些结果证实了本公开的TriNKET与靶向相同抗原的mAb相比在促进靶向细胞死亡中的提高的效能。
通过参考并入
本文中提到的每个专利文献和科学论文的整个公开内容为所有目的通过参考并入本文。
等同性
本发明可以以其他特定形式体现而不背离其精神或本质特征。因此,前述实施方式应该在所有情况下被认为是说明性的而不是限制本文描述的发明。因此,本发明的范围由随附的权利要求书而不是上面的描述指明,并且打算将进入权利要求书的意义和等同性范围之内的所有变化涵盖在其中。
序列表
<110> 蜻蜓疗法股份有限公司
<120> 结合NKG2D、CD16和EGFR、CCR4或PD-L1的蛋白质
<130> AJ4309PT2003-DIV
<150> 62/555,114
<151> 2017-09-07
<150> 62/552,152
<151> 2017-08-30
<150> 62/546,297
<151> 2017-08-16
<150> 62/546,300
<151> 2017-08-16
<160> 277
<170> PatentIn version 3.5
<210> 1
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 1
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> 2
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 2
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 Ile
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 3
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 3
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> 4
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 4
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
Ile Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 5
<211> 117
<212> PRT
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<220>
<223> 人工序列的描述:合成多肽
<400> 5
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> 6
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 6
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 Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 7
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 7
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> 8
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 8
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 Ser Asn Ser Tyr Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 9
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 9
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> 10
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 10
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> 11
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 11
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> 12
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 12
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> 13
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 13
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> 14
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 14
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> 15
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 15
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> 16
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 16
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> 17
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 17
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> 18
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 18
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> 19
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 19
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> 20
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 20
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> 21
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 21
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> 22
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 22
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> 23
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 23
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> 24
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 24
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> 25
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 25
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> 26
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 26
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> 27
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 27
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> 28
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 28
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> 29
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 29
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> 30
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 30
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> 31
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 31
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> 32
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 32
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> 33
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 33
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> 34
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 34
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> 35
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 35
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> 36
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 36
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> 37
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 37
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> 38
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 38
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> 39
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 39
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> 40
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 40
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> 41
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 41
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> 42
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 42
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> 43
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 43
Gly Thr Phe Ser Ser Tyr Ala Ile Ser
1 5
<210> 44
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 44
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 45
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 45
Ala Arg Gly Asp Ser Ser Ile Arg His Ala Tyr Tyr Tyr Tyr Gly Met
1 5 10 15
Asp Val
<210> 46
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 46
Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 47
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 47
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 48
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 48
Gln Gln Tyr Tyr Ser Thr Pro Ile Thr
1 5
<210> 49
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 49
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> 50
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 50
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> 51
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 51
Gly Ser Ile Ser Ser Ser Ser Tyr Tyr Trp Gly
1 5 10
<210> 52
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 52
Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 53
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 53
Ala Arg Gly Ser Asp Arg Phe His Pro Tyr Phe Asp Tyr
1 5 10
<210> 54
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 54
Arg Ala Ser Gln Ser Val Ser Arg Tyr Leu Ala
1 5 10
<210> 55
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 55
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 56
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 56
Gln Gln Phe Asp Thr Trp Pro Pro Thr
1 5
<210> 57
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 57
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> 58
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 58
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> 59
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 59
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> 60
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 60
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> 61
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 61
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> 62
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 62
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> 63
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 63
Tyr Thr Phe Thr Ser Tyr Tyr Met His
1 5
<210> 64
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 64
Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 65
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 65
Ala Arg Gly Ala Pro Asn Tyr Gly Asp Thr Thr His Asp Tyr Tyr Tyr
1 5 10 15
Met Asp Val
