CN115073596A - 一种人源化Claudin 18.2抗体及其应用 - Google Patents
一种人源化Claudin 18.2抗体及其应用 Download PDFInfo
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- CN115073596A CN115073596A CN202110262451.2A CN202110262451A CN115073596A CN 115073596 A CN115073596 A CN 115073596A CN 202110262451 A CN202110262451 A CN 202110262451A CN 115073596 A CN115073596 A CN 115073596A
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Abstract
本发明公开了一种人源化Claudin 18.2抗体及其应用。具体地，本发明公开了靶向细胞表达的Claudin 18.2的人源化Claudin 18.2单克隆抗体、编码抗体或其片段的核酸序列及其制备方法。体外实验证明本发明的抗体能够以高亲和力特异性结合细胞表面表达的Claudin 18.2，并且经过人源化改造降低了异源性抗体的免疫原性，更有利于应用到人体。
Description
技术领域
本发明涉及生物工程和抗体领域，具体地涉及一种人源化的抗Claudin 18.2抗体及其制备方法。
背景技术
胃肠道和胰腺肿瘤对于人类生命是很大的威胁，虽然手术治疗、放化疗、介入治疗等治疗手段对于该类肿瘤有一定疗效，但患者生存率仍无显著改善。
细胞免疫治疗是一种正在兴起的肿瘤治疗方法，其通过分子生物学技术构建嵌合抗原受体(chimeric antigen receptor，CAR)的表达载体，并将该表达载体导入到从人体分离的免疫细胞中，使其细胞表面表达CAR后进行扩增培养，将其回输至人体。CAR由抗原识别域、铰链区和跨膜区及胞内信号域依次连接组成,表达CAR的免疫细胞能够特异性识别并结合靶细胞，通过释放特异的免疫因子对其进行杀伤。
胃癌是世界上最常见的癌症之一，在中国，胃癌是第二大常见恶性肿瘤,被认为是全世界最难治愈的癌症之一。尽管近年来在治疗选择方面取得了进步，但是胃癌复发难以避免，晚期胃癌患者的五年生存率约为5–20％，中位总体生存期约为10个月。随着胃癌发生、发展分子机制研究的深入，靶向治疗成为一种有效的晚期癌症的治疗方案，靶点主要包括EGFR、HER-2、VEGF、VEGFR等。CLDN18.2作为一个高度特异性表达的细胞表面分子，在正常的组织中仅表达在分化的胃粘膜上皮细胞上，因此需要开发具有更大抗胃癌潜力、更低毒性、更低用药剂量的针对CLDN18.2的治疗性抗体。
鼠源单抗对人体具有异源性反应，可诱发人抗鼠抗体效应(Human anti-mouseantibodies,HAMA反应)，使得抗体或者CART的治疗效果滞后。
综上所述，本领域急需开发一种新的CLDN18.2抗体用于肿瘤治疗。
发明内容
本发明的目的在于提供一种靶向表达Claudin 18.2(CLDN 18.2)的细胞的人源化抗体及其应用。
本发明的第一方面，提供了一种人源化Claudin 18.2(CLDN 18.2)抗体或其抗原结合片段，所述抗体或其抗原结合片段包含重链和轻链，
其中，所述重链的重链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:12所示的CDR1；
如SEQ ID NO:13所示的CDR2；和
如SEQ ID NO:14所示的CDR3；
以及，所述轻链的轻链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:15所示的CDR1’；
如SEQ ID NO:16所示的CDR2’；和
如SEQ ID NO:17所示的CDR3’。
在另一优选例中，所述抗体或其抗原结合片段包含SEQ ID NO:1至6中任一所示的抗体重链可变区。
在另一优选例中，所述抗体或其抗原结合片段包含SEQ ID NO:7至9中任一所示的抗体轻链可变区。
在另一优选例中，所述重链可变区的亲和力与鼠源的SEQ ID NO:10所示的重链可变区的亲和力在一个数量级；
在另一优选例中，所述轻链可变区的亲和力与鼠源的SEQ ID NO:11所示的轻链可变区的亲和力在一个数量级。
在另一优选例中，所述SEQ ID NO:13的序列为MIHPNX1GSTN，其中X1为Ser(S)或Thr(T)。
在另一优选例中，所述SEQ ID NO:14的序列为GGYYGNX2LDF，其中X2为Ser(S)或Thr(T)。
在另一优选例中，所述SEQ ID NO:16的序列为WASX3X4X5S，其中X3为Ser(S)或Thr(T)；X4为Arg(R)或Leu(L)；X5为Glu(E)或Gln(Q)。
在另一优选例中，所述抗体重链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:12所示的CDR1；
如SEQ ID NO:38所示的CDR2；和
如SEQ ID NO:39所示的CDR3；
以及，所述抗体轻链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:15所示的CDR1’；
如SEQ ID NO:40所示的CDR2’；和
如SEQ ID NO:17所示的CDR3’。
在另一优选例中，所述抗体重链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:12所示的CDR1；
如SEQ ID NO:41所示的CDR2；和
如SEQ ID NO:42所示的CDR3；
以及，所述抗体轻链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:15所示的CDR1’；
如SEQ ID NO:40所示的CDR2’；和
如SEQ ID NO:17所示的CDR3’。
在另一优选例中，所述抗体重链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:12所示的CDR1；
如SEQ ID NO:38所示的CDR2；和
如SEQ ID NO:39所示的CDR3；
以及，所述抗体轻链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:15所示的CDR1’；
如SEQ ID NO:43所示的CDR2’；和
如SEQ ID NO:17所示的CDR3’。
在另一优选例中，所述抗体重链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:12所示的CDR1；
如SEQ ID NO:38所示的CDR2；和
如SEQ ID NO:39所示的CDR3；
以及，所述抗体轻链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:15所示的CDR1’；
如SEQ ID NO:44所示的CDR2’；和
如SEQ ID NO:17所示的CDR3’。
在另一优选例中，所述抗体重链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:12所示的CDR1；
如SEQ ID NO:41所示的CDR2；和
如SEQ ID NO:42所示的CDR3；
以及，所述抗体轻链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:15所示的CDR1’；
如SEQ ID NO:44所示的CDR2’；和
如SEQ ID NO:17所示的CDR3’。
在另一优选例中，所述抗体的重链可变区和轻链可变区内还包含人源或鼠源的FR区。
在另一优选例中，所述抗体的FR区是将鼠源的FR区人源化得到的FR区。
在另一优选例中，所述抗体的重链和轻链还包含恒定区。
在另一优选例中，所述恒定区为人源或鼠源的。
在另一优选例中，所述抗体还包含位于重链可变区和轻链可变区之间的连接肽。
在另一优选例中，所述抗体或其抗原结合片段具有如SEQ ID NO:18、19、20、21、22、23、24、25、26或27所示的氨基酸序列。
在另一优选例中，所述抗体或其抗原结合片段具有如SEQ ID NO:22所示的氨基酸序列。
在另一优选例中，所述抗体或其抗原结合片段包括如SEQ ID NO:5所示的抗体重链可变区和如SEQ ID NO:7所示的抗体轻链可变区。
在另一优选例中，所述抗体或其抗原结合片段具有如SEQ ID NO:21所示的氨基酸序列。
在另一优选例中，所述抗体或其抗原结合片段包括如SEQ ID NO:4所示的抗体重链可变区和如SEQ ID NO:7所示的抗体轻链可变区。
在另一优选例中，所述抗体或其抗原结合片段具有如SEQ ID NO:19所示的氨基酸序列。
在另一优选例中，所述抗体或其抗原结合片段包括如SEQ ID NO:2所示的抗体重链可变区和如SEQ ID NO:7所示的抗体轻链可变区。
在另一优选例中，所述抗体或其抗原结合片段包含选自下表A的抗体重链可变区和抗体轻链可变区：
表A
在另一优选例中，所述的抗体为双链抗体、或单链抗体。
在另一优选例中，所述抗体为抗体全长蛋白、或抗原结合片段。
