CN113968914A - 用于分选/清除工程化的免疫细胞的mAb驱动的嵌合抗原受体系统 - Google Patents

用于分选/清除工程化的免疫细胞的mAb驱动的嵌合抗原受体系统 Download PDF

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CN113968914A
CN113968914A CN202111328553.6A CN202111328553A CN113968914A CN 113968914 A CN113968914 A CN 113968914A CN 202111328553 A CN202111328553 A CN 202111328553A CN 113968914 A CN113968914 A CN 113968914A
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巴尔布拉·约翰逊·萨苏
阿尔温德·拉吉帕尔
菲利普·迪沙托
亚历山大·朱耶拉特
朱利安·瓦尔顿
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Allogeneic Therapy Co ltd
Cellectis SA
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Allogeneic Therapy Co ltd
Cellectis SA
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Abstract

本发明涉及用于分选/清除工程化的免疫细胞的mAb驱动的嵌合抗原受体系统。具体地，本发明涉及包含至少一个胞外结合结构域的编码嵌合抗原受体(CAR)的多肽，所述胞外结合结构域包含至少由抗原特异性的VH链和VL链形成的scFv，其中所述胞外结合结构域包含至少一个mAb特异性表位。

Description

用于分选/清除工程化的免疫细胞的mAb驱动的嵌合抗原受体 系统
本申请是申请日为2016年01月25日的题为“用于分选/清除工程化的免疫细胞的mAb驱动的嵌合抗原受体系统”的中国专利申请号201680006992.6的分案申请。
技术领域
本发明涉及用于免疫治疗的改善的嵌合抗原受体(chimeric antigen receptor)(CAR)，其胞外结合结构域(scFv)已通过mAb特异性表位的插入加以修饰，以允许分选和/或清除(depletion)具有所述CAR的免疫细胞。本发明还涉及表达所述CAR的免疫细胞，涉及体内清除和/或体外分选所述CAR表达免疫细胞的方法，以及涉及它们的治疗用途。
背景技术
过继免疫治疗(adotive immunotherapy)(其涉及离体生成的自体抗原特异性T细胞的转移)，是很有前途的用来治疗病毒感染和癌症的策略。可以通过抗原特异性T细胞的扩增(expansion)或T细胞的重定向(通过基因工程)来生成用于过继免疫治疗的T细胞(Park,Rosenberg et al.2011)。病毒抗原特异性T细胞的转移是用于治疗移植相关的病毒感染和罕见病毒相关的恶性肿瘤的完善建立的程序。类似地，在治疗黑色素瘤中，肿瘤特异性T细胞的分离和转移已被证明是成功的。
通过转基因T细胞受体或嵌合抗原受体(CAR)的基因转移，已在T细胞中成功生成新型特异性(Jena,Dotti et al.2010)。CAR是合成受体，上述合成受体由靶向部分组成，所述靶向部分与在单一融合分子中的一个或多个信号结构域关联。一般来说，CAR的结合部分由单链抗体(scFv)的抗原结合结构域组成，所述单链抗体包含通过柔性接头连接的单克隆抗体的轻和重可变片段。也已成功使用基于受体或配体结构域的结合部分。用于第一代CAR的信号结构域源自CD3ζ或Fc受体γ链的胞质区。第一代CAR已显示成功重定向T细胞细胞毒性，然而，它们没有提供延长的扩展和抗肿瘤活性(体内)。已经单独(第二代)或组合地(第三代)添加来自共刺激分子(其包括CD28、OX-40(CD134)、ICOS和4-1BB(CD137))的信号结构域，以增强CAR修饰T细胞的存活和增加CAR修饰T细胞的增殖。CAR已成功允许针对表达在肿瘤细胞的表面上的抗原重定向T细胞，其中上述肿瘤细胞来自包括淋巴瘤和实体瘤的各种恶性肿瘤(Jena,Dotti et al.2010)。
然而，尽管它们具有用于体内肿瘤根除的前所未有的功效，但在被转移进入患者以后，CAR T细胞可促进急性不良事件。在有据可查的不良事件中有移植物抗宿主病(GvHD)、靶向肿瘤外活性(on-target off-tumor activity)或异常淋巴细胞增殖能力(由于载体衍生插入诱变)。因此，有必要发展细胞特异性清除系统，来防止体内发生这样的有害事件。
有很多正在进行的用来开发更安全的基于CAR的免疫治疗的研究，如关于抑制信号，其被称为免疫检查点(immune checkpoint)(如CTLA-4–或PD-1)，其对于自身耐受性的维持是至关重要的以及还限制免疫介导的侧支组织(collateral tissue)损伤(Dolan etal,2014)。最近，设计了抑制性嵌合抗原受体(iCARs)，旨在遇到离靶细胞以后对T细胞功能施加制动(Federov et al.2013)。在Budde et al.(2013)中描述了另一系统，其中CD20嵌合抗原受体与诱导型半胱氨酸天冬氨酸蛋白水解酶(caspase)9(iC9)自杀开关结合。在申请US 2014/0286987中，在药物前体AP1903(他克莫司(tacrolimus))的存在下，通过结合于突变的FK506结合蛋白(FKBP1)，来使后者基因具有功能。由Bellicum公司赞助的临床试验正在进行中，其中将上述半胱氨酸天冬氨酸蛋白水解酶技术(CaspaCIDeTM)设计成GD2靶向第三代CAR T细胞。在申请WO 2014/152177中描述了基于多聚化剂的类似的凋亡诱导系统。
Philip等(2014)描述了RQR8系统，其被用作紧凑标记/自杀基因，从而允许转导细胞的选择。RQR8源自来自CD34和CD20抗原的靶表位的组合。这种构建体允许借助于临床批准的CliniMACS CD34系统(Miltenyi)来进行选择。此外，这种RQR8构建体结合广泛应用的药物抗体利妥昔单抗，从而导致转基因表达细胞的选择性缺失。在此系统内，借助于在逆转录病毒载体中的CAR并利用口蹄疫2A肽，来共表达RQR8，从而导致在T细胞表面上两种独立的转基因(RQR8和CAR)的表达。从产业视角看，此系统存在一些局限性：首先，它需要克隆大型逆转录病毒插入片段，以及其次，需要确保转化细胞表达RQR8和CAR多肽两者，以消除可能的“假阳性”即不会表达两种多肽的T细胞，尤其是RQR8自杀基因，从而允许在不良影响的情况下清除工程化免疫细胞。
在诊所中，在自身免疫疾病和移植的情况下，已经成功实践清除T细胞的构想几十年。为了清除细胞介导免疫性，包括T细胞，广泛使用了免疫抑制药物如糖皮质激素或细胞抑制剂如烷基化剂(环磷酰胺、亚硝基脲、铂化合物…)或抗代谢物(甲氨蝶呤、硫唑嘌呤、氟尿嘧啶…)。然而，尽管它们具有免疫抑制功效，但这些药物并不具有辨别力，因为它们影响所有T和B细胞的增殖。抗体有时用作快速和有效的免疫抑制治疗以防止急性排斥反应以及淋巴增生性或自身免疫性疾病的靶向治疗，尤其是抗CD20单克隆抗体(monoclonal)。T细胞亚群的体内消除由Benjamin和Waldmann(1986)进行以确定CD4+T细胞在产生对可溶性蛋白的抗体反应中的作用，以及由Cobbold等(1986)进行以确定CD4+和CD8+T细胞在排斥骨髓和组织同种异体移植物中的作用。已经广泛地进行体内清除以研究不同话题，包括抗病毒细胞毒性T淋巴细胞(CTL)反应的控制(Buller et al.,1987)。然而，到目前为止对T细胞已经使用的抗体涉及抗原(CD3、CD4、CD52)，其都广泛存在于静止或激活T细胞上以及在其它细胞类型上。因此，上述抗体的使用不会允许具有CAR的工程化免疫细胞的选择性消除。
如在其后呈现的，本发明人已寻求“集成(all-in-one)”系统，通过减少“假阳性”，同时允许在不利的临床事件的情况下表达所述CAR的免疫细胞的体内清除，其允许CAR表达免疫细胞的优化体外分选。
发明内容
本发明涉及嵌合抗原受体(CAR)，以这样的方式修饰其胞外结合结构域(scFv)以允许细胞分选和细胞清除(关于说明性实施方式，见图2)。这种结构(称为mAb驱动分选/清除系统)，由在scFv内插入选择的表位构成；此表位具有由特异性抗体(优选mAb)识别的特异性。鉴于以下事实(主要地，修饰CAR的外部配体结合结构域以包括表位)，可以设想不同的CAR结构：单链或多链。本发明的嵌合scFv(其由VH和VL多肽以及特异性表位形成)，本身可能有不同的结构，其取决于表位的插入位置和接头的使用。本发明还涉及得到的方法，其用于分选和/或清除具有修饰CAR的工程化免疫细胞。
多种表位-mAb对可以用来生成这样的系统；尤其是已经批准用于医疗用途的那些系统，如CD20/利妥昔单抗(作为非限制性实例)。
为了进一步增强工程化免疫细胞的细胞毒性，表位-特异性抗体可以与细胞毒性药物结合。还可以通过利用其上移植有补体系统的组件的工程抗体来促进CDC细胞毒性。
最后，本发明包括治疗方法，其中通过使用抗体(其针对所述CAR的外部配体结合结构域)，来清除细胞以调节具有CAR的工程化免疫细胞的激活。
可以通过以下项目来总结本发明。
1.一种编码包含至少一个胞外结合结构域的嵌合抗原受体(CAR)的多肽，所述胞外结合结构域包含通过对于抗原为特异性的至少VH链和VL链形成的scFv，其中所述胞外结合结构域包含至少一个mAb特异性表位。
2.根据项目1的多肽，其中所述mAb特异性表位位于VH和VL链之间。
3.根据项目1或2的多肽，其中由至少一个接头，将所述VH和VL链、以及mAb特异性表位结合在一起以及通过铰链结合于所述CAR的跨膜结构域。
4.根据项目3的多肽，其中，由两个接头，将mAb表位连接于VH和VL链。
5.根据项目1至3中任一项的多肽，其中mAb特异性表位是通过表位特异性mAb结合的表位，用于体外细胞分选和/或体内细胞清除表达包含这样的表位的CAR的T细胞。
6.根据项目1至5中任一项的多肽，其中多肽包含一个胞外结合结构域，其中所述胞外结合结构域进一步包含铰链，以及所述多肽进一步包含
-跨膜结构域，以及，
-胞内结构域。
7.根据项目1至6中任一项的多肽，其中胞外结合结构域包含1、2、3、4、5、6、7、8、9或10个mAb特异性表位。
8.根据项目1至7中任一项的多肽，其中胞外结合结构域包含1、2、3、或4个mAb特异性表位。
9.根据项目1至8中任一项的多肽，其中胞外结合结构域包含2、3、或4个mAb特异性表位。
10.根据项目1至9中任一项的多肽，其中胞外结合结构域包含以下序列
V1-L1-V2-(L)x-表位1-(L)x-；
V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x-；
V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x-表位3-(L)x-；
(L)x-表位1-(L)x-V1-L1-V2；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2；
表位1-(L)x-表位2-(L)x-表位3-(L)x-V1-L1-V2；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x-；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x-；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x-；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x-表位4-(L)x-；
V1-(L)x-表位1-(L)x-V2；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x；
(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2；或，
(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2-(L)x-表位3-(L)x；
其中，
V1是VL以及V2是VH或V1是VH以及V2是VL；
L1是适合将VH链连接于VL链的接头；
L是包含甘氨酸和丝氨酸残基的接头，以及在胞外结合结构域中L的每次出现可以与在相同胞外结合结构域中L的其它出现相同或不同，以及，
x是0或1以及x的每次出现独立地选自其它；以及，
表位1、表位2和表位3是mAb特异性表位并且可以是相同的或不同的。
11.根据项目10的多肽，其中胞外结合结构域包含以下序列
V1-L1-V2-L-表位1；V1-L1-V2-L-表位1-L；V1-L1-V2-L-表位1-L-表位2；V1-L1-V2-L-表位1-L-表位2-L；V1-L1-V2-L-表位1-L-表位2-L-表位3；V1-L1-V2-L-表位1-L-表位2-L-表位3-L；V1-L1-V2-表位1；V1-L1-V2-表位1-L；V1-L1-V2-表位1-L-表位2；V1-L1-V2-表位1-L-表位2-L；V1-L1-V2-表位1-L-表位2-L-表位3；V1-L1-V2-表位1-L-表位2-L-表位3-L；表位1-V1-L1-V2；表位1-L-V1-L1-V2；L-表位1-V1-L1-V2；L-表位1-L-V1-L1-V2；表位1-L-表位2-V1-L1-V2；表位1-L-表位2-L-V1-L1-V2；L-表位1-L-表位2-V1-L1-V2；L-表位1-L-表位2-L-V1-L1-V2；表位1-L-表位2-L-表位3-V1-L1-V2；表位1-L-表位2-L-表位3-L-V1-L1-V2；L-表位1-L-表位2-L-表位3-V1-L1-V2；L-表位1-L-表位2-L-表位3-L-V1-L1-V2；V1-L-表位1-L-V2；L-表位1-L-V1-L-表位2-L-V2；V1-L-表位1-L-V2-L-表位2-L；V1-L-表位1-L-V2-L-表位2-L-表位3；V1-L-表位1-L-V2-L-表位2-表位3；V1-L-表位1-L-V2-L-表位2-L-表位3-表位4；L-表位1-L-V1-L-表位2-L-V2-L-表位3-L；表位1-L-V1-L-表位2-L-V2-L-表位3-L；L-表位1-L-V1-L-表位2-L-V2-L-表位3；L-表位1-L-V1-L1-V2-L-表位2-L；L-表位1-L-V1-L1-V2-L-表位2-L-表位3；L-表位1-L-V1-L1-V2-L-表位2-表位3，或表位1-L-V1-L1-V2-L-表位2-L-表位3-表位4，其中
V1是VL以及V2是VH或V1是VH以及V2是VL；
L1是适合将VH链连接于VL链的任何接头；
L是包含甘氨酸和丝氨酸残基的接头，以及L在胞外结合结构域中的每次出现可以与L在相同胞外结合结构域中的其它出现相同或不同，以及，
表位1、表位2和表位3是mAb特异性表位并且可以是相同的或不同的。
12.根据项目10的多肽，其中L1是包含甘氨酸和/或丝氨酸的接头。
13.根据项目12的多肽，其中L1是包含氨基酸序列(Gly-Gly-Gly-Ser)n或(Gly-Gly-Gly-Gly-Ser)n的接头，其中n是1、2、3、4或5，或包含氨基酸序列(Gly4Ser)4或(Gly4Ser)3的接头。
14.根据项目10至13中任一项的多肽，其中L是包含甘氨酸和/或丝氨酸的接头。
15.根据项目14的多肽，其中L是具有选自以下各项的氨基酸序列的接头：SGG、GGS、SGGS、SSGGS、GGGG、SGGGG、GGGGS、SGGGGS、GGGGGS、SGGGGGS、SGGGGG、GSGGGGS、GGGGGGGS、SGGGGGGG、SGGGGGGGS、或SGGGGSGGGGS。
16.根据项目14的多肽，其中L是SGGGG、GGGGS或SGGGGS。
17.根据项目10至16中任一项的多肽，其中表位1、表位2、表位3和表位4独立地选自被以下各项特异性识别的mAb特异性表位：替伊莫单抗(ibritumomab)、伊莫单抗(tiuxetan)、莫罗单抗-CD3(muromonab-CD3)、托西莫单抗(tositumomab)、阿昔单抗(abciximab)、巴利昔单抗(basiliximab)、本妥昔单抗(brentuximab vedotin)、西妥昔单抗(cetuximab)、英夫利昔单抗(infliximab)、利妥昔单抗(rituximab)、阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、妥珠单抗(certolizumab pegol)、达克珠单抗(daclizumab)、依库珠单抗(eculizumab)、依法利珠单抗(efalizumab)、吉姆单抗(gemtuzumab)、那他珠单抗(natalizumab)、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、兰尼单抗(ranibizumab)、托珠单抗(tocilizumab)、曲妥单抗(trastuzumab)、维多珠单抗(vedolizumab)、阿达木单抗(adalimumab)、贝利单抗(belimumab)、康纳单抗(canakinumab)、地诺单抗(denosumab)、戈利木单抗(golimumab)、易普利单抗(ipilimumab)、奥法木单抗(ofatumumab)、帕尼单抗(panitumumab)、QBEND-10和优特克单抗(ustekinumab)。
18.根据项目10至16中任一项的多肽，其中表位1、表位2、表位3和表位4独立地选自具有以下各项的氨基酸序列的mAb特异性表位：SEQ ID NO 35、SEQ ID NO 36、SEQ ID NO37、SEQ ID NO 38、SEQ ID NO 39、SEQ ID NO 40、SEQ ID NO 41、SEQ ID NO 42、SEQ ID NO144或SEQ ID NO 174。
19.根据项目10至18中任一项的多肽，其中表位1是mAb特异性表位，其具有SEQ IDNO 35的氨基酸序列。
20.根据项目10至19中任一项的多肽，其中表位2是mAb特异性表位，其具有SEQ IDNO 35的氨基酸序列。
21.根据项目10至20中任一项的多肽，其中表位3是mAb特异性表位，其具有SEQ IDNO 35或SEQ ID NO 144的氨基酸序列。
22.根据项目10至21中任一项的多肽，其中表位4是mAb特异性表位，其具有SEQ IDNO 35的氨基酸序列。
23.根据项目22的多肽，其中表位1、表位2和表位4是mAb特异性表位，其具有SEQID NO 35的氨基酸序列，以及表位3是mAb特异性表位，其具有SEQ ID NO 144的氨基酸序列。
24.根据项目1至9中任一项的多肽，其中mAb特异性表位是来自选自列在表1中的那些多肽的一种多肽。
25.根据项目1至9中任一项的多肽，其中mAb特异性表位选自被以下各项特异性识别的mAb特异性表位：替伊莫单抗、伊莫单抗、莫罗单抗-CD3、托西莫单抗、阿昔单抗、巴利昔单抗、本妥昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿仑单抗、贝伐单抗、妥珠单抗、达克珠单抗、依库珠单抗、依法利珠单抗、吉姆单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、兰尼单抗、托珠单抗、曲妥单抗、维多珠单抗、阿达木单抗、贝利单抗、康纳单抗、地诺单抗、戈利木单抗、易普利单抗、奥法木单抗、帕尼单抗、QBEND-10和优特克单抗。
26.根据项目1至9中任一项的多肽，其中mAb特异性表位选自具有以下各项的氨基酸序列的mAb特异性表位：SEQ ID NO 35、SEQ ID NO 36、SEQ ID NO 37、SEQ ID NO 38、SEQID NO 39、SEQ ID NO 40、SEQ ID NO41、SEQ ID NO 42、SEQ ID NO 144或SEQ ID NO 174。
27.根据项目1至9中任一项的多肽，其中mAb特异性表位具有SEQ ID NO35的氨基酸序列。
28.根据项目1至27中任一项目的多肽，其中所述VH和VL链具有与以下各项超过80％，优选超过90％，以及更优选超过95％一致性的抗原靶序列：SEQ ID NO 43(CD19抗原)、SEQ ID NO 44(CD38抗原)、SEQ ID NO45(CD123抗原)、SEQ ID NO 46(CS1抗原)、SEQID NO 47(BCMA抗原)、SEQ ID NO 48(FLT-3抗原)、SEQ ID NO 49(CD33抗原)、SEQ ID NO50(CD70抗原)、SEQ ID NO 51(EGFR-3v抗原)和SEQ ID NO 52(WT1抗原)。
29.根据项目1至27中任一项的多肽，其中所述抗原是细胞表面标记抗原。
30.根据项目1至27中任一项的多肽，其中所述抗原是肿瘤相关表面抗原。
31.根据项目1至27中任一项的多肽，其中所述抗原选自ErbB2(HER2/neu)、癌胚抗原(CEA)、上皮细胞黏附分子(EpCAM)、表皮生长因子受体(EGFR)、EGFR变体III(EGFRvIII)、CD19、CD20、CD30、CD40、双唾液酸神经节苷脂GD2、GD3、C型凝集素样分子-1(CLL-1)、导管上皮粘蛋白、gp36、TAG-72、鞘糖脂、胶质瘤相关抗原、β-人绒毛膜促性腺激素、甲胎蛋白(AFP)、凝集素反应性AFP、甲状腺球蛋白、RAGE-1、MN-CA IX、人端粒酶逆转录酶、RU1、RU2(AS)、肠羧基酯酶、mut hsp70-2、M-CSF、前列腺酶(prostase)、前列腺酶特异性抗原(PSA)、PAP、NY-ESO-1、LAGA-1a、p53、前列腺蛋白、PSMA、存活蛋白和端粒酶、前列腺癌肿瘤抗原-1(PCTA-1)、MAGE、ELF2M、中性粒细胞弹性蛋白酶、肝配蛋白B2、CD22、胰岛素生长因子(IGF1)-I、IGF-II、IGFI受体、间皮素、呈递肿瘤特异性肽表位的主要组织相容性复合物(MHC)分子、5T4、ROR1、Nkp30、NKG2D、肿瘤基质抗原、纤连蛋白的额外结构域A(EDA)和额外结构域B(EDB)以及肌腱蛋白-C的A1结构域(TnC A1)和成纤维细胞相关蛋白(fap)、LRP6、黑素瘤相关硫酸软骨素蛋白聚糖(MCSP)、CD38/CS1、MART1、WT1、MUC1、LMP2、独特型(idiotype)、NY-ESO-1、Ras突变体、gp100、蛋白酶3、bcr-abl、酪氨酸酶、hTERT、EphA2、ML-TAP、ERG、NA17、PAX3、ALK、雄激素受体；谱系特异性或组织特异性抗原如CD3、CD4、CD8、CD24、CD25、CD33、CD34、CD70、CD79、CD116、CD117、CD135、CD123、CD133、CD138、CTLA-4、B7-1(CD80)、B7-2(CD86)、内皮糖蛋白(endoglin)、主要组织相容性复合物(MHC)分子、BCMA(CD269、TNFRSF 17)或FLT-3。
32.根据项目1至27中任一项的多肽，其中VH和VL选自
SEQ ID NO 65的VH和SEQ ID NO 66的VL；SEQ ID NO 67的VH和SEQ ID NO 68的VL；SEQ ID NO 69的VH和SEQ ID NO 70的VL；SEQ ID NO 71的VH和SEQ ID NO 72的VL；SEQID NO 77的VH和SEQ ID NO 78的VL；SEQ ID NO 79的VH和SEQ ID NO 80的VL；SEQ ID NO81的VH和SEQ ID NO 82的VL；SEQ ID NO 83的VH和SEQ ID NO 84的VL；SEQ ID NO 85的VH和SEQ ID NO 86的VL；SEQ ID NO 87的VH和SEQ ID NO 88的VL；SEQ ID NO 89的VH和SEQ IDNO 90的VL；SEQ ID NO 91的VH和SEQ ID NO 92的VL；SEQ ID NO 93的VH和SEQ ID NO 94的VL；SEQ ID NO 95的VH和SEQ ID NO 96的VL；SEQ ID NO 97的VH和SEQ ID NO 98的VL；SEQID NO 99的VH和SEQ ID NO 100的VL；SEQ ID NO 101的VH和SEQ ID NO 102的VL；SEQ IDNO 103的VH和SEQ ID NO 104的VL；SEQ ID NO 105的VH和SEQ ID NO 106的VL；SEQ ID NO107的VH和SEQ ID NO 108的VL；SEQ ID NO109的VH和SEQ ID NO 110的VL；SEQ ID NO 111的VH和SEQ ID NO112的VL；SEQ ID NO 113的VH和SEQ ID NO 114的VL；SEQ ID NO 115的VH和SEQ ID NO 116的VL；SEQ ID NO 117的VH和SEQ ID NO 118的VL；SEQ ID NO 119的VH和SEQ ID NO 120的VL；SEQ ID NO 121的VH和SEQ ID NO 122的VL；或，SEQ ID NO 123的VH和SEQ ID NO124的VL；SEQ ID NO 170的VH和SEQ ID NO 171的VL；SEQ ID NO 172的VH和SEQID NO 173的VL；或，SEQ ID NO 174的VH和SEQ ID NO175的VL。
33.根据项目2至32中任一项的多肽，其中铰链包含PD-1铰链、IgG4铰链、CD8α铰链或FcγRIIIα铰链。
34.根据项目2至33中任一项的多肽，其中跨膜结构域包含T细胞受体、PD-1、4-1BB、OX40、ICOS、CTLA-4、LAG3、2B4、BTLA4、TIM-3、TIGIT、SIRPA、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154的α、β或ζ链的跨膜区。
35.根据项目2至33中任一项的多肽，其中跨膜结构域包含PD-1或CD8α的跨膜区。
36.根据项目2至33中任一项的多肽，其中跨膜结构域包含CD8α的跨膜区。
37.根据项目2至37中任一项的多肽，其中胞内结构域包含CD3ζ信号结构域。
38.根据项目2至37中任一项的多肽，其中胞内结构域包含4-1BB结构域。
39.根据项目1-38中任一项的多肽，其中CAR是单链CAR。
40.根据项目1的多肽，其中所述多肽与以下各项具有超过80％，超过90％，超过95％一致性，或相同：SEQ ID NO 1至10、SEQ ID NO 125至141或SEQ ID no 145至150或SEQID NO 152至169。
41.根据项目1-38中任一项的多肽，其中CAR是多链CAR。
42.一种编码项目1至41中任一项的多肽的多核苷酸。
43.一种编码项目1至41中任一项的嵌合抗原受体的多核苷酸，其中所述CAR包含CD3ζ信号结构域和来自4-1BB的共刺激结构域。
44.一种表达载体，包含项目42或43的核酸。
45.一种工程化免疫细胞，在其细胞表面上表达项目1至41中任一项的多肽。
46.根据项目45的工程化免疫细胞，其中所述细胞源自炎性T淋巴细胞、细胞毒性T淋巴细胞、调节性T淋巴细胞或辅助性T淋巴细胞。
47.根据项目45或46的工程化免疫细胞，作为药剂的应用。
48.一种用于工程化项目45-47中任一项的免疫细胞的方法，包括：
(a)提供免疫细胞；
(b)将编码项目1-41中任一项的嵌合抗原受体的至少一种多核苷酸引入所述细胞；
(c)将所述多核苷酸表达进入所述细胞。
49.项目48的用于工程化免疫细胞的方法，其中免疫细胞是T细胞。
50.一种用于体外分选工程化免疫细胞的方法，上述工程化免疫细胞在其细胞表面上表达包含至少一个根据项目1至41中任一项的mAb特异性表位的多肽，包括
-使包含所述工程化免疫细胞的免疫细胞的群体接触对于mAb特异性表位具有特异性的单克隆抗体；
-选择结合于单克隆抗体的细胞，以获得富集有工程化免疫细胞的细胞群体。
51.根据项目50的方法，其中对于mAb特异性表位具有特异性的单克隆抗体结合于荧光团以及通过荧光激活细胞分选术(FACS)来进行选择结合于单克隆抗体的细胞的步骤。
52.根据项目50的方法，其中对于mAb特异性表位具有特异性的单克隆抗体结合于磁性颗粒以及通过磁性激活细胞分选术(MACS)来进行选择结合于单克隆抗体的细胞的步骤。
53.根据项目50至52中任一项的方法，其中多肽包含mAb特异性表位，其具有SEQID NO 35的氨基酸序列，以及单克隆抗体是利妥昔单抗。
54.根据项目50至52中任一项的方法，其中多肽包含mAb特异性表位，其具有SEQID NO 144的氨基酸序列，以及用来接触免疫细胞群体的抗体是QBEND-10。
55.根据项目50至54中任一项的方法，其中富集有工程化免疫细胞的细胞群体包含至少70％、75％、80％、85％、90％、95％的CAR表达免疫细胞。
56.一种用于在患者中体内清除在其细胞表面上表达包含至少一个项目1至41中任一项的mAb特异性表位的多肽的工程化免疫细胞的方法，包括使所述工程化免疫细胞接触至少一种表位特异性mAb。
57.根据项目56的方法，其中mAb特异性表位是CD20表位或模拟表位，以及表位特异性mAb是利妥昔单抗。
58.根据项目57的方法，其中mAb特异性表位具有SEQ ID NO 35的氨基酸序列。
59.根据项目56至58中任一项的方法，其中通过能够激活补体系统的分子来结合表位特异性mAb。
60.根据项目56至59中任一项的方法，其中将细胞毒性药物结合于表位特异性mAb。
61.一种用于在患者中体内清除在其细胞表面上表达包含至少一个项目1至41中任一项的mAb特异性表位的多肽的工程化免疫细胞的方法，包括使所述工程化免疫细胞接触能够结合于在所述细胞上携带的mAb特异性表位以及结合于由效应细胞(和细胞毒性细胞)携带的表面抗原两者的双特异性mAb(BsAb)。
62.根据项目48至61中任一项所述的方法，其中所述免疫细胞是T细胞。
附图说明
图1：本发明的mAb驱动分选/清除系统的示意性结构，在此使用单链CAR支架(scaffold)；对于具有VH、VL链和mAb特异性表位的不同位置的嵌合scFv，给出了多种配置。
图2：通过利用本发明的mAb驱动系统，细胞分选和细胞清除起作用的示意图。特异性mAb(+/-补体)的添加允许通过识别其在嵌合scFv内的表位来纯化CAR+T细胞。在细胞清除步骤期间，通过结合于其在嵌合scFv内的特异性表位，相同的特异性mAb(+/-补体)引起CAR+T细胞的特异性溶解。
图3：利用双特异性抗体，细胞清除的示意图。通过结合于CAR表达免疫细胞和结合于效应细胞两者，此系统允许在CAR表达免疫细胞的表面上募集效应细胞并触发它们的特异性体内清除。
图4：在实施例1-2中使用的表达具有CD20模拟表位的抗CD123 scFv的10种CAR的CAR结构。设计了一系列的10种嵌合scFv，其中在抗CD123 scFv和铰链之间插入一个或两个拷贝的CD20模拟表位(黑色框，名为“模拟表位(mimotope)”)。如图4所示，所有10种CAR具有相同的铰链(CD8铰链)、跨膜结构域(CD8 TM)、共刺激结构域(4-1BB)和刺激结构域(ITAMCD3ζ)。SEQ ID NO 1-10包含前导序列MALPVTALLLPLALLLHAARP，当最初表达CAR时其是存在的，但其不是表达在细胞的表面上的CAR的一部分。
鉴于scFv，取决于模拟表位的位置，设计了3个系列的CAR(抗CD123No 1、2、3、4、5、6、7、8、9和10分别对应于SEQ ID NO:1、2、3、4、5、6、7、8、9和10)：
-第一系列：SEQ ID NO 1-2和SEQ ID NO 3-4对应于这样的构象，其中分别将一个和两个CD20模拟表位插入在抗CD123 scFv和铰链之间；在SEQ ID NO 2中，GS接头将CD20模拟表位连接于铰链。在SEQ ID NO3-4中，GS接头间隔两个模拟表位以及在SEQ ID NO 4中，具有在模拟表位和铰链之间的额外的GS接头。
-第二系列：SEQ ID NO 5-6对应于这样的构象，其中一个拷贝的CD20模拟表位被插入在抗CD123 scFv内；来自分别地短GS接头(SEQ ID NO 5)和长GS接头(SEQ ID NO 6)的存在的序列差异在于两边。
-第三系列：SEQ ID NO 7至10对应于这样的构象，其中抗CD123 scFv是位于CD模拟表位和铰链之间。在SEQ ID NO.7-8和SEQ ID NO.9-10中，分别插入一个拷贝和两个拷贝的CD20模拟表位。GS接头被插入在两个CD20模拟表位之间，以及对于SEQ ID NO.10，补充GS接头将模拟表位连接于抗CD123 scFv。
图5示出表达SEQ ID NO 1-4或142的抗CD123 CAR的T细胞或不表达任何抗CD123CAR(模拟T细胞，没有任何mRNA的转染步骤)的对照T细胞的细胞溶解活性。细胞溶解活性被表示为特异性细胞溶解的频率，如在实施例1中详述的。
图6显示CDC测定的结果，其中连同利妥昔单抗(RTX)和幼兔补体(Baby RabbitComplement)(BRC)一起来温育表达SEQ ID NO 1-4的抗CD123 CAR的T细胞或不表达任何抗CD123 CAR的对照T细胞(模拟T细胞(转染步骤，没有任何mRNA))。结果表示为在抗CD123CAR阳性T细胞中活细胞的相对频率(相对于对照实验)，如在实施例3中详述的。
图7A、图7B和图7C公开了在实施例4至6中已设计和测试的SEQ ID NO 125至141的CAR的一般结构。在所有这些CAR中均使用抗BCMA ScFV。在不同位置(即ScFv的上游，ScFv的下游或在ScFv的可变链(称为V1和V2)之间)包括选自CD20模拟表位(黑色框，称为“模拟表位”)和/或CD34表位(灰色框，称为“CD34”)的一个、两个、三个或四个表位。如图7A、图7B和图7C所示，所有CAR具有相同的铰链(CD8铰链)、跨膜结构域(CD8 TM)、共刺激结构域(4-1BB)和刺激结构域(ITAM CD3ζ)。
图8A和图8B显示CDC测定的结果，其中连同RTX和BRC一起来温育表达SEQ ID NO125或130至141的抗BCMA CAR的T细胞。结果表示为在抗BCMA CAR阳性T细胞中活细胞的相对频率(相对于对照实验)，如在实施例4中详述的。
图9示出表达SEQ ID NO 125或130至139的抗BCMA CAR的T细胞或不表达任何抗BCM A CAR的对照T细胞(T细胞)的细胞溶解活性。细胞溶解活性表示为活细胞H929的频率，如在实施例4中详述的。
图10的小图A示出在借助于CD34 MicroBead试剂盒的纯化以前或以后或在流过部分(flow through fraction)中，表达包含CD34表位和两个CD20模拟表位的SEQ ID NO 128的CAR的T细胞的频率。
图10的小图B示出在借助于CD34 MicroBead试剂盒纯化以前或以后或在流过部分中，表达包含CD34表位的SEQ ID NO 128的CAR的T细胞的数目。
图11示出在RTX、植物血凝素(PHA)的存在下或在没有RTX和PHA的情况下，由表达SEQ ID NO 125或130至139的抗BCMA CAR的T细胞产生的INFγ的浓度。
图12示出，利用BCMA-Fc融合蛋白和标记抗Fc抗体体或RTX和标记抗Fc抗体，产生自表达SEQ ID NO 125或130至139的CAR的T细胞的检测的CAR阳性T细胞的频率。
图13示出，利用RTX和标记抗Fc抗体或标记QBEND-10，产生自表达SEQ ID NO 128的CAR的T细胞的检测的CAR阳性T细胞的频率。
图14A和图14B示出，通过流式细胞术，表达SEQ ID NO 145(BC30，野生型)、146(LM)、147(LML)、148(LMLM)和149(LMLML)的BCMA CAR(其含有CD20模拟表位)的T细胞的检测。通过流式细胞术并利用可溶性生物素化BCMA蛋白接着PE结合的链霉亲合素(sBCMA生物素(PE))或抗CD20抗体利妥昔单抗接着FITC结合的抗人IgG(利妥昔单抗(FITC))，来检测CAR T细胞。
图15示出，通过流式细胞术，对没有转导的、用慢病毒加以转导的T细胞的SEQ IDNO 145的抗BCMA CAR和RQR8(SEQ ID NO150)(BC30-RQR8)、或SEQ ID NO 149的BCMA CAR(其含有CD20模拟表位)的共表达的检测。通过流式细胞术并利用可溶性生物素化BCMA蛋白接着PE结合的链霉亲合素(sBCMA生物素(PE))或抗CD20抗体利妥昔单抗接着FITC结合的抗人IgG(利妥昔单抗(FITC))，来检测CAR-T细胞。
图16显示CDC测定的结果，其中连同RTX和BRC一起来温育表达SEQ ID NO 149的抗BCMA CAR(BC30-R2)、SEQ ID NO 145的抗BCMA CAR或共表达SEQ ID NO 145的抗BCMA CAR和RQR8(SEQ ID NO150)(BC30-RQR8)的T细胞。通过流式细胞术分析并利用生物素化BCMA蛋白，来确定细胞毒性的百分比。结果表示为，相对于对照(仅用BRC加以温育的细胞)，在抗BCMA CAR阳性T细胞中细胞溶解的频率。
图17示出在有/无RTX的情况下T细胞的细胞溶解活性，其中上述T细胞表达SEQ IDNO 149的抗BCMA CAR(BC30-R2)或共表达SEQ ID NO145的抗BCMA CAR(BC30)和RQR8(SEQID NO 150)(BC30-RQR8)。细胞溶解活性表示为计算的细胞溶解的百分比，如在实施例7.5中所披露的，以及在效应子(CAR T细胞):靶(表达BCMA的MM1S细胞)的不同比率下加以确定。
图18示出，在PBS(对照)、抗CD3 OKT3抗体(αCD3)、或利妥昔单抗(RTX)的存在下，表达SEQ ID NO 149的抗BCMA CAR的激活的T细胞的百分比。利用流式细胞术，通过测量激活标记CD25和CD69的表达，来评估T细胞激活。
表1：药物批准的mAb与其抗原靶标的清单。提供了后者的序列，以及它们中的一些的表位。
表2：对应于在实施例2中提供的它们的mAb的多种模拟表位和表位的清单。
表3：靶向CD19、CD33、5T4、ROR1、EGFRvIII、BCMA、CS1和CD123抗原的scFv的VH和VL链的清单。
表4:CAR组件的示例性序列
具体实施方式
本发明涉及编码包含至少一个胞外结合结构域的嵌合抗原受体(CAR)的多肽，其包含通过对于抗原，优选细胞表面标记抗原，为特异性的至少VH链和VL链的形成的scFv，其中所述胞外结合结构域包含至少一个mAb特异性表位。在一种实施方式中，mAb特异性表位是将通过表位特异性mAb所结合的表位，用于体外细胞分选和/或体内细胞清除表达包含这样的表位的CAR的T细胞。
本发明涉及多肽，该多肽编码嵌合抗原受体(CAR)，其包含至少一个胞外结合结构域，其包含通过对于细胞表面标记抗原为特异性的至少VH链和VL链所形成的scFv，其中所述胞外结合结构域包含将通过表位特异性mAb所结合的至少一个mAb特异性表位，用于体外细胞分选和/或体内细胞清除表达所述CAR的T细胞。
在一些实施方式中，本发明涉及CAR，其包含
-胞外结构域，其包含
-至少一个，优选一个，胞外结合结构域，其包含通过对于抗原，优选细胞表面标记抗原，为特异性的至少VH链和VL链所形成的scFv，其中所述胞外结合结构域包含至少一个mAb特异性表位，以及，
-铰链，
-跨膜结构域，以及，
-胞内结构域。
在一些实施方式中，本发明涉及CAR，其包含
-胞外结构域，包含
-至少一个胞外结合结构域，其包含通过对于细胞表面标记抗原为特异性的至少VH链和VL链所形成的scFv，其中所述胞外结合结构域包含将通过表位特异性mAb所结合的至少一个mAb特异性表位，用于体外细胞分选和/或体内细胞清除表达所述CAR的T细胞，以及，
-铰链，
-跨膜结构域，以及，
-胞内结构域。
在实施方式中，本发明的CAR包含一个胞外结合结构域。
“嵌合scFv”是指多肽，该多肽对应于单链可变片段，其组成自重和轻链(分别为VH和VL)以及表位，其并不原来包括在所述VH和VL链中。当能够被抗体，特别是单克隆抗体，特异性地结合时，后者表位被称为“mAb特异性表位”。在一些实施方式中，mAb特异性表位不是由ScFv识别的表位。在一些实施方式中，mAb特异性表位不是源自CAR的胞外结构域。可以通过至少一个接头，通常柔性接头，将此嵌合scFv的组件(即，配体结合结构域的轻和重可变片段以及mAb特异性表位)连接在一起。通过铰链，这些组件通常连接于CAR的跨膜结构域。
嵌合scFv构象
本发明的嵌合scFv的结构可以是各种各样的，如图1所示，其取决于主要组件(VH和VL以及m-Ab特异性表位)的位置。
本发明的嵌合scFv可能有几种构象，当考虑一个VH、一个VL和一个表位的可能排列的数目时，有至少9种。
优选地，通过至少一个如前所述的柔性接头，每个组件(VH、VL和表位)互连与其近邻。根据本发明的合适的组合是这样的组合，其提供在两种结合中的良好的亲和力/特异性：在mAb特异性表位和注入mAb之间，以及在嵌合scFv的VH和VL链与细胞靶配体的抗原之间。
根据一种实施方式，CAR的胞外结合结构域包含至少两个接头，两个都将表位连接于VH和VL链；以及铰链，其将scFv-表位连接于CAR的跨膜结构域。
例如，如果预计的CAR构象是如此以致mAb特异性表位位于在VH和VL链附近，则当表达和测试CAR的细胞毒性和/或mAb清除时进行筛查。
当寻求位于VH和VL链之间的mAb特异性表位时，可以在CAR构建体的测试和/或瞬时表达以前，通过噬菌体展示来进行筛查。这可以通过mRNA的转染来获得，其对于原代细胞毒性和/或mAb清除测试是足够的。
在一些实施方式中，胞外结合结构域包含至少1、2、3、4、5、6、7、8、9或10个mAb特异性表位。
在一些实施方式中，胞外结合结构域包含1、2、3、4、5、6、7、8、9或10个mAb特异性表位。
在一些实施方式中，胞外结合结构域包含1、2或3个mAb特异性表位。
在一些实施方式中，当胞外结合结构域包含多种mAb特异性表位时，所有mAb特异性表位是相同的。
在一些实施方式中，当胞外结合结构域包含多种mAb特异性表位时，mAb特异性表位是不相同的。例如，胞外结合结构域可以包含三个mAb特异性表位，其中两个是相同的以及第三个是不同的。
在一些实施方式中，胞外结合结构域包含VH、VL、以及一个或多个mAb特异性表位，优选1、2或3个，更优选2或3个mAb特异性表位。
在一些实施方式中，胞外结合结构域包含以下序列(N端是位于左手边)：
V1-L1-V2-(L)x-表位1-(L)x；V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x；V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x-表位3-(L)x；(L)x-表位1-(L)x-V1-L1-V2；(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2；表位1-(L)x-表位2-(L)x-表位3-(L)x-V1-L1-V2；(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x；(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x；(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x；(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x；(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x-表位4-(L)x；V1-(L)x-表位1-(L)x-V2；V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x；V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x；V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x；(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2；(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2-(L)x-表位3-(L)x；V1-L1-V2-L-表位1；V1-L1-V2-L-表位1-L；V1-L1-V2-L-表位1-L-表位2；V1-L1-V2-L-表位1-L-表位2-L；V1-L1-V2-L-表位1-L-表位2-L-表位3；V1-L1-V2-L-表位1-L-表位2-L-表位3-L；V1-L1-V2-表位1；V1-L1-V2-表位1-L；V1-L1-V2-表位1-L-表位2；V1-L1-V2-表位1-L-表位2-L；V1-L1-V2-表位1-L-表位2-L-表位3；V1-L1-V2-表位1-L-表位2-L-表位3-L；表位1-V1-L1-V2；表位1-L-V1-L1-V2；L-表位1-V1-L1-V2；L-表位1-L-V1-L1-V2；表位1-L-表位2-V1-L1-V2；表位1-L-表位2-L-V1-L1-V2；L-表位1-L-表位2-V1-L1-V2；L-表位1-L-表位2-L-V1-L1-V2；表位1-L-表位2-L-表位3-V1-L1-V2；表位1-L-表位2-L-表位3-L-V1-L1-V2；L-表位1-L-表位2-L-表位3-V1-L1-V2；L-表位1-L-表位2-L-表位3-L-V1-L1-V2；V1-L-表位1-L-V2；L-表位1-L-V1-L-表位2-L-V2；V1-L-表位1-L-V2-L-表位2-L；V1-L-表位1-L-V2-L-表位2-L-表位3；V1-L-表位1-L-V2-L-表位2-表位3；V1-L-表位1-L-V2-L-表位2-L-表位3-表位4；L-表位1-L-V1-L-表位2-L-V2-L-表位3-L；表位1-L-V1-L-表位2-L-V2-L-表位3-L；L-表位1-L-V1-L-表位2-L-V2-L-表位3；L-表位1-L-V1-L1-V2-L-表位2-L；L-表位1-L-V1-L1-V2-L-表位2-L-表位3；L-表位1-L-V1-L1-V2-L-表位2-表位3，或表位1-L-V1-L1-V2-L-表位2-L-表位3-表位4。
其中，
V1和V2是ScFv的VH和VL(即，V1是VL以及V2是VH或V1是VH以及V2是VL)；
L1是在ScFv中适合将VH链连接于VL链的任何接头；
L是接头，其优选包含甘氨酸和丝氨酸残基，以及L在胞外结合结构域中的每次出现可以相同或不同于L在相同胞外结合结构域中的其它出现，以及，
x是0或1以及x的每次出现独立地来自其它；以及，
表位1、表位2和表位3是mAb特异性表位并且可以是相同的或不同的。
在一些实施方式中，胞外结合结构域包含以下序列(N端是位于左手边)：
VH-L1-VL-L-表位1-L-表位2-L；L-表位1-L-VH-L-表位2-L-VL-L-表位3-L；VL-L1-VH-L-表位1-L-表位2-L；或，L-表位1-L-VL-L-表位2-L-VH-L-表位3-L，
其中L、L1、表位1、表位2和表位3是如上文所定义。
在一些实施方式中，L1是包含甘氨酸和/或丝氨酸的接头。在一些实施方式中，L1是包含氨基酸序列(Gly-Gly-Gly-Ser)n或(Gly-Gly-Gly-Gly-Ser)n的接头，其中n是1、2、3、4或5。在一些实施方式中，L1是(Gly4Ser)4或(Gly4Ser)3。
在一些实施方式中，L是柔性接头，其优选包含甘氨酸和/或丝氨酸。在一些实施方式中，L具有氨基酸序列，其选自SGG、GGS、SGGS、SSGGS、GGGG、SGGGG、GGGGS、SGGGGS、GGGGGS、SGGGGGS、SGGGGG、GSGGGGS、GGGGGGGS、SGGGGGGG、SGGGGGGGS、或SGGGGSGGGGS，优选SGG、SGGS、SSGGS、GGGG、SGGGGS、SGGGGGS、SGGGGG、GSGGGGS或SGGGGSGGGGS。在一些实施方式中，当胞外结合结构域包含L的几次出现时，所有L是相同的。在一些实施方式中，当胞外结合结构域包含L的几次出现时，L不是都相同的。在一些实施方式中，L是SGGGGS。在一些实施方式中，胞外结合结构域包含L的几次出现并且所有L都是SGGGGS。
在一些实施方式中，表位1、表位2和表位3是相同的或不同的并且选自mAb特异性表位，其具有以下氨基酸序列：SEQ ID NO 35、SEQ ID NO 36、SEQ ID NO 37、SEQ ID NO38、SEQ ID NO 39、SEQ ID NO 40、SEQ ID NO 41或SEQ ID NO 42、SEQ ID NO 144或SEQ IDNO 174。
在一些实施方式中，表位1、表位2和表位3是相同的或不同的并且选自mAb特异性表位，其由替伊莫单抗、伊莫单抗、莫罗单抗-CD3、托西莫单抗、阿昔单抗、巴利昔单抗、本妥昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿仑单抗、贝伐单抗、妥珠单抗、达克珠单抗、依库珠单抗、依法利珠单抗、吉姆单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、兰尼单抗、托珠单抗、曲妥单抗、维多珠单抗、阿达木单抗、贝利单抗、康纳单抗、地诺单抗、戈利木单抗、易普利单抗、奥法木单抗、帕尼单抗、QBEND-10和优特克单抗特异性识别。
在一些实施方式中，表位1是mAb特异性表位，其具有SEQ ID NO 35的氨基酸序列。
在一些实施方式中，表位2是mAb特异性表位，其具有SEQ ID NO 35的氨基酸序列。
在一些实施方式中，表位3是mAb特异性表位，其具有SEQ ID NO 35的氨基酸序列。
在一些实施方式中，表位4是mAb特异性表位，其具有SEQ ID NO 35的氨基酸序列。
在一些实施方式中，表位2是mAb特异性表位，其具有SEQ ID NO 35的氨基酸序列，以及表位3是mAb特异性表位，其具有SEQ ID NO 144的氨基酸序列。
在一些实施方式中，表位1、表位2、表位3和表位4之一是CD34表位，优选SEQ ID144的表位。在一些实施方式中，表位1、表位2、表位3和表位4之一是CD34表位，优选SEQ ID144的表位以及其它mAb特异性表位是CD20模拟表位，优选SEQ ID NO 35的模拟表位。
插入的mAb特异性表位
根据本发明，待插入嵌合scFv内的表位是对于单克隆抗体(mAb)为特异性的，其用于细胞分选和/或细胞清除过程。
在优选实施方式中，就监管/安全性而言，在它们的由国家卫生机构批准的基础上，选择在嵌合scFv内引入的表位，作为mAb特异性表位/表位特异性mAb对的一部分。这样的对在下表1中给出。
表1：药学上批准的具有抗原靶的单克隆抗体的清单
Figure BDA0003347832690000201
Figure BDA0003347832690000211
Figure BDA0003347832690000221
表2：mAb特异性表位(和它们的相应的mAb)的实例，其可以用于本发明的CAR的胞外结合结构域，如例如模拟表位和具有它们的相应mAb的表位，如在实施例1-2中使用的。
Figure BDA0003347832690000222
在优选实施方式中，在嵌合scFv内引入的表位是CD20抗原，优选SEQ ID NO 35以及注入mAb，其用来靶它，用于分选和/或清除目的，是利妥昔单抗。
在一些实施方式中，mAb特异性表位具有以下氨基酸序列：SEQ ID NO 35、SEQ IDNO 36、SEQ ID NO 37、SEQ ID NO 38、SEQ ID NO 39、SEQ ID NO 40、SEQ ID NO 41、SEQ IDNO 42、SEQ ID NO 144或SEQ ID NO 174。
在一些实施方式中，本发明的CAR的胞外结合结构域包含SEQ ID NO 35的一个mAb特异性表位、SEQ ID NO 35的两个mAb特异性表位、SEQ ID NO 35的三个mAb特异性表位、SEQ ID NO 35的一个mAb特异性表位和SEQ ID NO 144的一个mAb特异性表位、SEQ ID NO35的两个mAb特异性表位和SEQ ID NO 144的一个mAb特异性表位、SEQ ID NO35的三个mAb特异性表位和SEQ ID NO 144的一个mAb特异性表位。
根据另一种实施方式，表位是模拟表位。作为大分子，经常为肽，其模拟表位的结构，模拟表位具有比常规表位更小的优点，因此可能有益于非构象序列以及更容易地以长多肽的形式来复制这样的CAR。已知模拟表位用于几种药物批准的mAb如用于西妥昔单抗的两个10氨基酸肽(Riemer et al.,2005)，或用于帕利珠单抗的24aa(Arbiza et al,1992)。因为可以通过噬菌体展示来确定这些模拟表位，所以可以尝试其中的几个以获得不会扰乱用于相同mAb的scFv的序列。此外，它们的使用可以增强补体依赖性细胞毒性(CDC)。
scFv
如在本文中所使用的，术语“胞外配体结合结构域”是指能够结合配体的寡或多肽。优选地，寻求能够相互作用与细胞表面分子的所述域。例如，可以选择胞外配体结合结构域以识别作为在与特定疾病状态相关的靶细胞上的细胞表面标记的配体。因而可以作为配体的细胞表面标记的实例包括与病毒、细菌和寄生虫感染、自身免疫疾病和癌细胞相关的那些细胞表面标记。尤其是，胞外配体结合结构域可以包含源自针对靶抗原的抗体的抗原结合结构域。作为非限制性实例，靶的抗原可以是如上所述的肿瘤相关表面抗原。在一些实施方式中，胞外结合结构域是如上文所定义的胞外配体结合结构域。根据本发明，所述胞外配体结合结构域是单链抗体片段(scFv)，其包含靶抗原特异性单克隆抗体的轻(VL)和重(VH)可变片段，以及mAb表位特异性抗原。在一些实施方式中，胞外结合结构域包含单链抗体片段(scFv)，其包含细胞表面靶抗原特异性单克隆抗体的轻(VL)和重(VH)可变片段。
不同于的scFv的结合结构域还可以用于淋巴细胞的预定靶向，如骆驼单域抗体片段、受体配体像血管内皮生长因子多肽、整联蛋白结合肽、神经调节蛋白(heregulin，神经生长因子)或IL-13突变蛋白、抗体结合结构域、抗体高变环或CDR(作为非限制性实例)。
在另一种实施方式中，所述胞外结合结构域可以是DARPin(工程锚蛋白重复序列蛋白)。DARPin是基因工程抗体模拟蛋白，其通常展示高度特异性和高亲和力靶蛋白结合。它们源自天然锚蛋白并且包含这些蛋白质的至少三个，通常四个或五个重复基序。DARPin是小的单结构域蛋白，其可以加以选择以高亲和力和特异性地结合任何给定靶蛋白(Epa,Dolezal et al.2013；Friedrich,Hanauer et al.2013；Jost,Schilling et al.2013)。根据本发明，可以设计DARPin以包含多个抗原识别位点。因而，所述DARPin可以用来识别一系列的连续不同抗原以及独特的抗原。因而，本发明涉及一种方法，该方法包括提供免疫细胞，以及在所述免疫细胞的表面上表达嵌合抗原受体，其包含工程锚蛋白重复序列蛋白，其能够识别至少一种特异性配体，优选两种特异性配体。
作为非限制性实例，靶的配体或由胞外结合结构域，优选由ScFv，识别的抗原可以是肿瘤相关表面抗原，如ErbB2(HER2/neu)、癌胚抗原(CEA)、上皮细胞黏附分子(EpCAM)、表皮生长因子受体(EGFR)、EGFR变体III(EGFRvIII)、CD19、CD20、CD30、CD40、双唾液酸神经节苷脂GD2、GD3、C型凝集素样分子-1(CLL-1)、导管上皮粘蛋白、gp36、TAG-72、鞘糖脂、胶质瘤相关抗原、β-人绒毛膜促性腺激素、甲胎蛋白(AFP)、凝集素反应性AFP、甲状腺球蛋白、RAGE-1、MN-CA IX、人端粒酶逆转录酶、RU1、RU2(AS)、肠羧基酯酶、mut hsp70-2、M-CSF、前列腺酶,前列腺酶特异性抗原(PSA)、PAP、NY-ESO-1、LAGA-1a、p53、前列腺蛋白、PSMA、存活和端粒酶、前列腺癌肿瘤抗原-1(PCTA-1)、MAGE、ELF2M、中性粒细胞弹性蛋白酶、肝配蛋白B2、CD22、胰岛素生长因子(IGF1)-I、IGF-II、IGFI受体、间皮素、呈递肿瘤特异性肽表位的主要组织相容性复合物(MHC)分子、5T4、ROR1、Nkp30、NKG2D、肿瘤基质抗原、纤连蛋白的额外结构域A(EDA)和额外结构域B(EDB)以及肌腱蛋白-C的A1结构域(TnC A1)和成纤维细胞相关蛋白(fap)、LRP6、黑素瘤相关硫酸软骨素蛋白聚糖(MCSP)、CD38/CS1、MART1、WT1、MUC1、LMP2、独特型、NY-ESO-1、Ras突变体、gp100、蛋白酶3、bcr-abl、酪氨酸酶、hTERT、EphA2、ML-TAP、ERG、NA17、PAX3、ALK、雄激素受体；谱系特异性或组织特异性抗原如CD3、CD4、CD8、CD24、CD25、CD33、CD34、CD70、CD79、CD116、CD117、CD135、CD123、CD133、CD138、CTLA-4、B7-1(CD80)、B7-2(CD86)、内皮糖蛋白、主要组织相容性复合物(MHC)分子、BCMA(CD269、TNFRSF 17)、FLT-3、或病毒特异性表面抗原如HIV特异性抗原(如HIV gp120)；EBV特异性抗原、CMV特异性抗原、HPV特异性抗原、拉沙病毒特异性抗原、流感病毒特异性抗原以及这些表面标记的任何衍生物或变体。在具体情况下，嵌合抗原受体识别的配体是存在在靶细胞的表面上，特别是癌细胞或病毒细胞。在一些实施方式中，嵌合抗原受体识别的配体是存在在肿瘤微环境中。在本发明的一些方面，嵌合抗原受体识别的配体是生长因子。
在一种优选实施方式中，所述VH和VL链，作为抗原靶序列，相对于SEQ ID NO 43(CD19抗原)、SEQ ID NO 44(CD38抗原)、SEQ ID NO45(CD123抗原)、SEQ ID NO 46(CS1抗原)、SEQ ID NO 47(BCMA抗原)、SEQ ID NO 48(FLT-3抗原)、SEQ ID NO 49(CD33抗原)、SEQID NO50(CD70抗原)、SEQ ID NO 51(EGFR-3v抗原)、SEQ ID NO 52(WT1抗原)，具有80％以上一致性，优选90％以上，以及更优选95％以上。
在一种更优选的实施方式中，所述VH和VL链，作为抗原靶序列，相对于如表3所示的SEQ ID NO 53-64(CD19抗原)、SEQ ID NO65-76(CD33抗原)、SEQ ID NO 77-84(5T4抗原)、SEQ ID NO 85-90(ROR1抗原)、SEQ ID NO 91-94(EGFRvIII抗原)、SEQ ID NO 95-102(BCMA抗原)、SEQ ID NO 103-112(CS1抗原)和SEQ ID NO 113-124(CD123抗原)，具有80％以上一致性，优选90％以上，以及更优选95％以上，或相同于如表3所示的SEQ ID NO 53-64(CD19抗原)、SEQ ID NO 65-76(CD33抗原)、SEQ ID NO 77-84(5T4抗原)、SEQ ID NO 85-90(ROR1抗原)、SEQ ID NO91-94(EGFRvIII抗原)、SEQ ID NO 95-102(BCMA抗原)、SEQ IDNO103-112(CS1抗原)和SEQ ID NO 113-124(CD123抗原)。
在一些实施方式中，由胞外结合结构域，优选由ScFv，识别的抗原选自SEQ ID NO43(CD19抗原)、SEQ ID NO 44(CD38抗原)、SEQ ID NO45(CD123抗原)、SEQ ID NO 46(CS1抗原)、SEQ ID NO 47(BCMA抗原)、SEQ ID NO 48(FLT-3抗原)、SEQ ID NO 49(CD33抗原)、SEQID NO50(CD70抗原)、SEQ ID NO 51(EGFR-vIII抗原)或SEQ ID NO 52(WT1抗原)。
在一些实施方式中，胞外结合结构域包含：
-SEQ ID NO 65的VH和SEQ ID NO 66的VL；SEQ ID NO 67的VH和SEQ ID NO 68的VL；SEQ ID NO 69的VH和SEQ ID NO 70的VL；SEQ ID NO 71的VH和SEQ ID NO 72的VL；SEQID NO 77的VH和SEQ ID NO 78的VL；SEQ ID NO 79的VH和SEQ ID NO 80的VL；
-SEQ ID NO 81的VH和SEQ ID NO 82的VL；SEQ ID NO 83的VH和SEQ ID NO 84的VL；SEQ ID NO 85的VH和SEQ ID NO 86的VL；SEQ ID NO 87的VH和SEQ ID NO 88的VL；SEQID NO 89的VH和SEQ ID NO 90的VL；SEQ ID NO 91的VH和SEQ ID NO 92的VL；SEQ ID NO93的VH和SEQ ID NO 94的VL；SEQ ID NO 95的VH和SEQ ID NO 96的VL；SEQ ID NO 97的VH和SEQ ID NO 98的VL；SEQ ID NO 99的VH和SEQ ID NO 100的VL；SEQ ID NO 101的VH和SEQID NO 102的VL；SEQ ID NO 103的VH和SEQ ID NO 104的VL；SEQ ID NO 105的VH和SEQ IDNO 106的VL；SEQ ID NO 107的VH和SEQ ID NO 108的VL；SEQ ID NO 109的VH和SEQ ID NO110的VL；SEQ ID NO 111的VH和SEQ ID NO 112的VL；SEQ ID NO 113的VH和SEQ ID NO 114的VL；SEQ ID NO 115的VH和SEQ ID NO 116的VL；SEQ ID NO 117的VH和SEQ ID NO 118的VL；SEQ ID NO 119的VH和SEQ ID NO 120的VL；SEQ ID NO 121的VH和SEQ ID NO 122的VL；SEQ ID NO 123的VH和SEQ ID NO 124的VL；SEQ ID NO 170的VH和SEQ ID NO 171的VL；SEQID NO 172的VH和SEQ ID NO 173的VL；或，SEQ ID NO174的VH和SEQ ID NO 175的VL。
表3：靶向CD19、CD33、5T4、ROR1、EGFRvIII、BCMA、CS1和CD123抗原的scFv的VH和VL链的清单
Figure BDA0003347832690000261
Figure BDA0003347832690000271
Figure BDA0003347832690000281
Figure BDA0003347832690000291
Figure BDA0003347832690000301
Figure BDA0003347832690000311
在另一种优选实施方式中，所述VH和VL链，作为表位靶序列，具有相对于SEQ IDNO 11(CD20抗原)的80％以上一致性，优选90％以上，以及更优选95％以上。
胞外配体结合结构域还可以包含靶的肽结合抗原、结合靶的抗原的肽或蛋白结合抗体、肽或蛋白配体如生长因子、细胞因子或激素(作为非限制性实例)，其结合在靶上的受体，或源自受体的域如生长因子受体、细胞因子受体或激素受体(作为非限制性实例)，其结合在靶上的肽或蛋白配体。优选地，靶是细胞或病毒。
CAR的抗原结合结构域可以是任何域，其结合于细胞靶抗原，包括但不限于单克隆抗体、重组抗体、人抗体、人源化抗体、以及它们的功能片段。
可以使用本领域已知的各种技术来产生人源化抗体，包括但不限于CDR移植(见，例如，欧洲专利号EP 239,400；国际公开号WO 91/09967；以及美国专利号5,225,539、5,530,101、和5,585,089，其各自的全部内容通过引用并入本文)、覆盖或再涂层(见，例如，欧洲专利号EP 592,106和EP 519,596；Padlan,1991,Molecular Immunology,28(4/5):489-498；Studnicka et al.,1994,Protein Engineering,7(6):805-814；和Roguska et al.,1994,PNAS,91:969-973，其各自的全部内容通过引用并入本文)、链改组(见，例如，美国专利号5,565,332，其全部内容通过引用并入本文)、以及在例如美国专利申请公开号US2005/0042664、美国专利申请公开号US2005/0048617、美国专利号.6,407,213、美国专利号5,766,886、国际公开号WO 9317105、Tan et al.,J.Immunol.,169:1119-25(2002)、Caldaset al.,Protein Eng.,13(5):353-60(2000)、Morea et al.,Methods,20(3):267-79(2000)、Baca et al.,J.Biol.Chem.,272(16):10678-84(1997)、Roguska et al.,ProteinEng.,9(10):895-904(1996)、Couto et al.,Cancer Res.,55(23Supp):5973s-5977s(1995)、Couto et al.,Cancer Res.,55(8):1717-22(1995)、Sandhu J S,Gene,150(2):409-10(1994)、和Pedersen et al.,J.Mol.Biol.,235(3):959-73(1994)中披露的技术，其各自的全部内容通过引用并入本文。经常，在构架区中的构架残基将被来自CDR供体抗体的相应残基替代，以改变，例如改善，抗原结合。通过本领域中众所周知的方法来确定这些构架取代，例如，通过建模CDR和构架残基的相互作用以确定构架残基，其对于抗原结合是重要的，以及序列比较以确定在特定位置处的异常构架残基(见，例如，Queen et al.,美国专利号5,585,089；以及Riechmann et al.,1988,Nature,332:323，其全部内容通过引用并入本文)。
根据本发明，scFv可以是纳米体(天然单域抗体)，其可以通过单峰骆驼、骆驼、美洲驼、羊驼或鲨鱼的免疫来获得。
在嵌合scFv内的接头
scFv接头工程的柔性可以结合与表面耦合化学的固有的快速适应性特征(例如，静电、氢键、或共价连接)。肽接头的长度可以为10至25个氨基酸并且通常但不总是组成自亲水性氨基酸如甘氨酸(G)和丝氨酸(S)。还已使用较短长度(0–4个氨基酸)的肽接头。然而，携带较短接头的scFv可能形成多聚体。通常，(GGGGS)3肽用作scFv肽接头。这种15个氨基酸接头序列[指定为(GGGGS)3接头]用于市售自Amersham的重组噬菌体抗体系统(RPAS试剂盒)。以前的研究表明，在scFv肽接头中含有金属结合氨基酸(即，半胱氨酸或组氨酸)的scFv(MW～27 000)可以，以有利的抗原结合取向，在高密度下，其分别显著增加全IgG或Fab抗体片段的测定灵敏度3–5倍以上，直接固定到金表面上(Shen Z,Mernaugh RL,Yan H,YuL,Zhang Y,Zeng X.Anal.Chem.2005；77:6834–6842；Shen Z,Stryker GA,Mernaugh RL,YuL,Yan H,Zeng X.Anal.Chem.2005；77:797–805)。
在适用于本发明的其它接头中有15聚体肽接头(RGRGRGRGRSRGGGS)(ZhihongShen,Heping Yan,Ying Zhang,Raymond L.Mernaugh,and Xiangqun Zeng(2008),AnalChem.80(6):1910–1917)。
在一些实施方式中，如在scFv的情况下使用的，“接头"是指肽接头，其组成自氨基酸如单独使用或组合使用的甘氨酸和/或丝氨酸残基，以将可变重链区和可变轻链区连接在一起。在一种实施方式中，柔性多肽接头是甘氨酸/丝氨酸接头并且包含氨基酸序列(Gly-Gly-Gly-Ser)n或(Gly-Gly-Gly-Gly-Ser)n，其中n是等于或大于1的正整数。例如，n＝1、n＝2、n＝3、n＝4、n＝5、n＝6、n＝7、n＝8、n＝9以及n＝10。在一种实施方式中，柔性多肽接头包括但不限于(Gly4Ser)4或(Gly4Ser)3。在另一种实施方式中，接头包括(GlyxSer)n的多次重复，其中x＝1、2、3、4或5以及n是1、2、3、4、5、6、7、8、9或10，如(GlySer)、(Gly2Ser)或(Gly5Ser)的多次重复。在本发明的范围内还包括在通过引用并入本文的WO2012/138475中描述的接头。
嵌合抗原受体(CAR)
寻求根据本发明的CAR以使得工程化免疫细胞能够触发病理细胞的破坏，尤其是恶性细胞。可以按照单链或多链结构来设计它们。在一些实施方式中，胞外配体结合结构域、跨膜结构域、和胞内信号结构域是在一个多肽中，即，在单链中。在WO2014039523中，更具体地披露了多链结构。
多链CAR通常形成自不同的多肽如：
-一个跨膜多肽，其包含至少一个胞外配体结合结构域以及；
-一个跨膜多肽，其包含至少一个信号转导域。
信号多肽负责工程化免疫细胞的正常功能的至少一种功能的激活。例如，T细胞的功能可以是细胞溶解活性或辅助细胞活性，其包括细胞因子的分泌。因而，术语“信号蛋白”是指这样的蛋白质，其转导递质域功能信号并指导细胞进行专门功能。在特定实施方式中，所述递质域可以是信号蛋白。信号的传递可以产生自：蛋白质/蛋白质相互作用、蛋白质/DNA相互作用、蛋白质/RNA相互作用、蛋白质/小分子相互作用、翻译后蛋白修饰、构象变化、亚细胞再定位。
信号蛋白可以激活在细胞核中的基因。信号蛋白的实例可以是NFAT转录因子家族的成员，它们是诱导因子，其可以结合在激活的T细胞中的白细胞介素-2启动子。NFAT蛋白的调节涉及代谢物和蛋白质如钙、钙调磷酸酶和Homer支架蛋白。所述信号蛋白可以是NFAT的激活工程形式，从而避免通过钙调磷酸酶和Homer蛋白的调节。所述信号蛋白可以是NF-κB工程的以在细胞质中避免Iκb的螯合，从而允许T细胞的激活。所述信号蛋白还可以是三种IKK亚基(IKKα、IKKδ、IKKγ)的表达。重建IKK复合体激活NF-κB途径，其中通过触发IκB的遍在蛋白化。此外，可以通过信号蛋白AP-1(转录因子)的直接表达来触发JNK信号的激活。所述信号蛋白可以是工程转录激活物像效应子(TALE)结合结构域，其将特异性地靶向和激活相同基因的转录，如针对NFAT和NF-kb。
根据本发明，所述信号蛋白可以通过蛋白质-蛋白质相互作用来抑制信号途径或可以激活在细胞核中的基因以抑制信号途径。所述信号蛋白可以是牛痘H1相关蛋白(VHR)，丝裂原活化蛋白激酶磷酸酶(MKP)家族的成员，其去磷酸化和灭活细胞外信号调节激酶(ERK)信号蛋白。
根据本发明，供在CAR中使用的信号转导域可以是T细胞受体的细胞质序列和共受体，其一致行动以在抗原受体衔接以后引发信号转导，以及这些序列的任何衍生物或变体，以及具有相同的功能能力的任何合成序列。信号转导域可以包含两种不同类的细胞质信号序列，那些引发抗原依赖性初级激活的细胞质信号序列，以及那些以抗原非依赖性方式起作用来提供次级或共刺激信号的细胞质信号序列。
在特定实施方式中，本发明的CAR的信号转导域包含共刺激信号分子。共刺激分子是不同于抗原受体或它们的配体的细胞表面分子，其是为有效的免疫反应所需要的。
“共刺激配体”是指在抗原呈递细胞上的分子，其特异性地结合在T细胞上的同源共刺激分子，从而提供信号，除通过，例如，TCR/CD3复合物与MHC分子加载肽的结合所提供的初级信号之外，其还介导T细胞反应，包括但不限于增殖激活、分化等。“共刺激分子”是指在T细胞上的相关结合配偶体，其特异性地结合与共刺激配体，从而介导通过细胞的共刺激反应，如但不限于增殖。共刺激分子包括但不限于MHC I类分子、BTLA和Toll配体受体。
例如，多链CAR可以源自Fc受体的结构，优选FcεRI，并且包含至少两种以下组件：
a)一种多肽，其包含融合于胞外配体结合结构域的FcRIα链的跨膜结构域，
b)一种多肽，其包含融合于FcRIβ链的跨膜结构域的N端和C端胞质尾区的一部分，和/或
c)两种额外的多肽，其各自包含胞质内尾区和/或FcRIγ链的跨膜结构域的一部分。
一般来说，这些不同的多肽自发多聚在一起以形成二聚体、三聚体或四聚体结构，其以近膜位置出现在细胞表面上。
在一些实施方式中，发明涉及免疫细胞，其包含单链CAR，其是如在现有技术中以及在任何以下文献中很好地定义的：US7446190、WO2008/121420、US8252592、US20140024809、WO2012/079000、WO2014153270、WO2012/099973、WO2014/011988、WO2014/011987、WO2013/067492、WO2013/070468、WO2013/040557、WO2013/126712、WO2013/126729、WO2013/126726、WO2013/126733、US8399645、US20130266551、US20140023674、WO2014039523、US7514537、US8324353、WO2010/025177、US7446179、WO2010/025177、WO2012/031744、WO2012/136231A1、WO2012/050374A2、WO2013074916、WO/2009/091826A3、WO2013/176915或WO/2013/059593。
在一些实施方式中，本发明涉及CAR，其包含：
-胞外结构域，其包含
-至少一个胞外结合结构域，其包含通过对于抗原，优选细胞表面标记抗原，为特异性的，至少VH链和VL链所形成的scFv，其中所述胞外结合结构域包含至少一个mAb特异性表位，以及，
-铰链，
-跨膜结构域，以及，
-胞内结构域。
在一种实施方式中，跨膜结构域包含以下各项的α、β或ζ链的跨膜区：T细胞受体、PD-1、4-1BB、OX40、ICOS、CTLA-4、LAG3、2B4、BTLA4、TIM-3、TIGIT、SIRPA、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154。
在另一种实施方式中，铰链是IgG4铰链或CD8α铰链，优选CD8α铰链。
适当的跨膜结构域的明显特征包括以下能力：表达在细胞的表面上，在本发明中优选为免疫细胞，特别是淋巴细胞或自然杀伤(NK)细胞，以及一起相互作用，以指导免疫细胞针对预定义靶细胞的细胞反应。跨膜结构域可以衍生自天然或合成来源。跨膜结构域可以源自任何膜结合或跨膜蛋白。作为非限制性实例，跨膜多肽可以是T细胞受体的亚基如α、β、γ或δ，构成CD3复合物的多肽，IL2受体p55(α链)，p75(β链)或γ链，Fc受体的亚基链，尤其是Fcγ受体III或CD蛋白。可替换地，跨膜结构域可以是合成的并且可以包含主要为疏水性残基如亮氨酸和缬氨酸。在优选实施方式中，所述跨膜结构域源自人CD8α链(例如NP_001139345.1)。所述跨膜结构域还可以是CD8跨膜结构域(α和β链)。可以设计所述跨膜结构域以产生专性杂二聚体或同源二聚体。在特定实施方式中，所述CAR可以包含跨膜结构域或胞内结构域，其可以在配体识别以后仅二聚化。跨膜结构域的另一实例可以是NKG2-D受体。NKG2D(自然杀伤细胞组2D)是在NK细胞、γδ-TcR+T细胞、和CD8+αβ-TcR+T细胞上表达的C型凝集素样受体(Bauer,Groh et al.,1999,Science 285(5428):727-9)。NKG2D关联与跨膜衔接子蛋白DAP10(Wu,Song et al.1999,Science 285(5428):730-2)，其细胞质域结合于PI-3激酶的p 85亚基。
