CN110964109A - 抗pd-l1抗体 - Google Patents
抗pd-l1抗体 Download PDFInfo
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- CN110964109A CN110964109A CN201911310366.8A CN201911310366A CN110964109A CN 110964109 A CN110964109 A CN 110964109A CN 201911310366 A CN201911310366 A CN 201911310366A CN 110964109 A CN110964109 A CN 110964109A
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Abstract
本公开涉及结合PD‑L1的抗体和其抗原结合片段,并且涉及使用这类抗体和抗原结合片段的方法。例如,本发明提供了人源化抗PD‑L1抗体和其使用方法。
Description
本申请是申请日为2015年8月5日、中国申请号为201580042278.8、发明名称为“抗PD-L1抗体”的发明申请的分案申请。
相关申请的交叉引用
本申请要求2014年8月5日提交的国际申请号PCT/CN2014/083715的优先权,所述国际申请出于所有目的以引用的方式整体并入本文。
发明领域
本发明涉及结合PD-L1的抗体和其抗原结合片段,并且涉及使用这类抗体和抗原结合片段的方法。
电子呈送的文本文件的描述
此处电子呈送的文本文件的内容以引用的方式整体并入本文:序列表的计算机可读格式拷贝(文件名:CRBI_007_01WO_SeqList_ST25.txt);记录日期:2015年8月4日;文件大小153KB)。
背景
程序性死亡受体配体1(PD-L1)是程序性死亡受体1(PD-1)的配体。PD-1主要在淋巴细胞上表达并且具有两个配体,PD-L1和PD-L2。PD-L2不如PD-L1常见。PD-L1也称为分化簇274(CD274)或B7同系物1(B7-H1),并且是由CD274基因编码的40kDa的1型跨膜蛋白。PD-L1和PD-1两者都属于免疫球蛋白超家族并且都由两个细胞外Ig结构域,即N末端V结构域和C末端恒定结构域组成。PD-L1与程序性死亡1(PD-1)和B7-1(CD80)的结合界面是在IgV样结构域上(Lin等(2008)PNAS 105:3011-3016)。虽然PD-L1含有保守的短的细胞内尾区(约30个氨基酸),但PD-1含有两个基于细胞质酪氨酸的信号基序,即基于免疫受体酪氨酸的抑制基序(ITIM)和基于免疫受体酪氨酸的转换基序(ITSM)。在T细胞刺激之后,PD-1将酪氨酸磷酸酶SHP-2募集到其胞质尾区内的ITSM基序,导致参与CD3 T细胞信号传导级联的效应分子(诸如CD3ζ、PKCθ和ZAP70)的去磷酸化(Freeman等(2000)J Exp Med 192:1027-34;Latchman等(2001)Nat Immunol 2:261-8;Carter等(2002)Eur J Immunol 32:634-43)。
PD-L1不仅在淋巴和非淋巴组织中的白细胞和非造血细胞上广泛分布,而且还在各种癌细胞中广泛分布。临床数据表明PD-L1的高肿瘤表达与增加的肿瘤侵袭性和较差的预后相关联。PD-1/PD-L1复合物的形成传输抑制信号并负调节T细胞免疫应答;它抑制TCR介导的T细胞活化、细胞因子产生和T细胞增殖(Fife等(2011)Nature Immunology 10:1185-1193);诱导同源抗原特异性T细胞之中的衰竭或无反应性(Hofmeyer等(2011)Journal of Biomedicine and Biotechnology 2011:1-9);促进Th1细胞分化成Foxp3+调节性T细胞(Armanath等(2011)Science TransMed 3:1-13;Francisco等(2009)J.Exp.Med.206:3015-3029);并诱导效应T细胞的凋亡。PD-L1基因的破坏导致上调的T细胞应答和自身反应性T细胞的产生(Latchman等(2004)PNAS 101:10691–10696)。PD-1或PD-L1的抗体阻断导致增加的抗肿瘤免疫性(Iwai等(2002)PNAS 99:12293–12297)。
因此,PD-1/PD-L1途径在控制免疫应答中具有重要作用。PD-1/PD-L1信号传导的功能障碍似乎与疾病(诸如癌症和病毒感染)的引发和发展相关。敲除动物的分析已经使得理解了PD-1/PD-L1主要在诱导和调节外周耐受中起作用。因此,PD-1/PD-L1途径的治疗性阻断将有助于克服免疫耐受和癌症或感染的治疗以及增强疫苗接种(预防性或治疗性)期间的免疫性。本领域需要用于阻断PD-1/PD-L1途径的改进方法。
发明概述
在一方面,本发明提供了结合程序性死亡-1配体1(PD-L1)的抗体和其抗原结合片段。在一些实施方案中,抗体和其抗原结合片段结合人PD-L1。在一些实施方案中,抗体和其抗原结合片段结合PD-L1并阻断PD-1和/或CD80与PD-L1的结合。在另外的实施方案中,抗PD-L1抗体和其片段结合PD-L1并破坏PD-L1/PD-1或PD-L1/CD80途径。在一个实施方案中,抗体或其片段是鼠类抗体、嵌合抗体、人抗体或人源化抗体。在一个实施方案中,抗PD-L1抗体或其片段是单克隆抗体、scFv、Fab片段、Fab'片段、F(ab)'片段、双特异性抗体、免疫缀合物或其组合
在一个实施方案中,本发明提供了包含选自由SEQ ID NO:81-140组成的组的一个或多个CDR的分离的抗体或其片段。
在一个实施方案中,抗体或其片段包含重链CDR1序列,所述重链CDR1序列与选自由SEQ ID NO:81、87、93、99、105、111、117、123、129和135组成的组的氨基酸序列具有至少80%同源性、至少81%同源性、至少82%同源性、至少83%同源性、至少84%同源性、至少85%同源性、至少86%同源性、至少87%同源性、至少88%同源性、至少89%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性。