<210> 66
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 66
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 67
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 67
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 68
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 68
Gln Gln Tyr Asp Asp Trp Pro Phe Thr
1 5
<210> 69
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 69
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 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> 70
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 70
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> 71
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 71
Tyr Thr Phe Thr Gly Tyr Tyr Met His
1 5
<210> 72
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 72
Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 73
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 73
Ala Arg Asp Thr Gly Glu Tyr Tyr Asp Thr Asp Asp His Gly Met Asp
1 5 10 15
Val
<210> 74
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 74
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 75
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 75
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 76
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 76
Gln Gln Asp Asp Tyr Trp Pro Pro Thr
1 5
<210> 77
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 77
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> 78
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 78
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> 79
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 79
Phe Thr Phe Ser Ser Tyr Ala Met Ser
1 5
<210> 80
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 80
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 81
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 81
Ala Lys Asp Gly Gly Tyr Tyr Asp Ser Gly Ala Gly Asp Tyr
1 5 10
<210> 82
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 82
Arg Ala Ser Gln Gly Ile Asp Ser Trp Leu Ala
1 5 10
<210> 83
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 83
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 84
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 84
Gln Gln Gly Val Ser Tyr Pro Arg Thr
1 5
<210> 85
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 85
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> 86
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 86
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> 87
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 87
Phe Thr Phe Ser Ser Tyr Ser Met Asn
1 5
<210> 88
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 88
Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 89
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 89
Ala Arg Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 90
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 90
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 91
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 91
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 92
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 92
Gln Gln Gly Val Ser Phe Pro Arg Thr
1 5
<210> 93
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 93
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> 94
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 94
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> 95
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 95
Tyr Thr Phe Thr Ser Tyr Tyr Met His
1 5
<210> 96
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 96
Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 97
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 97
Ala Arg Glu Gly Ala Gly Phe Ala Tyr Gly Met Asp Tyr Tyr Tyr Met
1 5 10 15
Asp Val
<210> 98
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 98
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 99
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 99
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 100
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 100
Gln Gln Ser Asp Asn Trp Pro Phe Thr
1 5
<210> 101
<211> 121
<212> PRT
<213> 智人
<400> 101
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> 102
<211> 110
<212> PRT
<213> 智人
<400> 102
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> 103
<211> 115
<212> PRT
<213> 智人
<400> 103
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> 104
<211> 108
<212> PRT
<213> 智人
<400> 104
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> 105
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 105
Gly Ser Phe Ser Gly Tyr Tyr Trp Ser
1 5
<210> 106
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 106
Glu Ile Asp His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 107
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 107
Ala Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro
1 5 10
<210> 108
<211> 246
<212> PRT
<213> 智人
<400> 108
Met Ala Ala Ala Ala Ile Pro Ala Leu Leu Leu Cys Leu Pro Leu Leu
1 5 10 15
Phe Leu Leu Phe Gly Trp Ser Arg Ala Arg Arg Asp Asp Pro His Ser
20 25 30
Leu Cys Tyr Asp Ile Thr Val Ile Pro Lys Phe Arg Pro Gly Pro Arg
35 40 45
Trp Cys Ala Val Gln Gly Gln Val Asp Glu Lys Thr Phe Leu His Tyr
50 55 60
Asp Cys Gly Asn Lys Thr Val Thr Pro Val Ser Pro Leu Gly Lys Lys
65 70 75 80
Leu Asn Val Thr Met Ala Trp Lys Ala Gln Asn Pro Val Leu Arg Glu
85 90 95
Val Val Asp Ile Leu Thr Glu Gln Leu Leu Asp Ile Gln Leu Glu Asn
100 105 110
Tyr Thr Pro Lys Glu Pro Leu Thr Leu Gln Ala Arg Met Ser Cys Glu
115 120 125
Gln Lys Ala Glu Gly His Ser Ser Gly Ser Trp Gln Phe Ser Ile Asp
130 135 140
Gly Gln Thr Phe Leu Leu Phe Asp Ser Glu Lys Arg Met Trp Thr Thr
145 150 155 160
Val His Pro Gly Ala Arg Lys Met Lys Glu Lys Trp Glu Asn Asp Lys
165 170 175
Asp Val Ala Met Ser Phe His Tyr Ile Ser Met Gly Asp Cys Ile Gly
180 185 190
Trp Leu Glu Asp Phe Leu Met Gly Met Asp Ser Thr Leu Glu Pro Ser
195 200 205
Ala Gly Ala Pro Leu Ala Met Ser Ser Gly Thr Thr Gln Leu Arg Ala
210 215 220
Thr Ala Thr Thr Leu Ile Leu Cys Cys Leu Leu Ile Ile Leu Pro Cys
225 230 235 240
Phe Ile Leu Pro Gly Ile
245
<210> 109
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 109
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
100 105
<210> 110
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 110
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
1 5 10
<210> 111
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 111
Tyr Ala Ser Glu Ser Ile Ser
1 5
<210> 112
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 112
Gln Gln Asn Asn Asn Trp Pro Thr Thr
1 5
<210> 113
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 113
Gln Val 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 Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Ala
115 120
<210> 114
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 114
Ser Gly Asp Tyr Tyr Trp Thr
1 5
<210> 115
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 115
His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 116
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 116
Asp Arg Val Thr Gly Ala Phe Asp Ile
1 5
<210> 117
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 117
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 Gln 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 Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 118
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 118
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 119
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 119
Asp Ala Ser Asn Leu Glu Thr
1 5
<210> 120
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 120
Gln His Phe Asp His Leu Pro Leu Ala
1 5
<210> 121
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 121
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120
<210> 122
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 122
Ser Gly Asp Tyr Tyr Trp Ser
1 5
<210> 123
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 123
Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 124
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 124
Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr
1 5 10
<210> 125
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 125
Glu Ile Val Met 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 His Gln Tyr Gly Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys Arg