所述跨膜结构域还可以是整联蛋白。整联蛋白是异二聚体整合膜蛋白，组成自α和β链，其结合在一起形成LFA-1(整联蛋白淋巴细胞功能相关抗原-1)，其表达在所有白细胞上。LFA-1在白细胞细胞间粘附中起着核心的作用，其中通过与其配体，ICAM1-3(细胞间粘附分子1至3)，的相互作用，以及它还在淋巴细胞共刺激信号中具有重要作用(Chen andFlies2013,Nat Rev Immunol 13(4):227-42)。LAF-1与其免疫球蛋白ICAM-1的结合的分子细节是众所周知的，从而允许LAF-1结合位点的细心设计。通过置换其C端螺旋，其构象相关于在LAF-1中的特定环的改变，来调节αL域对于ICAM-1的亲和力。活性和低构象相差500和10,000倍。还有趣的是注意到，对于LFA-1，两种类型的拮抗剂是已知的，并且它们的作用机制是已知的。整联蛋白细胞表面粘附受体可以从外到内地传输信号，但反之亦然。存在细胞骨架蛋白，作为Talin，其结合于整联蛋白尾LFA-1以从内到外地转移信息。
根据一种实施方式，跨膜结构域包含PD-1的跨膜区或CD8α的跨膜区。
在本发明的一个方面，通过铰链，例如，来自人蛋白的铰链，将跨膜结构域连接于CAR的胞外结构域。例如，在一种实施方式中，铰链可以是人Ig(免疫球蛋白)铰链，例如，PD-1铰链、IgG4铰链、或CD8α铰链。
在优选实施方式中，CAR的铰链是人免疫球蛋白铰链。
在更优选的实施方式中，CAR的铰链是IgG4铰链或CD8α铰链。
在一些实施方式中，铰链是FcγRIIIα铰链。
在一些实施方式中，铰链是CD8α铰链。
在一些实施方式中，铰链是CD8α铰链，其具有氨基酸序列，并且相对于在SEQ.IDNO:179、180或181中示出的氨基酸序列，其具有至少约70％的序列一致性，优选至少80％，更优选至少90％、95％、97％、或99％。
在本文中使用的术语“铰链区”(在文献中还名为茎区)通常是指任何寡或多肽，其用来将跨膜结构域连接于胞外配体结合结构域。尤其是，茎区用来为胞外配体结合结构域提更大的柔性和可达性。茎区可以包含多达300个氨基酸，优选10至100个氨基酸以及最优选25至50个氨基酸。茎区可以源自全部或部分自然发生的分子，如源自CD8、CD4、CD28或RTK的全部或部分的胞外区，或源自全部或部分的抗体恒定区。可替换地，茎区可以是对应于自然发生的茎序列的合成序列，或可以是完全合成的茎序列。
胞内结构域(在本文中还称为“细胞质信号结构域”或"胞内信号结构域")包含功能信号结构域，其源自如下所定义的刺激分子。在一些实施方式中，刺激分子是与T细胞受体复合物相关的ζ链。在一些实施方式中，细胞质信号结构域进一步包含一个或多个功能信号结构域，其源自至少一种如下所定义的共刺激分子。在一些实施方式中，共刺激分子选自4-1BB(即，CD137)、CD27和/或CD28。
术语"刺激分子"是指由T细胞所表达的分子，其提供阳性细胞质信号序列，对于T细胞信号途径的至少一些方面，以刺激的方式，上述阳性细胞质信号序列调节TCR复合物的阳性激活。在一些实施方式中，通过，例如，TCR/CD3复合物与MHC分子加载肽的结合，来引发正信号，并且其导致T细胞反应的介导，包括但不限于增殖、激活、分化等。以刺激的方式起作用的阳性细胞质信号序列(还被称为"阳性信号结构域"或阳性胞内信号结构域)可以含有信号基序，其被称为基于免疫受体酪氨酸的激活基序或ITAM。含有阳性细胞质信号序列的ITAM的实例包括但不限于那些ITAM，其源自TCRζ(或CD3ζ)、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b、CD278(还称为"ICOS")和CD66d。在一些实施方式中，CAR的胞内信号结构域可以包含CD3ζ信号结构域，其具有氨基酸序列，上述氨基酸序列，相对于SEQ.IDNO:175所示的氨基酸序列，具有至少约70％，优选至少80％，更优选至少90％、95％、97％、或99％，的序列一致性。
在一些方面，CAR的胞内信号结构域生成信号，其促进含有CAR的细胞的免疫效应子功能。免疫效应子功能的实例，例如，在CAR T细胞中，包括细胞溶解活性和辅助细胞活性，其包括细胞因子的分泌。
术语"共刺激分子"是指在T细胞上的相关结合配偶体，其特异性地结合与共刺激配体，从而介导T细胞的共刺激反应，如但不限于增殖。共刺激分子是不同于抗原受体的细胞表面分子，或它们的配体，其是为有效的免疫反应所需要的。共刺激分子包括但不限于MHC I类分子、BTLA和Toll配体受体，以及OX40、CD2、CD27、CD28、CDS、ICAM-1、LFA-1(CD11a/CD18)和4-IBB(CD137)。
共刺激胞内信号结构域可以是共刺激分子的细胞内部分。可以以以下蛋白家族来表示共刺激分子：TNF受体蛋白、免疫球蛋白样蛋白、细胞因子受体、整联蛋白、信号淋巴细胞激活分子(SLAM蛋白)、和激活NK细胞受体。上述分子的实例包括CD27、CD28、4-1BB(CD137)、OX40、GITR、CD30、CD40、ICOS、BAFFR、HVEM、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、SLAMF7、NKp80、CD160、B7-H3、和特异性地结合与CD83的配体等。在一些实施方式中，本发明的CAR的胞内信号结构域包含氨基酸序列，其，相对于SEQ.ID NO:176和SEQ.ID NO:177所示的氨基酸序列，其具有至少70％，优选至少80％，更优选至少90％、95％、97％、或99％，的序列一致性。
表4提供CAR组件的示例性序列
Figure BDA0003347832690000381
CAR和包含它们的免疫细胞已被广泛披露并且可以由技术人员按照已知方法加以制备。例如，用来制备CAR和包含这样的CAR的细胞的方法披露于US7446190、WO2008/121420、US8252592、US20140024809、WO2012/079000、WO2014153270、WO2012/099973、WO2014/011988、WO2014/011987、WO2013/067492、WO2013/070468、WO2013/040557、WO2013/126712、WO2013/126729、WO2013/126726、WO2013/126733、US8399645、US20130266551、US20140023674、WO2014039523、US7514537、US8324353、WO2010/025177、US7446179、WO2010/025177、WO2012/031744、WO2012/136231A1、WO2012/050374A2、WO2013074916、WO2009/091826A3、WO2013/176915或WO/2013/059593，其全部内容通过引用并入本文。
本发明包括重组DNA构建体，上述重组DNA构建体包含序列，其编码如上文所定义的CAR，其中CAR包含胞外结构域如抗体片段，其特性性地结合于细胞靶抗原，以及其中胞外结构域的序列是邻接与核酸序列并在和核酸序列相同的可读框中，其中上述核酸序列编码跨膜结构域和胞内结构域。示例性CAR构建体可以包含可选的前导序列、胞外细胞靶抗原结合结构域、铰链、跨膜结构域、和细胞内抑制信号结构域。
在一些实施方式中，本发明涉及重组DNA构建体，该构建体包含序列，其编码如上文所定义的CAR。在一些实施方式中，CAR包含胞外结构域，其包含
-至少一个胞外结合结构域，其包含通过对于细胞表面标记抗原为特异性的至少VH链和VL链所形成的scFv，其中所述胞外结合结构域包含待通过表位特异性mAb所结合的至少一个mAb特异性表位，用于体外细胞分选和/或体内细胞清除表达所述CAR的T细胞，以及其中包含胞外结合结构域，以及，
-铰链，
-跨膜结构域，以及，
-胞内结构域。
用于分选CAR阳性免疫细胞的方法
根据一个方面，本发明涉及用于体外分选CAR表达免疫细胞的方法，上述方法包括使所述工程化免疫的群体接触抗原特异性抗体(优选单克隆抗体)，以仅收集表达CAR的细胞。
在一些实施方式中，本发明涉及用于体外分选CAR表达免疫细胞的方法，其中所述CAR包含至少一个胞外结合结构域，其包含如上所述的至少一个mAb特异性表位，上述方法包括
-使所述免疫细胞的群体接触对于所述mAb特异性表位具有特异性的单克隆抗体，以仅收集所述CAR表达免疫细胞。
在一些实施方式中，本发明涉及用于体外分选CAR表达免疫细胞的方法，其中所述CAR包含至少一个胞外结合结构域，其包含至少一个mAb特异性表位，上述方法包括
-使所述免疫细胞的群体接触对于所述mAb特异性表位具有特异性的单克隆抗体(表位特异性mAb)，
-选择结合于单克隆抗体的细胞，
以获得富集有CAR表达免疫细胞的细胞群体。
在一些实施方式中，对于所述mAb特异性表位具有特异性的所述单克隆抗体结合于荧光团以及通过荧光激活细胞分选术(FACS)来进行选择结合于单克隆抗体的细胞的步骤。
在一些实施方式中，对于所述mAb特异性表位具有特异性的所述单克隆抗体结合于磁性颗粒以及通过磁性激活细胞分选术(MACS)来进行选择结合于单克隆抗体的细胞的步骤。
在一些实施方式中，CAR的胞外结合结构域包含SEQ ID NO 144的mAb特异性表位。
在一些实施方式中，CAR的胞外结合结构域包含SEQ ID NO 144的mAb特异性表位以及用来接触免疫细胞的群体的抗体是QBEND-10。
在一些实施方式中，CAR的胞外结合结构域包含SEQ ID NO 35的mAb特异性表位。
在一些实施方式中，CAR的胞外结合结构域包含SEQ ID NO 35的mAb特异性表位以及用来接触免疫细胞的群体的抗体是利妥昔单抗。
在一些实施方式中，当利用上文所描述的用于体外分选CAR表达免疫细胞的方法时所获得的群体CAR表达免疫细胞包含至少70％、75％、80％、85％、90％、95％的CAR表达免疫细胞。在一些实施方式中，当利用上文所描述的用于体外分选CAR表达免疫细胞时所获得的群体CAR表达免疫细胞包含至少85％的CAR表达免疫细胞。
在一些实施方式中，相比与初始(未分选的)细胞群体，并利用在实施例7.5中描述的协议，当利用上文所描述的用于体外分选CAR表达免疫细胞的方法时所获得的CAR表达免疫细胞的群体显示体外增加的细胞毒活性。在优选实施方式中，所述细胞毒活性体外增加10％、20％、30％或50％。
优选地，如由本领域技术人员常规实现的，将mAb先前结合在载体如柱或珠上。
根据一种有利的实施方式，免疫细胞是T细胞。
根据本发明，待给予受者的细胞可以体外富集自源群体。
扩大源群体的方法是本领域众所周知的，并且可以包括选择表达抗原如CD34抗原的细胞，其中利用本领域技术人员已知的密度离心、免疫磁珠纯化、亲和层析、和荧光激活细胞分选术的结合。
流式细胞术
流式细胞术被广泛用于本领域并且是普通技术人员用来分选和量化在细胞群体内的特定细胞类型的众所周知的方法。一般来说，流式细胞术是主要通过光学方式来量化细胞的组件或结构特征的方法。因为可以通过量化结构特征来区分不同的细胞类型，所以流式细胞术和细胞分选术可以用来计数和分选在混合物中的不同表型的细胞。
流式细胞术分析涉及两个基本步骤：1)用一种或多种标记标志物来标记细胞类型，以及T)相对于在群体中细胞的总数来确定标记细胞的数目。
标记细胞类型的主要方法是通过将标记抗体结合于由特定细胞类型表达的标记物。用荧光化合物来直接标记抗体，或利用，例如，识别一抗的荧光标记的二抗来间接标记抗体。
在优选实施方式中，用于分选表达CAR的T细胞的方法是磁性激活细胞分选术(MACS)。
磁性激活细胞分选术(MACS)是通过使用超顺磁性纳米颗粒和柱来分开各种细胞群体的方法，其取决于它们的表面抗原(CD分子)。为了得到纯细胞群体，只需要几个简单的步骤。用微珠来磁性标记在单细胞悬液中的细胞。将样品施加于组成自铁磁球体的柱，其覆盖有细胞友好的涂层，从而允许快速和温和地分开细胞。未标记细胞通过而磁性标记细胞则被保留在柱内。可以收集流过物作为未标记细胞部分。在短洗涤步骤以后，从分离器除去柱，然后从柱洗脱磁性标记细胞。
在其它技术中，FACS是选择的用来纯化已知表型的细胞群体的技术，因为可以实现所期望的群体的非常高纯度，或当靶细胞群体表达非常低水平的识别标记物时，或当需要基于有差别的标记物密度来分开细胞群体时。此外，FACS是基于内部染色或细胞内蛋白质表达，如基因修饰荧光蛋白标记物，来分离细胞的仅有的可用的纯化技术。FACS允许基于尺寸、粒度和荧光，来纯化单种细胞。为了纯化感兴趣的细胞，首先用荧光标记的单克隆抗体(mAb)来染色它们，其识别在所期望的细胞群体上的特定的表面标记物。
用于纯化特定细胞群体如T细胞的详细协议可以见Basu S et al.(2010).(BasuS,Campbell HM,Dittel BN,Ray A.Purification of specific cell population byfluorescence activated cell sorting(FACS).J Vis Exp.(41):1546)。
在本发明的优选实施方式中，在用于分选表达CAR的T细胞的方法中使用的mAb选自替伊莫单抗、伊莫单抗、莫罗单抗-CD3、托西莫单抗、阿昔单抗、巴利昔单抗、本妥昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿仑单抗、贝伐单抗、妥珠单抗、达克珠单抗、依库珠单抗、依法利珠单抗、吉姆单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、兰尼单抗、托珠单抗、曲妥单抗、维多珠单抗、阿达木单抗、贝利单抗、康纳单抗、地诺单抗、戈利木单抗、易普利单抗、奥法木单抗、帕尼单抗、QBEND-10和优特克单抗。
在更优选的实施方式中，所述mAb是利妥昔单抗。
在更优选的实施方式中，所述mAb是QBEND-10。
用于清除CAR表达免疫细胞的方法
在本发明中，“体内清除”是指对哺乳动物生物体给予治疗，其旨在通过抑制或消除来停止CAR表达免疫细胞的增殖。
本发明的一个方面涉及用于体内清除表达CAR的工程化免疫细胞的方法，上述CAR包含如前所述的mAb特异性表位，其中上述方法包括使所述工程化免疫细胞或所述CAR表达免疫细胞接触至少一种表位特异性mAb。本发明的另一个方面涉及用于体内清除免疫CAR表达免疫细胞的方法，上述细胞包含上述嵌合scFv(通过插入mAb特异性表位所形成的)，其中通过使所述工程化免疫细胞接触表位特异性抗体。
优选地，所述免疫细胞是T细胞和/或抗体是单克隆。
根据一种实施方式，对以前已经利用本发明的体外方法加以分选的工程化免疫细胞进行免疫工程细胞的体内清除。在这种情况下，这将是使用的相同的注入mAb。
根据优选实施方式，mAb特异性抗原是CD20抗原以及表位特异性mAb是利妥昔单抗。
在一些实施方式中，本发明涉及用于在患者中体内清除表达CAR的工程化免疫细胞的方法，其中上述CAR包含如前所述的,mAb特异性表位(CAR表达免疫细胞)，上述方法包括使所述CAR表达免疫细胞接触至少一种表位特异性mAb。
在本发明的优选实施方式中，在清除表达CAR的工程化免疫细胞的方法中使用的mAb选自替伊莫单抗、伊莫单抗、莫罗单抗-CD3、托西莫单抗、阿昔单抗、巴利昔单抗、本妥昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿仑单抗、贝伐单抗、妥珠单抗、达克珠单抗、依库珠单抗、依法利珠单抗、吉姆单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、兰尼单抗、托珠单抗、曲妥单抗、维多珠单抗、阿达木单抗、贝利单抗、康纳单抗、地诺单抗、戈利木单抗、易普利单抗、奥法木单抗、帕尼单抗、QBEND-10和优特克单抗。
在一些实施方式中，所述mAb特异性表位是CD20表位或模拟表位，优选SEQ ID NO35以及表位特异性mAb是利妥昔单抗。
在一些实施方式中，使所述工程化免疫细胞或所述CAR表达免疫细胞接触至少一种表位特异性mAb的步骤包括将表位特异性mAb优选利妥昔单抗，注入患者。在一些实施方式中，给予患者的表位特异性mAb的量足以在患者中消除至少20％、30％、40％、50％、60％、70％、80％或90％的CAR表达免疫细胞。
在一些实施方式中，使所述工程化免疫细胞或所述CAR表达免疫细胞接触至少一种表位特异性mAb的步骤包括将375mg/m2的利妥昔单抗注入患者，一次或几次，优选每周一次。
在一些实施方式中，当在CDC测定中利用表位特异性mAb来清除表达CAR(其包含mAb特异性表位)的免疫细胞(CAR表达免疫细胞)时，能存在的CAR表达免疫细胞的量降低，优选至少10％、20％、30％、40％、50％、60％、70％、80％或90％。优选地，CDC测定是在实施例3、实施例4或实施例7.4中披露的测定。在一些实施方式中，所述mAb特异性表位是CD20表位或模拟表位，优选SEQ ID NO 35，以及表位特异性mAb是利妥昔单抗。
在一种特定实施方式中，通过注入双特异性抗体来进行CAR工程化免疫细胞的体内清除。根据定义，双特异性单克隆抗体(BsAb)是人造蛋白，其组成自两种不同的单克隆抗体的片段，因此结合于两种不同类型的抗原。这些BsAb和它们在免疫治疗中的应用已经被广泛评论于Müller D and Kontermann R.E.(2010)Bispecific Antibodies for CancerImmunotherapy,BioDrugs 24(2):89-98。
术语“效应细胞”包括免疫细胞如淋巴细胞、巨噬细胞、树突状细胞、自然杀伤细胞(NK细胞)、细胞毒性T淋巴细胞(CTL)。
根据另一种特定实施方式，注入双特异性mAb能够结合于由表达嵌合scFv的工程化免疫细胞携带的mAb特异性表位和结合于在效应和细胞毒性细胞上的表面抗原。这个方面在图3中示出。通过这样做，可以通过抗体依赖性细胞毒性(ADCC)来发生借助于BsAb所触发的工程化免疫细胞的清除。这样的构象可以见例如Deo Y M,Sundarapandiyan K,KelerT,Wallace PK,and Graziano RF,(2000),Journal of Immunology,165(10):5954-5961]。
根据特定实施方式，将细胞毒性药物耦联于表位特异性mAb，其用来清除CAR表达免疫细胞。通过结合单克隆抗体的靶向能力与细胞毒性药物的杀癌能力，当相比与仅使用药物时，抗体-药物偶联物(ADC)允许在健康和病变组织之间进行敏感区分。几种ADC收到市场认可；用于制作它们的技术，尤其是关于接头，大量地呈现在以下现有技术中(Payne,G.(2003)Cancer Cell 3:207-212；Trail et al(2003)Cancer Immunol.Immunother.52:328-337；Syrigos and Epenetos(1999)Anticancer Research 19:605-614；Niculescu-Duvaz and Springer(1997)Adv.Drug Del.Rev.26:151-172；美国专利号4,975,278)。
根据另一种特定实施方式，待注入的表位特异性mAb预先结合与能够促进补体依赖性细胞毒性(CDC)的分子。因此，补体系统帮助或补充抗体从生物体清除病原体的能力。当受到多种之一的刺激时，激活级联被触发，作为细胞杀伤膜攻击复合体的回应和激活的大规模扩增。
不同的分子可以用来结合mAb，如聚糖[Courtois,A,Gac-Breton,S.,Berthou,C.,Guézennec,J.,Bordron,A.and Boisset,C.(2012),Complement dependent cytotoxitityactivity of therapeutic antidody fragments is acquired by immunogenic glycancoupling,Electronic Journal of Biotechnology ISSN:0717-3458；http://www.ejbiotechnology.info DOI:10.2225/vol15-issue5)。
在本发明的一些实施方式中，在用于分选和清除表达CAR的工程化免疫细胞的方法中所使用的表位特异性mAb是相同的并且选自替伊莫单抗、伊莫单抗、莫罗单抗-CD3、托西莫单抗、阿昔单抗、巴利昔单抗、本妥昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿仑单抗、贝伐单抗、妥珠单抗、达克珠单抗、依库珠单抗、依法利珠单抗、吉姆单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、兰尼单抗、托珠单抗、曲妥单抗、维多珠单抗、阿达木单抗、贝利单抗、康纳单抗、地诺单抗、戈利木单抗、易普利单抗、奥法木单抗、帕尼单抗、QBEND-10和优特克单抗。
在本发明的一些实施方式中，不同抗体用于分选和清除细胞。在一些实施方式中，胞外结合结构域包含至少一个通过利妥昔单抗所特异性地结合的表位，如mAb特异性表位，其具有SEQ ID NO 35的氨基酸序列，以及至少一个通过QBEND10所特异性地结合的表位，如SEQ ID NO 144，以及用于分选细胞的mAb是QBEND10以及用来清除细胞的mAb是利妥昔单抗。
设计免疫细胞的方法
本发明人开发了设计免疫细胞的方法，上述免疫细胞表达嵌合抗原受体(CAR)，优选如上所述的CAR，并具有为触发细胞表面靶抗原和为扩展/扩增所必要的所有组件。而且，这种CAR具有携带嵌合scFv的特性，其中修饰scFv以包括能够由抗体特异性识别的表位，用于细胞分选和/或细胞清除目的。
在一种实施方式中，用于设计免疫细胞嵌合抗原受体(CAR)，其包含至少一个胞外结合结构域，其包含通过对于细胞表面标记抗原为特异性的至少VH链和VL链所形成的scFv以及待通过表位特异性mAb所结合的一个mAb特异性表位，的方法包括：
(a)提供免疫细胞；
(b)将至少一种编码所述嵌合抗原受体的多核苷酸引入所述细胞；
(c)将所述多核苷酸表达进入所述细胞。
在一种实施方式中，用于设计免疫细胞，其表达如上所述的嵌合抗原受体(CAR)，优选包含至少一个胞外结合结构域，其包含通过对于细胞表面标记抗原为特异性的至少VH链和VL链形成的scFv以及待通过表位特异性mAb所结合的一个mAb特异性表位，的方法包括：
(a)提供免疫细胞；
(b)将至少一种编码所述嵌合抗原受体的多核苷酸引入所述细胞；以及，
(c)将所述多核苷酸表达进入所述细胞。
已广泛披露了CAR和包含它们的免疫细胞，并且可以按照已知方法由技术人员加以制备。例如，早先披露了用于制备CAR和包含上述CAR的细胞的方法。可以根据上述参考文献中公开的方法由技术人员来制备包含CAR的免疫细胞。在优选实施方式中，可以按照在WO2013/176915中披露的方法由技术人员来制备包含CAR的免疫细胞。
在一些实施方式中，免疫细胞可以源自炎性T淋巴细胞、细胞毒性T淋巴细胞、调节性T淋巴细胞、或辅助性T淋巴细胞。
在一些实施方式中，免疫细胞获自健康供体。在一些实施方式中，免疫细胞获自患者。
在一些实施方式中，设计本发明的细胞的方法进一步包括一个或多个另外的基因组修饰步骤。通过另外的基因组修饰步骤，可以旨在将一种或多种感兴趣的蛋白质引入细胞。所述感兴趣的蛋白质可以是CAR。
在一些实施方式中，用于设计本发明的T细胞的方法可以包括：
(a)修饰T细胞，其中通过灭活至少：
-第一基因，其表达用于免疫抑制剂的靶，以及
-第二基因，其编码T细胞受体(TCR)的组件
(b)扩大所述细胞，可选地在所述免疫抑制剂的存在下。
免疫抑制剂是一种制剂，其通过几种作用机制之一来抑制免疫功能。换句话说，免疫抑制剂是通过化合物来发挥的角色，其是通过减少免疫反应的程度和/或贪婪(voracity)的能力来呈现。作为非限制性实例，免疫抑制剂可以是钙调磷酸酶抑制剂、雷帕霉素的靶、白细胞介素-2u链阻滞剂、肌苷单磷酸脱氢酶的抑制剂、二氢叶酸还原酶的抑制剂、皮质类固醇或免疫抑制抗代谢物。
在特定实施方式中，上述方法的基因修饰步骤依赖于一种基因的失活，其选自由CD52、GR、TCRα和TCRβ组成的组。在另一种实施方式中，上述方法的基因修饰步骤依赖于两种基因的失活，其选自由CD52和GR、CD52和TCRα、CDR52和TCRβ、GR和TCRα、GR和TCRβ、TCRα和TCRβ组成的组。在另一种实施方式中，上述方法的基因修饰步骤依赖于两种以上的基因的失活。优选离体操作基因修饰。
用于灭活T细胞中的基因的稀切内切核酸酶优选是转录激活因子样效应子(TALE)，但还可以是耦联于RNA引导的Cas9，如在WO2013/176915和WO 2014/191128中分别描述的。
递送方法
上文所描述的不同方法涉及在细胞的表面上表达CAR。作为非限制性实例，可以通过将其引入细胞来表达所述CAR。可以引入CAR，作为由一种质粒载体编码的转基因。所述质粒载体还可以含有选择标记物，其提供接受所述载体的细胞的识别和/或选择。
由于在细胞中引入编码所述多肽的多核苷酸的结果，可以在细胞中原位合成多肽。可替换地，可以在细胞外产生所述多肽，然后引入其中。用于将多核苷酸构建体引入细胞的方法是本领域已知的并且包括，作为非限制性实例，稳定转化方法，其中将多核苷酸构建体整合进入细胞的基因组，瞬时转化方法，其中并不将多核苷酸构建体整合进入细胞的基因组，以及病毒介导的方法。可以通过例如，重组病毒载体(例如逆转录病毒、腺病毒)、脂质体等，将所述多核苷酸引入细胞。例如，瞬时转化方法包括例如微注射、电穿孔或粒子轰击。鉴于被表达在细胞中，可以将所述多核苷酸包括在载体中，更具体地质粒或病毒。
多核苷酸和载体
在一种实施方式中，根据本发明的所述分离的细胞包含多核苷酸，其编码携带嵌合scFv的嵌合抗原受体。
本发明还涉及多核苷酸，载体，其编码根据本发明的上述CAR。
多核苷酸可以存在于表达盒或表达载体中(例如用于引入细菌宿主细胞的a质粒，或病毒载体如用于昆虫宿主细胞的转染的杆状病毒载体，或质粒或病毒载体如用于哺乳动物宿主细胞的转染的慢病毒)。
本领域技术人员将明了，鉴于遗传密码的简并性，在这些多核苷酸分子中相当大的序列变化是可能的。优选地，密码子优化本发明的核酸序列，用于在哺乳动物细胞中的表达，优选用于在人细胞中的表达。密码子优化是指在感兴趣的序列中，在给定物种的高表达基因中通常稀有的密码子与在上述物种的高表达基因中通常是频繁的密码子的交换，这样的密码子编码氨基酸作为正被交换的密码子。
治疗应用
在另一种实施方式中，如本文所述的通过不同方法所获得的表达CAR的分离的细胞或免疫细胞，或源自所述分离的细胞(如前所述的)的细胞系可以用作药剂。
在另一种实施方式中，在对其需要的患者中，所述药剂可以用于治疗疾病如癌症。
在另一种实施方式中，在对其需要的患者中，所述分离的细胞或免疫细胞，其表达如本文所述的根据本发明的CAR，或源自所述分离的细胞的细胞系可以用于制造用于治疗疾病如癌症的药剂。
在另一方面，本发明依赖于用于治疗对其需要的患者的方法，所述方法包括以下步骤的至少之一：
(a)提供可以通过上述任何一种方法所获得的免疫细胞；
(b)将所述转化免疫细胞给予所述患者。
在一种实施方式中，本发明的所述免疫细胞，优选T细胞，可以经受强大的体内T细胞扩增并且可以持续延长的时间。
所述治疗可以是改善、治愈或预防。它可以是自体免疫治疗的一部分或同种异体免疫治疗的一部分。自体的，它是指，用于治疗患者的细胞、细胞系或细胞群体源自所述患者或源自人白细胞抗原(HLA)相容供体。同种异体的，则是指，用于治疗患者的细胞或细胞群体不是源自所述患者而是源自供体。
所述治疗可以用来治疗诊断为患有癌症、病毒感染、自身免疫性疾病或移植物抗宿主病(GvHD)的患者。可以加以治疗的癌症包括没有血管化、或还未基本上血管化、以及血管化的肿瘤。癌症可以包含非实体瘤(如血液肿瘤，例如，白血病和淋巴瘤)或可以包含实体瘤。待用本发明的CAR加以治疗的癌症的类型包括但不限于癌、母细胞瘤、和肉瘤、以及某些白血病或淋巴样恶性肿瘤、良性和恶性肿瘤、以及恶性肿瘤例如，肉瘤、癌、和黑色素瘤。还包括成人肿瘤/癌症和儿童肿瘤/癌症。它可以是连同一种或多种针对癌症的治疗一起的治疗，其中上述针对癌症的治疗选自：抗体治疗、化疗、细胞因子治疗、树突细胞治疗、基因治疗、激素治疗、激光治疗和放射治疗。
可以以任何方便的方式来给予根据本发明的细胞或细胞群体，包括通过气雾剂吸入、注射、摄入、输注、植入或移植。可以皮下、皮内、瘤内、结节内、髓内、肌内、通过静脉内或淋巴内注射、或腹腔内，将在本文中所描述的组合物给予患者。在一种实施方式中，优选通过静脉注射来给予本发明的细胞组合物。
细胞或细胞群体的给予可以包括给予104-109个细胞/kg体重，优选105至106个细胞/kg体重，包括在那些范围内细胞数目的所有整数值。可以以一个或多个剂量来给予细胞或细胞群体。在另一种实施方式中，作为单剂量来给予所述有效量的细胞。在另一种实施方式中，作为一个以上剂量，在一段时间内，给予所述有效量的细胞。给予的时间是在管理医师的判断范围内并且取决于患者的临床情况。细胞或细胞群体可以获得任何来源，如血库或供体。虽然个别需求各不相同，但对于特定疾病或病症的给定细胞类型的有效量的最佳范围的确定是在本领域的技术范围内。有效量是指提供治疗或预防益处的量。给予的剂量将依赖于受者的年龄、健康状况和体重，同时治疗的种类(如果有的话)，治疗频率和所需效果的特性。
在另一种实施方式中，胃肠道外给予所述有效量的细胞或包含那些细胞的组合物。所述给予可以是静脉内给予。可以通过在肿瘤内的注射来直接进行所述给予。
在本发明的某些实施方式中，连同(例如，以前、同时或以后)任何数目的相关治疗方式一起，将细胞给予患者，包括但不限于借助于药剂的治疗如用于MS患者的抗病毒治疗、西多福韦和白细胞介素-2、阿糖胞苷(还称为ARA-C)或那他珠单抗治疗，或用于银屑病患者的依法利珠单抗治疗，或用于PML患者的其它治疗。在进一步的实施方式中，可以连同化疗，辐射，免疫抑制剂，如环孢素、硫唑嘌呤、甲氨蝶呤、麦考酚酯、和FK506、抗体，或其它免疫清除剂如CAMPATH、抗CD3抗体，或其它抗体疗法，细胞毒素，氟达拉滨，环孢素，FK506，雷帕霉素，麦可酚酸，类固醇，FR901228，细胞因子，以及辐射一起，来使用本发明的T细胞。这些药物抑制钙依赖性磷酸酶钙调磷酸酶(环孢素和FK506)或抑制p70S6激酶，其对于生长因子诱导信号是重要的(雷帕霉素)(Henderson,Naya et al.1991,Immunology 73(3):316-21；Liu,Albers et al.1992,31(16):3896-901；Bierer,Hollander et al.1993,Curr OpinImmunol 5(5):763-73)。在进一步的实施方式中，连同(例如，以前、同时或以后)骨髓移植、T细胞消融治疗，其中使用化疗剂如、氟达拉滨、外束放射治疗(XRT)、环磷酰胺、或抗体如OKT3或CAMPATH，一起将本发明的细胞组合物给予患者。在另一种实施方式中，在B细胞消融治疗如反应与CD20的药剂，例如，利妥昔单抗，以后，给予本发明的细胞组合物。例如，在一种实施方式中，主体可以经受标准治疗：高剂量化疗，接着外周血干细胞移植。在某些实施方式中，移植后，主体接受本发明的扩大免疫细胞的输注。在另外的实施方式中，在手术以前或以后，给予扩大细胞。
其他定义
-在本文中按照单字母代码来指定在多肽序列中的氨基酸残基，其中，例如，Q是指Gln或谷氨酰胺残基，R是指Arg或精氨酸残基，以及D是指Asp或天冬氨酸残基。
-核苷酸被指定如下：单字母代码用于指定核苷的碱基：a是腺嘌呤，t是胸腺嘧啶，c是胞嘧啶，以及g是鸟嘌呤。对于简并核苷酸，r表示g或a(嘌呤核苷酸)，k表示g或t，s表示g或c，w表示a或t，m表示a或c，y表示t或c(嘧啶核苷酸)，d表示g、a或t，v表示g、a或c，b表示g、t或c，h表示a、t或c，以及n表示g、a、t或c。
-“如在本文中所使用的，“核酸”或“多核苷酸”是指核苷酸和/或多核苷酸，如脱氧核糖核酸(DNA)或核糖核酸(RNA)、寡核苷酸、通过聚合酶链反应(PCR)生成的片段、以及通过连接、切割、内切核酸酶作用、和外切核酸酶作用的任何之一所生成的片段。核酸分子可以组成自单体，其是天然存在的核苷酸(如DNA和RNA)、或天然存在的核苷酸的类似物(例如，天然存在的核苷酸的对映体形式)、或两者的组合。修饰核苷酸可以具有在糖部分中和/或在嘧啶或嘌呤碱基部分中的改变。糖修饰包括，例如，用卤素、烷基、胺、和叠氮基来替代一个或多个羟基，糖可以被官能化为醚或酯。此外，可以用空间和电子类似的结构，如氮杂糖和碳环糖类似物，来替代整个糖部分。在碱基部分中的修饰的实例包括烷基化嘌呤和嘧啶、酰化嘌呤或嘧啶、或其它公知的杂环替代物。可以通过磷酸二酯键或上述键的类似物来连接核酸单体。核酸可以是单链或双链。-嵌合抗原受体(CAR)是指这样的分子，其结合相对于在靶细胞上存在的组件的结合结构域，例如基于抗体的对于所期望的抗原(例如，肿瘤抗原)的特异性，与T细胞受体激活胞内结构域，以生成嵌合蛋白，其呈现特异性抗靶细胞免疫活性。通常，CAR组成自胞外单链抗体(scFv)，其融合于T细胞抗原受体复合物ζ链(scFv:ζ)的胞内信号结构域，以及，基于单克隆抗体的特异性，当表达在T细胞中时，具有重定向抗原识别的能力。
-“递送载体”是指任何递送载体，其可以在本发明中用来进入细胞接触(即“接触”)或在细胞内或亚细胞室内递送(即“引入”)在本发明中需要的制剂/化学品和分子(蛋白质或核酸)。它包括但不限于脂质体递送载体、病毒递送载体、药物递送载体、化学载体、聚合物载体、阳离子脂质体(lipoplex)、聚合复合物(polyplex)、树突状聚合物、微泡(超声造影剂)、纳米颗粒、乳浊液或其它适当的转移载体。这些递送载体允许递送分子、化学品、大分子(基因、蛋白质)、或其它载体如质粒、由Diatos开发的肽。在这些情况下，递送载体是分子载体。“递送载体”还旨在指用来进行转染.的递送方法。-术语"载体"是指核酸分子，其能够转运它已与其连接的另一核酸。在本发明中，“载体”包括但不限于病毒载体、质粒、RNA载体或线性或环状DNA或RNA分子，其可以组成自染色体、非染色体、半合成或合成核酸。优选的载体是那些载体，其能够自主复制(附加型载体)和/或表达它们对其所连接的核酸(表达载体)。大量的适宜的载体是本领域技术人员已知的并且可商购的。
病毒载体包括逆转录病毒，腺病毒，细小病毒(例如腺相关病毒)，冠状病毒，负链RNA病毒如正粘病毒(例如，流感病毒)，弹状病毒(例如，狂犬病和水泡性口炎病毒)，副粘病毒(例如麻疹和仙台)，正链RNA病毒如微小RNA病毒和α病毒，和双链DNA病毒，其包括腺病毒，疱疹病毒(例如，单纯疱疹病毒类型1和2、EB病毒、巨细胞病毒)，和痘苗病毒(例如，牛痘、鸡痘和金丝雀痘)。其它病毒包括，例如，诺沃克病毒、披膜病毒、黄病毒、呼肠孤病毒、乳多空病毒、嗜肝DNA病毒、和肝炎病毒。逆转录病毒的实例包括：禽白血病肉瘤、哺乳动物C型、B型病毒、D型病毒，HTLV-BLV组，慢病毒，泡沫病毒(Coffin,J.M.,Retroviridae:Theviruses and their replication,In Fundamental Virology,Third Edition,B.N.Fields,et al.,Eds.,Lippincott-Raven Publishers,Philadelphia,1996)。
“慢病毒载体”是指基于HIV的慢病毒载体，其用于基因递送是非常有前途的，这是由于它们的相对较大的包装能力、降低的免疫原性以及它们高效率地稳定转导大范围的不同细胞类型的能力。通常在三种(包装、包膜和转运)或更多种质粒瞬时转染进入生产者细胞以后生成慢病毒载体。像HIV，通过病毒表面糖蛋白与在细胞表面上的受体的相互作用，慢病毒载体进入靶细胞。在进入以后，病毒RNA经历逆转录，其是由病毒逆转录酶复合物所介导。逆转录的产物是双链线性病毒DNA，其是在感染细胞的DNA中用于病毒整合的底物。“整合型慢病毒载体(或LV)”是指这样的载体，作为非限制性实例，其能够整合靶细胞的基因组。相反，“非整合型慢病毒载体(或NILV)”是指有效的基因递送载体，其并不通过病毒整合酶的作用来整合靶细胞的基因组。
可以借助于任何细胞透化技术如声致孔或电穿孔或这些技术的衍生技术来关联或组合递送载体和载体。
“突变”是指在多核苷酸(cDNA，基因)或多肽序列中多达一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个、十五个、二十个、二十五个、三十个、四十个、五十个、或更多核苷酸/氨基酸的替代、缺失、插入。突变可以影响基因的编码序列或它的调节序列。它还可能影响基因组序列的结构或编码的mRNA的结构/稳定性。
“功能变体”是指蛋白质或蛋白质结构域的催化活性突变体；相比与它的母蛋白质或蛋白质结构域或另外的性能，这样的突变体可能具有相同的活性，或更高或更低的活性。
"一致性"是指在两个核酸分子或多肽之间的序列一致性。可以通过比较在为比较目的可以加以对齐的每个序列中的位置来确定一致性。当在比较序列中的位置由相同碱基占据时，那么在上述位置处分子是相同的。在核酸或氨基酸序列之间的相似性或一致性的程度是在由核酸序列共享的位置处相同或匹配的核苷酸的数目的函数。多种比对算法和/或程序可以用来计算在两个序列之间的一致性，包括FASTA、或BLAST，其可用作GCG序列分析包(University of Wisconsin,Madison,Wis.)的一部分，并且可以连同，例如，默认设置一起加以使用。例如，设想，相对于本文中所描述的具体多肽具有至少70％、85％、90％、95％、98％或99％一致性并且优选表现出基本相同的功能的多肽，以及编码这样的多肽的多核苷酸。
如在本文中所使用的，术语"主体"或“患者”包括动物界的所有成员，其包括非人类灵长类动物和人类。在一些实施方式中，患者是人。
除以上特征之外，本发明包含进一步的特点，其将来自以下实施例，其说明体外分选或体内清除表达CAR的免疫细胞，用于免疫治疗，的方法，以及附图。
实施例1.嵌入抗CD123 CAR中的利妥昔单抗驱动的清除系统的产生
就嵌合scFv(抗CD123 scFv，具有CD20模拟表位)而言，具有不同构象的所有10种CAR示于图4：它们的导致的多肽序列显示于SEQ ID NO1至10。
通过体外转录，将10种CAR的DNA构建体转录进入它们的相应的mRNA，并借助于电穿孔用来转染通过标准菲可程序新鲜分离自白细胞层的原代T细胞。转染后一天，T细胞被回收并用来进行如下所述的基于流动的细胞毒性测定。
抗CD123 CAR T细胞的产生
为了产生表达抗CD123 CAR的原代T细胞，首先自白细胞层样品纯化原代T细胞，然后利用Dynabeads人T激活子CD3/CD28加以激活。激活后3天，在Ef1α启动子的控制之下，在为1的感染复数(MOI)下，用含有抗CD123 CAR表达盒的慢病毒载体来转导1百万个激活的T细胞。在37℃下，在5％CO2、20ng/ml IL-2(最终浓度)和5％的X-vivo-15培养基(Lonza).在中的人AB血清的存在下，将T细胞保持在培养物中，用于进一步表征。转导后5天，细胞用来进行基于流动的细胞毒性测定。
基于流动的细胞毒性测定
如常规进行的，按照基于流式细胞术的细胞毒性测定来评估抗CD123CAR T细胞的细胞溶解活性和特异性(见例如Valton.et Al(2015)Mol Ther；23(9):1507–1518)。此测定包括，用0.5mM CellTraceTM CFSE和0.5mM CellTraceTM紫色(Life Technology)来标记104个CD123阳性肿瘤细胞和104个CD123阴性对照细胞，然后，在37℃下，在100μl X-Vivo-15培养基的最终容积中，连同105个效应CAR T细胞一起(E/T比率为10:1)来共温育它们5小时。然后回收细胞并在通过4％PFA加以固定以前用eFluor780活力标记物加以标记(如上所述)。然后通过流式细胞术来分析固定细胞以确定它们的生存力。按照下述来计算和显示特异性细胞溶解的频率：
特异性细胞溶解的频率＝(生存力CD123+具有T/CD123的细胞-具有T的细胞)/(生存力CD123+细胞/生存力CD123-细胞)
其中生存力CD123+具有T和生存力CD123-具有T分别对应于在CAR T细胞的存在下在5小时以后获得的活CD123+细胞和CD123-细胞的％，以及其中生存力CD123+细胞和生存力CD123-细胞分别对应于在没有CAR T细胞的情况下在5小时以后获得的CD123+细胞和CD123-细胞的％。
结果显示，用工程抗CD123 CAR加以转染的细胞能够杀伤CD123阳性肿瘤细胞模型。如图5所示，来自上文所描述的基于流动的细胞毒性测定的结果表明，表达SEQ ID 1-4的T细胞表现出和表达未修饰抗CD123CAR SEQ ID 142的T细胞相同的活性(图5)。这些数据表明，在抗CD123CAR(SEQ ID 142)的序列中CD20模拟表位的插入没有显著损害它特异性地识别CD123抗原和杀伤CD123表达肿瘤细胞的能力。在一些实施方式中，本发明的包含两个mAb特异性表位之一，优选SEQ ID NO 35，的CAR能够特异性地识别由CAR靶向的抗原以及杀伤表达所述抗原的细胞。
与这些发现相一致，测试转染的CAR T细胞，当暴露于涂布在96孔板上的CD123重组蛋白时，它们的脱颗粒的能力。一起，我们的实验旨在表明，在抗CD123 CAR的序列中，CD20模拟表位的插入没有显著损害它特异性地识别CD123抗原的能力。
为了证明，通过CD20模拟表位的特异性识别，利妥昔单抗抑制T细胞细胞毒性功能的能力，在CD123阳性肿瘤细胞的存在下，在存在利妥昔单抗和幼兔补体的情况下或在没有利妥昔单抗和幼兔补体的情况下，温育转染的T细胞。目的是表明，在利妥昔单抗和幼兔补体的存在下，转染的T细胞的细胞毒活性和脱颗粒能力受到损害，其进一步表明，利妥昔单抗对工程抗CD123 CAR的有效识别导致T细胞清除。
实施例2.在抗CD123嵌合抗原受体中mAb驱动清除系统的柔性
为了进一步证明mAb驱动清除系统的柔性，利用和在实施例1中描述的用于CD20模拟表位的相同的程序和结构，将对于西妥昔单抗、帕利珠单抗和纳武单抗mAb具有特异性的不同表位或模拟表位(SEQ ID NO35-42)插入在抗CD123 CAR构建体内。结果旨在表明，转染的T细胞保留它们的针对CD123阳性肿瘤细胞的细胞溶解活性和脱颗粒能力。此外，实验还旨在表明，通过一些上述mAb，清除了转染的T细胞。
实施例3.含有mAb驱动清除系统的抗CD123 CAR的利妥昔单抗依赖性清除
为了探讨mAb驱动清除系统允许清除抗CD123 CAR T细胞的能力，对表达SEQ IDNO 1、2、3或4的CAR，或未修饰抗CD123 CAR(SEQ ID NO 142)，的转导的T细胞进行补体依赖性细胞毒性测定(CDC)。
CDC测定
The CDC测定包括，在37℃下，在400μL的Xvivo 10％FBS的最终容积中，单独或在利妥昔单抗(RTX，ROCHE，400ng)和幼兔补体(BRC，AbD Serotec，ref#C12CA，100μL的溶液，按照制造商的协议稀释的)的存在下，温育0.2 106个转导的T细胞3小时。在温育结束时，回收抗CD123-CAR T细胞，并用融合于FC片段(SEQ ID 143)的重组CD123蛋白和PE标记抗FC次级单克隆抗体(Jackson ImmunoResearch，ref#115-115-164，1/200稀释的)加以标记。然后在通过流式细胞术加以分析以前，在PFA 4％中回收细胞。流式细胞术门控策略包括在总细胞群体中发现的单纯态中确定抗CD123 CAR阳性T细胞(PE阳性细胞)的生存力。对单独以及在RTX和BRC的存在下温育的细胞进行这种分析。结果表达为比率，其名为“在抗CD123 CAR阳性T细胞中活细胞的相对频率(相对于对照实验)”，描述如下：
(在RTX和BRC的存在下获得的抗CD123 CAR阳性T细胞中活细胞的频率)x100/(在没有RTX和BRC的情况下获得的抗CD123 CAR阳性T细胞中活细胞的频率)。
结果表明，所有CAR结构允许CAR T细胞的RTX依赖性清除(图6)。表达SEQ ID NO 3和4的CAR T细胞比表达SEQ ID NO 1和2的CAR T细胞被更有效地清除，其提示，在CAR结构中存在的CD20模拟表位的数目影响了T细胞清除的程度和/或动力学。
在一些实施方式中，本发明的CAR，其具有图4所示的结构，允许CAR T细胞的利妥昔单抗依赖性清除。在一些实施方式中，本发明的CAR，其包含至少2个mAb特异性表位，优选具有SEQ ID NO 3或4的CAR结构，被特别有效地清除。
实施例4.在表达抗BCMA CAR的细胞中mAb驱动清除系统的效率，其中上述抗BCMACAR包含在胞外结构域中的一个或多个mAb特异性表位。
为了探讨mAb驱动清除系统允许清除抗BCMA CAR T细胞的能力，构建了15种不同的CAR结构(SEQ ID 125-139，图7A、图7B和图7C)。设计这些结构以含有1、2或3个CD20模拟表位，其位于抗BCMA CAR(SEQ ID NO 125)的胞外结构域的不同部分处，即在N端域中，在分开ScFv的V1和V2的接头域中，或在将ScFv连接于CAR的跨膜结构域的CD8铰链的上游。
为了产生表达抗BCMA CAR的原代T细胞，原代T细胞首先纯化自白细胞层样品并利用Dynabeads人T激活子CD3/CD28加以激活。激活后3天，用15或30μg的聚腺苷酸化mRNA，其编码不同抗BCMA CAR结构(SEQ ID 125-139，图7A、图7B和图7C)来转染5百万个激活的T细胞。然后，在37℃下，在5％CO2、20ng/ml IL-2(最终浓度)和在X-vivo-15培养基(Lonza)中的5％人AB血清的存在下，将T细胞保持在培养物中，用于进一步表征。转染后一天，细胞用来进行CDC测定、基于流动的细胞毒性测定、检测测定和干扰素γ(IFNγ)释放测定。
CDC测定
CDC测定包括，在37℃下，在400μL的Xvivo 10％FBS的最终容积中，单独或在利妥昔单抗(RTX，ROCHE，400ng)和幼兔补体(BRC，AbD Serotec，ref#C12CA，100μL的溶液，按照制造商的协议稀释的)的存在下，温育0.2 106个转染细胞2小时。在温育结束时，回收抗BCMA-CAR T细胞并用融合于FC片段(SEQ ID NO 151)的重组BCMA蛋白和PE标记抗FC次级单克隆抗体(Jackson ImmunoResearch，ref#115-115-164，1/200稀释的)加以标记。然后，在通过流式细胞术加以分析以前，将细胞回收在PFA 4％中。流式细胞术门控策略是在总细胞群体中发现的单纯态中确定抗BCMA CAR阳性T细胞(PE阳性细胞)的生存力。对单独以及在RTX和BRC的存在下温育的细胞进行这种分析。结果表达为比率，其名为“在BCMA CAR阳性T细胞中活细胞的相对频率(相对于对照实验)”，描述如下：
(在RTX和BRC的存在下获得的抗BCMA CAR阳性T细胞中活细胞的频率)x100/(在没有RTX和BRC的情况下获得的抗BCMA CAR阳性T细胞中活细胞的频率)
基于流动的细胞毒性测定
按照在Valton.et Al(2015)Mol Ther；23(9):1507–1518中报道的基于流式细胞术的细胞毒性测定，评估了抗BCMA CAR T细胞的细胞溶解活性和特异性。这种测定包括用0.5mM CellTraceTMCFSE(Life Technology，在37℃下，按照制造商协议，温育10分钟)用标记BCMA阳性肿瘤靶细胞(T，H929)，然后，在37℃下，在100μl X-Vivo-15培养基的最终容积中，用105个抗BCMA CAR T效应(E)细胞(E/T比率为10:1)来共温育它们5小时。然后回收细胞，并在通过4％PFA加以固定以前，用eFluor780活力标记物加以标记。然后通过流式细胞术来分析固定细胞以确定它们的生存力。
IFNγ释放测定
为了研究表达各种抗BCMA CAR的T细胞的自激活，其中上述抗BCMA CAR包含RTX特异性表位，通过临床相关剂量的RTX，转染后一天，在补充有5％AB血清、20ng/mL IL2的X-vivo-15培养基中，在没有500μg/mL RTX的情况下或在500μg/mL RTX的存在下，在0.1 106个细胞/孔的浓度下，在100μl的最终容积中，温育用编码SEQ ID 125、130-139的mRNA转染的原代T细胞72小时。然后离心CAR T细胞，回收上清并通过ELISA(利用人IFN-γQuantikine ELISA试剂盒，RandD systems，ref#DIF50)加以分析，以确定在培养基中释放的IFNγ的量。作为用于CAR T细胞激活和IFNγ释放的阳性对照，用10μg/mL植物血凝素(PHA)来温育细胞。
利用Miltenyi CD34纯化试剂盒，抗BCMA CAR T细胞的纯化
为了测试某些抗BCMA CAR结构(含有CD34表位，SEQ ID NO 144，由QBEND10抗体识别的)被纯化的能力，利用CD34 MicroBead试剂盒(Miltenyi，ref#130-046-702)并按照制造商的协议，来纯化稳定地表达SEQ ID 128的100 106个原代T细胞。
结果
抗BCMA CAR阳性T细胞的清除性(depletability)
结果表明，相比与未修饰抗BCMA CAR(SEQ ID NO 125)，其未被显著清除(depletion，耗尽)，表达SEQ ID 126-139的T细胞在不同程度上均由BRC和RTX所清除(图8A)。结果显示，清除的效率随着在CAR结构中存在的CD20模拟表位的数目的增加而增加。此外，结果显示，通过大于GS接头的域来分离多个CD20模拟表位会增加清除的效率，如当比较借助于T细胞所获得的清除程度时所看到的，其中上述T细胞表达含有3个CD20模拟表位的SEQ ID NO 127和SEQ ID NO 137、以及含有2个CD20模拟表位的SEQ ID NO 139和SEQ IDNO 136(图7A-图8A)。
在一些实施方式中，本发明的CAR，其具有SEQ ID NO126-139的CAR结构，允许CART细胞的利妥昔单抗依赖性清除。在一些实施方式中，本发明的CAR，其具有如在SEQ ID,136、137、138中的CAR结构，即其中CAR包含至少两个相同的mAb特异性表位，其由一个或多个其它域(如VH、VL、VH-L1-VL…)所分开，被特别有效地清除。
抗BCMA CAR+T细胞的细胞毒活性
基于流动的细胞毒性测定结果表明，相比与表达抗BCMA CAR结构的未修饰版本(SEQ ID NO 125，图9)的T细胞，所有结构(SEQ ID 126-139)能够在类似的程度上识别和杀伤BCMA表达H929肿瘤细胞。一致与在实施例1中获得的结果，在CAR结构内1、2或3个mAb特异性表位以及尤其是1、2或3个CD20模拟表位的存在，没有显著影响抗BCMA CAR T细胞的细胞溶解活性。
在一些实施方式中，相比与没有mAb特异性表位的CAR如SEQ ID125的CAR，本发明的CAR，其具有SEQ ID NO126-139的CAR结构，具有类似的细胞毒活性。
分选自异质细胞群体的抗BCMA阳性CAR T细胞
为了测试表达SEQ ID 128的抗BCMA CAR(图7A)的T细胞被纯化自异质细胞群体的能力，利用CD34 MicroBead试剂盒并按照制造商的协议，来纯化不同种类(heterogeneous)群体的含有31.5％的CAR阳性细胞的100x106个原代T细胞。结果表明，纯化部分含有约90％的抗BCMA CAR阳性T细胞，其表明，纯化过程是有效的(图10)。在纯化以后，从31.5x106个抗BCMA CAR阳性T细胞，回收了约20x106个抗BCMA CAR阳性T细胞，其表明，在整个纯化过程中，失去了小于40％的抗BCMA CAR阳性T细胞。
IFNγ释放测定
ELISA测定结果表明，在CAR结构内一个或多个CD20模拟表位的存在没有影响CART细胞被RTX所激活的倾向(图11)。确实，结果表明，在RTX的存在下，由所有结构所释放的IFNγ的水平是类似于在没有RTX的情况下释放的IFNγ的基础水平。
实施例5.用于CAR T细胞的最佳清除和纯化的杂合抗BCMA嵌合抗原受体结构。
为了改善抗BCMA CAR T细胞的清除性，以及同时允许分选它们，设计了两种新的杂合CAR结构SEQ ID NO 140和141(图7C)。这两种结构含有彼此由蛋白质域分开的三个CD20模拟表位，以及一个CD34表位。通过CDC测定，并按照在实施例4中描述的协议，评估了它们由RTX和BRC所清除的能力。结果表明，在和表达SEQ ID 137的T细胞的类似的程度上，这两种结构被有效地清除(图8B)。利用前面描述的基于流动的测定还评估了它们的细胞溶解性能。结果表明，它们和表达未修饰抗BCMA CAR T细胞(SEQ ID NO 125)的T细胞共享类似的细胞毒活性，其表明，CD20模拟表位和CD34表位(分别为SEQ ID NO 35和144)的存在没有负面影响CAR T细胞的细胞溶解活性。
在一些实施方式中，本发明的CAR，其具有CAR结构如在SEQ ID140、141中，即其中CAR包含三个相同的mAb特异性表位，其由认可的抗体如利妥昔单抗所识别，其可以用于细胞的清除，以一个mAb特异性表位，其可以用于纯化，被特别有效地清除并且还可以被有效纯化。
按照在实施例4中描述的协议，来组装另外的CAR，其基于SEQ ID NO 140和141的结构，并且包含对于CD19(SEQ ID NO 162-163和168-169的CAR)、CD123(SEQ ID NO 164-165的CAR)、CD20(SEQ ID NO 166-167的CAR)具有特异性的ScFv的VH和VL。可以通过CDC测定，并按照在实施例4中描述的协议，来评估它们被RTX和BRC所清除的能力。
实施例6.携带mAb驱动清除系统的CAR T细胞的通用检测
由于缺乏通用检测系统，体内监测和比较不同的CAR T细胞的增殖一直是冗长乏味的和缓慢复杂的。通过流式细胞术来测试待检测的不同的CAR结构的能力，其中使用RTX作为一抗和FITC偶联抗Fab’2单克隆抗体(Life technologies，ref#H10101C，1/200稀释的)，或使用APC标记抗CD34单克隆抗体，其名为QBEND10(Miltenyi Biotec，ref#130-090-954，1/25稀释的)。并排与用融合于FC片段(SEQ ID NO 151)的重组BCMA蛋白和PE标记抗FC次级单克隆抗体(Jackson ImmunoResearch，ref#115-115-164，1/200稀释的)所进行的检测来比较结果。
结果表明，借助于RTX所检测的表达SEQ ID NO 128和130-139的阳性CAR T细胞的频率是类似于当借助于重组BCMA蛋白来检测它们所获得的频率(图12)。当借助于QBEND10和利妥昔单抗来检测表达SEQ ID NO 128的CAR T细胞时，发现类似的结果(图13)。总而言之，结果表明，CD20模拟表位或CD34表位的存在允许不同的CAR结构的有效和通用检测。
实施例7-表达抗BCMA CAR的抗BCMA CAR T细胞，其中上述抗BCMA CAR包含一个、两个或三个mAB特异性表位
7.1-质粒
利用EcoRI(5’)和MluI(3’)限制位点(因而除去IRES-Puro盒)来密码子优化以下含有CD20模拟表位的CAR，合成并亚克隆进入慢病毒载体pLVX-EF1a-IRES-Puro(Clontech)。利用psPAX2，一种HIV-1gag-pol包装质粒，和pMD2.G，一种VSV-G表达质粒，来产生慢病毒。
BC30(SEQ ID NO 145)包含以下域：
前导序列-BCMA30 VH-接头-BCMA30 VL-CD8铰链-CD8TM-4-1BB-CD3z，其中BCMA30VH和BCMA30 VL分别是SEQ ID NO 97和SEQ ID NO 98。
BC30-LM(SEQ ID NO 146)包含以下域：
前导序列-BCMA30 VH-接头-BCMA30 VL-接头(L)-模拟表位(M)-CD8铰链-CD8 TM-4-1BB-CD3z，其中BCMA30 VH和BCMA30 VL分别是SEQ ID NO 97和SEQ ID NO 98以及模拟表位是SEQ ID NO35。
BC30-LML(SEQ ID NO 147)包含以下域：
前导序列-BCMA30 VH-接头-BCMA30 VL-接头(L)-模拟表位(M)-接头(L)-CD8铰链-CD8 TM-4-1BB-CD3z，其中BCMA30 VH和BCMA30 VL分别是SEQ ID NO 97和SEQ ID NO 98以及模拟表位是SEQ ID NO35。
BC30-LMLM(SEQ ID NO 148)包含以下域：
前导序列-BCMA30 VH-接头-BCMA30 VL-接头(L)-模拟表位(M)-接头(L)-模拟表位(M)-CD8铰链-CD8 TM-4-1BB-CD3z，其中BCMA30 VH和BCMA30 VL分别是SEQ ID NO 97和SEQ ID NO 98以及模拟表位均是SEQ ID NO 35。
BC30-LMLML(SEQ ID NO 149)包含以下域：
前导序列-BCMA30 VH-接头-BCMA30 VL-接头(L)-模拟表位(M)-接头(L)-模拟表位(M)-接头(L)-CD8铰链-CD8 TM-4-1BB-CD3z，其中BCMA30 VH和BCMA30 VL分别是SEQ IDNO 97和SEQ ID NO 98以及模拟表位均是SEQ ID NO 35。
7.2-T细胞激活和慢病毒转导
利用Pan T细胞分离试剂盒(Miltenyi Biotec)，未触动的T细胞分离自人外周血单核细胞(PBMC)，并借助于针对人CD2、CD3、和CD28的抗体(T细胞激活/扩增试剂盒-Miltenyi Biotec)来激活三天。通过亚汇合HEK-293T/17(American Type CultureCollection(ATCC))细胞在6孔板中的瞬时转染来产生慢病毒载体(LV)。简要地，利用Lipofectamine2000(Invitrogen)，遵循制造商的说明，并分别以4:3:1比率来转染pLVX、psPAX2、和pMD2.G质粒。第二天，用T细胞培养基(5％人AB血清，在X-vivo-15培养基(Lonza)中)来替代培养基，以及在转染以后48小时，收获LV上清并通过0.45μm针筒式滤器(Millipore)加以过滤。以0.25x 106个细胞/mL，将激活的T细胞接种于含有40ng/ml IL-2的T细胞培养基，然后通过添加等容积的新鲜LV上清加以转导。细胞在37℃和5％CO2下培养三天并用于流式细胞术分析，或在含有20ng/ml IL-2的新鲜T细胞培养基中加以扩增。
7.3-通过流式细胞术来检测含有CD20模拟表位的BCMA CAR
为了测试内部CAR CD20模拟表位用于检测和追踪CAR-T细胞的实用性，利用生物素化BCMA蛋白，其结合CAR的scFV区，接着PE结合的链霉亲合素，或抗CD20抗体利妥昔单抗，接着FITC结合的抗人IgG(利妥昔单抗(FITC))，对转导的T细胞进行流式细胞术分析。图14A和图14B示出，通过流式细胞术，并利用生物素化BCMA，接着PE结合的链霉亲合素，具有可比效率地来检测用含有不同的CD20模拟表位的CAR来转导的T细胞。在用LM构建体转导的细胞中借助于利妥昔单抗对内部CAR CD20模拟表位的检测是弱的(15.5％)，但在测试的所有其它格式中则非常高。例如，在85.6％的细胞中检测到LMLML CAR，其表明，这种格式允许识别几乎所有的表达CAR的细胞(图14A和图14B)。因此，通过柔性接头分开的两个CD20表位的存在允许与利妥昔单抗的增强的结合并提供最佳系统来检测CAR+细胞。
通过比较与RQR8标记物/自杀基因系统(SEQ ID NO 150)，其组成自紧密蛋白，该紧密蛋白含有两个CD20表位和CD34表位，其通常连同CAR一起共表达(Philip,Blood2014)，来评估CAR内CD20表位用于CAR-T细胞检测的功能。对于此实验，T细胞的转导是借助于慢病毒，其允许共表达BCMA30 CAR(SEQ ID NO 145)和RQR8蛋白(SEQ ID NO150)(BC30-RQR8构建体)。为了比较，借助于BCMA30 LMLML CAR构建体(BC30-R2构建体–SEQ ID NO149)来转导T细胞并转导后三天通过流式细胞术加以分析。此外，非转导(NT)T细胞作为阴性对照。图15旨在表明，在CAR分子中并入CD20表位会显著改善借助于抗CD20抗体利妥昔单抗对CAR-T细胞的检测。此外，相比与用编码RQR8的载体和CAR加以转导的那些细胞，在用BC30-R2构建体所转导的细胞中观测到增加的转导效率和CAR表达，如通过借助于生物素化BCMA的流式细胞术分析所表明的(图15)。因而，CD20表位插入CAR分子使得能够提供增加的转导、改善的检测、以及在CAR表达和mAb特异性表位表达之间的绝对相关。
7.4-CAR内CD20表位使CAR-T细胞对补体依赖性细胞毒性变得敏感
利用CDC测定，体外评估了CAR内CD20表位能够选择性消除CAR-T细胞的能力。目的是表明，在CAR分子中CD20表位的存在使得CAR-T细胞高度易感利妥昔单抗介导清除。对于此实验，在存在或没有利妥昔单抗(100μg/mL)的情况下，使借助于BC30-R2构建体或BC30-RQR8构建体加以转导的T细胞混合与25％幼兔补体(AbD serotec)，然后在在37℃和5％CO2下温育4小时。通过流式细胞术分析，并利用生物素化BCMA蛋白，来确定CAR-T细胞的选择性缺失。图16示出，当RQR8和CAR内CD20表位自杀基因系统均使CAR-T细胞能够清除时，相比与表达RQR8的那些细胞，会更有效地清除借助于BC30-R2构建体加以转导的细胞。如预期的，表达BCMA30 CAR但没有CD20表位(BC30构建体)的T细胞是多余的。这些差异可能是因为BC30-R2 CAR的高表达以及在CAR表达和自杀基因表达之间的绝对相关。
7.5-CD20表位并入CAR并不损害CAR-T细胞的细胞溶解活性
在细胞毒性测定中，评估了在铰链和CAR的scFv区之间CD20表位的插入可能会损害CAR活性的可能性。简要地，在不同比率下，连同萤光素酶阳性MM1S靶细胞一起来温育表达BC30-R2构建体或BC30-RQR8构建体的T细胞。对于这些杀伤测定，以100μl的5％人AB血清(在X-vivo-15培养基(Lonza)中)的最终容积，将细胞接种在96孔白色不透明组织培养板中。在4小时以后，将细胞平衡至室温并将一容积的Bright-GloTMReagent(Promega)加入每个孔。用GLOMAX 96微量板光度计(Promega)来测量荧光并根据下面的公式来计算细胞溶解的百分比：
100x(1–(样品溶解–最大溶解)/(自发性溶解–最大溶解))。通过将8％Triton X-100(Sigma)加入Luc+MM1S细胞来确定最大溶解。对于自发性溶解，在没有效应CAR-T细胞的情况下，温育MM1S细胞。
结果显示，BC30-R2 CAR-T细胞有效地体外消除BCMA表达MM1S细胞(图17)。此外，利妥昔单抗(100μg/mL)，在这些细胞混合与靶细胞以前2小时，其被加入效应细胞群体，并不影响BC30-R2 CAR-T细胞的细胞溶解活性(图17)。此实验旨在证明，甚至在利妥昔单抗的存在下，CD20表位插入BC30 CAR分子并不影响其介导杀伤BCMA+靶细胞的能力。
7.6利妥昔单抗结合于CAR内CD20表位并不导致CAR-T细胞激活
为了研究通过利妥昔单抗的CAR的交联是否可能会导致T细胞激活，其是由于在细胞表面上的CAR聚集，在利妥昔单抗的存在下，生长BC30-R2 CAR-T细胞。抗CD3 OKT3抗体(eBioscience)引起T细胞受体(TCR)的交联，从而导致细胞激活和增殖，并用作阳性对照。简要地，在有/无利妥昔单抗的情况下，在T细胞培养基中培养BC30-R2 CAR-T细胞三天。然后，利用流式细胞术，通过测量激活标记CD25和CD69的表达，来评估T细胞激活。此实验表明，在RTX的存在下的激活的T细胞的百分比并不显著不同于对照(PBS)。因此，可溶性利妥昔单抗对于BC30-R2CAR-T细胞的激活状态没有显著影响(图18)。
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本发明的实施方式
1.一种多肽，编码嵌合抗原受体(CAR)，其包含至少一个胞外结合结构域，该胞外结合结构域包含通过对于细胞表面标记抗原为特异性的至少VH链和VL链所形成的scFv，其中所述胞外结合结构域包括将通过表位特异性mAb所结合的至少一个mAb特异性表位，用于体外细胞分选和/或体内细胞清除表达所述CAR的免疫细胞。
2.根据实施方式1的多肽，其中所述mAb特异性表位是位于VH和VL链之间。
3.根据实施方式1或2的多肽，其中所述VH和VL链，以及mAb特异性表位由至少一个接头结合在一起以及通过铰链结合于所述CAR的跨膜结构域。
4.根据实施方式3的多肽，其中通过两个接头，mAb表位连接于VH和VL链。
5.根据实施方式1至4中任一实施方式的多肽，其中mAb表位是来自选自列在表1中的那些多肽的一种多肽。
6.根据实施方式1至4中任一实施方式的多肽，其中所述VH和VL链，作为抗原靶序列，相对于SEQ ID NO 43(CD19抗原)、SEQ ID NO44(CD38抗原)、SEQ ID NO 45(CD123抗原)、SEQ ID NO 46(CS1抗原)、SEQ ID NO 47(BCMA抗原)、SEQ ID NO 48(FLT-3抗原)、SEQID NO49(CD33抗原)、SEQ ID NO 50(CD70抗原)、SEQ ID NO 51(EGFR-3v抗原)和SEQ ID NO52(WT1抗原)，具有80％以上的一致性，优选90％以上，以及更优选95％以上。
7.根据实施方式1至5中任一实施方式的多肽，其中所述VH和VL链，作为抗原靶序列，相对于SEQ ID NO 53-64(CD19抗原)、SEQ ID NO65-76(CD33抗原)、SEQ ID NO 77-84(5T4抗原)、SEQ ID NO 85-90(ROR1抗原)、SEQ ID NO 91-94(EGFRvIII抗原)、SEQ ID NO95-102(BCMA抗原)、SEQ ID NO 103-112(CS1抗原)和SEQ ID NO 113-124(CD123抗原)，具有80％以上的一致性，优选90％以上，以及更优选95％以上。
8.根据实施方式1-7中任一实施方式的多肽，其中所述VH和VL链，作为表位靶序列，相对于SEQ ID NO.11的CD20抗原，具有80％以上的一致性，优选90％以上，以及更优选95％以上的一致性。
9.根据实施方式1-8中任一实施方式的多肽，其中CAR是单链CAR。
10.根据实施方式9的多肽，其中所述CAR多肽，相对于SEQ ID NO1至10，共享80％以上一致性，优选90％以上，以及更优选95％以上。
11.根据实施方式1-10中任一实施方式的多肽，其中CAR是多链CAR。
12.根据实施方式1至9中任一实施方式的编码嵌合抗原受体的多核苷酸，其中所述CAR包含CD3ζ信号结构域和共刺激结构域，其来自4-1BB。
13.一种表达载体，包含实施方式12的核酸。
14.一种工程化免疫细胞，在其细胞表面表达根据实施方式1至12中任一实施方式的嵌合抗原受体。
15.根据实施方式14的工程化免疫细胞，源自炎性T淋巴细胞、细胞毒性T淋巴细胞、调节性T淋巴细胞或辅助性T淋巴细胞。
16.根据实施方式14或15的工程化免疫细胞，供用作药剂。
17.一种用于设计实施方式14-16中任一实施方式的免疫细胞的方法，包括：
(a)提供免疫细胞；
(b)将编码根据实施方式1-12中任一实施方式的嵌合抗原受体的至少一种多核苷酸引入所述细胞；
(c)将所述多核苷酸表达进入所述细胞。
18.一种用于设计实施方式17的免疫细胞的方法，其中免疫细胞是T细胞。
19.一种用于分选CAR表达免疫细胞的方法，包括使根据实施方式14-16中任一实施方式设计的免疫细胞的群体接触抗原特异性mAb，以仅收集CAR表达免疫细胞。
20.一种用于分选根据实施方式19的CAR表达免疫细胞的方法，其中mAb是利妥昔单抗。
21.一种用于分选根据实施方式19-20中任一实施方式的CAR表达免疫细胞的方法，其中免疫细胞是T细胞。
22.一种用于清除根据实施方式14-16中任一实施方式设计的免疫细胞或根据实施方式19-21中任一实施方式分选的CAR表达免疫细胞的方法，包括使所述免疫细胞或所述CAR表达免疫细胞接触表位特异性mAb。
23.一种用于清除根据实施方式22的免疫细胞或CAR表达免疫细胞的方法，其中通过能够激活补体系统的分子来结合所述表位特异性mAb。
24.一种用于清除根据实施方式22-23中任一实施方式的免疫细胞CAR表达免疫细胞的方法，其中细胞毒性药物耦联于表位特异性mAb。
25.一种用于清除根据实施方式22-24中任一实施方式的免疫细胞CAR表达免疫细胞的方法，其中mAb特异性抗原是CD20抗原以及表位特异性mAb是利妥昔单抗。
26.一种用于清除根据实施方式22-25中任一实施方式的免疫细胞CAR表达免疫细胞的方法，包括使所述免疫细胞或CAR表达免疫细胞接触双特异性mAb(BsAb)，其能够结合于由所述细胞携带的mAb特异性表位以及结合于由效应(和细胞毒性)细胞携带的表面抗原。
27.一种用于清除根据实施方式22-26中任一实施方式的免疫细胞CAR表达免疫细胞的方法，其中所述免疫细胞是T细胞。
28.一种用于调节工程化免疫细胞的激活的方法，包括至少以下步骤：
(i)使所述免疫细胞赋予有CAR，其胞外结合结构域包含scFv，其识别连接于mAb特异性表位的细胞表面标记
(ii)扩大所述免疫细胞，其在它的表面上表达所述CAR和所述mAb表位
(iii)使产生的免疫细胞接触对于所述表位为特异性的mAb，以固定所述免疫细胞。
序列表
<110> 塞勒克提斯公司；異基因治疗有限公司
<120> 用于分选/清除工程化的免疫细胞的mAb驱动的嵌合抗原受体系统
<130> P81500233PCT00
<150> PA201570044
<151> 2015-01-26
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Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
435 440 445
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
450 455 460
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
465 470 475 480
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
485 490 495
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
500 505 510
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
515 520 525
Pro Pro Arg Glu
530
<210> 5
<211> 495
<212> PRT
<213> 人工序列
<220>
<223> 抗CD123 No5
<400> 5
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
20 25 30
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
50 55 60
Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
65 70 75 80
Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr
100 105 110
Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Cys Pro
130 135 140
Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser Asp Ile Val Leu
145 150 155 160
Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr
165 170 175
Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe
180 185 190
Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
195 200 205
Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly
210 215 220
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala
225 230 235 240
Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro
245 250 255
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr
260 265 270
Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser
275 280 285
Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly
290 295 300
Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp
305 310 315 320
Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile
325 330 335
Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
340 345 350
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
355 360 365
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
370 375 380
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
385 390 395 400
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
405 410 415
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
420 425 430
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
435 440 445
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
450 455 460
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
465 470 475 480
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
485 490 495
<210> 6
<211> 501
<212> PRT
<213> 人工序列
<220>
<223> 抗CD123 No6
<400> 6
