CN109384846A - 能够结合tigit的抗体或其抗原结合片段及用途 - Google Patents
能够结合tigit的抗体或其抗原结合片段及用途 Download PDFInfo
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- CN109384846A CN109384846A CN201811116733.6A CN201811116733A CN109384846A CN 109384846 A CN109384846 A CN 109384846A CN 201811116733 A CN201811116733 A CN 201811116733A CN 109384846 A CN109384846 A CN 109384846A
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Abstract
能够结合TIGIT的抗体或其抗原结合片段及用途。本发明涉及抗体领域，公开了一种能够结合TIGIT的抗体及其用途。所述抗体包括重链CDR1、重链CDR2和重链CDR3，以及轻链CDR1、轻链CDR2和轻链CDR3。本发明的抗体具有以下特性：能够以高亲和力阻断TIGIT和CD155的相互作用；能够与TIGIT以高特异性结合，而与其它CD28家族成员(如CD28、PD‑1和CTLA4)不发生结合；激活免疫细胞，从而杀伤肿瘤细胞。
Description
技术领域
本发明涉及抗体领域，具体地，涉及一种能够结合TIGIT的抗体或其抗原结合片段及用途。
背景技术
肿瘤免疫治疗是肿瘤治疗领域一个长时间的热点。利用抗体阻断免疫抑制性受体(包括 PD-1、CTLA4等)的策略在临床肿瘤治疗中取得了巨大的成功，但是仍有很大一部分病人对 PD-1抗体、CTLA4抗体及两者的联合治疗无应答，这可能是由于T细胞、NK细胞表面表达多种免疫抑制性受体造成的。PD-1、CTLA4、TIGIT等抑制性受体可能协同作用抑制免疫了免疫细胞包括T细胞、NK细胞的活化，因而开发针对TIGIT等免疫抑制性受体的治疗性抗体具有极大的意义。
TIGIT(T cell Ig and ITIM domain)分子是2009年发现的表达在T细胞、NK细胞表面的抑制性受体，主要包含胞外IgV样结构域，跨膜区和含有ITIM基序(Immunoreceptortyrosine-based inhibitory motif)的胞内段。TIGIT以高亲和力结合配体PVR(polivirusreceptor， CD155)，并通过胞内ITIM基序传递抑制性信号，从而抑制T细胞、NK细胞的功能。
研究表明，TIGIT的表达与肿瘤的发展相关。肺癌患者的肿瘤浸润T细胞表面高表达 TIGIT分子，并且其表达和PD-1的表达存在显著的正相关。结肠癌患者的肿瘤浸润NK细胞表面TIGIT表达显著高于外周血NK细胞。在多种小鼠肿瘤模型中，利用抗体阻断TIGIT能够抑制肿瘤生长和转移，同时阻断TIGIT和PD-1能够有效治疗肿瘤。因此，开发抗TIGIT 抗体显得尤为必要。
发明内容
本发明的目的是克服现有技术的不足，提供一种能够介导多种抗肿瘤机制的抗体及其用途。
本发明提供的抗体通过阻断TIGIT/CD155的结合，提供患者自身对肿瘤的免疫反应。在人源化小鼠肿瘤模型中，本发明的抗体具有抑制肿瘤生长的作用，这表明本发明的抗体对肿瘤有积极的疗效。
因此，为了实现上述目的，第一方面，本发明提供了一种能够结合TIGIT的抗体或其抗原结合片段，其特征在于，该抗体包括重链CDR1、重链CDR2和重链CDR3，以及轻链CDR1、轻链CDR2和轻链CDR3；
其中，所述重链CDR1的氨基酸序列与SEQ ID NO:2、SEQ ID NO:10、SEQ ID NO:20、SEQ ID NO:26、SEQ ID NO:32、SEQ ID NO:39、SEQ ID NO:50、SEQ ID NO:57、SEQ ID NO:59或SEQ ID NO:79所示的序列具有至少80％的同源性，
所述重链CDR2的氨基酸序列与SEQ ID NO:3、SEQ ID NO:11、SEQ ID NO:21、SEQID NO:27、SEQ ID NO:37、SEQ ID NO:40、SEQ ID NO:51、SEQ ID NO:60、SEQ ID NO:73 或SEQ ID NO:80所示的序列具有至少80％的同源性，
所述重链CDR3的氨基酸序列与SEQ ID NO:4、SEQ ID NO:12、SEQ ID NO:16、SEQID NO:22、SEQ ID NO:28、SEQ ID NO:33、SEQ ID NO:41、SEQ ID NO:52、SEQ ID NO:62、SEQ ID NO:66、SEQ ID NO:77、SEQ ID NO:81或SEQ ID NO:87所示的序列具有至少80％的同源性，
所述轻链CDR1的氨基酸序列与SEQ ID NO:6、SEQ ID NO:14、SEQ ID NO:18、SEQID NO:30、SEQ ID NO:35、SEQ ID NO:43、SEQ ID NO:47、SEQ ID NO:54、SEQ ID NO:68、SEQ ID NO:83或SEQ ID NO:85所示的序列具有至少80％的同源性，
所述轻链CDR2的氨基酸序列与SEQ ID NO:7、SEQ ID NO:44或SEQ ID NO:69所示的序列具有至少80％的同源性，
所述轻链CDR3的氨基酸序列与SEQ ID NO:8、SEQ ID NO:24、SEQ ID NO:48、SEQID NO:55、SEQ ID NO:64、SEQ ID NO:70或SEQ ID NO:75所示的序列具有至少80％的同源性。
第二方面，本发明提供了一种免疫缀合物，该免疫缀合物含有治疗剂以及与治疗剂偶联的第一方面所述的抗体或其抗原结合片段。
第三方面，本发明提供了一种组合物，该组合物含有第一方面所述的抗体或其抗原结合片段、和/或上述免疫缀合物以及药学上可接受的载体。
第四方面，本发明提供了一种用于检测样品中TIGIT的试剂盒，该试剂盒含有第一方面所述的抗体或其抗原结合片段。
第五方面，本发明提供了第一方面所述的抗体或其抗原结合片段在制备用于检测样品中 TIGIT的试剂中的用途。
第六方面，本发明提供了第一方面所述的抗体或其抗原结合片段在制备用于预防和/或治疗TIGIT介导的疾病的药物中的用途。
第七方面，本发明提供了编码第一方面所述的抗体或其抗原结合片段的核酸。
第八方面，本发明提供了含有第七方面所述的核酸的重组载体或转化子。
通过上述技术方案，本发明提供了能够结合TIGIT的抗TIGIT抗体或抗体片段。本发明的抗体具有以下特性的至少一种：能够以高亲和力阻断TIGIT和CD155的相互作用；能够与 TIGIT以高特异性结合，而与其它CD28家族成员(如CD28、PD-1和CTLA4)不发生结合；激活免疫细胞，从而杀伤肿瘤细胞。
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。
附图说明
附图是用来提供对本发明的进一步理解，并且构成说明书的一部分，与下面的具体实施方式一起用于解释本发明，但并不构成对本发明的限制。在附图中：
图1为根据本发明具体实施方式的TIGIT抗体的ELISA结果图；
图2为根据本发明具体实施方式的TIGIT抗体结合293T-TIGIT细胞的结果图；
图3为根据本发明具体实施方式的TIGIT抗体阻断配体CD155结合的结果图；
图4为根据本发明具体实施方式的TIGIT抗体结合人自然杀伤细胞的结果图；
图5为根据本发明具体实施方式的TIGIT抗体不与小鼠TIGIT蛋白结合的结果图；
图6为根据本发明具体实施方式的TIGIT抗体不与同家族其他蛋白结合的结果图；
图7为根据本发明具体实施方式的TIGIT抗体竞争关系的结果图；
图8为根据本发明具体实施方式的TIGIT抗体促进人外周血单个核细胞的抗癌功能；
图9为根据本发明具体实施方式的TIGIT抗体抑制结肠癌SW620细胞的生长；
图10为根据本发明具体实施方式的人源化TIGIT抗体结合293T-TIGIT细胞的结果图；
图11为根据本发明具体实施方式的人源化TIGIT抗体阻断配体CD155结合的结果图。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。
为了更容易理解本发明，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文中使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。氨基酸残基的缩写是本领域中所用的指代20个常用L-氨基酸之一的标准3字母和/或1字母代码。
在本发明中，在未作相反说明的情况下，使用的术语抗原结合片段也即“抗体片段”，抗体片段通常是指抗原结合性抗体片段，可以包括完整抗体的一部分，一般是抗原结合区或可变区，抗体片段的实例包括Fab、Fab’、F(ab’)2、Fv或scFv，双抗体，线性抗体，单链抗体分子等。
术语“互补决定区”或“CDR”或“CDR序列”是指抗体中负责抗原结合的氨基酸序列，例如，通常包括：轻链可变区中23-34(L1)、50-56(L2)和89-97(L3)附近，和重链可变区中31-35B(H1)、50-65(H2)和95-102(H3)附近的氨基酸残基(Kabat等人，Sequences ofProteins of Immunological Interest，5th Ed.Public Health Service，NationalInstitutes of Health，Bethesda， MD.(1991))；和/或来自“高变环”(例如，轻链可变区中26-32(LI)、50-52(L2)和91-96(L3)，和重链可变区中26-32(H1)、53-55(H2)和96-101(H3)附近的氨基酸残基(Chothia和Lesk J.Mol.Biol.196：901-917(1987))。
在不实质性影响抗体活性(保留至少95％的活性)的前提下，本领域技术人员可以对本发明的序列替换、添加和/或缺失一个或更多个(例如1、2、3、4、5、6、7、8、9或10个或更多个)氨基酸，以获得所述抗体或其功能性片段之序列的变体。它们都被视为包括在本发明保护的范围内。如在可变区将具有类似性质的氨基酸进行替换。本发明所述变体的序列可以与参比序列具有至少80％、85％、90％、95％、96％、97％、98％或99％的一致性(或同源性)。本发明所述的序列一致性可以使用序列分析软件测量。例如使用缺省参数的计算机程序BLAST，尤其是BLASTP或TBLASTN。本发明述及的氨基酸序列均按照N端至C端的方式示出。
如前所述，本发明的抗体可以是全长的(例如，IgG1或IgG4抗体)或可仅包含抗原结合部分(例如，Fab、F(ab’)2或scFv片段)，或可以被修饰以影响功能。本发明包括具有修饰的糖基化模式的抗TIGIT抗体。在一些应用中，进行修饰以除去不期望的糖基化位点可以是有用的，或在寡糖链上不存在岩藻糖部分以例如增强抗体依赖性细胞毒性(ADCC)功能的抗体。在另一些应用中，可进行半乳糖基化修饰以改变补体依赖性细胞毒性(CDC)。
本文所使用的术语“功能性片段”尤其是指抗体片段如Fv、scFv(sc指单链)、Fab、F(ab’)2、 Fab’、scFv-Fc片段或者双抗体(diabody)、或者通过化学修饰或通过掺入脂质体中应能够增加半寿期的任何片段，所述化学修饰例如添加聚(亚烷基)二醇，如聚乙二醇(“聚乙二醇化，PEG 化”)(被称为Fv-PEG、scFv-PEG、Fab-PEG、F(ab’)2-PEG或Fab’-PEG的聚乙二醇化片段)(“PEG”为聚乙二醇)，所述片段具有TIGIT结合活性。优选地，所述功能性片段将由其来源抗体的重链可变区或轻链可变区的部分序列构成或者包含它们，所述部分序列足以保留与其来源抗体相同的结合特异性和充分的亲和力，对于TIGIT，优选至少等于其来源抗体亲和力的1/100，在更优选方式中至少等于1/10。这种功能片段将包含最少5个氨基酸，优选其来源的抗体序列的10、15、25、50和100个连续氨基酸。
如前所述，本发明提供了一种能够结合TIGIT的抗体或其抗原结合片段，其特征在于，该抗体包括重链CDR1、重链CDR2和重链CDR3，以及轻链CDR1、轻链CDR2和轻链CDR3。优选情况下，重链CDR1、重链CDR2、重链CDR3、轻链CDR1、轻链CDR2和轻链CDR3 同时与表1各列所示的序列具有至少80％的同源性。
优选地，各个CDR序列与参比序列具有100％的一致性(同源性)，也即，所述重链CDR1 的氨基酸序列如SEQ ID NO:2、SEQ ID NO:10、SEQ ID NO:20、SEQ ID NO:26、SEQ IDNO: 32、SEQ ID NO:39、SEQ ID NO:50、SEQ ID NO:57、SEQ ID NO:59或SEQ ID NO:79所示，
和/或，所述重链CDR2的氨基酸序列如SEQ ID NO:3、SEQ ID NO:11、SEQ ID NO:21、 SEQ ID NO:27、SEQ ID NO:37、SEQ ID NO:40、SEQ ID NO:51、SEQ ID NO:60、SEQ IDNO:73或SEQ ID NO:80所示，
和/或，所述重链CDR3的氨基酸序列如SEQ ID NO:4、SEQ ID NO:12、SEQ ID NO:16、 SEQ ID NO:22、SEQ ID NO:28、SEQ ID NO:33、SEQ ID NO:41、SEQ ID NO:52、SEQ IDNO:62、SEQ ID NO:66、SEQ ID NO:77、SEQ ID NO:81或SEQ ID NO:87所示，
和/或，所述轻链CDR1的氨基酸序列如SEQ ID NO:6、SEQ ID NO:14、SEQ ID NO:18、 SEQ ID NO:30、SEQ ID NO:35、SEQ ID NO:43、SEQ ID NO:47、SEQ ID NO:54、SEQ IDNO:68、SEQ ID NO:83或SEQ ID NO:85所示，
和/或，所述轻链CDR2的氨基酸序列如SEQ ID NO:7、SEQ ID NO:44或SEQ ID NO:69 所示，
和/或，所述轻链CDR3的氨基酸序列如SEQ ID NO:8、SEQ ID NO:24、SEQ ID NO:48、 SEQ ID NO:55、SEQ ID NO:64、SEQ ID NO:70或SEQ ID NO:75所示。
根据本发明更优选的实施方式，CDR序列各自如表1各列所示，也即，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:3所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:12所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:16所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:20所示，所述重链CDR2的氨基酸序列如SEQ ID NO:21所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:22所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:28所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:32所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:33所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:37所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:39所示，所述重链CDR2的氨基酸序列如SEQ ID NO:40所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:41所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:50所示，所述重链CDR2的氨基酸序列如SEQ ID NO:51所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:52所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:57所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:59所示，所述重链CDR2的氨基酸序列如SEQ ID NO:60所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:62所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:66所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:73所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:77所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:79所示，所述重链CDR2的氨基酸序列如SEQ ID NO:80所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:81所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:87所示；
和/或，
所述轻链CDR1的氨基酸序列如SEQ ID NO:6所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:14所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:18所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:6所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:24所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:35所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:43所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:44所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:47所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:48所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:54所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:55所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:64所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:68所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:69所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:70所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:75所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:83所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:44所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:85所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示。
根据本发明进一步优选的实施方式，CDR序列各自同时满足表1各列所示，也即，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:3所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1 的氨基酸序列如SEQ ID NO:6所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:12所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:14所示，所述轻链CDR2的氨基酸序列如SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:16所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:18所示，所述轻链CDR2的氨基酸序列如SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:20所示，所述重链CDR2的氨基酸序列如SEQ ID NO:21所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:22所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:6所示，所述轻链CDR2的氨基酸序列如 SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:24所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:28所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:32所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:33所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:35所示，所述轻链CDR2的氨基酸序列如SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:37所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:39所示，所述重链CDR2的氨基酸序列如SEQ ID NO:40所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:41所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:43所示，所述轻链CDR2的氨基酸序列如SEQID NO:44所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:47所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:48所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:50所示，所述重链CDR2的氨基酸序列如SEQ ID NO:51所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:52所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:54所示，所述轻链CDR2的氨基酸序列如SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:55所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:57所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ IDNO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:59所示，所述重链CDR2的氨基酸序列如SEQ ID NO:60所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如 SEQ IDNO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:62所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:64所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:66所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:68所示，所述轻链CDR2的氨基酸序列如SEQID NO:69所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:70所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如 SEQ IDNO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:73所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:75所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:77所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:64所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:3所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:79所示，所述重链CDR2的氨基酸序列如SEQ ID NO:80所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:81所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:83所示，所述轻链CDR2的氨基酸序列如SEQID NO:44所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:85所示，所述轻链CDR2的氨基酸序列如 SEQ IDNO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:87所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:35所示，所述轻链CDR2的氨基酸序列如SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示。