在一个实施方案中,抗体或其片段包含重链CDR2序列,所述重链CDR2序列与选自由SEQ ID NO:82、88、94、100、106、112、118、124、130和136组成的组的氨基酸序列具有至少80%同源性、至少81%同源性、至少82%同源性、至少83%同源性、至少84%同源性、至少85%同源性、至少86%同源性、至少87%同源性、至少88%同源性、至少89%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性。
在一个实施方案中,抗体或其片段包含重链CDR3序列,所述重链CDR3序列与选自由SEQ ID NO:83、89、95、101、107、113、119、125、131和137组成的组的氨基酸序列具有至少80%同源性、至少81%同源性、至少82%同源性、至少83%同源性、至少84%同源性、至少85%同源性、至少86%同源性、至少87%同源性、至少88%同源性、至少89%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性。
在一个实施方案中,抗体或其片段包含轻链CDR1序列,所述轻链CDR1序列与选自由SEQ ID NO:84、90、96、102、108、114、120、126、132和138组成的组的氨基酸序列具有至少80%同源性、至少81%同源性、至少82%同源性、至少83%同源性、至少84%同源性、至少85%同源性、至少86%同源性、至少87%同源性、至少88%同源性、至少89%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性。
在一个实施方案中,抗体或其片段包含轻链CDR2序列,所述轻链CDR2序列与选自由SEQ ID NO:85、91、97、103、109、115、121、127、133和139组成的组的氨基酸序列具有至少80%同源性、至少81%同源性、至少82%同源性、至少83%同源性、至少84%同源性、至少85%同源性、至少86%同源性、至少87%同源性、至少88%同源性、至少89%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性。
在一个实施方案中,抗体或其片段包含轻链CDR3序列,所述轻链CDR3序列与选自由SEQ ID NO:86、92、98、104、110、116、122、128、134和140组成的组的氨基酸序列具有至少80%同源性、至少81%同源性、至少82%同源性、至少83%同源性、至少84%同源性、至少85%同源性、至少86%同源性、至少87%同源性、至少88%同源性、至少89%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性。
在一个实施方案中,抗体或其片段包含以下项:重链CDR1,其由选自由SEQ ID NO:81、87、93、99、105、111、117、123、129和135组成的组的氨基酸序列组成;重链CDR2,其由选自由SEQ ID NO:82、88、94、100、106、112、118、124、130和136组成的组的氨基酸序列组成;重链CDR3,其由选自由SEQ ID NO:83、89、95、101、107、113、119、125、131和137组成的组的氨基酸序列组成;轻链CDR1,其由选自由SEQ ID NO:84、90、96、102、108、114、120、126、132和138组成的组的氨基酸序列组成;轻链CDR2,其由选自由SEQ ID NO:85、91、97、103、109、115、121、127、133和139组成的组的氨基酸序列组成;以及轻链CDR3,其由选自由SEQ IDNO:86、92、98、104、110、116、122、128、134和140组成的组的氨基酸序列组成。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:81、82和83的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:84、85和86的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQ IDNO:81、82和83的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:84、85和86的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:87、88和89的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:90、91和92的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQ IDNO:87、88和89的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:90、91和92的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:93、94和95的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:96、97和98的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQ IDNO:93、94和95的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:96、97和98的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:99、100和101的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:102、103和104的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQID NO:99、100和101的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:102、103和104的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:105、106和107的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:108、109和110的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQID NO:105、106和107的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:108、109和110的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:111、112和113的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:114、115和116的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQID NO:111、112和113的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:114、115和116的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:117、118和119的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:120、121和122的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQID NO:117、118和119的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:120、121和122的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:123、124和125的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:126、127和128的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQID NO:123、124和125的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:126、127和128的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:129、130和131的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:132、133和134的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQID NO:129、130和131的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:132、133和134的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:135、136和137的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:138、139和140的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,抗体或其抗体片段包含分别根据SEQID NO:135、136和137的重链CDR1、CDR2和CDR3,以及分别根据SEQ ID NO:138、139和140的轻链CDR1、CDR2和CDR3。
在一个实施方案中,抗体或其片段结合PD-L1,并且包含重链可变区,所述重链可变区包含与选自由SEQ ID NO:2、6、10、14、18、22、26、30、34、38、42和46组成的组的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链可变区,所述轻链可变区包含与选自由SEQ ID NO:4、8、12、16、20、24、28、32、36、40、44和48组成的组的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,分离的抗体或其片段结合PD-L1,并且包含重链可变区,所述重链可变区包含以下序列、基本上由以下序列组成或由以下序列组成:选自由SEQ ID NO:2、6、10、14、18、22、26、30、34、38、42和46组成的组的氨基酸序列;以及轻链可变区,所述轻链可变区包含以下序列、基本上由以下序列组成或由以下序列组成:选自由SEQ ID NO:4、8、12、16、20、24、28、32、36、40、44和48组成的组的氨基酸序列。
在一个实施方案中,本发明提供了抗PD-L1抗体,其包含选自由13C5、5G9、5G11、8C6、7B4、4D1、4A8、8H4、8H3和15F1组成的组的抗体的可变重链和选自由13C5、5G9、5G11、8C6、7B4、4D1、4A8、8H4、8H3和15F1组成的组的抗体的可变轻链。因此,在一个实施方案中,本发明提供了抗体或其片段,其包含含有SEQ ID NO:2的重链可变区和含有SEQ ID NO:4的轻链可变区;含有SEQ ID NO:6的重链可变区和含有SEQ ID NO:8的轻链可变区;含有SEQID NO:10的重链可变区和含有SEQ ID NO:12的轻链可变区;含有SEQ ID NO:14的重链可变区和含有SEQ ID NO:16的轻链可变区;含有SEQ ID NO:18的重链可变区和含有SEQ ID NO:20的轻链可变区;含有SEQ ID NO:22的重链可变区和含有SEQ ID NO:24的轻链可变区;含有SEQ ID NO:26的重链可变区和含有SEQ ID NO:28的轻链可变区;含有SEQ ID NO:30的重链可变区和含有SEQ ID NO:32的轻链可变区;含有SEQ ID NO:34的重链可变区和含有SEQID NO:36的轻链可变区;或含有SEQ ID NO:38的重链可变区和含有SEQ ID NO:40的轻链可变区。