在另一优选例中，所述抗体为单克隆抗体。
本发明的第二方面，提供了一种嵌合抗原受体(CAR)，所述嵌合抗原受体包含本发明第一方面所述的抗体或抗原结合片段的重链可变区和轻链可变区。
本发明的第三方面，提供了一种核酸分子，所述的核酸分子编码如本发明第一方面所述的人源化Claudin 18.2抗体或其抗原结合片段或如本发明第二方面所述的CAR。
在另一优选例中，所述核酸分子含有如SEQ ID NO:28、29、30、31、32、33、34、35、36或37所示的核苷酸序列。
本发明的第四方面，提供了一种载体，所述载体含有如本发明第三方面所述的核酸分子。
在另一优选例中，所述的载体选自下组：DNA、RNA、质粒、真核表达载体、原核表达载体、慢病毒载体、腺病毒载体、腺相关病毒载体、逆转录病毒载体、转座子、或其组合。
在另一优选例中，所述的载体为真核表达载体。
本发明的第五方面，提供了一种工程化的宿主细胞，所述的宿主细胞含有如本发明第四方面所述的载体、或染色体中整合有外源的如本发明第三方面所述的核酸分子、或表达如本发明第一方面所述的人源化Claudin 18.2抗体或抗原结合片段或如本发明第二方面所述的嵌合抗原受体。
在另一优选例中，所述的宿主细胞为免疫细胞。
在另一优选例中，所述的免疫细胞为T细胞、NK细胞或其组合。
在另一优选例中，所述免疫细胞为嵌合抗原受体T细胞(CAR-T细胞)。
本发明的第六方面，提供了一种药物组合物，所述药物组合物含有本发明第一方面所述人源化Claudin 18.2抗体或其抗原结合片段、或如本发明第二方面所述的嵌合抗原受体、或如本发明第三方面所述的核酸分子、或如本发明第四方面所述的载体，或本发明第五方面所述的工程化的宿主细胞，以及药学上可接受的载体、稀释剂或赋形剂。
本发明的第七方面，提供了一种如本发明第一方面所述的人源化Claudin18.2抗体或其抗原结合片段、本发明第二方面所述的靶向Claudin 18.2的嵌合抗原受体(CAR)、本发明第三方面所述的核酸分子、本发明第四方面所述的载体、本发明第五方面所述的工程化的免疫细胞的用途，用于制备预防和/或治疗癌症或肿瘤的药物或制剂。
在另一优选例中，所述癌症或肿瘤选自下组：血液肿瘤、淋巴瘤、实体瘤、或其组合。
在另一优选例中，所述血液肿瘤选自下组：急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性淋巴白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、或其组合。
在另一优选例中，所述淋巴瘤选自下组：霍奇金淋巴瘤(HL)，弥漫大B细胞淋巴瘤(DLBCL)、滤泡淋巴瘤(FL)、慢性淋巴细胞白细胞(CLL)、小淋巴细胞淋巴瘤(SLL)、边缘区淋巴瘤(MZL)、套细胞淋巴瘤(MCL)、伯基特淋巴瘤(BL)以及其他复杂B细胞非霍奇金淋巴瘤。
在另一优选例中，所述实体瘤选自下组：胃癌、胃癌腹膜转移、肝癌、肾脏肿瘤、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、宫颈癌、卵巢癌、淋巴癌、鼻咽癌、肾上腺肿瘤、膀胱肿瘤、非小细胞肺癌(NSCLC)、脑胶质瘤、子宫内膜癌、睾丸癌、结直肠癌、尿路肿瘤、甲状腺癌、或其组合。
本发明的第八方面，提供了一种制备如本发明第一方面所述的人源化Claudin18.2抗体或其抗原结合片段的方法，包括在适合产生所述抗体或其抗原结合片段的条件下，培养包含编码所述抗体或其抗原结合片段的核酸的细胞，并从细胞或培养物中回收抗体或抗原结合片段。
本发明的第九方面，提供了一种制备如本发明第五方面所述的工程化的免疫细胞的方法，包括以下步骤：将如本发明第三方面所述的核酸分子或如本发明第四方面所述的载体转导入免疫细胞内，从而获得所述工程化的免疫细胞。
在另一优选例中，所述的宿主细胞为免疫细胞。
在另一优选例中，所述的免疫细胞为T细胞、NK细胞或其组合。
在另一优选例中，所述免疫细胞为嵌合抗原受体T细胞(CAR-T细胞)。
本发明的第十方面，提供了一种预防和/或治疗疾病的方法，包括给需要的对象施用治疗有效量的如本发明第一方面所述的人源化Claudin 18.2抗体或其抗原结合片段、如本发明第五方面所述的工程化的免疫细胞、或如权利要求6所述的药物组合物。
在另一优选例中，所述疾病为癌症或肿瘤。
在另一优选例中，所述癌症或肿瘤选自下组：血液肿瘤、淋巴瘤、实体瘤、或其组合。
在另一优选例中，所述血液肿瘤选自下组：急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性淋巴白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、或其组合。
在另一优选例中，所述淋巴瘤选自下组：霍奇金淋巴瘤(HL)，弥漫大B细胞淋巴瘤(DLBCL)、滤泡淋巴瘤(FL)、慢性淋巴细胞白细胞(CLL)、小淋巴细胞淋巴瘤(SLL)、边缘区淋巴瘤(MZL)、套细胞淋巴瘤(MCL)、伯基特淋巴瘤(BL)以及其他复杂B细胞非霍奇金淋巴瘤。
在另一优选例中，所述实体瘤选自下组：胃癌、胃癌腹膜转移、肝癌、肾脏肿瘤、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、宫颈癌、卵巢癌、淋巴癌、鼻咽癌、肾上腺肿瘤、膀胱肿瘤、非小细胞肺癌(NSCLC)、脑胶质瘤、子宫内膜癌、睾丸癌、结直肠癌、尿路肿瘤、甲状腺癌、或其组合。
在另一优选例中，所述需要的对象为人类或非人类哺乳动物。
在另一优选例中，所述需要的对象患有癌症或肿瘤。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1.LF001可变区结构模型
图2.LF001序列CDR区域在结构模拟中的位置：灰色标记为CDR区域，左边为VH，右边为VL。
图3.LF001鼠源重链序列分析对比图
图4.LF001鼠源轻链序列分析对比图
图5.抗体与18.2-K562结合FACS鉴定结果图
图6.抗体与18.1-K562结合FACS鉴定结果图
图7.抗体与K562结合FACS鉴定结果图
具体实施方式
本发明人经过广泛而深入的研究，通过筛选和人源化设计，首次意外地研发了一种靶向表达Claudin 18.2(CLDN 18.2)的细胞的人源化抗体。通过体外实验证明，所述人源化抗体能够有效并且特异性地靶向表达CLDN 18.2表面抗原的恶性细胞(例如肿瘤细胞)，且具有高亲和力，并可表达于免疫细胞例如T细胞表面，对表达CLDN 18.2表面抗原的恶性细胞进行特异性杀伤。在此基础上，完成了本发明。
术语
Claudin 18.2(CLDN 18.2)
Claudin 18.2简称为CLDN 18.2，在正常组织表达的高度特异性及在多种癌症中被激活表达，因此针对上皮性肿瘤，CLDN 18.2成为极具潜力的靶点，CLDN18.2是一种广谱性肿瘤标志物，可在多种肿瘤中表达。
如本文所用，“人源化Claudin 18.2抗体”即为本文实施例中所述抗体“LF001”。
抗体
如本文所用，术语“抗体”或“免疫球蛋白”是有相同结构特征的约150000道尔顿的异四聚糖蛋白，其由两个相同的轻链(L)和两个相同的重链(H)组成。每条轻链通过一个共价二硫键与重链相连，而不同免疫球蛋白同种型的重链间的二硫键数目不同。每条重链和轻链也有规则间隔的链内二硫键。每条重链的一端有可变区(VH)，其后是多个恒定区。每条轻链的一端有可变区(VL)，另一端有恒定区；轻链的恒定区与重链的第一个恒定区相对，轻链的可变区与重链的可变区相对。特殊的氨基酸残基在轻链和重链的可变区之间形成界面。
如本文所用，术语“可变”表示抗体中可变区的某些部分在序列上有所不同，它形成了各种特定抗体对其特定抗原的结合和特异性。然而，可变性并不均匀地分布在整个抗体可变区中。它集中于轻链和重链可变区中称为互补决定区(CDR)或超变区中的三个片段中。可变区中较保守的部分称为构架区(FR)。天然重链和轻链的可变区中各自包含四个FR区，它们大致上呈β-折叠构型，由形成连接环的三个CDR相连，在某些情况下可形成部分β折叠结构。每条链中的CDR通过FR区紧密地靠在一起并与另一链的CDR一起形成了抗体的抗原结合部位(参见Kabat等,NIH Publ.No.91-3242,卷I，647-669页(1991))。恒定区不直接参与抗体与抗原的结合，但是它们表现出不同的效应功能，例如参与抗体的依赖于抗体的细胞毒性。
脊椎动物抗体(免疫球蛋白)的“轻链”可根据其恒定区的氨基酸序列归为明显不同的两类(称为κ和λ)中的一类。根据其重链恒定区的氨基酸序列，免疫球蛋白可以分为不同的种类。主要有5类免疫球蛋白：IgA,IgD,IgE,IgG和IgM，其中一些还可进一步分成亚类(同种型)，如IgG1,IgG2,IgG3,IgG4,IgA和IgA2。对应于不同类免疫球蛋白的重链恒定区分别称为α、δ、ε、γ、和μ。不同类免疫球蛋白的亚单位结构和三维构型是本领域人员所熟知的。
本发明抗体的重链和/或轻链的可变区特别令人感兴趣，因为它们中至少部分涉及结合抗原。因此，本发明包括那些具有带CDR的单克隆抗体轻链和重链可变区的分子，只要其CDR与此处鉴定的CDR具有90％以上(较佳地95％以上，最佳地98％以上)的同源性。
如本文所用，术语“重链可变区”与“VH”可互换使用。
如本文所用，术语“轻链可变区”与“VL”可互换使用。