抗体包括重链可变区和轻链可变区，本发明的抗体的重链可变区或轻链可变区的氨基酸序列可以分别与表1所示的序列具有至少80％的同源性。也即，根据本发明一种特别优选的实施方式，所述抗体的重链可变区的氨基酸序列如SEQ ID NO:1、SEQ ID NO:9、SEQID NO: 15、SEQ ID NO:19、SEQ ID NO:25、SEQ ID NO:31、SEQ ID NO:36、SEQ ID NO:38、SEQ ID NO:45、SEQ ID NO:49、SEQ ID NO:56、SEQ ID NO:58、SEQ ID NO:61、SEQ ID NO:65、 SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:76、SEQ ID NO:78或SEQ ID NO:86所示；和/或，所述抗体的轻链可变区的氨基酸序列如SEQ ID NO:5、SEQ ID NO:13、SEQ ID NO:17、SEQ ID NO:23、SEQ ID NO:29、SEQ ID NO:34、SEQ ID NO:42、SEQ ID NO:46、SEQ ID NO:53、SEQ ID NO:63、SEQ ID NO:67、SEQ ID NO:74、SEQ ID NO:82或SEQ ID NO:84 所示。
优选情况下，本发明的抗体的重链可变区和轻链可变区的氨基酸序列同时与表1所示的序列具有至少80％的同源性。也即，根据本发明一种特别优选的实施方式，所述重链可变区的氨基酸序列如SEQ ID NO:1所示且所述轻链可变区的氨基酸序列如SEQ ID NO:5所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:9所示且所述轻链可变区的氨基酸序列如SEQ ID NO:13所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:15所示且所述轻链可变区的氨基酸序列如SEQ ID NO:17所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:19所示且所述轻链可变区的氨基酸序列如SEQ ID NO:23所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:25所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:31所示且所述轻链可变区的氨基酸序列如SEQ ID NO:34所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:36所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:38所示且所述轻链可变区的氨基酸序列如SEQ ID NO:42所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:45所示且所述轻链可变区的氨基酸序列如SEQ ID NO:46所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:49所示且所述轻链可变区的氨基酸序列如SEQ ID NO:53所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:56所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:58所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:61所示且所述轻链可变区的氨基酸序列如SEQ ID NO:63所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:65所示且所述轻链可变区的氨基酸序列如SEQ ID NO:67所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:71所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:72所示且所述轻链可变区的氨基酸序列如SEQ ID NO:74所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:76所示且所述轻链可变区的氨基酸序列如SEQ ID NO:63所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:1所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:45所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:78所示且所述轻链可变区的氨基酸序列如SEQ ID NO:82所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:71所示且所述轻链可变区的氨基酸序列如SEQ ID NO:84所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:86所示且所述轻链可变区的氨基酸序列如SEQ ID NO:34所示。
表1抗体的氨基酸序列编号
注：表1中的数字即为序列表“SEQ ID NO:”编号。
根据本发明，所述抗体能够结合TIGIT(抗原)，特别是SEQ ID NO:121所示的氨基酸序列。
本发明的优选实施方式中，为了进一步提高抗体的生物可接受性，还可以对抗体进行人源化，即，所述抗体为嵌合抗体或人源化抗体。术语“嵌合抗体”是指利用重组DNA技术，将来自一个物种(如小鼠)的单克隆抗体的恒定区氨基酸序列替换为来自另一个物种(如人) 的抗体的恒定区(重链恒定区如SEQ ID NO：124所示，轻链恒定区如SEQ ID NO：125所示)而获得的重组抗体。术语“人源化抗体”是指利用重组DNA技术，将来自一个物种(如小鼠)的单克隆抗体的恒定区和可变区的非CDR(Fv骨架区(FR))氨基酸序列全部替换为来自另一个物种(如人)的抗体的恒定区和可变区的非CDR氨基酸序列而获得的重组抗体。也即，一个抗体的恒定区被人源化时称为嵌合抗体，而恒定区和可变区的非CDR氨基酸序列全部人源化后称为人源化抗体。人源化的方法可以参照常规的抗体工程技术进行，在此不再赘述。
举例而言，本发明提供的嵌合抗体的氨基酸序列可以如下述SEQ ID NO：126(重链)和 SEQ ID NO：127(轻链)所示。
本发明提供的人源化抗体的重链可变区的序列如SEQ ID NO:122所示，轻链可变区的序列如SEQ ID NO:123所示。
本发明提供的免疫缀合物含有治疗剂以及与治疗剂偶联的如前所述的抗体或其抗原结合片段。所述抗体或其抗原结合片段与治疗剂偶联的方式可以为常规的方式。
本发明提供的组合物含有如前所述的抗体或其抗原结合片段、和/或上述免疫缀合物、以及药学上可接受的载体。在某些实施方式中，所述组合物包括在时间和/或空间上分开的组合，只要其能够共同作用以实现本发明的目的。例如，所述组合物中所含的成分可以以整体施用于受试者，或者分开施用于受试者。当所述组合物中所含的成分分开地施用于受试者时，各个成分可以同时或依次施用于受试者。
术语“药学上可接受的”表明组合物能够给药至受试者而不产生妨碍组合物给药的不良生理反应。例如，“药学上可接受的载体”是指在制备一般安全、无毒、可取的药物组合物中有用的载体，优选地，这些载体或稀释剂的实例包括但不限于：水、盐水、林格氏溶液、葡萄糖、甘露醇、右旋葡萄糖、乳糖、淀粉、硬脂酸镁、纤维素、碳酸镁、0.3％甘油、透明质酸、乙醇、聚亚烷基二醇如聚丙二醇、甘油三酯、5％人血清白蛋白，也可以使用脂质体和非水媒介物，例如不挥发油。
本发明的组合物也可以相互组合、或与一种或多种其它的治疗化合物组合地给药，例如，与化疗剂组合给药。因此，所述组合物还可以含有化疗剂。本发明的抗体或其抗原结合片段、或免疫缀合物还可以与第二治疗剂组合，所述第二治疗剂的示例性试剂包括但不限于抑制 TIGIT活性的其他试剂(包括其他抗体或其抗原结合片段、肽抑制剂、小分子拮抗剂等)和/ 或干扰TIGIT上游或下游信号转导的试剂。
通常，所述抗体或其抗原结合片段以有效量给药，即足以实现期望的治疗和/或预防效果的量，例如，引起与被治疗的疾病相关的症状的预防或缓解的量，所述疾病例如与TIGIT相关的疾病。给药至受试者的组合物的有效量将取决于疾病的类型和严重度，以及取决于个体的特征，例如一般健康状态、年龄、性别、体重和对药物的耐受性；还将取决于疾病的严重程度和类型，本领域技术人员将能够根据这些因素等确定合适的剂量。
本发明提供的用于检测样品中TIGIT的试剂盒含有如上所述的抗体或其抗原结合片段。所述样品可以为患有TIGIT介导的疾病的患者(特别是癌症患者，更优选是患有肺癌，肝癌，卵巢癌，宫颈癌，皮肤癌，膀胱癌，结肠癌，乳腺癌，神经胶质瘤，肾癌，胃癌，食道癌，口腔鳞状细胞癌和头颈癌中的至少一种的患者)的组织。所述试剂盒还可以包括常规用于检测TIGIT的试剂，如包被液等。
本发明还提供了如上所述的抗体或其抗原结合片段在制备用于检测样品中TIGIT的试剂中的用途。如前所述，所述样品可以为患有TIGIT介导的疾病的患者的组织，在此不再赘述。本发明的抗体或其抗原结合片段与TIGIT具有良好的亲和性，能够有效地检测样品中的 TIGIT。
本发明还提供了所述的抗体或其抗原结合片段在制备用于预防和/或治疗TIGIT介导的疾病的药物中的用途。优选地，所述TIGIT介导的疾病为癌症或感染性疾病。更优选地，所述癌症为表达CD155的癌症。进一步优选地，所述癌症为肺癌，肝癌，卵巢癌，宫颈癌，皮肤癌，膀胱癌，结肠癌，乳腺癌，神经胶质瘤，肾癌，胃癌，食道癌，口腔鳞状细胞癌和头颈癌中的至少一种。进一步优选地，所述感染性疾病包括但不限于HIV病毒感染和/或乙型肝炎病毒感染。
另外，本发明还涉及一种(在体外)抑制癌细胞的方法，该方法包括：将癌细胞(如前所述)与有效量的本发明的抗体或其抗原结合片段、免疫缀合物和组合物中的至少一种接触。使用的术语“抑制”包括抑制癌细胞的增殖、生长和/或转移。
本发明还涉及一种预防和/或治疗TIGIT介导的疾病(如前所述)的方法，该方法包括：将有效量的本发明的抗体或其抗原结合片段、免疫缀合物和组合物中的至少一种给药至患者。其中，给药的方式可以为口服给药、经鼻给药、皮内给药、皮下给药、肌内给药或静脉给药或腹腔内给药。
本发明中涉及的“患者”或“受试者”一般指哺乳动物，如灵长类动物和/或啮齿类动物，特别是人或鼠。
本领域技术人员可以将编码本发明所述抗体或其抗原结合片段的DNA分子克隆到载体 (特别是表达载体)中，进而转化宿主细胞，通过诱导表达可获得所述抗体或其抗原结合片段。因此，本发明还提供了编码上述抗体或其抗原结合片段的(分离的)核酸以及含有该核酸的重组载体和转化子。所述核酸优选为基因工程手段获得的表达盒。
重组载体可以指克隆载体，也可以指表达载体，可以通过将所述核酸与商购的载体(如质粒或病毒载体)可操作地连接而获得，常用的质粒包括pSeTag2、PEE14、pMH3等。
本发明的表达载体可以含有编码的所述抗体的重链可变区、轻链可变区和/或恒定区的 DNA序列。然而，也可以分别构建两种表达载体，一种含有重链可变区和恒定区，另一种含有轻链可变区和恒定区，一同转染哺乳动物细胞。在一个优选的实施方式中，所述表达载体进一步含有启动子和编码分泌信号肽的DNA序列，以及至少一种用于筛选的抗药基因。
本发明所述宿主细胞可以为原核宿主细胞、真核宿主细胞或噬菌体。所述原核宿主细胞可以为大肠杆菌、枯草杆菌、链霉菌或奇异变形菌等。所述真核宿主细胞可以为包括巴斯德毕赤酵母、酿酒酵母、裂殖酵母、木霉等真菌，草地粘虫等昆虫细胞，烟草等植物细胞，BHK 细胞、CHO细胞、COS细胞、骨髓瘤细胞等哺乳动物细胞。在一些实施方式中，本发明所述宿主细胞优选为哺乳动物细胞，更优选BHK细胞、CHO细胞、NSO细胞或COS细胞。
编码本发明的抗体的重链和/或轻链的核酸在本发明的范围内，根据重链和/或轻链的氨基酸序列，本领域技术人员能够很容易得到相应的核酸序列，如表2所示。
表2抗体的基因序列编号
注：表2中的数字即为序列表“SEQ ID NO:”编号。
以下将通过实施例对本发明进行详细描述。实施例或测试例中，未注明具体条件的实验方法的，均按照常规条件进行。
实施例1：抗体的制备
生成针对人TIGIT的鼠源单克隆抗体，用纯化的重组TIGIT胞外区Fc融合蛋白(TIGIT-Fc)(重组TIGIT胞外区Fc融合蛋白，氨基酸序列如SEQ ID NO:121所示)作为抗原，免疫Balb/c小鼠(9周龄，购自上海莱斯克，体重20g左右)。
免疫小鼠使用纯化抗原和完全弗氏佐剂进行3次免疫，通过尾静脉放血后检测免疫应答。通过ELISA、流式细胞术筛选血清，获取有抗人TIGIT免疫球蛋白的小鼠。并对有最高的抗 TIGIT免疫球蛋白的小鼠取出脾细胞与鼠骨髓瘤细胞SP2/0细胞(ATCC编号CRL-1581)进行融合。融合后的杂交瘤细胞进行抗体筛选，得到鼠单抗1H6、2B11、3A10、4A5、4A9、4H5、6A2、6B7、7F4、8E1、8G3、9F4、9G6、10C1、10F10、11G4、12B7、12C8、15E9、 16C11、16D6和16E10。
将候选杂交瘤细胞总数量培养到106，800rpm离心10分钟收集细胞，并以Trizol试剂盒 (Invitrogen)提取总RNA；以总RNA为模板，逆转录合成cDNA文库(Invitrogen)，又以cDNA为模板PCR扩增杂交瘤细胞的所对应的可变区核酸序列。PCR扩增反应中所使用的引物序列与抗体可变区第一框架区或信号肽区和恒定区互补(Larrick，J.W.，et al.，(1990)Scand.J.Immunol.，32，121-128和Coloma，J.J.et al.，(1991)BioTechniques，11，152-156)。在50μl反应体系中，分别加入cDNA2μl，10×PCR缓冲液5μl，上游及下游引物2μl(5μmol)， dNTP 2μl，Taq酶1μl(Takara，Ex Taq)，H2O 38μl；95℃预变性5min，进入温度循环，进行 PCR扩增。反应条件为：94℃变性30S，58℃退火45S，72℃延伸50S，共32个循环，然后72℃延长7min。将扩增产物测序后，得到鼠单抗的重链和轻链可变区序列(包括氨基酸序列和核酸序列)如表1和表2所示。
实施例2：抗体的结合能力筛选
TIGIT抗体ELISA结合实验
ELISA实验被用于检测TIGIT抗体的结合特性。TIGIT胞外区Fc融合蛋白(TIGIT-Fc) 包被到96孔板中，抗体加入后信号的强弱用于判断抗体和TIGIT的结合特性。
用PBS缓冲液将TIGIT-Fc融合蛋白(氨基酸序列如SEQ ID NO:121所示)稀释为1μg/ml，以100μl/孔的体积加于96孔板中，于4℃放置过夜。将96孔板中PBS缓冲液吸掉，用PBST (pH7.2PBS含0.1％Tween 20)缓冲液洗板6次后，加入200μl/孔PBS/10％BSA，37℃孵育 2h进行封闭。移去封闭液，用PBST洗板6次后，加入100μl/孔用PBST/0.05％BSA稀释至合适浓度的待测TIGIT抗体，37℃孵育1h。移去反应体系，用PBST洗板6次后，以100μl/ 孔用PBST/0.05％BSA稀释HRP(辣根过氧化物酶)标记的抗鼠抗体二抗，37℃孵育1h。用 PBST洗板6次后，加入80μl/孔TMB(四甲基联苯胺)，于室温孵育3min，加入80μl/孔4M 硫酸终止反应。用酶标仪在450mm处读取吸光值。结果(图1)表明本发明的抗体能够结合 TIGIT。
TIGIT抗体流式细胞术结合实验
流式细胞术实验被用于检测TIGIT抗体的结合特性，于HEK293T细胞(ATCC编号CRL-3249)中过表达TIGIT蛋白(HEK293T-TIGIT)，抗体加入后信号的强弱用于判断抗体和TIGIT的结合特性。
HEK293T细胞按照5×105细胞/孔铺六孔板，用不含双抗的DMEM培养基培养过夜。转染前弃去培养基，加入1ml新鲜的不含双抗的DMEM培养基。将pLVX-TIGIT-IRES-ZsGreen(pLVX-IRES-ZsGreen1载体的酶切位点EcoRI与BamHI之间插入有TIGIT蛋白(SEQ ID NO:121)的编码序列(如SEQ ID NO:128所示)、pMD2G、psPAX2载体(共3μg)按照2:1:1 的比例加入200μl无血清DMEM培养基中，加入12μg聚醚酰亚胺(PEI，Polysciences有限公司)。混匀后静置16min，然后将全部液体加入铺有HEK293T细胞的六孔板中。培养6h后，弃去培养基，加入新鲜的完全DMEM培养基培养。转染48h后，收细胞培养上清，过0.45μm 滤器(Millipore)，即为病毒上清。将病毒上清全部加入含有1×104HEK293T细胞的6孔板中，加入终浓度4μg/ml的聚凝胺(Sigma)，培养12h。随后弃尽上清，加入新鲜的完全DMEM 培养基。所得细胞即为HEK293T-TIGIT细胞。
用PBS将HEK293T-TIGIT细胞稀释为2×106/ml，以100μl/管的体积加于1.5ml EP管中，向其中加入10μl/管山羊血清，于4℃封闭30min。加入1μg/管的TIGIT抗体，于4℃孵育30min。向EP管中加入1ml PBS，4℃3500rpm×5min离心，弃尽上清，再用PBS洗一遍。离心后弃尽上清，用100μl/管PBS重悬细胞，向其中加入0.1μl/管Alexa-647标记的山羊抗小鼠抗体二抗(Invitrogen)，4℃避光孵育30min。用PBS洗两遍，离心后弃尽上清。用200μl/管PBS重悬细胞，用流式细胞仪进行检测，结果如图2所示，进一步显示本发明的抗体能够结合TIGIT。
实施例3：体外结合亲和力和动力学实验
Biacore方法是公认的客观检测蛋白相互间亲和力和动力学的检测方法，通过Biacore T200分析本发明TIGIT抗体表征亲和力及结合动力学。
采用标准氨基偶联法将TIGIT胞外段Fc融合蛋白(TIGIT-Fc)共价连接至CM5(GE)芯片上。然后将稀释于PBS中的一系列浓度梯度的TIGIT抗体与各个循环进样，进样后以10mM NaOH溶液再生。追踪抗原-抗体结合动力学3分钟并追踪解离动力学10分钟，使用 GE的BIAevaluation软件以1∶1(Langmuir)结合模型分析所得数据，以此法测定的ka(kon)、kd(koff)和KD值显示于下表3。
表3TIGIT抗体亲和力
| 克隆号 | ka(1/Ms) | kd(1/s) | KD(M) |
| 1H6 | 1.545×10<sup>5</sup> | 7.736×10<sup>-4</sup> | 5.007×10<sup>-9</sup> |
| 3A10 | 2.813×10<sup>4</sup> | 9.031×10<sup>-4</sup> | 3.210×10<sup>-8</sup> |
| 4A5 | 6.212×10<sup>5</sup> | 2.318×10<sup>-4</sup> | 3.732×10<sup>-10</sup> |
| 4A9 | 6.725×10<sup>5</sup> | 4.376×10<sup>-3</sup> | 6.507×10<sup>-9</sup> |
| 4H5 | 5.222×10<sup>4</sup> | 8.422×10<sup>-4</sup> | 1.613×10<sup>-8</sup> |
| 6A2 | 2.745E×10<sup>5</sup> | 8.188×10<sup>-4</sup> | 2.983×10<sup>-9</sup> |
| 687 | 1.571×10<sup>6</sup> | 2.941×10<sup>-4</sup> | 1.872×10<sup>-10</sup> |
| 7F4 | 2.327×10<sup>5</sup> | 2.707×10<sup>-3</sup> | 1.163×10<sup>-9</sup> |
| 8E1 | 1.017×10<sup>5</sup> | 2.640×10<sup>-3</sup> | 2.597×10<sup>-9</sup> |
| 8G3 | 2.434×10<sup>5</sup> | 8.918×10<sup>-4</sup> | 3.664×10<sup>-9</sup> |
| 9F4 | 3.990×10<sup>5</sup> | 8.017×10<sup>-4</sup> | 2.009×10<sup>-9</sup> |
| 9G6 | 1.266×10<sup>5</sup> | 3.404×10<sup>-4</sup> | 2.689×10<sup>-9</sup> |
| 10F10 | 2.303×10<sup>6</sup> | 3.581×10<sup>-3</sup> | 1.555×10<sup>-9</sup> |
| 11G4 | 7.577×10<sup>5</sup> | 9.884×10<sup>-4</sup> | 1.305×10<sup>-9</sup> |
| 12B7 | 3.671×10<sup>3</sup> | 1.842×10<sup>-4</sup> | 5.019×10<sup>-8</sup> |
| 12C8 | 1.332×10<sup>5</sup> | 7.673×10<sup>-4</sup> | 5.761×10<sup>-9</sup> |
| 15E9 | 1.896×10<sup>6</sup> | 7.022×10<sup>-3</sup> | 3.705×10<sup>-9</sup> |
| 16D6 | 2.080×10<sup>5</sup> | 3.362×10<sup>-3</sup> | 1.617×10<sup>-8</sup> |
| 16E10 | 1.959×10<sup>5</sup> | 4.095×10<sup>-4</sup> | 2.091×10<sup>-9</sup> |
实施例4：抗体阻断能力的筛选
TIGIT抗体是通过和TIGIT胞外区的结合，从而阻断TIGIT和其配体的信号通路，流式细胞术实验被用于检测TIGIT抗体对配体CD155结合的阻断。
用PBS将HEK293T-TIGIT细胞(同上)稀释为2×106/ml，以100μl/管的体积加于1.5ml EP管中，向其中加入10μl/管小鼠血清，于4℃封闭30min。加入4μg/管CD155胞外区Fc融合蛋白(CD155-Fc，序列如SEQ ID NO:129所示)，4℃孵育30min。加入TIGIT抗体(6A2 和4A5)，于4℃孵育30min。向EP管中加入1ml PBS，4℃3500rpm×5min离心，弃尽上清，再用PBS洗一遍。离心后弃尽上清，用100μl/管PBS重悬细胞，向其中加入1μl/管647标记的小鼠抗人抗体二抗(Biolegend)，4℃避光孵育30min。用PBS洗两遍，离心后弃尽上清。用200μl/管PBS重悬细胞，用流式细胞仪进行检测，结果如图3所示，可以看出，本发明的抗体能够阻断TIGIT与配体CD155的结合。
实施例5：体外结合NK细胞的实验
本测试用于检测本发明的TIGIT抗体和人细胞表面表达的天然TIGIT结合活性，本测试所用的细胞为人外周血单个核细胞。
利用Ficoll密度梯度离心方法获得的人外周血单个核细胞用PBS稀释为1×107/ml，以 100μl/管的体积加于1.5ml EP管中，向其中加入10μl/管小鼠血清，于4℃封闭30min。加入1μg/ 管Alexa-647标记的TIGIT抗体(4A5)及其他荧光抗体(Brilliant Violet421TM-CD56， BioLegend；APC-CY7-CD3，BioLegend)，4℃避光孵育30min。向EP管中加入1mlPBS，4℃ 3500rpm×5min离心，弃尽上清，再用PBS洗一遍。离心后弃尽上清，用200μl/管PBS重悬细胞，用流式细胞仪进行检测，结果如图4所示，可以看出，本发明的抗体能够结合人自然杀伤细胞。
实施例6：抗体竞争关系检测实验
利用流式细胞术方法获得的TIGIT抗体的竞争关系。
用PBS将HEK293T-TIGIT细胞(同上)稀释为1×106/ml，以100μl/管的体积加于1.5ml EP管中，向其中加入10μl/管小鼠血清，于4℃封闭30min。加入1μg/管的无荧光标记的TIGIT 抗体，4℃孵育30min。加入0.1μg/管的Andy Flour 647(GeneCopoeia)标记的TIGIT抗体，于4℃孵育30min。用PBS洗两遍，离心后弃尽上清。用200μl/管PBS重悬细胞，用流式细胞仪进行检测。结果如图7所示，可以看出，本发明的抗体根据其竞争关系分为三组，1H6、 3A10、4A5、4A9、4H5、6A2、7F4、8G3、9F4、10C1、10F10、12B7、12C8、15E9、16D6、 16E10为一组，彼此均有竞争关系；6B7、16C11为一组，彼此有竞争关系，并与前述一组没有竞争关系；2B11、8E1、9G6、11G4为一组，彼此有竞争关系，并与其它两组抗体均有竞争关系。
实施例7：TIGIT抗体体外结合选择性实验
为检测TIGIT抗体(6A2、4A5和9F4)对于TIGIT同一家族其他蛋白的特异结合活性，人CD28，人PD-1，人CTLA4被用于进行结合检测。同时，为了检测TIGIT抗体对于人以外的不同种属的差异性，小鼠的TIGIT也进行了结合检测。