100 105
<210> 126
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 126
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 127
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 127
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 128
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 128
His Gln Tyr Gly Ser Thr Pro Leu Thr
1 5
<210> 129
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 129
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly 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 Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 130
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 130
Gly Phe Thr Phe Ser Thr Tyr
1 5
<210> 131
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 131
Trp Asp Asp Gly Ser Tyr
1 5
<210> 132
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 132
Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe Asp Tyr
1 5 10 15
<210> 133
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 133
Ala Ile Gln Leu 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 Ile Ser Ser Ala
20 25 30
Leu Val 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 Glu 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 Phe Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 134
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 134
Gly Thr Phe Ser Ser Tyr Ala Ile Ser
1 5
<210> 135
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 135
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 136
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 136
Ala Arg Arg Gly Arg Lys Ala Ser Gly Ser Phe Tyr Tyr Tyr Tyr Gly
1 5 10 15
Met Asp Val
<210> 137
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 137
Glu Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 138
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 138
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 139
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 139
Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr
1 5
<210> 140
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 140
Gln Asp Ile Ser Ser Ala Leu Val
1 5
<210> 141
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 141
Asp Ala Ser Ser Leu Glu Ser
1 5
<210> 142
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 142
Gln Gln Phe Asn Ser Tyr Pro Leu Thr
1 5
<210> 143
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 143
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 His
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Met Thr Val Asp Thr 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 Ser Arg Asp Tyr Asp Tyr Ala Gly Arg Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120
<210> 144
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 144
Gly Tyr Thr Phe Thr Ser His
1 5
<210> 145
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 145
Asn Pro Ser Asn Gly Arg
1 5
<210> 146
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 146
Arg Asp Tyr Asp Tyr Ala Gly Arg Tyr Phe Asp Tyr
1 5 10
<210> 147
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 147
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 Ser Ser Val Thr Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser His Ile Phe Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 148
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 148
Ser Ser Val Thr Tyr Met Tyr
1 5
<210> 149
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 149
Asp Thr Ser Asn Leu Ala Ser
1 5
<210> 150
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 150
Gln Gln Trp Ser Ser His Ile Phe Thr
1 5
<210> 151
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 151
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 Ser Ile Ile Pro Ile Phe Gly Thr Val 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 Asp Pro Ser Val Asn Leu Tyr Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Arg Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 152
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 152
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
Trp 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 His Ala His Pro Thr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 153
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 153
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 Gly 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 Ser Ile Ile Pro Ile Phe Gly Ala Ala Asn Pro Ala Gln Lys Ser
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 Lys Met Gly Arg Gly Lys Val Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 154
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 154
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
Pro 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 Gly Ser Pro Ile Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 155
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 155
Gln Val 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 Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 156
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 156
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 Gln 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 Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 157
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 157
Gln Val 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 Val Ser Ser Gly
20 25 30
Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn 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 Thr Asn Leu Tyr Ser Thr Pro Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 158
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 158
Asp Ile Gln Leu 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 Asp 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 Glu His Asp Phe Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 159
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 159
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 160
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 160
Glu Ile Val Met 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 His Gln Tyr Gly Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys
100 105
<210> 161
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 161
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 162
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 162
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 163
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 163
Gln Val 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 Val Asn Ser Gly
20 25 30
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn 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 Thr Asn Leu Tyr Ser Thr Pro Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 164
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 164
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 His Gln Tyr Gln Ser Tyr Ser Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 165
<211> 1210
<212> PRT
<213> 智人
<400> 165
Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala
1 5 10 15
Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln
20 25 30
Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe
35 40 45
Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn
50 55 60
Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys
65 70 75 80
Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val
85 90 95
Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr
100 105 110
Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn
115 120 125
Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu
130 135 140
His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu
145 150 155 160
Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met
165 170 175
Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro
180 185 190
Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln
195 200 205
Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg
210 215 220
Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys
225 230 235 240
Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp
245 250 255
Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro
260 265 270
Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly
275 280 285
Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His
290 295 300
Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu
305 310 315 320
Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val