如本文所用，术语“可变区”与“互补决定区(complementarity determiningregion,CDR)”可互换使用。
本发明不仅包括完整的抗体，还包括具有免疫活性的抗体的片段或抗体与其他序列形成的融合蛋白。因此，本发明还包括所述抗体的片段、衍生物和类似物。
在本发明中，抗体包括用本领域技术人员熟知技术所制备的鼠的、嵌合的、人源化的或者全人的抗体。重组抗体，例如嵌合的和人源化的单克隆抗体，包括人的和非人的部分，可以通过标准的DNA重组技术获得，它们都是有用的抗体。
在本发明中，本发明的抗体还包括其保守性变异体，指与本发明抗体的氨基酸序列相比，有至多10个，较佳地至多8个，更佳地至多5个，最佳地至多3个氨基酸被性质相似或相近的氨基酸所替换而形成多肽。这些保守性变异多肽最好根据表A进行氨基酸替换而产生。
嵌合抗原受体(CAR)
本发明的嵌合抗原受体(CAR)包括细胞外结构域、跨膜结构域、和细胞内结构域。胞外结构域包括靶-特异性结合元件(也称为抗原结合结构域)。细胞内结构域包括共刺激信号传导区和ζ链部分。共刺激信号传导区指包括共刺激分子的细胞内结构域的一部分。共刺激分子为淋巴细胞对抗原的有效应答所需要的细胞表面分子，而不是抗原受体或它们的配体。
在CAR的胞外结构域和跨膜结构域之间，或在CAR的胞浆结构域和跨膜结构域之间，可并入接头。如本文所用的，术语“接头”通常指起到将跨膜结构域连接至多肽链的胞外结构域或胞浆结构域作用的任何寡肽或多肽。接头可包括0-300个氨基酸，优选地2至100个氨基酸和最优选地3至50个氨基酸。
在本发明的一个较佳的实施方式中，本发明提供的CAR的胞外结构域包括靶向Claudin 18.2的抗原结合结构域。本发明的CAR当在T细胞中表达时，能够基于抗原结合特异性进行抗原识别。当其结合其关联抗原时，影响肿瘤细胞，导致肿瘤细胞不生长、被促使死亡或以其他方式被影响，并导致患者的肿瘤负荷缩小或消除。抗原结合结构域优选与来自共刺激分子和ζ链中的一个或多个的细胞内结构域融合。优选地，抗原结合结构域与4-1BB信号传导结构域、和CD3ζ信号结构域组合的细胞内结构域融合。
如本文所用，“抗原结合结构域”、“单链抗体片段”均指具有抗原结合活性的Fab片段，Fab’片段，F(ab’)2片段，或单一Fv片段。Fv抗体含有抗体重链可变区、轻链可变区，但没有恒定区，并具有全部抗原结合位点的最小抗体片段。一般的，Fv抗体还包含VH和VL结构域之间的多肽接头，且能够形成抗原结合所需的结构。抗原结合结构域通常是scFv(single-chain variable fragment)。scFv的大小一般是一个完整抗体的1/6。单链抗体优选是由一条核苷酸链编码的一条氨基酸链序列。作为本发明的优选方式，所述抗原结合结构域包含特异性识别Claudin 18.2的抗体，较佳地为单链抗体。
对于绞链区和跨膜区(跨膜结构域)，CAR可被设计以包括融合至CAR的胞外结构域的跨膜结构域。在一个实施方式中，使用天然与CAR中的结构域之一相关联的跨膜结构域。在一些例子中，可选择跨膜结构域，或通过氨基酸置换进行修饰，以避免将这样的结构域结合至相同或不同的表面膜蛋白的跨膜结构域，从而最小化与受体复合物的其他成员的相互作用。本发明的CAR中的胞内结构域包括4-1BB的信号传导结构域和CD3ζ的信号传导结构域。
多核苷酸分子和载体
本发明还提供了编码上述抗体或其抗原结合片段或其融合蛋白以及上述嵌合抗原受体的多核苷酸分子。本发明的多核苷酸可以是DNA形式或RNA形式。DNA形式包括cDNA、基因组DNA或人工合成的DNA。DNA可以是单链的或是双链的。DNA可以是编码链或非编码链。编码成熟多肽的编码区序列可以与SEQ ID NO:28、29、30、31、32、33、34、35、36或37所示的编码区序列相同或者是简并的变异体。如本文所用，“简并的变异体”在本发明中是指编码具有与本发明的多肽相同的氨基酸序列，但与SEQ ID NO:28、29、30、31、32、33、34、35、36或37所示的编码区序列有差别的核酸序列。
编码本发明的成熟多肽的多核苷酸包括：只编码成熟多肽的编码序列；成熟多肽的编码序列和各种附加编码序列；成熟多肽的编码序列(和任选的附加编码序列)以及非编码序列。
术语“编码多肽的多核苷酸”可以是包括编码此多肽的多核苷酸，也可以是还包括附加编码和/或非编码序列的多核苷酸。
本发明还涉及与上述的序列杂交且两个序列之间具有至少50％，较佳地至少70％，更佳地至少80％相同性的多核苷酸。本发明特别涉及在严格条件下与本发明所述多核苷酸可杂交的多核苷酸。在本发明中，“严格条件”是指：(1)在较低离子强度和较高温度下的杂交和洗脱，如0.2×SSC,0.1％SDS,60℃；或(2)杂交时加有变性剂,如50％(v/v)甲酰胺，0.1％小牛血清/0.1％Ficoll，42℃等；或(3)仅在两条序列之间的相同性至少在90％以上,更好是95％以上时才发生杂交。并且,可杂交的多核苷酸编码的多肽与SEQ ID NO:18、19、20、21、22、23、24、25、26或27所示的成熟多肽有相同的生物学功能和活性。
本发明的抗体的核苷酸全长序列或其片段通常可以用PCR扩增法、重组法或人工合成的方法获得。一种可行的方法是用人工合成的方法来合成有关序列，尤其是片段长度较短时。通常，通过先合成多个小片段，然后再进行连接可获得序列很长的片段。此外，还可将重链的编码序列和表达标签(如6His)融合在一起，形成融合蛋白。
一旦获得了有关的序列，就可以用重组法来大批量地获得有关序列。这通常是将其克隆入载体，再转入细胞，然后通过常规方法从增殖后的宿主细胞中分离得到有关序列。本发明所涉及的生物分子(核酸、蛋白等)包括以分离的形式存在的生物分子。目前，已经可以完全通过化学合成来得到编码本发明蛋白(或其片段，或其衍生物)的DNA序列。然后可将该DNA序列引入本领域中已知的各种现有的DNA分子(或如载体)和细胞中。此外，还可通过化学合成将突变引入本发明蛋白序列中。
本发明还涉及包含上述的适当DNA序列以及适当启动子或者控制序列的载体。这些载体可以用于转化适当的宿主细胞，以使其能够表达蛋白质。
宿主细胞可以是原核细胞，如细菌细胞；或是低等真核细胞，如酵母细胞；或是高等真核细胞，如哺乳动物细胞。代表性例子有：大肠杆菌，链霉菌属；鼠伤寒沙门氏菌的细菌细胞；真菌细胞如酵母；果蝇S2或Sf9的昆虫细胞；CHO、COS7、293细胞、T细胞、NK细胞的动物细胞等。
药物组合物
本发明第一方面所述人源化Claudin 18.2抗体或其抗原结合片段、或如本发明第二方面所述的嵌合抗原受体、或如本发明第三方面所述的核酸分子、或如本发明第四方面所述的载体，或本发明第五方面所述的工程化的宿主细胞，以及药学上可接受的载体、稀释剂或赋形剂。
通常，可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中，其中pH通常约为5-8，较佳地pH约为6-8，尽管pH值可随被配制物质的性质以及待治疗的病症而有所变化。配制好的药物组合物可以通过常规途径进行给药，其中包括(但并不限于)：口服、呼吸道、瘤内、腹膜内、静脉内、或局部给药。
本发明的药物组合物含有安全有效量(如0.001-99wt％,较佳地0.01-90wt％，更佳地0.1-80wt％)的本发明上述的抗体(或其偶联物)、嵌合抗原受体、或嵌合抗原受体T细胞以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于)：盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。药物制剂应与给药方式相匹配。本发明的药物组合物可以被制成针剂形式，例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。药物组合物如针剂、溶液宜在无菌条件下制造。活性成分的给药量是治疗有效量，例如每天约1微克/千克体重-约10毫克/千克体重。此外，本发明的药物组合物还可与其他治疗剂一起使用。
使用药物组合物时，是将安全有效量的免疫物施用于哺乳动物，其中该安全有效量通常至少约10微克/千克体重，而且在大多数情况下不超过约8毫克/千克体重，较佳地该剂量是约10微克/千克体重-约1毫克/千克体重。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点在于：
(1)本发明中的CLDN 18.2鼠源性抗体经过抗体的人源化改造，在保留与抗原结合的高亲和力和特异性的基础上，减少异源性抗体的免疫原性，有利应用于人体。
(2)基于本发明的人源化抗体构建的CLDN 18.2CAR-T细胞拥有比阳性对照CAR-T细胞更强的杀伤和细胞因子释放功能，预示着CAR-T细胞在体内更有效的效果。
(3)基于本发明的人源化抗体构建的CLDN 18.2CAR-T细胞在整个体外培养过程中，持续保持着很高比例的CAR阳性表达，表明CAR-T细胞在体外培养中能够保持着高比例增长，同样预示着CAR-T细胞能够在体内有很好的疗效。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York：Cold Spring Harbor LaboratoryPress，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例中所用的材料、试剂、仪器等，如无特殊说明，均可从商业途径得到。
实施例1