利用Lipofectaimine 2000试剂(Thermo Fisher)将含有人CD28(HG11524-CF，义翘神州)、PD-1(HG10377-CF，义翘神州)、CTLA4(HG11159-CF，义翘神州)、鼠TIGIT(MG50939-CF，义翘神州)编码序列的表达载体转染到CHO-S细胞(Thermo Fisher)中，于CHO-S细胞表面过表达人CD28、人PD-1、人CTLA4和鼠TIGIT。具体步骤为：CHO-S 细胞铺六孔板，1×106细胞/孔，用不含双抗的DMEM培养基培养过夜。转染前，弃去培养基，加入1mL新鲜的不含双抗的DMEM培养基。将3μg质粒、3μl Lipofectaimine 2000脂质体各加入一个含有250μl无血清DMEM的EP管中。静置5min后，将两管液体混合。随后静置 20min，将液体全部加入铺有CHO-S细胞的六孔板中。培养5h后，弃尽培养基，加入新鲜的完全DMEM培养基。转染后48h，收CHO-S细胞用于检测。
用PBS将过表达相应蛋白的CHO-S细胞稀释为2×106/ml，以100μl/管的体积加于1.5ml EP管中，向其中加入10μl/管山羊血清，于4℃封闭30min。加入2μg/管TIGIT抗体，于4℃孵育30min。向EP管中加入1ml PBS，4℃3500rpm×5min离心，弃尽上清，再用PBS洗一遍。离心后弃尽上清，用100μl/管PBS重悬细胞，向其中加入0.1μl/管Alexa-647标记的山羊抗小鼠抗体二抗(Invitrogen)，4℃避光孵育30min。用PBS洗两遍，离心后弃尽上清。用200μl/管PBS重悬细胞，用流式细胞仪进行检测，结果如图5和图6所示，可以看出，本发明的抗体特异性结合人TIGIT，而不结合小鼠TIGIT，并且也不结合TIGIT同家族的CD28、PD-1 和CTLA4。
实施例8：TIGIT抗体对肿瘤细胞生长的抑制(体外杀伤)
体外杀伤实验，用于检测TIGIT抗体(6A2和4A5)促进人外周血单个核细胞杀伤肿瘤细胞的作用。其中，使用的肿瘤细胞分别为卵巢癌细胞HO8910(中国科学院细胞库编号TCHu24)、人非小细胞肺癌细胞NCl-H358(ATCC编号CRL5807)和人非小细胞肺癌细胞 NCl-H1650(ATCC编号CRL-5883)。
(1)肿瘤细胞用无血清DMEM培养基洗两遍，4℃3500rpm×5min离心，弃尽上清。用1ml无血清DMEM培养基重悬，加入终浓度5μM CFSE(琥珀酰亚胺酯)，37℃孵育30min。
(2)加入200μl预冷的胎牛血清终止标记，4℃3500rpm×5min离心，弃尽上清。用含10％胎牛血清的完全RPMI-1640培养基洗两遍，弃尽上清。用完全RPMI-1640培养基重悬，计数。用完全RPMI-1640培养基稀释为1.25×105/ml。
(3)利用Ficoll密度梯度离心方法获得的人外周血单个核细胞(PBMC)计数，用含10％胎牛血清的完全RPMI-1640培养基稀释为一系列浓度。
(4)将稀释后的PBMC，以100μl/孔的体积加入96孔圆底板中。
(5)用完全RPMI-1640培养基稀释TIGIT抗体或对照鼠IgG，以20μl/孔的体积将稀释后的TIGIT抗体或鼠IgG加入96孔圆底板中。
(6)将稀释后的肿瘤细胞以80μl/孔的体积加入96孔圆底板中。
(7)4℃1500rpm×1min离心，37℃孵育4h。
(8)以1μl/孔的体积向96孔圆底板中加入7-AAD，混匀。将孔中所有液体转入流式管，利用流式细胞仪进行检测，结果如图8所示，可以看出，本发明的抗体能够促进人外周血单个核细胞的抗癌功能。
实施例9：对皮下移植瘤抑制实验
将SW620细胞(ATCC编号CCL-227)按照1×106/只接种于NOG小鼠(6-8周，中国科学技术大学生命科学学院实验动物中心繁殖，体重20g左右)右肋部皮下，第4天肿瘤长至约30mm3后，去除体重、肿瘤过大和过小的，按肿瘤体积将小鼠随机分为无处理(control) 组、PBMC+IgG组、PBMC+4A5mg/kg组和PBMC+6A2组，每组5只。将PBMC以1.5×106个细胞/只注射到小鼠尾静脉中，并于第5天开始尾静脉注射抗体(6A2和4A5)，3天一次，共给药8次。每周测4次瘤体积，称鼠重，记录数据。肿瘤体积(V)计算公式为：V＝1/2×a×b2，其中a、b分别表示长、宽。
结果见图9：治疗后的肿瘤体积变化图，显示抗体可以很好的抑制肿瘤SW620的生长。
实施例10：小鼠抗体人源化实验
参照4A5抗体轻链可变区序列和重链可变区序列，选取与其非CDR区匹配最好的人源化模板。将鼠源抗体CDR区移植到选择的人源化模板上，替换人源模板的CDR区，得到人源化的抗体hu4A5。然后，以鼠源抗体的三维结构为基础，对包埋残基、与CDR区有直接相互作用的残基，以及对VL和VH的构象有重要影响的残基进行回复突变，得到人源化之后的抗体，人源化4A5抗体重链可变区的序列如SEQ ID NO：122所示，人源化4A5抗体轻链可变区的序列如SEQ ID NO：123所示，重链序列如‘SEQ ID NO：122-SEQ ID NO：124’所示，轻链序列如‘SEQ ID NO：123-SEQ ID NO：125’所示。将鼠源4A5抗体可变区与人IgG4 的恒定区融合，为嵌合抗体ch4A5(重链序列如SEQ ID NO：126所示，轻链序列如SEQ ID NO： 127所示)。
实施例11：人源化抗体活性数据
对实施例10获得的嵌合抗体和人源化抗体在体外进行ELISA结合实验，配体结合阻断实验(方法步骤同前述实施例)，结果分别如图10和图11所示；亲和力动力学实验的结果显示于下表4，从中可以看出，本发明获得的嵌合抗体和人源化抗体均能够结合TIGIT并阻断 TIGIT与配体CD155的结合。
表4人源化4A5抗体亲和力
| ka(1/Ms) | kd(1/s) | KD(M) | |
| ch4A5 | 2.610×10<sup>5</sup> | 1.160×10<sup>-4</sup> | 4.450×10<sup>-10</sup> |
| hu4A5 | 1.200×10<sup>5</sup> | 3.693×10<sup>-4</sup> | 3.079×10<sup>-9</sup> |
从以上实验结果可以看出，本发明得到的抗体的能够以高亲和力阻断TIGIT和CD155的相互作用；能够与TIGIT以高特异性结合，而与其它CD28家族成员(如CD28、PD-1和CTLA4) 不发生结合；并能够激活免疫细胞，从而杀伤肿瘤细胞。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于此。在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，包括各个技术特征以任何其它的合适方式进行组合，这些简单变型和组合同样应当视为本发明所公开的内容，均属于本发明的保护范围。
序列
SEQ ID NO:1，重链可变区
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYINPYNDDTNYNEKFKGKATLTSDKSSSTAYMELTSLTSEDSAVYFCARRLSVNSFPYWGQGTLVTVSA
SEQ ID NO:2，重链CDR1
GYTFTSYV
SEQ ID NO:3，重链CDR2
INPYNDDT
SEQ ID NO:4，重链CDR3
ARRLSVNSFPY
SEQ ID NO:5，轻链可变区
DIVMTQSHKFMSISVGDRVSISCKASQDVFTAVAWYQQKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTDF TFTISSVQAEDLAVYYCQQHYSTPWTFGGGSNLEIK
SEQ ID NO:6，轻链CDR1
QDVFTA
SEQ ID NO:7，轻链CDR2
SAS
SEQ ID NO:8，轻链CDR3
QQHYSTPWT
SEQ ID NO:9，重链可变区
AVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGSTSYNPSLKSRISITR DTSKNQFFLQLNSVTTEDTATYYCARRGVGRGMDYWGQGTSVTVSS
SEQ ID NO:10，重链CDR1
GYSITSDYA
SEQ ID NO:11，重链CDR2
ISYSGST
SEQ ID NO:12，重链CDR3
ARRGVGRGMDY
SEQ ID NO:13，轻链可变区
DIVMTQSHKFMSTLVGDRVSITCKASQDIFTTVAWYQQKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTDF TFTISSVQAEDLAVYYCQQHYSTPWTFGGGTKLEIK
SEQ ID NO:14，轻链CDR1
QDIFTT
SEQ ID NO:15，重链可变区
DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGSTSYNPSLKSRISITR DTSKNQFFLQLNSVTTEDTATYYCARREVGQGFAHWGQGTLVTVSA
SEQ ID NO:16，重链CDR3
ARREVGQGFAH
SEQ ID NO:17，轻链可变区
DIVMTQSHKFMSTSVGDRVSITCKASQDLSTAVAWYQQKPGQSPKVLIYSASYRYTGVPDRFTGSGSGTD FTFTISSVQAEDLAVYYCQQHYSTPWTFGGGTKLEIK
SEQ ID NO:18，轻链CDR1
QDLSTA
SEQ ID NO:19，重链可变区
LQESGPGLVKPSQSLSLTCTVTGSSITSDYAWNWIRQFPGNKLEWMGYITYSGRTTYNPSLKSRISITRDTS KNQFFLQLNSVTTEDTATYYCARWGLLRRYFDYWGQGTTLTVSS
SEQ ID NO:20，重链CDR1
GSSITSDYA
SEQ ID NO:21，重链CDR2
ITYSGRT
SEQ ID NO:22，重链CDR3
ARWGLLRRYFDY
SEQ ID NO:23，轻链可变区
DIVMTQSHKFMSTSVGDRVSITCKASQDVFTAVAWYQQKPGQSPKLLIYSASFRYTGVPDRFTGSGSGTD FTFTISSVQAEDLAVYYCQQHYSTPLTFGAGTKLELK
SEQ ID NO:24，轻链CDR3
QQHYSTPLT
SEQ ID NO:25，重链可变区
EVQLQQSGPELVKPGASVKMSCKASGYTFTSFVMHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDKSSSTAYMELSSLTSADSAVYYCARRLSVSSFPYWGQGTLVTVSA
SEQ ID NO:26，重链CDR1
GYTFTSFV
SEQ ID NO:27，重链CDR2
INPYNDGT
SEQ ID NO:28，重链CDR3
ARRLSVSSFPY
SEQ ID NO:29，轻链可变区
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWYQQKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTD FTFTISSVQAEDLAVYYCQQHYSTPWTFGGGSKLEIK
SEQ ID NO:30，轻链CDR1
QDVSTA
SEQ ID NO:31，重链可变区
DVQLQESGPGLVKPSQSLSLTCTVTGYSITNDYAWNWIRQFPGNKLEWMGYISYSGSTSYNPSLKSRISIT RDTSKNQFFLQLNSVTTEDTATYYCARRGVGRTMDYWGQGTSVTVSS
SEQ ID NO:32，重链CDR1
GYSITNDYA
SEQ ID NO:33，重链CDR3
ARRGVGRTMDY
SEQ ID NO:34，轻链可变区
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTVVGWYQQKPGQSPKSLIYSASYRYTGVPDRFTGSGSGTD FTFTISSVQAEDLAVYYCQQHYSTPWTFGGGTKLEIK
SEQ ID NO:35，轻链CDR1
QDVSTV
SEQ ID NO:36，重链可变区
EVQLQQSGPELVKPGTSVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYINPYNDGAKYNEKFKGKVTLTSDKSSSTAYMELSSLTSEDSAVYYCARRLSVNSFPYWGQGTLVTVSA
SEQ ID NO:37，重链CDR2
INPYNDGA
SEQ ID NO:38，重链可变区
VQLKESGPGLVAPSQSLSITCTVSGFSLSTYSVHWIRQPPGEGLEWLGMIWGRGSTDYNSALRSRLSISKD NSKSQVFLKMNSLQTDDTAMYYCARNRGNLGYGGWFANWGQGTLVTVSA
SEQ ID NO:39，重链CDR1
GFSLSTYS
SEQ ID NO:40，重链CDR2
IWGRGST
SEQ ID NO:41，重链CDR3
ARNRGNLGYGGWFAN
SEQ ID NO:42，轻链可变区
DIVMTQSPSSLALSVGQKVTMSCKSSQSLLHSDNQKNYLAWYQQKPGQSPKLLVYFASTRESGVPDRFMGSGSGTDFTLTISGVQAEDLADYFCQQHYSTPWTFGGGTKLEIK
SEQ ID NO:43，轻链CDR1
QSLLHSDNQKNY
SEQ ID NO:44，轻链CDR2
FAS
SEQ ID NO:45，重链可变区
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARRLSVNSFPYWGQGTLVTVSA
SEQ ID NO:46，轻链可变区
DIVMTQSHKFMSTSVGDRVSITCKASQDVSNAVAWYQQKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTD FTFTISSVQAEDLAVFYCQHHYSTPPTFGAGTKLELK
SEQ ID NO:47，轻链CDR1
QDVSNA
SEQ ID NO:48，轻链CDR3
QHHYSTPPT
SEQ ID NO:49，重链可变区
DVQLQESGPGLVKPSQSLSLTCTVTGFSITSDYVWNWIRQFPGNKLEWMGYISYSDTTMYNPSLKSRISIT RDTSKNQFFLQLNSVTTEDTATYFCARRDWAAWFVYWGQGTLVTVSA
SEQ ID NO:50，重链CDR1
GFSITSDYV
SEQ ID NO:51，重链CDR2
ISYSDTT
SEQ ID NO:52，重链CDR3
ARRDWAAWFVY
SEQ ID NO:53，轻链可变区
DIVMTQSHKFMSTSVGDRVTITCKASQDVSIAVAWYQQKPGQSPKLLVYSASFRYTGVPDRFTGSGSGTD FTFTISSVRAEDLAVYYCQQHYGTPWTFGGGTKLEIK
SEQ ID NO:54，轻链CDR1
QDVSIA
SEQ ID NO:55，轻链CDR3
QQHYGTPWT
SEQ ID NO:56，重链可变区
EVQLQQSGPELVKPGASVKMSCKASGYIFTSYVMHWVKQKPGQGLEWIGYINPYNDGTKYYEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARRLSVNSFPYWGQGTLVTVSA
SEQ ID NO:57，重链CDR1
GYIFTSYV
SEQ ID NO:58，重链可变区
EVQLQQSGPELVKPGASVKMSCKASGYTFSSYVMHWVKQKPGQGLEWIGYINPYNDGSKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARRLSVNSFPYWGQGTLVTVSA
SEQ ID NO:59，重链CDR1
GYTFSSYV
SEQ ID NO:60，重链CDR2
INPYNDGS
SEQ ID NO:61，重链可变区
DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGSTNYNPSLKSRISIT RDTSKNQFFLQLNSVTTEDTATYYCARRDWAAWFAYWGQGTLVTVSA
SEQ ID NO:62，重链CDR3
ARRDWAAWFAY
SEQ ID NO:63，轻链可变区
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWYQQKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTD FSFTISSVQAEDLAVYYCQQQYSTPWTFGGGTKLEIK
SEQ ID NO:64，轻链CDR3
QQQYSTPWT
SEQ ID NO:65，重链可变区
DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGSTSYNPSLKSRISISR DTSKNQFFLQLNSVTTEDTATYYCVRRDWAAWFAYWGQGTLVTVSA
SEQ ID NO:66，重链CDR3
VRRDWAAWFAY
SEQ ID NO:67，轻链可变区
SVPGDPLEIVSGAHGERVTMTCSASSSVSSSYFYWYQQKSGSSPKLWIYSISNLASGVPARFSGSGSGTSYS LKINSMEAEDAATYYCQQWSSNPPTFGGGTKLEIK
SEQ ID NO:68，轻链CDR1
SSVSSSY
SEQ ID NO:69，轻链CDR2
SIS
SEQ ID NO:70，轻链CDR3
QQWSSNPPT
SEQ ID NO:71，重链可变区
EVQLQQSGPELVKPGASVKMSCKASGYTFTSFVVHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDRSSSTAYMELSSLTSEDSAVYYCARRLSVNSFPYWGQGTLVTVSA
SEQ ID NO:72，重链可变区
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVLHWVKQKPGQGLEWIGYINPNNDVSKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARRLSVNSFPYWGQGTLVTVSS
SEQ ID NO:73，重链CDR2
INPNNDVS
SEQ ID NO:74，轻链可变区
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWYQQKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTD FTFTISSVQAEDLAVYYCQQHYSAPWTFGGGSKLEIK
SEQ ID NO:75，轻链CDR3
QQHYSAPWT
SEQ ID NO:76，重链可变区
DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGSTSYNPSLKSRISITR DTSKNQFFLQLNSVTTEDTATYYCARRDWAAWFAHWGQGTLVTVSA
SEQ ID NO:77，重链CDR3
ARRDWAAWFAH
SEQ ID NO:78，重链可变区
QVQLKESGPGLVAPSQSLSITCTVSGFSLSVYSIHWIRQPPGKGLEWLGMIWGGGITDYNSPLKSRLSISKD NSKSQVFLEMNGLQTDDTAIYYCARNRGNLGYGGWFADWGQGTLVTVS
SEQ ID NO:79，重链CDR1
GFSLSVYS
SEQ ID NO:80，重链CDR2
IWGGGIT
SEQ ID NO:81，重链CDR3
ARNRGNLGYGGWFAD
SEQ ID NO:82，轻链可变区
DIVMTQSPSSLALSVGQKVTMTCKSSQSLLNGSNQVNYLAWYQQKPGQSPKLLVYFASTRESGVPDRFIG SGSGTDFTLTISSVQAEDLADYFCQQHYSTPWTFGGGTKLEIR
SEQ ID NO:83，轻链CDR1
QSLLNGSNQVNY
SEQ ID NO:84，轻链可变区
DIVMTQSHKFMSTSVGDRVSITCKASQDVLTSVAWYQQKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTD FTFTISSVQAEDLAVYYCQQHYSTPWTFGGGSKLEIK
SEQ ID NO:85，轻链CDR1
QDVLTS
SEQ ID NO:86，重链可变区
DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYISYSGSTRYNPSLKSRISITR DTSKNQFFLQLNSVTTEDTATYYCARRELGQGFPYWGQGTLVTVSA
SEQ ID NO:87，重链CDR3
ARRELGQGFPY
SEQ ID NO:88，重链可变区编码序列
gaggtccagctacagcagtctggacctgagctggtgaagcctggggcttcagtgaagatgtcctgcaaggcttctggatacacattcactagctatgttatgcactggg tgaagcagaagcctgggcagggccttgagtggattggatatattaatccttacaatgatgatactaactacaatgagaagttcaaaggcaaggccacactgacttcagacaaatcctccagcacagcctacatggagctcaccagcctgacctctgaggactctgcggtctatttctgtgcaagaagactgtctgttaactcgtttccttactggggcca agggactctggtcactgtctctgcag
SEQ ID NO:89，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccatatcagtaggagacagggtcagcatctcctgcaaggccagtcaggatgtgtttactgctgtagcctggtatca acagaaaccaggacaatctcctaaactcctgatttactcggcatcctaccgatacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcac catcagcagtgtgcaggctgaggacctggcagtttattactgtcagcaacattatagtactccgtggacgttcggtggaggctccaacctggaaatcaaac
SEQ ID NO:90，重链可变区编码序列
gctgtgcagcttcaggagtcgggacctggcctggtgaaaccttctcagtctctgtccctcacctgcactgtcactggctactcaatcaccagtgattatgcctggaactg gatccggcagtttccaggaaacaaactggagtggatgggctacataagctacagtggtagcactagctacaacccatctctcaaaagtcgaatctctatcacgcgagacacatccaagaaccagttcttcctgcagttgaattctgtgactactgaggacacagccacatattactgtgcaagacgaggggtgggaagaggtatggactactgggg tcaaggaacctcagtcaccgtctcctcag
SEQ ID NO:91，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacattagtaggagacagggtcagcatcacctgcaaggccagtcaggatatatttactactgtagcctggtatca acagaaaccaggacaatctcctaaactactgatttattcggcatcctaccggtacactggagtccctgatcgtttcactggcagtggatctgggacggatttcactttcac catcagcagtgtgcaggctgaagacctggcagtttattattgtcagcaacattatagtactccgtggacgttcggtggaggcaccaagctggaaatcaaac
SEQ ID NO:92，重链可变区编码序列
gatgtgcagcttcaggagtcgggacctggcctggtgaaaccttctcagtctctgtccctcacctgcactgtcactggctactcaatcaccagtgattatgcctggaactg gatccggcagtttccaggaaacaaactggagtggatgggctacataagctacagtggtagcactagctacaacccatctctcaaaagtcgaatctctatcactcgagacacatccaagaaccagttcttcctgcagttgaattctgtgactactgaggacacagccacatattactgtgcaagaagggaagtgggacaggggtttgctcactgggg ccaagggactctggtcactgtctctgcag
SEQ ID NO:93，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacatcagtaggagacagggtcagcatcacctgcaaggccagtcaggatctgagtactgctgtagcctggtatc aacagaaaccaggacaatctcctaaagtactgatttactcggcatcctaccggtacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcaccatcagcagtgtgcaggctgaagacctggcagtttattactgtcagcaacattatagtactccgtggacgttcggtggaggcaccaagctggaaatcaaac