在一个实施方案中,本发明提供嵌合抗PD-L1抗体,其中所述抗体包含重链,所述重链具有与选自由SEQ ID NO:50、54、58、60、64和66组成的组的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列;以及轻链,所述轻链具有与选自由SEQ ID NO:52、56、62和68组成的组的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。
在一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含重链可变区,其具有与选自由SEQ ID NO:42和46组成的组的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含轻链可变区,其具有与选自由SEQ ID NO:44和48组成的组的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。
在另一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含重链可变区,其与SEQ ID NO:42具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性;以及轻链可变区,其与SEQ ID NO:44具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含重链可变区,其与SEQ ID NO:46具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性;以及轻链可变区,其与SEQ ID NO:48具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。
在一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含完整的重链,其具有与选自由SEQ ID NO:70、72、76和78组成的组的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。在另一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含完整的轻链,其具有与选自由SEQ ID NO:74和80组成的组的氨基酸序列具有至少80%同源性、至少85%同源性、至少90%同源性、至少91%同源性、至少92%同源性、至少93%同源性、至少94%同源性、至少95%同源性、至少96%同源性、至少97%同源性、至少98%同源性或至少99%同源性的氨基酸序列。
在一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含根据SEQ ID NO:70的重链和根据SEQ ID NO:74的轻链。在另一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含根据SEQ ID NO:72的重链和根据SEQ ID NO:74的轻链。在另一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含根据SEQID NO:76的重链和根据SEQ ID NO:80的轻链。在另一个实施方案中,本发明提供了人源化抗PD-L1抗体,其中所述抗体包含根据SEQ ID NO:78的重链和根据SEQ ID NO:80的轻链。
在一个实施方案中,本发明提供了与本文提供的任何示例性抗体结合PD-L1上的相同表位的抗PD-L1抗体或其片段。在一个实施方案中,抗体或其片段与本文提供的用于结合PD-L1的任何示例性抗体竞争。可以通过ELISA、流式细胞术、表面等离子体共振(SPR)测定或本领域已知的任何其他方法测量与PD-L1的结合。
在一个实施方案中,本发明提供以约10nM至约0.01nM的结合亲和力kD与PD-L1结合的抗PD-L1抗体和其片段。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约10nM至约0.05nM的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约8nM至约0.1nM的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约5nM至约0.2nM的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约10nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约6nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约4nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约2nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约1nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.75nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.5nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.25nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.2nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.15nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.1nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.075nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.05nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.025nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.02nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.015nM或更小的结合亲和力kD与PD-L1结合。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段以约0.01nM或更小的结合亲和力kD与PD-L1结合。在一个实施方案中,通过Biacore测定来测量本文提供的抗PD-L1抗体和片段的结合亲和力kD。