人源化Claudin 18.2抗体制备
1.1技术方案：
本人源化设计是利用3D建模的方法，经数据库比对，将原始鼠源序列突变成人源序列。主要方法是先进行结构模拟，选出最优结构模型，下一步对原始鼠源序列进行分析，明确不同部分的序列组成，最后进行人源化序列的设计，将鼠源序列突变成人源化序列。本设计结果将同源度最高的重链IGHV1序列设计为6个人源化序列(VH1、VH2、VH3、VH4、VH5、VH6)，LF001抗体选择IGKV1为人源化设计模板，设计为3个人源化序列(VL1、VL2、VL3)，将设计的9条序列组合为10对人源化抗体进行后续表达验证。
1.2实验步骤：
1.2.1模拟结构模型
(1)结构模拟方法
分别使用Discovery Studio和
Antibody Modeling，采用同源建模方法选取5-10个最优结构解，Loop区域一般使用同源建模方法建模，如CDR氨基酸序列比对结果显示低于50％Identity，则使用从头建模方法搭建CDR3结构模型。使用PDB BLAST调取序列最接近的10个抗体晶体结构模型(结构分辨率高于2.5埃)，对比自动建模模型，选取最优的结构模型。
(2)结构模型结果
比对数据库已有抗体结构，模拟的抗体结构模型如图1和图2所示，抗体可变区结构卡通图(图1)、抗体互补决定区(Complementarity Determining Region，CDR)结构卡通图(图2)均使用
Pymol制作。图1显示LF001抗体序列与抗体结构数据库同源度(Identity)为90％，模拟模型可信度(Confidence)高于95％。
1.2.2鼠源抗体序列分析
(1)LF001抗体鼠源重链序列分析
使用IgBLAST与人Germline序列比对，结果如图3所示。比对结果显示：VH与人Germline IGHV1大类序列同源度最高，含24个鼠源氨基酸位点，V区比对结果如图3所示。其中24个鼠源氨基酸位点是指图中比对的FR1，FR2和FR3区序列，CDR区没有计算进去。
(2)LF001抗体鼠源轻链序列分析
使用IgBLAST与人Germline序列比对，结果如图4所示。比对结果显示：VL与人Germline IGKV1对比，含24个鼠源氨基酸位点，V区基因比对结果如图4所示。其中24个鼠源氨基酸位点是指图中比对的FR1，FR2和FR3区序列，CDR区没有计算进去。
1.2.3人源化设计结果
(1)人源化模板的选择
重链设计模板选取IGHV1大类。
轻链设计模板采用IGKV1大类。
(2)人源化突变策略与原则
1)不影响抗体结构稳定性；2)不影响抗体与抗原结合；3)不引入糖基化、磷酸化等蛋白修饰位点；4)不引入易被氧化、氨基化等位点；5)增强结构稳定性。
(3)免疫原性分析
预测VH为中免疫原性
预测VL为低免疫原性
预测VH具有免疫原性肽段包括：SLDFWGQGTSL、FTSYWMHWV、QLQQPGAEL
预测VL具有免疫原性肽段为：FTFGSGTKL、KLLIYWAST
预测轻重链含潜在Deamidation位点：MIHPNSGST、GGYYGNSLD、KSSQSLLNSGNQ
(4)人源化抗体序列
表1为LF001重链设计序列比对表，其中灰色底纹部分是鼠源序列，加粗倾斜部分是CDR区序列，黑色底纹部分是人源化后序列，其余部分为原始人源序列。
表1.LF001重链设计序列比对表
表2为LF001轻链设计序列比对表，其中灰色底纹部分是鼠源序列，加粗倾斜部分是CDR区序列，黑色底纹部分是人源化后序列，其余部分为原始人源序列。
表2.LF001轻链设计序列比对表
(5)人源化抗体人源化程度计算
将设计好的人源化序列轻重链进行配对组合后与人源Germline序列进行比对，计算出每个部分及全长抗体的人源化程度百分比，汇总结果如下：
表3.人源化程度信息汇总表
| 蛋白名称 | 回复突变 | 人源化比率(ScFv-Fc) |
| LF001-H1L1 | 16 | 96.55％ |
| LF001-H2L1 | 13 | 97.20％ |
| LF001-H3L1 | 11 | 97.63％ |
| LF001-H4L1 | 10 | 97.84％ |
| LF001-H5L1 | 7 | 98.49％ |
| LF001-H6L1 | 7 | 98.49％ |
| LF001-H2L2 | 10 | 97.84％ |
| LF001-H3L3 | 6 | 98.71％ |
| LF001-H5L3 | 2 | 99.57％ |
| LF001-H6L3 | 2 | 99.57％ |
(6)构建表达方案
构建序列为：LF001-H1、LF001-H2、LF001-H3、LF001-H4、LF001-H5、LF001-H6、LF001-L1、LF001-L2、LF001-L3。载体：pcDNA3.4；亚型：mIgG2c。
表达组合为：LF001-H1L1、LF001-H2L1、LF001-H3L1、LF001-H4L1、LF001-H5L1、LF001-H6L1、LF001-H2L2、LF001-H3L3、LF001-H5L3、LF001-H6L3。
实施例2
人源化抗体亲和力检测
采用FACS方法对LF001项目11个抗体蛋白(PcDNA3.4-LF001-MHL，PcDNA3.4-LF001-H1L1、PcDNA3.4-LF001-H2L1、PcDNA3.4-LF001-H3L1、PcDNA3.4-LF001-H4L1、PcDNA3.4-LF001-H5L1、PcDNA3.4-LF001-H6L1、PcDNA3.4-LF001-H2L2、PcDNA3.4-LF001-H3L3、PcDNA3.4-LF001-H5L3、pcDNA3.4-LF001-H6L3)与细胞(18.2-K562，18.1-K562，K562)的亲和力测定及排序。
2.1试剂与仪器
RPMI1640培养基(购自Gibco)，FBS(购自Bovogen)，PBS(购自源培)，Goat-Anti-Human-IgG-Fc-FITC(购自Jackson)，流式细胞仪(购自BD)。
2.2待检测样品
待检测样品信息如下表所示：
表4.样品信息表
| 样品名称 | 浓度(mg/mL) |
| LF001-MHL | 2.35 |
| LF001-H1L1 | 1.57 |
| LF001-H2L1 | 1.33 |
| LF001-H3L1 | 2.72 |
| LF001-H4L1 | 2.94 |
| LF001-H5L1 | 2.23 |
| LF001-H6L1 | 2.00 |
| LF001-H2L2 | 1.57 |
| LF001-H3L3 | 2.48 |
| LF001-H5L3 | 2.13 |
| LF001-H6L3 | 2.25 |
| hIgG1 | 1.15 |
备注：hIgG1为发明人所在公司内部纯化的阴性对照抗体。
2.3实验方法
1)细胞铺板：将18.2-K562、18.1-K562、K562制成细胞悬液，将密度调整为1×106/mL。取3块96孔圆底板，标记为plate1、plate2、plate3。采用100μL的移液排枪在plate1、plate2、plate3中分别加入100μL的18.2-K562、18.1-K562、K562的悬液。在离心机中采用300g的转速离心5min。甩去上清。
2)加抗体稀释液：将抗体用FACS Buffer稀释成20μg/mL、6.667μg/mL、2.222μg/mL、0.741μg/mL、0.247μg/mL、0.082μg/mL、0.027μg/mL、0.002μg/mL等8个浓度梯度的稀释液。采用100μL的移液排枪将抗体稀释液分别加到18.2-K562、18.1-K562、K562中，每孔100μL，4℃孵育60min。洗板：FACS Buffer洗板2次。
3)加二抗：采用FACS Buffer 1：150稀释二抗Anti-Human IgG FITC，100μL/孔加入到各孔中，4℃孵育30min。洗板：FACS buffer洗板3次。
4)上机：打开流式细胞仪及软件，清洗完成之后，建立本实验的文件夹，在该文件夹下进行样品检测。
2.4实验结果与分析
图5是抗体与18.2-K562的FACS结合的鉴定结果图，结果显示抗体亲和力排序为：LF001-H5L1>LF001-H4L1>LF001-H2L1>LF001-MHL≈LF001-H2L2≈LF001-H1L1≈LF001-H5L3>LF001-H3L3，LF001-H6L3、LF001-H3L1、LF001-H6L1三个分子与18.2-K562亲和力较差。其中hIgG1为阴性对照。
与18.2-K562结合的各个抗体的EC50值如下表所示：
表5.抗体与18.2-K562结合的EC50值
| 抗体 | EC<sub>50</sub>：μg/mL | 抗体 | EC<sub>50</sub>：μg/mL |
| LF001-MHL | 0.6753 | LF001-H6L1 | 1.3230 |
| LF001-H1L1 | 0.6961 | LF001-H2L2 | 0.6127 |
| LF001-H2L1 | 0.6705 | LF001-H3L3 | 0.7072 |
| LF001-H3L1 | 0.8360 | LF001-H5L3 | 0.5781 |
| LF001-H4L1 | 0.5812 | LF001-H6L3 | 0.8252 |
