CN112423788A - 结合nkg2d、cd16和成纤维细胞激活蛋白的蛋白质 - Google Patents
结合nkg2d、cd16和成纤维细胞激活蛋白的蛋白质 Download PDFInfo
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Abstract
描述了结合NKG2D受体、CD16和成纤维细胞激活蛋白(FAP)的多特异性结合蛋白,以及可用于治疗癌症、自身免疫性疾病或纤维化的所述多特异性结合蛋白的药物组合物和治疗方法。
Description
相关申请的交叉引用
本申请要求2018年5月16日提交的美国临时专利申请号62/672,299的权益和优先权。
序列表
本申请含有序列表,所述序列表以ASCII格式电子提交并且由此以引用的方式整体并入。于2019年5月13日创建的所述ASCII副本命名为DFY_056WO_SL25.txt并且大小为121,670字节。
技术领域
本发明涉及与NKG2D、CD16和成纤维细胞激活蛋白(FAP)结合的多特异性结合蛋白。
背景技术
尽管在文献中报道了用于治疗癌症的大量研究努力和科学进展,但是这种疾病仍然是一个重要的健康问题。一些最常被诊断的癌症包括前列腺癌、乳腺癌和肺癌。前列腺癌是男性中最常见的癌症形式。乳腺癌仍然是女性死亡的主要原因。这些癌症的当前治疗选择不是对所有患者都有效,且/或可能具有严重的不良副作用。使用现有的治疗选择来治疗其他类型的癌症也仍然具有挑战性。癌症中的癌症相关成纤维细胞常常促进恶性肿瘤并抑制癌症治疗。
癌症免疫疗法是理想的,因为它们具有高度特异性,并且可利用患者自身免疫系统来促进癌细胞的破坏。融合蛋白如双特异性T细胞接合剂是文献中描述的与肿瘤细胞和T细胞结合以促进肿瘤细胞破坏的癌症免疫疗法。在文献中已描述了与某些肿瘤相关抗原、免疫细胞和肿瘤微环境中的其他细胞(例如癌症相关成纤维细胞)结合的抗体。参见,例如,WO 2016/134371和WO 2015/095412。
自然杀伤(NK)细胞是先天免疫系统的组分,并构成循环淋巴细胞的约15%。NK细胞几乎浸润所有组织,并且最初的特征是它们在不需要预先致敏的情况下有效杀死肿瘤细胞的能力。激活的NK细胞通过类似于细胞毒性T细胞的方式杀死靶细胞,即通过包含穿孔素和颗粒酶的溶细胞颗粒以及通过死亡受体途径。激活的NK细胞还分泌促进其他白细胞募集到靶组织的炎性细胞因子如IFN-γ和趋化因子。
NK细胞对于通过其表面上的各种激活和抑制受体的信号作出响应。例如,当NK细胞遇到健康的自身细胞时,它们的活性通过杀伤细胞免疫球蛋白样受体(KIR)的激活而得到抑制。替代地,当NK细胞遇到外来细胞或癌细胞时,它们通过其激活受体(例如NKG2D、自然细胞毒性受体(NCR)、DNAX辅助分子1(DNAM1))而得到激活。NK细胞还通过其表面上的CD16受体而被一些免疫球蛋白的恒定区域激活。NK细胞对激活的总体敏感性取决于刺激信号和抑制信号的总和。
成纤维细胞激活蛋白α(FAP)是属于丝氨酸蛋白酶家族的同二聚体整合膜明胶酶。该蛋白被认为参与在发育、组织修复和上皮癌变期间控制成纤维细胞生长或上皮-间质相互作用。所有人类癌瘤中90%以上在激活的基质成纤维细胞上具有FAP表达。基质成纤维细胞在癌瘤的发展、生长和转移中起重要作用。FAP在骨和软组织肉瘤的恶性细胞中也有表达。
本发明提供了改善对上述癌症的治疗的某些优点。
发明内容
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FAP的多特异性结合蛋白。此类蛋白可与一种以上的NK激活受体结合,并可能阻断天然配体与NKG2D的结合。在某些实施方案中,这些蛋白可激动人的NK细胞。在一些实施方案中,这些蛋白可激动人和其他物种诸如啮齿动物和食蟹猴中的NK细胞。以下进一步详细描述本发明的各个方面和实施方案。
因此,在某些实施方案中,本发明提供了并入以下项的蛋白质:结合NKG2D的第一抗原结合位点;结合FAP的第二抗原结合位点;和足以结合CD16的抗体可结晶片段(Fc)结构域、其部分,或结合CD16的第三抗原结合位点。
抗原结合位点可各自并入抗体重链可变结构域和抗体轻链可变结构域(例如,如在抗体中排列,或融合在一起以形成scFv),或一个或多个抗原结合位点可以是单结构域抗体,诸如VHH抗体如骆驼科动物抗体或VNAR抗体如在软骨鱼中发现的那些抗体。
在某些方面,本发明提供了结合自然杀伤细胞上的NKG2D受体和CD16受体以及癌细胞上的FAP的多特异性结合蛋白。NKG2D结合位点可包括与选自以下的氨基酸序列至少90%相同的重链可变结构域: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、SEQ ID NO:85、SEQ ID NO:167、SEQ ID NO:171、SEQ ID NO:175、SEQ ID NO:179、SEQ ID NO:183、SEQ ID NO:187和SEQ ID NO:93。
在一些实施方案中,与NKG2D结合的第一抗原结合位点可并入与SEQ ID NO:1相关的重链可变结构域,诸如通过具有与SEQ ID NO:1至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同的氨基酸序列和/或并入与SEQ ID NO:1的CDR1(SEQ ID NO:105或SEQ ID NO:151)、CDR2(SEQ ID NO:106)和CDR3(SEQ ID NO:107或SEQ ID NO:152)序列相同的氨基酸序列。与SEQ ID NO:1相关的重链可变结构域可与多种轻链可变结构域偶联以形成NKG2D结合位点。例如,并入与SEQ ID NO:1相关的重链可变结构域的第一抗原结合位点可进一步并入选自与SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36和40相关的序列中的任一个的轻链可变结构域。例如,第一抗原结合位点并入具有与SEQ ID NO:1至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同的氨基酸序列的重链可变结构域和具有与选自SEQ IDNO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36和40的序列中的任一个至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同的氨基酸序列的轻链可变结构域。
替代地,在某些实施方案中,第一抗原结合位点可并入与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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:41至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:41的CDR1(SEQ ID NO:43或SEQ IDNO:153)、CDR2(SEQ ID NO:44)和CDR3(SEQ ID NO:45或SEQ ID NO:154)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:42至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQID 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。
在某些实施方案中,第一抗原结合位点可并入与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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:49至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:49的CDR1(SEQ ID NO:51或SEQ ID NO:155)、CDR2(SEQ ID NO:52)和CDR3(SEQ ID NO:53或SEQ ID NO:156)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:50至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与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。
替代地,第一抗原结合位点可并入与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,诸如通过具有分别与SEQ ID NO:57至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同和与SEQ ID NO:58至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同的氨基酸序列。在另一实施方案中,第一抗原结合位点可并入与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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:59至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:59的CDR1(SEQ ID NO:108)、CDR2(SEQID NO:109)和CDR3(SEQ ID NO:110)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:60至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:60的CDR1(SEQ ID NO:111)、CDR2(SEQ ID NO:112)和CDR3(SEQ ID NO:113)序列相同的氨基酸序列。
在一些实施方案中,第一抗原结合位点可并入与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,诸如通过具有分别与SEQ ID NO:101至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同和与SEQ ID NO:102至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同的氨基酸序列。在一些实施方案中,第一抗原结合位点可并入与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,诸如通过具有分别与SEQ ID NO:103至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同和与SEQ ID NO:104至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同的氨基酸序列。
在一些实施方案中,结合NKG2D的第一抗原结合位点可并入与SEQ ID NO: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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:61至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:61的CDR1(SEQ ID NO:63或SEQ ID NO:157)、CDR2(SEQ ID NO:64)和CDR3(SEQ ID NO:65或SEQ ID NO:158)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:62至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与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。在一些实施方案中,第一抗原结合位点可并入与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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:69至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:69的CDR1(SEQ ID NO:71或SEQ IDNO:159)、CDR2(SEQ ID NO:72)和CDR3(SEQ ID NO:73或SEQ ID NO:160)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:70至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQID 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。
在一些实施方案中,第一抗原结合位点可并入与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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:77至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:77的CDR1(SEQ ID NO:79或SEQ ID NO:161)、CDR2(SEQ ID NO:80)和CDR3(SEQ ID NO:81或SEQ ID NO:162)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:78至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与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。
在一些实施方案中,第一抗原结合位点可并入与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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:85至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:85的CDR1(SEQ ID NO:87或SEQ ID NO:163)、CDR2(SEQ ID NO:88)和CDR3(SEQ ID NO:89或SEQ ID NO:164)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:86至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与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。
在一些实施方案中,第一抗原结合位点可并入与SEQ ID NO:167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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:167至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:167的CDR1(SEQ ID NO:87或SEQ ID NO:168)、CDR2(SEQ ID NO:88)和CDR3(SEQ ID NO:169或SEQ ID NO:170)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:86至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ IDNO: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。
在一些实施方案中,第一抗原结合位点可并入与SEQ ID NO:171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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:171至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:171的CDR1(SEQ ID NO:87或SEQ ID NO:172)、CDR2(SEQ ID NO:88)和CDR3(SEQ ID NO:173或SEQ ID NO:174)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:86至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ IDNO: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。
在一些实施方案中,第一抗原结合位点可并入与SEQ ID NO:175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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:175至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:175的CDR1(SEQ ID NO:87或SEQ ID NO:176)、CDR2(SEQ ID NO:88)和CDR3(SEQ ID NO:177或SEQ ID NO:178)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:86至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ IDNO: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。
在一些实施方案中,第一抗原结合位点可并入与SEQ ID NO:179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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:179至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:179的CDR1(SEQ ID NO:87或SEQ ID NO:180)、CDR2(SEQ ID NO:88)和CDR3(SEQ ID NO:181或SEQ ID NO:182)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:86至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ IDNO: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。
在一些实施方案中,第一抗原结合位点可并入与SEQ ID NO:183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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:183至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:183的CDR1(SEQ ID NO:87或SEQ ID NO:184)、CDR2(SEQ ID NO:88)和CDR3(SEQ ID NO:185或SEQ ID NO:186)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:86至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ IDNO: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。