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
20 25 30
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
50 55 60
Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
65 70 75 80
Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr
100 105 110
Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Gly
130 135 140
Gly Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Gly Gly
145 150 155 160
Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser
165 170 175
Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp
180 185 190
Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln
195 200 205
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile
210 215 220
Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr
225 230 235 240
Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln
245 250 255
Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
260 265 270
Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
275 280 285
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
290 295 300
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
305 310 315 320
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
325 330 335
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys
340 345 350
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
355 360 365
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
370 375 380
Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
385 390 395 400
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
405 410 415
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
420 425 430
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
435 440 445
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
450 455 460
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
465 470 475 480
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
485 490 495
Leu Pro Pro Arg Glu
500
<210> 7
<211> 508
<212> PRT
<213> 人工序列
<220>
<223> 抗CD123 No7
<400> 7
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro
20 25 30
Ser Leu Cys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys
35 40 45
Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile
50 55 60
Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser
65 70 75 80
Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr
85 90 95
Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala
100 105 110
Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala
115 120 125
Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp
130 135 140
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
145 150 155 160
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser
165 170 175
Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys
180 185 190
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp
195 200 205
Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala
210 215 220
Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
225 230 235 240
Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val
245 250 255
Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly
260 265 270
Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro
275 280 285
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
290 295 300
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
305 310 315 320
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
325 330 335
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
340 345 350
Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
355 360 365
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
370 375 380
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
385 390 395 400
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
405 410 415
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
420 425 430
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
435 440 445
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
450 455 460
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
465 470 475 480
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
485 490 495
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
500 505
<210> 8
<211> 514
<212> PRT
<213> 人工序列
<220>
<223> 抗CD123 No8
<400> 8
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro
20 25 30
Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln
35 40 45
Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys
50 55 60
Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys
65 70 75 80
Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr
85 90 95
Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe
100 105 110
Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu
115 120 125
Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr
130 135 140
Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
145 150 155 160
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
165 170 175
Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln
180 185 190
Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly
195 200 205
Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys
210 215 220
Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg
225 230 235 240
Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro
245 250 255
Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu
260 265 270
Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser
275 280 285
Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
290 295 300
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
305 310 315 320
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
325 330 335
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
340 345 350
Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr
355 360 365
Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu
370 375 380
Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu
385 390 395 400
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
405 410 415
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
420 425 430
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
435 440 445
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
450 455 460
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
465 470 475 480
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
485 490 495
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
500 505 510
Arg Glu
<210> 9
<211> 523
<212> PRT
<213> 人工序列
<220>
<223> 抗CD123 No9
<400> 9
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro
20 25 30
Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser
35 40 45
Leu Cys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys
50 55 60
Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe
65 70 75 80
Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe
85 90 95
Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser
100 105 110
Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser
115 120 125
Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr
130 135 140
Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly
145 150 155 160
Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro
180 185 190
Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg
195 200 205
Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr
210 215 220
Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser
225 230 235 240
Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg
245 250 255
Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala
260 265 270
Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala
275 280 285
Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala
290 295 300
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
305 310 315 320
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
325 330 335
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
340 345 350
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
355 360 365
Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
370 375 380
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
385 390 395 400
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg
405 410 415
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
420 425 430
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
435 440 445
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
450 455 460
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
465 470 475 480
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
485 490 495
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
500 505 510
Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
515 520
<210> 10
<211> 529
<212> PRT
<213> 人工序列
<220>
<223> 抗CD123 No10
<400> 10
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro
20 25 30
Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser
35 40 45
Leu Cys Ser Gly Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser
50 55 60
Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys
65 70 75 80
Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln
85 90 95
Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr
100 105 110
Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser
115 120 125
Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys
130 135 140
Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp
145 150 155 160
Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly
165 170 175
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
180 185 190
Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg
195 200 205
Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn
210 215 220
Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
225 230 235 240
Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe
245 250 255
Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val
260 265 270
Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp
275 280 285
Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp
290 295 300
Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
305 310 315 320
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
325 330 335
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
340 345 350
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
355 360 365
Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile
370 375 380
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
385 390 395 400
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
405 410 415
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
420 425 430
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
435 440 445
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
450 455 460
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
465 470 475 480
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
485 490 495
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
500 505 510
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
515 520 525
Glu
<210> 11
<211> 297
<212> PRT
<213> 智人
<400> 11
Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro
1 5 10 15
Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg
20 25 30
Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu
35 40 45
Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile
50 55 60
Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile
65 70 75 80
Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile
85 90 95
Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu
100 105 110
Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile
115 120 125
Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser
130 135 140
His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro
145 150 155 160
Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn
165 170 175
Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly
180 185 190
Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile
195 200 205
Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys
210 215 220
Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile
225 230 235 240
Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro
245 250 255
Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu
260 265 270
Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser
275 280 285
Ser Pro Ile Glu Asn Asp Ser Ser Pro
290 295
<210> 12
<211> 207
<212> PRT
<213> 智人
<400> 12
Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser
1 5 10 15
Val Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Gly Ile Thr
20 25 30
Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr
35 40 45
Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys
50 55 60
Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp
65 70 75 80
His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr
85 90 95
Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu
100 105 110
Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met
115 120 125
Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu
130 135 140
Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala Lys
145 150 155 160
Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln Asn
165 170 175
Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile Arg
180 185 190
Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile
195 200 205
<210> 13
<211> 1039
<212> PRT
<213> 智人
<400> 13
Met Ala Arg Ala Leu Cys Pro Leu Gln Ala Leu Trp Leu Leu Glu Trp
1 5 10 15
Val Leu Leu Leu Leu Gly Pro Cys Ala Ala Pro Pro Ala Trp Ala Leu
20 25 30
Asn Leu Asp Pro Val Gln Leu Thr Phe Tyr Ala Gly Pro Asn Gly Ser
35 40 45
Gln Phe Gly Phe Ser Leu Asp Phe His Lys Asp Ser His Gly Arg Val
50 55 60
Ala Ile Val Val Gly Ala Pro Arg Thr Leu Gly Pro Ser Gln Glu Glu
65 70 75 80
Thr Gly Gly Val Phe Leu Cys Pro Trp Arg Ala Glu Gly Gly Gln Cys
85 90 95
Pro Ser Leu Leu Phe Asp Leu Arg Asp Glu Thr Arg Asn Val Gly Ser
100 105 110
Gln Thr Leu Gln Thr Phe Lys Ala Arg Gln Gly Leu Gly Ala Ser Val
115 120 125
Val Ser Trp Ser Asp Val Ile Val Ala Cys Ala Pro Trp Gln His Trp
130 135 140
Asn Val Leu Glu Lys Thr Glu Glu Ala Glu Lys Thr Pro Val Gly Ser
145 150 155 160
Cys Phe Leu Ala Gln Pro Glu Ser Gly Arg Arg Ala Glu Tyr Ser Pro
165 170 175
Cys Arg Gly Asn Thr Leu Ser Arg Ile Tyr Val Glu Asn Asp Phe Ser
180 185 190
Trp Asp Lys Arg Tyr Cys Glu Ala Gly Phe Ser Ser Val Val Thr Gln
195 200 205
Ala Gly Glu Leu Val Leu Gly Ala Pro Gly Gly Tyr Tyr Phe Leu Gly
210 215 220
Leu Leu Ala Gln Ala Pro Val Ala Asp Ile Phe Ser Ser Tyr Arg Pro
225 230 235 240
Gly Ile Leu Leu Trp His Val Ser Ser Gln Ser Leu Ser Phe Asp Ser
245 250 255
Ser Asn Pro Glu Tyr Phe Asp Gly Tyr Trp Gly Tyr Ser Val Ala Val
260 265 270
Gly Glu Phe Asp Gly Asp Leu Asn Thr Thr Glu Tyr Val Val Gly Ala
275 280 285
Pro Thr Trp Ser Trp Thr Leu Gly Ala Val Glu Ile Leu Asp Ser Tyr
290 295 300
Tyr Gln Arg Leu His Arg Leu Arg Gly Glu Gln Met Ala Ser Tyr Phe
305 310 315 320
Gly His Ser Val Ala Val Thr Asp Val Asn Gly Asp Gly Arg His Asp
325 330 335
Leu Leu Val Gly Ala Pro Leu Tyr Met Glu Ser Arg Ala Asp Arg Lys
340 345 350
Leu Ala Glu Val Gly Arg Val Tyr Leu Phe Leu Gln Pro Arg Gly Pro
355 360 365
His Ala Leu Gly Ala Pro Ser Leu Leu Leu Thr Gly Thr Gln Leu Tyr
370 375 380
Gly Arg Phe Gly Ser Ala Ile Ala Pro Leu Gly Asp Leu Asp Arg Asp
385 390 395 400
Gly Tyr Asn Asp Ile Ala Val Ala Ala Pro Tyr Gly Gly Pro Ser Gly
405 410 415
Arg Gly Gln Val Leu Val Phe Leu Gly Gln Ser Glu Gly Leu Arg Ser
420 425 430
Arg Pro Ser Gln Val Leu Asp Ser Pro Phe Pro Thr Gly Ser Ala Phe
435 440 445
Gly Phe Ser Leu Arg Gly Ala Val Asp Ile Asp Asp Asn Gly Tyr Pro
450 455 460
Asp Leu Ile Val Gly Ala Tyr Gly Ala Asn Gln Val Ala Val Tyr Arg
465 470 475 480
Ala Gln Pro Val Val Lys Ala Ser Val Gln Leu Leu Val Gln Asp Ser
485 490 495
Leu Asn Pro Ala Val Lys Ser Cys Val Leu Pro Gln Thr Lys Thr Pro
500 505 510
Val Ser Cys Phe Asn Ile Gln Met Cys Val Gly Ala Thr Gly His Asn
515 520 525
Ile Pro Gln Lys Leu Ser Leu Asn Ala Glu Leu Gln Leu Asp Arg Gln
530 535 540
Lys Pro Arg Gln Gly Arg Arg Val Leu Leu Leu Gly Ser Gln Gln Ala
545 550 555 560
Gly Thr Thr Leu Asn Leu Asp Leu Gly Gly Lys His Ser Pro Ile Cys
565 570 575
His Thr Thr Met Ala Phe Leu Arg Asp Glu Ala Asp Phe Arg Asp Lys
580 585 590
Leu Ser Pro Ile Val Leu Ser Leu Asn Val Ser Leu Pro Pro Thr Glu
595 600 605
Ala Gly Met Ala Pro Ala Val Val Leu His Gly Asp Thr His Val Gln
610 615 620
Glu Gln Thr Arg Ile Val Leu Asp Cys Gly Glu Asp Asp Val Cys Val
625 630 635 640
Pro Gln Leu Gln Leu Thr Ala Ser Val Thr Gly Ser Pro Leu Leu Val
645 650 655
Gly Ala Asp Asn Val Leu Glu Leu Gln Met Asp Ala Ala Asn Glu Gly
660 665 670
Glu Gly Ala Tyr Glu Ala Glu Leu Ala Val His Leu Pro Gln Gly Ala
675 680 685
His Tyr Met Arg Ala Leu Ser Asn Val Glu Gly Phe Glu Arg Leu Ile
690 695 700
Cys Asn Gln Lys Lys Glu Asn Glu Thr Arg Val Val Leu Cys Glu Leu
705 710 715 720
Gly Asn Pro Met Lys Lys Asn Ala Gln Ile Gly Ile Ala Met Leu Val
725 730 735
Ser Val Gly Asn Leu Glu Glu Ala Gly Glu Ser Val Ser Phe Gln Leu
740 745 750
Gln Ile Arg Ser Lys Asn Ser Gln Asn Pro Asn Ser Lys Ile Val Leu
755 760 765
Leu Asp Val Pro Val Arg Ala Glu Ala Gln Val Glu Leu Arg Gly Asn
770 775 780
Ser Phe Pro Ala Ser Leu Val Val Ala Ala Glu Glu Gly Glu Arg Glu
785 790 795 800
Gln Asn Ser Leu Asp Ser Trp Gly Pro Lys Val Glu His Thr Tyr Glu
805 810 815
Leu His Asn Asn Gly Pro Gly Thr Val Asn Gly Leu His Leu Ser Ile
820 825 830
His Leu Pro Gly Gln Ser Gln Pro Ser Asp Leu Leu Tyr Ile Leu Asp
835 840 845
Ile Gln Pro Gln Gly Gly Leu Gln Cys Phe Pro Gln Pro Pro Val Asn
850 855 860
Pro Leu Lys Val Asp Trp Gly Leu Pro Ile Pro Ser Pro Ser Pro Ile
865 870 875 880
His Pro Ala His His Lys Arg Asp Arg Arg Gln Ile Phe Leu Pro Glu
885 890 895
Pro Glu Gln Pro Ser Arg Leu Gln Asp Pro Val Leu Val Ser Cys Asp
900 905 910
Ser Ala Pro Cys Thr Val Val Gln Cys Asp Leu Gln Glu Met Ala Arg
915 920 925
Gly Gln Arg Ala Met Val Thr Val Leu Ala Phe Leu Trp Leu Pro Ser
930 935 940
Leu Tyr Gln Arg Pro Leu Asp Gln Phe Val Leu Gln Ser His Ala Trp
945 950 955 960
Phe Asn Val Ser Ser Leu Pro Tyr Ala Val Pro Pro Leu Ser Leu Pro
965 970 975
Arg Gly Glu Ala Gln Val Trp Thr Gln Leu Leu Arg Ala Leu Glu Glu
980 985 990
Arg Ala Ile Pro Ile Trp Trp Val Leu Val Gly Val Leu Gly Gly Leu
995 1000 1005
Leu Leu Leu Thr Ile Leu Val Leu Ala Met Trp Lys Val Gly Phe
1010 1015 1020
Phe Lys Arg Asn Arg Pro Pro Leu Glu Glu Asp Asp Glu Glu Gly
1025 1030 1035
Glu
<210> 14
<211> 272
<212> PRT
<213> 智人
<400> 14
Met Asp Ser Tyr Leu Leu Met Trp Gly Leu Leu Thr Phe Ile Met Val
1 5 10 15
Pro Gly Cys Gln Ala Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro
20 25 30
His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn
35 40 45
Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr
50 55 60
Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys
65 70 75 80
Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro
85 90 95
Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro
100 105 110
Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro
115 120 125
Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val
130 135 140
Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His
145 150 155 160
Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr Arg
165 170 175
Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser Gln
180 185 190
Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro Glu
195 200 205
Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln Ile Gln Thr
210 215 220
Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr Glu Tyr Gln
225 230 235 240
Val Ala Val Ala Gly Cys Val Phe Leu Leu Ile Ser Val Leu Leu Leu
245 250 255
Ser Gly Leu Thr Trp Gln Arg Arg Gln Arg Lys Ser Arg Arg Thr Ile
260 265 270
<210> 15
<211> 595
<212> PRT
<213> 智人
<400> 15
Met Arg Val Leu Leu Ala Ala Leu Gly Leu Leu Phe Leu Gly Ala Leu
1 5 10 15
Arg Ala Phe Pro Gln Asp Arg Pro Phe Glu Asp Thr Cys His Gly Asn
20 25 30
Pro Ser His Tyr Tyr Asp Lys Ala Val Arg Arg Cys Cys Tyr Arg Cys
35 40 45
Pro Met Gly Leu Phe Pro Thr Gln Gln Cys Pro Gln Arg Pro Thr Asp
50 55 60
Cys Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Asp Arg
65 70 75 80
Cys Thr Ala Cys Val Thr Cys Ser Arg Asp Asp Leu Val Glu Lys Thr
85 90 95
Pro Cys Ala Trp Asn Ser Ser Arg Val Cys Glu Cys Arg Pro Gly Met
100 105 110
Phe Cys Ser Thr Ser Ala Val Asn Ser Cys Ala Arg Cys Phe Phe His
115 120 125
Ser Val Cys Pro Ala Gly Met Ile Val Lys Phe Pro Gly Thr Ala Gln
130 135 140
Lys Asn Thr Val Cys Glu Pro Ala Ser Pro Gly Val Ser Pro Ala Cys
145 150 155 160
Ala Ser Pro Glu Asn Cys Lys Glu Pro Ser Ser Gly Thr Ile Pro Gln
165 170 175
Ala Lys Pro Thr Pro Val Ser Pro Ala Thr Ser Ser Ala Ser Thr Met
180 185 190
Pro Val Arg Gly Gly Thr Arg Leu Ala Gln Glu Ala Ala Ser Lys Leu
195 200 205
Thr Arg Ala Pro Asp Ser Pro Ser Ser Val Gly Arg Pro Ser Ser Asp
210 215 220
Pro Gly Leu Ser Pro Thr Gln Pro Cys Pro Glu Gly Ser Gly Asp Cys
225 230 235 240
Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Gly Arg Cys
245 250 255
Thr Ala Cys Val Ser Cys Ser Arg Asp Asp Leu Val Glu Lys Thr Pro
260 265 270
Cys Ala Trp Asn Ser Ser Arg Thr Cys Glu Cys Arg Pro Gly Met Ile
275 280 285
Cys Ala Thr Ser Ala Thr Asn Ser Cys Ala Arg Cys Val Pro Tyr Pro
290 295 300
Ile Cys Ala Ala Glu Thr Val Thr Lys Pro Gln Asp Met Ala Glu Lys
305 310 315 320
Asp Thr Thr Phe Glu Ala Pro Pro Leu Gly Thr Gln Pro Asp Cys Asn
325 330 335
Pro Thr Pro Glu Asn Gly Glu Ala Pro Ala Ser Thr Ser Pro Thr Gln
340 345 350
Ser Leu Leu Val Asp Ser Gln Ala Ser Lys Thr Leu Pro Ile Pro Thr
355 360 365
Ser Ala Pro Val Ala Leu Ser Ser Thr Gly Lys Pro Val Leu Asp Ala
370 375 380
Gly Pro Val Leu Phe Trp Val Ile Leu Val Leu Val Val Val Val Gly
385 390 395 400
Ser Ser Ala Phe Leu Leu Cys His Arg Arg Ala Cys Arg Lys Arg Ile
405 410 415
Arg Gln Lys Leu His Leu Cys Tyr Pro Val Gln Thr Ser Gln Pro Lys
420 425 430
Leu Glu Leu Val Asp Ser Arg Pro Arg Arg Ser Ser Thr Gln Leu Arg
435 440 445
Ser Gly Ala Ser Val Thr Glu Pro Val Ala Glu Glu Arg Gly Leu Met
450 455 460
Ser Gln Pro Leu Met Glu Thr Cys His Ser Val Gly Ala Ala Tyr Leu
465 470 475 480
Glu Ser Leu Pro Leu Gln Asp Ala Ser Pro Ala Gly Gly Pro Ser Ser
485 490 495
Pro Arg Asp Leu Pro Glu Pro Arg Val Ser Thr Glu His Thr Asn Asn
500 505 510
Lys Ile Glu Lys Ile Tyr Ile Met Lys Ala Asp Thr Val Ile Val Gly
515 520 525
Thr Val Lys Ala Glu Leu Pro Glu Gly Arg Gly Leu Ala Gly Pro Ala
530 535 540
Glu Pro Glu Leu Glu Glu Glu Leu Glu Ala Asp His Thr Pro His Tyr
545 550 555 560
Pro Glu Gln Glu Thr Glu Pro Pro Leu Gly Ser Cys Ser Asp Val Met
565 570 575
Leu Ser Val Glu Glu Glu Gly Lys Glu Asp Pro Leu Pro Thr Ala Ala
580 585 590
Ser Gly Lys
595
<210> 16
<211> 1091
<212> PRT
<213> 智人
<400> 16
Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala
1 5 10 15
Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln
20 25 30
Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe
35 40 45
Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn
50 55 60
Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys
65 70 75 80
Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val
85 90 95
Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr
100 105 110
Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn
115 120 125
Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Gly Gln Lys
130 135 140
Cys Asp Pro Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu
145 150 155 160
Asn Cys Gln Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly
165 170 175
Arg Cys Arg Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala
180 185 190
Ala Gly Cys Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys
195 200 205
Phe Arg Asp Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu
210 215 220
Tyr Asn Pro Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr
225 230 235 240
Ser Phe Gly Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val
245 250 255
Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu
260 265 270
Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys
275 280 285
Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu
290 295 300
Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile
305 310 315 320
Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe
325 330 335
Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr
340 345 350
Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn
355 360 365
Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg
370 375 380
Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile
385 390 395 400
Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val
405 410 415
Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp
420 425 430
Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn
435 440 445
Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu
450 455 460
Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser
465 470 475 480
Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu
485 490 495
Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln
500 505 510
Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly
515 520 525
Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro
530 535 540
His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr
545 550 555 560
Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His
565 570 575
Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro
580 585 590
Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala
595 600 605
Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg
610 615 620
Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu
625 630 635 640
Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln
645 650 655
Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val
660 665 670
Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro
675 680 685
Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu
690 695 700
Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val
705 710 715 720
Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys
725 730 735
Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys
740 745 750
Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr
755 760 765
Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu
770 775 780
Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val
785 790 795 800
Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu
805 810 815
Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro
820 825 830
Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His
835 840 845
Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr
850 855 860
Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser
865 870 875 880
Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile
885 890 895
Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser
900 905 910
Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg
915 920 925
Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu
930 935 940
Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu
945 950 955 960
Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln
965 970 975
Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser
980 985 990
Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn
995 1000 1005
Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg
1010 1015 1020
Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp
1025 1030 1035
Asp Thr Phe Leu Pro Val Pro Gly Glu Trp Leu Val Trp Lys Gln
1040 1045 1050
Ser Cys Ser Ser Thr Ser Ser Thr His Ser Ala Ala Ala Ser Leu
1055 1060 1065
Gln Cys Pro Ser Gln Val Leu Pro Pro Ala Ser Pro Glu Gly Glu
1070 1075 1080
Thr Val Ala Asp Leu Gln Thr Gln
1085 1090
<210> 17
<211> 233
<212> PRT
<213> 智人
<400> 17
Met Ser Thr Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala
1 5 10 15
Leu Pro Lys Lys Thr Gly Gly Pro Gln Gly Ser Arg Arg Cys Leu Phe
20 25 30
Leu Ser Leu Phe Ser Phe Leu Ile Val Ala Gly Ala Thr Thr Leu Phe
35 40 45
Cys Leu Leu His Phe Gly Val Ile Gly Pro Gln Arg Glu Glu Phe Pro
50 55 60
Arg Asp Leu Ser Leu Ile Ser Pro Leu Ala Gln Ala Val Arg Ser Ser
65 70 75 80
Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro
85 90 95
Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu
100 105 110
Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser
115 120 125
Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly
130 135 140
Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala
145 150 155 160
Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro
165 170 175
Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu
180 185 190
Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu
195 200 205
Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly
210 215 220
Gln Val Tyr Phe Gly Ile Ile Ala Leu
225 230
<210> 18
<211> 61
<212> PRT
<213> 智人
<400> 18
Met Lys Arg Phe Leu Phe Leu Leu Leu Thr Ile Ser Leu Leu Val Met
1 5 10 15
Val Gln Ile Gln Thr Gly Leu Ser Gly Gln Asn Asp Thr Ser Gln Thr
20 25 30
Ser Ser Pro Ser Ala Ser Ser Asn Ile Ser Gly Gly Ile Phe Leu Phe
35 40 45
Phe Val Ala Asn Ala Ile Ile His Leu Phe Cys Phe Ser
50 55 60
<210> 19
<211> 232
<212> PRT
<213> 智人
<400> 19
Met Asn Phe Leu Leu Ser Trp Val His Trp Ser Leu Ala Leu Leu Leu
1 5 10 15
Tyr Leu His His Ala Lys Trp Ser Gln Ala Ala Pro Met Ala Glu Gly
20 25 30
Gly Gly Gln Asn His His Glu Val Val Lys Phe Met Asp Val Tyr Gln
35 40 45
Arg Ser Tyr Cys His Pro Ile Glu Thr Leu Val Asp Ile Phe Gln Glu
50 55 60
Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys Pro Ser Cys Val Pro Leu
65 70 75 80
Met Arg Cys Gly Gly Cys Cys Asn Asp Glu Gly Leu Glu Cys Val Pro
85 90 95
Thr Glu Glu Ser Asn Ile Thr Met Gln Ile Met Arg Ile Lys Pro His
100 105 110
Gln Gly Gln His Ile Gly Glu Met Ser Phe Leu Gln His Asn Lys Cys
115 120 125
Glu Cys Arg Pro Lys Lys Asp Arg Ala Arg Gln Glu Lys Lys Ser Val
130 135 140
Arg Gly Lys Gly Lys Gly Gln Lys Arg Lys Arg Lys Lys Ser Arg Tyr
145 150 155 160
Lys Ser Trp Ser Val Tyr Val Gly Ala Arg Cys Cys Leu Met Pro Trp
165 170 175
Ser Leu Pro Gly Pro His Pro Cys Gly Pro Cys Ser Glu Arg Arg Lys
180 185 190
His Leu Phe Val Gln Asp Pro Gln Thr Cys Lys Cys Ser Cys Lys Asn
195 200 205
Thr Asp Ser Arg Cys Lys Ala Arg Gln Leu Glu Leu Asn Glu Arg Thr
210 215 220
Cys Arg Cys Asp Lys Pro Arg Arg
225 230
<210> 20
<211> 1676
<212> PRT
<213> 智人
<400> 20
Met Gly Leu Leu Gly Ile Leu Cys Phe Leu Ile Phe Leu Gly Lys Thr
1 5 10 15
Trp Gly Gln Glu Gln Thr Tyr Val Ile Ser Ala Pro Lys Ile Phe Arg
20 25 30
Val Gly Ala Ser Glu Asn Ile Val Ile Gln Val Tyr Gly Tyr Thr Glu
35 40 45
Ala Phe Asp Ala Thr Ile Ser Ile Lys Ser Tyr Pro Asp Lys Lys Phe
50 55 60
Ser Tyr Ser Ser Gly His Val His Leu Ser Ser Glu Asn Lys Phe Gln
65 70 75 80
Asn Ser Ala Ile Leu Thr Ile Gln Pro Lys Gln Leu Pro Gly Gly Gln
85 90 95
Asn Pro Val Ser Tyr Val Tyr Leu Glu Val Val Ser Lys His Phe Ser
100 105 110
Lys Ser Lys Arg Met Pro Ile Thr Tyr Asp Asn Gly Phe Leu Phe Ile
115 120 125
His Thr Asp Lys Pro Val Tyr Thr Pro Asp Gln Ser Val Lys Val Arg
130 135 140
Val Tyr Ser Leu Asn Asp Asp Leu Lys Pro Ala Lys Arg Glu Thr Val
145 150 155 160
Leu Thr Phe Ile Asp Pro Glu Gly Ser Glu Val Asp Met Val Glu Glu
165 170 175
Ile Asp His Ile Gly Ile Ile Ser Phe Pro Asp Phe Lys Ile Pro Ser
180 185 190
Asn Pro Arg Tyr Gly Met Trp Thr Ile Lys Ala Lys Tyr Lys Glu Asp
195 200 205
Phe Ser Thr Thr Gly Thr Ala Tyr Phe Glu Val Lys Glu Tyr Val Leu
210 215 220
Pro His Phe Ser Val Ser Ile Glu Pro Glu Tyr Asn Phe Ile Gly Tyr
225 230 235 240
Lys Asn Phe Lys Asn Phe Glu Ile Thr Ile Lys Ala Arg Tyr Phe Tyr
245 250 255
Asn Lys Val Val Thr Glu Ala Asp Val Tyr Ile Thr Phe Gly Ile Arg
260 265 270
Glu Asp Leu Lys Asp Asp Gln Lys Glu Met Met Gln Thr Ala Met Gln
275 280 285
Asn Thr Met Leu Ile Asn Gly Ile Ala Gln Val Thr Phe Asp Ser Glu
290 295 300
Thr Ala Val Lys Glu Leu Ser Tyr Tyr Ser Leu Glu Asp Leu Asn Asn
305 310 315 320
Lys Tyr Leu Tyr Ile Ala Val Thr Val Ile Glu Ser Thr Gly Gly Phe
325 330 335
Ser Glu Glu Ala Glu Ile Pro Gly Ile Lys Tyr Val Leu Ser Pro Tyr
340 345 350
Lys Leu Asn Leu Val Ala Thr Pro Leu Phe Leu Lys Pro Gly Ile Pro
355 360 365
Tyr Pro Ile Lys Val Gln Val Lys Asp Ser Leu Asp Gln Leu Val Gly
370 375 380
Gly Val Pro Val Thr Leu Asn Ala Gln Thr Ile Asp Val Asn Gln Glu
385 390 395 400
Thr Ser Asp Leu Asp Pro Ser Lys Ser Val Thr Arg Val Asp Asp Gly
405 410 415
Val Ala Ser Phe Val Leu Asn Leu Pro Ser Gly Val Thr Val Leu Glu
420 425 430
Phe Asn Val Lys Thr Asp Ala Pro Asp Leu Pro Glu Glu Asn Gln Ala
435 440 445
Arg Glu Gly Tyr Arg Ala Ile Ala Tyr Ser Ser Leu Ser Gln Ser Tyr
450 455 460
Leu Tyr Ile Asp Trp Thr Asp Asn His Lys Ala Leu Leu Val Gly Glu
465 470 475 480
His Leu Asn Ile Ile Val Thr Pro Lys Ser Pro Tyr Ile Asp Lys Ile
485 490 495
Thr His Tyr Asn Tyr Leu Ile Leu Ser Lys Gly Lys Ile Ile His Phe
500 505 510
Gly Thr Arg Glu Lys Phe Ser Asp Ala Ser Tyr Gln Ser Ile Asn Ile
515 520 525
Pro Val Thr Gln Asn Met Val Pro Ser Ser Arg Leu Leu Val Tyr Tyr
530 535 540
Ile Val Thr Gly Glu Gln Thr Ala Glu Leu Val Ser Asp Ser Val Trp
545 550 555 560
Leu Asn Ile Glu Glu Lys Cys Gly Asn Gln Leu Gln Val His Leu Ser
565 570 575
Pro Asp Ala Asp Ala Tyr Ser Pro Gly Gln Thr Val Ser Leu Asn Met
580 585 590
Ala Thr Gly Met Asp Ser Trp Val Ala Leu Ala Ala Val Asp Ser Ala
595 600 605
Val Tyr Gly Val Gln Arg Gly Ala Lys Lys Pro Leu Glu Arg Val Phe
610 615 620
Gln Phe Leu Glu Lys Ser Asp Leu Gly Cys Gly Ala Gly Gly Gly Leu
625 630 635 640
Asn Asn Ala Asn Val Phe His Leu Ala Gly Leu Thr Phe Leu Thr Asn
645 650 655
Ala Asn Ala Asp Asp Ser Gln Glu Asn Asp Glu Pro Cys Lys Glu Ile
660 665 670
Leu Arg Pro Arg Arg Thr Leu Gln Lys Lys Ile Glu Glu Ile Ala Ala
675 680 685
Lys Tyr Lys His Ser Val Val Lys Lys Cys Cys Tyr Asp Gly Ala Cys
690 695 700
