CN112979807A - Bcma结合抗体及其用途 - Google Patents
Bcma结合抗体及其用途 Download PDFInfo
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- CN112979807A CN112979807A CN202011484592.0A CN202011484592A CN112979807A CN 112979807 A CN112979807 A CN 112979807A CN 202011484592 A CN202011484592 A CN 202011484592A CN 112979807 A CN112979807 A CN 112979807A
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Abstract
本发明涉及一种抗体,其能够特异性结合BCMA,并对该结合蛋白的制备、应用等方面进行研究。本发明所提供的BCMA抗体能够特异性地与BCMA的胞外段结合,并具有优秀的亲和力与特异性;且该抗体为功能性抗体,其具有阻断BCMA与其配体APRIL结合的活性。基于该抗体构建的免疫细胞对于BCMA阳性的肿瘤细胞有非常好的特异性杀伤功能。
Description
技术领域
本发明涉及生物医疗领域,具体而言,涉及一种能够特异性结合BCMA的抗体,包含所述抗体的嵌合抗原受体及免疫细胞。
背景技术
多发性骨髓瘤(MM)是常见的恶性血液病,占所有癌症死亡例的2%,据Globaldata 2019年统计,2017年全球发病人数为353890人,预计2027年将达到555243例,其主要病状是骨髓中的浆细胞无限增殖,进而导致骨坏死。目前对于该病的治疗方案主要为对症治疗、化疗、放疗和干细胞移植,但将近100%的复发率让对该病的治疗变得极为艰难。
B细胞成熟抗原(BCMA,B-cell maturation antigen)是TNF超家族受体成员(TNFRSF17,III型跨膜蛋白,全长185个氨基酸,胞外段54个氨基酸)。特异性高表达于浆细胞和多发性骨髓瘤细胞表面;并且记忆B细胞,造血干细胞和其他正常组织细胞中均不表达。其功能与同家族受体TACI、BAFFR以及配体APRIL/BAFF一起调节B细胞的活化,分化以及转化成浆细胞和延长浆细胞寿命;B细胞分化成浆细胞过程中,细胞表面BCMA表达上调,缺乏BCMA的小鼠有正常数量的B细胞健康且外观正常,但浆细胞的生存周期缩短。
目前对于多发性骨髓瘤患者的治疗,效果差,成本高,周期长;BCMA因其特异性高表达于浆细胞和骨髓瘤细胞的表面,所以BCMA是治疗多发性骨髓瘤非常理想的靶点,现有临床结果显示对于多发性骨髓瘤患者的免疫细胞治疗明显优于化疗和放疗;鉴于此,本领域急需一种靶向BCMA的功能抗体,以及其衍生的免疫细胞治疗产品。
发明内容
本发明涉及一种抗体,其能够特异性结合BCMA,且选自a)和/或b):
a)包含氨基酸序列依次如SEQ ID NO:1~3所示的重链互补决定区CDR-VH1、CDR-VH2、CDR-VH3,以及氨基酸序列依次如SEQ ID NO:4~6所示的轻链互补决定区CDR-VL1、CDR-VL2、CDR-VL3;
b)包含氨基酸序列依次如SEQ ID NO:19~21所示的重链互补决定区CDR-VH1、CDR-VH2、CDR-VH3,以及氨基酸序列依次如SEQ ID NO:22~24所示的轻链互补决定区CDR-VL1、CDR-VL2、CDR-VL3。
本发明还涉及包含所述抗体的嵌合抗原受体。
本发明还涉及用于表达生产所述抗体和嵌合抗原受体的核酸、载体及宿主细胞。
本发明还涉及免疫细胞,其包含如上所述的嵌合抗原受体。
本发明还涉及药物组合物,其包括如上所述的抗体或如上所述的免疫细胞,以及药学上可接受的赋形剂、稀释剂或载体中的一种或多种。
与现有技术相比,本发明的有益效果为:
(1)本发明所提供的BCMA抗体能够特异性地与BCMA的胞外段结合,并具有优秀的亲和力与特异性(其基本不与细胞膜表面的其他抗原发生结合);且该抗体为功能性抗体,其具有阻断BCMA与其配体APRIL结合的活性。
(2)基于该抗体构建的能够表达嵌合抗原受体的免疫细胞对于BCMA阳性的肿瘤细胞有非常好的特异性杀伤功能。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明一个实施例中通过ELISA方式检测BCMA抗体(5E2、5F4)针对BCMA的亲和力;
图2为本发明一个实施例中通过Fortebio方式检测BCMA抗体(5E2、5F4)针对BCMA的亲和力;
图3为本发明一个实施例中通过FACs方式检测BCMA抗体(5E2、5F4)针对BCMA的亲和力;
图4为本发明一个实施例中BCMA抗体(5E2、5F4)与BCMA配体APRIL竞争性结合实验结果;
图5为本发明一个实施例中BCMA抗体(5E2、5F4)的特异性检测结果;
图6为本发明一个实施例中所采用的C11D5.3 CAR质粒的结构示意图;
图7为本发明一个实施例中所采用的5E2 CAR质粒的结构示意图;
图8为本发明一个实施例中流式检测CART细胞CAR阳性率的实验结果;
图9为本发明一个实施例中CART与靶细胞共培养8h后靶细胞凋亡检测结果;
图10为本发明一个实施例中CART细胞与靶细胞共培养8h后IL-2检测结果;
图11为本发明一个实施例中CART细胞与靶细胞共培养8h后IFNγ检测结果;
图12为本发明一个实施例中ELISA检测BCMA人源化抗体体针对BCMA抗原的亲和力结果;
图13为本发明一个实施例中Fortebio检测BCMA人源化抗体体针对BCMA抗原的亲和力结果;
图14为本发明一个实施例中FACs检测抗体与肿瘤细胞系的结合结果;
图15为本发明一个实施例中人源化BCMA抗体与BCMA配体APRIL竞争性结合结果;
图16为本发明一个实施例中流式细胞仪进行检测人源化BCMA抗体能够特异性地结合BCMA表达阳性的细胞的结果;
图17为本发明一个实施例中PCDHF-42结构示意图;
图18为本发明一个实施例中PCDHF-73结构示意图;
图19为本发明一个实施例中PCDHF-74结构示意图;
图20为本发明一个实施例中CART细胞CAR阳性率CAR+;
图21为本发明一个实施例中CART与靶细胞共培养6h后靶细胞凋亡检测结果;
图22为本发明一个实施例中CART细胞与靶细胞共培养6h后IL-2检测结果;
图23为本发明一个实施例中CART细胞与靶细胞共培养6h后IFNγ检测结果。
具体实施方式
现将详细地提供本发明实施方式的参考,其一个或多个实例描述于下文。提供每一实例作为解释而非限制本发明。实际上,对本领域技术人员而言,显而易见的是,可以对本发明进行多种修改和变化而不背离本发明的范围或精神。例如,作为一个实施方式的部分而说明或描述的特征可以用于另一实施方式中,来产生更进一步的实施方式。
因此,旨在本发明覆盖落入所附权利要求的范围及其等同范围中的此类修改和变化。本发明的其它对象、特征和方面公开于以下详细描述中或从中是显而易见的。本领域普通技术人员应理解本讨论仅是示例性实施方式的描述,而非意在限制本发明更广阔的方面。
本发明涉及一种抗体,其能够特异性结合BCMA,且选自a)和/或b):
a)包含氨基酸序列依次如SEQ ID NO:1~3所示的重链互补决定区CDR-VH1、CDR-VH2、CDR-VH3,以及氨基酸序列依次如SEQ ID NO:4~6所示的轻链互补决定区CDR-VL1、CDR-VL2、CDR-VL3;
b)包含氨基酸序列依次如SEQ ID NO:19~21所示的重链互补决定区CDR-VH1、CDR-VH2、CDR-VH3,以及氨基酸序列依次如SEQ ID NO:22~24所示的轻链互补决定区CDR-VL1、CDR-VL2、CDR-VL3。
在本发明中,“抗体”泛指包含CDR区的一切蛋白/蛋白片段,特别是全长抗体或抗体功能片段。“全长抗体”此用语包括多克隆抗体及单克隆抗体,术语“抗体功能片段”是包含抗体CDR的一部分或全部的物质,其缺乏至少一些存在于全长链中的氨基酸但仍能够特异性结合至抗原。此类片段具生物活性,因为其结合至靶抗原,且可与其他抗原结合分子(包括完整抗体)竞争结合至给定表位。在一些实施方式中,片段是具有阻断BCMA与其配体APRIL结合功能的片段。在一些实施方案中,片段可阻断或降低BCMA的活性。在一个方面中,此类片段将包含单个重链和单个轻链,或其部分。所述片段可通过重组核酸技术产生,或可通过抗原结合分子(包括完整抗体)的酶裂解或化学裂解产生。
抗体的变体也在本发明范围内,例如各自与本文所述的序列的氨基酸序列具有至少70%~80%、80%~85%、85%~90%、90%~95%、95%~97%、97%~99%或高于99%同一性的可变轻链和/或可变重链。在一些情况下,抗体的变体至少包括上述6个CDR;在一些情况下,抗体的变体至少包括一个重链和一个轻链,而在其他情况下,变体形式含有两个相同的轻链和两个相同的重链(或其子部分)。在一些情况下,变体保留阻断BCMA与其配体APRIL结合的能力。所属领域技术人员将能够使用熟知的技术确定如本文所阐明的抗原结合分子的合适变体。在某些实施方案中,所属领域技术人员可鉴别分子的可通过靶据信对于活性而言不重要的区来改变而不破坏活性的合适区域。
本发明所提供的抗体能够特异性地与BCMA的胞外段结合,并具有优秀的特异性(其基本不与细胞膜表面的其他抗原发生结合)。特别地,该抗体的一个重要优点在于其具有阻断BCMA与其配体APRIL结合的活性,因而优选可作为抗体药物使用。
在另外一些实施方案中,鉴于本发明已经验证了抗体与BCMA的亲和力,因而本领域技术人员也可以在不付出创造性的前提下判断其也可用作诊断或验证工具。抗体可用于分析样品和/或受试者中存在的BCMA的量。在一些实施方案中,诊断性抗体不是用于阻断BCMA与其配体APRIL结合功能的抗体。在一些实施方案中,本文所公开的抗体可用于或提供于用于检测哺乳动物特别是人组织或细胞中的BCMA以筛检/诊断与BCMA水平变化相关的疾病或病症的分析试剂盒和/或方法中。试剂盒可包含结合BCMA的抗原结合分子,连同用于指示抗原结合分子与BCMA的结合(若存在)及任选地BCMA蛋白水平的构件。
当在本文中使用时,“骨架区”或“FR”区意味着抗体可变结构域的排除被定义为CDR的那些区域之外的区域。每个抗体可变结构域构架可以被进一步细分成被CDR分隔开的毗邻区域(FR1、FR2、FR3和FR4)。
通常情况下,重链和轻链的可变区VL/VH可由以下编号的CDR与FR按如下组合排列连接获得:FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。
当在本文中使用时,与多肽或核酸相关联的术语“分离的”是指多肽或核酸不是处于其天然介质中或天然形式下。因此,术语“分离的”包括从其原始环境,例如如果它是天然存在的,从天然环境取出的多肽或核酸。
在一些实施方式中,所述抗体a包含序列如SEQ ID NO:7~10、SEQ ID NO:41~44、或SEQ ID NO:45~48所示的重链骨架区FR-H1、FR-H2、FR-H3及FR-H4;和/或;序列依次如SEQ ID NO:11~14、SEQ ID NO:49~52、SEQ ID NO:53~56或SEQ ID NO:57~60所示的轻链骨架区FR-L1、FR-L2、FR-L3及FR-L4。