在一个实施方案中,本文提供的抗PD-L1抗体和其片段对PD-L1具有约1ng/mL至约2000ng/mL的结合EC50。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段对PD-L1具有约1ng/mL至约1500ng/mL的结合EC50。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段对PD-L1具有约1ng/mL至约1000ng/mL的结合EC50。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段对PD-L1具有约2ng/mL至约500ng/mL的结合EC50。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段对PD-L1具有约2ng/mL至约250ng/mL的结合EC50。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段对PD-L1具有约5ng/mL至约200ng/mL的结合EC50。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段对PD-L1具有约5ng/mL至约50ng/mL的结合EC50。在一个实施方案中,本文提供的抗PD-L1抗体和其片段对PD-L1具有约500ng/mL或更小、约400ng/mL或更小、约300ng/mL或更小、约250ng/mL或更小、约200ng/mL或更小、约150ng/mL或更小、约100ng/mL或更小、约75ng/mL或更小、约60ng/mL或更小、约50ng/mL或更小、约40ng/mL或更小或约30ng/mL或更小的结合EC50。在一个实施方案中,通过ELISA或FACS来测量本文提供的抗PD-L1抗体和片段的EC50。
在一个实施方案中,本文提供的抗PD-L1抗体和其片段抑制PDL1/PD-1结合,其中IC50为约1ng/mL至约1500ng/mL。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段抑制PDL1/PD-1结合,其中IC50为约2ng/mL至约1200ng/mL。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段抑制PDL1/PD-1结合,其中IC50为约5ng/mL至约500ng/mL。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段抑制PDL1/PD-1结合,其中IC50为约5ng/mL至约100ng/mL。在另一个实施方案中,本文提供的抗PD-L1抗体和其片段抑制PDL1/PD-1结合,其中IC50为约10ng/mL至约50ng/mL。在一个实施方案中,本文提供的抗PD-L1抗体和其片段抑制PDL1/PD-1结合,其中IC50为约1200ng/mL或更小、约1000ng/mL或更小、约800ng/mL或更小、约400ng/mL或更小、约300ng/mL或更小、约250ng/mL或更小、约200ng/mL或更小、约150ng/mL或更小、约100ng/mL或更小、约75ng/mL或更小、约60ng/mL或更小、约50ng/mL或更小、约40ng/mL或更小、约30ng/mL或更小、约20ng/mL或更小、或约10ng/mL或更小。在一个实施方案中,通过ELISA或FACS来测量本文提供的抗PD-L1抗体和片段的IC50。
在一个实施方案中,本文提供的抗PD-L1抗体是人源化抗体,其具有根据SEQ IDNO:42的重链可变区氨基酸序列和根据SEQ ID NO:44的轻链可变区氨基酸;或具有根据SEQID NO:46的重链可变区氨基酸序列和根据SEQ ID NO:48的轻链可变区氨基酸序列;其中所述抗PD-L1抗体具有如通过ELISA或FACS所测量的下述PD-L1结合EC50:约200ng/mL或更小、或约150ng/mL或更小、或约100ng/mL或更小、或约80ng/mL或更小、或约60ng/mL或更小、或约50ng/mL或更小。在另一个实施方案中,本文提供的抗PD-L1抗体是人源化抗体,其具有根据SEQ ID NO:42的重链可变区氨基酸序列和根据SEQ ID NO:44的轻链可变区氨基酸;或具有根据SEQ ID NO:46的重链可变区氨基酸序列和根据SEQ ID NO:48的轻链可变区氨基酸序列;其中所述抗PD-L1抗体具有如通过ELISA或FACS所测量的下述PDL1/PD-1阻断IC50:约1200ng/mL或更小、约1000ng/mL或更小、约800ng/mL或更小、约600ng/mL或更小、约500ng/mL或更小、或约400ng/mL或更小、或约300ng/mL或更小、或约200ng/mL或更小、或约100ng/mL或更小、或约60ng/mL或更小、或约30ng/mL或更小、或约25ng/mL或更小、或约20ng/mL或更小、或约10ng/mL或更小。在另一个实施方案中,本文提供的抗PD-L1抗体是人源化抗体,其具有根据SEQ ID NO:42的重链可变区氨基酸序列和根据SEQ ID NO:44的轻链可变区氨基酸;或具有根据SEQ ID NO:46的重链可变区氨基酸序列和根据SEQ ID NO:48的轻链可变区氨基酸序列;其中所述抗PD-L1抗体对PD-L1具有如通过Biacore测定所测量的下述结合亲和力kD:约10nM或更小、或约5nM或更小、或约2nM或更小、或约1nM或更小、或约0.5nM或更小、或约0.1nM或更小、或约0.05nM或更小。在一个实施方案中,人源化抗PD-L1抗体对PD-L1具有约2nM的结合亲和力kD。在另一个实施方案中,人源化抗PD-L1抗体对PD-L1具有约1nM的结合亲和力kD。在另一个实施方案中,人源化抗PD-L1抗体对PD-L1具有约0.5nM的结合亲和力kD。在另一个实施方案中,人源化抗PD-L1抗体对PD-L1具有约0.1nM的结合亲和力kD。