在一些实施方案中,第一抗原结合位点可并入与SEQ ID NO:187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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:187至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:187的CDR1(SEQ ID NO:87或SEQ ID NO:188)、CDR2(SEQ ID NO:88)和CDR3(SEQ ID NO:189或SEQ ID NO:190)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:86至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ IDNO: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。
在一些实施方案中,第一抗原结合位点可并入与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,第一抗原结合位点的重链可变结构域可与SEQ ID NO:93至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:93的CDR1(SEQ ID NO:95或SEQ ID NO:165)、CDR2(SEQ ID NO:96)和CDR3(SEQ ID NO:97或SEQ ID NO:166)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:94至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与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。
在某些实施方案中,第二抗原结合位点可结合至FAP并可任选地并入与SEQ IDNO:114相关的重链可变结构域和与SEQ ID NO:118相关的轻链可变结构域。例如,第二抗原结合位点的重链可变结构域可与SEQ ID NO:114至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:114的CDR1(SEQID NO:115或SEQ ID NO:147)、CDR2(SEQ ID NO:116或SEQ ID NO 148)和CDR3(SEQ ID NO:117)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ IDNO:118至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:118的CDR1(SEQ ID NO:119或SEQ ID NO:149)、CDR2(SEQ IDNO:120)和CDR3(SEQ ID NO:121)序列相同的氨基酸序列。
替代地,与FAP结合的第二抗原结合位点可任选地并入与SEQ ID NO:131相关的重链可变结构域和与SEQ ID NO:135相关的轻链可变结构域。例如,第二抗原结合位点的重链可变结构域可与SEQ ID NO:131至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:131的CDR1(SEQ ID NO:132)、CDR2(SEQ ID NO:133)和CDR3(SEQ ID NO:134)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:135至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:135的CDR1(SEQ IDNO:136)、CDR2(SEQ ID NO:137)和CDR3(SEQ ID NO:138)序列相同的氨基酸序列。
替代地,与FAP结合的第二抗原结合位点可任选地并入与SEQ ID NO:139相关的重链可变结构域和与SEQ ID NO:143相关的轻链可变结构域。例如,第二抗原结合位点的重链可变结构域可与SEQ ID NO:139至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:139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。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:143至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:143的CDR1(SEQ IDNO:144)、CDR2(SEQ ID NO:145)和CDR3(SEQ ID NO:146)序列相同的氨基酸序列。
替代地,与FAP结合的第二抗原结合位点可任选地并入与SEQ ID NO:122相关的重链可变结构域和与SEQ ID NO:126相关的轻链可变结构域。例如,第二抗原结合位点的重链可变结构域可与SEQ ID NO:122至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:122的CDR1(SEQ ID NO:123)、CDR2(SEQ ID NO:124)和CDR3(SEQ ID NO:125)序列相同的氨基酸序列。类似地,第二抗原结合位点的轻链可变结构域可与SEQ ID NO:126至少90%(例如,90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)相同,和/或并入与SEQ ID NO:126的CDR1(SEQ IDNO:127)、CDR2(SEQ ID NO:128)和CDR3(SEQ ID NO:129)序列相同的氨基酸序列。
在一些实施方案中,第二抗原结合位点并入具有与存在于第一抗原结合位点中的轻链可变结构域的氨基酸序列相同的氨基酸序列的轻链可变结构域。
在一些实施方案中,所述蛋白质并入足以结合CD16的抗体Fc结构域的一部分,其中抗体Fc结构域包含铰链和CH2结构域,和/或与人IgG抗体的氨基酸序列234-332至少90%相同的氨基酸序列。
在某些实施方案中,所述蛋白质进一步并入与肿瘤相关抗原结合的第四抗原结合位点,所述肿瘤相关抗原包括与癌症相关的任何抗原。例如,第四抗原结合位点可结合到人表皮生长因子受体2(HER2)、CD20、CD33、B细胞成熟抗原(BCMA)、前列腺特异性膜抗原(PSMA)、δ样典型notch配体3(DLL3)、神经节苷脂GD2(GD2)、CD123、钙离子激活氯离子通道蛋白1(anoctamin-1)(Ano1)、间皮素、碳酸酐酶IX(CAIX)、肿瘤相关钙信号转导因子2(TROP2)、癌胚抗原(CEA)、紧密连接蛋白-18.2(claudin-18.2)、受体酪氨酸激酶样孤儿受体1(ROR1)、滋养层糖蛋白(5T4)、糖蛋白非转移性黑色素瘤蛋白B(GPNMB)、叶酸受体-α(FR-α)、妊娠相关血浆蛋白A(PAPP-A)、CD37、上皮细胞粘附分子(EpCAM)、CD2、CD19、CD30、CD38、CD40、CD52、CD70、CD79b、fms样酪氨酸激酶3(FLT3)、磷脂酰肌醇蛋白聚糖3(glypican 3,GPC3)、B7同源蛋白6(B7H6)、C-C趋化因子受体4型(CCR4)、C-X-C基序趋化因子受体4(CXCR4)、受体酪氨酸激酶样孤儿受体2(ROR2)、CD133、HLA I类组织相容性抗原、α链E(HLA-E)、表皮生长因子受体(EGFR/ERBB1)、胰岛素样生长因子1受体(IGF1R)、人表皮生长因子受体3(HER3)/ERBB3、人表皮生长因子受体4(HER4)/ERBB4、粘蛋白1(MUC1)、酪氨酸蛋白激酶MET(cMET)、信号传导淋巴细胞激活分子F7(SLAMF7)、前列腺干细胞抗原(PSCA)、MHC I类多肽相关序列A(MICA)、MHC I类多肽相关序列B(MICB)、TNF相关凋亡诱导配体受体1(TRAILR1)、TNF相关凋亡诱导配体受体2(TRAILR2)、黑色素瘤相关抗原3(MAGE-A3)、B淋巴细胞抗原B7.1(B7.1)、B淋巴细胞抗原B7.2(B74.2)、细胞毒性T淋巴细胞相关蛋白4(CTLA4)、程序性细胞死亡蛋白1(PD1)、程序性细胞死亡1配体1(PD-L1)或癌细胞表达CD25抗原。
还提供了含有本文所述的蛋白质中的任一种的制剂;含有表达所述蛋白质的一种或多种核酸的细胞,以及使用所述蛋白质增强肿瘤细胞死亡的方法。
本发明的另一方面提供了一种治疗患者癌症的方法。方法包括向有此需要的患者施用治疗有效量的本文所述的多特异性结合蛋白。待使用靶向FAP的多特异性结合蛋白治疗的癌症包括任何表达FAP的癌症,例如浸润性导管癌、胰腺导管腺癌、胃癌、子宫癌、宫颈癌、结直肠癌、乳腺癌、卵巢癌、膀胱癌、肺癌、头颈癌、间皮瘤、胃癌、胰腺癌、肝癌、子宫内膜癌、神经内分泌癌、纤维肉瘤、恶性纤维组织细胞瘤、平滑肌肉瘤、骨肉瘤、软骨肉瘤、脂肪肉瘤、滑膜肉瘤、神经鞘瘤、黑色素瘤和神经胶质瘤。
在某些实施方案中,本发明提供了一种治疗患者自身免疫性疾病的方法。方法包括向有此需要的患者施用治疗有效量的本文所述的多特异性结合蛋白。在某些实施方案中,自身免疫性疾病选自由以下组成的组:类风湿性关节炎、格雷夫斯病(Grave’sdisease)、干燥综合征(syndrome)、原发性胆汁性肝硬化、原发性硬化性胆管炎和炎性破坏性关节炎。
在某些实施方案中,本发明提供了一种治疗患者纤维化的方法,所述方法包括向有此需要的患者施用治疗有效量的本文所述的多特异性结合蛋白。在某些实施方案中,纤维化选自由以下组成的组:特发性肺纤维化、肾纤维化、肝纤维化和心脏纤维化。
附图说明
图1是异二聚体多特异性结合蛋白的表示。每个臂可表示NKG2D结合结构域或FAP结合结构域。多特异性结合蛋白还包含与CD16结合的Fc结构域或其一部分。在一些实施方案中,NKG2D结合结构域和FAP结合结构域可共享共同轻链。
图2是异二聚体多特异性结合蛋白的表示。NKG2D结合结构域或FAP结合结构域都可采用scFv格式(右臂)。
图3是示出在ELISA测定中NKG2D结合结构域(以克隆形式列出)与人重组NKG2D的结合亲和力的线状图。
图4是示出在ELISA测定中NKG2D结合结构域(以克隆形式列出)与食蟹猴重组NKG2D的结合亲和力的线状图。
图5是示出在ELISA测定中NKG2D结合结构域(以克隆形式列出)与小鼠重组NKG2D的结合亲和力的线状图。
图6是示出通过流式细胞术测量为平均荧光强度(MFI)背景倍数(FOB)的NKG2D结合结构域(以克隆形式列出)与表达人NKG2D的EL4细胞的结合的柱状图。
图7是示出通过流式细胞术测量为平均荧光强度(MFI)背景倍数(FOB)的NKG2D结合结构域(以克隆形式列出)与表达小鼠NKG2D的EL4细胞的结合的柱状图。
图8是示出在用NKG2D天然配体ULBP-6的竞争性结合测定中NKG2D结合结构域(以克隆形式列出)对重组人NKG2D-Fc的结合亲和力的线状图。
图9是示出在用NKG2D天然配体MICA的竞争性结合测定中NKG2D结合结构域(以克隆形式列出)对重组人NKG2D-Fc的结合亲和力的线状图。
图10是示出在用NKG2D天然配体Rae-1δ的竞争性结合测定中NKG2D结合结构域(以克隆形式列出)对重组小鼠NKG2D-Fc的结合亲和力的线状图。
图11是示出如通过流式细胞术测量并量化为TNF-α阳性细胞的百分比的NKG2D结合结构域(以克隆形式列出)对表达人NKG2D-CD3ζ融合蛋白的细胞的激活的柱状图。
图12是示出如通过流式细胞术测量并量化为TNF-α阳性细胞的百分比的NKG2D结合结构域(以克隆形式列出)对表达小鼠NKG2D-CD3ζ融合蛋白的细胞的激活的柱状图。
图13是示出如通过流式细胞术测量并量化为IFN-γ+/CD107a+细胞的百分比的NKG2D结合结构域(以克隆形式列出)对人NK细胞的激活的柱状图。
图14是示出如通过流式细胞术测量并量化为IFN-γ+/CD107a+细胞的百分比的NKG2D结合结构域(以克隆形式列出)对人NK细胞的激活的柱状图。
图15是示出如通过流式细胞术测量并量化为IFN-γ+/CD107a+细胞的百分比的NKG2D结合结构域(以克隆形式列出)对小鼠NK细胞的激活的柱状图。
图16是示出如通过流式细胞术测量并量化为IFN-γ+/CD107a+细胞的百分比的NKG2D结合结构域(以克隆形式列出)对小鼠NK细胞的激活的柱状图。
图18是示出通过差示扫描荧光法测量的NKG2D结合结构域(以克隆形式列出)的解链温度的柱状图。
图19A至图19C是示出如通过流式细胞术测量并量化为针对NK激活标记物的阳性细胞的百分比的CD16和NKG2D结合对NK细胞的协同激活的柱状图。图19A示出用单独的板结合抗CD16单克隆抗体、单独的抗NKG2D抗体或抗CD16抗体与抗NKG2D抗体组合治疗后4小时CD107a+细胞的百分比。图19B示出用单独的板结合抗CD16单克隆抗体、单独的抗NKG2D抗体或抗CD16抗体与抗NKG2D抗体组合治疗后4小时IFN-γ+细胞的百分比。图19C示出用单独的板结合抗CD16单克隆抗体、单独的抗NKG2D抗体或抗CD16抗体与抗NKG2D抗体组合治疗后4小时CD107a+/IFN-γ+细胞的百分比。图表示平均值(n=2)±SD。数据代表使用五个不同健康供体的五个独立实验。
图20是呈Triomab形式的多特异性结合蛋白的代表性图示。
图21是呈KiH共同轻链(LC)形式的多特异性结合蛋白的代表性图示。
图22是呈双可变结构域免疫球蛋白(DVD-IgTM)形式的多特异性结合蛋白的代表性图示。
图23是呈正交Fab界面(Ortho-Fab)形式的多特异性结合蛋白的代表性图示。
图24是呈2-in-1Ig形式的多特异性结合蛋白的代表性图示。
图25是呈静电转向(ES)形式的多特异性结合蛋白的代表性图示。
图26是呈受控Fab臂交换(cFAE)形式的多特异性结合蛋白的代表性图示。
图27是呈链交换工程化结构域(SEED)体形式的多特异性结合蛋白的代表性图示。
图28是呈LuZ-Y形式的多特异性结合蛋白的代表性图示。
图29是呈Cov-X体形式的多特异性结合蛋白的代表性图示。
图30A和图30B是呈Kλ体形式的多特异性结合蛋白的代表性图示。图30A是Kλ体的一种形式的示例性代表性图示;图30B是另一种Kλ体的示例性代表性图示。
图31是呈单臂单链(OAsc)-Fab形式的多特异性结合蛋白的代表性图示。
图32是呈DuetMab形式的多特异性结合蛋白的代表性图示。
图33是呈CrossmAb形式的多特异性结合蛋白的代表性图示。
图34是呈Fit-Ig形式的多特异性结合蛋白的代表性图示。
图35A至图35C是示出在人细胞系LL86(图35A)、COLO 829(图35B)和U-87MG(图35C)上FAP表达的直方图。
图36A至图36C是示出抗FAP单克隆抗体(FAP-mAb)和抗FAP多特异性结合蛋白(FAP多特异性BP)对人细胞系LL86(图36A)、COLO 829(图36B)和U-87MG(图36C)上表达的FAP的结合亲和力的线状图。
图37A至图37D是示出用多特异性结合蛋白(FAP多特异性BP)、单克隆抗体(FAP-mAb)或同种型对照抗体刺激时,来自两个单独的供体(供体RR01612,图37A至图37C;和供体55109,图37D)的原代人NK细胞针对表达FAP的LL86(图37A)、COLO829(图37B)、U-87MG(图37C)和COLO829(图37D)细胞的细胞毒性活性的线状图。
具体实施方式
本发明提供了结合自然杀伤细胞上的NKG2D受体和CD16受体以及癌细胞上的FAP的多特异性结合蛋白。在某些实施方案中,多特异性结合蛋白还包括结合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此类多特异性结合蛋白的药物组合物,以及为了诸如治疗癌症的目的而使用此类多特异性结合蛋白和药物组合物的治疗方法。本发明的多个方面在以下部分中阐述;然而,在一个特定部分中描述的本发明的方面不限于任何特定部分。
为了促进对本发明的理解,下面定义了许多术语和短语。
除非上下文不适当,否则本文所用的术语“一(a)”和“一(an)”表示“一个或多个”并且包括复数。
如本文所用,术语“抗原结合位点”是指免疫球蛋白分子中参与抗原结合的部分。在人抗体中,抗原结合位点由重链(“H”)和轻链(“L”)的N末端可变(“V”)区的氨基酸残基形成。在重链和轻链的V区内的三个非常不同的片段被称为“高变区”,它们插入在称为“框架区”或“FR”的更保守的侧翼片段之间。因此,术语“FR”是指天然存在于免疫球蛋白中的高变区之间和附近的氨基酸序列。在人抗体分子中,轻链的三个高变区和重链的三个高变区在三维空间中相对于彼此布置以形成抗原结合表面。抗原结合表面与结合抗原的三维表面互补,并且每条重链和轻链的三个高变区被称为“互补决定区”或“CDR”。在某些动物如骆驼和软骨鱼中,抗原结合位点由单抗体链形成,从而提供“单结构域抗体”。抗原结合位点可存在于完整抗体中,存在于保留抗原结合表面的抗体的抗原结合片段中,或存在于重组多肽如scFv中,所述重组多肽使用肽接头以便在单个多肽中将重链可变结构域连接到轻链可变结构域。
如本文所用,术语“肿瘤相关抗原”是指与癌症相关的任何抗原,包括但不限于蛋白质、糖蛋白、神经节苷脂、碳水化合物或脂质。此类抗原可在恶性细胞上或在肿瘤微环境中表达,诸如在肿瘤相关的血管、细胞外基质、间充质基质或免疫浸润物上表达。
如本文所用,术语“受试者”和“患者”是指待通过本文所述的方法和组合物治疗的生物体。此类生物体优选包括但不限于哺乳动物(例如,鼠、猿、马、牛、猪、犬、猫等),并且更优选包括人。
如本文所用,术语“有效量”是指足以实现有益或期望结果的化合物(例如,本发明的化合物)的量。有效量可以一次或多次施用、应用或剂量施用,并且不旨在限于特定的制剂或施用途径。如本文所用,术语“治疗”包括导致病状、疾病、病症等的改善或减轻其症状的任何效果,例如减轻、减少、调节、改善或消除。
如本文所用,术语“药物组合物”是指活性剂与惰性或活性载剂的组合,使得组合物特别适合于体内或离体的诊断或治疗应用。
如本文所用,术语“药学上可接受的载剂”是指任何标准药物载剂,诸如磷酸盐缓冲盐水溶液、水、乳液(例如,诸如油/水或水/油乳液)和各种类型的润湿剂。组合物还可包含稳定剂和防腐剂。对于载剂、稳定剂和佐剂的实例,参见例如Remington'sPharmaceutical Sciences,第15版,MackPublishing Co.,Easton,PA(1975)。
如本文所用,术语“药学上可接受的盐”是指本发明化合物的任何药学上可接受的盐(例如酸或碱),在向受试者施用时能够提供本发明的化合物或其活性代谢物或残余物。如本领域技术人员所知的,本发明化合物的“盐”可来源于无机或有机酸和碱。示例性酸包括但不限于盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、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,如草酸,虽然本身不是药学上可接受的,但是可用于制备盐,这些盐可在获得本发明的化合物和其药学上可接受的酸加成盐中用作中间体。
示例性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 +化合物,其中W为C1-4烷基等。
示例性盐包括但不限于:乙酸盐、己二酸盐、海藻酸盐、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、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、氟庚酸盐、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、特戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一酸盐等。盐的其他实例包括与合适阳离子如Na+、NH4 +和NW4 +(其中W是C1-4烷基)等化合的本发明化合物的阴离子。