在一些实施方式中,所述抗体b包含序列依次如SEQ ID NO:25~28所示的重链骨架区FR-H1、FR-H2、FR-H3及FR-H4;和/或;序列依次如SEQ ID NO:29~32所示的轻链骨架区FR-L1、FR-L2、FR-L3及FR-L4。
在一些实施方式中,所述抗体为F(ab’)2、Fab、Fv、scFv以及双特异抗体中的一种。在进一步实施方案中,所述抗体是单链可变片段(scFv)。
在一些实施方式中,所述抗体具有恒定区,恒定区序列选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任何其中之一恒定区的序列。
在一些实施方式中,所述恒定区的种属来源独立地选自牛、马、乳牛、猪、绵羊、山羊、大鼠、小鼠、狗、猫、兔、骆驼、驴、鹿、貂、鸡、鸭、鹅、火鸡、斗鸡或人。
本发明还涉及嵌合抗原受体,其包含如上所述的抗体。
应当理解,根据本发明的嵌合抗原受体的一个优选取向包含的抗体类型为sc-Fv。
在一些实施方式中,所述嵌合抗原受体还包含一个或多个选自由以下组成的组的元件:前导肽、接头序列、跨膜结构域、共刺激结构域和信号传导结构域。
在一些实施方式中,所述前导肽选自CD8 leader嵌合受体信号肽。
在一些实施方式中,所述前导肽选自接头序列选自CD8的hinge区。
在一些实施方式中,所述跨膜结构域选自CD8的跨膜区。
在一些实施方式中,共刺激域是以下项的信号传送区:CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程序性死亡-1(PD-1)、可诱导型T细胞共刺激因子(ICOS)、淋巴细胞功能相关抗原-1(LFA-1、CDl-la/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受体、MHC 1类分子、TNF受体蛋白、免疫球蛋白蛋白质、细胞因子受体、整联蛋白、信号淋巴细胞活化分子(SLAM蛋白)、活化NK细胞受体、BTLA、Toll配体受体、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDlld、ITGAE、CD103、ITGAL、CDlla、LFA-1、ITGAM、CDllb、ITGAX、CDllc、ITGBl、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Lyl08)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、与CD83特异性结合的配体或其任何组合。
在一些实施方式中,所述信号传导结构域选自PKCθ、FcεRIγ、ZAP70、CD3ζ中的任一种,或其任意组合。
在一些实施方式中,所述功能片段包括CD8 leader嵌合受体信号肽、CD8的hinge区、CD8的跨膜区、CD137以及CD3ζ。
本发明还涉及分离的核酸,其编码如上所述的抗体,或如上所述的嵌合抗原受体。
本发明还涉及载体,其包含如上所述的分离的核酸。
术语“载体(vector)”是指,可将多聚核苷酸插入其中的一种核酸运载工具。当载体能使插入的多核苷酸编码的蛋白获得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。可用作载体的动物病毒包括但不限于,逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。在一些实施方式中,本发明所述载体中包含基因工程中常用的调控元件,例如增强子、启动子、内部核糖体进入位点(IRES)和其他表达控制元件(例如转录终止信号,或者多腺苷酸化信号和多聚U序列等)。
在一些实施方式中,本发明所述载体中还可以包含筛选所用的基因(例如抗生素抗性基因)、用于生成荧光蛋白的核酸等片段。荧光蛋白可以选择绿色荧光蛋白、蓝色荧光蛋白、黄色荧光蛋白、橙色荧光蛋白或红色荧光蛋白。
特别地,当所述载体中包含编码如上所述的嵌合抗原受体的核酸时,所述载体优选为逆转录病毒载体,更优选为慢病毒载体。
在一个具体的实施方式中,所述慢病毒载体的核苷酸序列为SEQ ID NO:18所示。
本发明还涉及宿主细胞,其包含如上所述的载体。
术语“宿主细胞”是指,可用于导入载体的细胞,其包括但不限于,如大肠杆菌或枯草菌等的原核细胞,如酵母细胞或曲霉菌等的真菌细胞,如S2果蝇细胞或Sf9等的昆虫细胞,或者如纤维原细胞,CHO细胞,COS细胞,NSO细胞,HeLa细胞,BHK细胞,HEK 293细胞或人细胞等的动物细胞。宿主细胞优选为真核细胞,更优选为哺乳动物细胞。
本发明还涉及免疫细胞,其包含如上所述的嵌合抗原受体;
在一些实施方式中,所述免疫细胞为T细胞、肿瘤浸润淋巴细胞(TIL细胞)、NK细胞、树突状细胞或NK-T细胞。
在一些实施方式中,所述免疫细胞为自体T细胞或同种异体T细胞。
在一些实施方案中,所述免疫细胞是获自外周血或由其制备。
在一些实施方案中,所述免疫细胞是获自外周血单核细胞(PBMC)或由其制备。
在一些实施方案中,所述免疫细胞是获自骨髓或由其制备。
在一些实施方案中,所述免疫细胞是获自脐带血或由其制备。
在一些实施方案中,所述免疫细胞是人细胞。
本发明还涉及药物组合物,其包括如上所述的抗体或如上所述的免疫细胞,以及药学上可接受的赋形剂、稀释剂或载体中的一种或多种。
术语“药学上可接受的赋形剂、稀释剂或载体”是指在药理学和/或生理学上与受试者和活性成分相容的赋形剂、稀释剂或载体,其是本领域公知的,包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲液;表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80;离子强度增强剂包括但不限于氯化钠。
所述药用组合物可用于BCMA相关疾病,特别是多发性骨髓瘤。因而特别地,本发明还是涉及一种用于治疗有此需要的主体中的多发性骨髓瘤的方法,所述方法包括:
a)提供所述药用组合物;以及
b)向所述主体的施用治疗有效量的所述药用组合物。
术语“有效量”是指足以获得或至少部分获得期望的效果的量。期望的效果例如,预防或治疗多发性骨髓瘤,有效量通常是足以预防,阻止,或延迟疾病的发生的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途有效的量将取决于待治疗的疾病的严重度、主体自己的免疫系统的总体状态、主体的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
在一些实施方式中,施用的方法可以采用注射给予等。
在本发明中“主体”、“受试者”、“患者”等词汇可根据需要通用。主体可以为哺乳动物,优选为人。
下面将结合实施例对本发明的实施方案进行详细描述。
实施例1靶向BCMA抗体的获得
将人BCMA胞外段与小鼠抗体Fc片段(Fragment crystallizable)的缀合物(以下简称hBCMA-mFc,ACRO,BCA-H5253)腹腔注射BALB/c小鼠(广东省医学实验动物中心),每周一次,每次100μg/200μl/只,免疫3周后每周取小鼠尾血并检测血清中BCMA抗体的表达;选择血清中BCMA抗体表达量高的小鼠取脾细胞与瘤细胞(SP20,ATCC HB-12546)融合形成融合子,融合子培养10~14天后选择培养上清中表达BCMA抗体的融合子进行单克隆;选择表达BCMA抗体的单克隆杂交瘤细胞株进行扩大培养,培养7~10天后收集细胞培养液纯化获得BCMA抗体,对所得的大量抗体经过筛选后,获得两个候选抗体(5E2和5F4),5E2测序重链可变区氨基酸序列VH为SEQ ID NO:15所示,轻链可变区氨基酸序列VL为序列SEQ ID NO:16所示;5F4测序重链可变区氨基酸序列VH为SEQ ID NO:33所示,轻链可变区氨基酸序列VL为序列SEQ ID NO:34所示。
实施例2、BCMA抗体的筛选
1)BCMA抗体(5E2,5F4)亲和力检测:
通过ELISA、Fortebio和FACs三种方式检测不同抗体针对BCMA的亲和力,具体方法如下:
抗体亲和力ELISA检测:将hBCMA ECD hFc,ACRO,BC7-H5254包被在96孔酶联包被板中,浓度为2μg/ml,100μl/孔,将3倍梯度稀释(前一个浓度是后一个浓度的3倍,用1%BSA稀释)的抗体与抗原结合,检测各抗体的EC50值(具体操作步骤为一般ELISA操作步骤)。R0317为C11D5.3 BCMA鼠单抗,其具体序列和信息可以公开查找到,待测抗体由深圳市菲鹏治疗股份有限公司合成。结果如图1所示,结果显示BCMA抗体5E2和5F4与R0317具有处于同一水平的EC50。
抗体亲和力Fortebio检测,利用带ProG biosensor(Pall ForteBIO,18-1502),先Loading Buffer(PBS+0.02%Tween20),再加入h BCMA ECD hFc(R0341)5μg/mL,然后分别加入3种抗体,分别检测3种抗体的KD,Kon和Kdis。具体操作步骤为使用Fortebio仪器(forteBio,Serial NO:FB-40476)的常规操作。检测结果如图2所示,说明5E2 5F4与BCMA抗原的亲和力较强并且和R0317处于同一水平。
FACs检测抗体与肿瘤细胞系的结合:
RPMI8226细胞(CRM-CCL-155TM)为人多发性骨髓瘤外周血B淋巴细胞,H929细胞(CRL-9068TM)为人多发性骨髓瘤骨髓B淋巴细胞。具体检测方法如下:收获细胞,PBS洗涤1次,然后用PBS按照2E+5cells/200μl将细胞重悬。将3种抗体梯度稀释(抗体起始浓度为10μg/ml,1%BSA 3倍稀释,共9个梯度)后分别与细胞4℃孵育30min。其后与PE标记的抗小鼠IgG第二抗体(Biolegend,B288920)孵育,洗涤2次,Beckman Coulter(型号:CytoFLEX)流式细胞仪检测。如图3所示,5E2、5F4与RPMI8226和H929细胞有浓度梯度依赖的结合并且EC50显著低于R0317,说明5E2、5F4和RPMI8226和H929细胞的亲和力优于R0317。
2)BCMA抗体(5E2、5F4)与BCMA配体APRIL竞争性结合实验:
购买ACRO重组人APRIL Ala-Leu 250+N端连接人IgG1 Fc(货号APL-H5267)。将hBCMA-mFc以4μg/ml包被于ELISA板中,4℃包被过夜。PBS洗涤1次后,用1%BSA封闭1h,然后再PBS洗涤1次。将抗体5E2和5F4梯度稀释,起始浓度为200μg/ml,1%BSA进行3倍梯度稀释,共7个梯度,稀释液用h APRIL hFc 4μg/ml(此浓度在APRIL与hBCMA-mFc结合的EC50和饱和之间),37℃孵育30min,洗涤5次,加入1:1500稀释的HRP标记的羊抗人Fc抗体(Goat Anti-Human IgG Antibody,Fc,HRP conjugate Sigma,AP113P),37℃孵育30min,洗涤5次,TMB显色,终止后多功能酶标仪读数。结果如图4所示,5E2、5F4阻断APRIL的IC50与R0317相当,并且5E2、5F4对APRIL与hBCMA-mFc的阻断效果明显且呈浓度梯度依赖性。