SEQ ID NO:94，重链可变区编码序列
gcttcaggagtcgggacctggcctggtgaaaccttctcagtctctgtccctcacctgcactgtcactggctcctcaatcaccagtgattatgcctggaactggatccggc agtttccaggaaacaaactggagtggatgggctacataacttacagtggtcgcactacctacaacccatctctcaaaagtcgaatctctatcactcgagacacatccaagaaccagttcttcctgcagttgaattctgtgactactgaggacacagccacatattactgtgcaagatgggggttactacgtcgatactttgactactggggccaaggca ccactctcacagtctcctcag
SEQ ID NO:95，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacatcagtaggagacagggtcagcatcacctgcaaggccagtcaggatgtttttactgctgtggcctggtatca acagaaaccaggacaatctcctaaactactgatttactcggcatccttccggtacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcac catcagcagtgtgcaggctgaagacctggcagtttattactgtcagcaacattatagtactccgctcacgttcggtgctgggaccaagctggagctgaaac
SEQ ID NO:96，重链可变区编码序列
gaggtccagctgcagcagtctggacctgagctggtaaagcctggggcttcagtgaagatgtcctgcaaggcttctggatacacattcactagctttgttatgcactgggt gaagcagaagcctgggcagggccttgagtggattggatatattaatccttacaatgatggtactaagtacaatgagaagttcaaaggcaaggccacactgacttcagacaaatcctccagcacagcctacatggagctcagcagcctgacctctgcggactctgcggtctattactgtgcaagaaggctgtctgttagctcgtttccttactggggcc aagggactctggtcactgtctctgcag
SEQ ID NO:97，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacatcagtaggagacagggtcagcatcacctgcaaggccagtcaggatgtgagtactgctgtagcctggtatc aacagaaaccagggcaatctcctaaactcctgatttactcggcatcctaccgatacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcaccatcagcagtgtgcaggctgaagacctggcagtttattactgtcagcaacattatagtactccgtggacgttcggtggaggctccaagctggaaatcaaac
SEQ ID NO:98，重链可变区编码序列
gatgtgcagcttcaggagtcgggacctggcctggtgaaaccttctcagtctctgtccctcacctgcactgtcactggctactcaatcaccaatgattatgcctggaactg gatccggcagtttccaggaaacaaactggagtggatgggctacataagctacagtggtagcactagctacaacccatctctcaaaagtcgaatctctatcactcgagacacatccaagaaccaattcttcctgcagttgaattctgtgactactgaggacacagccacatattactgtgcaagacgaggggtgggaagaactatggactactggggt caaggaacctcagtcaccgtctcctcag
SEQ ID NO:99，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacatcagtaggagacagggtcagcatcacctgcaaggccagtcaggatgtgagtactgttgtaggctggtatc aacagaaaccaggacaatctccaaaatcactgatttattcggcatcctaccggtacactggagtccctgatcgtttcactggcagtggatctgggacggatttcactttcaccatcagcagtgtgcaggctgaagacctggcagtttattactgtcagcaacattatagtactccgtggacgttcggtggaggcaccaagctggaaatcaaac
SEQ ID NO:100，重链可变区编码序列
gaggtccagctgcagcagtctggacctgagctggtaaagcctgggacttcagtgaagatgtcctgcaaggcttctggctacacattcactagctatgttatgcactggg tgaagcagaagcctgggcagggccttgagtggattggatatattaatccttacaatgatggtgctaagtacaatgagaagttcaaaggcaaggtcacactgacttcagacaaatcctccagcacagcctacatggagctcagcagcctgacctctgaggactctgcggtctattactgtgcaagaaggctgtctgttaactcgtttccttactggggcc aagggactctggtcactgtctctgcag
SEQ ID NO:101，重链可变区编码序列
gtgcagctgaaggagtcaggacctggcctggtggcaccctcacagagcctgtccatcacatgcactgtctctgggttctcattatccacatatagtgtacactggattcg ccagcctccaggagagggtctggagtggctgggaatgatctggggtcgtggaagcacagactataattcagctctcagatccagactgagcatcagcaaggacaac tccaagagtcaagttttcttaaaaatgaacagtctgcaaactgatgacacagccatgtactactgtgccagaaataggggtaatttgggttacggaggctggtttgctaac tggggccaagggactctggtcactgtctctgca
SEQ ID NO:102，轻链可变区编码序列
gacattgtgatgacacagtctccatcctccctggctttgtcagtaggacagaaggtcactatgagctgcaagtccagtcagagccttttacatagtgacaatcaaaagaa ctatttggcctggtaccagcagaaaccaggacagtctcctaaacttctggtatactttgcatccactagggaatctggggtccctgatcgcttcatgggcagtggatctgggacagatttcactcttaccatcagcggtgtgcaggctgaagacctggcagattacttctgtcagcaacattatagcactccgtggacgttcggtggaggcaccaagct ggaaatcaaac
SEQ ID NO:103，重链可变区编码序列
gaggtccagctgcagcagtctggacctgagctggtaaagcctggggcttcagtgaagatgtcctgcaaggcttctggatacacattcactagctatgttatgcactggg tgaagcagaagcctgggcagggccttgagtggattggatatattaatccttacaatgatggtactaagtacaatgagaagttcaaagggaaggccacactgacttcag acaaatcctccagcacagcctacatggagctcagcagcctgacctctgaggactctgcggtctattactgtgcaagaaggctgtctgttaactcgtttccttactggggc caagggactctggtcactgtctctgcag
SEQ ID NO:104，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacatcagtaggagacagggtcagcatcacctgcaaggccagtcaggatgtgagtaatgctgtagcctggtatc aacagaaaccaggacaatctcctaaactactgatttactcggcatcctaccggtacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcaccatcagcagtgtgcaggctgaagacctggcagttttttactgtcagcaccattatagtactcctcccacgttcggtgctgggaccaagctggagctgaaac
SEQ ID NO:105，重链可变区编码序列
gatgtgcagcttcaggagtcgggacctggcctggtgaaaccttctcagtctctgtccctcacctgcactgtcactggcttctcaatcaccagtgattacgtctggaactgg atccggcagtttccaggaaacaaactggagtggatgggctacataagctatagtgataccactatgtacaacccatctctcaaaagtcgaatctctatcactcgagacac atccaagaaccagttcttcctgcagttgaattctgtgactactgaggacacagccacatatttctgtgcaagaagggactgggccgcctggtttgtttactggggccaag ggactctggtcactgtctctgcag
SEQ ID NO:106，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacatcagttggagacagggtcactatcacctgcaaggccagtcaggatgtgagtattgctgtagcctggtatca acagaaaccaggacaatctcctaaactactagtttactcggcatccttccggtacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcac catcagcagtgtgcgggctgaagacctggcagtttattactgtcagcaacattatggtactccgtggacgttcggtggaggcaccaagctggaaatcaaac
SEQ ID NO:107，重链可变区编码序列
gaggtccagctgcagcagtctggacctgagctggtaaagcctggggcttcagtgaagatgtcctgcaaggcttctggatacatattcactagctatgttatgcactgggt gaagcagaagcctgggcagggccttgagtggattggatatattaatccttacaatgatggtactaagtactatgagaagttcaaaggcaaggccacactgacttcagacaaatcctccagcacagcctacatggagctcagcagcctgacctctgaggactctgcggtctattactgtgcaagaaggctgtctgttaactcgtttccttactggggcca agggactctggtcactgtctctgcag
SEQ ID NO:108，重链可变区编码序列
gaggtccaactgcagcagtctggacctgagctggtaaagcctggggcttcagtgaagatgtcctgcaaggcttctggatacacattcagtagctatgttatgcactggg tgaagcagaagcctgggcagggccttgagtggattggatatattaatccttacaatgatggtagtaagtacaatgagaagttcaaaggcaaggccacactgacttcag acaaatcctccagcacagcctacatggagctcagcagcctgacctctgaggactctgcggtctattactgtgcaagaaggctgtctgttaactcgtttccttactggggc caagggactctggtcactgtctctgcag
SEQ ID NO:109，重链可变区编码序列
gatgtgcagcttcaggagtcgggacctggcctggtgaaaccttctcagtctctgtccctcacctgcactgtcactggctactcaatcaccagtgattatgcctggaactg gatccgacagtttccaggaaacaagctggagtggatgggctacataagctacagtggtagcactaactacaacccatctctcaaaagtcgaatctctatcactcgagacacatccaagaaccagttcttcctgcagttgaattctgtgactactgaggacacagccacatattactgtgcaagaagggactgggccgcctggtttgcttactggggcc aagggactctggtcactgtctctgcag
SEQ ID NO:110，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacatcagtaggagacagggtcagcatcacctgcaaggccagtcaggatgtgagtactgctgtagcctggtatc aacagaaaccaggacaatctcctaaactactgatttactcggcatcctaccggtacactggagtccctgatcgcttcactggcagtggatctgggacggatttcagtttcaccatcagcagtgtgcaggctgaagacctggcagtttattactgtcagcaacaatatagtactccgtggacgttcggtggaggcaccaagctggaaatcaaac
SEQ ID NO:111，重链可变区编码序列
gatgtgcagcttcaggagtcgggacctggcctggtgaaaccttctcagtctctgtccctcacctgcactgtcactggctactcaatcaccagtgattatgcctggaactg gatccggcagtttccaggaaacaaactggagtggatgggctacataagctacagtggtagcactagctacaacccatctctcaaaagtcgaatctctatcagtcgagacacatccaagaaccagttcttcctgcagttgaattctgtgactactgaggacacagccacatattactgtgtaagaagggactgggccgcctggtttgcttactggggcc aagggactctggtcactgtctctgcag
SEQ ID NO:112，轻链可变区编码序列
ctcggtacccggggatcctctagagattgtgtctggtgctcatggggaacgggtcaccatgacctgcagtgccagctcaagtgtgagttccagctacttttactggtacc agcagaagtcaggatcctccccaaaactctggatttatagcatatccaacctggcttctggagtcccagctcgcttcagtggcagtgggtctgggacctcttactctctca aaatcaacagcatggaggctgaagatgctgccacttattactgccagcagtggagtagtaacccaccgacgttcggtggaggcaccaagctggaaatcaaac
SEQ ID NO:113，重链可变区编码序列
gaggtccagctgcagcagtctggacctgagctggtaaagcctggggcttcagtgaagatgtcctgcaaggcttctggatacacattcactagctttgttgtgcactggg tgaagcagaagcctgggcagggccttgagtggattggatatattaatccttacaatgatggtactaagtacaatgagaagttcaaaggcaaggccacactgacttcagacaggtcctccagcacagcctacatggagctcagcagcctgacctctgaggactctgcggtctattactgtgcaagaaggctgtctgttaactcgtttccttactggggcc aagggactctggtcactgtctctgcag
SEQ ID NO:114，重链可变区编码序列
gaggtccagctgcagcagtctggacctgagctggtaaagcctggggcttcagtgaagatgtcctgcaaggcttctggatacacattcactagctatgttttgcactgggt gaagcagaagcctgggcagggccttgagtggattggatacattaatcctaacaatgatgttagtaagtacaatgagaagttcaaaggcaaggccacactgacttcagacaaatcctccagcacagcctacatggaactcagcagcctgacctctgaggactctgcggtctattactgtgcaagaaggctgtctgttaactcgtttccttactggggcc aagggactctggtcactgtctcttcag
SEQ ID NO:115，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacatcagtcggagacagggtcagcatcacctgcaaggccagtcaggatgtgagtactgctgtagcctggtatc aacagaaaccagggcaatctcctaaactcctgatttactcggcatcctaccgatacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcaccatcagcagtgtgcaggctgaagacctggcagtttattactgtcagcaacattatagtgctccgtggacgttcggtggaggctccaagctggaaatcaaac
SEQ ID NO:116，重链可变区编码序列
gatgtgcagcttcaggagtcgggacctggcctggtgaaaccttctcagtctctgtccctcacctgcactgtcactggctactcaatcaccagtgattatgcctggaactg gatccggcagtttccaggaaacaaactggagtggatgggctacataagctacagtggtagcactagctacaacccatctctcaaaagtcgaatttctatcactcgagacacatccaagaaccagttcttcctgcagttgaattctgtgactactgaagacacagccacatattactgtgcaagaagggactgggccgcctggtttgctcactggggcc aagggactctggtcactgtctctgcag
SEQ ID NO:117，重链可变区编码序列
caggtgcagctgaaggagtcaggacctggcctggtggcaccctcacagagcctgtccatcacatgcactgtctctgggttctcattatccgtatatagtatacactggat tcgccagcctccaggaaagggtctggagtggctgggaatgatctggggtggtggaatcacagactataattcacctctcaaatccagactgagcatcagcaaggaca actccaagagccaagttttcttagaaatgaacggtctgcaaactgatgacacagccatctactactgtgccagaaataggggtaatttgggttacggaggctggtttgct gactggggccaagggactctggtcactgtctctgcag
SEQ ID NO:118，轻链可变区编码序列
gacattgtgatgacacagtctccatcctccctggctctgtcagtaggacagaaggtcactatgacctgcaagtccagtcagagccttttaaatggtagcaatcaagtgaa ctatttggcctggtaccaacagaaaccaggacagtctcctaaacttctggtgtactttgcgtccactagggaatctggggtccctgatcgcttcataggcagtggatctgggacagatttcactcttaccatcagcagtgtgcaggctgaagacctggcagattacttctgtcagcaacattatagcactccgtggacgttcggtggaggcaccaagct ggaaatcagac
SEQ ID NO:119，轻链可变区编码序列
gacattgtgatgacccagtctcacaaattcatgtccacatcagtaggagacagggtcagcatcacctgcaaggccagtcaggatgttcttacatctgtagcctggtatca acagaaaccagggcaatctcctaaactcctgatttactcggcatcctaccgatacactggagtccctgatcgcttcactggcagtggatctgggacggatttcactttcaccatcagcagtgtgcaggctgaagacctggcagtttattactgtcagcaacattatagtactccgtggacgttcggtggaggctccaagctggaaatcaaac
SEQ ID NO:120，重链可变区编码序列
Gatgtgcagcttcaggagtcgggacctggcctggtgaaaccttctcagtctctgtccctcacctgcactgtcactggctactcaatcaccagtgattatgcctggaactg gatccggcagtttccaggaaacaaactggagtggatgggctacataagctacagtggtagcactaggtacaacccatctctcaaaagtcgaatctctatcactcgagacacatccaagaaccagttcttcctgcagttgaattctgtgactactgaggacacagccacatattactgtgcaagaagggaactgggacaggggtttccttactggggc caagggactctggtcactgtctctgcag
SEQ ID NO:121，重组TIGIT胞外区Fc融合蛋白
MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGLG LTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLELEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:122，人源化4A5抗体重链可变区序列
QVQLQESGPGLVKPSQTLSLTCTVTGSSITSDYAWNWIRQFPGKKLEWMGYITYSGRTTYNPSLKSRITISR DTSKNQFSLKLSSVTAADTATYYCARWGLLRRYFDYWGQGTLLTVSS
SEQ ID NO:123，人源化4A5抗体轻链可变区序列
DIVMTQSPSSMSTSVGDRVTITCRASQDVFTAVAWYQQKPGKSPKLLIYSASFRYTGVPDRFSGSGSGTDF TFTISSVQAEDFATYYCQQHYSTPLTFGAGTKLELK
SEQ ID NO:124，人IgG4重链恒定区序列
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:125，人IgG4κ链恒定区序列
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:126，4A5嵌合抗体的重链序列
QVQLQESGPGLVKPSQSLSLTCTVTGSSITSDYAWNWIRQFPGNKLEWMGYITYSGRTTYNPSLKSRISITR DTSKNQFFLQLNSVTTEDTATYYCARWGLLRRYFDYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:127，4A5嵌合抗体的轻链序列
DIVMTQSHKFMSTSVGDRVSITCKASQDVFTAVAWYQQKPGQSPKLLIYSASFRYTGVPDRFTGSGSGTD FTFTISSVQAEDLAVYYCQQHYSTPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC
SEQ ID NO:128，TIGIT蛋白编码序列