就治疗用途而言,本发明化合物的盐预期为药学上可接受的。然而,非药学上可接受的酸和碱的盐也可适用于例如制备或纯化药学上可接受的化合物。
在整个说明书中,当组合物被描述为具有、包括或包含特定组分时,或当过程和方法被描述为具有、包括或包含特定步骤时,可以预期,另外存在基本上由所述组分组成或由其组成的本发明的组合物,并且存在基本上由所述处理步骤组成或由其组成的根据本发明的过程和方法。
通常,除非另有说明,否则指定百分比的组合物以重量计。此外,如果变量没有定义,则以变量的先前定义为准。
I.蛋白质
本发明提供了结合自然杀伤细胞上的NKG2D受体和CD16受体以及癌细胞上的FAP的多特异性结合蛋白。多特异性结合蛋白可用于本文所述的药物组合物和治疗方法。多特异性结合蛋白与自然杀伤细胞上的NKG2D受体和CD16受体的结合增强了自然杀伤细胞破坏表达FAP抗原的肿瘤细胞的活性。多特异性结合蛋白与FAP表达细胞的结合使癌细胞接近自然杀伤细胞,这促进了自然杀伤细胞对癌细胞的直接和间接破坏。以下提供一些示例性多特异性结合蛋白的进一步描述。
在某些其他实施方案中,本发明提供了结合自然杀伤细胞上的NKG2D受体和CD16受体以及成纤维细胞上的FAP的多特异性结合蛋白。例如,在患有自身免疫性疾病或纤维化的患者中,成纤维细胞可为激活的基质成纤维细胞。多特异性结合蛋白与自然杀伤细胞上的NKG2D受体和CD16受体的结合增强了自然杀伤细胞破坏表达FAP抗原的成纤维细胞的活性。多特异性结合蛋白与FAP表达细胞的结合使成纤维细胞接近自然杀伤细胞,这促进了自然杀伤细胞对成纤维细胞的直接和间接破坏。
多特异性结合蛋白的第一组分结合表达NKG2D受体的细胞,所述细胞可包括但不限于NK细胞、γδT细胞和CD8+αβT细胞。在NKG2D结合后,多特异性结合蛋白可阻断天然配体诸如ULBP6和MICA与NKG2D结合并激活NKG2D受体。
在某些实施方案中,多特异性结合蛋白的第二组分与FAP表达细胞结合。FAP表达细胞可发现于例如但不限于浸润性导管癌、胰腺导管腺癌、胃癌、子宫癌、宫颈癌、结直肠癌、乳腺癌、卵巢癌、膀胱癌、肺癌、间皮瘤、胃癌、胰腺癌、子宫内膜癌、神经内分泌癌、纤维肉瘤、恶性纤维组织细胞瘤、平滑肌肉瘤、骨肉瘤、软骨肉瘤、脂肪肉瘤、滑膜肉瘤、神经鞘瘤、黑色素瘤和神经胶质瘤。
在一些实施方案中,本文所述的多特异性结合蛋白进一步并入与肿瘤相关抗原结合的另外的抗原结合位点,所述肿瘤相关抗原包括与癌症相关的任何抗原,诸如但不限于蛋白质、糖蛋白、神经节苷脂、碳水化合物或脂质。此类抗原可在恶性细胞上或在肿瘤微环境中表达,诸如在肿瘤相关的血管、细胞外基质、间充质基质或免疫浸润物上表达。例如,另外的抗原结合位点可结合到癌细胞上表达的HER2、CD20、CD33、BCMA、PSMA、DLL3、GD2、CD123、Ano1、间皮素、CAIX、TROP2、CEA、紧密连接蛋白-18.2、ROR1、5T4、GPNMB、FR-α、PAPP-A、CD37、EpCAM、CD2、CD19、CD30、CD38、CD40、CD52、CD70、CD79b、FLT3、GPC3、B7H6、CCR4、CXCR4、ROR2、CD133、HLA-E、EGFR/ERBB1、IGF1R、HER3/ERBB3、HER4/ERBB4、MUC1、cMET、SLAMF7、PSCA、MICA、MICB、TRAILR1、TRAILR2、MAGE-A3、B7.1、B7.2、CTLA4、PD1、PD-L1或CD25抗原。因此,在一些实施方案中,多特异性结合蛋白与癌细胞上表达的肿瘤相关抗原的结合使细胞接近自然杀伤细胞,除了通过自然杀伤细胞破坏髓系来源抑制细胞(MDSC)和/或肿瘤相关巨噬细胞(TAM)之外,这还促进了自然杀伤细胞对癌细胞的直接和间接破坏。
多特异性结合蛋白的第三组分结合表达CD16的细胞,CD16是白细胞表面上的Fc受体,所述白细胞包括自然杀伤细胞、巨噬细胞、嗜中性粒细胞、嗜酸性粒细胞、肥大细胞和滤泡树突细胞。
本文所述的多特异性结合蛋白可采取几种形式。例如,一种形式是异二聚体、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)。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。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。第一免疫球蛋白轻链与第一免疫球蛋白重链一起形成结合NKG2D的抗原结合位点。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。在某些实施方案中,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。第二免疫球蛋白轻链与第二免疫球蛋白重链一起形成结合FAP的抗原结合位点。第一Fc结构域和第二Fc结构域一起能够结合CD16(图1)。在一些实施方案中,第一免疫球蛋白轻链与第二免疫球蛋白轻链相同。
另一示例性形式涉及异二聚体、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)。第一免疫球蛋白重链包括经由接头或抗体铰链与单链可变片段(scFv)融合的第一Fc(铰链-CH2-CH3)结构域,所述单链可变片段由配对并结合NKG2D或结合FAP的重链可变结构域和轻链可变结构域组成。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。免疫球蛋白轻链包括轻链可变结构域和轻链恒定结构域。第二免疫球蛋白重链与免疫球蛋白轻链配对并结合NKG2D或结合FAP。第一Fc结构域和第二Fc结构域一起能够结合CD16(图2)。
一个或多个另外的结合基序可任选地经由接头序列融合至恒定区CH3结构域的C末端。在某些实施方案中,抗原结合位点可为单链或二硫键稳定的可变区(scFv)或可形成四价或三价分子。
在一些实施方案中,多特异性结合蛋白为Triomab形式,其为保持IgG样形状的三功能双特异性抗体(例如,图20中所示的多特异性结合蛋白)。这种嵌合双特异性抗体由源自两个亲本抗体的两个半抗体组成,每个半抗体具有一个轻链和一个重链。Triomab形式可为异二聚体,其由1/2的大鼠抗体的和1/2的小鼠抗体组成。
在一些实施方案中,多特异性结合蛋白呈KiH共同轻链(LC)形式,其并入了杵臼(knobs-into-holes,KiH)技术(例如,图21中所示的多特异性结合蛋白)。KiH共同LC形式是异二聚体,其包含与第一靶标结合的Fab、与第二靶标结合的Fab和通过异二聚化突变稳定的Fc结构域。这两个Fab各自包含重链和轻链,其中每个Fab的重链彼此不同,而与每个各自重链配对的轻链对于两个Fab来说是共同的。
KiH技术涉及CH3结构域的工程化,以在每个重链中创建“杵”或“臼”来促进异二聚化。在一个CH3结构域(CH3A)中引入“杵”包括用大残基取代小残基(例如,EU编号中的T366WCH3A)。为了容纳“杵”,通过用较小的残基(例如T366S/L368A/Y407VCH3B)替换最靠近杵的残基来在另一个CH3结构域(CH3B)上引入互补的“臼”表面。通过结构导向的噬菌体文库筛选来优化“臼”突变(Atwell S.等人(1997)J.Mol.Biol.270(1):26–35.)。KiH Fc变体的X射线晶体结构(Elliott J.M.等人(2014)J.Mol.Biol.426(9):1947–57.;Mimoto F.等人(2014)Mol.Immunol;58(1):132–8.)表明,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在热力学上有利于异二聚化,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化。
在一些实施方案中,多特异性结合蛋白为双可变结构域免疫球蛋白(DVD-IgTM)形式,其为包含两个单克隆抗体的靶结合结构域和柔性的天然存在接头的四价IgG样结构(例如,图22)。DVD-IgTM形式为同二聚体,其包含融合到Fab可变结构域靶向抗原1的N端的可变结构域靶向抗原2。图22所示的代表性多特异性结合蛋白包含未修饰的Fc。
在一些实施方案中,多特异性结合蛋白为正交Fab界面(Ortho-Fab)形式(例如,图23中所示的多特异性结合蛋白)。在Ortho-Fab IgG方法(Lewis S.M.等人(2014),Nat.Biotechnol.;32(2):191–8.)中,基于结构的区域设计仅在一个Fab中的LC和HCVH-CH1界面处引入互补突变,而对另一个Fab不进行任何改变。
在一些实施方案中,多特异性结合蛋白呈2-in-1Ig形式(例如,图24中所示的多特异性结合蛋白)。
在一些实施方案中,多特异性结合蛋白呈静电转向(ES)形式,其为包含与靶标1和靶标2结合的两个不同Fab以及Fc结构域的异二聚体(例如,图25中所示的多特异性结合蛋白)。通过Fc结构域中的静电转向突变确保异二聚化。
在一些实施方案中,多特异性结合蛋白呈受控Fab臂交换(cFAE)形式(例如,图26中所示的多特异性结合蛋白)。cFAE形式为双特异性异二聚体,其包含与靶标1和2结合的两个不同的Fab,其中LC-HC对(半分子)已与来自另一分子的LC-HC对互换。通过Fc中的突变确保异二聚化。
在一些实施方案中,多特异性结合蛋白呈链交换工程化结构域(SEED)体形式(例如,图27中所示的多特异性结合蛋白)。SEED平台被设计为产生不对称和双特异性抗体样分子,以便扩展天然抗体的治疗应用。该蛋白质工程化平台基于在保守的CH3结构域内交换免疫球蛋白种类的结构相关序列(例如,IgA和IgG CH3结构域序列的交替片段)。SEED设计允许高效生成异二聚体,同时不利于SEED CH3结构域的同二聚化(Muda M.等人(2011)Protein Eng.Des.Sel.;24(5):447-54.)。在一些实施方案中,多特异性结合蛋白呈LuZ-Y形式(例如,图28中所示的多特异性结合蛋白)。LuZ-Y形式为异二聚体,其包含与Fc结构域融合的结合靶标1和2的两个不同scFab。通过引入与Fc结构域的C端融合的亮氨酸拉链基序来确保异二聚化(Wranik,B.J.等人(2012)J.Biol.Chem.;287:43331-9.)。
在一些实施方案中,多特异性结合蛋白呈Cov-X体形式(例如,图29中所示的多特异性结合蛋白)。双特异性CovX体包含具有共价连接到每个Fab臂的药效团肽异二聚体的支架抗体,其中肽异二聚体的一个分子与第一靶标结合,而肽异二聚体的另一个分子与第二靶标结合,并且其中两个分子通过氮杂环丁酮接头连接。尽管药效团负责功能活性,但抗体支架赋予长的半衰期和Ig样分布。药效团可进行化学优化或用其他药效团替代,以生成优化的或独特的双特异性抗体(Doppalapudi V.R.等人(2010)PNAS;107(52):22611-22616.)。
在一些实施方案中,多特异性结合蛋白呈Kλ体形式,其为包含与由异二聚化突变稳定的Fc结构域融合的两个不同的Fab的异二聚体(例如,图30中所示的多特异性结合蛋白)。第一Fab结合靶标1包含κLC,并且第二Fab结合靶标2包含λLC。图30A是Kλ体的一种形式的示例性表示;图30B是另一种Kλ体的示例性表示。
在一些实施方案中,多特异性结合蛋白呈单臂单链(OAsc)-Fab形式(例如,图31中所示的多特异性结合蛋白)。OAsc-Fab形式是异二聚体,其包括与Fc结构域融合的结合靶标1的Fab和结合靶标2的scFab。通过Fc结构域中的突变确保异二聚化。
在一些实施方案中,多特异性结合蛋白呈DuetMab形式(例如,图32中所示的多特异性结合蛋白)。DuetMab形式是异二聚体,其包含结合靶标1和2的两个不同的Fab,以及通过异二聚化突变来稳定的Fc结构域。两个不同的Fab包含不同的S-S桥,其确保正确的LC和HC配对。
在一些实施方案中,多特异性结合蛋白呈CrossmAb形式(例如,图33中所示的多特异性结合蛋白)。CrossmAb形式是异二聚体,其包含结合靶标1和2的两个不同的Fab,以及通过异二聚化突变来稳定的Fc结构域。CL和CH1结构域与VH和VL结构域进行交换,例如CH1与VL串联(in-line)融合,而CL与VH串联融合。
在一些实施方案中,多特异性结合蛋白呈Fit-Ig形式(例如,图34中所示的多特异性结合蛋白)。Fit-Ig形式是同二聚体,其包含与结合靶标1的Fab的HC的N端融合的结合靶标2的Fab。图34的代表性多特异性结合蛋白包含未修饰的Fc结构域。
表1列出了可组合地结合NKG2D的重链可变结构域和轻链可变结构域的肽序列。除非另有说明,否则表1中提供的CDR序列是在Kabat下测定的。NKG2D结合结构域与NKG2D的结合亲和力可变化,但是它们都激活人NKG2D和NK细胞。
替代地,由SEQ ID NO:101表示的重链可变结构域可与由SEQ ID NO:102表示的轻链可变结构域配对,以形成可结合NKG2D的抗原结合位点,如US 9,273,136中所示。
替代地,由SEQ ID NO:103表示的重链可变结构域可与由SEQ ID NO:104表示的轻链可变结构域配对,以形成可结合NKG2D的抗原结合位点,如US 7,879,985中所示。
在某些实施方案中,本公开提供了结合自然杀伤细胞上的NKG2D受体和CD16受体以及癌细胞上的抗原FAP的多特异性结合蛋白。表2列出了可组合地结合FAP的重链可变结构域和轻链可变结构域的一些示例性序列。在下表2中列出并在对应的专利和出版物中描述的重链和轻链可变结构域氨基酸序列的CDR序列以引用的方式并入本文。除非另有说明,否则表2中提供的CDR序列是在Kabat下测定的。
替代地,可通过筛选与SEQ ID NO:130定义的氨基酸序列的结合来识别可结合FAP的新抗原结合位点。
SEQ ID NO:130
MKTWVKIVFGVATSAVLALLVMCIVLRPSRVHNSEENTMRALTLKDILNGTFSYKTFFPNWISGQEYLHQSADNNIVLYNIETGQSYTILSNRTMKSVNASNYGLSPDRQFVYLESDYSKLWRYSYTATYYIYDLSNGEFVRGNELPRPIQYLCWSPVGSKLAYVYQNNIYLKQRPGDPPFQITFNGRENKIFNGIPDWVYEEEMLATKYALWWSPNGKFLAYAEFNDTDIPVIAYSYYGDEQYPRTINIPYPKAGAKNPVVRIFIIDTTYPAYVGPQEVPVPAMIASSDYYFSWLTWVTDERVCLQWLKRVQNVSVLSICDFREDWQTWDCPKTQEHIEESRTGWAGGFFVSTPVFSYDAISYYKIFSDKDGYKHIHYIKDTVENAIQITSGKWEAINIFRVTQDSLFYSSNEFEEYPGRRNIYRISIGSYPPSKKCVTCHLRKERCQYYTASFSDYAKYYALVCYGPGIPISTLHDGRTDQEIKILEENKELENALKNIQLPKEEIKKLEVDEITLWYKMILPPQFDRSKKYPLLIQVYGGPCSQSVRSVFAVNWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVEDQITAVRKFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVYTERFMGLPTKDDNLEHYKNSTVMARAEYFRNVDYLLIHGTADDNVHFQNSAQIAKALVNAQVDFQAMWYSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSD
在Fc结构域内,CD16结合由铰链区和CH2结构域介导。例如,在人IgG1内,与CD16的相互作用主要集中在氨基酸残基Asp 265-Glu 269、Asn 297-Thr 299、Ala 327-Ile 332、Leu 234-Ser 239和CH2结构域中的碳水化合物残基N-乙酰基-D-葡糖胺(参见例如,SondermannP.等人(2000)Nature;406(6793):267-273.)。基于已知结构域,可选择突变来增强或降低与CD16的结合亲和力,诸如通过使用噬菌体展示文库或酵母表面展示cDNA文库,或可基于已知的相互作用的三维结构进行设计。
异二聚体抗体重链的装配可通过在同一细胞中表达两种不同的抗体重链序列来完成,这可导致每个抗体重链的同二聚体的装配以及异二聚体的装配。可通过在每个抗体重链恒定区的CH3结构域中并入不同的突变来促进异二聚体的优先装配,如US13/494,870、US16/028,850、US11/533,709、US12/875,015、US13/289,934、US14/773,418、US12/811,207、US13/866,756、US14/647,480和US14/830,336所示。例如,可基于人IgG1在CH3结构域中进行突变,并在第一多肽和第二多肽内并入不同的氨基酸取代对,从而使这两条链选择性地彼此异二聚化。如下所示的氨基酸取代位置均如在Kabat中按照EU索引进行编号。
在一种情况下,第一多肽中的氨基酸取代用较大的氨基酸替换原始氨基酸,所述较大的氨基酸选自精氨酸(R)、苯丙氨酸(F)、酪氨酸(Y)或色氨酸(W),并且第二多肽中的至少一个氨基酸取代用较小的氨基酸替换原始氨基酸,所述较小的氨基酸选自丙氨酸(A)、丝氨酸(S)、苏氨酸(T)或缬氨酸(V),使得较大的氨基酸取代(突起)适合较小的氨基酸取代的表面(空腔)。例如,一个多肽可并入T366W取代,而另一个可并入三个取代,包括T366S、L368A和Y407V。
本发明的抗体重链可变结构域可任选地偶联与抗体恒定区具有至少90%同一性的氨基酸序列,所述抗体恒定区诸如包括铰链、CH2和CH3结构域、具有或不具有CH1结构域的IgG恒定区。在一些实施方案中,恒定区的氨基酸序列与人抗体恒定区具有至少90%同一性,所述人抗体恒定区诸如人IgG1恒定区、IgG2恒定区、IgG3恒定区或IgG4恒定区。在一些其他实施方案中,恒定区的氨基酸序列与来自另一种哺乳动物的抗体恒定区具有至少90%同一性,所述另一种哺乳动物诸如兔、狗、猫、小鼠或马。与人IgG1恒定区相比,可将一个或多个突变并入恒定区,例如位于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。示例性取代包括,例如,Q347E、Q347R、Y349S、Y349K、Y349T、Y349D、Y349E、Y349C、T350V、L351K、L351D、L351Y、S354C、E356K、E357Q、E357L、E357W、K360E、K360W、Q362E、S364K、S364E、S364H、S364D、T366V、T366I、T366L、T366M、T366K、T366W、T366S、L368E、L368A、L368D、K370S、N390D、N390E、K392L、K392M、K392V、K392F、K392D、K392E、T394F、T394W、D399R、D399K、D399V、S400K、S400R、D401K、F405A、F405T、Y407A、Y407I、Y407V、K409F、K409W、K409D、T411D、T411E、K439D和K439E。
在某些实施方案中,可并入人IgG1恒定区的CH1中的突变可位于氨基酸V125、F126、P127、T135、T139、A140、F170、P171和/或V173。在某些实施方案中,可并入人IgG1恒定区的Cκ中的突变可位于氨基酸E123、F116、S176、V163、S174和/或T164。
替代地,氨基酸取代可选自表3所示的以下取代组。
替代地,氨基酸取代可选自表4所示的以下取代组。
表4 | ||
第一多肽 | 第二多肽 | |
组1 | K409W | D399V/F405T |
组2 | Y349S | E357W |
组3 | K360E | Q347R |
组4 | K360E/K409W | Q347R/D399V/F405T |
组5 | Q347E/K360E/K409W | Q347R/D399V/F405T |
组6 | Y349S/K409W | E357W/D399V/F405T |
替代地,氨基酸取代可以选自表5所示的以下取代组。
表5 | ||
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 |
替代地,每个多肽链中的至少一个氨基酸取代可选自表6。