3)BCMA抗体(5E2,5F4)特异性
对本发明的BCMA抗体进行特异性流式检测。体外合成人BCMA全长基因,并引入酶切位点,通过双酶切将合成的人BCMA全长基因插入慢病毒包装质粒载体(PCDHF)中,进行慢病毒包装(具体操作步骤为一般4质粒慢病毒包装步骤,具体可参考吉凯基因官网中关于慢病毒包装的部分)。将制备得到的慢病毒侵染K562细胞(ATCC,货号CCL-243)以构建K562-BCMA细胞,对所述细胞进行单克隆挑取和鉴定,获得稳定表达BCMA的稳定细胞株K562-BCMA。将5E2,5F4抗体分别与K562,H929,RPMI8226和K562-BCMA细胞于4℃孵育30min,之后用PBS洗涤2次,之后加入二抗PE山羊抗小鼠IgG1(Biolegend,B288920)于4℃孵育30min,之后用PBS洗涤2次。然后利用Beckman Coulter流式细胞仪进行检测。检测结果如下图5所示,5E2,5F4能够特异性地结合BCMA表达阳性的细胞。
实施例3、构建BCMA CART细胞并进行体外功能验证
1)获取5E2和5F4抗体序列:
复苏表达5E2和5F4的杂交瘤细胞株,正常培养72h后,裂解细胞提取RNA(提取试剂盒:TOYOBO LIFE SCIENCE,货号836700,提取步骤按说明书)。对提取的RNA进行逆转录以获得cDNA(逆转录试剂盒:TOYOBO LIFE SCIENCE,货号11141ES10),对获得的cDNA进行PCR扩增(使用针对小鼠IgG1序列的特异性引物)以获得抗体序列并对其进行测序,抗体测序VH和VL见实施例1中标记5E2和5F4的VH,VL序列。由于两个抗体的亲和力、特异性及功能特性相似,后续以5E2为例做CART功能验证。
2)慢病毒包装:
将5E2抗体的scFv序列(通过连接肽将VH的C端与VL的N端相连得到,连接肽的核苷酸序列如SEQ ID NO:35所示)以及C11D5.3的scFv序列(SEQ ID NO:17)分别构建在慢病毒载体(PCDHF)上获得CAR质粒,C11D5.3 CAR质粒和5E2 CAR质粒的结构示意图如图6和图7所示。利用293T细胞(CRL-3216TM)包装慢病毒,包装体系和包装步骤如下所示:
a,接种293T细胞5E6于10cm细胞培养皿中,加入10mL含10%FBS的DMEM培养基(DMEM Gibco,11995040-1L;FBS Gibco,10091-148),5%CO2,37℃条件下CO2培养箱中培养48h;
b,慢病毒包装体系
其中“*1、*2、*3”分别为慢病毒包装质粒PMD2.G,pMDLg/pRRE,pRSV-Rev序列,可以通过公开途径(网址http://www.miaolingbio.com/)获得。
c,包装后48h收细胞上清,25000rpm超速离心后检测慢病毒滴度,检测方法如下:将收集的慢病毒原液梯度体积同样条件下感染293T细胞,48h后流式检测293T细胞GFP阳性率百分比,根据计算公式原液滴度(TU/mL)=1.5×10E+05×293T细胞GFP阳性率百分比/慢病毒原液体积μl×1000来计算慢病毒原液滴度。
3)CART细胞制备
Ficoll淋巴分离液(达科为,AS1114546)从血液(菲鹏生物员工0038号志愿者献血50mL)中分离PBMC细胞,偶联CD3/CD28抗体的磁珠正选法分离获得T细胞,将慢病毒按MOI=5:1感染T细胞以制备CART细胞,CART细胞培养7天后用二抗APC山羊抗小鼠IgG(H+L)(Jackson,115-136-146)流式检测CART细胞CAR阳性率,如图8所示。
4)CART细胞体外功能评价
分别取4种靶细胞K562,K562-BCMA,H929和RPMI8226各2×10E+06个细胞,先利用CytoCalceinTM Violet 550对靶细胞进行染色,1×10E+05细胞/100μl/孔。将效应细胞(CAR+CART,T细胞为对照)分别与上述靶细胞按照0.25:1、1:1、5:1及10:1的比率加入96孔板中混匀,终体积200μl。培养8h后,将细胞混匀离心。上清利用Human IL-2 ELISA检测试剂盒(invitrogen,REF 88-7025-88)Human IFN gamma ELISA试剂盒(invitrogen,REF 88-7316-88)检测各孔中IL-2及IFN-γ浓度,沉淀部分用100μl Annexin V Binding Buffer(Biolegend,B274722)重悬,300g离心5min,之后添加2.0μl APC-Annexin V(Biolegend,Cat 640920)和1.2μl PI染料(Biolegend,Cat 421301),避光孵育15min,添加100μlAnnexin V Binding Buffer重悬,之后利用Beckman Coulter流式细胞仪检测各靶细胞凋亡比例(结果如图9所示),利用ELISA检测各孔上清IL-2及IFN-γ浓度(结果如图10和图11所示)。其中K562为BCMA阴性细胞,K562-BCMA,H929,RPMI8226均为BCMA阳性细胞。结果显示5E2 CART和C11D5.3 CART对BCMA阳性靶细胞有较强的特异性杀伤,并且2种CART细胞的杀伤阳性靶细胞能力基本一致,对BCMA阴性细胞几乎无杀伤作用。
实施例4靶向BCMA人源化抗体的获得
将鼠源5E2抗体进行人源化后获得4个抗体序列,包括2条重链可变区(SEQ ID NO:36-SEQ ID NO:37)和3条轻链可变区(EQ ID NO:38-SEQ ID NO:40)。
实施例5 BCMA人源化抗体评价
1)人源化BCMA抗体亲和力检测
通过ELISA、Fortebio和FACs三种方式检测4个BCMA人源化抗体(hu VH1-VL1;huVH2-VL1;hu VH1-VL2;huVH1-VL3)针对BCMA抗原的亲和力,具体方法如下:
抗体亲和力ELISA检测:将hu(人)BCMA ECD His,ACRO,BCA-H522y包被在96孔酶联包被板中,浓度为2μg/mL,100μL/孔,将4个人源化抗体分别用1%BSA配制成起始浓度20μg/mL,1%BSA 3倍梯度稀释(前一梯度抗体浓度为后一梯度抗体浓度的3倍),抗体与抗原结合,检测4个抗体的EC50值(具体操作步骤为一般ELISA操作步骤)。其中mVH-mVL为鼠源BCMA抗体,是人源化之前的鼠源抗体,结果如下图12所示,结果显示4个人源化BCMA抗体与鼠源BCMA抗体mVH-mVL具有处于同一水平的EC50,并且huVH1-VL2亲和力最高。
抗体亲和力Fortebio检测,利用带AMC biosensor(Pall,lot:1907292)先Loadingh BCMA ECD mFc 3ug/mL,然后分别结合4种人源化抗体,分别检测4种抗体的KD,Kon和Kdis。具体操作步骤为使用Fortebio仪器(forteBio,Serial NO:FB-40476)的常规操作。检测结果如下图13所示,说明4个BCMA人源化抗体与抗原的亲和力较强并且和鼠源BCMA抗体mVH-mVL处于同一水平,huVH1-VL2亲和力最高。
FACs检测抗体与肿瘤细胞系的结合:
K562细胞(CCL-243TM)为人慢性髓系白血病细胞,CHO细胞(CRL-12023TM)为中国仓鼠卵巢细胞,分别将含有人BCMA全长序列的慢病毒感染K562细胞和CHO细胞,感染后挑单克隆,获得稳定表达BCMA的K562-BCMA细胞株和CHO-BCMA细胞株,检测4人源化抗体分别与K562-BCMA和CHO-BCMA的亲和力(EC50),具体检测方法如下:收获细胞,PBS洗涤1次,然后用PBS按照2E+5cells/200μL将细胞重悬。将4种BCMA人源化抗体用1%BSA 3倍梯度稀释,前一梯度抗体浓度为后一梯度抗体浓度的3倍,(抗体起始浓度为30μg/ml,共11个梯度)后分别与细胞4℃孵育30min。其后与APC anti-human IgG Fc Antibody(Biolegend,409306)4℃孵育30min,1×PBS洗涤2次,Beckman Coulter(型号:CytoFLEX)流式细胞仪检测。如下图14所示,3个人源化抗体与K562-BCMA细胞和CHO-BCMA细胞有浓度梯度依赖的结合并且EC50与鼠源BCMA抗体处于同一水平,huVH1VL2与K562-BCMA亲和力EC50稍弱一些,但huVH1-VL2与CHO-BCMA亲和力EC50与其它3个人源化抗体处于同一水平,4个人源化抗体和鼠源BCMA抗体与CHO-BCMA结合表达丰度上,从高到低的顺序为m VH-m VL,huVH1-VL1,hu VH2-VL1,hu VH1-VL2,hu VH1-VL3。
2)4个人源化BCMA抗体与BCMA配体APRIL竞争性结合实验:
购买ACRO重组人APRIL Ala-Leu 250+N端His标签(Human APRIL/TNFSF13Protein,His Tag货号APL-H5244)。将hBCMA-mFc以4μg/ml包被于ELISA板中,4℃包被过夜。1×PBS洗涤1次后,用1%BSA(Sangon Biotech,A500023-0100)封闭1h,然后再用1×PBS洗涤1次。将4个人源化抗体3倍梯度稀释,前一梯度抗体浓度为后一梯度抗体浓度的3倍,起始浓度为100μg/ml,共11个梯度,稀释液用h APRIL His 0.2μg/ml,(此浓度在APRIL与hBCMA-mFc结合的EC50和饱和之间),h APRIL His用1%BSA溶解,37℃孵育30min,1×PBS洗涤5次,加入1:1500稀释的HRP标记的抗His抗体(Anti-his tag HRP,Biolegend,652504),37℃孵育30min,洗涤5次,TMB显色,终止后多功能酶标仪读数。结果如下图15所示,4个人源化BCMA抗体阻断APRIL的IC50与鼠源BCMA抗体m VH-m VL相当,并且4个人源化BCMA抗体对APRIL与hBCMA-mFc的阻断效果明显且呈浓度梯度依赖性。
3)4个人源化BCMA抗体特异性
对4个人源化BCMA抗体进行特异性流式检测,将4个人源化BCMA抗体10ug/ml100ul分别与K562,K562-BCMA,CHO,CHO-BCMA和K562-BCMA细胞于4℃孵育30min,之后用1×PBS洗涤2次,之后加入APC anti-human IgG Fc Antibody(Biolegend,409306)于4℃孵育30min,之后用1×PBS洗涤2次。然后利用Beckman Coulter流式细胞仪进行检测。检测结果如下图16所示,4个人源化BCMA抗体能够特异性地结合BCMA表达阳性的细胞。
实施例6构建BCMA CART细胞并进行体外功能验证
1)慢病毒包装:
经过亲和力,阻断功能和特异性比较,优选将m VH-m VL,hu VH1-VL1,hu VH2-VL1抗体的scFv序列分别构建在慢病毒载体(PCDHF,含有GFP序列)上获得CAR质粒,m VH-m VL,hu VH1-VL1,hu VH2-VL1抗体的scFv序列构建得CAR质粒分别为PCDHF-42,PCDHF-73,PCDHF-74,结构示意图如图17、18、19所示。利用293T细胞(CRL-3216TM)包装慢病毒,包装体系和包装步骤如下所示:
a接种293T细胞5E6于10cm细胞培养皿中,加入10mL含10%FBS的DMEM培养基(DMEMGibco,11995040-1L;FBS Gibco,10091-148),5%CO2,37℃条件下CO2培养箱中培养24h;
b慢病毒包装体系
c包装后48h收细胞上清,25000rpm超速离心后检测慢病毒滴度,检测方法如下:将收集的慢病毒原液梯度体积同样条件下感染293T细胞,48h后流式检测293T细胞GFP阳性率百分比,根据计算公式原液滴度(TU/mL)=1.5×10E+05×293T细胞GFP阳性率百分比/慢病毒原液体积μl×1000来计算慢病毒原液滴度。
2)CART细胞制备
Ficoll淋巴分离液(达科为,AS1114546)从血液(志愿者献血50mL)中分离PBMC细胞,偶联CD3/CD28抗体的磁珠正选法分离获得T细胞,将慢病毒按MOI=5:1感染T细胞以制备CART细胞,CART细胞培养7天后通过检测CART细胞的GFP阳性率来确定CART细胞CAR阳性率,如图20所示,
3)CART细胞体外功能评价
分别取4种靶细胞K562,K562-BCMA,RPMI8226各2×10E+06个细胞,先利用CytoCalceinTM Violet 550对靶细胞进行染色,1×10E+05细胞/100ul/孔。将效应细胞(CAR+CART,T细胞为对照)分别与上述靶细胞按照0.25:1、1:1、5:1及10:1的比率加入96孔板中混匀,终体积200ul。培养6h后,将细胞混匀离心。上清利用Human IL-2 ELISA检测试剂盒(invitrogen,REF 88-7025-88)Human IFN gamma ELISA试剂盒(invitrogen,REF 88-7316-88)检测各孔中IL-2及IFN-γ浓度,沉淀部分用100ul Annexin V Binding Buffer(Biolegend,B274722)重悬,300g离心5min,之后添加3ul APC-Annexin V(Biolegend,Cat640920)和1.5ul PI染料(Biolegend,Cat 421301),避光孵育15min,添加100ul Annexin VBinding Buffer重悬,之后利用Beckman Coulter流式细胞仪检测各靶细胞凋亡比例(结果如图21所示),利用ELISA检测各孔上清IL-2及IFN-γ浓度(结果如图22和图23所示)。其中K562为BCMA阴性细胞,K562-BCMA,RPMI8226均为BCMA阳性细胞。结果显示PCDHF-73 CART、PCDHF-74 CART和PCDHF-42 CART对BCMA阳性靶细胞有较强的特异性杀伤,并且3种CART细胞的杀伤阳性靶细胞能力基本一致,对BCMA阴性细胞几乎无杀伤作用;PCDHF-42 CART,PCDHF-73 CART和PCDHF-74 CART杀伤BCMA阳性靶细胞时IL-2和IFN-γ分泌量处于同一水平,综合特异性杀伤和因子分泌的检测结果说明,人源化BCMA CART PCDHF-73 CART和PCDHF-74 CART与鼠源BCMA CART PCDHF-42 CART对BCMA阳性靶细胞有同等的杀伤效果。
本发明所涉及的序列如下表所示
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
序列表
<110> 深圳市菲鹏生物治疗股份有限公司
<120> BCMA结合抗体及其用途
<130> 2020
<150> CN201911298620.7
<151> 2019-12-17
<160> 60
<170> SIPOSequenceListing 1.0
<210> 1
<211> 10
<212> PRT
<213> artificial sequence
<400> 1
Gly Tyr Thr Phe Thr Ser Tyr Val Val His
1 5 10
<210> 2
<211> 9
<212> PRT
<213> artificial sequence
<400> 2
Ile Ile Pro Tyr Asn Asp Asp Thr Lys
1 5
<210> 3
<211> 3
<212> PRT
<213> artificial sequence
<400> 3
Ala Arg Trp
1
<210> 4
<211> 12
<212> PRT
<213> artificial sequence
<400> 4
Ser Gln Ser Leu Leu His Ser Asn Gly Asn Thr Tyr
1 5 10
<210> 5
<211> 7
<212> PRT
<213> artificial sequence
<400> 5
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 6
<211> 9
<212> PRT
<213> artificial sequence
<400> 6
Gln Ile Thr His Ile Pro Phe Thr Phe
1 5
<210> 7
<211> 25
<212> PRT
<213> artificial sequence
<400> 7
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
20 25
<210> 8
<211> 15
<212> PRT
<213> artificial sequence
<400> 8
Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr
1 5 10 15
<210> 9
<211> 37
<212> PRT
<213> artificial sequence
<400> 9
Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser
1 5 10 15
Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser
20 25 30
Ala Val Tyr Tyr Cys
35
<210> 10
<211> 20
<212> PRT
<213> artificial sequence
<400> 10
Asp Tyr Asp Asp Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu
1 5 10 15
Thr Val Ser Ser
20
<210> 11
<211> 25
<212> PRT
<213> artificial sequence
<400> 11
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser
20 25
<210> 12
<211> 17
<212> PRT
<213> artificial sequence
<400> 12
Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
1 5 10 15
Tyr
<210> 13
<211> 33
<212> PRT
<213> artificial sequence
<400> 13
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
20 25 30
Ser
<210> 14
<211> 10
<212> PRT
<213> artificial sequence
<400> 14
Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
1 5 10
<210> 15
<211> 119
<212> PRT
<213> artificial sequence
<400> 15
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 Val His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ile Pro Tyr Asn Asp Asp 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 Trp Asp Tyr Asp Asp Gly Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 16
<211> 113
<212> PRT
<213> artificial sequence
<400> 16
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu 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 Lys 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 Leu Gly Val Tyr Phe Cys Ser Gln Ile
85 90 95
Thr His Ile Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 17
<211> 729
<212> DNA
<213> artificial sequence
<400> 17
cagatccagc tggtgcagtc tggcccagag ctgaagaagc ccggcgagac cgtgaagatc 60
agctgcaagg cctccggcta caccttcaca gactatagca tcaactgggt gaagagggcc 120
cctggcaagg gcctgaagtg gatgggctgg atcaataccg agacacgcga gccagcctac 180
gcctatgact tccggggcag attcgccttt tccctggaga cctctgccag cacagcctac 240
ctgcagatca acaatctgaa gtacgaggat accgccacat atttttgcgc cctggactac 300
agctatgcca tggattattg gggccagggc acctccgtga cagtgagctc cggaggagga 360
ggctccggcg gcggaggctc tggcggcggc ggcagcgaca tcgtgctgac ccagtcccca 420
gcctctctgg ccatgtccct gggcaagcgg gccacaatct cttgtagagc ctccgagtct 480
gtgagcgtga tcggcgccca cctgatccac tggtaccagc agaagcctgg ccagccccct 540
aagctgctga tctatctggc cagcaacctg gagaccggag tgccagcacg gttctccggc 600