atgcgctggtgtctcctcctgatctgggcccaggggctgaggcaggctcccctcgcctcaggaatgatgacaggcacaatagaaacaacggggaacatttctgcag agaaaggtggctctatcatcttacaatgtcacctctcctccaccacggcacaagtgacccaggtcaactgggagcagcaggaccagcttctggccatttgtaatgctga cttggggtggcacatctccccatccttcaaggatcgagtggccccaggtcccggcctgggcctcaccctccagtcgctgaccgtgaacgatacaggggagtacttct gcatctatcacacctaccctgatgggacgtacactgggagaatcttcctggaggtcctagaaagctcagtggctgagcacggtgccaggttccagattccattgcttgg agccatggccgcgacgctggtggtcatctgcacagcagtcatcgtggtggtcgcgttgactagaaagaagaaagccctcagaatccattctgtggaaggtgacctca ggagaaaatcagctggacaggaggaatggagccccagtgctccctcacccccaggaagctgtgtccaggcagaagctgcacctgctgggctctgtggagagcag cggggagaggactgtgccgagctgcatgactacttcaatgtcctgagttacagaagcctgggtaactgcagcttcttcacagagactggttag
SEQ ID NO:129，CD155-Fc蛋白序列
WPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSMAVFHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGSRSVDIWLRVLAKPQNTAEVQKVQLT GEPVPMARCVSTGGRPPAQITWHSDLGGMPNTSQVPGFLSGTVTVTSLWILVPSSQVDGKNVTCKVEHES FEKPQLLTVNLTVYYPPEVSISGYDNNWYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQL LIRPVDKPINTTLICNVTNALGARQAELTVQVKEGPPSEHSGLEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK。
序列表
<110> 合肥瑞达免疫药物研究所有限公司
<120> 能够结合TIGIT的抗体或其抗原结合片段及用途
<141> 2018-09-25
<160> 129
<170> SIPOSequenceListing 1.0
<210> 1
<211> 118
<212> PRT
<213> 重链可变区
<400> 1
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Asn 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 Thr Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Arg Leu Ser Val Asn Ser Phe Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 2
<211> 8
<212> PRT
<213> 重链CDR1
<400> 2
Gly Tyr Thr Phe Thr Ser Tyr Val
1 5
<210> 3
<211> 8
<212> PRT
<213> 重链CDR2
<400> 3
Ile Asn Pro Tyr Asn Asp Asp Thr
1 5
<210> 4
<211> 11
<212> PRT
<213> 重链CDR3
<400> 4
Ala Arg Arg Leu Ser Val Asn Ser Phe Pro Tyr
1 5 10
<210> 5
<211> 107
<212> PRT
<213> 轻链可变区
<400> 5
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Ile Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Ser Cys Lys Ala Ser Gln Asp Val Phe Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Ser Asn Leu Glu Ile Lys
100 105
<210> 6
<211> 6
<212> PRT
<213> 轻链CDR1
<400> 6
Gln Asp Val Phe Thr Ala
1 5
<210> 7
<211> 3
<212> PRT
<213> 轻链CDR2
<400> 7
Ser Ala Ser
1
<210> 8
<211> 9
<212> PRT
<213> 轻链CDR3
<400> 8
Gln Gln His Tyr Ser Thr Pro Trp Thr
1 5
<210> 9
<211> 118
<212> PRT
<213> 重链可变区
<400> 9
Ala Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Arg Gly Val Gly Arg Gly Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 10
<211> 9
<212> PRT
<213> 重链CDR1
<400> 10
Gly Tyr Ser Ile Thr Ser Asp Tyr Ala
1 5
<210> 11
<211> 7
<212> PRT
<213> 重链CDR2
<400> 11
Ile Ser Tyr Ser Gly Ser Thr
1 5
<210> 12
<211> 11
<212> PRT
<213> 重链CDR3
<400> 12
Ala Arg Arg Gly Val Gly Arg Gly Met Asp Tyr
1 5 10
<210> 13
<211> 107
<212> PRT
<213> 轻链可变区
<400> 13
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Leu Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Ile Phe Thr Thr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 14
<211> 6
<212> PRT
<213> 轻链CDR1
<400> 14
Gln Asp Ile Phe Thr Thr
1 5
<210> 15
<211> 118
<212> PRT
<213> 重链可变区
<400> 15
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Arg Glu Val Gly Gln Gly Phe Ala His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 16
<211> 11
<212> PRT
<213> 重链CDR3
<400> 16
Ala Arg Arg Glu Val Gly Gln Gly Phe Ala His
1 5 10
<210> 17
<211> 107
<212> PRT
<213> 轻链可变区
<400> 17
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Leu Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 18
<211> 6
<212> PRT
<213> 轻链CDR1
<400> 18
Gln Asp Leu Ser Thr Ala
1 5
<210> 19
<211> 116
<212> PRT
<213> 重链可变区
<400> 19
Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser Leu Ser
1 5 10 15
Leu Thr Cys Thr Val Thr Gly Ser Ser Ile Thr Ser Asp Tyr Ala Trp
20 25 30
Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met Gly Tyr
35 40 45
Ile Thr Tyr Ser Gly Arg Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg
50 55 60
Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu Gln Leu
65 70 75 80
Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Trp
85 90 95
Gly Leu Leu Arg Arg Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser
115
<210> 20
<211> 9
<212> PRT
<213> 重链CDR1
<400> 20
Gly Ser Ser Ile Thr Ser Asp Tyr Ala
1 5
<210> 21
<211> 7
<212> PRT
<213> 重链CDR2
<400> 21
Ile Thr Tyr Ser Gly Arg Thr
1 5
<210> 22
<211> 12
<212> PRT
<213> 重链CDR3
<400> 22
Ala Arg Trp Gly Leu Leu Arg Arg Tyr Phe Asp Tyr
1 5 10
<210> 23
<211> 107
<212> PRT
<213> 轻链可变区
<400> 23
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Phe Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 24
<211> 9
<212> PRT
<213> 轻链CDR3
<400> 24
Gln Gln His Tyr Ser Thr Pro Leu Thr
1 5
<210> 25
<211> 118
<212> PRT
<213> 重链可变区
<400> 25
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Leu Ser Val Ser Ser Phe Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 26
<211> 8
<212> PRT
<213> 重链CDR1
<400> 26
Gly Tyr Thr Phe Thr Ser Phe Val
1 5
<210> 27
<211> 8
<212> PRT
<213> 重链CDR2
<400> 27
Ile Asn Pro Tyr Asn Asp Gly Thr
1 5
<210> 28
<211> 11
<212> PRT
<213> 重链CDR3
<400> 28
Ala Arg Arg Leu Ser Val Ser Ser Phe Pro Tyr
1 5 10
<210> 29
<211> 107
<212> PRT
<213> 轻链可变区
<400> 29
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Ser Lys Leu Glu Ile Lys
100 105
<210> 30
<211> 6
<212> PRT
<213> 轻链CDR1
<400> 30
Gln Asp Val Ser Thr Ala
1 5
<210> 31
<211> 6
<212> PRT
<213> 重链可变区
<400> 31
Gln Asp Val Ser Thr Ala
1 5
<210> 32
<211> 9
<212> PRT
<213> 重链CDR1
<400> 32
Gly Tyr Ser Ile Thr Asn Asp Tyr Ala
1 5
<210> 33
<211> 11
<212> PRT
<213> 重链CDR3
<400> 33
Ala Arg Arg Gly Val Gly Arg Thr Met Asp Tyr
1 5 10
<210> 34
<211> 107
<212> PRT
<213> 轻链可变区
<400> 34
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Val
20 25 30
Val Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 35
<211> 6
<212> PRT
<213> 轻链CDR1
<400> 35
Gln Asp Val Ser Thr Val
1 5
<210> 36
<211> 118
<212> PRT
<213> 重链可变区
<400> 36
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Ala Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val 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 Arg Leu Ser Val Asn Ser Phe Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 37
<211> 8
<212> PRT
<213> 重链CDR2
<400> 37
Ile Asn Pro Tyr Asn Asp Gly Ala
1 5
<210> 38
<211> 120
<212> PRT
<213> 重链可变区
<400> 38
Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
1 5 10 15
Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr Ser
20 25 30
Val His Trp Ile Arg Gln Pro Pro Gly Glu Gly Leu Glu Trp Leu Gly
35 40 45
Met Ile Trp Gly Arg Gly Ser Thr Asp Tyr Asn Ser Ala Leu Arg Ser
50 55 60
Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
65 70 75 80
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala Arg
85 90 95
Asn Arg Gly Asn Leu Gly Tyr Gly Gly Trp Phe Ala Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 39
<211> 8
<212> PRT
<213> 重链CDR1
<400> 39
Gly Phe Ser Leu Ser Thr Tyr Ser
1 5
<210> 40
<211> 7
<212> PRT
<213> 重链CDR2
<400> 40
Ile Trp Gly Arg Gly Ser Thr
1 5
<210> 41
<211> 7
<212> PRT
<213> 重链CDR3
<400> 41
Ile Trp Gly Arg Gly Ser Thr
1 5
<210> 42
<211> 113
<212> PRT
<213> 轻链可变区
<400> 42
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Leu Ser Val Gly
1 5 10 15
Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asp Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Met Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Gly Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln
85 90 95
His Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 43
<211> 12
<212> PRT
<213> 轻链CDR1
<400> 43
Gln Ser Leu Leu His Ser Asp Asn Gln Lys Asn Tyr
1 5 10
<210> 44
<211> 3
<212> PRT
<213> 轻链CDR2
<400> 44
Phe Ala Ser
1
<210> 45
<211> 118
<212> PRT
<213> 重链可变区
<400> 45
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Leu Ser Val Asn Ser Phe Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 46
<211> 107
<212> PRT
<213> 轻链可变区
<400> 46
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Asn Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Phe Tyr Cys Gln His His Tyr Ser Thr Pro Pro
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 47
<211> 6
<212> PRT
<213> 轻链CDR1
<400> 47
Gln Asp Val Ser Asn Ala
1 5
<210> 48
<211> 9
<212> PRT
<213> 轻链CDR3
<400> 48
Gln His His Tyr Ser Thr Pro Pro Thr
1 5
<210> 49
<211> 118
<212> PRT
<213> 重链可变区
<400> 49
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Phe Ser Ile Thr Ser Asp
20 25 30
Tyr Val Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Asp Thr Thr Met Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Arg Asp Trp Ala Ala Trp Phe Val Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 50
<211> 9
<212> PRT
<213> 重链CDR1
<400> 50
Gly Phe Ser Ile Thr Ser Asp Tyr Val
1 5
<210> 51
<211> 7
<212> PRT
<213> 重链CDR2
<400> 51
Ile Ser Tyr Ser Asp Thr Thr
1 5
<210> 52
<211> 11
<212> PRT
<213> 重链CDR3
<400> 52
Ala Arg Arg Asp Trp Ala Ala Trp Phe Val Tyr
1 5 10
<210> 53
<211> 107
<212> PRT
<213> 轻链可变区
<400> 53
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Val
35 40 45
Tyr Ser Ala Ser Phe Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Arg Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Gly Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 54
<211> 6
<212> PRT
<213> 轻链CDR1
<400> 54
Gln Asp Val Ser Ile Ala
1 5
<210> 55
<211> 9
<212> PRT
<213> 轻链CDR3
<400> 55
Gln Gln His Tyr Gly Thr Pro Trp Thr
1 5
<210> 56
<211> 118
<212> PRT
<213> 重链可变区
<400> 56
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Tyr 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 Arg Leu Ser Val Asn Ser Phe Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 57
<211> 8
<212> PRT
<213> 重链CDR1
<400> 57
Gly Tyr Ile Phe Thr Ser Tyr Val
1 5
<210> 58
<211> 118
<212> PRT
<213> 重链可变区
<400> 58
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Ser 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 Arg Leu Ser Val Asn Ser Phe Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 59
<211> 8
<212> PRT
<213> 重链CDR1
<400> 59
Gly Tyr Thr Phe Ser Ser Tyr Val
1 5
<210> 60
<211> 8
<212> PRT
<213> 重链CDR2
<400> 60
Ile Asn Pro Tyr Asn Asp Gly Ser
1 5
<210> 61
<211> 118
<212> PRT
<213> 重链可变区
<400> 61
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Trp Ala Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 62
<211> 11
<212> PRT
<213> 重链CDR3
<400> 62
Ala Arg Arg Asp Trp Ala Ala Trp Phe Ala Tyr
1 5 10
<210> 63
<211> 107
<212> PRT
<213> 轻链可变区
<400> 63
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Gln Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 64
<211> 9
<212> PRT
<213> 轻链CDR3
<400> 64
Gln Gln Gln Tyr Ser Thr Pro Trp Thr
1 5
<210> 65
<211> 118
<212> PRT
<213> 重链可变区
<400> 65
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Val Arg Arg Asp Trp Ala Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 66
<211> 11
<212> PRT
<213> 重链CDR3
<400> 66
Val Arg Arg Asp Trp Ala Ala Trp Phe Ala Tyr
1 5 10
<210> 67
<211> 107
<212> PRT
<213> 轻链可变区
<400> 67
Ser Val Pro Gly Asp Pro Leu Glu Ile Val Ser Gly Ala His Gly Glu
1 5 10 15
Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Ser Ser Tyr
20 25 30
Phe Tyr Trp Tyr Gln Gln Lys Ser Gly Ser Ser Pro Lys Leu Trp Ile
35 40 45
Tyr Ser Ile Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Ser Tyr Ser Leu Lys Ile Asn Ser Met Glu Ala
65 70 75 80
Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 68
<211> 7
<212> PRT
<213> 轻链CDR1
<400> 68
Ser Ser Val Ser Ser Ser Tyr
1 5
<210> 69
<211> 3
<212> PRT
<213> 轻链CDR2
<400> 69
Ser Ile Ser
1
<210> 70
<211> 9
<212> PRT
<213> 轻链CDR3
<400> 70
Gln Gln Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 71
<211> 118
<212> PRT
<213> 重链可变区
<400> 71
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Phe