替代地,至少一个氨基酸取代可选自表7中的以下取代组,其中第一多肽列中所示的位置被任何已知的带负电荷的氨基酸替换,并且第二多肽列中所示的位置被任何已知的带正电荷的氨基酸替换。
表7 | |
第一多肽 | 第二多肽 |
K392、K370、K409或K439 | D399、E356或E357 |
替代地,至少一个氨基酸取代可选自表8中的以下取代组,其中第一多肽列中所示的位置被任何已知的带正电荷的氨基酸替换,并且第二多肽列中所示的位置被任何已知的带负电荷的氨基酸替换。
表8 | |
第一多肽 | 第二多肽 |
D399、E356或E357 | K409、K439、K370或K392 |
替代地,氨基酸取代可选自表9中的以下组。
替代地,或另外地,可通过在第一或第二多肽链中的任一个上引入S354C和在相反的多肽链上引入Y349C,从而在两个多肽的界面内形成人工二硫键来增加异源多聚体蛋白的结构稳定性。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在位置T366处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由T366、L368和Y407组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由T366、L368和Y407组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在位置T366处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由E357、K360、Q362、S364、L368、K370、T394、D401、F405和T411组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由Y349、E357、S364、L368、K370、T394、D401、F405和T411组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由Y349、E357、S364、L368、K370、T394、D401、F405和T411组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由E357、K360、Q362、S364、L368、K370、T394、D401、F405和T411组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由L351、D399、S400和Y407组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由T366、N390、K392、K409和T411组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由T366、N390、K392、K409和T411组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由L351、D399、S400和Y407组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由Q347、Y349、K360和K409组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由Q347、E357、D399和F405组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由Q347、E357、D399和F405组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由Y349、K360、Q347和K409组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由K370、K392、K409和K439组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由D356、E357和D399组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由D356、E357和D399组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由K370、K392、K409和K439组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由L351、E356、T366和D399组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由Y349、L351、L368、K392和K409组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列在选自由Y349、L351、L368、K392和K409组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列在选自由L351、E356、T366和D399组成的组的一个或多个位置处与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列通过S354C取代与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列通过Y349C取代与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列通过Y349C取代与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列通过S354C取代与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列通过K360E和K409W取代与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列通过Q347R、D399V和F405T取代与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列通过Q347R、D399V和F405T取代与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列通过K360E和K409W取代与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列通过T366W取代与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列通过T366S、T368A和Y407V取代与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列通过T366S、T368A和Y407V取代与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列通过T366W取代与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列通过T350V、L351Y、F405A和Y407V取代与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列通过T350V、T366L、K392L和T394W取代与IgG1恒定区的氨基酸序列不同。
在一些实施方案中,抗体恒定区的一个多肽链的氨基酸序列通过T350V、T366L、K392L和T394W取代与IgG1恒定区的氨基酸序列不同,并且其中抗体恒定区的另一个多肽链的氨基酸序列通过T350V、L351Y、F405A和Y407V取代与IgG1恒定区的氨基酸序列不同。
可使用本领域技术人员众所周知的重组DNA技术来制备上述多特异性结合蛋白。例如,可将编码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;可将编码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;可将编码免疫球蛋白轻链的第三核酸序列克隆到第三表达载体中;以及可将第一、第二和第三表达载体一起稳定地转染到宿主细胞中以产生多聚体蛋白。
为了获得多特异性蛋白质的最高产量,可探索第一、第二和第三表达载体的不同比率,以确定转染到宿主细胞中的最佳比率。转染后,可使用本领域已知的方法(诸如有限稀释、ELISA、流式细胞术、显微镜或Clonepix)分离单个克隆以用于产生细胞库。
克隆可在适合生物反应器放大并保持多特异性蛋白的表达的条件下培养。可使用本领域已知的方法分离和纯化多特异性结合蛋白质,包括离心、深度过滤、细胞裂解、均质化、冻融、亲和纯化、凝胶过滤、离子交换色谱、疏水相互作用交换色谱和混合模式色谱。
II.多特异性结合蛋白的特征
本文所述的多特异性结合蛋白包括NKG2D结合位点、CD16结合位点和FAP的结合位点。在某些实施方案中,多特异性结合蛋白同时结合表达NKG2D和/或CD16的细胞(诸如NK细胞)和表达FAP的肿瘤细胞。多特异性结合蛋白与NK细胞的结合可增强NK细胞对癌细胞破坏的活性。
在某些实施方案中,本文所述的多特异性结合蛋白以与具有相同FAP结合位点的对应单克隆抗体相似的亲和力结合FAP。在某些实施方案中,与具有相同FAP结合位点的对应单克隆抗体相比,本文所述的多特异性结合蛋白在减少肿瘤生长和杀死表达FAP的肿瘤细胞方面可更有效。
在某些实施方案中,当与表达FAP的肿瘤细胞共培养时,本文所述的包括NKG2D结合位点和FAP结合位点的多特异性结合蛋白激活原代人NK细胞。NK细胞激活以CD107a表达、脱粒和IFN-γ细胞因子产生的增加为特征。此外,与具有相同FAP结合位点的对应单克隆抗体相比,本文所述的多特异性结合蛋白可在表达FAP的肿瘤细胞存在下显示出对人NK细胞的优异激活。
在某些实施方案中,本文所述的包括NKG2D结合位点和FAP结合位点的多特异性结合蛋白可在表达FAP的肿瘤细胞存在下增强静息的和IL-2激活的人NK细胞的激活。
在某些实施方案中,与具有相同FAP结合位点的对应单克隆抗体相比,本文所述的多特异性结合蛋白可对表达FAP的肿瘤细胞具有更强的细胞毒性活性。
III.治疗应用
本发明提供了使用本文所述的多特异性结合蛋白和/或本文所述的药物组合物来治疗癌症的方法。所述方法可用于治疗多种表达FAP的癌症。待治疗的示例性癌症可为胃癌、结肠直肠癌、胰腺癌、乳腺癌、子宫内膜癌、肺癌、前列腺癌、膀胱癌、宫颈癌、头颈癌、卵巢癌、食道癌、肾癌、肝癌、睾丸癌和口腔癌、多发性骨髓瘤、白血病、急性髓系白血病、黑色素瘤、皮肤基底细胞和鳞状细胞癌、神经胶质瘤、尤因氏肉瘤(Ewing sarcoma)、卡波西氏肉瘤(Kaposi’s sarcoma)和间皮瘤。
在一些其他实施方案中,待治疗的示例性癌症可为肢端雀斑样黑色素瘤、光化性角化病、急性淋巴母细胞白血病、急性淋巴细胞性白血病、急性髓系白血病、腺癌、腺样囊性癌、腺肉瘤、腺鳞癌、肛管癌、间变性大细胞淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、血管肉瘤、肛门直肠癌、星形细胞瘤、前庭大腺癌、基底细胞癌(例如,皮肤)、B细胞淋巴瘤、胆道癌、膀胱癌、骨癌、骨髓癌、脑癌、乳腺癌、支气管癌、支气管腺癌、伯基特淋巴瘤(Burkittlymphoma)、类癌、宫颈癌、胆管癌、软骨肉瘤、脉络丛乳头状瘤/癌、慢性淋巴细胞性白血病、慢性髓系白血病、慢性中性粒细胞白血病、透明细胞癌、结肠癌、结肠直肠癌、结缔组织癌、皮肤T细胞淋巴瘤、囊腺瘤、弥漫性大B细胞淋巴瘤、消化系统癌、十二指肠癌、内分泌系统癌、内胚窦瘤、子宫内膜癌/增生、子宫内膜间质肉瘤、子宫内膜样腺癌、内皮细胞癌、肠病型T细胞淋巴瘤、室管膜癌、上皮细胞癌、食管癌、尤因氏肉瘤、结外边缘区B细胞淋巴瘤、结外自然杀伤细胞/T细胞淋巴瘤、眼眶癌、女性生殖器癌、局灶性结节性增生、滤泡性淋巴瘤、胆囊癌、胃窦癌、胃癌、胃底癌、胃泌素瘤、成胶质细胞瘤、神经胶质瘤、胰高血糖素瘤、毛细胞白血病、头颈部癌、心脏癌、血管母细胞瘤、血管内皮瘤、血管瘤、血液肿瘤、肝腺瘤、肝腺瘤病、肝细胞癌、肝胆道癌、霍奇金氏病、回肠癌、胰岛素瘤、上皮内瘤变、上皮间鳞状细胞癌、肝内胆管癌、浸润性鳞状细胞癌、空肠癌、关节癌、卡波西氏肉瘤、肾癌、大细胞癌、大肠癌、平滑肌肉瘤、雀斑恶性黑色素瘤、白血病、肝癌、肺癌、淋巴瘤、淋巴浆细胞淋巴瘤、男性生殖器癌、恶性黑色素瘤、恶性间皮瘤、套细胞淋巴瘤、边缘区B细胞淋巴瘤、成神经管细胞瘤、髓上皮瘤、黑色素瘤、脑膜癌、间皮癌、间皮瘤、转移癌、口腔癌、粘液表皮样癌、多发性骨髓瘤、肌肉癌、骨髓增生异常赘瘤、骨髓增生性赘瘤、鼻道癌、神经系统癌、神经母细胞瘤、神经上皮腺癌、结内边缘区B细胞淋巴瘤、结节性黑色素瘤、非上皮性皮肤癌、非霍奇金氏淋巴瘤、燕麦细胞癌、少突胶质癌、口腔癌、骨肉瘤、卵巢癌、胰腺癌、乳头状浆液性腺癌、腮腺癌、盆腔癌、阴茎癌、外周T细胞淋巴瘤、咽癌、垂体瘤、浆细胞瘤、前体T淋巴母细胞淋巴瘤、原发性中枢神经系统淋巴瘤、原发性纵隔B细胞淋巴瘤、前列腺癌、假性肉瘤、肺母细胞瘤、直肠癌、肾癌、肾细胞癌、呼吸系统癌、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、浆液性癌、鼻窦癌、皮肤癌、小细胞癌、小肠癌、小淋巴细胞淋巴瘤、平滑肌癌、软组织癌、生长抑素分泌肿瘤、脊柱癌、脾边缘区B细胞淋巴瘤、鳞状细胞癌(例如,皮肤)、横纹肌癌、皮下脂膜炎样T细胞淋巴瘤、间皮下癌、浅表扩散性黑色素瘤、T细胞白血病、T细胞淋巴瘤、睾丸癌、甲状腺癌、舌癌、未分化癌、输尿管癌、尿道癌、膀胱癌、子宫癌、子宫体癌、葡萄膜黑色素瘤、阴道癌、疣状癌、VIP瘤、外阴癌、高分化癌或维尔姆斯瘤(Wilms tumor)。
在某些实施方案中,本发明提供了一种治疗患者自身免疫性疾病的方法。待治疗的示例性自身免疫性疾病包括
关节炎、类风湿性关节炎、青少年类风湿性关节炎、炎性破坏性关节炎、动脉粥样硬化、自身免疫性心肌炎、白细胞粘附缺陷、青少年型糖尿病、多发性硬化症、骨关节炎、银屑病性关节炎、牛皮癣、皮炎、系统性红斑狼疮(SLE)、多发性肌炎/皮肌炎、中毒性表皮坏死松解症、系统性硬皮病和硬化症、炎症性肠病相关反应、克罗恩病氏(Crohn's disease)、溃疡性结肠炎、呼吸窘迫综合征、成人呼吸窘迫综合征(ARDS)、脑膜炎、脑炎、葡萄膜炎、结肠炎、肾小球肾炎、过敏性病症、湿疹、哮喘、T细胞浸润和慢性炎症反应相关的病症、过敏性脑脊髓炎、细胞因子和T淋巴细胞介导的急性和迟发性超敏反应相关的免疫反应、结核病、肉样瘤病、包括韦格纳肉芽肿病(Wegener's granulomatosis)的肉芽肿病、粒细胞缺乏症、血管炎(包括ANCA)、再生障碍性贫血、先天性纯红细胞再生障碍性贫(Diamond Blackfananemia)、包括自身免疫性溶血性贫血(AIHA)的免疫性溶血性贫血、恶性贫血、纯红细胞再生障碍(PRCA)、因子VIII缺乏症、血友病A、自身免疫性中性粒细胞减少症、细胞减少症、白细胞减少症、白细胞渗出相关的疾病、中枢神经系统(CNS)炎症性病症、多器官损伤综合征、重症肌无力综合征、抗原抗体复合物介导的疾病、抗肾小球基底膜疾病、抗磷脂抗体综合征、过敏性神经炎、白塞氏病(Bechet disease)、卡斯特曼综合征(Castleman'ssyndrome)、古德帕斯彻氏综合征(Goodpasture's syndrome)、兰伯特-伊顿肌无力综合征(Lambert-Eaton Myasthenic Syndrome)、雷诺氏综合征(Reynaud's syndrome)、干燥综合征(Sjorgen's syndrome)、史蒂文斯-约翰逊综合征(Stevens-Johnson syndrome)、实体器官移植排斥反应、移植物抗宿主病(GVHD)、大疱性类天疱疮、天疱疮、自身免疫性多内分泌腺病、赖特尔病(Reiter's disease)、僵人综合征、巨细胞动脉炎、免疫复合物肾炎、IgA肾病、IgM多发性神经病或IgM介导的神经病变、特发性血小板减少性紫癜(ITP)、血栓性血小板减少性紫癜(TTP)、自身免疫性血小板减少症、包括自身免疫性睾丸炎和卵巢炎的睾丸和卵巢自身免疫性疾病、原发性甲状腺功能减退症;包括自身免疫性甲状腺炎的自身免疫性内分泌疾病、慢性甲状腺炎(桥本氏甲状腺炎(Hashimoto's Thyroiditis))、原发性硬化性胆管炎、亚急性甲状腺炎、特发性甲状腺机能减退、阿狄森氏病(Addison's disease)、格雷夫斯病、自身免疫性多腺综合征(或多腺内分泌病综合征)、I型糖尿病也称为胰岛素依赖型糖尿病(IDDM)和席汉氏综合征(Sheehan's syndrome);自身免疫性肝炎、淋巴样间质性肺炎(HIV)、闭塞性细支气管炎(非移植)与NSIP、格林-巴利综合征(Guillain-Barre'Syndrome)、大血管血管炎(包括风湿性多肌痛和巨细胞(高安氏(Takayasu's))动脉炎)、中血管血管炎(包括川琦氏病(Kawasaki's disease)和结节性多动脉炎)、强直性脊柱炎、贝格尔病(Berger's disease)(IgA肾病)、急进性肾小球肾炎、原发性胆汁性肝硬化、乳糜泻(Celiac sprue)(麸质肠病)、冷球蛋白血症、肌萎缩性侧索硬化症(ALS)或冠状动脉疾病。
在某些实施方案中,本发明提供了一种治疗患者纤维化的方法。方法包括向有此需要的患者施用治疗有效量的本文所述的多特异性结合蛋白。待使用靶向FAP的多特异性结合蛋白治疗的纤维化可能与间质性肺病、肝硬化、肾病、心脏病、眼病、硬皮病、瘢痕疙瘩和增生性疤痕、动脉粥样硬化和再狭窄、手术疤痕、化疗药物的使用、放射疗法、物理损伤或灼伤有关。例如,纤维化可为特发性肺纤维化、肾纤维化、肝纤维化或心脏纤维化。
IV.联合疗法
本发明的另一方面提供了联合疗法。本文所述的多特异性结合蛋白可与另外的治疗剂组合使用来治疗癌症。
可用作治疗癌症的联合疗法的一部分的示例性治疗剂包括,例如辐射、丝裂霉素(mitomycin)、维甲酸(tretinoin)、盐酸苯达莫司汀(ribomustin)、吉西他滨(gemcitabine)、长春新碱(vincristine)、依托泊苷(etoposide)、克拉屈滨(cladribine)、二溴甘露醇(mitobronitol)、甲氨蝶呤(methotrexate)、阿霉素(doxorubicin)、卡波醌(carboquone)、喷司他汀(pentostatin)、硝氨吖啶(nitracrine)、净司他丁(zinostatin)、西曲瑞克(cetrorelix)、来曲唑(letrozole)、雷替曲塞(raltitrexed)、柔红霉素(daunorubicin)、法屈唑(fadrozole)、福莫司汀(fotemustine)、腺法新(thymalfasin)、索布佐生(sobuzoxane)、奈达铂(nedaplatin)、阿糖胞苷(cytarabine)、比卡鲁胺(bicalutamide)、长春瑞滨(vinorelbine)、维司立农(vesnarinone)、氨鲁米特(aminoglutethimide)、安吖啶(amsacrine)、丙谷胺(proglumide)、依利醋铵(elliptiniumacetate)、酮舍林(ketanserin)、去氧氟尿苷(doxifluridine)、依曲替酯(etretinate)、异维甲酸(isotretinoin)、链佐星(streptozocin)、尼莫司汀(nimustine)、长春地辛(vindesine)、氟他米特(flutamide)、氟他胺(drogenil)、甘氨硫嘌呤(butocin)、卡莫氟(carmofur)、雷佐生(razoxane)、裂褶菌素(sizofilan)、卡铂(carboplatin)、二溴卫矛醇(mitolactol)、替加氟(tegafur)、异磷酰胺(ifosfamide)、泼尼莫司汀(prednimustine)、毕西巴尼(picibanil)、左旋咪唑(levamisole)、替尼泊苷(teniposide)、英丙舒凡(improsulfan)、依诺他滨(enocitabine)、麦角乙脲(lisuride)、羟甲烯龙(oxymetholone)、他莫昔芬(tamoxifen)、黄体酮(progesterone)、美雄烷(mepitiostane)、环硫雄醇(epitiostanol)、福美司坦(formestane)、干扰素-α、干扰素-2α、干扰素-β、干扰素-γ、集落刺激因子-1、集落刺激因子-2、地尼白介素-白喉毒素连接物(denileukin diftitox)、白介素-2、促黄体激素释放因子和可能表现出与其同源受体的不同结合以及增加或减少的血清半衰期的上述剂的各种变体。