tctggcagcg gcacagactt taccctgaca atcgatcctg tggaggagga cgatgtggcc 660
atctactctt gtctgcagag caggatcttc ccacgcacct ttggcggcgg cacaaagctg 720
gagatcaag 729
<210> 18
<211> 8134
<212> DNA
<213> artificial sequence
<400> 18
cgataccgtc gacctcgaga cctagaaaaa catggagcaa tcacaagtag caatacagca 60
gctaccaatg ctgattgtgc ctggctagaa gcacaagagg aggaggaggt gggttttcca 120
gtcacacctc aggtaccttt aagaccaatg acttacaagg cagctgtaga tcttagccac 180
tttttaaaag aaaagggggg actggaaggg ctaattcact cccaacgaag acaagatatc 240
cttgatctgt ggatctacca cacacaaggc tacttccctg attggcagaa ctacacacca 300
gggccaggga tcagatatcc actgaccttt ggatggtgct acaagctagt accagttgag 360
caagagaagg tagaagaagc caatgaagga gagaacaccc gcttgttaca ccctgtgagc 420
ctgcatggga tggatgaccc ggagagagaa gtattagagt ggaggtttga cagccgccta 480
gcatttcatc acatggcccg agagctgcat ccggactcga gataacttcg tataatgtat 540
gctatacgaa gttattccgg actgtactgg gtctctctgg ttagaccaga tctgagcctg 600
ggagctctct ggctaactag ggaacccact gcttaagcct caataaagct tgccttgagt 660
gcttcaagta gtgtgtgccc gtctgttgtg tgactctggt aactagagat ccctcagacc 720
cttttagtca gtgtggaaaa tctctagcag ggcccgttta aacccgctga tcagcctcga 780
ctgtgccttc tagttgccag ccatctgttg tttgcccctc ccccgtgcct tccttgaccc 840
tggaaggtgc cactcccact gtcctttcct aataaaatga ggaaattgca tcgcattgtc 900
tgagtaggtg tcattctatt ctggggggtg gggtggggca ggacagcaag ggggaggatt 960
gggaagacaa tagcaggcat gtgagcaaaa ggccagcaaa aggccaggaa ccgtaaaaag 1020
gccgcgttgc tggcgttttt ccataggctc cgcccccctg acgagcatca caaaaatcga 1080
cgctcaagtc agaggtggcg aaacccgaca ggactataaa gataccaggc gtttccccct 1140
ggaagctccc tcgtgcgctc tcctgttccg accctgccgc ttaccggata cctgtccgcc 1200
tttctccctt cgggaagcgt ggcgctttct catagctcac gctgtaggta tctcagttcg 1260
gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac cccccgttca gcccgaccgc 1320
tgcgccttat ccggtaacta tcgtcttgag tccaacccgg taagacacga cttatcgcca 1380
ctggcagcag ccactggtaa caggattagc agagcgaggt atgtaggcgg tgctacagag 1440
ttcttgaagt ggtggcctaa ctacggctac actagaagaa cagtatttgg tatctgcgct 1500
ctgctgaagc cagttacctt cggaaaaaga gttggtagct cttgatccgg caaacaaacc 1560
accgctggta gcggtggttt ttttgtttgc aagcagcaga ttacgcgcag aaaaaaagga 1620
tctcaagaag atcctttgat cttttctacg gggtctgacg ctcagtggaa cgaaaactca 1680
cgttaaggga ttttggtcat gagattatca aaaaggatct tcacctagat ccttttaaat 1740
taaaaatgaa gttttaaatc aatctaaagt atatatgagt aaacttggtc tgacagttac 1800
caatgcttaa tcagtgaggc acctatctca gcgatctgtc tatttcgttc atccatagtt 1860
gcctgactcc ccgtcgtgta gataactacg atacgggagg gcttaccatc tggccccagt 1920
gctgcaatga taccgcgaga cccacgctca ccggctccag atttatcagc aataaaccag 1980
ccagccggaa gggccgagcg cagaagtggt cctgcaactt tatccgcctc catccagtct 2040
attaattgtt gccgggaagc tagagtaagt agttcgccag ttaatagttt gcgcaacgtt 2100
gttgccattg ctacaggcat cgtggtgtca cgctcgtcgt ttggtatggc ttcattcagc 2160
tccggttccc aacgatcaag gcgagttaca tgatccccca tgttgtgcaa aaaagcggtt 2220
agctccttcg gtcctccgat cgttgtcaga agtaagttgg ccgcagtgtt atcactcatg 2280
gttatggcag cactgcataa ttctcttact gtcatgccat ccgtaagatg cttttctgtg 2340
actggtgagt actcaaccaa gtcattctga gaatagtgta tgcggcgacc gagttgctct 2400
tgcccggcgt caatacggga taataccgcg ccacatagca gaactttaaa agtgctcatc 2460
attggaaaac gttcttcggg gcgaaaactc tcaaggatct taccgctgtt gagatccagt 2520
tcgatgtaac ccactcgtgc acccaactga tcttcagcat cttttacttt caccagcgtt 2580
tctgggtgag caaaaacagg aaggcaaaat gccgcaaaaa agggaataag ggcgacacgg 2640
aaatgttgaa tactcatact cttccttttt caatattatt gaagcattta tcagggttat 2700
tgtctcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg 2760
cgcacatttc cccgaaaagt gccacctgac gtcgacggat cgggagatct cccgatcccc 2820
tatggtgcac tctcagtaca atctgctctg atgccgcata gttaagccag tatctgctcc 2880
ctgcttgtgt gttggaggtc gctgagtagt gcgcgagcaa aatttaagct acaacaaggc 2940
aaggcttgac cgacaattgc atgaagaatc tgcttagggt taggcgtttt gcgctgcttc 3000
gcgatgtacg ggccagatat acgcgttgac attgattatt gactagttat taatagtaat 3060
caattacggg gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg 3120
taaatggccc gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt 3180
atgttcccat agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac 3240
ggtaaactgc ccacttggca gtacatcaag tgtatcatat gccaagtacg ccccctattg 3300
acgtcaatga cggtaaatgg cccgcctggc attatgccca gtacatgacc ttatgggact 3360
ttcctacttg gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt 3420
ggcagtacat caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc 3480
ccattgacgt caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc 3540
gtaacaactc cgccccattg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata 3600
taagcagcgc gttttgcctg tactgggtct ctctggttag accagatctg agcctgggag 3660
ctctctggct aactagggaa cccactgctt aagcctcaat aaagcttgcc ttgagtgctt 3720
caagtagtgt gtgcccgtct gttgtgtgac tctggtaact agagatccct cagacccttt 3780
tagtcagtgt ggaaaatctc tagcagtggc gcccgaacag ggacttgaaa gcgaaaggga 3840
aaccagagga gctctctcga cgcaggactc ggcttgctga agcgcgcacg gcaagaggcg 3900