在一个实施方案中,本文提供的抗PD-L1抗体和其片段结合PD-L1,从而破坏了PD-1/PD-L1相互作用并使得T细胞活化增加。在另一个实施方案中,抗体和其片段结合PD-L1并且使得T细胞增殖和/或细胞因子产生增加。在另一个实施方案中,抗体和其片段结合PD-L1并且使得选自由以下组成的组的一种或多种细胞因子增加:IL-2、IFNγ、TNF、IL-1、IL-4、IL-5、IL-6、IL-12、IL-13、IL-17和GM-CSF。因此,在一方面,本发明提供了用于调节免疫应答的方法,其包括使T细胞和抗原呈递细胞与抗PD-L1抗体或其片段接触。在一个实施方案中,可以在混合淋巴细胞(MLR)反应中测量本文提供的抗PD-L1抗体和片段对免疫应答的调节。在一个实施方案中,本文提供的抗PD-L1抗体增加MLR中淋巴细胞的细胞因子产生的水平。在另一个实施方案中,抗PD-L1抗体增加MLR中IL-2产生和/或IFNγ产生的水平。在另一个实施方案中,抗PD-L1抗体增加MLR中IL-2产生和IFNγ产生的水平。在一个实施方案中,抗PD-L1抗体增强记忆T细胞应答。在另一个实施方案中,如通过记忆T细胞的IFNγ产生的增加所测量的,抗PD-L1抗体增强记忆T细胞应答。
在一个实施方案中,本文提供的抗PD-L1抗体和其片段抑制调节T细胞功能。在另一个实施方案中,抗PD-L1抗体和其片段抑制调节T细胞对效应T细胞的遏制。在另一个实施方案中,抗PD-L1抗体和其片段在调节T细胞的存在下恢复T细胞的效应子功能。在另一个实施方案中,抗PD-L1抗体和其片段在调节T细胞的存在下恢复效应T细胞增殖和/或产生细胞因子的能力。因此,在一个实施方案中,本发明提供了在体外或在有需要的受试者中抑制调节T细胞的阻遏作用的方法。
在一方面,提供了结合PD-L1的分离的抗体或其片段,其中所述抗体由杂交瘤产生,所述杂交瘤选自由本文称为13C5、5G9、5G11、8C6、7B4、4D1、4A8、8H4、8H3和15F1的杂交瘤组成的组。因此,本发明还包括杂交瘤13C5、5G9、5G11、8C6、7B4、4D1、4A8、8H4、8H3和15F1,以及产生本文公开的抗体的任何杂交瘤。本发明还提供了编码本文提供的抗体和其片段的分离的多核苷酸。本发明还包括包含分离的多核苷酸的表达载体,和包含所述表达载体的宿主细胞。
在一个实施方案中,本发明提供了抗PD-L1抗体免疫缀合物。因此,本发明提供了结合PD-L1并与治疗剂连接或缀合的抗体或其片段。可以与抗PD-L1抗体连接或缀合的治疗剂可以包括但不限于细胞毒性药物、放射性同位素、免疫调节剂或抗体。
在一方面,本发明提供了包含本文提供的一种或多种抗PD-L1抗体或其片段和药学上可接受的载体的组合物。
在一方面,本发明提供了用于在受试者中调节免疫应答的方法,所述方法包括向受试者施用治疗有效量的本文提供的抗PD-L1抗体或其片段。在一个实施方案中,本发明提供了用于在有需要的受试者中治疗或预防疾病或病症的方法,所述方法包括向受试者施用治疗有效量的本文提供的抗PD-L1抗体或其片段。
在一个实施方案中,本发明提供了用于在有需要的受试者中增强抗肿瘤应答的方法,所述方法包括向受试者施用治疗有效量的本发明的抗PD-L1抗体或片段。在另一个实施方案中,本发明提供了用于在有需要的受试者中减少肿瘤或抑制肿瘤细胞的生长的方法,所述方法包括向受试者施用治疗有效量的本发明的抗PD-L1抗体或片段。在另一个实施方案中,本发明提供了用于在有需要的受试者中治疗癌症的方法,所述方法包括向受试者施用治疗有效量的本发明的抗PD-L1抗体或片段。在另一个实施方案中,所述癌症选自由以下组成的组:淋巴瘤、白血病、黑色素瘤、神经胶质瘤、乳腺癌、肺癌、结肠癌、骨癌、卵巢癌、膀胱癌、肾癌、肝癌、胃癌(stomach cancer)、直肠癌、睾丸癌、唾液腺癌、甲状腺癌、胸腺癌、上皮癌、头或颈癌、胃癌(gastric cancer)、胰腺癌或其组合。
在一个实施方案中,本发明提供了用于在有需要的受试者中治疗传染病的方法,所述方法包括向受试者施用治疗有效量的本发明的抗PD-L1抗体或片段。在另一个实施方案中,所述传染病选自由以下组成的组:念珠菌病、念珠菌血症、曲霉菌病、链球菌性肺炎、链球菌性皮肤和口咽病状、革兰氏阴性脓毒症、结核病、单核细胞增多症、流行性感冒、由呼吸道合胞病毒引起的呼吸道疾病、疟疾、血吸虫病和锥虫病。
具体地,本发明涉及如下各项:
1.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含以下项:重链CDR1序列,其与选自由SEQ ID NO:81、87、93、99、105、111、117、123、129和135组成的组的氨基酸序列具有至少80%同源性;重链CDR2序列,其与选自由SEQ ID NO:82、88、94、100、106、112、118、124、130和136组成的组的氨基酸序列具有至少80%同源性;重链CDR3序列,其与选自由SEQ ID NO:83、89、95、101、107、113、119、125、131和137组成的组的氨基酸序列具有至少80%同源性;轻链CDR1序列,其与选自由SEQ ID NO:84、90、96、102、108、114、120、126、132和138组成的组的氨基酸序列具有至少80%同源性;轻链CDR2序列,其与选自由SEQID NO:85、91、97、103、109、115、121、127、133和139组成的组的氨基酸序列具有至少80%同源性;以及轻链CDR3序列,其与选自由SEQ ID NO:86、92、98、104、110、116、122、128、134和140组成的组的氨基酸序列具有至少80%同源性。