可用作治疗癌症的联合疗法的一部分的另一类剂是免疫检查点抑制剂。示例性免疫检查点抑制剂包括抑制以下一种或多种的剂:(i)细胞毒性T淋巴细胞相关抗原4(CTLA4)、(ii)程序性细胞死亡蛋白1(PD1)、(iii)PDL1、(iv)LAG3、(v)B7-H3、(vi)B7-H4和(vii)TIM3。CTLA4抑制剂伊匹木单抗已被美国食品和药物管理局批准用于治疗黑色素瘤。
可用作治疗癌症的联合疗法的一部分的其他剂是靶向非检查点靶标的单克隆抗体剂(例如赫赛汀(herceptin))和非细胞毒性剂(例如酪氨酸激酶抑制剂)。
其他类别的抗癌剂包括例如:(i)选自ALK抑制剂、ATR抑制剂、A2A拮抗剂、碱基切除修复抑制剂、Bcr-Abl酪氨酸激酶抑制剂、布鲁顿酪氨酸激酶抑制剂、CDC7抑制剂、CHK1抑制剂、细胞周期蛋白依赖性激酶抑制剂、DNA-PK抑制剂、DNA-PK和mTOR抑制剂、DNMT1抑制剂、DNMT1抑制剂加2-氯-脱氧腺苷、HDAC抑制剂、Hedgehog信号传导通路抑制剂、IDO抑制剂、JAK抑制剂、mTOR抑制剂、MEK抑制剂、MELK抑制剂、MTH1抑制剂、PARP抑制剂、磷酸肌醇3-激酶抑制剂、PARP1和DHODH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手术切除原发病灶的辅助物。
可选择多特异性结合蛋白和另外的治疗剂的量以及施用的相对时间,以便获得期望的联合治疗效果。例如,当向需要这种施用的患者施用联合疗法时,组合中的治疗剂或包含治疗剂的一种或多种药物组合物可以任何顺序,例如依次、共同、一起、同时等施用。此外,例如,多特异性结合蛋白可在另外的治疗剂发挥其预防或治疗作用期间施用,反之亦然。
V.药物组合物
本公开的特征还在于含有治疗有效量的本文所述的蛋白质的药物组合物。组合物可配制用于各种药物递送系统。一种或多种生理上可接受的赋形剂或载剂也可包括在组合物中以进行适当配制。用于本公开的合适制剂参见Remington's PharmaceuticalSciences,第17版MackPublishing Company,Easton,PA(1985)。关于药物递送方法的简要综述,参见,例如,Langer T.,Science;249(4976):1527-1533。
本公开的静脉内药物递送制剂可包含在袋、笔或注射器中。在某些实施方案中,袋可连接到包括管和/或针的通道。在某些实施方案中,制剂可为冻干制剂或液体制剂。在某些实施方案中,可将制剂冷冻干燥(冻干)并包含在约12-60个小瓶中。在某些实施方案中,可将制剂冷冻干燥,并且45mg冷冻干燥制剂可包含在一个小瓶中。在某些实施方案中,约40mg至约100mg的冷冻干燥制剂可包含在一个小瓶中。在某些实施方案中,将来自12、27或45个小瓶的冷冻干燥制剂组合以获得在静脉内药物制剂中的治疗剂量的蛋白质。在某些实施方案中,制剂可为液体制剂并且以约250mg/小瓶至约1000mg/小瓶储存。在某些实施方案中,制剂可为液体制剂并且以约600mg/小瓶储存。在某些实施方案中,制剂可为液体制剂并且以约250mg/小瓶储存。
本公开可以液体水性药物制剂存在,其在缓冲溶液中包括治疗有效量的多特异性蛋白。
本文所公开的组合物可通过常规灭菌技术来灭菌,或可进行无菌过滤。可将得到的水溶液包装用于原样使用,或冻干,其中将冻干的制剂在施用之前与无菌水性载剂合并。制剂的pH通常在3与11之间,更优选在5与9之间或在6与8之间,并且最优选在7与8之间,诸如7至7.5。可将固体形式的所得组合物包装在多个单剂量单位中,每个单位包含固定量的上述一种或多种剂。固体形式的组合物也可包装在容器中以灵活取量。
在某些实施方案中,本公开提供了具有延长的保质期的制剂,其包括本公开的多特异性蛋白以及甘露醇、柠檬酸一水合物、柠檬酸钠、磷酸氢二钠二水合物、磷酸二氢钠二水合物、氯化钠、聚山梨酸酯80、水和氢氧化钠。
在某些实施方案中,制备在pH缓冲溶液中包含本公开的蛋白质的水性制剂。本发明的缓冲剂可具有约4至约8,例如约4.5至约6.0,或约4.8至约5.5的pH,或可具有约5.0至约5.2的pH。上述pH值的中间范围也意图成为本公开的一部分。例如,意图包括使用上述任意值的组合作为上限和/或下限的值的范围。将pH控制在该范围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。
在某些实施方案中,制剂包括含有柠檬酸盐和磷酸盐的缓冲体系,以将pH保持在约4至约8的范围内。在某些实施方案中,pH范围可为约4.5至约6.0,或约pH4.8至约5.5,或在约5.0至约5.2的pH范围内。在某些实施方案中,缓冲体系包括柠檬酸一水合物、柠檬酸钠、磷酸二钠二水合物和/或磷酸二氢钠二水合物。在某些实施方案中,缓冲体系包含约1.3mg/mL的柠檬酸(例如1.305mg/mL)、约0.3mg/mL的柠檬酸钠(例如0.305mg/mL)、约1.5mg/mL的磷酸二钠二水合物(例如1.53mg/mL)、约0.9mg/mL的磷酸二氢钠二水合物(例如0.86)和约6.2mg/mL的氯化钠(例如6.165mg/mL)。在某些实施方案中,缓冲体系包括1-1.5mg/mL的柠檬酸、0.25至0.5mg/mL的柠檬酸钠、1.25至1.75mg/mL的磷酸二钠二水合物、0.7至1.1mg/mL的磷酸二氢钠二水合物以及6.0至6.4mg/mL的氯化钠。在某些实施方案中,制剂的pH用氢氧化钠调节。
在本文所述的制剂中还可包括多元醇,其可用作张力剂并可稳定抗体。将多元醇以相对于制剂的所需等渗性可变化的量加入到制剂中。在某些实施方案中,水性制剂可为等渗的。相对于多元醇的分子量,多元醇的添加量也可改变。例如,与二糖(诸如海藻糖)相比,可加入较少量的单糖(例如甘露醇)。在某些实施方案中,可在制剂中用作张度剂的多元醇是甘露醇。在某些实施方案中,甘露醇浓度可为约5至约20mg/mL。在某些实施方案中,甘露醇的浓度可为约7.5至15mg/mL。在某些实施方案中,甘露醇的浓度可为约10至14mg/mL。在某些实施方案中,甘露醇的浓度可为约12mg/mL。在某些实施方案中,多元醇山梨糖醇可包含在制剂中。
也可将洗涤剂或表面活性剂加入本发明的制剂中。示例性洗涤剂包括非离子型洗涤剂,诸如聚山梨酸酯(例如聚山梨酸酯20、80等)或泊洛沙姆(例如泊洛沙姆188)。添加的洗涤剂的量应使得其减少配制的抗体的聚集和/或最小化制剂中颗粒的形成和/或减少吸附。在某些实施方案中,制剂可包含表面活性剂,其为聚山梨酸酯。在某些实施方案中,制剂可包含洗涤剂聚山梨酸酯80或吐温80。吐温80是用于描述聚氧乙烯(20)失水山梨醇单油酸酯的术语(例如,Fiedler H.P.,Lexikon der Hifsstoffe für Pharmazie,Kosmetik undandrenzende Gebiete,第4版,Editio Cantor,Aulendorf,Germany(1996))。在某些实施方案中,制剂可包含约0.1mg/mL与约10mg/mL之间或约0.5mg/mL与约5mg/mL之间的聚山梨酸酯80。在某些实施方案中,可在制剂中添加约0.1%的聚山梨酸酯80。
在某些实施方案中,本公开的多特异性蛋白产品被配制为液体制剂。液体制剂可以10mg/mL的浓度存在于USP/Ph Eur I型50R小瓶中,所述小瓶用橡胶塞封闭,并用铝卷边密封封口密封。塞子可由符合USP和PhEur的弹性体制成。在某些实施方案中,小瓶可填充有61.2mL的多特异性蛋白产品溶液,以允许60mL的可提取体积。在某些实施方案中,液体制剂可用0.9%盐水溶液稀释。
在某些实施方案中,本公开的液体制剂可与稳定水平的糖组合制成10mg/mL浓度的溶液。在某些实施方案中,液体制剂可在水性载剂中制备。在某些实施方案中,稳定剂可以不大于可能导致不希望的或不适合静脉内施用的粘度的量加入。在某些实施方案中,糖可为二糖,例如蔗糖。在某些实施方案中,液体制剂还可包含缓冲剂、表面活性剂和防腐剂中的一种或多种。
在某些实施方案中,液体制剂的pH可通过添加药学上可接受的酸和/或碱来设定。在某些实施方案中,药学上可接受的酸可为盐酸。在某些实施方案中,碱可为氢氧化钠。
除聚集外,脱氨基是肽和蛋白质的常见产物变化,其可能在发酵、收获/细胞澄清、纯化、原料药/药品储存以及样品分析期间发生。在生理条件下,脱氨基是蛋白质天冬酰胺残基失去氨(NH3),导致质量降低17道尔顿并形成琥珀酰亚胺中间体。琥珀酰亚胺随后的水解导致质量增加18道尔顿,并形成天冬氨酸或异天冬氨酸。影响脱氨基速率的参数包括pH、温度、溶剂介电常数、离子强度、一级序列、局部多肽构象和三级结构。肽链中与Asn相邻的氨基酸残基也可能影响脱氨基速率,例如,Asn残基之后的Gly和Ser导致对脱氨基具有更高敏感性。
在某些实施方案中,本公开的液体制剂可在防止蛋白质产物的脱氨基的pH和湿度的条件下保存。
本文所关注的水性载剂是药学上可接受的(即对于施用于人而言是安全且无毒的)并且可用于制备液体制剂。示例性载剂包括无菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH缓冲溶液(例如磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液或右旋糖溶液。
可将防腐剂任选地添加到本文的制剂中以减少细菌作用。防腐剂的添加可例如促进多用途(多剂量)制剂的生产。
在特定情况下,诸如当患者在移植后在医院通过IV途径接受所有药物时,静脉内(IV)制剂可能是优选的施用途径。在某些实施方案中,液体制剂在施用前用0.9%氯化钠溶液稀释。在某些实施方案中,用于注射的稀释药品是等渗的并且适合于通过静脉内输注进行施用。
在某些实施方案中,可以约10mM至约200mM的量添加盐或缓冲液组分。盐和/或缓冲液是药学上可接受的,并且衍生自具有“碱形成”金属或胺的各种已知酸(无机和有机)。在某些实施方案中,缓冲液可为磷酸盐缓冲液。在某些实施方案中,缓冲液可为甘氨酸盐、碳酸盐或柠檬酸盐缓冲液,在这种情况下,钠、钾或铵离子可用作抗衡离子。
可将防腐剂任选地添加到本文的制剂中以减少细菌作用。防腐剂的添加可例如促进多用途(即多剂量)制剂的生产。
本文所关注的水性载剂是药学上可接受的(即对于施用于人而言是安全且无毒的)并且可用于制备液体制剂。示例性载剂包括SWFI、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。
本公开可以包含蛋白质和冻干保护剂的冻干制剂存在。冻干保护剂可为糖,例如二糖。在某些实施方案中,冻干保护剂可为蔗糖或麦芽糖。冻干制剂还可包含缓冲剂、表面活性剂、填充剂和/或防腐剂中的一种或多种。
可用于稳定冻干药品的蔗糖或麦芽糖的量可为至少1:2蛋白质与蔗糖或麦芽糖的重量比。在某些实施方案中,蛋白质与蔗糖或麦芽糖的重量比可为1:2至1:5。
在某些实施方案中,可在冻干之前通过添加药学上可接受的酸和/或碱来设定冻干制剂的pH。在某些实施方案中,药学上可接受的酸可为盐酸。在某些实施方案中,药学上可接受的碱可为氢氧化钠。
在冻干之前,可将包含本公开的蛋白质的溶液的pH调节在6与8之间。在某些实施方案中,冻干药品的pH范围可为7至8。
在冻干制剂的某些实施方案中,可以10mM至200mM的量添加盐或缓冲液组分。盐和/或缓冲液是药学上可接受的,并且衍生自具有“碱形成”金属或胺的各种已知酸(无机和有机)。在某些实施方案中,缓冲液可为磷酸盐缓冲液。在某些实施方案中,缓冲液可为甘氨酸盐、碳酸盐、柠檬酸盐缓冲液,在这种情况下,钠、钾或铵离子可用作抗衡离子。
在某些实施方案中,可将“填充剂”添加到冻干制剂中。“填充剂”是这样的化合物,其增加冻干混合物质量并且有助于冻干饼的物理结构(例如,促进维持开孔结构的基本上均匀的冻干饼的生产)。示例性填充剂包括甘露醇、甘氨酸、聚乙二醇和山梨醇。本发明的冻干制剂可包含此类填充剂。
可将防腐剂任选地添加到本文的冻干制剂中以减少细菌作用。防腐剂的添加可例如促进多用途(即多剂量)制剂的生产。
在某些实施方案中,冻干药品可用水性稀释剂构制。本文所关注的水性稀释剂是药学上可接受的(例如对于施用于人而言是安全且无毒的)并且在冻干后可用于制备复水液体制剂。示例性稀释剂包括SWFI、BWFI、pH缓冲溶液(例如磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液或右旋糖溶液。
在某些实施方案中,将本公开的冻干药品用SWFI或0.9%氯化钠注射液USP复水。在复水期间,冻干粉末溶解成溶液。
在某些实施方案中,将本公开的冻干蛋白产品构制到约4.5mL注射用水中,并用0.9%盐水溶液(氯化钠溶液)稀释。
本发明药物组合物中活性成分的实际剂量水平可能有所变化,以便获得对于特定患者、组合物和施用方式有效达到期望治疗反应而对患者不具毒性的活性成分的量。
对于每个患者,特定剂量可为统一剂量,例如50至5000mg蛋白质。替代地,患者的剂量可根据患者的近似体重或表面积进行调整。确定合适剂量的其他因素可包括待治疗或预防的疾病或病状、疾病的严重程度、施用途径以及患者的年龄、性别和医疗状况。确定合适的治疗剂量所必需的计算的进一步改进是本领域技术人员常规进行的,尤其是根据本文公开的剂量信息和测定法。剂量也可通过使用已知的用于确定剂量的测定法结合适当的剂量-反应数据来确定。可在监测疾病进展时调整个体患者的剂量。可测量患者中可靶向构建体或复合物的血液水平,以查看是否需要调整剂量以达到或维持有效浓度。药物基因组学可用于确定哪种可靶向的构建体和/或复合物及其剂量对于给定个体最可能有效(参见,例如,Schmitz等人(2001)Clinica ChimicaActa;308:43-53.;Steimer等人(2001)ClinicaChimica Acta;308:33-41.)。
通常,基于体重的剂量为每kg体重约0.01μg至约100mg,诸如约0.01μg至约100mg/kg体重、约0.01μg至约50mg/kg体重、约0.01μg至约10mg/kg体重、约0.01μg至约1mg/kg体重、约0.01μg至约100μg/kg体重、约0.01μg至约50μg/kg体重、约0.01μg至约10μg/kg体重、约0.01μg至约1μg/kg体重、约0.01μg至约0.1μg/kg体重、约0.1μg至约100mg/kg体重、约0.1μg至约50mg/kg体重、约0.1μg至约10mg/kg体重、约0.1μg至约1mg/kg体重、约0.1μg至约100μg/kg体重、约0.1μg至约10μg/kg体重、约0.1μg至约1μg/kg体重、约1μg至约100mg/kg体重、约1μg至约50mg/kg体重、约1μg至约10mg/kg体重、约1μg至约1mg/kg体重、约1μg至约100μg/kg体重、约1μg至约50μg/kg体重、约1μg至约10μg/kg体重、约10μg至约100mg/kg体重、约10μg至约50mg/kg体重、约10μg至约10mg/kg体重、约10μg至约1mg/kg体重、约10μg至约100μg/kg体重、约10μg至约50μg/kg体重、约50μg至约100mg/kg体重、约50μg至约50mg/kg体重、约50μg至约10mg/kg体重、约50μg至约1mg/kg体重、约50μg至约100μg/kg体重、约100μg至约100mg/kg体重、约100μg至约50mg/kg体重、约100μg至约10mg/kg体重、约100μg至约1mg/kg体重、约1mg至约100mg/kg体重、约1mg至约50mg/kg体重、约1mg至约10mg/kg体重、约10mg至约100mg/kg体重、约10mg至约50mg/kg体重或约50mg至约100mg/kg体重。
剂量可每天、每周、每月或每年给药一次或多次,或甚至每2至20年给药一次。本领域普通技术人员可基于体液或组织中可靶向构建体或复合物的测得停留时间和浓度轻易地估算给药的重复率。本发明的施用可为静脉内、动脉内、腹膜内、肌内、皮下、胸膜内、鞘内、腔内、通过导管灌注或通过病灶内直接注射。可每天施用一次或多次、每周施用一次或多次、每月施用一次或多次或每年施用一次或多次。
上面的说明描述了本发明的多个方面和实施方案。本专利申请具体地涵盖所述方面和实施方案的所有组合和排列。
实施例
现在参考以下实施例将更容易理解本发明的一般描述,所述实施例仅出于说明本发明的某些方面和实施方案的目的,而无意于限制本发明。
实施例1-NKG2D结合结构域与NKG2D结合
NKG2D结合结构域与纯化的重组NKG2D结合
将人、小鼠或食蟹猴NKG2D胞外域的核酸序列与编码人IgG1 Fc结构域的核酸序列融合,并导入哺乳动物细胞中进行表达。纯化后,将NKG2D-Fc融合蛋白吸附到微孔板的孔中。用牛血清白蛋白封闭孔以防止非特异性结合后,将NKG2D结合结构域滴定并添加到预先吸附有NKG2D-Fc融合蛋白的孔中。使用缀合至辣根过氧物酶并特异性识别人κ轻链以避免Fc交叉反应性的二抗来检测一抗结合。将作为辣根过氧物酶底物的3,3',5,5'-四甲基联苯胺(TMB)添加至孔以便观测结合信号,在450nM下测量其吸光度并在540nM下校正。将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,或抗小鼠NKG2D克隆MI-6和CX-5(eBioscience,San Diego,CA))添加到每个孔中。
同种型对照显示与重组NKG2D-Fc蛋白的结合最小,而阳性对照与重组抗原的结合最强。尽管克隆之间的亲和力各不相同,但所有克隆产生的NKG2D结合结构域均能在人、小鼠和食蟹猴重组NKG2D-Fc蛋白中证实结合。通常,每个抗NKG2D克隆以相似的亲和力结合人(图3)和食蟹猴(图4)重组NKG2D-Fc,但是与小鼠(图5)重组NKG2D-Fc的亲和力较低。
NKG2D结合结构域与表达NKG2D的细胞结合
将EL4小鼠淋巴瘤细胞系工程化以表达人或小鼠NKG2D-CD3ζ信号传导结构域嵌合抗原受体。以100nM浓度使用NKG2D结合克隆、同种型对照或阳性对照来染色EL4细胞上表达的细胞外NKG2D。使用荧光团缀合的抗人IgG二抗检测抗体结合。通过流式细胞术分析细胞,并与亲代EL4细胞相比,使用表达NKG2D的细胞的平均荧光强度(MFI)计算背景倍数(FOB)。
由所有克隆产生的NKG2D结合结构域与表达人和小鼠NKG2D的EL4细胞结合。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,或抗小鼠NKG2D克隆MI-6和CX-5(eBioscience,San Diego,CA))给出了最佳的FOB结合信号。在表达人NKG2D(图6)和小鼠(图7)NKG2D的细胞之间,每个克隆的NKG2D结合亲和力是相似的。
实施例2-NKG2D结合结构域阻断天然配体与NKG2D的结合与ULBP-6竞争
将重组人NKG2D-Fc蛋白吸附到微孔板的孔中,并用牛血清白蛋白封闭孔以减少非特异性结合。将饱和浓度的ULBP-6-His-生物素添加到孔中,然后添加NKG2D结合结构域克隆。孵育2小时后,洗涤孔,并通过与辣根过氧化物酶缀合的链霉亲和素和TMB底物检测仍与NKG2D-Fc包被的孔结合的ULBP-6-His-生物素。在450nM下测量吸光度,并在540nM下校正。减去背景后,由被阻断与孔中NKG2D-Fc蛋白结合的ULBP-6-His-生物素的百分比计算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NKG2D结合结构域阻断了ULBP-6与NKG2D的结合,而同种型对照显示与ULBP-6的竞争很小(图8)。
ULBP-6序列由SEQ ID NO:150表示。
MAAAAIPALLLCLPLLFLLFGWSRARRDDPHSLCYDITVIPKFRPGPRWCAVQGQVDEKTFLHYDCGNKTVTPVSPLGKKLNVTMAWKAQNPVLREVVDILTEQLLDIQLENYTPKEPLTLQARMSCEQKAEGHSSGSWQFSIDGQTFLLFDSEKRMWTTVHPGARKMKEKWENDKDVAMSFHYISMGDCIGWLEDFLMGMDSTLEPSAGAPLAMSSGTTQLRATATTLILCCLLIILPCFILPGI(SEQ ID NO:150)