aggggcggcg actggtgagt acgccaaaaa ttttgactag cggaggctag aaggagagag 3960
atgggtgcga gagcgtcagt attaagcggg ggagaattag atcgcgatgg gaaaaaattc 4020
ggttaaggcc agggggaaag aaaaaatata aattaaaaca tatagtatgg gcaagcaggg 4080
agctagaacg attcgcagtt aatcctggcc tgttagaaac atcagaaggc tgtagacaaa 4140
tactgggaca gctacaacca tcccttcaga caggatcaga agaacttaga tcattatata 4200
atacagtagc aaccctctat tgtgtgcatc aaaggataga gataaaagac accaaggaag 4260
ctttagacaa gatagaggaa gagcaaaaca aaagtaagac caccgcacag caagcggccg 4320
ctgatcttca gacctggagg aggagatatg agggacaatt ggagaagtga attatataaa 4380
tataaagtag taaaaattga accattagga gtagcaccca ccaaggcaaa gagaagagtg 4440
gtgcagagag aaaaaagagc agtgggaata ggagctttgt tccttgggtt cttgggagca 4500
gcaggaagca ctatgggcgc agcgtcaatg acgctgacgg tacaggccag acaattattg 4560
tctggtatag tgcagcagca gaacaatttg ctgagggcta ttgaggcgca acagcatctg 4620
ttgcaactca cagtctgggg catcaagcag ctccaggcaa gaatcctggc tgtggaaaga 4680
tacctaaagg atcaacagct cctggggatt tggggttgct ctggaaaact catttgcacc 4740
actgctgtgc cttggaatgc tagttggagt aataaatctc tggaacagat ttggaatcac 4800
acgacctgga tggagtggga cagagaaatt aacaattaca caagcttaat acactcctta 4860
attgaagaat cgcaaaacca gcaagaaaag aatgaacaag aattattgga attagataaa 4920
tgggcaagtt tgtggaattg gtttaacata acaaattggc tgtggtatat aaaattattc 4980
ataatgatag taggaggctt ggtaggttta agaatagttt ttgctgtact ttctatagtg 5040
aatagagtta ggcagggata ttcaccatta tcgtttcaga cccacctccc aaccccgagg 5100
ggacccgaca ggcccgaagg aatagaagaa gaaggtggag agagagacag agacagatcc 5160
attcgattag tgaacggatc ggcactgcgt gcgccaattc tgcagacaaa tggcagtatt 5220
catccacaat tttaaaagaa aaggggggat tggggggtac agtgcagggg aaagaatagt 5280
agacataata gcaacagaca tacaaactaa agaattacaa aaacaaatta caaaaattca 5340
aaattttcgg gtttattaca gggacagcag agatccagtt tggttaatta acgtgaggct 5400
ccggtgcccg tcagtgggca gagcgcacat cgcccacagt ccccgagaag ttggggggag 5460
gggtcggcaa ttgacccggt gcctagagaa ggtggcgcgg ggtaaactgg gaaagtgatg 5520
tcgtgtactg gctccgcctt tttcccgagg gtgggggaga accgtatata agtgcagtag 5580
tcgccgtgaa cgttcttttt cgcaacgggt ttgccgccag aacacaggta agtgccgtgt 5640
gtggttcccg cgggcctggc ctctttacgg gttatggccc ttgcgtgcct tgaattactt 5700
ccacctggct gcagtacgtg attcttgatc ccgagcttcg ggttggaagt gggtgggaga 5760
gttcgaggcc ttgcgcttaa ggagcccctt cgcctcgtgc ttgagttgag gcctggcctg 5820
ggcgctgggg ccgccgcgtg cgaatctggt ggcaccttcg cgcctgtctc gctgctttcg 5880
ataagtctct agccatttaa aatttttgat gacctgctgc gacgcttttt ttctggcaag 5940
atagtcttgt aaatgcgggc caagatctgc acactggtat ttcggttttt ggggccgcgg 6000
gcggcgacgg ggcccgtgcg tcccagcgca catgttcggc gaggcggggc ctgcgagcgc 6060
ggccaccgag aatcggacgg gggtagtctc aagctcgccg gcctgctctg gtgcctggcc 6120
tcgcgccgcc gtgtatcgcc ccgccctggg cggcaaggct ggcccggtcg gcaccagttg 6180
cgtgagcgga aagatggccg cttcccggcc ctgctgcagg gagctcaaaa tggaggacgc 6240
ggcgctcggg agagcgggcg ggtgagtcac ccacacaaag gaaaagggcc tttccgtcct 6300
cagccgtcgc ttcatgtgac tccactgagt accgggcgcc gtccaggcac ctcgattagt 6360
tctcgagctt ttggagtacg tcgtctttag gttgggggga ggggttttat gcgatggagt 6420
ttccccacac tgagtgggtg gagactgaag ttaggccagc ttggcacttg atgtaattct 6480
ccttggaatt tgcccttttt gagtttggat cttggttcat tctcaagcct cagacagtgg 6540
ttcaaagttt ttttcttcca tttcaggtgt cgtgagggat ccccggaatt catcgatgcc 6600
actaacttct ccctgttgaa acaagcaggg gatgtcgaag agaatcccgg gccaatggtg 6660
agcaagggcg aggagctgtt caccggggtg gtgcccatcc tggtcgagct ggacggcgac 6720
gtaaacggcc acaagttcag cgtgtccggc gagggcgagg gcgatgccac ctacggcaag 6780
ctgaccctga agttcatctg caccaccggc aagctgcccg tgccctggcc caccctcgtg 6840
accaccctga cctacggcgt gcagtgcttc agccgctacc ccgaccacat gaagcagcac 6900
gacttcttca agtccgccat gcccgaaggc tacgtccagg agcgcaccat cttcttcaag 6960
gacgacggca actacaagac ccgcgccgag gtgaagttcg agggcgacac cctggtgaac 7020
cgcatcgagc tgaagggcat cgacttcaag gaggacggca acatcctggg gcacaagctg 7080
gagtacaact acaacagcca caacgtctat atcatggccg acaagcagaa gaacggcatc 7140
aaggtgaact tcaagatccg ccacaacatc gaggacggca gcgtgcagct cgccgaccac 7200
taccagcaga acacccccat cggcgacggc cccgtgctgc tgcccgacaa ccactacctg 7260
agcacccagt ccgccctgag caaagacccc aacgagaagc gcgatcacat ggtcctgctg 7320
gagttcgtga ccgccgccgg gatcactctc ggcatggacg agctgtacaa gtaacttaag 7380
gccggccgac gcccttgacg attttgactt agacatgctc ccagccgatg cccttgacga 7440
ctttgacctt gatatgctgc ctgctgacgc tcttgacgat tttgaccttg acatgctccc 7500
cgggtaacta agtaaggatc aattcgatat caagcttatc gataatcaac ctctggatta 7560
caaaatttgt gaaagattga ctggtattct taactatgtt gctcctttta cgctatgtgg 7620
atacgctgct ttaatgcctt tgtatcatgc tattgcttcc cgtatggctt tcattttctc 7680
ctccttgtat aaatcctggt tgctgtctct ttatgaggag ttgtggcccg ttgtcaggca 7740
acgtggcgtg gtgtgcactg tgtttgctga cgcaaccccc actggttggg gcattgccac 7800
cacctgtcag ctcctttccg ggactttcgc tttccccctc cctattgcca cggcggaact 7860
catcgccgcc tgccttgccc gctgctggac aggggctcgg ctgttgggca ctgacaattc 7920
cgtggtgttg tcggggaaat catcgtcctt tccttggctg ctcgcctgtg ttgccacctg 7980