Val Asn Asn Asp Glu Thr Cys Glu Gln Arg Ala Ala Arg Ile Ser Leu
705 710 715 720
Gly Pro Arg Cys Ile Lys Ala Phe Thr Glu Cys Cys Val Val Ala Ser
725 730 735
Gln Leu Arg Ala Asn Ile Ser His Lys Asp Met Gln Leu Gly Arg Leu
740 745 750
His Met Lys Thr Leu Leu Pro Val Ser Lys Pro Glu Ile Arg Ser Tyr
755 760 765
Phe Pro Glu Ser Trp Leu Trp Glu Val His Leu Val Pro Arg Arg Lys
770 775 780
Gln Leu Gln Phe Ala Leu Pro Asp Ser Leu Thr Thr Trp Glu Ile Gln
785 790 795 800
Gly Val Gly Ile Ser Asn Thr Gly Ile Cys Val Ala Asp Thr Val Lys
805 810 815
Ala Lys Val Phe Lys Asp Val Phe Leu Glu Met Asn Ile Pro Tyr Ser
820 825 830
Val Val Arg Gly Glu Gln Ile Gln Leu Lys Gly Thr Val Tyr Asn Tyr
835 840 845
Arg Thr Ser Gly Met Gln Phe Cys Val Lys Met Ser Ala Val Glu Gly
850 855 860
Ile Cys Thr Ser Glu Ser Pro Val Ile Asp His Gln Gly Thr Lys Ser
865 870 875 880
Ser Lys Cys Val Arg Gln Lys Val Glu Gly Ser Ser Ser His Leu Val
885 890 895
Thr Phe Thr Val Leu Pro Leu Glu Ile Gly Leu His Asn Ile Asn Phe
900 905 910
Ser Leu Glu Thr Trp Phe Gly Lys Glu Ile Leu Val Lys Thr Leu Arg
915 920 925
Val Val Pro Glu Gly Val Lys Arg Glu Ser Tyr Ser Gly Val Thr Leu
930 935 940
Asp Pro Arg Gly Ile Tyr Gly Thr Ile Ser Arg Arg Lys Glu Phe Pro
945 950 955 960
Tyr Arg Ile Pro Leu Asp Leu Val Pro Lys Thr Glu Ile Lys Arg Ile
965 970 975
Leu Ser Val Lys Gly Leu Leu Val Gly Glu Ile Leu Ser Ala Val Leu
980 985 990
Ser Gln Glu Gly Ile Asn Ile Leu Thr His Leu Pro Lys Gly Ser Ala
995 1000 1005
Glu Ala Glu Leu Met Ser Val Val Pro Val Phe Tyr Val Phe His
1010 1015 1020
Tyr Leu Glu Thr Gly Asn His Trp Asn Ile Phe His Ser Asp Pro
1025 1030 1035
Leu Ile Glu Lys Gln Lys Leu Lys Lys Lys Leu Lys Glu Gly Met
1040 1045 1050
Leu Ser Ile Met Ser Tyr Arg Asn Ala Asp Tyr Ser Tyr Ser Val
1055 1060 1065
Trp Lys Gly Gly Ser Ala Ser Thr Trp Leu Thr Ala Phe Ala Leu
1070 1075 1080
Arg Val Leu Gly Gln Val Asn Lys Tyr Val Glu Gln Asn Gln Asn
1085 1090 1095
Ser Ile Cys Asn Ser Leu Leu Trp Leu Val Glu Asn Tyr Gln Leu
1100 1105 1110
Asp Asn Gly Ser Phe Lys Glu Asn Ser Gln Tyr Gln Pro Ile Lys
1115 1120 1125
Leu Gln Gly Thr Leu Pro Val Glu Ala Arg Glu Asn Ser Leu Tyr
1130 1135 1140
Leu Thr Ala Phe Thr Val Ile Gly Ile Arg Lys Ala Phe Asp Ile
1145 1150 1155
Cys Pro Leu Val Lys Ile Asp Thr Ala Leu Ile Lys Ala Asp Asn
1160 1165 1170
Phe Leu Leu Glu Asn Thr Leu Pro Ala Gln Ser Thr Phe Thr Leu
1175 1180 1185
Ala Ile Ser Ala Tyr Ala Leu Ser Leu Gly Asp Lys Thr His Pro
1190 1195 1200
Gln Phe Arg Ser Ile Val Ser Ala Leu Lys Arg Glu Ala Leu Val
1205 1210 1215
Lys Gly Asn Pro Pro Ile Tyr Arg Phe Trp Lys Asp Asn Leu Gln
1220 1225 1230
His Lys Asp Ser Ser Val Pro Asn Thr Gly Thr Ala Arg Met Val
1235 1240 1245
Glu Thr Thr Ala Tyr Ala Leu Leu Thr Ser Leu Asn Leu Lys Asp
1250 1255 1260
Ile Asn Tyr Val Asn Pro Val Ile Lys Trp Leu Ser Glu Glu Gln
1265 1270 1275
Arg Tyr Gly Gly Gly Phe Tyr Ser Thr Gln Asp Thr Ile Asn Ala
1280 1285 1290
Ile Glu Gly Leu Thr Glu Tyr Ser Leu Leu Val Lys Gln Leu Arg
1295 1300 1305
Leu Ser Met Asp Ile Asp Val Ser Tyr Lys His Lys Gly Ala Leu
1310 1315 1320
His Asn Tyr Lys Met Thr Asp Lys Asn Phe Leu Gly Arg Pro Val
1325 1330 1335
Glu Val Leu Leu Asn Asp Asp Leu Ile Val Ser Thr Gly Phe Gly
1340 1345 1350
Ser Gly Leu Ala Thr Val His Val Thr Thr Val Val His Lys Thr
1355 1360 1365
Ser Thr Ser Glu Glu Val Cys Ser Phe Tyr Leu Lys Ile Asp Thr
1370 1375 1380
Gln Asp Ile Glu Ala Ser His Tyr Arg Gly Tyr Gly Asn Ser Asp
1385 1390 1395
Tyr Lys Arg Ile Val Ala Cys Ala Ser Tyr Lys Pro Ser Arg Glu
1400 1405 1410
Glu Ser Ser Ser Gly Ser Ser His Ala Val Met Asp Ile Ser Leu
1415 1420 1425
Pro Thr Gly Ile Ser Ala Asn Glu Glu Asp Leu Lys Ala Leu Val
1430 1435 1440
Glu Gly Val Asp Gln Leu Phe Thr Asp Tyr Gln Ile Lys Asp Gly
1445 1450 1455
His Val Ile Leu Gln Leu Asn Ser Ile Pro Ser Ser Asp Phe Leu
1460 1465 1470
Cys Val Arg Phe Arg Ile Phe Glu Leu Phe Glu Val Gly Phe Leu
1475 1480 1485
Ser Pro Ala Thr Phe Thr Val Tyr Glu Tyr His Arg Pro Asp Lys
1490 1495 1500
Gln Cys Thr Met Phe Tyr Ser Thr Ser Asn Ile Lys Ile Gln Lys
1505 1510 1515
Val Cys Glu Gly Ala Ala Cys Lys Cys Val Glu Ala Asp Cys Gly
1520 1525 1530
Gln Met Gln Glu Glu Leu Asp Leu Thr Ile Ser Ala Glu Thr Arg
1535 1540 1545
Lys Gln Thr Ala Cys Lys Pro Glu Ile Ala Tyr Ala Tyr Lys Val
1550 1555 1560
Ser Ile Thr Ser Ile Thr Val Glu Asn Val Phe Val Lys Tyr Lys
1565 1570 1575
Ala Thr Leu Leu Asp Ile Tyr Lys Thr Gly Glu Ala Val Ala Glu
1580 1585 1590
Lys Asp Ser Glu Ile Thr Phe Ile Lys Lys Val Thr Cys Thr Asn
1595 1600 1605
Ala Glu Leu Val Lys Gly Arg Gln Tyr Leu Ile Met Gly Lys Glu
1610 1615 1620
Ala Leu Gln Ile Lys Tyr Asn Phe Ser Phe Arg Tyr Ile Tyr Pro
1625 1630 1635
Leu Asp Ser Leu Thr Trp Ile Glu Tyr Trp Pro Arg Asp Thr Thr
1640 1645 1650
Cys Ser Ser Cys Gln Ala Phe Leu Ala Asn Leu Asp Glu Phe Ala
1655 1660 1665
Glu Asp Ile Phe Leu Asn Gly Cys
1670 1675
<210> 21
<211> 1170
<212> PRT
<213> 智人
<400> 21
Met Lys Asp Ser Cys Ile Thr Val Met Ala Met Ala Leu Leu Ser Gly
1 5 10 15
Phe Phe Phe Phe Ala Pro Ala Ser Ser Tyr Asn Leu Asp Val Arg Gly
20 25 30
Ala Arg Ser Phe Ser Pro Pro Arg Ala Gly Arg His Phe Gly Tyr Arg
35 40 45
Val Leu Gln Val Gly Asn Gly Val Ile Val Gly Ala Pro Gly Glu Gly
50 55 60
Asn Ser Thr Gly Ser Leu Tyr Gln Cys Gln Ser Gly Thr Gly His Cys
65 70 75 80
Leu Pro Val Thr Leu Arg Gly Ser Asn Tyr Thr Ser Lys Tyr Leu Gly
85 90 95
Met Thr Leu Ala Thr Asp Pro Thr Asp Gly Ser Ile Leu Ala Cys Asp
100 105 110
Pro Gly Leu Ser Arg Thr Cys Asp Gln Asn Thr Tyr Leu Ser Gly Leu
115 120 125
Cys Tyr Leu Phe Arg Gln Asn Leu Gln Gly Pro Met Leu Gln Gly Arg
130 135 140
Pro Gly Phe Gln Glu Cys Ile Lys Gly Asn Val Asp Leu Val Phe Leu
145 150 155 160
Phe Asp Gly Ser Met Ser Leu Gln Pro Asp Glu Phe Gln Lys Ile Leu
165 170 175
Asp Phe Met Lys Asp Val Met Lys Lys Leu Ser Asn Thr Ser Tyr Gln
180 185 190
Phe Ala Ala Val Gln Phe Ser Thr Ser Tyr Lys Thr Glu Phe Asp Phe
195 200 205
Ser Asp Tyr Val Lys Arg Lys Asp Pro Asp Ala Leu Leu Lys His Val
210 215 220
Lys His Met Leu Leu Leu Thr Asn Thr Phe Gly Ala Ile Asn Tyr Val
225 230 235 240
Ala Thr Glu Val Phe Arg Glu Glu Leu Gly Ala Arg Pro Asp Ala Thr
245 250 255
Lys Val Leu Ile Ile Ile Thr Asp Gly Glu Ala Thr Asp Ser Gly Asn
260 265 270
Ile Asp Ala Ala Lys Asp Ile Ile Arg Tyr Ile Ile Gly Ile Gly Lys
275 280 285
His Phe Gln Thr Lys Glu Ser Gln Glu Thr Leu His Lys Phe Ala Ser
290 295 300
Lys Pro Ala Ser Glu Phe Val Lys Ile Leu Asp Thr Phe Glu Lys Leu
305 310 315 320
Lys Asp Leu Phe Thr Glu Leu Gln Lys Lys Ile Tyr Val Ile Glu Gly
325 330 335
Thr Ser Lys Gln Asp Leu Thr Ser Phe Asn Met Glu Leu Ser Ser Ser
340 345 350
Gly Ile Ser Ala Asp Leu Ser Arg Gly His Ala Val Val Gly Ala Val
355 360 365
Gly Ala Lys Asp Trp Ala Gly Gly Phe Leu Asp Leu Lys Ala Asp Leu
370 375 380
Gln Asp Asp Thr Phe Ile Gly Asn Glu Pro Leu Thr Pro Glu Val Arg
385 390 395 400
Ala Gly Tyr Leu Gly Tyr Thr Val Thr Trp Leu Pro Ser Arg Gln Lys
405 410 415
Thr Ser Leu Leu Ala Ser Gly Ala Pro Arg Tyr Gln His Met Gly Arg
420 425 430
Val Leu Leu Phe Gln Glu Pro Gln Gly Gly Gly His Trp Ser Gln Val
435 440 445
Gln Thr Ile His Gly Thr Gln Ile Gly Ser Tyr Phe Gly Gly Glu Leu
450 455 460
Cys Gly Val Asp Val Asp Gln Asp Gly Glu Thr Glu Leu Leu Leu Ile
465 470 475 480
Gly Ala Pro Leu Phe Tyr Gly Glu Gln Arg Gly Gly Arg Val Phe Ile
485 490 495
Tyr Gln Arg Arg Gln Leu Gly Phe Glu Glu Val Ser Glu Leu Gln Gly
500 505 510
Asp Pro Gly Tyr Pro Leu Gly Arg Phe Gly Glu Ala Ile Thr Ala Leu
515 520 525
Thr Asp Ile Asn Gly Asp Gly Leu Val Asp Val Ala Val Gly Ala Pro
530 535 540
Leu Glu Glu Gln Gly Ala Val Tyr Ile Phe Asn Gly Arg His Gly Gly
545 550 555 560
Leu Ser Pro Gln Pro Ser Gln Arg Ile Glu Gly Thr Gln Val Leu Ser
565 570 575
Gly Ile Gln Trp Phe Gly Arg Ser Ile His Gly Val Lys Asp Leu Glu
580 585 590
Gly Asp Gly Leu Ala Asp Val Ala Val Gly Ala Glu Ser Gln Met Ile
595 600 605
Val Leu Ser Ser Arg Pro Val Val Asp Met Val Thr Leu Met Ser Phe
610 615 620
Ser Pro Ala Glu Ile Pro Val His Glu Val Glu Cys Ser Tyr Ser Thr
625 630 635 640
Ser Asn Lys Met Lys Glu Gly Val Asn Ile Thr Ile Cys Phe Gln Ile
645 650 655
Lys Ser Leu Ile Pro Gln Phe Gln Gly Arg Leu Val Ala Asn Leu Thr
660 665 670
Tyr Thr Leu Gln Leu Asp Gly His Arg Thr Arg Arg Arg Gly Leu Phe
675 680 685
Pro Gly Gly Arg His Glu Leu Arg Arg Asn Ile Ala Val Thr Thr Ser
690 695 700
Met Ser Cys Thr Asp Phe Ser Phe His Phe Pro Val Cys Val Gln Asp
705 710 715 720
Leu Ile Ser Pro Ile Asn Val Ser Leu Asn Phe Ser Leu Trp Glu Glu
725 730 735
Glu Gly Thr Pro Arg Asp Gln Arg Ala Gln Gly Lys Asp Ile Pro Pro
740 745 750
Ile Leu Arg Pro Ser Leu His Ser Glu Thr Trp Glu Ile Pro Phe Glu
755 760 765
Lys Asn Cys Gly Glu Asp Lys Lys Cys Glu Ala Asn Leu Arg Val Ser
770 775 780
Phe Ser Pro Ala Arg Ser Arg Ala Leu Arg Leu Thr Ala Phe Ala Ser
785 790 795 800
Leu Ser Val Glu Leu Ser Leu Ser Asn Leu Glu Glu Asp Ala Tyr Trp
805 810 815
Val Gln Leu Asp Leu His Phe Pro Pro Gly Leu Ser Phe Arg Lys Val
820 825 830
Glu Met Leu Lys Pro His Ser Gln Ile Pro Val Ser Cys Glu Glu Leu
835 840 845
Pro Glu Glu Ser Arg Leu Leu Ser Arg Ala Leu Ser Cys Asn Val Ser
850 855 860
Ser Pro Ile Phe Lys Ala Gly His Ser Val Ala Leu Gln Met Met Phe
865 870 875 880
Asn Thr Leu Val Asn Ser Ser Trp Gly Asp Ser Val Glu Leu His Ala
885 890 895
Asn Val Thr Cys Asn Asn Glu Asp Ser Asp Leu Leu Glu Asp Asn Ser
900 905 910
Ala Thr Thr Ile Ile Pro Ile Leu Tyr Pro Ile Asn Ile Leu Ile Gln
915 920 925
Asp Gln Glu Asp Ser Thr Leu Tyr Val Ser Phe Thr Pro Lys Gly Pro
930 935 940
Lys Ile His Gln Val Lys His Met Tyr Gln Val Arg Ile Gln Pro Ser
945 950 955 960
Ile His Asp His Asn Ile Pro Thr Leu Glu Ala Val Val Gly Val Pro
965 970 975
Gln Pro Pro Ser Glu Gly Pro Ile Thr His Gln Trp Ser Val Gln Met
980 985 990
Glu Pro Pro Val Pro Cys His Tyr Glu Asp Leu Glu Arg Leu Pro Asp
995 1000 1005
Ala Ala Glu Pro Cys Leu Pro Gly Ala Leu Phe Arg Cys Pro Val
1010 1015 1020
Val Phe Arg Gln Glu Ile Leu Val Gln Val Ile Gly Thr Leu Glu
1025 1030 1035
Leu Val Gly Glu Ile Glu Ala Ser Ser Met Phe Ser Leu Cys Ser
1040 1045 1050
Ser Leu Ser Ile Ser Phe Asn Ser Ser Lys His Phe His Leu Tyr
1055 1060 1065
Gly Ser Asn Ala Ser Leu Ala Gln Val Val Met Lys Val Asp Val
1070 1075 1080
Val Tyr Glu Lys Gln Met Leu Tyr Leu Tyr Val Leu Ser Gly Ile
1085 1090 1095
Gly Gly Leu Leu Leu Leu Leu Leu Ile Phe Ile Val Leu Tyr Lys
1100 1105 1110
Val Gly Phe Phe Lys Arg Asn Leu Lys Glu Lys Met Glu Ala Gly
1115 1120 1125
Arg Gly Val Pro Asn Gly Ile Pro Ala Glu Asp Ser Glu Gln Leu
1130 1135 1140
Ala Ser Gly Gln Glu Ala Gly Asp Pro Gly Cys Leu Lys Pro Leu
1145 1150 1155
His Glu Lys Asp Ser Glu Ser Gly Gly Gly Lys Asp
1160 1165 1170
<210> 22
<211> 364
<212> PRT
<213> 智人
<400> 22
Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala
1 5 10 15
Met Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln
20 25 30
Glu Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro
35 40 45
Tyr Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly
50 55 60
Ala Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln
65 70 75 80
Glu Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro
85 90 95
Ser Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp
100 105 110
Asn Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser
115 120 125
Tyr Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg
130 135 140
Pro Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn
145 150 155 160
Leu Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile
165 170 175
Phe Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr
180 185 190
His Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr
195 200 205
Asn Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu
210 215 220
Arg Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr
225 230 235 240
Gly Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly
245 250 255
Val Val His Gly Ala Ile Gly Gly Ala Gly Val Thr Ala Leu Leu Ala
260 265 270
Leu Cys Leu Cys Leu Ile Phe Phe Ile Val Lys Thr His Arg Arg Lys
275 280 285
Ala Ala Arg Thr Ala Val Gly Arg Asn Asp Thr His Pro Thr Thr Gly
290 295 300
Ser Ala Ser Pro Lys His Gln Lys Lys Ser Lys Leu His Gly Pro Thr
305 310 315 320
Glu Thr Ser Ser Cys Ser Gly Ala Ala Pro Thr Val Glu Met Asp Glu
325 330 335
Glu Leu His Tyr Ala Ser Leu Asn Phe His Gly Met Asn Pro Ser Lys
340 345 350
Asp Thr Ser Thr Glu Tyr Ser Glu Val Arg Thr Gln
355 360
<210> 23
<211> 1032
<212> PRT
<213> 智人
<400> 23
Met Ala Trp Glu Ala Arg Arg Glu Pro Gly Pro Arg Arg Ala Ala Val
1 5 10 15
Arg Glu Thr Val Met Leu Leu Leu Cys Leu Gly Val Pro Thr Gly Arg
20 25 30
Pro Tyr Asn Val Asp Thr Glu Ser Ala Leu Leu Tyr Gln Gly Pro His
35 40 45
Asn Thr Leu Phe Gly Tyr Ser Val Val Leu His Ser His Gly Ala Asn
50 55 60
Arg Trp Leu Leu Val Gly Ala Pro Thr Ala Asn Trp Leu Ala Asn Ala
65 70 75 80
Ser Val Ile Asn Pro Gly Ala Ile Tyr Arg Cys Arg Ile Gly Lys Asn
85 90 95
Pro Gly Gln Thr Cys Glu Gln Leu Gln Leu Gly Ser Pro Asn Gly Glu
100 105 110
Pro Cys Gly Lys Thr Cys Leu Glu Glu Arg Asp Asn Gln Trp Leu Gly
115 120 125
Val Thr Leu Ser Arg Gln Pro Gly Glu Asn Gly Ser Ile Val Thr Cys
130 135 140
Gly His Arg Trp Lys Asn Ile Phe Tyr Ile Lys Asn Glu Asn Lys Leu
145 150 155 160
Pro Thr Gly Gly Cys Tyr Gly Val Pro Pro Asp Leu Arg Thr Glu Leu
165 170 175
Ser Lys Arg Ile Ala Pro Cys Tyr Gln Asp Tyr Val Lys Lys Phe Gly
180 185 190
Glu Asn Phe Ala Ser Cys Gln Ala Gly Ile Ser Ser Phe Tyr Thr Lys
195 200 205
Asp Leu Ile Val Met Gly Ala Pro Gly Ser Ser Tyr Trp Thr Gly Ser
210 215 220
Leu Phe Val Tyr Asn Ile Thr Thr Asn Lys Tyr Lys Ala Phe Leu Asp
225 230 235 240
Lys Gln Asn Gln Val Lys Phe Gly Ser Tyr Leu Gly Tyr Ser Val Gly
245 250 255
Ala Gly His Phe Arg Ser Gln His Thr Thr Glu Val Val Gly Gly Ala
260 265 270
Pro Gln His Glu Gln Ile Gly Lys Ala Tyr Ile Phe Ser Ile Asp Glu
275 280 285
Lys Glu Leu Asn Ile Leu His Glu Met Lys Gly Lys Lys Leu Gly Ser
290 295 300
Tyr Phe Gly Ala Ser Val Cys Ala Val Asp Leu Asn Ala Asp Gly Phe
305 310 315 320
Ser Asp Leu Leu Val Gly Ala Pro Met Gln Ser Thr Ile Arg Glu Glu
325 330 335
Gly Arg Val Phe Val Tyr Ile Asn Ser Gly Ser Gly Ala Val Met Asn
340 345 350
Ala Met Glu Thr Asn Leu Val Gly Ser Asp Lys Tyr Ala Ala Arg Phe
355 360 365
Gly Glu Ser Ile Val Asn Leu Gly Asp Ile Asp Asn Asp Gly Phe Glu
370 375 380
Asp Val Ala Ile Gly Ala Pro Gln Glu Asp Asp Leu Gln Gly Ala Ile
385 390 395 400
Tyr Ile Tyr Asn Gly Arg Ala Asp Gly Ile Ser Ser Thr Phe Ser Gln
405 410 415
Arg Ile Glu Gly Leu Gln Ile Ser Lys Ser Leu Ser Met Phe Gly Gln
420 425 430
Ser Ile Ser Gly Gln Ile Asp Ala Asp Asn Asn Gly Tyr Val Asp Val
435 440 445
Ala Val Gly Ala Phe Arg Ser Asp Ser Ala Val Leu Leu Arg Thr Arg
450 455 460
Pro Val Val Ile Val Asp Ala Ser Leu Ser His Pro Glu Ser Val Asn
465 470 475 480
Arg Thr Lys Phe Asp Cys Val Glu Asn Gly Trp Pro Ser Val Cys Ile
485 490 495
Asp Leu Thr Leu Cys Phe Ser Tyr Lys Gly Lys Glu Val Pro Gly Tyr
500 505 510
Ile Val Leu Phe Tyr Asn Met Ser Leu Asp Val Asn Arg Lys Ala Glu
515 520 525
Ser Pro Pro Arg Phe Tyr Phe Ser Ser Asn Gly Thr Ser Asp Val Ile
530 535 540
Thr Gly Ser Ile Gln Val Ser Ser Arg Glu Ala Asn Cys Arg Thr His
545 550 555 560
Gln Ala Phe Met Arg Lys Asp Val Arg Asp Ile Leu Thr Pro Ile Gln
565 570 575
Ile Glu Ala Ala Tyr His Leu Gly Pro His Val Ile Ser Lys Arg Ser
580 585 590
Thr Glu Glu Phe Pro Pro Leu Gln Pro Ile Leu Gln Gln Lys Lys Glu
595 600 605
Lys Asp Ile Met Lys Lys Thr Ile Asn Phe Ala Arg Phe Cys Ala His
610 615 620
Glu Asn Cys Ser Ala Asp Leu Gln Val Ser Ala Lys Ile Gly Phe Leu
625 630 635 640
Lys Pro His Glu Asn Lys Thr Tyr Leu Ala Val Gly Ser Met Lys Thr
645 650 655
Leu Met Leu Asn Val Ser Leu Phe Asn Ala Gly Asp Asp Ala Tyr Glu
660 665 670
Thr Thr Leu His Val Lys Leu Pro Val Gly Leu Tyr Phe Ile Lys Ile
675 680 685
Leu Glu Leu Glu Glu Lys Gln Ile Asn Cys Glu Val Thr Asp Asn Ser
690 695 700
Gly Val Val Gln Leu Asp Cys Ser Ile Gly Tyr Ile Tyr Val Asp His
705 710 715 720
Leu Ser Arg Ile Asp Ile Ser Phe Leu Leu Asp Val Ser Ser Leu Ser
725 730 735
Arg Ala Glu Glu Asp Leu Ser Ile Thr Val His Ala Thr Cys Glu Asn
740 745 750
Glu Glu Glu Met Asp Asn Leu Lys His Ser Arg Val Thr Val Ala Ile
755 760 765
Pro Leu Lys Tyr Glu Val Lys Leu Thr Val His Gly Phe Val Asn Pro
770 775 780
Thr Ser Phe Val Tyr Gly Ser Asn Asp Glu Asn Glu Pro Glu Thr Cys
785 790 795 800
Met Val Glu Lys Met Asn Leu Thr Phe His Val Ile Asn Thr Gly Asn
805 810 815
Ser Met Ala Pro Asn Val Ser Val Glu Ile Met Val Pro Asn Ser Phe
820 825 830
Ser Pro Gln Thr Asp Lys Leu Phe Asn Ile Leu Asp Val Gln Thr Thr
835 840 845
Thr Gly Glu Cys His Phe Glu Asn Tyr Gln Arg Val Cys Ala Leu Glu
850 855 860
Gln Gln Lys Ser Ala Met Gln Thr Leu Lys Gly Ile Val Arg Phe Leu
865 870 875 880
Ser Lys Thr Asp Lys Arg Leu Leu Tyr Cys Ile Lys Ala Asp Pro His
885 890 895
Cys Leu Asn Phe Leu Cys Asn Phe Gly Lys Met Glu Ser Gly Lys Glu
900 905 910
Ala Ser Val His Ile Gln Leu Glu Gly Arg Pro Ser Ile Leu Glu Met
915 920 925
Asp Glu Thr Ser Ala Leu Lys Phe Glu Ile Arg Ala Thr Gly Phe Pro
930 935 940
Glu Pro Asn Pro Arg Val Ile Glu Leu Asn Lys Asp Glu Asn Val Ala
945 950 955 960
His Val Leu Leu Glu Gly Leu His His Gln Arg Pro Lys Arg Tyr Phe
965 970 975
Thr Ile Val Ile Ile Ser Ser Ser Leu Leu Leu Gly Leu Ile Val Leu
980 985 990
Leu Leu Ile Ser Tyr Val Met Trp Lys Ala Gly Phe Phe Lys Arg Gln
995 1000 1005
Tyr Lys Ser Ile Leu Gln Glu Glu Asn Arg Arg Asp Ser Trp Ser
1010 1015 1020
Tyr Ile Asn Ser Lys Ser Asn Asp Asp
1025 1030
<210> 24
<211> 257
<212> PRT
<213> 智人
<400> 24
Met Ala Pro Ala Met Glu Ser Pro Thr Leu Leu Cys Val Ala Leu Leu
1 5 10 15
Phe Phe Ala Pro Asp Gly Val Leu Ala Val Pro Gln Lys Pro Lys Val
20 25 30
Ser Leu Asn Pro Pro Trp Asn Arg Ile Phe Lys Gly Glu Asn Val Thr
35 40 45
Leu Thr Cys Asn Gly Asn Asn Phe Phe Glu Val Ser Ser Thr Lys Trp
50 55 60
Phe His Asn Gly Ser Leu Ser Glu Glu Thr Asn Ser Ser Leu Asn Ile
65 70 75 80
Val Asn Ala Lys Phe Glu Asp Ser Gly Glu Tyr Lys Cys Gln His Gln
85 90 95
Gln Val Asn Glu Ser Glu Pro Val Tyr Leu Glu Val Phe Ser Asp Trp
100 105 110
Leu Leu Leu Gln Ala Ser Ala Glu Val Val Met Glu Gly Gln Pro Leu
115 120 125
Phe Leu Arg Cys His Gly Trp Arg Asn Trp Asp Val Tyr Lys Val Ile
130 135 140
Tyr Tyr Lys Asp Gly Glu Ala Leu Lys Tyr Trp Tyr Glu Asn His Asn
145 150 155 160
Ile Ser Ile Thr Asn Ala Thr Val Glu Asp Ser Gly Thr Tyr Tyr Cys
165 170 175
Thr Gly Lys Val Trp Gln Leu Asp Tyr Glu Ser Glu Pro Leu Asn Ile
180 185 190
Thr Val Ile Lys Ala Pro Arg Glu Lys Tyr Trp Leu Gln Phe Phe Ile
195 200 205
Pro Leu Leu Val Val Ile Leu Phe Ala Val Asp Thr Gly Leu Phe Ile
210 215 220
Ser Thr Gln Gln Gln Val Thr Phe Leu Leu Lys Ile Lys Arg Thr Arg
225 230 235 240
Lys Gly Phe Arg Leu Leu Asn Pro His Pro Lys Pro Asn Pro Lys Asn
245 250 255
Asn
<210> 25
<211> 574
<212> PRT
<213> 智人
<400> 25
Met Glu Leu Leu Ile Leu Lys Ala Asn Ala Ile Thr Thr Ile Leu Thr
1 5 10 15
Ala Val Thr Phe Cys Phe Ala Ser Gly Gln Asn Ile Thr Glu Glu Phe
20 25 30
Tyr Gln Ser Thr Cys Ser Ala Val Ser Lys Gly Tyr Leu Ser Ala Leu
35 40 45
Arg Thr Gly Trp Tyr Thr Ser Val Ile Thr Ile Glu Leu Ser Asn Ile
50 55 60
Lys Glu Asn Lys Cys Asn Gly Thr Asp Ala Lys Val Lys Leu Ile Lys
65 70 75 80
Gln Glu Leu Asp Lys Tyr Lys Asn Ala Val Thr Glu Leu Gln Leu Leu
85 90 95
Met Gln Ser Thr Pro Pro Thr Asn Asn Arg Ala Arg Arg Glu Leu Pro
100 105 110
Arg Phe Met Asn Tyr Thr Leu Asn Asn Ala Lys Lys Thr Asn Val Thr
115 120 125
Leu Ser Lys Lys Arg Lys Arg Arg Phe Leu Gly Phe Leu Leu Gly Val
130 135 140
Gly Ser Ala Ile Ala Ser Gly Val Ala Val Ser Lys Val Leu His Leu
145 150 155 160
Glu Gly Glu Val Asn Lys Ile Lys Ser Ala Leu Leu Ser Thr Asn Lys
165 170 175
Ala Val Val Ser Leu Ser Asn Gly Val Ser Val Leu Thr Ser Lys Val
180 185 190
Leu Asp Leu Lys Asn Tyr Ile Asp Lys Gln Leu Leu Pro Ile Val Asn
195 200 205
Lys Gln Ser Cys Ser Ile Ser Asn Ile Glu Thr Val Ile Glu Phe Gln
210 215 220
Gln Lys Asn Asn Arg Leu Leu Glu Ile Thr Arg Glu Phe Ser Val Asn
225 230 235 240
Ala Gly Val Thr Thr Pro Val Ser Thr Tyr Met Leu Thr Asn Ser Glu
245 250 255
Leu Leu Ser Leu Ile Asn Asp Met Pro Ile Thr Asn Asp Gln Lys Lys
260 265 270
Leu Met Ser Asn Asn Val Gln Ile Val Arg Gln Gln Ser Tyr Ser Ile
275 280 285
Met Ser Ile Ile Lys Glu Glu Val Leu Ala Tyr Val Val Gln Leu Pro
290 295 300
Leu Tyr Gly Val Ile Asp Thr Pro Cys Trp Lys Leu His Thr Ser Pro
305 310 315 320
Leu Cys Thr Thr Asn Thr Lys Glu Gly Ser Asn Ile Cys Leu Thr Arg
325 330 335
Thr Asp Arg Gly Trp Tyr Cys Asp Asn Ala Gly Ser Val Ser Phe Phe
340 345 350
Pro Gln Ala Glu Thr Cys Lys Val Gln Ser Asn Arg Val Phe Cys Asp
355 360 365
Thr Met Asn Ser Leu Thr Leu Pro Ser Glu Ile Asn Leu Cys Asn Val
370 375 380
Asp Ile Phe Asn Pro Lys Tyr Asp Cys Lys Ile Met Thr Ser Lys Thr
385 390 395 400
Asp Val Ser Ser Ser Val Ile Thr Ser Leu Gly Ala Ile Val Ser Cys
405 410 415
Tyr Gly Lys Thr Lys Cys Thr Ala Ser Asn Lys Asn Arg Gly Ile Ile
420 425 430
Lys Thr Phe Ser Asn Gly Cys Asp Tyr Val Ser Asn Lys Gly Met Asp
435 440 445
Thr Val Ser Val Gly Asn Thr Leu Tyr Tyr Val Asn Lys Gln Glu Gly
450 455 460
Lys Ser Leu Tyr Val Lys Gly Glu Pro Ile Ile Asn Phe Tyr Asp Pro
465 470 475 480
Leu Val Phe Pro Ser Asp Glu Phe Asp Ala Ser Ile Ser Gln Val Asn
485 490 495
Glu Lys Ile Asn Gln Ser Leu Ala Phe Ile Arg Lys Ser Asp Glu Leu
500 505 510
Leu His Asn Val Asn Ala Gly Lys Ser Thr Thr Asn Ile Met Ile Thr
515 520 525
Thr Ile Ile Ile Val Ile Ile Val Ile Leu Leu Ser Leu Ile Ala Val
530 535 540
Gly Leu Leu Leu Tyr Cys Lys Ala Arg Ser Thr Pro Val Thr Leu Ser
545 550 555 560
Lys Asp Gln Leu Ser Gly Ile Asn Asn Ile Ala Phe Ser Asn
565 570
<210> 26
<211> 468
<212> PRT
<213> 智人
<400> 26
Met Leu Ala Val Gly Cys Ala Leu Leu Ala Ala Leu Leu Ala Ala Pro
1 5 10 15
Gly Ala Ala Leu Ala Pro Arg Arg Cys Pro Ala Gln Glu Val Ala Arg
20 25 30
Gly Val Leu Thr Ser Leu Pro Gly Asp Ser Val Thr Leu Thr Cys Pro
35 40 45
Gly Val Glu Pro Glu Asp Asn Ala Thr Val His Trp Val Leu Arg Lys
50 55 60
Pro Ala Ala Gly Ser His Pro Ser Arg Trp Ala Gly Met Gly Arg Arg
65 70 75 80
Leu Leu Leu Arg Ser Val Gln Leu His Asp Ser Gly Asn Tyr Ser Cys
85 90 95
Tyr Arg Ala Gly Arg Pro Ala Gly Thr Val His Leu Leu Val Asp Val
100 105 110
Pro Pro Glu Glu Pro Gln Leu Ser Cys Phe Arg Lys Ser Pro Leu Ser
115 120 125
Asn Val Val Cys Glu Trp Gly Pro Arg Ser Thr Pro Ser Leu Thr Thr
130 135 140
Lys Ala Val Leu Leu Val Arg Lys Phe Gln Asn Ser Pro Ala Glu Asp
145 150 155 160
Phe Gln Glu Pro Cys Gln Tyr Ser Gln Glu Ser Gln Lys Phe Ser Cys
165 170 175
Gln Leu Ala Val Pro Glu Gly Asp Ser Ser Phe Tyr Ile Val Ser Met
180 185 190
Cys Val Ala Ser Ser Val Gly Ser Lys Phe Ser Lys Thr Gln Thr Phe
195 200 205
Gln Gly Cys Gly Ile Leu Gln Pro Asp Pro Pro Ala Asn Ile Thr Val
210 215 220
Thr Ala Val Ala Arg Asn Pro Arg Trp Leu Ser Val Thr Trp Gln Asp
225 230 235 240
Pro His Ser Trp Asn Ser Ser Phe Tyr Arg Leu Arg Phe Glu Leu Arg
245 250 255
Tyr Arg Ala Glu Arg Ser Lys Thr Phe Thr Thr Trp Met Val Lys Asp
260 265 270
Leu Gln His His Cys Val Ile His Asp Ala Trp Ser Gly Leu Arg His
275 280 285
Val Val Gln Leu Arg Ala Gln Glu Glu Phe Gly Gln Gly Glu Trp Ser
290 295 300
Glu Trp Ser Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg Ser
305 310 315 320
Pro Pro Ala Glu Asn Glu Val Ser Thr Pro Met Gln Ala Leu Thr Thr
325 330 335
Asn Lys Asp Asp Asp Asn Ile Leu Phe Arg Asp Ser Ala Asn Ala Thr
340 345 350
Ser Leu Pro Val Gln Asp Ser Ser Ser Val Pro Leu Pro Thr Phe Leu
355 360 365
Val Ala Gly Gly Ser Leu Ala Phe Gly Thr Leu Leu Cys Ile Ala Ile
370 375 380
Val Leu Arg Phe Lys Lys Thr Trp Lys Leu Arg Ala Leu Lys Glu Gly
385 390 395 400
Lys Thr Ser Met His Pro Pro Tyr Ser Leu Gly Gln Leu Val Pro Glu
405 410 415
Arg Pro Arg Pro Thr Pro Val Leu Val Pro Leu Ile Ser Pro Pro Val
420 425 430
Ser Pro Ser Ser Leu Gly Ser Asp Asn Thr Ser Ser His Asn Arg Pro
435 440 445
Asp Ala Arg Asp Pro Arg Ser Pro Tyr Asp Ile Ser Asn Thr Asp Tyr
450 455 460
Phe Phe Pro Arg
465
<210> 27
<211> 1255
<212> PRT
<213> 智人
<400> 27
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys
625 630 635 640
Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser
645 650 655
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
660 665 670
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
675 680 685
Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
690 695 700
Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
705 710 715 720
Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
725 730 735
Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
740 745 750
Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
755 760 765
Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
770 775 780
Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
785 790 795 800
Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
805 810 815
Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
820 825 830
Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
835 840 845
Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
850 855 860
Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
865 870 875 880
Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
885 890 895
Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
900 905 910
Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
915 920 925
Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
930 935 940
Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
945 950 955 960
Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
965 970 975
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
980 985 990
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
995 1000 1005
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr
1010 1015 1020
Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly
1025 1030 1035
Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg
1040 1045 1050
Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu
1055 1060 1065
Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser
1070 1075 1080
Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu
1085 1090 1095
Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser
1100 1105 1110
Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val
1115 1120 1125
Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro
1130 1135 1140
Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro
1145 1150 1155
Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu
1160 1165 1170
Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly
1175 1180 1185
Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala
1190 1195 1200
Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp
1205 1210 1215
Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro
1220 1225 1230
Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
1235 1240 1245
Leu Gly Leu Asp Val Pro Val
1250 1255
<210> 28
<211> 798
<212> PRT
<213> 智人
<400> 28
Met Val Ala Leu Pro Met Val Leu Val Leu Leu Leu Val Leu Ser Arg
1 5 10 15
Gly Glu Ser Glu Leu Asp Ala Lys Ile Pro Ser Thr Gly Asp Ala Thr
20 25 30
Glu Trp Arg Asn Pro His Leu Ser Met Leu Gly Ser Cys Gln Pro Ala
35 40 45
Pro Ser Cys Gln Lys Cys Ile Leu Ser His Pro Ser Cys Ala Trp Cys
50 55 60
Lys Gln Leu Asn Phe Thr Ala Ser Gly Glu Ala Glu Ala Arg Arg Cys
65 70 75 80
Ala Arg Arg Glu Glu Leu Leu Ala Arg Gly Cys Pro Leu Glu Glu Leu
85 90 95
Glu Glu Pro Arg Gly Gln Gln Glu Val Leu Gln Asp Gln Pro Leu Ser
100 105 110
Gln Gly Ala Arg Gly Glu Gly Ala Thr Gln Leu Ala Pro Gln Arg Val
115 120 125
Arg Val Thr Leu Arg Pro Gly Glu Pro Gln Gln Leu Gln Val Arg Phe
130 135 140
Leu Arg Ala Glu Gly Tyr Pro Val Asp Leu Tyr Tyr Leu Met Asp Leu
145 150 155 160
Ser Tyr Ser Met Lys Asp Asp Leu Glu Arg Val Arg Gln Leu Gly His
165 170 175
Ala Leu Leu Val Arg Leu Gln Glu Val Thr His Ser Val Arg Ile Gly
180 185 190
Phe Gly Ser Phe Val Asp Lys Thr Val Leu Pro Phe Val Ser Thr Val
195 200 205
Pro Ser Lys Leu Arg His Pro Cys Pro Thr Arg Leu Glu Arg Cys Gln
210 215 220
Ser Pro Phe Ser Phe His His Val Leu Ser Leu Thr Gly Asp Ala Gln
225 230 235 240
Ala Phe Glu Arg Glu Val Gly Arg Gln Ser Val Ser Gly Asn Leu Asp
245 250 255
Ser Pro Glu Gly Gly Phe Asp Ala Ile Leu Gln Ala Ala Leu Cys Gln
260 265 270
Glu Gln Ile Gly Trp Arg Asn Val Ser Arg Leu Leu Val Phe Thr Ser
275 280 285
Asp Asp Thr Phe His Thr Ala Gly Asp Gly Lys Leu Gly Gly Ile Phe
290 295 300
Met Pro Ser Asp Gly His Cys His Leu Asp Ser Asn Gly Leu Tyr Ser
305 310 315 320
Arg Ser Thr Glu Phe Asp Tyr Pro Ser Val Gly Gln Val Ala Gln Ala
325 330 335
Leu Ser Ala Ala Asn Ile Gln Pro Ile Phe Ala Val Thr Ser Ala Ala
340 345 350
Leu Pro Val Tyr Gln Glu Leu Ser Lys Leu Ile Pro Lys Ser Ala Val
355 360 365
Gly Glu Leu Ser Glu Asp Ser Ser Asn Val Val Gln Leu Ile Met Asp
370 375 380
Ala Tyr Asn Ser Leu Ser Ser Thr Val Thr Leu Glu His Ser Ser Leu
385 390 395 400
Pro Pro Gly Val His Ile Ser Tyr Glu Ser Gln Cys Glu Gly Pro Glu
405 410 415
Lys Arg Glu Gly Lys Ala Glu Asp Arg Gly Gln Cys Asn His Val Arg
420 425 430
Ile Asn Gln Thr Val Thr Phe Trp Val Ser Leu Gln Ala Thr His Cys
435 440 445
Leu Pro Glu Pro His Leu Leu Arg Leu Arg Ala Leu Gly Phe Ser Glu
450 455 460
Glu Leu Ile Val Glu Leu His Thr Leu Cys Asp Cys Asn Cys Ser Asp
465 470 475 480
Thr Gln Pro Gln Ala Pro His Cys Ser Asp Gly Gln Gly His Leu Gln
485 490 495
Cys Gly Val Cys Ser Cys Ala Pro Gly Arg Leu Gly Arg Leu Cys Glu
500 505 510
Cys Ser Val Ala Glu Leu Ser Ser Pro Asp Leu Glu Ser Gly Cys Arg
515 520 525
Ala Pro Asn Gly Thr Gly Pro Leu Cys Ser Gly Lys Gly His Cys Gln
530 535 540
Cys Gly Arg Cys Ser Cys Ser Gly Gln Ser Ser Gly His Leu Cys Glu
545 550 555 560
Cys Asp Asp Ala Ser Cys Glu Arg His Glu Gly Ile Leu Cys Gly Gly
565 570 575
Phe Gly Arg Cys Gln Cys Gly Val Cys His Cys His Ala Asn Arg Thr
580 585 590
Gly Arg Ala Cys Glu Cys Ser Gly Asp Met Asp Ser Cys Ile Ser Pro
595 600 605
Glu Gly Gly Leu Cys Ser Gly His Gly Arg Cys Lys Cys Asn Arg Cys
610 615 620
Gln Cys Leu Asp Gly Tyr Tyr Gly Ala Leu Cys Asp Gln Cys Pro Gly
625 630 635 640
Cys Lys Thr Pro Cys Glu Arg His Arg Asp Cys Ala Glu Cys Gly Ala
645 650 655
Phe Arg Thr Gly Pro Leu Ala Thr Asn Cys Ser Thr Ala Cys Ala His
660 665 670
Thr Asn Val Thr Leu Ala Leu Ala Pro Ile Leu Asp Asp Gly Trp Cys
675 680 685
Lys Glu Arg Thr Leu Asp Asn Gln Leu Phe Phe Phe Leu Val Glu Asp
690 695 700
Asp Ala Arg Gly Thr Val Val Leu Arg Val Arg Pro Gln Glu Lys Gly
705 710 715 720
Ala Asp His Thr Gln Ala Ile Val Leu Gly Cys Val Gly Gly Ile Val
725 730 735
Ala Val Gly Leu Gly Leu Val Leu Ala Tyr Arg Leu Ser Val Glu Ile
740 745 750
Tyr Asp Arg Arg Glu Tyr Ser Arg Phe Glu Lys Glu Gln Gln Gln Leu
755 760 765
Asn Trp Lys Gln Asp Ser Asn Pro Leu Tyr Lys Ser Ala Ile Thr Thr
770 775 780
Thr Ile Asn Pro Arg Phe Gln Glu Ala Asp Ser Pro Thr Leu
785 790 795
<210> 29
<211> 285
<212> PRT
<213> 智人
<400> 29
Met Asp Asp Ser Thr Glu Arg Glu Gln Ser Arg Leu Thr Ser Cys Leu
1 5 10 15
Lys Lys Arg Glu Glu Met Lys Leu Lys Glu Cys Val Ser Ile Leu Pro
20 25 30
Arg Lys Glu Ser Pro Ser Val Arg Ser Ser Lys Asp Gly Lys Leu Leu
35 40 45
Ala Ala Thr Leu Leu Leu Ala Leu Leu Ser Cys Cys Leu Thr Val Val
50 55 60
Ser Phe Tyr Gln Val Ala Ala Leu Gln Gly Asp Leu Ala Ser Leu Arg
65 70 75 80
Ala Glu Leu Gln Gly His His Ala Glu Lys Leu Pro Ala Gly Ala Gly
85 90 95
Ala Pro Lys Ala Gly Leu Glu Glu Ala Pro Ala Val Thr Ala Gly Leu
100 105 110
Lys Ile Phe Glu Pro Pro Ala Pro Gly Glu Gly Asn Ser Ser Gln Asn
115 120 125
Ser Arg Asn Lys Arg Ala Val Gln Gly Pro Glu Glu Thr Val Thr Gln
130 135 140
Asp Cys Leu Gln Leu Ile Ala Asp Ser Glu Thr Pro Thr Ile Gln Lys
145 150 155 160
Gly Ser Tyr Thr Phe Val Pro Trp Leu Leu Ser Phe Lys Arg Gly Ser
165 170 175
Ala Leu Glu Glu Lys Glu Asn Lys Ile Leu Val Lys Glu Thr Gly Tyr
180 185 190
Phe Phe Ile Tyr Gly Gln Val Leu Tyr Thr Asp Lys Thr Tyr Ala Met
195 200 205
Gly His Leu Ile Gln Arg Lys Lys Val His Val Phe Gly Asp Glu Leu
210 215 220
Ser Leu Val Thr Leu Phe Arg Cys Ile Gln Asn Met Pro Glu Thr Leu
225 230 235 240
Pro Asn Asn Ser Cys Tyr Ser Ala Gly Ile Ala Lys Leu Glu Glu Gly
245 250 255
Asp Glu Leu Gln Leu Ala Ile Pro Arg Glu Asn Ala Gln Ile Ser Leu
260 265 270
Asp Gly Asp Val Thr Phe Phe Gly Ala Leu Lys Leu Leu
275 280 285
<210> 30
<211> 269
<212> PRT
<213> 智人
<400> 30
Met Ala Glu Val Pro Glu Leu Ala Ser Glu Met Met Ala Tyr Tyr Ser
1 5 10 15
Gly Asn Glu Asp Asp Leu Phe Phe Glu Ala Asp Gly Pro Lys Gln Met
20 25 30
Lys Cys Ser Phe Gln Asp Leu Asp Leu Cys Pro Leu Asp Gly Gly Ile
35 40 45
Gln Leu Arg Ile Ser Asp His His Tyr Ser Lys Gly Phe Arg Gln Ala
50 55 60
Ala Ser Val Val Val Ala Met Asp Lys Leu Arg Lys Met Leu Val Pro
65 70 75 80
Cys Pro Gln Thr Phe Gln Glu Asn Asp Leu Ser Thr Phe Phe Pro Phe
85 90 95
Ile Phe Glu Glu Glu Pro Ile Phe Phe Asp Thr Trp Asp Asn Glu Ala
100 105 110
Tyr Val His Asp Ala Pro Val Arg Ser Leu Asn Cys Thr Leu Arg Asp
115 120 125
Ser Gln Gln Lys Ser Leu Val Met Ser Gly Pro Tyr Glu Leu Lys Ala
130 135 140
Leu His Leu Gln Gly Gln Asp Met Glu Gln Gln Val Val Phe Ser Met
145 150 155 160
Ser Phe Val Gln Gly Glu Glu Ser Asn Asp Lys Ile Pro Val Ala Leu
165 170 175
Gly Leu Lys Glu Lys Asn Leu Tyr Leu Ser Cys Val Leu Lys Asp Asp
180 185 190
Lys Pro Thr Leu Gln Leu Glu Ser Val Asp Pro Lys Asn Tyr Pro Lys
195 200 205
Lys Lys Met Glu Lys Arg Phe Val Phe Asn Lys Ile Glu Ile Asn Asn
210 215 220
Lys Leu Glu Phe Glu Ser Ala Gln Phe Pro Asn Trp Tyr Ile Ser Thr
225 230 235 240
Ser Gln Ala Glu Asn Met Pro Val Phe Leu Gly Gly Thr Lys Gly Gly
245 250 255