| LF001-H5L1 | 0.5012 | hIgG1 | N.A |
图6是抗体与18.1-K562的FACS结合的鉴定结果图，结果显示LF001候选抗体与18.1-K562无结合。其中hIgG1为阴性对照。
图7是抗体与K562的FACS结合的鉴定结果图，结果显示LF001候选抗体与K562无结合。其中hIgG1为阴性对照。
2.5实验结果判定
阴性对照(hIgG1)与18.2-K562、18.1-K562、K562均无结合，实验组抗体与18.2-K562都有结合，实验组抗体与18.1-K562、K562细胞无结合，无人为操作导致试剂加错或漏孔等，所以该实验过程符合系统适用性，说明此实验结果有效。
本发明的序列信息如下表所示：
序列信息
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 上海莱馥医疗科技有限公司
<120> 一种人源化Claudin 18.2抗体及其应用
<130> P2020-1723
<160> 44
<170> PatentIn version 3.5
<210> 1
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 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 His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 2
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Ser Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 3
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 4
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 5
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 6
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Thr Gly Ser Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Thr Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 7
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Arg Ala Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 8
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Arg Ala Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Leu Gln Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 9
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
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 Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ser Leu Gln Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 10
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys 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 His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Ser Lys Ala Thr 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 Phe Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Ser Leu Thr Val Ser Ser
115
<210> 11
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Arg
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys 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 Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 12
<211> 10
<212> PRT
<213> 小鼠(Mus musculus)
<400> 12
Gly Tyr Thr Phe Thr Ser Tyr Trp Met His
1 5 10
<210> 13
<211> 10
<212> PRT
<213> 小鼠(Mus musculus)
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa = S or T
<400> 13
Met Ile His Pro Asn Xaa Gly Ser Thr Asn
1 5 10
<210> 14
<211> 10
<212> PRT
<213> 小鼠(Mus musculus)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = S or T
<400> 14
Gly Gly Tyr Tyr Gly Asn Xaa Leu Asp Phe
1 5 10
<210> 15
<211> 17
<212> PRT
<213> 小鼠(Mus musculus)
<400> 15
Arg Ala Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 16
<211> 7
<212> PRT
<213> 小鼠(Mus musculus)
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa = S or T
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = R or L
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa = E or Q
<400> 16
Trp Ala Ser Xaa Xaa Xaa Ser
1 5
<210> 17
<211> 9
<212> PRT
<213> 小鼠(Mus musculus)
<400> 17
Gln Asn Ala Tyr Ser Tyr Pro Phe Thr
1 5
<210> 18
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 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 His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Thr Arg Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 19
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Ser Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Thr Arg Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 20
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Thr Arg Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 21
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Thr Arg Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 22
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Thr Arg Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 23
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Thr Gly Ser Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Thr Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Thr Arg Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 24