gattctgcgc gggacgtcct tctgctacgt cccttcggcc ctcaatccag cggaccttcc 8040
ttcccgcggc ctgctgccgg ctctgcggcc tcttccgcgt cttcgccttc gccctcagac 8100
gagtcggatc tccctttggg ccgcctcccc gcat 8134
<210> 19
<211> 9
<212> PRT
<213> artificial sequence
<400> 19
Ala Gly Lys Trp Glu Arg Trp Ala His
1 5
<210> 20
<211> 8
<212> PRT
<213> artificial sequence
<400> 20
Lys Pro Ala Tyr Trp Thr Ser Ala
1 5
<210> 21
<211> 3
<212> PRT
<213> artificial sequence
<400> 21
Ala Thr Leu
1
<210> 22
<211> 12
<212> PRT
<213> artificial sequence
<400> 22
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 23
<211> 7
<212> PRT
<213> artificial sequence
<400> 23
Ser Asp Ala Thr Gly Ile Pro
1 5
<210> 24
<211> 9
<212> PRT
<213> artificial sequence
<400> 24
Gln Gln Tyr Gly Tyr Pro Pro Ser Tyr
1 5
<210> 25
<211> 25
<212> PRT
<213> artificial sequence
<400> 25
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
20 25
<210> 26
<211> 15
<212> PRT
<213> artificial sequence
<400> 26
Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr
1 5 10 15
<210> 27
<211> 37
<212> PRT
<213> artificial sequence
<400> 27
Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser
1 5 10 15
Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser
20 25 30
Ala Val Tyr Tyr Cys
35
<210> 28
<211> 20
<212> PRT
<213> artificial sequence
<400> 28
Asp Tyr Asp Asp Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu
1 5 10 15
Thr Val Ser Ser
20
<210> 29
<211> 23
<212> PRT
<213> artificial sequence
<400> 29
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys
20
<210> 30
<211> 18
<212> PRT
<213> artificial sequence
<400> 30
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gln
1 5 10 15
Ala Ser
<210> 31
<211> 29
<212> PRT
<213> artificial sequence
<400> 31
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
1 5 10 15
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
20 25
<210> 32
<211> 11
<212> PRT
<213> artificial sequence
<400> 32
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 33
<211> 117
<212> PRT
<213> artificial sequence
<400> 33
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 Ala Gly Lys Trp Glu Arg Trp
20 25 30
Ala His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile Gly
35 40 45
Tyr Lys Pro Ala Tyr Trp Thr Ser Ala Tyr Asn Glu Lys Phe Lys Gly
50 55 60
Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
65 70 75 80
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Thr
85 90 95
Leu Asp Tyr Asp Asp Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 34
<211> 109
<212> PRT
<213> artificial sequence
<400> 34
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gln Ala Ser Ser Asp Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro
85 90 95
Ser Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 35
<211> 45
<212> DNA
<213> artificial sequence
<400> 35
ggaggaggag gctccggcgg cggaggctct ggcggcggcg gcagc 45
<210> 36
<211> 119
<212> PRT
<213> artificial sequence
<400> 36
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys 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 Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ile Pro Tyr Asn Asp Asp 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 Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Tyr Asp Asp Gly Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 37
<211> 119
<212> PRT
<213> artificial sequence
<400> 37
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys 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 Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ile Pro Tyr Asn Asp Asp Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Ser Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Tyr Asp Asp Gly Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 38
<211> 112
<212> PRT
<213> artificial sequence
<400> 38
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu 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 Val Tyr Phe Cys Ser Gln Ile
85 90 95
Thr His Ile Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 39
<211> 112
<212> PRT
<213> artificial sequence
<400> 39
Asp Val 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 Leu 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 Val Tyr Phe Cys Ser Gln Ile
85 90 95
Thr His Ile Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 40
<211> 113
<212> PRT
<213> artificial sequence
<400> 40
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 Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Pro
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ile
85 90 95
Thr His Ile Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 41
<211> 25
<212> PRT
<213> artificial sequence
<400> 41
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser
20 25
<210> 42
<211> 15
<212> PRT
<213> artificial sequence
<400> 42
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr
1 5 10 15
<210> 43
<211> 37