325 330 335
Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn
340 345 350
Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp
355 360 365
Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr
370 375 380
Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu
385 390 395 400
Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp
405 410 415
Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln
420 425 430
His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu
435 440 445
Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser
450 455 460
Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu
465 470 475 480
Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu
485 490 495
Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro
500 505 510
Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn
515 520 525
Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly
530 535 540
Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro
545 550 555 560
Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro
565 570 575
Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val
580 585 590
Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp
595 600 605
Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys
610 615 620
Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly
625 630 635 640
Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu
645 650 655
Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His
660 665 670
Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu
675 680 685
Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu
690 695 700
Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser
705 710 715 720
Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu
725 730 735
Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser
740 745 750
Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser
755 760 765
Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser
770 775 780
Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp
785 790 795 800
Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn
805 810 815
Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg
820 825 830
Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro
835 840 845
Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala
850 855 860
Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp
865 870 875 880
Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp
885 890 895
Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser
900 905 910
Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu
915 920 925
Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr
930 935 940
Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys
945 950 955 960
Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln
965 970 975
Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro
980 985 990
Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp
995 1000 1005
Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe
1010 1015 1020
Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu
1025 1030 1035
Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn
1040 1045 1050
Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg
1055 1060 1065
Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp
1070 1075 1080
Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro
1085 1090 1095
Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln
1100 1105 1110
Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro
1115 1120 1125
His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln
1130 1135 1140
Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala
1145 1150 1155
Gln Lys Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln
1160 1165 1170
Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys
1175 1180 1185
Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln
1190 1195 1200
Ser Ser Glu Phe Ile Gly Ala
1205 1210
<210> 166
<211> 358
<212> PRT
<213> 智人
<400> 166
Met Val Asp Gly Thr Leu Leu Leu Leu Leu Ser Glu Ala Leu Ala Leu
1 5 10 15
Thr Gln Thr Trp Ala Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser
20 25 30
Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr
35 40 45
Val Asp Asp Thr Gln Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro
50 55 60
Arg Met Val Pro Arg Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr
65 70 75 80
Trp Asp Arg Glu Thr Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg
85 90 95
Val Asn Leu Arg Thr Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly
100 105 110
Ser His Thr Leu Gln Trp Met His Gly Cys Glu Leu Gly Pro Asp Arg
115 120 125
Arg Phe Leu Arg Gly Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr
130 135 140
Leu Thr Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala
145 150 155 160
Ala Gln Ile Ser Glu Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His
165 170 175
Gln Arg Ala Tyr Leu Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr
180 185 190
Leu Glu Lys Gly Lys Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr
195 200 205
His Val Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys
210 215 220
Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln
225 230 235 240
Asp Gly Glu Gly His Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro
245 250 255
Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser
260 265 270
Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro
275 280 285
Glu Pro Val Thr Leu Arg Trp Lys Pro Ala Ser Gln Pro Thr Ile Pro
290 295 300
Ile Val Gly Ile Ile Ala Gly Leu Val Leu Leu Gly Ser Val Val Ser
305 310 315 320
Gly Ala Val Val Ala Ala Val Ile Trp Arg Lys Lys Ser Ser Gly Gly
325 330 335
Lys Gly Gly Ser Tyr Ser Lys Ala Glu Trp Ser Asp Ser Ala Gln Gly
340 345 350
Ser Glu Ser His Ser Leu
355
<210> 167
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 167
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 Arg 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 Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 168
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 168
Gly Phe Thr Phe Ser Arg Tyr
1 5
<210> 169
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 169
Lys Gln Asp Gly Ser Glu
1 5
<210> 170
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 170
Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr
1 5 10
<210> 171
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 171
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 Arg 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 Asp 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 Leu Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 172
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 172
Gln Arg Val Ser Ser Ser Tyr Leu Ala
1 5
<210> 173
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 173
Asp Ala Ser Ser Arg Ala Thr
1 5
<210> 174
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 174
Gln Gln Tyr Gly Ser Leu Pro Trp Thr
1 5
<210> 175
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 175
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 Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr 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
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala
115
<210> 176
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 176
Gly Phe Thr Phe Ser Asp Ser
1 5
<210> 177
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 177
Ser Pro Tyr Gly Gly Ser
1 5
<210> 178
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 178
Arg His Trp Pro Gly Gly Phe Asp Tyr
1 5
<210> 179
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 179
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 Ser 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 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 Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 180
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 180
Gln Asp Val Ser Thr Ala Val Ala
1 5
<210> 181
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 181
Ser Ala Ser Phe Leu Tyr Ser
1 5
<210> 182
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 182
Gln Gln Tyr Leu Tyr His Pro Ala Thr
1 5
<210> 183
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 183
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
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr 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 Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala
115 120
<210> 184
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 184
Gly Phe Thr Phe Ser Ser Tyr
1 5
<210> 185
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 185
Tyr Pro Ser Gly Gly Ile
1 5
<210> 186
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 186
Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr
1 5 10
<210> 187
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 187
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 Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly
100 105 110
<210> 188
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 188
Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser
1 5 10
<210> 189
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 189
Asp Val Ser Asn Arg Pro Ser
1 5
<210> 190
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 190
Ser Ser Tyr Thr Ser Ser Ser Thr Arg Val
1 5 10
<210> 191
<211> 290
<212> PRT
<213> 智人
<400> 191
Met Arg Ile Phe Ala Val Phe Ile Phe Met Thr Tyr Trp His Leu Leu
1 5 10 15
Asn Ala Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr
20 25 30
Gly Ser Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu
35 40 45
Asp Leu Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile
50 55 60
Ile Gln Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser
65 70 75 80
Tyr Arg Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn
85 90 95
Ala Ala Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr
100 105 110
Arg Cys Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val
115 120 125
Lys Val Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val
130 135 140
Asp Pro Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr
145 150 155 160
Pro Lys Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser
165 170 175
Gly Lys Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn
180 185 190
Val Thr Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr
195 200 205
Cys Thr Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu
210 215 220
Val Ile Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr His
225 230 235 240
Leu Val Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala Leu Thr
245 250 255
Phe Ile Phe Arg Leu Arg Lys Gly Arg Met Met Asp Val Lys Lys Cys
260 265 270
Gly Ile Gln Asp Thr Asn Ser Lys Lys Gln Ser Asp Thr His Leu Glu
275 280 285
Glu Thr
290
<210> 192
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 192
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Ala Ser Thr Tyr Ser Tyr Tyr Pro 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 Val Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Gly Arg His Ser Asp Gly Asn Phe Ala Phe Gly Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala
115 120
<210> 193
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 193
Gly Phe Ile Phe Ser Asn Tyr
1 5
<210> 194
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 194
Ser Ser Ala Ser Thr Tyr
1 5
<210> 195
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 195
His Ser Asp Gly Asn Phe Ala Phe Gly Tyr
1 5 10
<210> 196
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 196
Asp Val Leu 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 Arg Asn Ile Val His Ile
20 25 30
Asn Gly Asp Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Leu Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 197
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 197
Arg Asn Ile Val His Ile Asn Gly Asp Thr Tyr Leu Glu
1 5 10
<210> 198
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 198
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 199
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 199
Phe Gln Gly Ser Leu Leu Pro Trp Thr
1 5
<210> 200
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 200
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 Glu Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Met 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 Val Asn 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 Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Gly Ala Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 201
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 201
Ser Tyr Ala Met Ser
1 5
<210> 202
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 202
Gly Ile Ile Pro Ile Phe Gly Thr Val Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
<210> 203
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 203
Arg Arg Gly Ala Lys Phe Asp Tyr
1 5
<210> 204
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 204
Ser Tyr Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser His
20 25 30
Tyr Val Val Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Asn His Gln Arg Pro Ser Gly Val Pro Asp Arg Leu Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Gly Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Val Trp Asp Asp Thr Leu
85 90 95
Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 205
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 205
Ser Gly Ser Thr Ser Asn Ile Gly Ser His Tyr Val Val
1 5 10
<210> 206
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 206
Arg Asn His Gln Arg Pro Ser
1 5
<210> 207
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 207
Ala Val Trp Asp Asp Thr Leu Ser Gly Trp Val
1 5 10
<210> 208
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 208
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 Ala Ser Gln
20 25 30
Trp Met His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Asn Pro Gly Asn Val Asn Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Val Asp Thr 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 Ser Thr Trp Tyr Arg Pro Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 209
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 209
Gly Tyr Thr Phe Ala Ser Gln Trp
1 5
<210> 210
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 210
Ile Asn Pro Gly Asn Val Asn Thr
1 5
<210> 211
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 211
Ser Thr Trp Tyr Arg Pro Leu Asp Tyr
1 5
<210> 212
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 212
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 Ile Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser 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 His Gln
85 90 95
Tyr Ile Ser Ser Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 213
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 213
Gln Ser Ile Leu Tyr Ser Ser Asn Gln Lys Asn Tyr
1 5 10
<210> 214
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 214
Trp Ala Ser Thr Arg Glu
1 5
<210> 215
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 215
His Gln Tyr Ile Ser Ser Tyr Thr
1 5
<210> 216
<211> 360
<212> PRT
<213> 智人
<400> 216
Met Asn Pro Thr Asp Ile Ala Asp Thr Thr Leu Asp Glu Ser Ile Tyr
1 5 10 15
Ser Asn Tyr Tyr Leu Tyr Glu Ser Ile Pro Lys Pro Cys Thr Lys Glu
20 25 30
Gly Ile Lys Ala Phe Gly Glu Leu Phe Leu Pro Pro Leu Tyr Ser Leu
35 40 45
Val Phe Val Phe Gly Leu Leu Gly Asn Ser Val Val Val Leu Val Leu
50 55 60
Phe Lys Tyr Lys Arg Leu Arg Ser Met Thr Asp Val Tyr Leu Leu Asn
65 70 75 80
Leu Ala Ile Ser Asp Leu Leu Phe Val Phe Ser Leu Pro Phe Trp Gly
85 90 95
Tyr Tyr Ala Ala Asp Gln Trp Val Phe Gly Leu Gly Leu Cys Lys Met
100 105 110
Ile Ser Trp Met Tyr Leu Val Gly Phe Tyr Ser Gly Ile Phe Phe Val
115 120 125
Met Leu Met Ser Ile Asp Arg Tyr Leu Ala Ile Val His Ala Val Phe
130 135 140
Ser Leu Arg Ala Arg Thr Leu Thr Tyr Gly Val Ile Thr Ser Leu Ala
145 150 155 160
Thr Trp Ser Val Ala Val Phe Ala Ser Leu Pro Gly Phe Leu Phe Ser
165 170 175
Thr Cys Tyr Thr Glu Arg Asn His Thr Tyr Cys Lys Thr Lys Tyr Ser
180 185 190
Leu Asn Ser Thr Thr Trp Lys Val Leu Ser Ser Leu Glu Ile Asn Ile
195 200 205
Leu Gly Leu Val Ile Pro Leu Gly Ile Met Leu Phe Cys Tyr Ser Met
210 215 220
Ile Ile Arg Thr Leu Gln His Cys Lys Asn Glu Lys Lys Asn Lys Ala
225 230 235 240
Val Lys Met Ile Phe Ala Val Val Val Leu Phe Leu Gly Phe Trp Thr
245 250 255
Pro Tyr Asn Ile Val Leu Phe Leu Glu Thr Leu Val Glu Leu Glu Val
260 265 270
Leu Gln Asp Cys Thr Phe Glu Arg Tyr Leu Asp Tyr Ala Ile Gln Ala
275 280 285
Thr Glu Thr Leu Ala Phe Val His Cys Cys Leu Asn Pro Ile Ile Tyr
290 295 300
Phe Phe Leu Gly Glu Lys Phe Arg Lys Tyr Ile Leu Gln Leu Phe Lys
305 310 315 320
Thr Cys Arg Gly Leu Phe Val Leu Cys Gln Tyr Cys Gly Leu Leu Gln
325 330 335