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Ser Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 25
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 26
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 27
<211> 484
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Asn Thr Gly Ser Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Gly Asn Thr Leu Asp Phe Trp Gly Gln Gly
100 105 110
Thr Thr 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 Gln Met Thr Gln Ser Pro Ser Ser
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
145 150 155 160
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Asn Ala Tyr Ser Tyr Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys Pro Arg Val Pro Ile Thr Gln Asn Pro
245 250 255
Cys Pro Pro Leu Lys Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu
260 265 270
Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu
275 280 285
Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser
290 295 300
Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu
305 310 315 320
Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr
325 330 335
Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser
340 345 350
Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro
355 360 365
Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln
370 375 380
Val Tyr Val Leu Pro Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe
385 390 395 400
Ser Leu Thr Cys Met Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val
405 410 415
Asp Trp Thr Ser Asn Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala
420 425 430
Thr Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg
435 440 445
Val Gln Lys Ser Thr Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val
450 455 460
Val His Glu Gly Leu His Asn His Leu Thr Thr Lys Thr Ile Ser Arg
465 470 475 480
Ser Leu Gly Lys
<210> 28
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 28
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaagctg 60
tcctgcaagg cttctggcta caccttcacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta actccggctc caccaactac 180
aacggcaagt tcaagtccaa ggctaccctg accgtggaca agtccacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca actccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatgacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gcctccacca gagaatctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga ccatctcctc cgtgcagcct 660
gaggatttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 29
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60
tcctgcaagg cttccggcta cacctttacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta actccggctc caccaactac 180
aacggcaagt tcaagtccag agtgaccctg accgtggaca agtccacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca actccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatgacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gcctccacca gagaatctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga ccatctcctc cgtgcagcct 660
gaggatttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 30
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 30
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60
tcctgcaagg cttccggcta cacctttacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta actccggctc caccaactac 180
aacggcaagt tccagggcag agtgaccctg accgtggaca agtctacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca actccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatgacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gcctccacca gagaatctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga ccatctcctc cgtgcagcct 660
gaggatttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 31
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60
tcctgcaagg cttccggcta cacctttacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta actccggctc caccaactac 180