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 Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Arg 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 Arg Leu Ser Val Asn Ser Phe Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 72
<211> 118
<212> PRT
<213> 重链可变区
<400> 72
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Leu His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Asn Asp Val Ser 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 Arg Leu Ser Val Asn Ser Phe Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 73
<211> 8
<212> PRT
<213> 重链CDR2
<400> 73
Ile Asn Pro Asn Asn Asp Val Ser
1 5
<210> 74
<211> 107
<212> PRT
<213> 轻链可变区
<400> 74
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Ser Lys Leu Glu Ile Lys
100 105
<210> 75
<211> 9
<212> PRT
<213> 轻链CDR3
<400> 75
Gln Gln His Tyr Ser Ala Pro Trp Thr
1 5
<210> 76
<211> 118
<212> PRT
<213> 重链可变区
<400> 76
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Trp Ala Ala Trp Phe Ala His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 77
<211> 11
<212> PRT
<213> 重链CDR3
<400> 77
Ala Arg Arg Asp Trp Ala Ala Trp Phe Ala His
1 5 10
<210> 78
<211> 120
<212> PRT
<213> 重链可变区
<400> 78
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Val Tyr
20 25 30
Ser Ile His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Gly Gly Gly Ile Thr Asp Tyr Asn Ser Pro Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Glu Met Asn Gly Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Asn Arg Gly Asn Leu Gly Tyr Gly Gly Trp Phe Ala Asp Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser
115 120
<210> 79
<211> 8
<212> PRT
<213> 重链CDR1
<400> 79
Gly Phe Ser Leu Ser Val Tyr Ser
1 5
<210> 80
<211> 7
<212> PRT
<213> 重链CDR2
<400> 80
Ile Trp Gly Gly Gly Ile Thr
1 5
<210> 81
<211> 15
<212> PRT
<213> 重链CDR3
<400> 81
Ala Arg Asn Arg Gly Asn Leu Gly Tyr Gly Gly Trp Phe Ala Asp
1 5 10 15
<210> 82
<211> 113
<212> PRT
<213> 轻链可变区
<400> 82
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Leu Ser Val Gly
1 5 10 15
Gln Lys Val Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn Gly
20 25 30
Ser Asn Gln Val Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ile 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 Asp Tyr Phe Cys Gln Gln
85 90 95
His Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Arg
<210> 83
<211> 12
<212> PRT
<213> 轻链CDR1
<400> 83
Gln Ser Leu Leu Asn Gly Ser Asn Gln Val Asn Tyr
1 5 10
<210> 84
<211> 107
<212> PRT
<213> 轻链可变区
<400> 84
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Leu Thr Ser
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Ser Lys Leu Glu Ile Lys
100 105
<210> 85
<211> 6
<212> PRT
<213> 轻链CDR1
<400> 85
Gln Asp Val Leu Thr Ser
1 5
<210> 86
<211> 118
<212> PRT
<213> 重链可变区
<400> 86
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Arg Glu Leu Gly Gln Gly Phe Pro Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 87
<211> 11
<212> PRT
<213> 重链CDR3
<400> 87
Ala Arg Arg Glu Leu Gly Gln Gly Phe Pro Tyr
1 5 10
<210> 88
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 88
gaggtccagc tacagcagtc tggacctgag ctggtgaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact agctatgtta tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt acaatgatga tactaactac 180
aatgagaagt tcaaaggcaa ggccacactg acttcagaca aatcctccag cacagcctac 240
atggagctca ccagcctgac ctctgaggac tctgcggtct atttctgtgc aagaagactg 300
tctgttaact cgtttcctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 89
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 89
gacattgtga tgacccagtc tcacaaattc atgtccatat cagtaggaga cagggtcagc 60
atctcctgca aggccagtca ggatgtgttt actgctgtag cctggtatca acagaaacca 120
ggacaatctc ctaaactcct gatttactcg gcatcctacc gatacactgg agtccctgat 180
cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240
gaggacctgg cagtttatta ctgtcagcaa cattatagta ctccgtggac gttcggtgga 300
ggctccaacc tggaaatcaa ac 322
<210> 90
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 90
gctgtgcagc ttcaggagtc gggacctggc ctggtgaaac cttctcagtc tctgtccctc 60
acctgcactg tcactggcta ctcaatcacc agtgattatg cctggaactg gatccggcag 120
tttccaggaa acaaactgga gtggatgggc tacataagct acagtggtag cactagctac 180
aacccatctc tcaaaagtcg aatctctatc acgcgagaca catccaagaa ccagttcttc 240
ctgcagttga attctgtgac tactgaggac acagccacat attactgtgc aagacgaggg 300
gtgggaagag gtatggacta ctggggtcaa ggaacctcag tcaccgtctc ctcag 355
<210> 91
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 91
gacattgtga tgacccagtc tcacaaattc atgtccacat tagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatatattt actactgtag cctggtatca acagaaacca 120
ggacaatctc ctaaactact gatttattcg gcatcctacc ggtacactgg agtccctgat 180
cgtttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240
gaagacctgg cagtttatta ttgtcagcaa cattatagta ctccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa ac 322
<210> 92
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 92
gatgtgcagc ttcaggagtc gggacctggc ctggtgaaac cttctcagtc tctgtccctc 60
acctgcactg tcactggcta ctcaatcacc agtgattatg cctggaactg gatccggcag 120
tttccaggaa acaaactgga gtggatgggc tacataagct acagtggtag cactagctac 180
aacccatctc tcaaaagtcg aatctctatc actcgagaca catccaagaa ccagttcttc 240
ctgcagttga attctgtgac tactgaggac acagccacat attactgtgc aagaagggaa 300
gtgggacagg ggtttgctca ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 93
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 93
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatctgagt actgctgtag cctggtatca acagaaacca 120
ggacaatctc ctaaagtact gatttactcg gcatcctacc ggtacactgg agtccctgat 180
cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240
gaagacctgg cagtttatta ctgtcagcaa cattatagta ctccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa ac 322
<210> 94
<211> 350
<212> DNA
<213> 重链可变区编码序列
<400> 94
gcttcaggag tcgggacctg gcctggtgaa accttctcag tctctgtccc tcacctgcac 60
tgtcactggc tcctcaatca ccagtgatta tgcctggaac tggatccggc agtttccagg 120
aaacaaactg gagtggatgg gctacataac ttacagtggt cgcactacct acaacccatc 180
tctcaaaagt cgaatctcta tcactcgaga cacatccaag aaccagttct tcctgcagtt 240
gaattctgtg actactgagg acacagccac atattactgt gcaagatggg ggttactacg 300
tcgatacttt gactactggg gccaaggcac cactctcaca gtctcctcag 350
<210> 95
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 95
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgttttt actgctgtgg cctggtatca acagaaacca 120
ggacaatctc ctaaactact gatttactcg gcatccttcc ggtacactgg agtccctgat 180
cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240
gaagacctgg cagtttatta ctgtcagcaa cattatagta ctccgctcac gttcggtgct 300
gggaccaagc tggagctgaa ac 322
<210> 96
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 96
gaggtccagc tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact agctttgtta tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt acaatgatgg tactaagtac 180
aatgagaagt tcaaaggcaa ggccacactg acttcagaca aatcctccag cacagcctac 240
atggagctca gcagcctgac ctctgcggac tctgcggtct attactgtgc aagaaggctg 300
tctgttagct cgtttcctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 97
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 97
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgagt actgctgtag cctggtatca acagaaacca 120
gggcaatctc ctaaactcct gatttactcg gcatcctacc gatacactgg agtccctgat 180
cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240
gaagacctgg cagtttatta ctgtcagcaa cattatagta ctccgtggac gttcggtgga 300
ggctccaagc tggaaatcaa ac 322
<210> 98
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 98
gatgtgcagc ttcaggagtc gggacctggc ctggtgaaac cttctcagtc tctgtccctc 60
acctgcactg tcactggcta ctcaatcacc aatgattatg cctggaactg gatccggcag 120
tttccaggaa acaaactgga gtggatgggc tacataagct acagtggtag cactagctac 180
aacccatctc tcaaaagtcg aatctctatc actcgagaca catccaagaa ccaattcttc 240
ctgcagttga attctgtgac tactgaggac acagccacat attactgtgc aagacgaggg 300
gtgggaagaa ctatggacta ctggggtcaa ggaacctcag tcaccgtctc ctcag 355
<210> 99
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 99
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgagt actgttgtag gctggtatca acagaaacca 120
ggacaatctc caaaatcact gatttattcg gcatcctacc ggtacactgg agtccctgat 180
cgtttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240
gaagacctgg cagtttatta ctgtcagcaa cattatagta ctccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa ac 322
<210> 100
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 100
gaggtccagc tgcagcagtc tggacctgag ctggtaaagc ctgggacttc agtgaagatg 60
tcctgcaagg cttctggcta cacattcact agctatgtta tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt acaatgatgg tgctaagtac 180
aatgagaagt tcaaaggcaa ggtcacactg acttcagaca aatcctccag cacagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aagaaggctg 300
tctgttaact cgtttcctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 101
<211> 360
<212> DNA
<213> 重链可变区编码序列
<400> 101
gtgcagctga aggagtcagg acctggcctg gtggcaccct cacagagcct gtccatcaca 60
tgcactgtct ctgggttctc attatccaca tatagtgtac actggattcg ccagcctcca 120
ggagagggtc tggagtggct gggaatgatc tggggtcgtg gaagcacaga ctataattca 180
gctctcagat ccagactgag catcagcaag gacaactcca agagtcaagt tttcttaaaa 240
atgaacagtc tgcaaactga tgacacagcc atgtactact gtgccagaaa taggggtaat 300
ttgggttacg gaggctggtt tgctaactgg ggccaaggga ctctggtcac tgtctctgca 360
<210> 102
<211> 355
<212> DNA
<213> 轻链可变区编码序列
<400> 102
gaggtccagc tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact agctatgtta tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt acaatgatgg tactaagtac 180
aatgagaagt tcaaagggaa ggccacactg acttcagaca aatcctccag cacagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aagaaggctg 300
tctgttaact cgtttcctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 103
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 103
gaggtccagc tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact agctatgtta tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt acaatgatgg tactaagtac 180
aatgagaagt tcaaagggaa ggccacactg acttcagaca aatcctccag cacagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aagaaggctg 300
tctgttaact cgtttcctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 104
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 104
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgagt aatgctgtag cctggtatca acagaaacca 120
ggacaatctc ctaaactact gatttactcg gcatcctacc ggtacactgg agtccctgat 180
cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240
gaagacctgg cagtttttta ctgtcagcac cattatagta ctcctcccac gttcggtgct 300
gggaccaagc tggagctgaa ac 322
<210> 105
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 105
gatgtgcagc ttcaggagtc gggacctggc ctggtgaaac cttctcagtc tctgtccctc 60
acctgcactg tcactggctt ctcaatcacc agtgattacg tctggaactg gatccggcag 120
tttccaggaa acaaactgga gtggatgggc tacataagct atagtgatac cactatgtac 180
aacccatctc tcaaaagtcg aatctctatc actcgagaca catccaagaa ccagttcttc 240
ctgcagttga attctgtgac tactgaggac acagccacat atttctgtgc aagaagggac 300
tgggccgcct ggtttgttta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 106
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 106
gacattgtga tgacccagtc tcacaaattc atgtccacat cagttggaga cagggtcact 60
atcacctgca aggccagtca ggatgtgagt attgctgtag cctggtatca acagaaacca 120
ggacaatctc ctaaactact agtttactcg gcatccttcc ggtacactgg agtccctgat 180
cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcgggct 240
gaagacctgg cagtttatta ctgtcagcaa cattatggta ctccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa ac 322
<210> 107
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 107
gaggtccagc tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata catattcact agctatgtta tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt acaatgatgg tactaagtac 180