Ile Tyr Ser Ala Asp Thr Pro Ser Ser Ser Tyr Thr Gln Ser Thr Met
340 345 350
Asp His Asp Leu His Asp Ala Leu
355 360
<210> 217
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 217
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala
115 120
<210> 218
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 218
Asn Tyr Gly Val His
1 5
<210> 219
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 219
Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn
1 5 10
<210> 220
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 220
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr
1 5 10
<210> 221
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 221
Ser Tyr Ala Ile Ser
1 5
<210> 222
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 222
Ser Ile Ile Pro Ile Phe Gly Thr Val Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 223
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 223
Asp Pro Ser Val Asn Leu Tyr Trp Tyr Phe Asp Leu
1 5 10
<210> 224
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 224
Arg Ala Ser Gln Ser Ile Ser Ser Trp Trp Ala
1 5 10
<210> 225
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 225
Asp Ala Ser Ser Leu Glu Ser
1 5
<210> 226
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 226
Gln Gln Tyr His Ala His Pro Thr Thr
1 5
<210> 227
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 227
Ser Tyr Ala Ile Ser
1 5
<210> 228
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 228
Ser Ile Ile Pro Ile Phe Gly Ala Ala Asn Pro Ala Gln Lys Ser Gln
1 5 10 15
Gly
<210> 229
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 229
Met Gly Arg Gly Lys Val Ala Phe Asp Ile
1 5 10
<210> 230
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 230
Lys Ser Ser Gln Ser Val Leu Tyr Ser Pro Asn Asn Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 231
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 231
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 232
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 232
Gln Gln Tyr Tyr Gly Ser Pro Ile Thr
1 5
<210> 233
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 233
Ser Gly Asp Tyr Tyr Trp Thr
1 5
<210> 234
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 234
His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 235
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 235
Asp Arg Val Thr Gly Ala Phe Asp Ile
1 5
<210> 236
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 236
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 237
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 237
Asp Ala Ser Asn Leu Glu Thr
1 5
<210> 238
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 238
Gln His Phe Asp His Leu Pro Leu Ala
1 5
<210> 239
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 239
Ser Gly Ser Tyr Tyr Trp Ser
1 5
<210> 240
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 240
Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 241
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 241
Thr Asn Leu Tyr Ser Thr Pro Phe Asp Ile
1 5 10
<210> 242
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 242
Arg Ala Ser Gln Asp Ile Ser Ser Trp Leu Ala
1 5 10
<210> 243
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 243
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 244
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 244
Gln Gln Glu His Asp Phe Pro Trp Thr
1 5
<210> 245
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 245
Ser Gly Asp Tyr Tyr Trp Ser
1 5
<210> 246
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 246
Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 247
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 247
Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr
1 5 10
<210> 248
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 248
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 249
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 249
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 250
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 250
His Gln Tyr Gly Ser Thr Pro Leu Thr
1 5
<210> 251
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 251
Asn Tyr Gly Val His
1 5
<210> 252
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 252
Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn
1 5 10
<210> 253
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 253
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr
1 5 10
<210> 254
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 254
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
1 5 10
<210> 255
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 255
Tyr Ala Ser Glu Ser Ile Ser
1 5
<210> 256
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 256
Gln Gln Asn Asn Asn Trp Pro Thr Thr
1 5
<210> 257
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 257
Ser Gly Asp Tyr Tyr Trp Ser
1 5
<210> 258
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 258
Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 259
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 259
Thr Asn Leu Tyr Ser Thr Pro Phe Asp Ile
1 5 10
<210> 260
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 260
Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 261
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 261
Asp Ala Ser Ser Leu Glu Ser
1 5
<210> 262
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 262
His Gln Tyr Gln Ser Tyr Ser Trp Thr
1 5
<210> 263
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成肽
<400> 263
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> 264
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 264
Glu Ile Val Met 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 His Gln Tyr Gly Ser Thr Pro Leu
85 90 95
Thr Phe Gly Cys Gly Thr Lys Ala 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 Gln
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Asp
145 150 155 160
Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
165 170 175
Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu
180 185 190
Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
195 200 205
Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly Cys
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser
245
<210> 265
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 265
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 Gln 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 Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala 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 Gln
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp
145 150 155 160
Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Cys Leu Glu Trp
165 170 175
Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
180 185 190
Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe Ser
195 200 205
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr Cys
210 215 220
Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr
225 230 235 240
Met Val Thr Val Ser Ser
245
<210> 266
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 266
Gln Val 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 Val Ser Ser Gly
20 25 30
Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn 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 Thr Asn Leu Tyr Ser Thr Pro Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Glu His Asp Phe Pro Trp Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
<210> 267
<211> 476
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 267
Glu Ile Val Met 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 His Gln Tyr Gly Ser Thr Pro Leu
85 90 95
Thr Phe Gly Cys Gly Thr Lys Ala 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 Gln
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly Asp
145 150 155 160
Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
165 170 175
Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu
180 185 190
Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
195 200 205
Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly Cys
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Asp Lys Thr His Thr Cys
245 250 255
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
260 265 270
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
275 280 285
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
290 295 300
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