aacggcaagt tcaagtcccg cgtgaccatg accagagaca cctctacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca actccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatgacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gcctccacca gagaatctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga ccatctcctc cgtgcagcct 660
gaggatttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 32
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 32
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60
tcctgcaagg cttccggcta cacctttacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta actccggctc caccaactac 180
gcccagaaat tccagggcag agtgaccctg accagagaca cctctacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca actccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatgacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gcctccacca gagaatctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga ccatctcctc cgtgcagcct 660
gaggatttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 33
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 33
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60
tcctgcaagg cttccggcta cacctttacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta acaccggctc caccaactac 180
gcccagaaat tccagggcag agtgaccctg accagagaca cctctacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca acaccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatgacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gcctccacca gagaatctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga ccatctcctc cgtgcagcct 660
gaggatttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 34
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 34
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60
tcctgcaagg cttccggcta cacctttacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta actccggctc caccaactac 180
aacggcaagt tcaagtccag agtgaccctg accgtggaca agtccacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca actccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatgacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gctagcacac tgcagtctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga caatctccag cctgcagcct 660
gaggacttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 35
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 35
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60
tcctgcaagg cttccggcta cacctttacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta actccggctc caccaactac 180
aacggcaagt tccagggcag agtgaccctg accgtggaca agtctacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca actccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatcacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gcttccagtc tgcagtctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga caatctccag cctgcagcct 660
gaggacttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 36
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 36
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60
tcctgcaagg cttccggcta cacctttacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta actccggctc caccaactac 180
gcccagaaat tccagggcag agtgaccctg accagagaca cctctacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca actccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatcacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gcttccagtc tgcagtctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga caatctccag cctgcagcct 660
gaggacttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 37
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 37
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60
tcctgcaagg cttccggcta cacctttacc agctactgga tgcactgggt ccgacaggct 120
ccaggacaag gcctggaatg gatcggcatg atccatccta acaccggctc caccaactac 180
gcccagaaat tccagggcag agtgaccctg accagagaca cctctacctc caccgcctac 240
atggaactgt ccagcctgag atctgaggac accgccgtgt actactgtgc cagaggcggc 300
tactacggca acaccctgga tttttggggc cagggcacca ccgtgacagt gtcatctgga 360
ggcggaggct ctggaggagg aggatctggc ggaggaggca gcgacatcca gatgacccag 420
tctccatcct ctctgtccgc ctctgtgggc gacagagtga ccatcacctg tcgggcttct 480
cagtccctgc tgaactccgg caaccagaag aactacctga cctggtatca gcagaagccc 540