2.如项1所述的抗体或其片段,其中所述抗体或其片段包含以下项:重链CDR1,其由选自由SEQ ID NO:81、87、93、99、105、111、117、123、129和135组成的组的氨基酸序列组成;重链CDR2,其由选自由SEQ ID NO:82、88、94、100、106、112、118、124、130和136组成的组的氨基酸序列组成;重链CDR3,其由选自由SEQ ID NO:83、89、95、101、107、113、119、125、131和137组成的组的氨基酸序列组成;轻链CDR1,其由选自由SEQ ID NO:84、90、96、102、108、114、120、126、132和138组成的组的氨基酸序列组成;轻链CDR2,其由选自由SEQ IDNO:85、91、97、103、109、115、121、127、133和139组成的组的氨基酸序列组成;以及轻链CDR3,其由选自由SEQ ID NO:86、92、98、104、110、116、122、128、134和140组成的组的氨基酸序列组成。
3.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:81、82和83的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:84、85和86的氨基酸序列具有至少80%同源性的氨基酸序列。
4.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:87、88和89的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:90、91和92的氨基酸序列具有至少80%同源性的氨基酸序列。
5.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:93、94和95的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:96、97和98的氨基酸序列具有至少80%同源性的氨基酸序列。
6.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:99、100和101的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:102、103和104的氨基酸序列具有至少80%同源性的氨基酸序列。
7.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:105、106和107的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:108、109、110的氨基酸序列具有至少80%同源性的氨基酸序列。
8.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:111、112和113的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:114、115和116的氨基酸序列具有至少80%同源性的氨基酸序列。
9.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:117、118和119的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:120、121和122的氨基酸序列具有至少80%同源性的氨基酸序列。
10.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:123、124和125的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:126、127和128的氨基酸序列具有至少80%同源性的氨基酸序列。
11.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:129、130和131的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:132、133和134的氨基酸序列具有至少80%同源性的氨基酸序列。
12.如项1所述的抗体或片段,其中所述抗体或其片段包含重链CDR1、CDR2和CDR3,所述重链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:135、136和137的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链CDR1、CDR2和CDR3,所述轻链CDR1、CDR2和CDR3包含与分别根据SEQ ID NO:138、139和140的氨基酸序列具有至少80%同源性的氨基酸序列。
13.如项1-12中任一项所述的分离的抗体或其片段,其中所述抗体或其片段是嵌合的或人源化的。
14.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含重链可变区,所述重链可变区包含与选自由SEQ ID NO:2、6、10、14、18、22、26、30、34、38、42和46组成的组的氨基酸序列具有至少80%的同源性的氨基酸序列;以及轻链可变区,所述轻链可变区包含与选自由SEQ ID NO:4、8、12、16、20、24、28、32、36、40、44和48组成的组的氨基酸序列具有至少80%的同源性的氨基酸序列。
15.如项14所述的分离的抗体或其片段,其中所述抗体或其片段包含重链可变区,所述重链可变区包含选自由SEQ ID NO:2、6、10、14、18、22、26、30、34、38、42和46组成的组的氨基酸序列;以及轻链可变区,所述轻链可变区包含选自由SEQ ID NO:4、8、12、16、20、24、28、32、36、40、44和48组成的组的氨基酸序列。
16.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQID NO:42的重链可变区和根据SEQ ID NO:44的轻链可变区。