<212> PRT
<213> artificial sequence
<400> 43
Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser
1 5 10 15
Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys
35
<210> 44
<211> 20
<212> PRT
<213> artificial sequence
<400> 44
Asp Tyr Asp Asp Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val
1 5 10 15
Thr Val Ser Ser
20
<210> 45
<211> 25
<212> PRT
<213> artificial sequence
<400> 45
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser
20 25
<210> 46
<211> 15
<212> PRT
<213> artificial sequence
<400> 46
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr
1 5 10 15
<210> 47
<211> 37
<212> PRT
<213> artificial sequence
<400> 47
Tyr Asn Glu Lys Phe Lys Gly Arg Val Thr Leu Thr Ser Asp Lys Ser
1 5 10 15
Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
20 25 30
Ala Val Tyr Tyr Cys
35
<210> 48
<211> 20
<212> PRT
<213> artificial sequence
<400> 48
Asp Tyr Asp Asp Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val
1 5 10 15
Thr Val Ser Ser
20
<210> 49
<211> 25
<212> PRT
<213> artificial sequence
<400> 49
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser
20 25
<210> 50
<211> 17
<212> PRT
<213> artificial sequence
<400> 50
Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile
1 5 10 15
Tyr
<210> 51
<211> 32
<212> PRT
<213> artificial sequence
<400> 51
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
1 5 10 15
Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Ser
20 25 30
<210> 52
<211> 9
<212> PRT
<213> artificial sequence
<400> 52
Gly Gln Gly Thr Lys Leu Glu Ile Lys
1 5
<210> 53
<211> 25
<212> PRT
<213> artificial sequence
<400> 53
Asp Val 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
20 25
<210> 54
<211> 17
<212> PRT
<213> artificial sequence
<400> 54
Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile
1 5 10 15
Tyr
<210> 55
<211> 32
<212> PRT
<213> artificial sequence
<400> 55
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
1 5 10 15
Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Ser
20 25 30
<210> 56
<211> 9
<212> PRT
<213> artificial sequence
<400> 56
Gly Gln Gly Thr Lys Leu Glu Ile Lys
1 5
<210> 57
<211> 25
<212> PRT
<213> artificial sequence
<400> 57
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
20 25
<210> 58
<211> 17
<212> PRT
<213> artificial sequence
<400> 58
Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Pro Pro Gln Leu Leu Ile
1 5 10 15
Tyr
<210> 59
<211> 32
<212> PRT
<213> artificial sequence
<400> 59
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
1 5 10 15
Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser
20 25 30
<210> 60
<211> 10
<212> PRT
<213> artificial sequence
<400> 60
Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
1 5 10
Claims (10)
1.一种BCMA抗体或其抗原结合片段,其能够特异性结合BCMA,且选自a)和/或b):
a)包含氨基酸序列依次如SEQ ID NO:1~3所示的重链互补决定区CDR-VH1、CDR-VH2、CDR-VH3,以及氨基酸序列依次如SEQ ID NO:4~6所示的轻链互补决定区CDR-VL1、CDR-VL2、CDR-VL3;
b)包含氨基酸序列依次如SEQ ID NO:19~21所示的重链互补决定区CDR-VH1、CDR-VH2、CDR-VH3,以及氨基酸序列依次如SEQ ID NO:22~24所示的轻链互补决定区CDR-VL1、CDR-VL2、CDR-VL3。
2.根据权利要求1所述的抗体或其抗原结合片段,a还包含序列如SEQ ID NO:7~10、SEQ ID NO:41~44、或SEQ ID NO:45~48所示的重链骨架区FR-H1、FR-H2、FR-H3及FR-H4;和/或;序列如SEQ ID NO:11~14、SEQ ID NO:49~52、SEQ ID NO:53~56或SEQ ID NO:57~60所示的轻链骨架区FR-L1、FR-L2、FR-L3及FR-L4;
b还包含序列依次如SEQ ID NO:25~28所示的重链骨架区FR-H1、FR-H2、FR-H3及FR-H4;和/或;序列依次如SEQ ID NO:29~32所示的轻链骨架区FR-L1、FR-L2、FR-L3及FR-L4。
3.根据权利要求1或2所述的抗体或其抗原结合片段,所述抗体为F(ab’)2、Fab、Fv、scFv以及双特异抗体中的一种。
4.根据权利要求1或2所述的抗体或其抗原结合片段,所述抗体具有恒定区,恒定区序列选自IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任何其中之一恒定区的序列;
可选的,所述恒定区的种属来源独立地选自牛、马、乳牛、猪、绵羊、山羊、大鼠、小鼠、狗、猫、兔、骆驼、驴、鹿、貂、鸡、鸭、鹅、火鸡、斗鸡或人。
5.嵌合抗原受体,其包含权利要求1~3任一项所述的抗体;
可选的,所述嵌合抗原受体还包含一个或多个选自由以下组成的组的元件:前导肽、接头序列、跨膜结构域、共刺激结构域和信号传导结构域。
6.分离的核酸,其编码权利要求1~4任一项所述的抗体,或权利要求5所述的嵌合抗原受体。
7.载体,其包含权利要求6所述的分离的核酸;
可选的,所述载体为慢病毒载体;
可选的,所述慢病毒载体的核苷酸序列为SEQ ID NO:18所示。
8.宿主细胞,其包含权利要求7所述的载体。
9.免疫细胞,其包含权利要求5所述的嵌合抗原受体;
可选的,所述免疫细胞为T细胞、肿瘤浸润淋巴细胞、NK细胞、树突状细胞或NK-T细胞;
可选的,所述免疫细胞为自体T细胞或同种异体T细胞。
10.药物组合物,其包括权利要求1~4任一项所述的抗体或权利要求9所述的免疫细胞,以及药学上可接受的赋形剂、稀释剂或载体中的一种或多种。
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Cited By (3)
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CN114634568A (zh) * | 2020-12-16 | 2022-06-17 | 深圳市菲鹏生物治疗股份有限公司 | Bcma的抗体及其应用 |
CN115521381A (zh) * | 2021-06-24 | 2022-12-27 | 益科思特(北京)医药科技发展有限公司 | 结合bcma和cd3的双特异性抗体及其制备方法与应用 |
CN117164714A (zh) * | 2023-10-08 | 2023-12-05 | 北京奇迈永华生物科技有限公司 | 一种靶向bcma的抗体及其应用 |
Citations (3)
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CN114634568A (zh) * | 2020-12-16 | 2022-06-17 | 深圳市菲鹏生物治疗股份有限公司 | Bcma的抗体及其应用 |
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CN117164714A (zh) * | 2023-10-08 | 2023-12-05 | 北京奇迈永华生物科技有限公司 | 一种靶向bcma的抗体及其应用 |
CN117164714B (zh) * | 2023-10-08 | 2024-04-23 | 北京奇迈永华生物科技有限公司 | 一种靶向bcma的抗体及其应用 |
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CN112979807B (zh) | 2022-07-26 |
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