ggcaaggctc ccaagctgct gatctactgg gcttccagtc tgcagtctgg cgtgccctct 600
agattctccg gctctggctc tggcaccgac tttaccctga caatctccag cctgcagcct 660
gaggacttcg ccacctacta ctgccagaac gcctacagct accccttcac ctttggccag 720
ggcaccaagc tggaaatcaa gcccagagtg cccataacac agaacccctg tcctccactc 780
aaagagtgtc ccccatgcgc agctccagac ctcttgggtg gaccatccgt cttcatcttc 840
cctccaaaga tcaaggatgt actcatgatc tccctgagcc ccatggtcac atgtgtggtg 900
gtggatgtga gcgaggatga cccagacgtc cagatcagct ggtttgtgaa caacgtggaa 960
gtacacacag ctcagacaca aacccataga gaggattaca acagtactct ccgggtggtc 1020
agtgccctcc ccatccagca ccaggactgg atgagtggca aggagttcaa atgcaaggtc 1080
aacaacagag ccctcccatc ccccatcgag aaaaccatct caaaacccag agggccagta 1140
agagctccac aggtatatgt cttgcctcca ccagcagaag agatgactaa gaaagagttc 1200
agtctgacct gcatgatcac aggcttctta cctgccgaaa ttgctgtgga ctggaccagc 1260
aatgggcgta cagagcaaaa ctacaagaac accgcaacag tcctggactc tgatggttct 1320
tacttcatgt acagcaagct cagagtacaa aagagcactt gggaaagagg aagtcttttc 1380
gcctgctcag tggtccacga gggtctgcac aatcacctta cgactaagac catctcccgg 1440
tctctgggta aa 1452
<210> 38
<211> 10
<212> PRT
<213> 小鼠(Mus musculus)
<400> 38
Met Ile His Pro Asn Ser Gly Ser Thr Asn
1 5 10
<210> 39
<211> 10
<212> PRT
<213> 小鼠(Mus musculus)
<400> 39
Gly Gly Tyr Tyr Gly Asn Ser Leu Asp Phe
1 5 10
<210> 40
<211> 7
<212> PRT
<213> 小鼠(Mus musculus)
<400> 40
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 41
<211> 10
<212> PRT
<213> 小鼠(Mus musculus)
<400> 41
Met Ile His Pro Asn Thr Gly Ser Thr Asn
1 5 10
<210> 42
<211> 10
<212> PRT
<213> 小鼠(Mus musculus)
<400> 42
Gly Gly Tyr Tyr Gly Asn Thr Leu Asp Phe
1 5 10
<210> 43
<211> 7
<212> PRT
<213> 小鼠(Mus musculus)
<400> 43
Trp Ala Ser Thr Leu Gln Ser
1 5
<210> 44
<211> 7
<212> PRT
<213> 小鼠(Mus musculus)
<400> 44
Trp Ala Ser Ser Leu Gln Ser
1 5
Claims (10)
1.一种人源化Claudin 18.2(CLDN 18.2)抗体或其抗原结合片段，其特征在于，所述抗体或其抗原结合片段包含重链和轻链，
其中，所述重链的重链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:12所示的CDR1；
如SEQ ID NO:13所示的CDR2；和
如SEQ ID NO:14所示的CDR3；
以及，所述轻链的轻链可变区包括以下三个互补决定区CDR：
如SEQ ID NO:15所示的CDR1’；
如SEQ ID NO:16所示的CDR2’；和
如SEQ ID NO:17所示的CDR3’。
2.如权利要求要求1所述的抗体，其特征在于，所述抗体或其抗原结合片段包含SEQ IDNO:1至6中任一所示的抗体重链可变区。
3.如权利要求要求1所述的抗体，其特征在于，所述抗体或其抗原结合片段包含SEQ IDNO:7至9中任一所示的抗体轻链可变区。
4.如权利要求1-3中任一项所述的抗体或其抗原结合片段，其特征在于，所述抗体或其抗原结合片段具有如SEQ ID NO:18、19、20、21、22、23、24、25、26或27所示的氨基酸序列。
5.一种嵌合抗原受体(CAR)，其特征在于，所述嵌合抗原受体包含如权利要求1-3中所述的抗体或抗原结合片段的重链可变区和轻链可变区。
6.一种核酸分子，其特征在于，所述的核酸分子编码如权利要求1-4所述的人源化Claudin 18.2抗体或其抗原结合片段或如权利要求5所述的CAR。
7.一种载体，其特征在于，所述载体含有如权利要求6所述的核酸分子。
8.一种工程化的宿主细胞，其特征在于，所述的宿主细胞含有如权利要求7所述的载体、或染色体中整合有外源的如权利要求6所述的核酸分子、或表达如权利要求1-4所述的抗体或抗原结合片段或如权利要求5所述的嵌合抗原受体。
9.一种药物组合物，其特征在于，所述药物组合物含有权利要求1-4所述人源化Claudin 18.2抗体或其抗原结合片段、或如权利要求6所述的核酸分子、或如权利要求7所述的载体，或权利要求8所述的工程化的宿主细胞，以及药学上可接受的载体、稀释剂或赋形剂。
10.一种如权利要求1-4所述的人源化Claudin 18.2抗体或其抗原结合片段、权利要求5所述嵌合抗原受体、权利要求6所述的核酸分子、权利要求7所述的载体、权利要求8所述的工程化的免疫细胞的用途，其特征在于，用于制备预防和/或治疗癌症或肿瘤的药物或制剂。
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| PCT/CN2021/106899 WO2022142272A1 (zh) | 2020-12-31 | 2021-07-16 | Cldn18.2抗体及其应用 |
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|---|---|---|---|---|
| EP2852408A1 (en) * | 2012-05-23 | 2015-04-01 | GANYMED Pharmaceuticals AG | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
| CN110606891A (zh) * | 2018-06-17 | 2019-12-24 | 上海健信生物医药科技有限公司 | 一种针对人cldn18.2的新型抗体分子, 抗原结合片段及其医药用途 |
| CN111110862A (zh) * | 2018-11-01 | 2020-05-08 | 上海健信生物医药科技有限公司 | 抗cldn18．2抗体的药物偶联体及其制备方法和用途 |
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| EP2852408A1 (en) * | 2012-05-23 | 2015-04-01 | GANYMED Pharmaceuticals AG | Combination therapy involving antibodies against claudin 18.2 for treatment of cancer |
| CN110606891A (zh) * | 2018-06-17 | 2019-12-24 | 上海健信生物医药科技有限公司 | 一种针对人cldn18.2的新型抗体分子, 抗原结合片段及其医药用途 |
| CN111110862A (zh) * | 2018-11-01 | 2020-05-08 | 上海健信生物医药科技有限公司 | 抗cldn18．2抗体的药物偶联体及其制备方法和用途 |
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| 王桂慧 等: "Claudin18.2分子特征概述及其作为治疗靶点在胃癌中的研究进展", 《肿瘤综合治疗电子杂志》, 30 April 2024 (2024-04-30), pages 146 - 154 * |
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