Gln Asp Ile Thr Asp Phe Thr Met Gln Phe Val Ser Ser
260 265
<210> 31
<211> 317
<212> PRT
<213> 智人
<400> 31
Met Arg Arg Ala Ser Arg Asp Tyr Thr Lys Tyr Leu Arg Gly Ser Glu
1 5 10 15
Glu Met Gly Gly Gly Pro Gly Ala Pro His Glu Gly Pro Leu His Ala
20 25 30
Pro Pro Pro Pro Ala Pro His Gln Pro Pro Ala Ala Ser Arg Ser Met
35 40 45
Phe Val Ala Leu Leu Gly Leu Gly Leu Gly Gln Val Val Cys Ser Val
50 55 60
Ala Leu Phe Phe Tyr Phe Arg Ala Gln Met Asp Pro Asn Arg Ile Ser
65 70 75 80
Glu Asp Gly Thr His Cys Ile Tyr Arg Ile Leu Arg Leu His Glu Asn
85 90 95
Ala Asp Phe Gln Asp Thr Thr Leu Glu Ser Gln Asp Thr Lys Leu Ile
100 105 110
Pro Asp Ser Cys Arg Arg Ile Lys Gln Ala Phe Gln Gly Ala Val Gln
115 120 125
Lys Glu Leu Gln His Ile Val Gly Ser Gln His Ile Arg Ala Glu Lys
130 135 140
Ala Met Val Asp Gly Ser Trp Leu Asp Leu Ala Lys Arg Ser Lys Leu
145 150 155 160
Glu Ala Gln Pro Phe Ala His Leu Thr Ile Asn Ala Thr Asp Ile Pro
165 170 175
Ser Gly Ser His Lys Val Ser Leu Ser Ser Trp Tyr His Asp Arg Gly
180 185 190
Trp Ala Lys Ile Ser Asn Met Thr Phe Ser Asn Gly Lys Leu Ile Val
195 200 205
Asn Gln Asp Gly Phe Tyr Tyr Leu Tyr Ala Asn Ile Cys Phe Arg His
210 215 220
His Glu Thr Ser Gly Asp Leu Ala Thr Glu Tyr Leu Gln Leu Met Val
225 230 235 240
Tyr Val Thr Lys Thr Ser Ile Lys Ile Pro Ser Ser His Thr Leu Met
245 250 255
Lys Gly Gly Ser Thr Lys Tyr Trp Ser Gly Asn Ser Glu Phe His Phe
260 265 270
Tyr Ser Ile Asn Val Gly Gly Phe Phe Lys Leu Arg Ser Gly Glu Glu
275 280 285
Ile Ser Ile Glu Val Ser Asn Pro Ser Leu Leu Asp Pro Asp Gln Asp
290 295 300
Ala Thr Tyr Phe Gly Ala Phe Lys Val Arg Asp Ile Asp
305 310 315
<210> 32
<211> 223
<212> PRT
<213> 智人
<400> 32
Met Ala Cys Leu Gly Phe Gln Arg His Lys Ala Gln Leu Asn Leu Ala
1 5 10 15
Thr Arg Thr Trp Pro Cys Thr Leu Leu Phe Phe Leu Leu Phe Ile Pro
20 25 30
Val Phe Cys Lys Ala Met His Val Ala Gln Pro Ala Val Val Leu Ala
35 40 45
Ser Ser Arg Gly Ile Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly
50 55 60
Lys Ala Thr Glu Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln
65 70 75 80
Val Thr Glu Val Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr
85 90 95
Phe Leu Asp Asp Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val
100 105 110
Asn Leu Thr Ile Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile
115 120 125
Cys Lys Val Glu Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly
130 135 140
Asn Gly Thr Gln Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser
145 150 155 160
Asp Phe Leu Leu Trp Ile Leu Ala Ala Val Ser Ser Gly Leu Phe Phe
165 170 175
Tyr Ser Phe Leu Leu Thr Ala Val Ser Leu Ser Lys Met Leu Lys Lys
180 185 190
Arg Ser Pro Leu Thr Thr Gly Val Tyr Val Lys Met Pro Pro Thr Glu
195 200 205
Pro Glu Cys Glu Lys Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn
210 215 220
<210> 33
<211> 189
<212> PRT
<213> 智人
<400> 33
Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr
1 5 10 15
Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln
20 25 30
Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His
35 40 45
Pro Leu Val Gly His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr
50 55 60
Thr Asn Asp Val Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln
65 70 75 80
Gly Leu Arg Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly
85 90 95
Leu Ile Phe Tyr Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu
100 105 110
Pro Ser Leu Leu Pro Asp Ser Pro Val Gly Gln Leu His Ala Ser Leu
115 120 125
Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr
130 135 140
Gln Gln Ile Pro Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu
145 150 155 160
Leu Arg Phe Lys Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala
165 170 175
Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Ser Pro
180 185
<210> 34
<211> 288
<212> PRT
<213> 智人
<400> 34
Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln
1 5 10 15
Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp
20 25 30
Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp
35 40 45
Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val
50 55 60
Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala
65 70 75 80
Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg
85 90 95
Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg
100 105 110
Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu
115 120 125
Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val
130 135 140
Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro
145 150 155 160
Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly
165 170 175
Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys
180 185 190
Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln Pro
195 200 205
Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly
210 215 220
Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro
225 230 235 240
Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly
245 250 255
Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg
260 265 270
Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu
275 280 285
<210> 35
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> mAb特异性表位
<400> 35
Cys Pro Tyr Ser Asn Pro Ser Leu Cys
1 5
<210> 36
<211> 24
<212> PRT
<213> 智人
<400> 36
Asn Ser Glu Leu Leu Ser Leu Ile Asn Asp Met Pro Ile Thr Asn Asp
1 5 10 15
Gln Lys Lys Leu Met Ser Asn Asn
20
<210> 37
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> mAb特异性表位
<400> 37
Cys Gln Phe Asp Leu Ser Thr Arg Arg Leu Lys Cys
1 5 10
<210> 38
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> mAb特异性表位
<400> 38
Cys Gln Tyr Asn Leu Ser Ser Arg Ala Leu Lys Cys
1 5 10
<210> 39
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> mAb特异性表位
<400> 39
Cys Val Trp Gln Arg Trp Gln Lys Ser Tyr Val Cys
1 5 10
<210> 40
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> mAb特异性表位
<400> 40
Cys Met Trp Asp Arg Phe Ser Arg Trp Tyr Lys Cys
1 5 10
<210> 41
<211> 25
<212> PRT
<213> 智人
<400> 41
Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp
1 5 10 15
Lys Leu Ala Ala Phe Pro Glu Asp Arg
20 25
<210> 42
<211> 19
<212> PRT
<213> 智人
<400> 42
Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln
1 5 10 15
Ile Lys Glu
<210> 43
<211> 557
<212> PRT
<213> 鼠科动物
<400> 43
Met Pro Pro Pro Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Pro Met
1 5 10 15
Glu Val Arg Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp
20 25 30
Asn Ala Val Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln
35 40 45
Gln Leu Thr Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu
50 55 60
Ser Leu Gly Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ile
65 70 75 80
Trp Leu Phe Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu
85 90 95
Cys Gln Pro Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr
100 105 110
Val Asn Val Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp
115 120 125
Leu Gly Gly Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro
130 135 140
Ser Ser Pro Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala
145 150 155 160
Lys Asp Arg Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Leu Pro Pro
165 170 175
Arg Asp Ser Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro
180 185 190
Gly Ser Thr Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser
195 200 205
Arg Gly Pro Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser
210 215 220
Leu Leu Ser Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp
225 230 235 240
Val Met Glu Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala
245 250 255
Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu
260 265 270
Glu Ile Thr Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly
275 280 285
Gly Trp Lys Val Ser Ala Val Thr Leu Ala Tyr Leu Ile Phe Cys Leu
290 295 300
Cys Ser Leu Val Gly Ile Leu His Leu Gln Arg Ala Leu Val Leu Arg
305 310 315 320
Arg Lys Arg Lys Arg Met Thr Asp Pro Thr Arg Arg Phe Phe Lys Val
325 330 335
Thr Pro Pro Pro Gly Ser Gly Pro Gln Asn Gln Tyr Gly Asn Val Leu
340 345 350
Ser Leu Pro Thr Pro Thr Ser Gly Leu Gly Arg Ala Gln Arg Trp Ala
355 360 365
Ala Gly Leu Gly Gly Thr Ala Pro Ser Tyr Gly Asn Pro Ser Ser Asp
370 375 380
Val Gln Ala Asp Gly Ala Leu Gly Ser Arg Ser Pro Pro Gly Val Gly
385 390 395 400
Pro Glu Glu Glu Glu Gly Glu Gly Tyr Glu Glu Pro Asp Ser Glu Glu
405 410 415
Asp Ser Glu Phe Tyr Glu Asn Asp Ser Asn Leu Gly Gln Asp Gln Leu
420 425 430
Ser Gln Asp Gly Ser Gly Tyr Glu Asn Pro Glu Asp Glu Pro Leu Gly
435 440 445
Pro Glu Asp Glu Asp Ser Phe Ser Asn Ala Glu Ser Tyr Glu Asn Glu
450 455 460
Asp Glu Glu Leu Thr Gln Pro Val Ala Arg Thr Met Asp Phe Leu Ser
465 470 475 480
Pro His Gly Ser Ala Trp Asp Pro Ser Arg Glu Ala Thr Ser Leu Ala
485 490 495
Gly Ser Gln Ser Tyr Glu Asp Met Arg Gly Ile Leu Tyr Ala Ala Pro
500 505 510
Gln Leu Arg Ser Ile Arg Gly Gln Pro Gly Pro Asn His Glu Glu Asp
515 520 525
Ala Asp Ser Tyr Glu Asn Met Asp Asn Pro Asp Gly Pro Asp Pro Ala
530 535 540
Trp Gly Gly Gly Gly Arg Met Gly Thr Trp Ser Thr Arg
545 550 555
<210> 44
<211> 300
<212> PRT
<213> 鼠科动物
<400> 44
Met Ala Asn Cys Glu Phe Ser Pro Val Ser Gly Asp Lys Pro Cys Cys
1 5 10 15
Arg Leu Ser Arg Arg Ala Gln Leu Cys Leu Gly Val Ser Ile Leu Val
20 25 30
Leu Ile Leu Val Val Val Leu Ala Val Val Val Pro Arg Trp Arg Gln
35 40 45
Gln Trp Ser Gly Pro Gly Thr Thr Lys Arg Phe Pro Glu Thr Val Leu
50 55 60
Ala Arg Cys Val Lys Tyr Thr Glu Ile His Pro Glu Met Arg His Val
65 70 75 80
Asp Cys Gln Ser Val Trp Asp Ala Phe Lys Gly Ala Phe Ile Ser Lys
85 90 95
His Pro Cys Asn Ile Thr Glu Glu Asp Tyr Gln Pro Leu Met Lys Leu
100 105 110
Gly Thr Gln Thr Val Pro Cys Asn Lys Ile Leu Leu Trp Ser Arg Ile
115 120 125
Lys Asp Leu Ala His Gln Phe Thr Gln Val Gln Arg Asp Met Phe Thr
130 135 140
Leu Glu Asp Thr Leu Leu Gly Tyr Leu Ala Asp Asp Leu Thr Trp Cys
145 150 155 160
Gly Glu Phe Asn Thr Ser Lys Ile Asn Tyr Gln Ser Cys Pro Asp Trp
165 170 175
Arg Lys Asp Cys Ser Asn Asn Pro Val Ser Val Phe Trp Lys Thr Val
180 185 190
Ser Arg Arg Phe Ala Glu Ala Ala Cys Asp Val Val His Val Met Leu
195 200 205
Asn Gly Ser Arg Ser Lys Ile Phe Asp Lys Asn Ser Thr Phe Gly Ser
210 215 220
Val Glu Val His Asn Leu Gln Pro Glu Lys Val Gln Thr Leu Glu Ala
225 230 235 240
Trp Val Ile His Gly Gly Arg Glu Asp Ser Arg Asp Leu Cys Gln Asp
245 250 255
Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile Ser Lys Arg Asn Ile Gln
260 265 270
Phe Ser Cys Lys Asn Ile Tyr Arg Pro Asp Lys Phe Leu Gln Cys Val
275 280 285
Lys Asn Pro Glu Asp Ser Ser Cys Thr Ser Glu Ile
290 295 300
<210> 45
<211> 378
<212> PRT
<213> 鼠科动物
<400> 45
Met Val Leu Leu Trp Leu Thr Leu Leu Leu Ile Ala Leu Pro Cys Leu
1 5 10 15
Leu Gln Thr Lys Glu Asp Pro Asn Pro Pro Ile Thr Asn Leu Arg Met
20 25 30
Lys Ala Lys Ala Gln Gln Leu Thr Trp Asp Leu Asn Arg Asn Val Thr
35 40 45
Asp Ile Glu Cys Val Lys Asp Ala Asp Tyr Ser Met Pro Ala Val Asn
50 55 60
Asn Ser Tyr Cys Gln Phe Gly Ala Ile Ser Leu Cys Glu Val Thr Asn
65 70 75 80
Tyr Thr Val Arg Val Ala Asn Pro Pro Phe Ser Thr Trp Ile Leu Phe
85 90 95
Pro Glu Asn Ser Gly Lys Pro Trp Ala Gly Ala Glu Asn Leu Thr Cys
100 105 110
Trp Ile His Asp Val Asp Phe Leu Ser Cys Ser Trp Ala Val Gly Pro
115 120 125
Gly Ala Pro Ala Asp Val Gln Tyr Asp Leu Tyr Leu Asn Val Ala Asn
130 135 140
Arg Arg Gln Gln Tyr Glu Cys Leu His Tyr Lys Thr Asp Ala Gln Gly
145 150 155 160
Thr Arg Ile Gly Cys Arg Phe Asp Asp Ile Ser Arg Leu Ser Ser Gly
165 170 175
Ser Gln Ser Ser His Ile Leu Val Arg Gly Arg Ser Ala Ala Phe Gly
180 185 190
Ile Pro Cys Thr Asp Lys Phe Val Val Phe Ser Gln Ile Glu Ile Leu
195 200 205
Thr Pro Pro Asn Met Thr Ala Lys Cys Asn Lys Thr His Ser Phe Met
210 215 220
His Trp Lys Met Arg Ser His Phe Asn Arg Lys Phe Arg Tyr Glu Leu
225 230 235 240
Gln Ile Gln Lys Arg Met Gln Pro Val Ile Thr Glu Gln Val Arg Asp
245 250 255
Arg Thr Ser Phe Gln Leu Leu Asn Pro Gly Thr Tyr Thr Val Gln Ile
260 265 270
Arg Ala Arg Glu Arg Val Tyr Glu Phe Leu Ser Ala Trp Ser Thr Pro
275 280 285
Gln Arg Phe Glu Cys Asp Gln Glu Glu Gly Ala Asn Thr Arg Ala Trp
290 295 300
Arg Thr Ser Leu Leu Ile Ala Leu Gly Thr Leu Leu Ala Leu Val Cys
305 310 315 320
Val Phe Val Ile Cys Arg Arg Tyr Leu Val Met Gln Arg Leu Phe Pro
325 330 335
Arg Ile Pro His Met Lys Asp Pro Ile Gly Asp Ser Phe Gln Asn Asp
340 345 350
Lys Leu Val Val Trp Glu Ala Gly Lys Ala Gly Leu Glu Glu Cys Leu
355 360 365
Val Thr Glu Val Gln Val Val Gln Lys Thr
370 375
<210> 46
<211> 335
<212> PRT
<213> 鼠科动物
<400> 46
Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp Gln
1 5 10 15
Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val Gly Ser
20 25 30
Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val Lys Gln Val
35 40 45
Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu Val Thr Ile Gln
50 55 60
Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg
65 70 75 80
Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys
85 90 95
Lys Asn Asp Ser Gly Ile Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu
100 105 110
Gln Gln Pro Ser Thr Gln Glu Tyr Val Leu His Val Tyr Glu His Leu
115 120 125
Ser Lys Pro Lys Val Thr Met Gly Leu Gln Ser Asn Lys Asn Gly Thr
130 135 140
Cys Val Thr Asn Leu Thr Cys Cys Met Glu His Gly Glu Glu Asp Val
145 150 155 160
Ile Tyr Thr Trp Lys Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn
165 170 175
Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr
180 185 190
Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro
195 200 205
Ile Leu Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser
210 215 220
Ser Met Val Leu Leu Cys Leu Leu Leu Val Pro Leu Leu Leu Ser Leu
225 230 235 240
Phe Val Leu Gly Leu Phe Leu Trp Phe Leu Lys Arg Glu Arg Gln Glu
245 250 255
Glu Tyr Ile Glu Glu Lys Lys Arg Val Asp Ile Cys Arg Glu Thr Pro
260 265 270
Asn Ile Cys Pro His Ser Gly Glu Asn Thr Glu Tyr Asp Thr Ile Pro
275 280 285
His Thr Asn Arg Thr Ile Leu Lys Glu Asp Pro Ala Asn Thr Val Tyr
290 295 300
Ser Thr Val Glu Ile Pro Lys Lys Met Glu Asn Pro His Ser Leu Leu
305 310 315 320
Thr Met Pro Asp Thr Pro Arg Leu Phe Ala Tyr Glu Asn Val Ile
325 330 335
<210> 47
<211> 184
<212> PRT
<213> 鼠科动物
<400> 47
Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser
1 5 10 15
Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr
20 25 30
Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser
35 40 45
Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu
50 55 60
Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile
65 70 75 80
Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu
85 90 95
Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu
100 105 110
Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys
115 120 125
Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe
130 135 140
Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys
145 150 155 160
Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu
165 170 175
Ile Glu Lys Ser Ile Ser Ala Arg
180
<210> 48
<211> 993
<212> PRT
<213> 鼠科动物
<400> 48
Met Pro Ala Leu Ala Arg Asp Gly Gly Gln Leu Pro Leu Leu Val Val
1 5 10 15
Phe Ser Ala Met Ile Phe Gly Thr Ile Thr Asn Gln Asp Leu Pro Val
20 25 30
Ile Lys Cys Val Leu Ile Asn His Lys Asn Asn Asp Ser Ser Val Gly
35 40 45
Lys Ser Ser Ser Tyr Pro Met Val Ser Glu Ser Pro Glu Asp Leu Gly
50 55 60
Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr Val Tyr Glu Ala Ala Ala
65 70 75 80
Val Glu Val Asp Val Ser Ala Ser Ile Thr Leu Gln Val Leu Val Asp
85 90 95
Ala Pro Gly Asn Ile Ser Cys Leu Trp Val Phe Lys His Ser Ser Leu
100 105 110
Asn Cys Gln Pro His Phe Asp Leu Gln Asn Arg Gly Val Val Ser Met
115 120 125
Val Ile Leu Lys Met Thr Glu Thr Gln Ala Gly Glu Tyr Leu Leu Phe
130 135 140
Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile Leu Phe Thr Val Ser Ile
145 150 155 160
Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg Pro Tyr Phe Arg Lys Met
165 170 175
Glu Asn Gln Asp Ala Leu Val Cys Ile Ser Glu Ser Val Pro Glu Pro
180 185 190
Ile Val Glu Trp Val Leu Cys Asp Ser Gln Gly Glu Ser Cys Lys Glu
195 200 205
Glu Ser Pro Ala Val Val Lys Lys Glu Glu Lys Val Leu His Glu Leu
210 215 220
Phe Gly Thr Asp Ile Arg Cys Cys Ala Arg Asn Glu Leu Gly Arg Glu
225 230 235 240
Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn Gln Thr Pro Gln Thr Thr
245 250 255
Leu Pro Gln Leu Phe Leu Lys Val Gly Glu Pro Leu Trp Ile Arg Cys
260 265 270
Lys Ala Val His Val Asn His Gly Phe Gly Leu Thr Trp Glu Leu Glu
275 280 285
Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe Glu Met Ser Thr Tyr Ser
290 295 300
Thr Asn Arg Thr Met Ile Arg Ile Leu Phe Ala Phe Val Ser Ser Val
305 310 315 320
Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys Ser Ser Ser Lys His Pro
325 330 335
Ser Gln Ser Ala Leu Val Thr Ile Val Glu Lys Gly Phe Ile Asn Ala
340 345 350
Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp Gln Tyr Glu Glu Phe Cys
355 360 365
Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln Ile Arg Cys Thr Trp Thr
370 375 380
Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln Lys Gly Leu Asp Asn Gly
385 390 395 400
Tyr Ser Ile Ser Lys Phe Cys Asn His Lys His Gln Pro Gly Glu Tyr
405 410 415
Ile Phe His Ala Glu Asn Asp Asp Ala Gln Phe Thr Lys Met Phe Thr
420 425 430
Leu Asn Ile Arg Arg Lys Pro Gln Val Leu Ala Glu Ala Ser Ala Ser
435 440 445
Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro Leu Pro Ser Trp Thr Trp
450 455 460
Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys Thr Glu Glu Ile Thr Glu
465 470 475 480
Gly Val Trp Asn Arg Lys Ala Asn Arg Lys Val Phe Gly Gln Trp Val
485 490 495
Ser Ser Ser Thr Leu Asn Met Ser Glu Ala Ile Lys Gly Phe Leu Val
500 505 510
Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr Ser Cys Glu Thr Ile Leu
515 520 525
Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile Gln Asp Asn Ile Ser Phe
530 535 540
Tyr Ala Thr Ile Gly Val Cys Leu Leu Phe Ile Val Val Leu Thr Leu
545 550 555 560
Leu Ile Cys His Lys Tyr Lys Lys Gln Phe Arg Tyr Glu Ser Gln Leu
565 570 575
Gln Met Val Gln Val Thr Gly Ser Ser Asp Asn Glu Tyr Phe Tyr Val
580 585 590
Asp Phe Arg Glu Tyr Glu Tyr Asp Leu Lys Trp Glu Phe Pro Arg Glu
595 600 605
Asn Leu Glu Phe Gly Lys Val Leu Gly Ser Gly Ala Phe Gly Lys Val
610 615 620
Met Asn Ala Thr Ala Tyr Gly Ile Ser Lys Thr Gly Val Ser Ile Gln
625 630 635 640
Val Ala Val Lys Met Leu Lys Glu Lys Ala Asp Ser Ser Glu Arg Glu
645 650 655
Ala Leu Met Ser Glu Leu Lys Met Met Thr Gln Leu Gly Ser His Glu
660 665 670
Asn Ile Val Asn Leu Leu Gly Ala Cys Thr Leu Ser Gly Pro Ile Tyr
675 680 685
Leu Ile Phe Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Tyr Leu Arg
690 695 700
Ser Lys Arg Glu Lys Phe His Arg Thr Trp Thr Glu Ile Phe Lys Glu
705 710 715 720
His Asn Phe Ser Phe Tyr Pro Thr Phe Gln Ser His Pro Asn Ser Ser
725 730 735
Met Pro Gly Ser Arg Glu Val Gln Ile His Pro Asp Ser Asp Gln Ile
740 745 750
Ser Gly Leu His Gly Asn Ser Phe His Ser Glu Asp Glu Ile Glu Tyr
755 760 765
Glu Asn Gln Lys Arg Leu Glu Glu Glu Glu Asp Leu Asn Val Leu Thr
770 775 780
Phe Glu Asp Leu Leu Cys Phe Ala Tyr Gln Val Ala Lys Gly Met Glu
785 790 795 800
Phe Leu Glu Phe Lys Ser Cys Val His Arg Asp Leu Ala Ala Arg Asn
805 810 815
Val Leu Val Thr His Gly Lys Val Val Lys Ile Cys Asp Phe Gly Leu
820 825 830
Ala Arg Asp Ile Met Ser Asp Ser Asn Tyr Val Val Arg Gly Asn Ala
835 840 845
Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Leu Phe Glu Gly Ile
850 855 860
Tyr Thr Ile Lys Ser Asp Val Trp Ser Tyr Gly Ile Leu Leu Trp Glu
865 870 875 880
Ile Phe Ser Leu Gly Val Asn Pro Tyr Pro Gly Ile Pro Val Asp Ala
885 890 895
Asn Phe Tyr Lys Leu Ile Gln Asn Gly Phe Lys Met Asp Gln Pro Phe
900 905 910
Tyr Ala Thr Glu Glu Ile Tyr Ile Ile Met Gln Ser Cys Trp Ala Phe
915 920 925
Asp Ser Arg Lys Arg Pro Ser Phe Pro Asn Leu Thr Ser Phe Leu Gly
930 935 940
Cys Gln Leu Ala Asp Ala Glu Glu Ala Met Tyr Gln Asn Val Asp Gly
945 950 955 960
Arg Val Ser Glu Cys Pro His Thr Tyr Gln Asn Arg Arg Pro Phe Ser
965 970 975
Arg Glu Met Asp Leu Gly Leu Leu Ser Pro Gln Ala Gln Val Glu Asp
980 985 990
Ser
<210> 49
<211> 364
<212> PRT
<213> 鼠科动物
<400> 49
Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala
1 5 10 15
Met Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln
20 25 30
Glu Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro
35 40 45
Tyr Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly
50 55 60
Ala Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln
65 70 75 80
Glu Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro
85 90 95
Ser Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp
100 105 110
Asn Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser
115 120 125
Tyr Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg
130 135 140
Pro Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn
145 150 155 160
Leu Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile
165 170 175
Phe Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr
180 185 190
His Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr
195 200 205
Asn Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu
210 215 220
Arg Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr
225 230 235 240
Gly Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly
245 250 255
Val Val His Gly Ala Ile Gly Gly Ala Gly Val Thr Ala Leu Leu Ala
260 265 270
Leu Cys Leu Cys Leu Ile Phe Phe Ile Val Lys Thr His Arg Arg Lys
275 280 285
Ala Ala Arg Thr Ala Val Gly Arg Asn Asp Thr His Pro Thr Thr Gly
290 295 300
Ser Ala Ser Pro Lys His Gln Lys Lys Ser Lys Leu His Gly Pro Thr
305 310 315 320
Glu Thr Ser Ser Cys Ser Gly Ala Ala Pro Thr Val Glu Met Asp Glu
325 330 335
Glu Leu His Tyr Ala Ser Leu Asn Phe His Gly Met Asn Pro Ser Lys
340 345 350
Asp Thr Ser Thr Glu Tyr Ser Glu Val Arg Thr Gln
355 360
<210> 50
<211> 193
<212> PRT
<213> 鼠科动物
<400> 50
Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly
1 5 10 15
Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile
20 25 30
Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu
35 40 45
Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His
50 55 60
Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala
65 70 75 80
Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu
85 90 95
Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu
100 105 110
Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu
115 120 125
Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg
130 135 140
Leu Ser Phe His Gln Gly Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro
145 150 155 160
Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu
165 170 175
Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg
180 185 190
Pro
<210> 51
<211> 943
<212> PRT
<213> 鼠科动物
<400> 51
Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala
1 5 10 15
Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Gly Asn Tyr
20 25 30
Val Val Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser
35 40 45
Tyr Glu Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly
50 55 60
Pro Cys Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp
65 70 75 80
Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr
85 90 95
Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp
100 105 110
Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu
115 120 125
Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro
130 135 140
Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg
145 150 155 160
Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu
165 170 175
Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly
180 185 190
Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile
195 200 205
Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile
210 215 220
Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His
225 230 235 240
Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys
245 250 255
Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys
260 265 270
Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys
275 280 285
Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys
290 295 300
Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp
305 310 315 320
Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn
325 330 335
Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu
340 345 350
Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly
355 360 365
Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val
370 375 380
Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe
385 390 395 400
Met Arg Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu
405 410 415
Gln Glu Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro
420 425 430
Asn Gln Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile
435 440 445
Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp
450 455 460
Ile Pro Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu
465 470 475 480
Arg Glu Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala
485 490 495
Tyr Val Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly
500 505 510
Ile Cys Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe
515 520 525
Gly Cys Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser
530 535 540
Gln Tyr Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr
545 550 555 560
Leu Glu Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val
565 570 575
Leu Val Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala
580 585 590
Lys Leu Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys
595 600 605
Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr
610 615 620
Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu
625 630 635 640
Met Thr Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile
645 650 655
Ser Ser Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys
660 665 670
Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala
675 680 685
Asp Ser Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met
690 695 700
Ala Arg Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met
705 710 715 720
His Leu Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp
725 730 735
Glu Glu Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro
740 745 750
Gln Gln Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu
755 760 765
Ser Ser Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp
770 775 780
Arg Asn Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln
785 790 795 800
Arg Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp
805 810 815
Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro Lys
820 825 830
Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln Pro Leu
835 840 845
Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro His Ser Thr
850 855 860
Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln Pro Thr Cys Val
865 870 875 880
Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala Gln Lys Gly Ser His
885 890 895
Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln Gln Asp Phe Phe Pro Lys
900 905 910
Glu Ala Lys Pro Asn Gly Ile Phe Lys Gly Ser Thr Ala Glu Asn Ala
915 920 925
Glu Tyr Leu Arg Val Ala Pro Gln Ser Ser Glu Phe Ile Gly Ala
930 935 940
<210> 52
<211> 497
<212> PRT
<213> 鼠科动物
<400> 52
Met Gln Asp Pro Ala Ser Thr Cys Val Pro Glu Pro Ala Ser Gln His
1 5 10 15
Thr Leu Arg Ser Gly Pro Gly Cys Leu Gln Gln Pro Glu Gln Gln Gly
20 25 30
Val Arg Asp Pro Gly Gly Ile Trp Ala Lys Leu Gly Ala Ala Glu Ala
35 40 45
Ser Ala Glu Arg Leu Gln Gly Arg Arg Ser Arg Gly Ala Ser Gly Ser
50 55 60
Glu Pro Gln Gln Met Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu
65 70 75 80
Pro Ala Val Pro Ser Leu Gly Gly Gly Gly Gly Cys Ala Leu Pro Val
85 90 95
Ser Gly Ala Ala Gln Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Gly
100 105 110
Ala Ser Ala Tyr Gly Ser Leu Gly Gly Pro Ala Pro Pro Pro Ala Pro
115 120 125
Pro Pro Pro Pro Pro Pro Pro Pro His Ser Phe Ile Lys Gln Glu Pro
130 135 140
Ser Trp Gly Gly Ala Glu Pro His Glu Glu Gln Cys Leu Ser Ala Phe
145 150 155 160
Thr Val His Phe Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg
165 170 175
Tyr Gly Pro Phe Gly Pro Pro Pro Pro Ser Gln Ala Ser Ser Gly Gln
180 185 190
Ala Arg Met Phe Pro Asn Ala Pro Tyr Leu Pro Ser Cys Leu Glu Ser
195 200 205
Gln Pro Ala Ile Arg Asn Gln Gly Tyr Ser Thr Val Thr Phe Asp Gly
210 215 220
Thr Pro Ser Tyr Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro
225 230 235 240
Asn His Ser Phe Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu
245 250 255
Gly Glu Gln Gln Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr
260 265 270
Pro Thr Asp Ser Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro
275 280 285
Tyr Ser Ser Asp Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met
290 295 300
Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu Lys Gly His Ser Thr
305 310 315 320
Gly Tyr Glu Ser Asp Asn His Thr Thr Pro Ile Leu Cys Gly Ala Gln
325 330 335
Tyr Arg Ile His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg
340 345 350
Arg Val Pro Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr
355 360 365
Ser Glu Lys Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg
370 375 380
Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His Thr Gly
385 390 395 400
Glu Lys Pro Tyr Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser
405 410 415
Arg Ser Asp Gln Leu Lys Arg His Gln Arg Arg His Thr Gly Val Lys
420 425 430
Pro Phe Gln Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His
435 440 445
Leu Lys Thr His Thr Arg Thr His Thr Gly Glu Lys Pro Phe Ser Cys
450 455 460
Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu Val
465 470 475 480
Arg His His Asn Met His Gln Arg Asn Met Thr Lys Leu Gln Leu Ala
485 490 495
Leu
<210> 53
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> CD19-1 VH 链
<400> 53
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val
115
<210> 54
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> CD19-1 VL 链
<400> 54
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 55
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD19-2 VH 链
<400> 55
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Ile Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Tyr Tyr Gly Ser Arg Val Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val
115
<210> 56
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD19-2 VL 链
<400> 56
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Ile Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 57
<211> 115
<212> PRT
<213> 鼠科动物
<400> 57
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Tyr Asp Ser Glu Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asn Trp Asp Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 58
<211> 107
<212> PRT
<213> 鼠科动物
<400> 58
Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly
1 5 10 15
Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Asp
20 25 30
Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser 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 Met Tyr Tyr Cys Gln Gln His Asn Lys Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 59
<211> 118
<212> PRT
<213> 鼠科动物
<400> 59
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 60
<211> 111
<212> PRT
<213> 鼠科动物
<400> 60
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 61
<211> 113
<212> PRT
<213> 鼠科动物
<400> 61
Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His Lys Phe Met
1 5 10 15
Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln
20 25 30
Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr
85 90 95
Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 62
<211> 127
<212> PRT
<213> 鼠科动物
<400> 62
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120 125
<210> 63
<211> 119
<212> PRT
<213> 鼠科动物
<400> 63
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser
1 5 10 15
Leu Ser Leu Thr Cys Ser Val Thr Asp Tyr Ser Ile Thr Ser Gly Tyr
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser
85 90 95
Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser Ala Arg Ser
115
<210> 64
<211> 113
<212> PRT
<213> 鼠科动物
<400> 64
Asp Ile Met Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Phe Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Phe Phe Gly
20 25 30
Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala
65 70 75 80
Ile Ser Ser Val Met Pro Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 65
<211> 115
<212> PRT
<213> 鼠科动物
<400> 65
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Asn Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Val Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser
115
<210> 66
<211> 111
<212> PRT
<213> 鼠科动物
<400> 66
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 67
<211> 117
<212> PRT
<213> 鼠科动物
<400> 67
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Phe Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asp Ile Asn Trp Val Asn Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Leu Gln Leu Asn Asn Leu Thr Ser Glu Asn Ser Ala Val Tyr Phe Cys
85 90 95
Ala Ser Gly Tyr Glu Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 68
<211> 108
<212> PRT
<213> 鼠科动物
<400> 68
Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ile Ile Asn Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
20 25 30
Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile
35 40 45
Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr
65 70 75 80
Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
100 105
<210> 69
<211> 120
<212> PRT
<213> 鼠科动物
<400> 69