与MICA竞争
将重组人MICA-Fc蛋白吸附到微孔板的孔中,并用牛血清白蛋白封闭孔以减少非特异性结合。将NKG2D-Fc-生物素加入孔中,然后加入NKG2D结合结构域。孵育和洗涤后,使用链霉亲和素-HRP和TMB底物检测仍与MICA-Fc包被的孔结合的NKG2D-Fc-生物素。在450nM下测量吸光度,并在540nM下校正。减去背景后,由被阻断与MICA-Fc包被的孔结合的NKG2D-Fc-生物素的百分比计算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NKG2D结合结构域阻断了MICA与NKG2D的结合,而同种型对照显示与MICA的竞争很小(图9)。
与Rae-1δ竞争
将重组小鼠Rae-1δ-Fc(R&D Systems,Minneapolis,MN)吸附到微孔板的孔中,并用牛血清白蛋白封闭孔以减少非特异性结合。将小鼠NKG2D-Fc-生物素添加到孔中,随后添加NKG2D结合结构域。孵育和洗涤后,使用链霉亲和素-HRP和TMB底物检测仍与Rae-1δ-Fc包被的孔结合的NKG2D-Fc-生物素。在450nM下测量吸光度,并在540nM下校正。减去背景后,由被阻断与Rae-1δ-Fc包被的孔结合的NKG2D-Fc-生物素的百分比计算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,或抗小鼠NKG2D克隆MI-6和CX-5,eBioscience,San Diego,CA)和各种NKG2D结合结构域克隆阻断Rae-1δ与小鼠NKG2D的结合,而同种型对照抗体显示与Rae-1δ的竞争很小(图10)。
实施例3-NKG2D结合结构域克隆激活NKG2D
将人和小鼠NKG2D的核酸序列与编码CD3ζ信号传导结构域的核酸序列融合,以获得嵌合抗原受体(CAR)构建体。然后,使用Gibson组装将NKG2D-CAR构建体克隆到逆转录病毒载体中,并转染到expi293细胞中以产生逆转录病毒。将EL4细胞用含有NKG2D-CAR和8μg/mL聚凝胺的病毒感染。感染后24小时,通过流式细胞术分析EL4细胞中NKG2D-CAR的表达水平,并选择在细胞表面表达高水平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中,并且在布雷菲德菌素A和莫能菌素存在下,将NKG2D-CAREL4细胞在抗体片段包被的孔中培养4小时。通过流式细胞术测定了细胞内TNF-α的产生(NKG2D激活的指示剂)。将TNF-α阳性细胞的百分比归一化至阳性对照处理的细胞。所有的NKG2D结合结构域都激活人NKG2D(图11)和小鼠NKG2D(图12)。
实施例4-NKG2D结合结构域激活NK细胞
原代人NK细胞
使用密度梯度离心从人外周血血沉棕黄层中分离出外周血单核细胞(PBMC)。用磁珠通过负选择从PBMC中分离出NK细胞(CD3-CD56+),并且分离出的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,然后将其转移到吸附了NKG2D结合结构域的微孔板的孔中,并在含有荧光团缀合的抗CD107a抗体、布雷菲德菌素A和莫能菌素的培养基中培养。培养后,使用抗CD3、CD56和IFN-γ的荧光团缀合的抗体,通过流式细胞术分析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双阳性细胞的增加表明通过两个激活受体而不是一个受体的接合,NK细胞的激活更好。NKG2D结合结构域和阳性对照(例如,由SEQ ID NO:101或SEQ IDNO: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)显示与同种型对照相比,更高百分比的NK细胞变为CD107a+和IFN-γ+(图13和图14代表来自两个独立实验的数据,每个实验使用不同供体的PBMC来制备NK细胞)。
原代小鼠NK细胞
从C57Bl/6小鼠获得脾脏,并通过70μm细胞过滤器压碎以获得单细胞悬液。将细胞沉淀并重悬于ACK裂解缓冲液(Thermo Fisher Scientific#A1049201,Carlsbad,CA;155mM氯化铵、10mM碳酸氢钾、0.01mM EDTA)中,以去除红细胞。将剩余细胞用100ng/mL hIL-2培养72小时,然后收获并制备用于NK细胞分离。然后采用磁珠、使用负消减技术从脾细胞中分离出NK细胞(CD3-NK1.1+),其通常产生具有>90%纯度的NK细胞群。将纯化的NK细胞在含有100ng/mL mIL-15的培养基中培养48小时,然后将其转移到吸附了NKG2D结合结构域的微孔板的孔中,并在含有荧光团缀合的抗CD107a抗体、布雷菲德菌素A和莫能菌素的培养基中进行培养。在NKG2D结合结构域包被的孔中培养后,使用抗CD3、NK1.1和IFN-γ的荧光团缀合抗体,通过流式细胞术分析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双阳性细胞的增加表明通过两个激活受体而不是一个受体的接合,NK细胞的激活更好。NKG2D结合结构域和阳性对照(选自抗小鼠NKG2D克隆MI-6和CX-5,eBioscience,San Diego,CA)显示与同种型对照相比,更高百分比的NK细胞变为CD107a+和IFN-γ+(图15和图16代表来自两个独立实验的数据,每个实验使用不同小鼠来制备NK细胞)。
实施例5-NKG2D结合结构域增强对靶肿瘤细胞的细胞毒性
人和小鼠原代NK细胞激活测定表明与NKG2D结合结构域孵育后,NK细胞上的细胞毒性标记物增加。为了解决这是否转化为增加的肿瘤细胞裂解,利用基于细胞的测定,其中将每个NKG2D结合结构域发展成单特异性抗体。Fc区用作一个靶向臂,而Fab区(NKG2D结合结构域)用作另一个靶向臂以激活NK细胞。人来源并表达高水平Fc受体的THP-1细胞用作肿瘤靶,并使用Perkin Elmer细胞毒性试剂盒(Waltham,MA)。THP-1细胞用BATDA试剂标记,并以105个/mL重悬于培养基中。然后将标记的THP-1细胞与NKG2D抗体和分离的小鼠NK细胞在微量滴定板的孔中于37℃混合3小时。孵育后,除去20μl培养上清液,与200μl铕溶液混合,并在黑暗中振荡孵育15分钟。通过配备有时间分辨荧光模块(激发337nm,发射620nm)的平板读数器随时间测量荧光,并根据试剂盒说明书计算特异性裂解。
阳性对照ULBP-6,即NKG2D的天然配体显示,小鼠NK细胞对THP-1靶细胞的特异性裂解增加。NKG2D抗体也增加了THP-1靶细胞的特异性裂解,而同种型对照抗体则显示出降低的特异性裂解。虚线表示在未添加抗体下小鼠NK细胞对THP-1细胞的特异性裂解(图17)。
实施例6-NKG2D抗体具有高热稳定性
使用差示扫描荧光法测定NKG2D结合结构域的解链温度。相对于典型的IgG1抗体,NKG2D结合结构域的外推的表观解链温度较高(图18)。
实施例7-通过交联NKG2D和CD16对人NK细胞的协同激活
原代人NK细胞激活测定
使用密度梯度离心从人外周血血沉棕黄层中分离出外周血单核细胞(PBMC)。使用负选择磁珠(StemCell Technologies,Vancouver,Canada;目录号17955)从PBMC中纯化NK细胞。通过流式细胞术测定,NK细胞>90%CD3-CD56+。然后将细胞在含有100ng/mL hIL-2(PeproTech,Inc.,Rocky Hill,NJ,目录号200-02)的培养基中扩增48小时,然后用于激活测定。将抗体在4℃下,在100μl无菌磷酸盐缓冲盐水(PBS)中以2μg/ml(抗CD16,BioLegend,San Diego,CA;目录号302013)和5μg/mL(抗NKG2D,R&D Systems,Minneapolis,MN;目录号MAB139)的浓度包被在96孔平底板上过夜,然后彻底洗涤孔以去除过量的抗体。为了评估脱粒,将IL-2-激活的NK细胞以5×105个细胞/ml重悬于补充有100ng/mL hIL2和1μg/mL APC缀合的抗CD107a mAb(BioLegend,San Diego,CA;目录号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。将蛋白质转运抑制剂布雷菲德菌素A(BFA,BioLegend,San Diego,CA;目录号420601)和莫能菌素(BioLegend,San Diego,CA;目录号420701)分别以1:1000和1:270的最终稀释度加入。将接种的细胞在5%CO2中于37℃孵育4小时。对于IFN-γ的细胞内染色,将NK细胞用抗CD3(BioLegend,San Diego,CA;目录号300452)和抗CD56 mAb(BioLegend,San Diego,CA;目录号318328)标记,然后固定、透化并用抗IFN-γmAb(BioLegend,San Diego,CA,目录号506507)标记。门控活CD56+CD3-细胞后,通过流式细胞术分析NK细胞的CD107a和IFN-γ表达。
为了研究受体组合的相对效力,通过板结合刺激进行NKG2D或CD16的交联以及两种受体的共交联。
如图19所示,在用抗CD16、抗NKG2D或两种单克隆抗体的组合进行板结合刺激4小时后,分析IL-2激活的NK细胞的CD107a和细胞内IFN-γ的表达。CD16和NKG2D的联合刺激导致CD107a+细胞(图19A)和IFN-γ+细胞(图19B)的百分比大于单独的CD16或NKG2D的单独刺激的累加效应(如虚线所示)。类似地,与单独的每个受体的单独刺激的累加效应相比,CD16和NKG2D的联合刺激导致更大百分比的CD107a+IFN-γ+双阳性细胞(图19C)。柱状图显示了平均(n=2)±SD,并代表使用五个不同健康供体的五个独立实验。
实施例8–FAP在人细胞系上的表达
在三种人细胞系上证实了FAP表达:来源于成骨肉瘤患者正常组织的LL86成纤维细胞;COLO 829黑色素瘤癌细胞;和来自成胶质细胞瘤的U-87MG上皮癌细胞。使用流式细胞术分析,通过用荧光团缀合的抗人FAP抗体(R&D Systems,Minneapolis,MN)对细胞进行染色来测量FAP表达。
如图35所示,与抗体同种型对照相比,在LL86(图35A)、COLO829(图35B)和U-87MG(图35C)细胞上检测到FAP表达。
实施例9–抗FAP多特异性结合蛋白和抗FAP单克隆抗体与FAP表达细胞系的结合。
使用FAP表达人细胞系LL86、COLO 829和U-87MG评估具有FAP结合位点的多特异性结合蛋白的肿瘤抗原结合,所述FAP结合位点包含与SEQ ID NO:114相同的重链可变结构域序列,其和与SEQ ID NO:118相同的轻链可变结构域序列配对(FAP多特异性BP西罗珠单抗);与SEQ ID NO:131相同的重链可变结构域序列,其和与SEQ ID NO:135相同的轻链可变结构域序列配对(FAP多特异性BP 4G8);或与SEQ ID NO:139相同的重链可变结构域序列,其和与SEQ ID NO:143相同的轻链可变结构域序列配对(FAP多特异性BP 29B11)。将具有相同FAP结合位点的多特异性结合蛋白或对应的单克隆抗体(mAb)稀释并与细胞孵育。使用荧光团缀合的抗人IgG二抗检测结合。通过流式细胞术分析细胞,并将其表达为针对人重组IgG1染色的对照归一化的平均荧光强度(MFI),以获得背景倍数(FOB)值。
如图36A至图36C所示,FAP多特异性BP西罗珠单抗、FAP多特异性BP 4G8、FAP多特异性BP 29B11和具有相同FAP结合位点的对应mAB结合FAP表达人LL86细胞(图36A)、COLO829细胞(图36B)和U-87MG细胞(图36C)。与对应的mAb相比,多特异性结合蛋白的总结合信号更高。
实施例10–多特异性结合蛋白增强NK细胞介导的FAP表达靶细胞裂解
使用密度梯度离心从人外周血血沉棕黄层中分离出PBMC。洗涤分离的PBMC并制备用于NK细胞分离。采用磁珠通过负选择分离NK细胞。通过流式细胞术测定,NK细胞>90%CD3-CD56+。分离的NK细胞在用于细胞毒性测定前,在无细胞因子培养基中孵育过夜。
DELFIA细胞毒性测定:
从培养物中收获FAP表达人癌细胞系。将细胞用PBS洗涤,并以106个细胞/mL重悬于生长培养基中,以按照制造商的说明书用BATDA试剂(PerkinElmer,Waltham,MA,目录号AD0116)进行标记。标记后,将细胞用HEPES生理盐水洗涤三次(3x),并以5x104个细胞/mL重悬于培养基中,并将100μl BATDA标记的细胞添加到96孔板的每个孔中。保留指定的孔用于从靶细胞自发释放,并通过添加1%Triton-X制备所有其他孔用于靶细胞的最大裂解。
在培养基中稀释抗FAP多特异性结合蛋白和具有相同FAP结合位点的对应mAb。将50μl稀释的抗FAP mAb或抗FAP多特异性结合蛋白加入到指定的孔中。从培养物中收获纯化的原代NK细胞,洗涤并以1×105-2.0×106个细胞/mL的浓度重悬于培养基中。将50μl原代NK细胞悬液加入到96孔板的指定孔中,以使得达到总200μl的培养体积和实现10:1的效应细胞与靶细胞的比率。在进行测定之前,将板在37℃、5%CO2下孵育2至4小时。
共培养之后,通过在500X G离心5分钟沉淀细胞。将20μl培养上清液转移至干净的微孔板中,并向每个孔中添加200μl室温铕溶液。将微孔板避光,并在板振荡器上以250rpm孵育15分钟。用SpectraMax i3X仪器(MolecularDevices,SanJose,CA)读取微孔板。特异性裂解%计算如下:
特异性裂解%=[(实验释放-自发释放)/(最大释放-自发释放)]×100%。
图37A显示,FAP多特异性BP西罗珠单抗、FAP多特异性BP 4G8和FAP多特异性BP29B11模拟了从供体RR01612分离的原代人NK细胞对FAP表达LL86细胞的细胞毒性活性。
类似地,图37D显示,FAP多特异性BP西罗珠单抗、FAP多特异性BP 4G8和FAP多特异性BP 29B11模拟了从供体55109分离的原代人NK细胞对FAP表达LL86细胞的细胞毒性活性。
图37B显示,FAP多特异性BP西罗珠单抗、FAP多特异性BP 4G8和FAP多特异性BP29B11模拟了从供体RR01612分离的原代人NK细胞对FAP表达COLO 829细胞的细胞毒性活性。
图37C显示,FAP多特异性BP西罗珠单抗、FAP多特异性BP 4G8和FAP多特异性BP29B11模拟了从供体RR01612分离的原代人NK细胞对FAP表达U-87MG细胞的细胞毒性活性。
与具有相同FAP结合位点的对应mAb相比,所有抗FAP多特异性结合蛋白均更有效地刺激原代NK细胞对人癌细胞的细胞毒性。
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等效方案
在不脱离本发明的精神或基本特征的情况下,本发明可以其他具体形式来实施。因此,前述实施方案在所有方面都应被视为说明性的,而非是对本文中描述的本发明的限制。因此,本发明的范围是由随附权利要求而非由上述描述所指定,并且属于权利要求的等效性含义和范围内的所有变化都意图包括在本文中。
序列表
<110> 蜻蜓治疗有限公司(DRAGONFLY THERAPEUTICS, INC.)
<120> 结合NKG2D、CD16和成纤维细胞激活蛋白的蛋白质
<130> AJ4309PT2013
<140>
<141>
<150> 62/672,299
<151> 2018-05-16
<160> 190
<170> PatentIn version 3.5
<210> 1
<211> 117
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Homo sapiens)
<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(Homo sapiens)
<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(Homo sapiens)
<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(Homo sapiens)
<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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述: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(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 107
Ala Arg Ala Arg Gly Pro Trp Ser Phe Asp Pro
1 5 10
<210> 108
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 108
Gly Thr Phe Ser Ser Tyr Ala Ile Ser
1 5
<210> 109
<211> 17
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 109
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 110
<211> 19
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 110
Ala Arg Arg Gly Arg Lys Ala Ser Gly Ser Phe Tyr Tyr Tyr Tyr Gly
1 5 10 15
Met Asp Val
<210> 111
<211> 17
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 111
Glu Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 112
<211> 7
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 112
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 113
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 113
Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr
1 5
<210> 114
<211> 124
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 114
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 115
<211> 7
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 115
Arg Tyr Thr Phe Thr Glu Tyr
1 5
<210> 116
<211> 6
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 116
Asn Pro Asn Asn Gly Ile
1 5
<210> 117
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 117
Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr
1 5 10 15
<210> 118
<211> 113
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 118
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe 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 Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 119