305 310 315 320
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
325 330 335
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
340 345 350
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
355 360 365
Ala Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro Cys
370 375 380
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
385 390 395 400
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
405 410 415
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp Gly
420 425 430
Ser Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
435 440 445
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
450 455 460
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 268
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 268
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 Gln 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 Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala 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 Gln
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Asp
145 150 155 160
Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Cys Leu Glu Trp
165 170 175
Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
180 185 190
Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe Ser
195 200 205
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr Cys
210 215 220
Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr
225 230 235 240
Met Val Thr Val Ser Ser Ala Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro Cys Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp Gly Ser Phe
420 425 430
Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470
<210> 269
<211> 475
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 269
Gln Val 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 Val Ser Ser Gly
20 25 30
Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn 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 Thr Asn Leu Tyr Ser Thr Pro Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Glu His Asp Phe Pro Trp Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys 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> 270
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 270
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 Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Glu Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Trp Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly
450
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<400> 271
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 Arg Thr Val Ala Ala
100 105 110
Pro Ser Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val
115 120 125
Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp
130 135 140
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
145 150 155 160
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
165 170 175
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
180 185 190
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
195 200 205
Glu Cys
210
<210> 272
<211> 248
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<400> 272
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly
100 105 110
Cys Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
130 135 140
Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
145 150 155 160
Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala
180 185 190
Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
210 215 220
Ala Val Tyr Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu Thr Phe Gly
225 230 235 240
Cys Gly Thr Lys Ala Glu Ile Lys
245
<210> 273
<211> 246
<212> PRT
<213> 人工序列
<220>
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<400> 273
Gln Val 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 Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Cys Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn
180 185 190
Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr
210 215 220
Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu Ala Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys
245
<210> 274
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 274
Asp Ile Gln Leu 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 Asp 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 Glu His Asp Phe Pro Trp
85 90 95
Thr Phe Gly Gly 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 Gln
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Ser
145 150 155 160
Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
165 170 175
Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
180 185 190
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
195 200 205
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Arg Thr Asn Leu Tyr Ser Thr Pro Phe Asp Ile Trp Gly Gln Gly
225 230 235 240
Thr Met Val Thr Val Ser Ser
245
<210> 275
<211> 476
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 275
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly
100 105 110
Cys Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
130 135 140
Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala
145 150 155 160
Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala
180 185 190
Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe
210 215 220
Ala Val Tyr Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu Thr Phe Gly
225 230 235 240
Cys Gly Thr Lys Ala Glu Ile Lys Ala Ser Asp Lys Thr His Thr Cys
245 250 255
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
260 265 270
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
275 280 285
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
290 295 300
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
305 310 315 320
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
325 330 335
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
340 345 350
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
355 360 365
Ala Lys Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro Cys
370 375 380
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
385 390 395 400
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
405 410 415
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp Gly
420 425 430
Ser Phe Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
435 440 445
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
450 455 460
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475
<210> 276
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成多肽
<400> 276
Gln Val 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 Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Cys Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn
180 185 190
Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr
210 215 220
Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu Ala Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys Ala Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Arg Val Tyr Thr Leu Pro Pro Cys Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Val Ser Asp Gly Ser Phe
420 425 430
Thr Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470
<210> 277
<211> 475
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<220>
<223> 人工序列的描述:合成多肽
<400> 277
Asp Ile Gln Leu 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 Asp 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 Glu His Asp Phe Pro Trp
85 90 95
Thr Phe Gly Gly 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 Gln
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly Ser
145 150 155 160
Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
165 170 175
Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
180 185 190
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
195 200 205
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Arg Thr Asn Leu Tyr Ser Thr Pro Phe Asp Ile Trp Gly Gln Gly
225 230 235 240
Thr Met 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
Claims (75)
1.一种蛋白质,其包含:
(a)结合NKG2D的第一抗原结合位点;
(b)结合EGFR、CCR4、或PD-L1的第二抗原结合位点;和
(c)抗体Fc结构域或其足以结合CD16的部分,或结合CD16的第三抗原结合位点。
2.一种蛋白质,其包含:
(a)结合NKG2D的第一抗原结合位点;
(b)结合EGFR的第二抗原结合位点;和
(c)抗体Fc结构域或其足以结合CD16的部分,或结合CD16的第三抗原结合位点。
3.一种蛋白质,其包含:
(a)结合NKG2D的第一抗原结合位点;
(b)结合CCR4的第二抗原结合位点;和
(c)抗体Fc结构域或其足以结合CD16的部分,或结合CD16的第三抗原结合位点。
4.一种蛋白质,其包含:
(a)结合NKG2D的第一抗原结合位点;
(b)结合PD-L1的第二抗原结合位点;和
(c)抗体Fc结构域或其足以结合CD16的部分,或结合CD16的第三抗原结合位点。
5.权利要求1-4中任一项所述的蛋白质,其中所述第一抗原结合位点结合到人类和食蟹猴的NKG2D。
6.权利要求1-5中任一项所述的蛋白质,其中所述第一抗原结合位点包含重链可变结构域和轻链可变结构域。