Glu Val Lys Leu Gln Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Lys Phe Thr Asp Tyr
20 25 30
Val Val His Trp Leu Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Arg Tyr Glu Val Tyr Gly Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 70
<211> 115
<212> PRT
<213> 鼠科动物
<400> 70
Asp Ile Val Leu Thr Gln Ser Pro Thr Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser Ser Val Asn Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Asp Ser Pro Leu Arg Trp Ile Phe
35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Thr Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Arg Ser Tyr Pro Leu Thr
85 90 95
Phe Gly Asp Gly Thr Arg Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser
115
<210> 71
<211> 118
<212> PRT
<213> 鼠科动物
<400> 71
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Ile His Trp Ile Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
Gly Val Ile Tyr Pro Gly Asn Asp Asp Ile Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Arg Leu Arg Tyr Phe Asp Val Trp Gly Ala Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 72
<211> 113
<212> PRT
<213> 鼠科动物
<400> 72
Asn Ile Met Leu Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Phe Phe Ser
20 25 30
Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ser Glu Asp Leu Ala Ile Tyr Tyr Cys His Gln
85 90 95
Tyr Leu Ser Ser Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 73
<211> 115
<212> PRT
<213> 鼠科动物
<400> 73
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Asn Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Val Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser
115
<210> 74
<211> 111
<212> PRT
<213> 鼠科动物
<400> 74
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 75
<211> 117
<212> PRT
<213> 鼠科动物
<400> 75
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Phe Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asp Ile Asn Trp Val Asn Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Leu Gln Leu Asn Asn Leu Thr Ser Glu Asn Ser Ala Val Tyr Phe Cys
85 90 95
Ala Ser Gly Tyr Glu Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 76
<211> 108
<212> PRT
<213> 鼠科动物
<400> 76
Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ile Ile Asn Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
20 25 30
Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile
35 40 45
Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr
65 70 75 80
Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
100 105
<210> 77
<211> 120
<212> PRT
<213> 鼠科动物
<400> 77
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asn Pro Asn Asn Gly Val Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Met Ile Thr Asn Tyr Val Met Asp Tyr Trp Gly Gln
100 105 110
Val Thr Ser Val Thr Val Ser Ser
115 120
<210> 78
<211> 108
<212> PRT
<213> 鼠科动物
<400> 78
Ser Ile Val Met Thr Gln Thr Pro Thr Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Thr Leu Leu Ile
35 40 45
Ser Tyr Thr Ser Ser Arg Tyr Ala Gly Val Pro Asp Arg Phe Ile Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Leu Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 79
<211> 119
<212> PRT
<213> 鼠科动物
<400> 79
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe
20 25 30
Gly Met Asn Trp Val Lys Gln Gly Pro Gly Glu Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Arg Tyr Ala Glu Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Thr Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Asp Trp Asp Gly Ala Tyr Phe Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 80
<211> 107
<212> PRT
<213> 鼠科动物
<400> 80
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Asn Phe Ala Thr Asn Arg Tyr Thr Gly Val Pro Asn Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 81
<211> 117
<212> PRT
<213> 鼠科动物
<400> 81
Gln Val Gln Leu Gln Gln Ser Arg Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Gly Ser Asn Ser Ile Tyr Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Met Gly Gly Asn Tyr Gly Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 82
<211> 108
<212> PRT
<213> 鼠科动物
<400> 82
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Leu Thr Cys Thr Ala Ser Ser Ser Val Asn Ser Asn
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Tyr His Arg Ser Pro
85 90 95
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 83
<211> 122
<212> PRT
<213> 鼠科动物
<400> 83
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met
65 70 75 80
Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg Gln Trp Asp Tyr Asp Val Arg Ala Met Asn Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 84
<211> 107
<212> PRT
<213> 鼠科动物
<400> 84
Asp Ile Val Met Thr Gln Ser His Ile Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asp Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg Leu Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 85
<211> 118
<212> PRT
<213> 鼠科动物
<400> 85
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Asp Tyr
20 25 30
Glu Met His Trp Val Ile Gln Thr Pro Val His Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Ile Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Gly Tyr Tyr Asp Tyr Asp Ser Phe Thr Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 86
<211> 107
<212> PRT
<213> 鼠科动物
<400> 86
Asp Ile Val Met Thr Gln Ser Gln Lys Ile Met Ser Thr Thr Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ala Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asp Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 87
<211> 119
<212> PRT
<213> 鼠科动物
<400> 87
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ile Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Arg Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Gly
85 90 95
Arg Tyr Asp Tyr Asp Gly Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 88
<211> 107
<212> PRT
<213> 鼠科动物
<400> 88
Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Pro Asp Ile Asn Ser Tyr
20 25 30
Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile
35 40 45
Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Gly Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Asn Ser Leu Glu Tyr
65 70 75 80
Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys
100 105
<210> 89
<211> 117
<212> PRT
<213> 鼠科动物
<400> 89
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Phe Thr Asn Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Leu Leu
65 70 75 80
Lys Met Thr Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Arg Gly Ser Ser Tyr Ser Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 90
<211> 106
<212> PRT
<213> 鼠科动物
<400> 90
Glu Ile Val Leu Ser Gln Ser Pro Ala Ile Thr Ala Ala Ser Leu Gly
1 5 10 15
Gln Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Asn Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Arg Ser Gly Thr Ser Pro Arg Pro Trp Ile Tyr
35 40 45
Glu Ile Ser Lys Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Ile Tyr Tyr Cys Gln Gln Trp Asn Tyr Pro Leu Ile Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Gln
100 105
<210> 91
<211> 116
<212> PRT
<213> 鼠科动物
<400> 91
Glu Val Gln Val 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 Asn 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 Gly Ser Ser Gly Trp Ser Glu Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 92
<211> 107
<212> PRT
<213> 鼠科动物
<400> 92
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile Val Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His His Ser Tyr Pro Leu
85 90 95
Thr Ser Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 93
<211> 118
<212> PRT
<213> 鼠科动物
<400> 93
Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Thr Ser Gly Phe Thr Phe Arg Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Ser Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Thr Gly Gly Tyr Asn Thr Tyr Tyr Ser Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Arg Gly Tyr Ser Ser Thr Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val
115
<210> 94
<211> 108
<212> PRT
<213> 鼠科动物
<400> 94
Asp Ile Glu Leu Thr Gln Ser Pro Ala Ser Leu Ser Val Ala Thr Gly
1 5 10 15
Glu Lys Val Thr Ile Arg Cys Met Thr Ser Thr Asp Ile Asp Asp Asp
20 25 30
Met Asn Trp Tyr Gln Gln Lys Pro Gly Glu Pro Pro Lys Phe Leu Ile
35 40 45
Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Ser
50 55 60
Ser Gly Thr Gly Thr Asp Phe Val Phe Thr Ile Glu Asn Thr Leu Ser
65 70 75 80
Glu Asp Val Gly Asp Tyr Tyr Cys Leu Gln Ser Phe Asn Val Pro Leu
85 90 95
Thr Phe Gly Asp Gly Thr Lys Leu Glu Lys Ala Leu
100 105
<210> 95
<211> 119
<212> PRT
<213> 鼠科动物
<400> 95
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 96
<211> 112
<212> PRT
<213> 鼠科动物
<400> 96
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Ser Gln Ser
85 90 95
Ser Ile Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 97
<211> 119
<212> PRT
<213> 鼠科动物
<400> 97
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 98
<211> 112
<212> PRT
<213> 鼠科动物
<400> 98
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Glu Thr
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 99
<211> 117
<212> PRT
<213> 鼠科动物
<400> 99
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe
50 55 60
Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 100
<211> 111
<212> PRT
<213> 鼠科动物
<400> 100
Asp Ile Val Leu Thr Gly Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 101
<211> 117
<212> PRT
<213> 鼠科动物
<400> 101
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr His Tyr
20 25 30
Ser Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Arg Ile Asn Thr Glu Thr Gly Glu Pro Leu Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Val Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Phe Phe Cys
85 90 95
Ser Asn Asp Tyr Leu Tyr Ser Cys Asp Tyr Trp Gly Arg Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 102
<211> 111
<212> PRT
<213> 鼠科动物
<400> 102
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 103
<211> 119
<212> PRT
<213> 鼠科动物
<400> 103
Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Thr Pro Ser Leu
50 55 60
Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Ala Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 104
<211> 107
<212> PRT
<213> 鼠科动物
<400> 104
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 105
<211> 120
<212> PRT
<213> 鼠科动物
<400> 105
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Met Ile Ala Thr Arg Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 106
<211> 107
<212> PRT
<213> 鼠科动物
<400> 106
Asp Ile Val Met Thr Gln Ser Gln Lys Ser Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ile Thr Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Asn Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 107
<211> 121
<212> PRT
<213> 鼠科动物
<400> 107
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asp Gly Asp Thr Arg Tyr Thr Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Lys Val Tyr Tyr Gly Ser Asn Pro Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 108
<211> 107
<212> PRT
<213> 鼠科动物
<400> 108
Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly
1 5 10 15
Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile
35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 109
<211> 120
<212> PRT
<213> 鼠科动物
<400> 109
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Lys Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ser Thr Met Ile Ala Thr Gly Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 110
<211> 107
<212> PRT
<213> 鼠科动物
<400> 110
Glu Thr Thr Val Thr Gln Ser Pro Ala Ser Leu Ser Met Ala Ile Gly
1 5 10 15
Glu Lys Val Thr Ile Arg Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp
20 25 30
Met Asn Trp Tyr Gln Gln Lys Pro Gly Glu Pro Pro Lys Leu Leu Ile
35 40 45
Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Ser
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Val Phe Thr Ile Glu Asn Met Leu Ser
65 70 75 80
Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 111
<211> 120
<212> PRT
<213> 鼠科动物
<400> 111
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Lys Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ser Thr Met Ile Ala Thr Gly Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 112
<211> 108
<212> PRT
<213> 鼠科动物
<400> 112
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Pro
85 90 95
Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 113
<211> 141
<212> PRT
<213> 鼠科动物
<400> 113
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Val Ser Gly Thr Gly Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu
50 55 60
Glu Trp Ile Gly Asp Ile Ile Pro Ser Asn Gly Ala Thr Phe Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Arg Ser Ser Ser
85 90 95
Thr Ala Tyr Met His Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Thr Arg Ser His Leu Leu Arg Ala Ser Trp Phe Ala Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser
130 135 140
<210> 114
<211> 134
<212> PRT
<213> 鼠科动物
<400> 114
Met Glu Ser Gln Thr Gln Val Leu Met Ser Leu Leu Phe Trp Val Ser
1 5 10 15
Gly Thr Cys Gly Asp Phe Val Met Thr Gln Ser Pro Ser Ser Leu Thr
20 25 30
Val Thr Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser
35 40 45
Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Leu Gln
50 55 60
Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
65 70 75 80
Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr
100 105 110
Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Leu Glu Ile Lys Arg
130
<210> 115
<211> 140
<212> PRT
<213> 鼠科动物
<400> 115
Trp Thr Trp Arg Phe Leu Phe Val Val Ala Ala Ala Thr Gly Val Gln
1 5 10 15
Ser Gln Val Gln Leu Leu Gln Ser Gly Ala Glu Val Lys Lys Pro Gly
20 25 30
Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr
35 40 45
Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
50 55 60
Met Gly Gly Ile Ile Pro Ile Phe Gly Ile Val Asn Tyr Ala Gln Lys
65 70 75 80
Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala
85 90 95
Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
100 105 110
Cys Ala Arg Gly Gly Gly Ser Gly Pro Asp Val Leu Asp Ile Trp Gly
115 120 125
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr
130 135 140
<210> 116
<211> 132
<212> PRT
<213> 鼠科动物
<400> 116
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys Val Ile Trp Met Thr Gln Ser Pro Ser Leu
20 25 30
Leu Ser Ala Ser Thr Gly Asp Arg Val Thr Ile Ser Cys Arg Met Ser
35 40 45
Gln Gly Ile Arg Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Glu Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Tyr Tyr Ser Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg Thr Val
130
<210> 117
<211> 115
<212> PRT
<213> 鼠科动物
<400> 117
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Tyr Asp Ser Glu Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asn Trp Asp Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 118
<211> 107
<212> PRT
<213> 鼠科动物
<400> 118
Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly
1 5 10 15
Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Asp
20 25 30
Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser 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 Met Tyr Tyr Cys Gln Gln His Asn Lys Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 119
<211> 118
<212> PRT
<213> 鼠科动物
<400> 119
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 120
<211> 111
<212> PRT
<213> 鼠科动物
<400> 120
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 121
<211> 127
<212> PRT
<213> 鼠科动物
<400> 121
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120 125
<210> 122
<211> 113
<212> PRT
<213> 鼠科动物
<400> 122
Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His Lys Phe Met
1 5 10 15
Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln
20 25 30
Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr
85 90 95
Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 123
<211> 119
<212> PRT
<213> 鼠科动物
<400> 123
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser
1 5 10 15
Leu Ser Leu Thr Cys Ser Val Thr Asp Tyr Ser Ile Thr Ser Gly Tyr
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser
85 90 95
Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser Ala Arg Ser
115
<210> 124
<211> 113
<212> PRT
<213> 鼠科动物
<400> 124
Asp Ile Met Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Phe Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Phe Phe Gly
20 25 30
Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala
65 70 75 80
Ile Ser Ser Val Met Pro Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 125
<211> 464
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 125
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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
130 135 140
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser
145 150 155 160
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
165 170 175
Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg
180 185 190
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
195 200 205
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser
210 215 220
Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ala Pro
225 230 235 240
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
245 250 255
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
260 265 270
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile
275 280 285
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
290 295 300
Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
305 310 315 320
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
325 330 335
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
340 345 350
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
355 360 365
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
370 375 380
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
385 390 395 400
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
405 410 415
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
420 425 430
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
435 440 445
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
450 455 460
<210> 126
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 126
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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
130 135 140
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser
145 150 155 160
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
165 170 175
Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg
180 185 190
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
195 200 205
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser
210 215 220
Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp
225 230 235 240
Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu
245 250 255
Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys
260 265 270
Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
275 280 285
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
290 295 300
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
305 310 315 320
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
325 330 335
Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr
340 345 350
Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu
355 360 365
Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu
370 375 380
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
385 390 395 400
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
405 410 415
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
420 425 430
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
435 440 445
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
450 455 460
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
465 470 475 480
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
485 490 495
Arg Glu
<210> 127
<211> 513
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 127
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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
130 135 140
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser
145 150 155 160
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
165 170 175
Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg
180 185 190
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
195 200 205
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser
210 215 220
Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp
225 230 235 240
Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu
245 250 255
Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys
260 265 270
Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala
275 280 285
Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
290 295 300
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
305 310 315 320
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
325 330 335
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
340 345 350
Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile
355 360 365
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
370 375 380
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
385 390 395 400
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
405 410 415
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
420 425 430
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
435 440 445
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
450 455 460
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
465 470 475 480
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
485 490 495
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
Glu
<210> 128
<211> 522
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 128
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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
130 135 140
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser
145 150 155 160
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
165 170 175
Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg
180 185 190
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
195 200 205
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser
210 215 220
Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp
225 230 235 240
Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu
245 250 255
Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser
260 265 270
Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys
275 280 285
Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro
290 295 300
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
305 310 315 320
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
325 330 335
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
340 345 350
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg
355 360 365
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
370 375 380
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
385 390 395 400
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
405 410 415
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
420 425 430
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
435 440 445
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
450 455 460
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
465 470 475 480
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
485 490 495
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
500 505 510
Leu His Met Gln Ala Leu Pro Pro Arg Glu
515 520
<210> 129
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 129
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly
20 25 30
Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
35 40 45
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
50 55 60
Ser Ser Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
65 70 75 80
Glu Trp Val Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala
85 90 95
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
100 105 110
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
115 120 125
Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr
130 135 140
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
145 150 155 160
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
165 170 175
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln
180 185 190
Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
195 200 205
Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile
210 215 220
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
225 230 235 240
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
245 250 255
Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
260 265 270
Lys Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg Glu
500
<210> 130
<211> 466
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 130
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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser
115 120 125
Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
130 135 140
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val
145 150 155 160
Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
165 170 175
Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln
210 215 220
Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
245 250 255
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
260 265 270
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
275 280 285
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
290 295 300
Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr
305 310 315 320
Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu
325 330 335
Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu
340 345 350
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
355 360 365
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
370 375 380
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
385 390 395 400
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
405 410 415
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
420 425 430
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
435 440 445
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
450 455 460
Arg Glu
465
<210> 131
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser
115 120 125
Leu Cys Ser Gly Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
130 135 140
Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
145 150 155 160
Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg
180 185 190
Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
210 215 220
Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr
225 230 235 240
Lys Val Glu Ile Lys Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro
245 250 255
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
260 265 270
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
275 280 285
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
290 295 300
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly
305 310 315 320
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
325 330 335
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
340 345 350
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
355 360 365
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
370 375 380
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
385 390 395 400
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
405 410 415
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
420 425 430
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
435 440 445
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
450 455 460
Met Gln Ala Leu Pro Pro Arg Glu
465 470
<210> 132
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 132
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
20 25 30
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
35 40 45
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln
50 55 60
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly
65 70 75 80
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
85 90 95
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
100 105 110
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp
115 120 125
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Cys
130 135 140
Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Glu Ile Val Leu
145 150 155 160
Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
165 170 175
Leu Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp
180 185 190
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala
195 200 205
Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe
225 230 235 240
Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly
245 250 255
Gln Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Thr Thr Thr Pro Ala
260 265 270
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
275 280 285
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
290 295 300
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
305 310 315 320
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
325 330 335
Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
340 345 350
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
355 360 365
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg
370 375 380
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
385 390 395 400
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
405 410 415
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
420 425 430
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
435 440 445
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
450 455 460
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
465 470 475 480
Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
485 490
<210> 133
<211> 497
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 133
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
20 25 30
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
35 40 45
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln
50 55 60
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly
65 70 75 80
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
85 90 95
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
100 105 110
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp
115 120 125
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly
145 150 155 160
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
165 170 175
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser
180 185 190
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
195 200 205
Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg
210 215 220
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
225 230 235 240
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser
245 250 255
Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp
260 265 270
Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
275 280 285
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
290 295 300
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
305 310 315 320
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
325 330 335
Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile
340 345 350
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
355 360 365
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
370 375 380
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
385 390 395 400
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
405 410 415
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
420 425 430
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
435 440 445
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
450 455 460
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
465 470 475 480
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
485 490 495
Glu
<210> 134
<211> 490
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 134
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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser
115 120 125
Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
130 135 140
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val
145 150 155 160
Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
165 170 175
Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln
210 215 220
Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser
245 250 255
Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro
260 265 270
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
275 280 285
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
290 295 300
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
305 310 315 320
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg
325 330 335
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
340 345 350
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
355 360 365
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
370 375 380
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
385 390 395 400
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
405 410 415
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
420 425 430
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
435 440 445
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
450 455 460
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
465 470 475 480
Leu His Met Gln Ala Leu Pro Pro Arg Glu
485 490
<210> 135
<211> 496
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 135
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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser
115 120 125
Leu Cys Ser Gly Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
130 135 140
Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
145 150 155 160
Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg
180 185 190
Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
210 215 220
Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr
225 230 235 240
Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys
245 250 255
Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro
260 265 270
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
275 280 285
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
290 295 300
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile
305 310 315 320
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
325 330 335
Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
340 345 350
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
355 360 365
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
370 375 380
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
385 390 395 400
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
405 410 415
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
420 425 430
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
435 440 445
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
450 455 460
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
465 470 475 480
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
485 490 495
<210> 136
<211> 514
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 136
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
20 25 30
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
35 40 45
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln
50 55 60
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly
65 70 75 80
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
85 90 95
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
100 105 110
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp
115 120 125
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
165 170 175
Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr
180 185 190
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser
195 200 205
Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
210 215 220
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
225 230 235 240
Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln
245 250 255
Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly
260 265 270
Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser
275 280 285
Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
290 295 300
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
305 310 315 320
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
325 330 335
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
340 345 350
Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr
355 360 365
Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu
370 375 380
Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu
385 390 395 400
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
405 410 415
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
420 425 430
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
435 440 445
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
450 455 460
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
465 470 475 480
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
485 490 495
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
500 505 510
Arg Glu
<210> 137
<211> 515
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 137
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
20 25 30
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
35 40 45
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln
50 55 60
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly
65 70 75 80
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
85 90 95
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
100 105 110
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp
115 120 125
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Cys
130 135 140
Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Glu Ile Val Leu
145 150 155 160
Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
165 170 175
Leu Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp
180 185 190
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala
195 200 205
Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser
210 215 220
Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe
225 230 235 240
Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly
245 250 255
Gln Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly
260 265 270
Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly
275 280 285
Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
290 295 300
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
305 310 315 320
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
325 330 335
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
340 345 350
Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu
355 360 365
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
370 375 380
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
385 390 395 400
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
405 410 415
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
420 425 430
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
435 440 445
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
450 455 460
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
465 470 475 480
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
485 490 495
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
500 505 510
Pro Arg Glu
515
<210> 138
<211> 521
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 138
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
20 25 30
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
35 40 45
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln
50 55 60
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly
65 70 75 80
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
85 90 95
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
100 105 110
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp
115 120 125
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly
145 150 155 160
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
165 170 175
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser
180 185 190
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
195 200 205
Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg
210 215 220
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
225 230 235 240
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser
245 250 255
Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp
260 265 270
Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu
275 280 285
Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg
290 295 300
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
305 310 315 320
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
325 330 335
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
340 345 350
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg
355 360 365
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
370 375 380
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
385 390 395 400
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
405 410 415
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
420 425 430
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
435 440 445
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
450 455 460
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
465 470 475 480
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
485 490 495
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
500 505 510
His Met Gln Ala Leu Pro Pro Arg Glu
515 520
<210> 139
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
130 135 140
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser
145 150 155 160
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
165 170 175
Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg
180 185 190
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
195 200 205
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser
210 215 220
Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp
225 230 235 240
Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu
245 250 255
Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys
260 265 270
Ser Gly Gly Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro
275 280 285
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
290 295 300
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
305 310 315 320
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
325 330 335
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly
340 345 350
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
355 360 365
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
370 375 380
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
385 390 395 400
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
405 410 415
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
420 425 430
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
435 440 445
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
450 455 460
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
465 470 475 480
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
485 490 495
Met Gln Ala Leu Pro Pro Arg Glu
500
<210> 140
<211> 547
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 140
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser
20 25 30
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
35 40 45
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln
50 55 60
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly
65 70 75 80
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
85 90 95
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
100 105 110
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp
115 120 125
Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
165 170 175
Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr
180 185 190
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser
195 200 205
Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
210 215 220
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
225 230 235 240
Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln
245 250 255
Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly
260 265 270
Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser
275 280 285
Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser
290 295 300
Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu
305 310 315 320
Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
325 330 335
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
340 345 350
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
355 360 365
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
370 375 380
Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu
385 390 395 400
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
405 410 415
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
420 425 430
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
435 440 445
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
450 455 460
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
465 470 475 480
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
485 490 495
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
500 505 510
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
515 520 525
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
530 535 540
Pro Arg Glu
545
<210> 141
<211> 523
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 141
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 Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ser 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 Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser
115 120 125
Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
130 135 140
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val
145 150 155 160
Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
165 170 175
Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln
210 215 220
Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser
245 250 255
Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe
260 265 270
Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala
275 280 285
Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala
290 295 300
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
305 310 315 320
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
325 330 335
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
340 345 350
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
355 360 365
Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
370 375 380
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
385 390 395 400
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg
405 410 415
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
420 425 430
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
435 440 445
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
450 455 460
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
465 470 475 480
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
485 490 495
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
500 505 510
Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
515 520
<210> 142
<211> 467
<212> PRT
<213> 人工序列
<220>
<223> 抗CD123-CAR
<400> 142
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
130 135 140
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe
195 200 205
Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys
225 230 235 240
Leu Glu Leu Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
245 250 255
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
260 265 270
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
275 280 285
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
290 295 300
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
305 310 315 320
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
325 330 335
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
340 345 350
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
355 360 365
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
370 375 380
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
385 390 395 400
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
405 410 415
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
420 425 430
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
435 440 445
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
450 455 460
Pro Pro Arg
465
<210> 143
<211> 518
<212> PRT
<213> 人工序列
<220>
<223> CD123 蛋白
<400> 143
Met Thr Lys Glu Asp Pro Asn Pro Pro Ile Thr Asn Leu Arg Met Lys
1 5 10 15
Ala Lys Ala Gln Gln Leu Thr Trp Asp Leu Asn Arg Asn Val Thr Asp
20 25 30
Ile Glu Cys Val Lys Asp Ala Asp Tyr Ser Met Pro Ala Val Asn Asn
35 40 45
Ser Tyr Cys Gln Phe Gly Ala Ile Ser Leu Cys Glu Val Thr Asn Tyr
50 55 60
Thr Val Arg Val Ala Asn Pro Pro Phe Ser Thr Trp Ile Leu Phe Pro
65 70 75 80
Glu Asn Ser Gly Lys Pro Trp Ala Gly Ala Glu Asn Leu Thr Cys Trp
85 90 95
Ile His Asp Val Asp Phe Leu Ser Cys Ser Trp Ala Val Gly Pro Gly
100 105 110
Ala Pro Ala Asp Val Gln Tyr Asp Leu Tyr Leu Asn Val Ala Asn Arg
115 120 125
Arg Gln Gln Tyr Glu Cys Leu His Tyr Lys Thr Asp Ala Gln Gly Thr
130 135 140
Arg Ile Gly Cys Arg Phe Asp Asp Ile Ser Arg Leu Ser Ser Gly Ser
145 150 155 160
Gln Ser Ser His Ile Leu Val Arg Gly Arg Ser Ala Ala Phe Gly Ile
165 170 175
Pro Cys Thr Asp Lys Phe Val Val Phe Ser Gln Ile Glu Ile Leu Thr
180 185 190
Pro Pro Asn Met Thr Ala Lys Cys Asn Lys Thr His Ser Phe Met His
195 200 205
Trp Lys Met Arg Ser His Phe Asn Arg Lys Phe Arg Tyr Glu Leu Gln
210 215 220
Ile Gln Lys Arg Met Gln Pro Val Ile Thr Glu Gln Val Arg Asp Arg
225 230 235 240
Thr Ser Phe Gln Leu Leu Asn Pro Gly Thr Tyr Thr Val Gln Ile Arg
245 250 255
Ala Arg Glu Arg Val Tyr Glu Phe Leu Ser Ala Trp Ser Thr Pro Gln
260 265 270
Arg Phe Glu Cys Asp Gln Glu Glu Gly Ala Asn Thr Arg Ala Trp Arg
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Cys Lys Pro Cys Ile Cys Thr
290 295 300
Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp
305 310 315 320
Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp
325 330 335
Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp
340 345 350
Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn
355 360 365
Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp
370 375 380
Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro
385 390 395 400
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala
405 410 415
Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp
420 425 430
Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile
435 440 445
Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn
450 455 460
Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys
465 470 475 480
Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys
485 490 495
Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu
500 505 510
Ser His Ser Pro Gly Lys
515
<210> 144
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> mAb特异性表位
<400> 144
Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser
1 5 10 15
<210> 145
<211> 469
<212> PRT
<213> 人工序列
<220>
<223> 抗BCMA-CAR
<400> 145
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser
130 135 140
Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser
145 150 155 160
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu
165 170 175
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn
180 185 190
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala
195 200 205
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
210 215 220
Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
245 250 255
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
260 265 270
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
275 280 285
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
290 295 300
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
305 310 315 320
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
325 330 335
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
340 345 350
Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro
355 360 365
Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly
370 375 380
Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro
385 390 395 400
Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr
405 410 415
Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
420 425 430
Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
435 440 445
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
450 455 460
Ala Leu Pro Pro Arg
465
<210> 146
<211> 485
<212> PRT
<213> 人工序列
<220>
<223> BC30-LM
<400> 146
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser
130 135 140
Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser
145 150 155 160
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu
165 170 175
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn
180 185 190
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala
195 200 205
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
210 215 220
Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr
245 250 255
Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
260 265 270
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
275 280 285
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
290 295 300
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
305 310 315 320
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
325 330 335
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
340 345 350
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
355 360 365
Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro
370 375 380
Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly
385 390 395 400
Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro
405 410 415
Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr
420 425 430
Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
435 440 445
Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
450 455 460
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
465 470 475 480
Ala Leu Pro Pro Arg
485
<210> 147
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> BC30-LML
<400> 147
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser
130 135 140
Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser
145 150 155 160
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu
165 170 175
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn
180 185 190
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala
195 200 205
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
210 215 220
Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr
245 250 255
Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr Thr Thr Pro
260 265 270
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
275 280 285
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
290 295 300
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
305 310 315 320
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
325 330 335
Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
340 345 350
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
355 360 365
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
370 375 380
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
385 390 395 400
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
405 410 415
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
420 425 430
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
435 440 445
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
450 455 460
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
465 470 475 480
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
485 490
<210> 148
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> BC30-LMLM
<400> 148
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser
130 135 140
Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser
145 150 155 160
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu
165 170 175
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn
180 185 190
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala
195 200 205
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
210 215 220
Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr
245 250 255
Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser
260 265 270
Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
275 280 285
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
290 295 300
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
305 310 315 320
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
325 330 335
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys
340 345 350
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
355 360 365
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
370 375 380
Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
385 390 395 400
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
405 410 415
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
420 425 430
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
435 440 445
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
450 455 460
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
465 470 475 480
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
485 490 495
Leu Pro Pro Arg
500
<210> 149
<211> 506
<212> PRT
<213> 人工序列
<220>
<223> BC30-LMLML
<400> 149
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asp Tyr
20 25 30
Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser
130 135 140
Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser
145 150 155 160
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu
165 170 175
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn
180 185 190
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala
195 200 205
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
210 215 220
Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr
245 250 255
Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser
260 265 270
Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr Thr Thr Pro Ala
275 280 285
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
290 295 300
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
305 310 315 320
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
325 330 335
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
340 345 350
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
355 360 365
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
370 375 380
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg
385 390 395 400
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
405 410 415
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
420 425 430
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
435 440 445
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
450 455 460
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
465 470 475 480
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
485 490 495
Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505
<210> 150
<211> 136
<212> PRT
<213> 人工序列
<220>
<223> BC30-RQR8
<400> 150
Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro
20 25 30
Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys
35 40 45
Ser Gly Gly Gly Gly Ser Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
50 55 60
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
65 70 75 80
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
85 90 95
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
100 105 110
Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg Asn Arg Arg Arg Val
115 120 125
Cys Lys Cys Pro Arg Pro Val Val
130 135
<210> 151
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> BCMA 蛋白
<400> 151
Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser
1 5 10 15
Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr
20 25 30
Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser
35 40 45
Val Lys Gly Thr Asn Ala Gly Gly Gly Gly Ala Gly Gly Gly Gly Cys
50 55 60
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val
85 90 95
Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe
100 105 110
Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro
115 120 125
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro
130 135 140
Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val
145 150 155 160
Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
165 170 175
Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys
180 185 190
Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp
195 200 205
Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro
210 215 220
Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser
225 230 235 240
Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala
245 250 255
Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
260 265 270
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
275 280
<210> 152
<211> 490
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 152
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
130 135 140
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe
195 200 205
Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys
225 230 235 240
Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys
245 250 255
Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro
260 265 270
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
275 280 285
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
290 295 300
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
305 310 315 320
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg
325 330 335
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
340 345 350
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
355 360 365
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
370 375 380
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
385 390 395 400
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
405 410 415
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
420 425 430
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
435 440 445
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
450 455 460
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
465 470 475 480
Leu His Met Gln Ala Leu Pro Pro Arg Glu
485 490
<210> 153
<211> 496
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 153
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
130 135 140
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe
195 200 205
Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys
225 230 235 240
Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys
245 250 255
Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro
260 265 270
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
275 280 285
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
290 295 300
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile
305 310 315 320
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
325 330 335
Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
340 345 350
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
355 360 365
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
370 375 380
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
385 390 395 400
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
405 410 415
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
420 425 430
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
435 440 445
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
450 455 460
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
465 470 475 480
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
485 490 495
<210> 154
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 154
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
130 135 140
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe
195 200 205
Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys
225 230 235 240
Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys
245 250 255
Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro
260 265 270
Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg
275 280 285
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
290 295 300
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
305 310 315 320
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
325 330 335
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg
340 345 350
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
355 360 365
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
370 375 380
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
385 390 395 400
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
405 410 415
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
420 425 430
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
435 440 445
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
450 455 460
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
465 470 475 480
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
485 490 495
His Met Gln Ala Leu Pro Pro Arg Glu
500 505
<210> 155
<211> 511
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 155
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
130 135 140
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu
180 185 190
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe
195 200 205
Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys
225 230 235 240
Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys
245 250 255
Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro
260 265 270
Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr
275 280 285
Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser
290 295 300
Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly
305 310 315 320
Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp
325 330 335
Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile
340 345 350
Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
355 360 365
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
370 375 380
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
385 390 395 400
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
405 410 415
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
420 425 430
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
435 440 445
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
450 455 460
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
465 470 475 480
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
485 490 495
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
500 505 510
<210> 156
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 156
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Gly Gly Gly Cys Pro Tyr Ser Asn Pro Ser
115 120 125
Leu Cys Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala
130 135 140
Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala
145 150 155 160
Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn
180 185 190
Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr
195 200 205
Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr
210 215 220
Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly
225 230 235 240
Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro
245 250 255
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
260 265 270
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
275 280 285
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
290 295 300
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg
305 310 315 320
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
325 330 335
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
340 345 350
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
355 360 365
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
370 375 380
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
385 390 395 400
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
405 410 415
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
420 425 430
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
435 440 445
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
450 455 460
Leu His Met Gln Ala Leu Pro Pro Arg Glu
465 470
<210> 157
<211> 480
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 157
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Gly Gly Cys Pro Tyr Ser
115 120 125
Asn Pro Ser Leu Cys Gly Gly Gly Gly Gly Gly Gly Ser Asp Ile Val
130 135 140
Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala
145 150 155 160
Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr
165 170 175
Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu
180 185 190
Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser
195 200 205
Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu
210 215 220
Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro
225 230 235 240
Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro
245 250 255
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
260 265 270
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
275 280 285
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile
290 295 300
Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val
305 310 315 320
Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
325 330 335
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
340 345 350
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
355 360 365
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
370 375 380
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
385 390 395 400
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
405 410 415
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
420 425 430
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
435 440 445
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
450 455 460
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
465 470 475 480
<210> 158
<211> 487
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 158
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gln
1 5 10 15
Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr
20 25 30
Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly
35 40 45
Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly
50 55 60
Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys
65 70 75 80
Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu
85 90 95
His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala
100 105 110
Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser
115 120 125
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
145 150 155 160
Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
165 170 175
Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro
180 185 190
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser
195 200 205
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr
210 215 220
Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys
225 230 235 240
Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu
245 250 255
Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
305 310 315 320
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg
325 330 335
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
340 345 350
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
355 360 365
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
370 375 380
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
385 390 395 400
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
405 410 415
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
420 425 430
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
435 440 445
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
450 455 460
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
465 470 475 480
Gln Ala Leu Pro Pro Arg Glu
485
<210> 159
<211> 493
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 159
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
20 25 30
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
50 55 60
Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
65 70 75 80
Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr
100 105 110
Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln
145 150 155 160
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser
165 170 175
Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg
195 200 205
Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly
210 215 220
Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp
225 230 235 240
Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe
245 250 255
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr
260 265 270
Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro
275 280 285
Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val
290 295 300
His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro
305 310 315 320
Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu
325 330 335
Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro
340 345 350
Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
355 360 365
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe
370 375 380
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
385 390 395 400
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
405 410 415
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
420 425 430
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
435 440 445
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
450 455 460
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
465 470 475 480
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
485 490
<210> 160
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 160
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gln Ile
20 25 30
Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val
35 40 45
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met
50 55 60
Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp
65 70 75 80
Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly
85 90 95
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His
100 105 110
Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
115 120 125
Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val
165 170 175
Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val
180 185 190
Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly
195 200 205
Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly
210 215 220
Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu
225 230 235 240
Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln
245 250 255
Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu
260 265 270
Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
275 280 285
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
290 295 300
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
305 310 315 320
Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
325 330 335
Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys
340 345 350
Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
355 360 365
Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
370 375 380
Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro
385 390 395 400
Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly
405 410 415
Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro
420 425 430
Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr
435 440 445
Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
450 455 460
Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
465 470 475 480
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
485 490 495
Ala Leu Pro Pro Arg Glu
500
<210> 161
<211> 508
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 161
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys
35 40 45
Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile
50 55 60
Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser
65 70 75 80
Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr
85 90 95
Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala
100 105 110
Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala
115 120 125
Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp
130 135 140
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
145 150 155 160
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser
165 170 175
Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys
180 185 190
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp
195 200 205
Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala
210 215 220
Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
225 230 235 240
Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val
245 250 255
Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly
260 265 270
Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro
275 280 285
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
290 295 300
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
305 310 315 320
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
325 330 335
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
340 345 350
Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
355 360 365
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
370 375 380
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
385 390 395 400
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
405 410 415
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
420 425 430
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
435 440 445
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
450 455 460
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
465 470 475 480
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
485 490 495
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
500 505
<210> 162
<211> 558
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 162
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser
20 25 30
Gly Pro Glu Leu Ile Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys
35 40 45
Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Val Met His Trp Val Lys Gln
50 55 60
Lys Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Tyr Asn
65 70 75 80
Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr
85 90 95
Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr
100 105 110
Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Gly Thr Tyr Tyr Tyr
115 120 125
Gly Ser Arg Val Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
130 135 140
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Asp Ile Val Met Thr Gln Ala Ala Pro Ser Ile Pro Val Thr Pro
165 170 175
Gly Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn
180 185 190
Ser Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln
195 200 205
Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val
210 215 220
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg
225 230 235 240
Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln
245 250 255
His Leu Glu Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
260 265 270
Lys Arg Ala Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser
275 280 285
Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln
290 295 300
Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr
305 310 315 320
Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr
325 330 335
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln
340 345 350
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
355 360 365
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
370 375 380
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
385 390 395 400
Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
405 410 415
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
420 425 430
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
435 440 445
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
450 455 460
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
465 470 475 480
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
485 490 495
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
500 505 510
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
515 520 525
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
530 535 540
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
545 550 555
<210> 163
<211> 536
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 163
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Ile Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Tyr Tyr Gly Ser Arg Val Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val Ser Ser Ser Ser Gly Gly Ser Cys Pro
115 120 125
Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Asp Ile Val Met Thr
130 135 140
Gln Ala Ala Pro Ser Ile Pro Val Thr Pro Gly Glu Ser Val Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn Ser Asn Gly Asn Thr Tyr
165 170 175
Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile
180 185 190
Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His Leu Glu Tyr Pro Phe
225 230 235 240
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Pro Gly
245 250 255
Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser
260 265 270
Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val
275 280 285
Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr
290 295 300
Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro
305 310 315 320
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
325 330 335
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
340 345 350
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
355 360 365
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly
370 375 380
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
385 390 395 400
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
405 410 415
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
420 425 430
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
435 440 445
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
450 455 460
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
465 470 475 480
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
485 490 495
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
500 505 510
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
515 520 525
Met Gln Ala Leu Pro Pro Arg Glu
530 535
<210> 164
<211> 554
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 164
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Gln Leu Val Gln Ser
20 25 30
Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys
35 40 45
Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln
50 55 60
Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr
65 70 75 80
Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser
85 90 95
Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys
100 105 110
Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp
115 120 125
Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg
165 170 175
Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn
180 185 190
Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
195 200 205
Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe
210 215 220
Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val
225 230 235 240
Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp
245 250 255
Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp
260 265 270
Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu
275 280 285
Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser
290 295 300
Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys
305 310 315 320
Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro
325 330 335
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
340 345 350
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
355 360 365
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
370 375 380
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg
385 390 395 400
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
405 410 415
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
420 425 430
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
435 440 445
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
450 455 460
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
465 470 475 480
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
485 490 495
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
500 505 510
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
515 520 525
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
530 535 540
Leu His Met Gln Ala Leu Pro Pro Arg Glu
545 550
<210> 165
<211> 532
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 165
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn
115 120 125
Pro Ser Leu Cys Ser Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro
130 135 140
Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg
145 150 155 160
Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser
180 185 190
Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg
195 200 205
Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala
225 230 235 240
Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly
245 250 255
Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly
260 265 270
Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val
275 280 285
Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser
290 295 300
Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
305 310 315 320
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
325 330 335
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
340 345 350
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
355 360 365
Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu
370 375 380
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
385 390 395 400
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
405 410 415
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
420 425 430
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
435 440 445
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
450 455 460
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
465 470 475 480
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
485 490 495
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
500 505 510
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
515 520 525
Pro Pro Arg Glu
530
<210> 166
<211> 553
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 166
Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
20 25 30
Gly Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala
35 40 45
Ala Ser Gly Phe Thr Phe Asn Asp Tyr Ala Met His Trp Val Arg Gln
50 55 60
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Trp Asn Ser
65 70 75 80
Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
85 90 95
Arg Asp Asn Ala Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
100 105 110
Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Ile Gln Tyr Gly
115 120 125
Asn Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
130 135 140
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser
165 170 175
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
180 185 190
Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
195 200 205
Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe
210 215 220
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
225 230 235 240
Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp
245 250 255
Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Ser Asp Pro
260 265 270
Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys
275 280 285
Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn
290 295 300
Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro
305 310 315 320
Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg
325 330 335
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
340 345 350
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
355 360 365
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
370 375 380
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg
385 390 395 400
Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro
405 410 415
Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu
420 425 430
Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala
435 440 445
Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
450 455 460
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
465 470 475 480
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
485 490 495
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
500 505 510
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
515 520 525
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
530 535 540
His Met Gln Ala Leu Pro Pro Arg Glu
545 550
<210> 167
<211> 531
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 167
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Ser Gly Gly Ser Cys
115 120 125
Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Glu Ile Val Leu
130 135 140
Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
145 150 155 160
Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser
180 185 190
Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala
210 215 220
Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe Gly Gln
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly
245 250 255
Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser
260 265 270
Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser
275 280 285
Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu
290 295 300
Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
305 310 315 320
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
325 330 335
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
340 345 350
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
355 360 365
Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu
370 375 380
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
385 390 395 400
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
405 410 415
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
420 425 430
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
435 440 445
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
450 455 460
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
465 470 475 480
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
485 490 495
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
500 505 510
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
515 520 525
Pro Arg Glu
530
<210> 168
<211> 552
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 168
Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu
20 25 30
Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys
35 40 45
Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
50 55 60
Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser
65 70 75 80
Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile
85 90 95
Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
100 105 110
Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
115 120 125
Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
130 135 140
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu
165 170 175
Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys
180 185 190
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu
195 200 205
Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser
210 215 220
Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu
225 230 235 240
Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro
245 250 255
Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Ser Asp Pro Gly
260 265 270
Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser
275 280 285
Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val
290 295 300
Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr
305 310 315 320
Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro
325 330 335
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
340 345 350
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
355 360 365
Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys
370 375 380
Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly
385 390 395 400
Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val
405 410 415
Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu
420 425 430
Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp
435 440 445
Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn
450 455 460
Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg
465 470 475 480
Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly
485 490 495
Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
500 505 510
Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
515 520 525
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
530 535 540
Met Gln Ala Leu Pro Pro Arg Glu
545 550
<210> 169
<211> 529
<212> PRT
<213> 人工序列
<220>
<223> 多肽
<400> 169
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ser Ser Gly Gly Ser Cys Pro Tyr
115 120 125
Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Asp Ile Gln Met Thr Gln
130 135 140
Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser
145 150 155 160
Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln
165 170 175
Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu
180 185 190
His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr
210 215 220
Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Thr Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys
245 250 255
Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu
260 265 270
Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala
275 280 285
Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala
290 295 300
Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
305 310 315 320
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
325 330 335
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
340 345 350
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
355 360 365
Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile
370 375 380
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
385 390 395 400
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
405 410 415
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
420 425 430
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
435 440 445
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
450 455 460
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
465 470 475 480
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
485 490 495
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
500 505 510
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
515 520 525
Glu
<210> 170
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 人源化 F19 VH 链
<400> 170
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> 171
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化 F19 VL 链
<400> 171
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> 172
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> FAP5 VH 链
<400> 172
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Thr Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr
85 90 95
Phe Cys Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 173
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> FAP5 VL 链
<400> 173
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 174
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> mAb特异性表位
<400> 174
Gly Gln Asn Asp Thr Ser Gln Thr Ser Ser Pro Ser
1 5 10
<210> 175
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3ζ细胞内信号结构域 (ISD)
<400> 175
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 176
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 41BB 细胞内信号结构域 (ISD)
<400> 176
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 177
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 41BB-IC (41BB 共刺激结构域)
<400> 177
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 178
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> CD8α信号肽
<400> 178
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 179
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> FcγRIIIα铰链
<400> 179
Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln
1 5 10 15
<210> 180
<211> 45
<212> PRT
<213> 人工序列
<220>
<223> CD8α铰链
<400> 180
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 181
<211> 231
<212> PRT
<213> 人工序列
<220>
<223> IgG1铰链
<400> 181
Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25 30
Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val
35 40 45
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
50 55 60
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
65 70 75 80
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
85 90 95
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
100 105 110
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
115 120 125
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
130 135 140
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
145 150 155 160
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
165 170 175
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
180 185 190
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
195 200 205
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
210 215 220
Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 182
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> CD8α跨膜(TM)结构域
<400> 182
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 183
<211> 52
<212> PRT
<213> 人工序列
<220>
<223> FcεRIα-TM-IC(FcεRIα链跨膜和胞内结构域)
<400> 183
Phe Phe Ile Pro Leu Leu Val Val Ile Leu Phe Ala Val Asp Thr Gly
1 5 10 15
Leu Phe Ile Ser Thr Gln Gln Gln Val Thr Phe Leu Leu Lys Ile Lys
20 25 30
Arg Thr Arg Lys Gly Phe Arg Leu Leu Asn Pro His Pro Lys Pro Asn
35 40 45
Pro Lys Asn Asn
50
<210> 184
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> FcεRIβ-(-)ITAM(FcεRI β链，没有ITAM)
<400> 184
Met Asp Thr Glu Ser Asn Arg Arg Ala Asn Leu Ala Leu Pro Gln Glu
1 5 10 15
Pro Ser Ser Val Pro Ala Phe Glu Val Leu Glu Ile Ser Pro Gln Glu
20 25 30
Val Ser Ser Gly Arg Leu Leu Lys Ser Ala Ser Ser Pro Pro Leu His
35 40 45
Thr Trp Leu Thr Val Leu Lys Lys Glu Gln Glu Phe Leu Gly Val Thr
50 55 60
Gln Ile Leu Thr Ala Met Ile Cys Leu Cys Phe Gly Thr Val Val Cys
65 70 75 80
Ser Val Leu Asp Ile Ser His Ile Glu Gly Asp Ile Phe Ser Ser Phe
85 90 95
Lys Ala Gly Tyr Pro Phe Trp Gly Ala Ile Phe Phe Ser Ile Ser Gly
100 105 110
Met Leu Ser Ile Ile Ser Glu Arg Arg Asn Ala Thr Tyr Leu Val Arg
115 120 125
Gly Ser Leu Gly Ala Asn Thr Ala Ser Ser Ile Ala Gly Gly Thr Gly
130 135 140
Ile Thr Ile Leu Ile Ile Asn Leu Lys Lys Ser Leu Ala Tyr Ile His
145 150 155 160
Ile His Ser Cys Gln Lys Phe Phe Glu Thr Lys Cys Phe Met Ala Ser
165 170 175
Phe Ser Thr Glu Ile Val Val Met Met Leu Phe Leu Thr Ile Leu Gly
180 185 190
Leu Gly Ser Ala Val Ser Leu Thr Ile Cys Gly Ala Gly Glu Glu Leu
195 200 205
Lys Gly Asn Lys Val Pro Glu
210 215
<210> 185
<211> 41
<212> PRT
<213> 人工序列
<220>
<223> CD28-IC(CD28共刺激结构域)
<400> 185
Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40

Claims (10)

1.一种包含至少一个胞外结合结构域的编码嵌合抗原受体(CAR)的多肽，所述胞外结合结构域包含至少由抗原特异性的VH链和VL链形成的scFv，其中所述胞外结合结构域包含至少一个mAb特异性表位。
2.根据权利要求1所述的多肽，其中，所述mAb特异性表位位于所述VH链和VL链之间。
3.根据权利要求1或2所述的多肽，其中，所述VH链和VL链、以及mAb特异性表位通过至少一个接头结合在一起并通过铰链结合于所述CAR的跨膜结构域。
4.根据权利要求3所述的多肽，其中，通过两个接头将所述mAb表位连接于所述VH链和VL链。
5.根据权利要求1至3中任一项所述的多肽，其中，所述mAb特异性表位是有待通过表位特异性mAb结合的表位，用于体外细胞分选和/或体内细胞清除表达包含这样的表位的CAR的T细胞。
6.根据权利要求1至5中任一项所述的多肽，其中，所述多肽包含一个胞外结合结构域，其中所述胞外结合结构域进一步包含铰链，以及所述多肽进一步包含
-跨膜结构域，以及，
-胞内结构域。
7.根据权利要求1至6中任一项所述的多肽，其中，所述胞外结合结构域包含1、2、3、4、5、6、7、8、9或10个mAb特异性表位。
8.根据权利要求1至7中任一项所述的多肽，其中，所述胞外结合结构域包含1、2、3、或4个mAb特异性表位。
9.根据权利要求1至8中任一项所述的多肽，其中，所述胞外结合结构域包含2、3、或4个mAb特异性表位。
10.根据权利要求1至9中任一项所述的多肽，其中，所述胞外结合结构域包含以下序列
V1-L1-V2-(L)x-表位1-(L)x-；
V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x-；
V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x-表位3-(L)x-；
(L)x-表位1-(L)x-V1-L1-V2；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2；
表位1-(L)x-表位2-(L)x-表位3-(L)x-V1-L1-V2；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x-；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x-；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x-；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x-表位4-(L)x-；
V1-(L)x-表位1-(L)x-V2；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x；
(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2；或，
(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2-(L)x-表位3-(L)x；
其中，
V1是VL以及V2是VH或V1是VH以及V2是VL；
L1是适合将所述VH链连接于所述VL链的接头；
L是包含甘氨酸和丝氨酸残基的接头，以及在所述胞外结合结构域中L的每次出现可以相同或不同于在相同的胞外结合结构域中L的其它出现，以及，
x是0或1以及x的每次出现独立地选自其它；以及，
表位1、表位2和表位3是mAb特异性表位并且可以是相同的或不同的。
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