<211> 14
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 119
Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala
1 5 10
<210> 120
<211> 7
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 120
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 121
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 121
Gln Gln Tyr Phe Ser Tyr Pro Leu Thr
1 5
<210> 122
<211> 120
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 122
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 Glu Asn
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Phe His Pro Gly Ser Gly Ser Ile Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Ala 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 His Gly Gly Thr Gly Arg Gly Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 123
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 123
Glu Asn Ile Ile His
1 5
<210> 124
<211> 17
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 124
Trp Phe His Pro Gly Ser Gly Ser Ile Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Asp
<210> 125
<211> 11
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 125
His Gly Gly Thr Gly Arg Gly Ala Met Asp Tyr
1 5 10
<210> 126
<211> 112
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 126
Asp Ile Gln Met Ile 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 Lys Ser Val Ser Thr Ser
20 25 30
Ala Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ile Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Arg
85 90 95
Glu Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 127
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 127
Arg Ala Ser Lys Ser Val Ser Thr Ser Ala Tyr Ser Tyr Met His
1 5 10 15
<210> 128
<211> 7
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 128
Leu Ala Ser Asn Leu Glu Ser
1 5
<210> 129
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 129
Gln His Ser Arg Glu Leu Pro Tyr Thr
1 5
<210> 130
<211> 760
<212> PRT
<213> 智人(Homo sapiens)
<400> 130
Met Lys Thr Trp Val Lys Ile Val Phe Gly Val Ala Thr Ser Ala Val
1 5 10 15
Leu Ala Leu Leu Val Met Cys Ile Val Leu Arg Pro Ser Arg Val His
20 25 30
Asn Ser Glu Glu Asn Thr Met Arg Ala Leu Thr Leu Lys Asp Ile Leu
35 40 45
Asn Gly Thr Phe Ser Tyr Lys Thr Phe Phe Pro Asn Trp Ile Ser Gly
50 55 60
Gln Glu Tyr Leu His Gln Ser Ala Asp Asn Asn Ile Val Leu Tyr Asn
65 70 75 80
Ile Glu Thr Gly Gln Ser Tyr Thr Ile Leu Ser Asn Arg Thr Met Lys
85 90 95
Ser Val Asn Ala Ser Asn Tyr Gly Leu Ser Pro Asp Arg Gln Phe Val
100 105 110
Tyr Leu Glu Ser Asp Tyr Ser Lys Leu Trp Arg Tyr Ser Tyr Thr Ala
115 120 125
Thr Tyr Tyr Ile Tyr Asp Leu Ser Asn Gly Glu Phe Val Arg Gly Asn
130 135 140
Glu Leu Pro Arg Pro Ile Gln Tyr Leu Cys Trp Ser Pro Val Gly Ser
145 150 155 160
Lys Leu Ala Tyr Val Tyr Gln Asn Asn Ile Tyr Leu Lys Gln Arg Pro
165 170 175
Gly Asp Pro Pro Phe Gln Ile Thr Phe Asn Gly Arg Glu Asn Lys Ile
180 185 190
Phe Asn Gly Ile Pro Asp Trp Val Tyr Glu Glu Glu Met Leu Ala Thr
195 200 205
Lys Tyr Ala Leu Trp Trp Ser Pro Asn Gly Lys Phe Leu Ala Tyr Ala
210 215 220
Glu Phe Asn Asp Thr Asp Ile Pro Val Ile Ala Tyr Ser Tyr Tyr Gly
225 230 235 240
Asp Glu Gln Tyr Pro Arg Thr Ile Asn Ile Pro Tyr Pro Lys Ala Gly
245 250 255
Ala Lys Asn Pro Val Val Arg Ile Phe Ile Ile Asp Thr Thr Tyr Pro
260 265 270
Ala Tyr Val Gly Pro Gln Glu Val Pro Val Pro Ala Met Ile Ala Ser
275 280 285
Ser Asp Tyr Tyr Phe Ser Trp Leu Thr Trp Val Thr Asp Glu Arg Val
290 295 300
Cys Leu Gln Trp Leu Lys Arg Val Gln Asn Val Ser Val Leu Ser Ile
305 310 315 320
Cys Asp Phe Arg Glu Asp Trp Gln Thr Trp Asp Cys Pro Lys Thr Gln
325 330 335
Glu His Ile Glu Glu Ser Arg Thr Gly Trp Ala Gly Gly Phe Phe Val
340 345 350
Ser Thr Pro Val Phe Ser Tyr Asp Ala Ile Ser Tyr Tyr Lys Ile Phe
355 360 365
Ser Asp Lys Asp Gly Tyr Lys His Ile His Tyr Ile Lys Asp Thr Val
370 375 380
Glu Asn Ala Ile Gln Ile Thr Ser Gly Lys Trp Glu Ala Ile Asn Ile
385 390 395 400
Phe Arg Val Thr Gln Asp Ser Leu Phe Tyr Ser Ser Asn Glu Phe Glu
405 410 415
Glu Tyr Pro Gly Arg Arg Asn Ile Tyr Arg Ile Ser Ile Gly Ser Tyr
420 425 430
Pro Pro Ser Lys Lys Cys Val Thr Cys His Leu Arg Lys Glu Arg Cys
435 440 445
Gln Tyr Tyr Thr Ala Ser Phe Ser Asp Tyr Ala Lys Tyr Tyr Ala Leu
450 455 460
Val Cys Tyr Gly Pro Gly Ile Pro Ile Ser Thr Leu His Asp Gly Arg
465 470 475 480
Thr Asp Gln Glu Ile Lys Ile Leu Glu Glu Asn Lys Glu Leu Glu Asn
485 490 495
Ala Leu Lys Asn Ile Gln Leu Pro Lys Glu Glu Ile Lys Lys Leu Glu
500 505 510
Val Asp Glu Ile Thr Leu Trp Tyr Lys Met Ile Leu Pro Pro Gln Phe
515 520 525
Asp Arg Ser Lys Lys Tyr Pro Leu Leu Ile Gln Val Tyr Gly Gly Pro
530 535 540
Cys Ser Gln Ser Val Arg Ser Val Phe Ala Val Asn Trp Ile Ser Tyr
545 550 555 560
Leu Ala Ser Lys Glu Gly Met Val Ile Ala Leu Val Asp Gly Arg Gly
565 570 575
Thr Ala Phe Gln Gly Asp Lys Leu Leu Tyr Ala Val Tyr Arg Lys Leu
580 585 590
Gly Val Tyr Glu Val Glu Asp Gln Ile Thr Ala Val Arg Lys Phe Ile
595 600 605
Glu Met Gly Phe Ile Asp Glu Lys Arg Ile Ala Ile Trp Gly Trp Ser
610 615 620
Tyr Gly Gly Tyr Val Ser Ser Leu Ala Leu Ala Ser Gly Thr Gly Leu
625 630 635 640
Phe Lys Cys Gly Ile Ala Val Ala Pro Val Ser Ser Trp Glu Tyr Tyr
645 650 655
Ala Ser Val Tyr Thr Glu Arg Phe Met Gly Leu Pro Thr Lys Asp Asp
660 665 670
Asn Leu Glu His Tyr Lys Asn Ser Thr Val Met Ala Arg Ala Glu Tyr
675 680 685
Phe Arg Asn Val Asp Tyr Leu Leu Ile His Gly Thr Ala Asp Asp Asn
690 695 700
Val His Phe Gln Asn Ser Ala Gln Ile Ala Lys Ala Leu Val Asn Ala
705 710 715 720
Gln Val Asp Phe Gln Ala Met Trp Tyr Ser Asp Gln Asn His Gly Leu
725 730 735
Ser Gly Leu Ser Thr Asn His Leu Tyr Thr His Met Thr His Phe Leu
740 745 750
Lys Gln Cys Phe Ser Leu Ser Asp
755 760
<210> 131
<211> 117
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 131
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 Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 132
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 132
Ser Tyr Ala Met Ser
1 5
<210> 133
<211> 14
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 133
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser
1 5 10
<210> 134
<211> 8
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 134
Gly Trp Leu Gly Asn Phe Asp Tyr
1 5
<210> 135
<211> 108
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 135
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 Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 136
<211> 12
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 136
Arg Ala Ser Gln Ser Val Ser Arg Ser Tyr Leu Ala
1 5 10
<210> 137
<211> 7
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 137
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 138
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 138
Gln Gln Gly Gln Val Ile Pro Pro Thr
1 5
<210> 139
<211> 117
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 139
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 Ile Gly Ser Gly Gly Ile 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 Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 140
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 140
Ser Tyr Ala Met Ser
1 5
<210> 141
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 141
Ala Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val
1 5 10 15
<210> 142
<211> 8
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 142
Gly Trp Phe Gly Gly Phe Asn Tyr
1 5
<210> 143
<211> 108
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 143
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 Thr 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 Asn Val Gly Ser Arg 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 Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 144
<211> 12
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 144
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu Ala
1 5 10
<210> 145
<211> 7
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 145
Val Gly Ser Arg Arg Ala Thr
1 5
<210> 146
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 146
Gln Gln Gly Ile Met Leu Pro Pro Thr
1 5
<210> 147
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 147
Glu Tyr Thr Ile His
1 5
<210> 148
<211> 17
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 148
Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 149
<211> 17
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 149
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 150
<211> 246
<212> PRT
<213> 智人(Homo sapiens)
<400> 150
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> 151
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 151
Gly Tyr Tyr Trp Ser
1 5
<210> 152
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 152
Ala Arg Gly Pro Trp Ser Phe Asp Pro
1 5
<210> 153
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 153
Ser Tyr Ala Ile Ser
1 5
<210> 154
<211> 16
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 154