7.权利要求6所述的蛋白质,其中所述重链可变结构域和轻链可变结构域存在于同一多肽上。
8.根据权利要求6或7所述的蛋白质,其中所述第二抗原结合位点包含重链可变结构域和轻链可变结构域。
9.权利要求8所述的蛋白质,其中所述第二抗原结合位点的重链可变结构域和轻链可变结构域存在于同一多肽上。
10.根据权利要求8或9所述的蛋白质,其中所述第一抗原结合位点的轻链可变结构域具有与所述第二抗原结合位点的轻链可变结构域的氨基酸序列相同的氨基酸序列。
11.一种蛋白质,其包含:
(a)包含结合NKG2D的Fab片段的第一抗原结合位点;
(b)包含结合EGFR的单链可变片段(scFv)的第二抗原结合位点;和
(c)抗体Fc结构域或其足以结合CD16的部分,或结合CD16的第三抗原结合位点。
12.权利要求11所述的蛋白质,其中所述scFv通过包含Ala-Ser的铰链连接到所述抗体Fc结构域或其足以结合CD16的部分或所述结合CD16的第三抗原结合位点,其中所述scFv包含重链可变结构域和轻链可变结构域。
13.权利要求12所述的蛋白质,其中所述scFv连接到所述抗体Fc结构域。
14.权利要求12或13所述的蛋白质,其中所述scFv的重链可变结构域与所述scFv的轻链可变结构域形成二硫桥。
15.权利要求14所述的蛋白质,其中所述二硫桥在来自于所述重链可变结构域的C44与来自于所述轻链可变结构域的C100之间形成。
16.权利要求15所述的蛋白质,其中所述scFv连接到所述抗体Fc结构域,其中所述scFv的轻链可变结构域位于所述scFv的重链可变结构域的N-端处,并通过柔性连接物(GlyGlyGlyGlySer)4((G4S)4)连接到所述scFv的重链可变结构域,并且所述Fab连接到所述抗体Fc结构域。
17.根据权利要求12-16中任一项所述的蛋白质,其中所述scFv的重链可变结构域通过柔性连接物连接到所述scFv的轻链可变结构域。
18.权利要求17所述的蛋白质,其中所述柔性连接物包含(GlyGlyGlyGlySer)4((G4S)4)。
19.根据权利要求12-18中任一项所述的蛋白质,其中所述scFv的重链可变结构域位于所述scFv的轻链可变结构域的N-端或C-端处。
20.权利要求19所述的蛋白质,其中所述scFv的轻链可变结构域位于所述scFv的重链可变结构域的N-端处。
21.根据权利要求11至20中任一项所述的蛋白质,其中所述Fab片段连接到所述抗体Fc结构域或其足以结合CD16的部分或所述结合CD16的第三抗原结合位点。
22.权利要求21所述的蛋白质,其中所述Fab片段的重链部分包含重链可变结构域和CH1结构域,并且其中所述重链可变结构域连接到所述CH1结构域。
23.根据权利要求21或22所述的蛋白质,其中所述Fab连接到所述抗体Fc结构域。
24.根据权利要求11至23中任一项所述的蛋白质,其包含选自SEQ ID NO:264、SEQ IDNO:265和SEQ ID NO:266的序列。
25.根据权利要求12-24中任一项所述的蛋白质,其包含连接到抗体Fc结构域的scFv,其中所述连接到抗体Fc结构域的scFv由选自SEQ ID NO:267、SEQ ID NO:268和SEQ ID NO:269序列表示。
26.根据权利要求12-24中任一项所述的蛋白质,其包含选自SEQ ID NO:267、SEQ IDNO:268和SEQ ID NO:269的序列。
27.根据权利要求12-23中任一项所述的蛋白质,其包含与选自SEQ ID NO:264、SEQ IDNO:265和SEQ ID NO:266的氨基酸序列至少90%同一性的序列。
28.根据权利要求12-23中任一项所述的蛋白质,其包含与选自SEQ ID NO:264、SEQ IDNO:265和SEQ ID NO:266的氨基酸序列至少95%同一性的序列。
29.根据权利要求12-23中任一项所述的蛋白质,其包含与选自SEQ ID NO:264、SEQ IDNO:265和SEQ ID NO:266的氨基酸序列至少99%同一性的序列。
30.根据权利要求12-25中任一项所述的蛋白质,其包含与选自SEQ ID NO:267、SEQ IDNO:268和SEQ ID NO:269的氨基酸序列至少90%同一性的序列。
31.根据权利要求12-28中任一项所述的蛋白质,其包含与选自SEQ ID NO:267、SEQ IDNO:268和SEQ ID NO:269的氨基酸序列至少95%同一性的序列。
32.根据权利要求12-28中任一项所述的蛋白质,其包含与选自SEQ ID NO:267、SEQ IDNO:268和SEQ ID NO:269的氨基酸序列至少99%同一性的序列。
33.根据权利要求1-32中任一项所述的蛋白质,其中所述第一抗原结合位点包含与选自SEQ ID NO:85、SEQ ID NO:1、SEQ ID NO:41、SEQ ID NO:49、SEQ ID NO:57、SEQ ID NO:59、SEQ ID NO:61、SEQ ID NO:69、SEQ ID NO:77、和SEQ ID NO:93的氨基酸序列至少90%同一性的重链可变结构域氨基酸序列。
34.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:85至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:86至少90%同一性的轻链可变结构域氨基酸序列。
35.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:41至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:42至少90%同一性的轻链可变结构域氨基酸序列。
36.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:49至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:50至少90%同一性的轻链可变结构域氨基酸序列。
37.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:57至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:58至少90%同一性的轻链可变结构域氨基酸序列。
38.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:59至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:60至少90%同一性的轻链可变结构域氨基酸序列。
39.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:61至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:62至少90%同一性的轻链可变结构域氨基酸序列。
40.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:69至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:70至少90%同一性的轻链可变结构域氨基酸序列。
41.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:77至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:78至少90%同一性的轻链可变结构域氨基酸序列。
42.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:93至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:94至少90%同一性的轻链可变结构域氨基酸序列。
43.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:101至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:102至少90%同一性的轻链可变结构域氨基酸序列。
44.根据权利要求1-31中任一项所述的蛋白质,其中所述第一抗原结合位点包含与SEQID NO:103至少90%同一性的重链可变结构域氨基酸序列和与SEQ ID NO:104至少90%同一性的轻链可变结构域氨基酸序列。
45.权利要求1-5中任一项所述的蛋白质,其中所述第一抗原结合位点包含单域抗体。
46.权利要求45所述的蛋白质,其中所述单域抗体包含VHH片段或VNAR片段。
47.根据权利要求1-5、45或46中任一项所述的蛋白质,其中所述第二抗原结合位点包含重链可变结构域和轻链可变结构域。
48.权利要求46所述的蛋白质,其中所述第二抗原结合位点的重链可变结构域和轻链可变结构域存在于同一多肽上。
49.根据权利要求1-23中任一项所述的蛋白质,其中所述第二抗原结合位点结合EGFR和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:151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:152至少90%同一性的氨基酸序列。
50.根据权利要求1-23中任一项所述的蛋白质,其中所述第二抗原结合位点结合EGFR和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:153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:154至少90%同一性的氨基酸序列。
51.根据权利要求1-23中任一项所述的蛋白质,其中所述第二抗原结合位点结合EGFR和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:155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:156至少90%同一性的氨基酸序列。
52.根据权利要求1-23中任一项所述的蛋白质,其中所述第二抗原结合位点结合EGFR和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:157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:158至少90%同一性的氨基酸序列。
53.根据权利要求1-23中任一项所述的蛋白质,其中所述第二抗原结合位点结合EGFR和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:159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:160至少90%同一性的氨基酸序列。
54.根据权利要求1-23中任一项所述的蛋白质,其中所述第二抗原结合位点结合EGFR和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:161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:162至少90%同一性的氨基酸序列。
55.根据权利要求1-23中任一项所述的蛋白质,其中所述第二抗原结合位点结合EGFR和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:163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:164至少90%同一性的氨基酸序列。
56.根据权利要求1-10和32-47中任一项所述的蛋白质,其中所述第二抗原结合位点结合PD-L1和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ IDNO:167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:171至少90%同一性的氨基酸序列。
57.根据权利要求1-10和32-47中任一项所述的蛋白质,其中所述第二抗原结合位点结合PD-L1和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ IDNO:175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:179至少90%同一性的氨基酸序列。
58.根据权利要求1-10和32-47中任一项所述的蛋白质,其中所述第二抗原结合位点结合PD-L1和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ IDNO:183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:187至少90%同一性的氨基酸序列。
59.根据权利要求1-10和32-47中任一项所述的蛋白质,其中所述第二抗原结合位点结合CCR4和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:192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:196至少90%同一性的氨基酸序列。
60.根据权利要求1-10和32-47中任一项所述的蛋白质,其中所述第二抗原结合位点结合CCR4和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:200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:204至少90%同一性的氨基酸序列。
61.根据权利要求1-10和32-47中任一项所述的蛋白质,其中所述第二抗原结合位点结合CCR4和包括重链可变结构域和轻链可变结构域,所述重链可变结构域包含与SEQ ID NO:208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:212至少90%同一性的氨基酸序列。
62.根据权利要求1-10中任一项所述的蛋白质,其中所述第二抗原结合位点包含单域抗体。
63.权利要求62所述的蛋白质,其中所述第二抗原结合位点的单域抗体包含VHH片段或VNAR片段。
64.根据权利要求1-63中任一项所述的蛋白质,其中所述抗体Fc结构域包含铰链和CH2结构域。
65.权利要求64所述的蛋白质,其中所述抗体Fc结构域包含人类IgG1抗体的铰链和CH2结构域。
66.权利要求64或65所述的蛋白质,其中所述Fc结构域包含与人类IgG1抗体的第234-332位氨基酸至少90%同一性的氨基酸序列。
67.权利要求66所述的蛋白质,其中所述Fc结构域包含与人类IgG1的Fc结构域至少90%同一性的氨基酸序列,并在选自Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411和K439的一个或多个位置处有差异。
68.根据权利要求1-67中任一项所述的蛋白质,其中所述蛋白质以10nM的KD或更弱的亲和力结合到NKG2D。
69.一种剂型,其包含根据前述权利要求中任一项所述的蛋白质和可药用载体。
70.一种细胞,其包含编码根据权利要求1-68中任一项所述的蛋白质的一种或多种核酸。
71.一种增加肿瘤细胞死亡的方法,所述方法包括将所述肿瘤细胞和自然杀伤细胞暴露于有效量的根据权利要求1-68中任一项所述的蛋白质,其中所述肿瘤细胞表达EGFR、CCR4或PD-L1中的至少一种。
72.一种治疗癌症的方法,其中所述方法包括向患者施用有效量的根据权利要求1-68中任一项所述的蛋白质或根据权利要求69所述的剂型。
73.权利要求72所述的方法,其中所述蛋白质的第二抗原结合位点结合EGFR,并且所述癌症选自头颈部癌、结肠直肠癌、非小细胞肺癌、神经胶质瘤、肾细胞癌、膀胱癌、宫颈癌、卵巢癌、胰腺癌和肝癌。
74.权利要求72所述的方法,其中所述蛋白质的第二抗原结合位点结合PD-L1,并且所述癌症选自淋巴瘤、白血病、多发性骨髓瘤、头颈部癌、膀胱癌、宫颈癌、肺癌、肾癌、黑素瘤、结肠直肠癌、卵巢癌、成胶质细胞瘤、肉瘤和胃癌。
75.权利要求72所述的方法,其中所述蛋白质的第二抗原结合位点结合CCR4,并且其中所述癌症选自成年人T-细胞淋巴瘤/白血病、外周T细胞淋巴瘤、皮肤T细胞淋巴瘤、慢性淋巴细胞性白血病、B细胞恶性肿瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、间变性大细胞淋巴瘤、成熟T/自然杀伤(NK)细胞肿瘤、胸腺瘤、胃癌和肾细胞癌。
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2021
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BR112020003050A2 (pt) | 2020-09-01 |
KR20210029298A (ko) | 2021-03-15 |
EP3882270A2 (en) | 2021-09-22 |
EP3882270A3 (en) | 2021-12-01 |
SG10202102251YA (en) | 2021-04-29 |
SG11201913969SA (en) | 2020-01-30 |
MX2021002969A (es) | 2021-05-12 |
JP2021098732A (ja) | 2021-07-01 |
US20200216544A1 (en) | 2020-07-09 |
MX2020001805A (es) | 2020-07-13 |
WO2019035939A1 (en) | 2019-02-21 |
IL281305A (en) | 2021-04-29 |
EP3668893A4 (en) | 2021-08-04 |
AU2018318698A1 (en) | 2020-02-20 |
AU2021201451A1 (en) | 2021-03-25 |
JP2020531438A (ja) | 2020-11-05 |
US20210261668A1 (en) | 2021-08-26 |
CA3073117A1 (en) | 2019-02-21 |
CN111065649A (zh) | 2020-04-24 |
CA3176049A1 (en) | 2019-02-21 |
EP3668893A1 (en) | 2020-06-24 |
CA3112990A1 (en) | 2019-02-21 |
IL272553A (en) | 2020-03-31 |
KR20200037388A (ko) | 2020-04-08 |
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