tatgagaagt tcaaaggcaa ggccacactg acttcagaca aatcctccag cacagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aagaaggctg 300
tctgttaact cgtttcctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 108
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 108
gaggtccaac tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcagt agctatgtta tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt acaatgatgg tagtaagtac 180
aatgagaagt tcaaaggcaa ggccacactg acttcagaca aatcctccag cacagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aagaaggctg 300
tctgttaact cgtttcctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 109
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 109
gatgtgcagc ttcaggagtc gggacctggc ctggtgaaac cttctcagtc tctgtccctc 60
acctgcactg tcactggcta ctcaatcacc agtgattatg cctggaactg gatccgacag 120
tttccaggaa acaagctgga gtggatgggc tacataagct acagtggtag cactaactac 180
aacccatctc tcaaaagtcg aatctctatc actcgagaca catccaagaa ccagttcttc 240
ctgcagttga attctgtgac tactgaggac acagccacat attactgtgc aagaagggac 300
tgggccgcct ggtttgctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 110
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 110
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgagt actgctgtag cctggtatca acagaaacca 120
ggacaatctc ctaaactact gatttactcg gcatcctacc ggtacactgg agtccctgat 180
cgcttcactg gcagtggatc tgggacggat ttcagtttca ccatcagcag tgtgcaggct 240
gaagacctgg cagtttatta ctgtcagcaa caatatagta ctccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa ac 322
<210> 111
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 111
gatgtgcagc ttcaggagtc gggacctggc ctggtgaaac cttctcagtc tctgtccctc 60
acctgcactg tcactggcta ctcaatcacc agtgattatg cctggaactg gatccggcag 120
tttccaggaa acaaactgga gtggatgggc tacataagct acagtggtag cactagctac 180
aacccatctc tcaaaagtcg aatctctatc agtcgagaca catccaagaa ccagttcttc 240
ctgcagttga attctgtgac tactgaggac acagccacat attactgtgt aagaagggac 300
tgggccgcct ggtttgctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 112
<211> 323
<212> DNA
<213> 轻链可变区编码序列
<400> 112
ctcggtaccc ggggatcctc tagagattgt gtctggtgct catggggaac gggtcaccat 60
gacctgcagt gccagctcaa gtgtgagttc cagctacttt tactggtacc agcagaagtc 120
aggatcctcc ccaaaactct ggatttatag catatccaac ctggcttctg gagtcccagc 180
tcgcttcagt ggcagtgggt ctgggacctc ttactctctc aaaatcaaca gcatggaggc 240
tgaagatgct gccacttatt actgccagca gtggagtagt aacccaccga cgttcggtgg 300
aggcaccaag ctggaaatca aac 323
<210> 113
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 113
gaggtccagc tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact agctttgttg tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt acaatgatgg tactaagtac 180
aatgagaagt tcaaaggcaa ggccacactg acttcagaca ggtcctccag cacagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aagaaggctg 300
tctgttaact cgtttcctta ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 114
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 114
gaggtccagc tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact agctatgttt tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatac attaatccta acaatgatgt tagtaagtac 180
aatgagaagt tcaaaggcaa ggccacactg acttcagaca aatcctccag cacagcctac 240
atggaactca gcagcctgac ctctgaggac tctgcggtct attactgtgc aagaaggctg 300
tctgttaact cgtttcctta ctggggccaa gggactctgg tcactgtctc ttcag 355
<210> 115
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 115
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtcggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgagt actgctgtag cctggtatca acagaaacca 120
gggcaatctc ctaaactcct gatttactcg gcatcctacc gatacactgg agtccctgat 180
cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240
gaagacctgg cagtttatta ctgtcagcaa cattatagtg ctccgtggac gttcggtgga 300
ggctccaagc tggaaatcaa ac 322
<210> 116
<211> 355
<212> DNA
<213> 重链可变区编码序列
<400> 116
gatgtgcagc ttcaggagtc gggacctggc ctggtgaaac cttctcagtc tctgtccctc 60
acctgcactg tcactggcta ctcaatcacc agtgattatg cctggaactg gatccggcag 120
tttccaggaa acaaactgga gtggatgggc tacataagct acagtggtag cactagctac 180
aacccatctc tcaaaagtcg aatttctatc actcgagaca catccaagaa ccagttcttc 240
ctgcagttga attctgtgac tactgaagac acagccacat attactgtgc aagaagggac 300
tgggccgcct ggtttgctca ctggggccaa gggactctgg tcactgtctc tgcag 355
<210> 117
<211> 364
<212> DNA
<213> 重链可变区编码序列
<400> 117
caggtgcagc tgaaggagtc aggacctggc ctggtggcac cctcacagag cctgtccatc 60
acatgcactg tctctgggtt ctcattatcc gtatatagta tacactggat tcgccagcct 120
ccaggaaagg gtctggagtg gctgggaatg atctggggtg gtggaatcac agactataat 180
tcacctctca aatccagact gagcatcagc aaggacaact ccaagagcca agttttctta 240
gaaatgaacg gtctgcaaac tgatgacaca gccatctact actgtgccag aaataggggt 300
aatttgggtt acggaggctg gtttgctgac tggggccaag ggactctggt cactgtctct 360
gcag 364
<210> 118
<211> 340
<212> DNA
<213> 轻链可变区编码序列
<400> 118
gacattgtga tgacacagtc tccatcctcc ctggctctgt cagtaggaca gaaggtcact 60
atgacctgca agtccagtca gagcctttta aatggtagca atcaagtgaa ctatttggcc 120
tggtaccaac agaaaccagg acagtctcct aaacttctgg tgtactttgc gtccactagg 180
gaatctgggg tccctgatcg cttcataggc agtggatctg ggacagattt cactcttacc 240
atcagcagtg tgcaggctga agacctggca gattacttct gtcagcaaca ttatagcact 300
ccgtggacgt tcggtggagg caccaagctg gaaatcagac 340
<210> 119
<211> 322
<212> DNA
<213> 轻链可变区编码序列
<400> 119
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgttctt acatctgtag cctggtatca acagaaacca 120
gggcaatctc ctaaactcct gatttactcg gcatcctacc gatacactgg agtccctgat 180
cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240
gaagacctgg cagtttatta ctgtcagcaa cattatagta ctccgtggac gttcggtgga 300
ggctccaagc tggaaatcaa ac 322
<210> 120
<211> 354
<212> DNA
<213> 重链可变区编码序列
<400> 120
atgtgcagct tcaggagtcg ggacctggcc tggtgaaacc ttctcagtct ctgtccctca 60
cctgcactgt cactggctac tcaatcacca gtgattatgc ctggaactgg atccggcagt 120
ttccaggaaa caaactggag tggatgggct acataagcta cagtggtagc actaggtaca 180
acccatctct caaaagtcga atctctatca ctcgagacac atccaagaac cagttcttcc 240
tgcagttgaa ttctgtgact actgaggaca cagccacata ttactgtgca agaagggaac 300
tgggacaggg gtttccttac tggggccaag ggactctggt cactgtctct gcag 354
<210> 121
<211> 340
<212> PRT
<213> 重组TIGIT胞外区Fc融合蛋白
<400> 121
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Leu Glu Pro Lys Ser
100 105 110
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
115 120 125
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
130 135 140
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
145 150 155 160
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
165 170 175
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
180 185 190
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
195 200 205
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
210 215 220
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
225 230 235 240
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
245 250 255
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
260 265 270
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
275 280 285
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
290 295 300
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
305 310 315 320
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
325 330 335
Ser Pro Gly Lys
340
<210> 122
<211> 119
<212> PRT
<213> 人源化4A5抗体重链可变区序列
<400> 122
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Thr Gly Ser Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Lys Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Thr Tyr Ser Gly Arg Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Leu Leu Arg Arg Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Leu Thr Val Ser Ser
115
<210> 123
<211> 107
<212> PRT
<213> 人源化4A5抗体轻链可变区序列
<400> 123
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Phe Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 124
<211> 327
<212> PRT
<213> 人IgG4重链恒定区序列
<400> 124
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 125
<211> 107
<212> PRT
<213> 人IgG4κ链恒定区序列
<400> 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 126
<211> 446
<212> PRT
<213> 4A5嵌合抗体的重链序列
<400> 126
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Ser Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Thr Tyr Ser Gly Arg Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Leu Leu Arg Arg Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 127
<211> 214
<212> PRT
<213> 4A5嵌合抗体的轻链序列
<400> 127
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Phe Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 128
<211> 735
<212> DNA
<213> TIGIT蛋白编码序列
<400> 128
atgcgctggt gtctcctcct gatctgggcc caggggctga ggcaggctcc cctcgcctca 60
ggaatgatga caggcacaat agaaacaacg gggaacattt ctgcagagaa aggtggctct 120
atcatcttac aatgtcacct ctcctccacc acggcacaag tgacccaggt caactgggag 180
cagcaggacc agcttctggc catttgtaat gctgacttgg ggtggcacat ctccccatcc 240
ttcaaggatc gagtggcccc aggtcccggc ctgggcctca ccctccagtc gctgaccgtg 300
aacgatacag gggagtactt ctgcatctat cacacctacc ctgatgggac gtacactggg 360
agaatcttcc tggaggtcct agaaagctca gtggctgagc acggtgccag gttccagatt 420
ccattgcttg gagccatggc cgcgacgctg gtggtcatct gcacagcagt catcgtggtg 480
gtcgcgttga ctagaaagaa gaaagccctc agaatccatt ctgtggaagg tgacctcagg 540
agaaaatcag ctggacagga ggaatggagc cccagtgctc cctcaccccc aggaagctgt 600
gtccaggcag aagctgcacc tgctgggctc tgtggagagc agcggggaga ggactgtgcc 660
gagctgcatg actacttcaa tgtcctgagt tacagaagcc tgggtaactg cagcttcttc 720
acagagactg gttag 735
<210> 129
<211> 552
<212> PRT
<213> CD155-Fc蛋白序列
<400> 129
Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln Ala Pro Thr Gln
1 5 10 15
Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro Cys Tyr Leu Gln
20 25 30
Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu Thr Trp Ala Arg
35 40 45
His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln Thr Gln Gly Pro
50 55 60
Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala Ala Arg Leu Gly
65 70 75 80
Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly Leu Arg Val Glu
85 90 95
Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe Pro Gln Gly Ser
100 105 110
Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys Pro Gln Asn Thr
115 120 125
Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro Val Pro Met Ala
130 135 140
Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln Ile Thr Trp His
145 150 155 160
Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val Pro Gly Phe Leu
165 170 175
Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu Val Pro Ser Ser
180 185 190
Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu His Glu Ser Phe
195 200 205
Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val Tyr Tyr Pro Pro
210 215 220
Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr Leu Gly Gln Asn
225 230 235 240
Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro Glu Pro Thr Gly
245 250 255
Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro Phe Ala Val Ala
260 265 270
Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys Pro Ile Asn Thr
275 280 285
Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala Arg Gln Ala Glu
290 295 300
Leu Thr Val Gln Val Lys Glu Gly Pro Pro Ser Glu His Ser Gly Leu
305 310 315 320
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
325 330 335
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
340 345 350
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
355 360 365
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
370 375 380
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
385 390 395 400
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
405 410 415