Gly Asp Ser Ser Ile Arg His Ala Tyr Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 155
<211> 7
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 155
Ser Ser Ser Tyr Tyr Trp Gly
1 5
<210> 156
<211> 11
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 156
Gly Ser Asp Arg Phe His Pro Tyr Phe Asp Tyr
1 5 10
<210> 157
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 157
Ser Tyr Tyr Met His
1 5
<210> 158
<211> 17
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 158
Gly Ala Pro Asn Tyr Gly Asp Thr Thr His Asp Tyr Tyr Tyr Met Asp
1 5 10 15
Val
<210> 159
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 159
Gly Tyr Tyr Met His
1 5
<210> 160
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 160
Asp Thr Gly Glu Tyr Tyr Asp Thr Asp Asp His Gly Met Asp Val
1 5 10 15
<210> 161
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 161
Ser Tyr Ala Met Ser
1 5
<210> 162
<211> 12
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 162
Asp Gly Gly Tyr Tyr Asp Ser Gly Ala Gly Asp Tyr
1 5 10
<210> 163
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 163
Ser Tyr Ser Met Asn
1 5
<210> 164
<211> 13
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 164
Gly Ala Pro Met Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 165
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 165
Ser Tyr Tyr Met His
1 5
<210> 166
<211> 16
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 166
Glu Gly Ala Gly Phe Ala Tyr Gly Met Asp Tyr Tyr Tyr Met Asp Val
1 5 10 15
<210> 167
<211> 122
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 167
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 168
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 168
Ser Tyr Ser Met Asn
1 5
<210> 169
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 169
Ala Arg Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 170
<211> 13
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 170
Gly Ala Pro Ile Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 171
<211> 122
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 171
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Gln Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 172
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 172
Ser Tyr Ser Met Asn
1 5
<210> 173
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 173
Ala Arg Gly Ala Pro Gln Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 174
<211> 13
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 174
Gly Ala Pro Gln Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 175
<211> 122
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 175
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Leu Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 176
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 176
Ser Tyr Ser Met Asn
1 5
<210> 177
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 177
Ala Arg Gly Ala Pro Leu Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 178
<211> 13
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 178
Gly Ala Pro Leu Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 179
<211> 122
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 179
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Phe Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 180
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 180
Ser Tyr Ser Met Asn
1 5
<210> 181
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 181
Ala Arg Gly Ala Pro Phe Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 182
<211> 13
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 182
Gly Ala Pro Phe Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 183
<211> 122
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<400> 183
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Val Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 184
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 184
Ser Tyr Ser Met Asn
1 5
<210> 185
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 185
Ala Arg Gly Ala Pro Val Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 186
<211> 13
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 186
Gly Ala Pro Val Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
<210> 187
<211> 122
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
多肽
<220>
<221> MOD_RES
<222> (102)..(102)
<223> Met、Leu、Ile、Val、Gln或Phe
<400> 187
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Pro Xaa Gly Ala Ala Ala Gly Trp Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 188
<211> 5
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<400> 188
Ser Tyr Ser Met Asn
1 5
<210> 189
<211> 15
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<220>
<221> MOD_RES
<222> (6)..(6)
<223> Met、Leu、Ile、Val、Gln或Phe
<400> 189
Ala Arg Gly Ala Pro Xaa Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10 15
<210> 190
<211> 13
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 人工序列描述:合成
肽
<220>
<221> MOD_RES
<222> (4)..(4)
<223> Met、Leu、Ile、Val、Gln或Phe
<400> 190
Gly Ala Pro Xaa Gly Ala Ala Ala Gly Trp Phe Asp Pro
1 5 10
Claims (43)
1.一种蛋白质,所述蛋白质包含:
(a)结合NKG2D的第一抗原结合位点;
(b)结合成纤维细胞激活蛋白(FAP)的第二抗原结合位点;和
(c)足以结合CD16的抗体Fc结构域或其部分,或结合CD16的第三抗原结合位点。
2.根据权利要求1所述的蛋白质,其中所述第一抗原结合位点结合至人的NKG2D。
3.根据权利要求1或2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。
4.根据权利要求3所述的蛋白质,其中所述重链可变结构域和所述轻链可变结构域存在于同一多肽上。
5.根据权利要求3或4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。
6.根据权利要求5所述的蛋白质,其中所述第二抗原结合位点的所述重链可变结构域和所述轻链可变结构域存在于同一多肽上。
7.根据权利要求5或6所述的蛋白质,其中所述第一抗原结合位点的所述轻链可变结构域的氨基酸序列与所述第二抗原结合位点的所述轻链可变结构域的氨基酸序列相同。
8.根据权利要求1至7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以下的氨基酸序列至少90%相同的重链可变结构域:SEQ ID NO:1、SEQ ID NO:41、SEQ IDNO:49、SEQ ID NO:57、SEQ ID NO:59、SEQ ID NO:61、SEQ ID NO:69、SEQ ID NO:77、SEQ IDNO:85、SEQ ID NO:167、SEQ ID NO:171、SEQ ID NO:175、SEQ ID NO:179、SEQ ID NO:183、SEQ ID NO:187和SEQ ID NO:93。
9.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:42至少90%相同的轻链可变结构域。
10.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:50至少90%相同的轻链可变结构域。
11.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:58至少90%相同的轻链可变结构域。
12.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:60至少90%相同的轻链可变结构域。
13.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:62至少90%相同的轻链可变结构域。
14.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:70至少90%相同的轻链可变结构域。
15.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:78至少90%相同的轻链可变结构域。
16.根据权利要求1至7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、SEQ ID NO:167、SEQ ID NO:171、SEQ ID NO:175、SEQ ID NO:179、SEQ ID NO:183或SEQ ID NO:187至少90%相同的重链可变结构域和与SEQ ID NO:86至少90%相同的轻链可变结构域。
17.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:94至少90%相同的轻链可变结构域。
18.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:102至少90%相同的轻链可变结构域。
19.根据权利要求1至7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%相同的重链可变结构域和与SEQ ID NO:104至少90%相同的轻链可变结构域。
20.根据权利要求1或2所述的蛋白质,其中所述第一抗原结合位点为单结构域抗体。
21.根据权利要求20所述的蛋白质,其中所述单结构域抗体为VHH片段或VNAR片段。
22.根据权利要求1至2或20至21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。
23.根据权利要求22所述的蛋白质,其中所述第二抗原结合位点的所述重链可变结构域和所述轻链可变结构域存在于同一多肽上。
24.根据权利要求1至23中任一项所述的蛋白质,其中所述第二抗原结合位点的所述重链可变结构域包含与SEQ ID NO:114至少90%相同的氨基酸序列,并且所述第二抗原结合位点的所述轻链可变结构域包含与SEQ ID NO:118至少90%相同的氨基酸序列。
25.根据权利要求1至23中任一项所述的蛋白质,其中所述第二抗原结合位点的所述重链可变结构域包含与SEQ ID NO:131至少90%相同的氨基酸序列,并且所述第二抗原结合位点的所述轻链可变结构域包含与SEQ ID NO:135至少90%相同的氨基酸序列。
26.根据权利要求1至23中任一项所述的蛋白质,其中所述第二抗原结合位点的所述重链可变结构域包含与SEQ ID NO:139至少90%相同的氨基酸序列,并且所述第二抗原结合位点的所述轻链可变结构域包含与SEQ ID NO:143至少90%相同的氨基酸序列。
27.根据权利要求1至23中任一项所述的蛋白质,其中所述第二抗原结合位点的所述重链可变结构域包含与SEQ ID NO:122至少90%相同的氨基酸序列,并且所述第二抗原结合位点的所述轻链可变结构域包含与SEQ ID NO:126至少90%相同的氨基酸序列。
28.根据权利要求1至23中任一项所述的蛋白质,其中所述第二抗原结合位点包含选自分别由SEQ ID NO:114和118、131和135、139和143以及122和126组成的组的重链可变结构域和轻链可变结构域的CDR1、CDR2和CDR3序列。
29.根据权利要求1至4或8至21中任一项所述的蛋白质,其中所述第二抗原结合位点为单结构域抗体。
30.根据权利要求29所述的蛋白质,其中所述第二抗原结合位点为VHH片段或VNAR片段。
31.根据权利要求1至30中任一项所述的蛋白质,其中所述蛋白质包含足以结合CD16的抗体Fc结构域的一部分,其中所述抗体Fc结构域包含铰链和CH2结构域。
32.根据权利要求31所述的蛋白质,其中所述抗体Fc结构域包含人IgG1抗体的铰链和CH2结构域。
33.根据权利要求31或32所述的蛋白质,其中所述Fc结构域包含与人IgG1抗体的氨基酸234-332至少90%相同的氨基酸序列。
34.根据权利要求33所述的蛋白质,其中所述Fc结构域包含与人IgG1的Fc结构域至少90%相同的氨基酸序列,并且在选自由Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411、K439组成的组的一个或多个位置处不同。
35.一种制剂,所述制剂包含根据权利要求1至34中任一项所述的蛋白质和药学上可接受的载剂。
36.一种细胞,所述细胞包含一种或多种编码根据权利要求1至34中任一项所述的蛋白质的核酸。
37.一种增强肿瘤细胞死亡的方法,所述方法包括使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至34中任一项所述的蛋白质。
38.一种治疗癌症的方法,其中所述方法包括向患者施用有效量的根据权利要求1至34中任一项所述的蛋白质或根据权利要求35所述的制剂。
39.根据权利要求38所述的方法,其中所述待治疗的癌症选自由以下组成的组:浸润性导管癌、胰腺导管腺癌、胃癌、子宫癌、宫颈癌、结直肠癌、乳腺癌、卵巢癌、膀胱癌、肺癌、间皮瘤、胃癌、胰腺癌、头颈癌、肝癌、子宫内膜癌、神经内分泌癌、纤维肉瘤、恶性纤维组织细胞瘤、平滑肌肉瘤、骨肉瘤、软骨肉瘤、脂肪肉瘤、滑膜肉瘤、神经鞘瘤、黑色素瘤和神经胶质瘤。
40.一种治疗自身免疫性疾病的方法,其中所述方法包括向患者施用有效量的根据权利要求1至34中任一项所述的蛋白质或根据权利要求35所述的制剂。
41.根据权利要求40所述的方法,其中所述自身免疫性疾病选自由以下组成的组:类风湿性关节炎、格雷夫斯病、干燥综合征、原发性胆汁性肝硬化、原发性硬化性胆管炎和炎性破坏性关节炎。
42.一种治疗纤维化的方法,其中所述方法包括向患者施用有效量的根据权利要求1至34中任一项所述的蛋白质或根据权利要求35所述的制剂。
43.根据权利要求42所述的方法,其中所述纤维化选自由以下组成的组:特发性肺纤维化、肾纤维化、肝纤维化和心脏纤维化。
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