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
420 425 430
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
435 440 445
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
450 455 460
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
465 470 475 480
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
485 490 495
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
500 505 510
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
515 520 525
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
530 535 540
Ser Leu Ser Leu Ser Pro Gly Lys
545 550
Claims (15)
1.一种能够结合TIGIT的抗体或其抗原结合片段，其特征在于，该抗体包括重链CDR1、重链CDR2和重链CDR3，以及轻链CDR1、轻链CDR2和轻链CDR3；
其中，所述重链CDR1的氨基酸序列与SEQ ID NO:2、SEQ ID NO:10、SEQ ID NO:20、SEQID NO:26、SEQ ID NO:32、SEQ ID NO:39、SEQ ID NO:50、SEQ ID NO:57、SEQ ID NO:59或SEQ ID NO:79所示的序列具有至少80％的同源性，
所述重链CDR2的氨基酸序列与SEQ ID NO:3、SEQ ID NO:11、SEQ ID NO:21、SEQ IDNO:27、SEQ ID NO:37、SEQ ID NO:40、SEQ ID NO:51、SEQ ID NO:60、SEQ ID NO:73或SEQID NO:80所示的序列具有至少80％的同源性，
所述重链CDR3的氨基酸序列与SEQ ID NO:4、SEQ ID NO:12、SEQ ID NO:16、SEQ IDNO:22、SEQ ID NO:28、SEQ ID NO:33、SEQ ID NO:41、SEQ ID NO:52、SEQ ID NO:62、SEQ IDNO:66、SEQ ID NO:77、SEQ ID NO:81或SEQ ID NO:87所示的序列具有至少80％的同源性，
所述轻链CDR1的氨基酸序列与SEQ ID NO:6、SEQ ID NO:14、SEQ ID NO:18、SEQ IDNO:30、SEQ ID NO:35、SEQ ID NO:43、SEQ ID NO:47、SEQ ID NO:54、SEQ ID NO:68、SEQ IDNO:83或SEQ ID NO:85所示的序列具有至少80％的同源性，
所述轻链CDR2的氨基酸序列与SEQ ID NO:7、SEQ ID NO:44或SEQ ID NO:69所示的序列具有至少80％的同源性，
所述轻链CDR3的氨基酸序列与SEQ ID NO:8、SEQ ID NO:24、SEQ ID NO:48、SEQ IDNO:55、SEQ ID NO:64、SEQ ID NO:70或SEQ ID NO:75所示的序列具有至少80％的同源性。
2.根据权利要求1所述的抗体或其抗原结合片段，其中，所述重链CDR1的氨基酸序列如SEQ ID NO:2、SEQ ID NO:10、SEQ ID NO:20、SEQ ID NO:26、SEQ ID NO:32、SEQ ID NO:39、SEQ ID NO:50、SEQ ID NO:57、SEQ ID NO:59或SEQ ID NO:79所示，
和/或，所述重链CDR2的氨基酸序列如SEQ ID NO:3、SEQ ID NO:11、SEQ ID NO:21、SEQID NO:27、SEQ ID NO:37、SEQ ID NO:40、SEQ ID NO:51、SEQ ID NO:60、SEQ ID NO:73或SEQ ID NO:80所示，
和/或，所述重链CDR3的氨基酸序列如SEQ ID NO:4、SEQ ID NO:12、SEQ ID NO:16、SEQID NO:22、SEQ ID NO:28、SEQ ID NO:33、SEQ ID NO:41、SEQ ID NO:52、SEQ ID NO:62、SEQID NO:66、SEQ ID NO:77、SEQ ID NO:81或SEQ ID NO:87所示，
和/或，所述轻链CDR1的氨基酸序列如SEQ ID NO:6、SEQ ID NO:14、SEQ ID NO:18、SEQID NO:30、SEQ ID NO:35、SEQ ID NO:43、SEQ ID NO:47、SEQ ID NO:54、SEQ ID NO:68、SEQID NO:83或SEQ ID NO:85所示，
和/或，所述轻链CDR2的氨基酸序列如SEQ ID NO:7、SEQ ID NO:44或SEQ ID NO:69所示，
和/或，所述轻链CDR3的氨基酸序列如SEQ ID NO:8、SEQ ID NO:24、SEQ ID NO:48、SEQID NO:55、SEQ ID NO:64、SEQ ID NO:70或SEQ ID NO:75所示。
3.根据权利要求1所述的抗体或其抗原结合片段，其中：
所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQID NO:3所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:12所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:16所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:20所示，所述重链CDR2的氨基酸序列如SEQ ID NO:21所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:22所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:28所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:32所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:33所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:37所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:39所示，所述重链CDR2的氨基酸序列如SEQ ID NO:40所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:41所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:50所示，所述重链CDR2的氨基酸序列如SEQ ID NO:51所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:52所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:57所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:59所示，所述重链CDR2的氨基酸序列如SEQ ID NO:60所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:62所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:66所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:73所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:77所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:79所示，所述重链CDR2的氨基酸序列如SEQ ID NO:80所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:81所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:87所示；
和/或，
所述轻链CDR1的氨基酸序列如SEQ ID NO:6所示，所述轻链CDR2的氨基酸序列如SEQID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:14所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:18所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:6所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:24所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:35所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:43所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:44所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:47所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:48所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:54所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:55所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:64所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:68所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:69所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:70所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:75所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:83所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:44所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述轻链CDR1的氨基酸序列如SEQ ID NO:85所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示。
4.根据权利要求1所述的抗体或其抗原结合片段，其特征在于：
所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQID NO:3所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:6所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:12所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:14所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:16所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:18所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:20所示，所述重链CDR2的氨基酸序列如SEQ ID NO:21所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:22所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:6所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:24所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:28所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:32所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:33所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:35所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:37所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:39所示，所述重链CDR2的氨基酸序列如SEQ ID NO:40所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:41所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:43所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:44所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:47所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:48所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:50所示，所述重链CDR2的氨基酸序列如SEQ ID NO:51所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:52所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:54所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:55所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:57所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:59所示，所述重链CDR2的氨基酸序列如SEQ ID NO:60所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:62所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:64所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:66所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:68所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:69所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:70所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:73所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:75所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:77所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:64所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:3所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:2所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:30所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:79所示，所述重链CDR2的氨基酸序列如SEQ ID NO:80所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:81所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:83所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:44所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:26所示，所述重链CDR2的氨基酸序列如SEQ ID NO:27所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:4所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:85所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示；
或者，所述重链CDR1的氨基酸序列如SEQ ID NO:10所示，所述重链CDR2的氨基酸序列如SEQ ID NO:11所示且所述重链CDR3的氨基酸序列如序列表SEQ ID NO:87所示；以及，所述轻链CDR1的氨基酸序列如SEQ ID NO:35所示，所述轻链CDR2的氨基酸序列如SEQ ID NO:7所示且所述轻链CDR3的氨基酸序列如序列表SEQ ID NO:8所示。
5.根据权利要求1所述的抗体或其抗原结合片段，其中，所述抗体包括重链可变区和轻链可变区，所述重链可变区的氨基酸序列如SEQ ID NO:1、SEQ ID NO:9、SEQ ID NO:15、SEQID NO:19、SEQ ID NO:25、SEQ ID NO:31、SEQ ID NO:36、SEQ ID NO:38、SEQ ID NO:45、SEQID NO:49、SEQ ID NO:56、SEQ ID NO:58、SEQ ID NO:61、SEQ ID NO:65、SEQ ID NO:71、SEQID NO:72、SEQ ID NO:76、SEQ ID NO:78或SEQ ID NO:86所示；和/或，所述轻链可变区的氨基酸序列如SEQ ID NO:5、SEQ ID NO:13、SEQ ID NO:17、SEQ ID NO:23、SEQ ID NO:29、SEQID NO:34、SEQ ID NO:42、SEQ ID NO:46、SEQ ID NO:53、SEQ ID NO:63、SEQ ID NO:67、SEQID NO:74、SEQ ID NO:82或SEQ ID NO:84所示。
6.根据权利要求1所述的抗体或其抗原结合片段，其中，所述重链可变区的氨基酸序列如SEQ ID NO:1所示且所述轻链可变区的氨基酸序列如SEQ ID NO:5所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:9所示且所述轻链可变区的氨基酸序列如SEQ ID NO:13所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:15所示且所述轻链可变区的氨基酸序列如SEQ ID NO:17所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:19所示且所述轻链可变区的氨基酸序列如SEQ ID NO:23所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:25所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:31所示且所述轻链可变区的氨基酸序列如SEQ ID NO:34所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:36所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:38所示且所述轻链可变区的氨基酸序列如SEQ ID NO:42所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:45所示且所述轻链可变区的氨基酸序列如SEQ ID NO:46所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:49所示且所述轻链可变区的氨基酸序列如SEQ ID NO:53所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:56所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:58所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:61所示且所述轻链可变区的氨基酸序列如SEQ ID NO:63所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:65所示且所述轻链可变区的氨基酸序列如SEQ ID NO:67所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:71所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:72所示且所述轻链可变区的氨基酸序列如SEQ ID NO:74所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:76所示且所述轻链可变区的氨基酸序列如SEQ ID NO:63所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:1所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:45所示且所述轻链可变区的氨基酸序列如SEQ ID NO:29所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:78所示且所述轻链可变区的氨基酸序列如SEQ ID NO:82所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:71所示且所述轻链可变区的氨基酸序列如SEQ ID NO:84所示；
或者，所述重链可变区的氨基酸序列如SEQ ID NO:86所示且所述轻链可变区的氨基酸序列如SEQ ID NO:34所示。
7.根据权利要求1所述的抗体或其抗原结合片段，其中，所述抗体或其抗原结合片段能够结合SEQ ID NO:121所示的氨基酸序列。
8.根据权利要求1-7中任意一项所述的抗体或其抗原结合片段，其中，所述抗体为嵌合抗体或人源化抗体。
9.一种免疫缀合物，其特征在于，该免疫缀合物含有治疗剂以及与治疗剂偶联的权利要求1-8中任一项所述的抗体或其抗原结合片段。
10.一种组合物，其特征在于，该组合物含有权利要求1-8中任意一项所述的抗体或其抗原结合片段、和/或权利要求9所述的免疫缀合物、以及药学上可接受的载体。
11.一种用于检测样品中TIGIT的试剂盒，该试剂盒含有权利要求1-8中任意一项所述的抗体或其抗原结合片段。
12.权利要求1-8中任意一项所述的抗体或其抗原结合片段在制备用于检测样品中TIGIT的试剂中的用途。
13.权利要求1-8中任意一项所述的抗体或其抗原结合片段在制备用于预防和/或治疗TIGIT介导的疾病的药物中的用途，优选地，所述TIGIT介导的疾病为癌症或感染性疾病，
更优选地，所述癌症为表达CD155的癌症，
进一步优选地，所述癌症为肺癌，肝癌，卵巢癌，宫颈癌，皮肤癌，膀胱癌，结肠癌，乳腺癌，神经胶质瘤，肾癌，胃癌，食道癌，口腔鳞状细胞癌和头颈癌中的至少一种；
进一步优选地，所述感染性疾病为HIV病毒感染和/或乙型肝炎病毒感染。
14.编码权利要求1-8中任意一项所述的抗体或其抗原结合片段的核酸。
15.一种重组载体或转化子，含有权利要求14所述的核酸。
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| CN109833480A (zh) * | 2019-03-22 | 2019-06-04 | 中国科学院上海巴斯德研究所 | 靶向nk细胞免疫检查点治疗感染性疾病的方法 |
| WO2021008523A1 (zh) * | 2019-07-15 | 2021-01-21 | 上海君实生物医药科技股份有限公司 | 抗tigit抗体及其应用 |
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| WO2021217893A1 (zh) * | 2020-04-29 | 2021-11-04 | 广州昂科免疫生物技术有限公司 | 结合tigit抗原的抗体及其制备方法与应用 |
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