17.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQID NO:46的重链可变区和根据SEQ ID NO:48的轻链可变区。
18.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQID NO:70的重链和根据SEQ ID NO:74的轻链。
19.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQID NO:72的重链和根据SEQ ID NO:74的轻链。
20.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQID NO:76的重链和根据SEQ ID NO:80的轻链。
21.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQID NO:78的重链和根据SEQ ID NO:80的轻链。
22.一种分离的抗体或其片段,其中所述抗体或其片段与如项1至21中任一项所述的抗体或其片段结合相同表位。
23.一种分离的抗体或其片段,其中所述抗体或其片段与如项1至21中任一项所述的抗体或其片段竞争结合PD-L1,其中所述竞争通过ELISA、流式细胞术或表面等离子体共振(SPR)测定进行测量。
24.如项1-21中任一项的分离的抗体或其片段,其中所述抗体或其片段选自由单克隆抗体、scFv、Fab片段、Fab'片段和F(ab)'片段组成的组。
25.根据项1-21中任一项所述的抗体或其片段,其中所述抗体或其片段与治疗剂连接或缀合。
26.根据项25所述的抗体或其片段,其中所述治疗剂是细胞毒性药物、放射性同位素、免疫调节剂或抗体。
27.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段对PD-L1具有约10nM至约0.01nM的亲和力。
28.根据项27所述的分离的抗体或其片段,其中所述抗体或其片段对PD-L1具有约10nM或更小的亲和力。
29.根据项27所述的分离的抗体或其片段,其中所述抗体或其片段对PD-L1具有约1.0nM或更小的亲和力。
30.一种结合PD-L1的分离的抗体或其片段,其中所述抗体具有约5ng/mL至约1000ng/mL的结合EC50。
31一种结合PD-L1的分离的抗体或其片段,其中所述抗体阻断PD-L1与PD-1的结合。
32.如项31所述的分离的抗体或其片段,其中所述抗体或其片段以约5ng/mL至约1000ng/mL的IC50阻断PD-L1与PD-1的结合。
33.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或片段增加T细胞活化,如通过炎性细胞因子产生所测量的。
34.根据项28所述的分离的抗体或其片段,其中所述抗体或其片段增加T细胞的IL-2和IFNγ产生。
35.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段由杂交瘤产生,所述杂交瘤选自由13C5、5G9、5G11、8C6、7B4、4D1、4A8、8H4、8H3和/或15F1组成的组。
36.一种组合物,其包含根据项1-35中任一项所述的抗体或其片段以及药学上可接受的载体。
37.一种分离的多核苷酸,其编码根据项1-35中任一项所述的抗体或其片段。
38.一种表达载体,其包含根据项37所述的分离的多核苷酸。
39.一种宿主细胞,其包含根据项38所述的表达载体。
40.一种分离的杂交瘤细胞系,其选自由13C5、5G9、5G11、8C6、7B4、4D1、4A8、8H4、8H3和15F1组成的组。
41.一种用于增加T细胞活化的方法,所述方法包括使T细胞与根据项1-35中任一项所述的抗体或其片段接触。
42.一种用于在受试者中减少肿瘤或抑制肿瘤细胞生长的方法,所述方法包括向所述受试者施用治疗有效量的根据项1-35中任一项所述的分离的抗体或其片段。
43一种用于在有需要的受试者中治疗癌症的方法,所述方法包括向所述受试者施用治疗有效量的根据项1-35中任一项所述的分离的抗体或其片段。
44根据项43所述的方法,其中所述癌症选自由以下组成的组:淋巴瘤、白血病、黑色素瘤、神经胶质瘤、乳腺癌、肺癌、结肠癌、骨癌、卵巢癌、膀胱癌、肾癌、肝癌、胃癌、直肠癌、睾丸癌、唾液腺癌、甲状腺癌、胸腺癌、上皮癌、头或颈癌、胃癌、胰腺癌或其组合。
45.一种用于在有需要的受试者中治疗传染病的方法,所述方法包括向所述受试者施用治疗有效量的根据项1-35中任一项所述的分离的抗体或其片段。
46.根据项45所述的方法,其中所述传染病选自由以下组成的组:念珠菌病、念珠菌血症、曲霉菌病、链球菌性肺炎、链球菌性皮肤和口咽病状、革兰氏阴性脓毒症、结核病、单核细胞增多症、流行性感冒、由呼吸道合胞病毒引起的呼吸道疾病、疟疾、血吸虫病和锥虫病。
附图简述
图1a-d是示出如通过ELISA测量的在一定抗体浓度内鼠类杂交瘤抗PD-L1抗体与PD-L1的结合的一组图。图1a示出杂交瘤抗体8H3-mIgG(m8H3)、15F1-mIgG(m15F1)、5G9-mIgG(m5G9)和4A8-mIgG(m4A8)的结合。图1b示出杂交瘤抗体5G11-mIgG(m5G11)、7B4-mIgG(m7B4)、4D1-mIgG(m4D1)和8H4-mIgG(m8H4)的结合。图1c示出杂交瘤抗体8C6-mIgG(m8C6)的结合。图1d示出杂交瘤抗体13C5-mIgG(m13C5)的结合。在图1a-1d的每一个中,mIgG1的结合作为阴性对照示出。
图2a-c是示出如通过ELISA测量的在一定浓度范围内嵌合抗PD-L1抗体与PD-L1的结合的一组图。图2a示出嵌合抗体ch5G11-hIgG4和ch5G11-hIgG1的结合。图2b示出嵌合抗体ch13C5-hIgG4、ch13C5-hIgG1和ch8H4-hIgG4的结合。图2c示出嵌合抗体ch8C6-hIgG4的结合。在图2a-2c的每一个中,hIgG4的结合作为阴性对照示出。
图3a-b是示出如通过ELISA测量的在一定抗体浓度范围内人源化抗PD-L1抗体与PD-L1的结合的一组图。图3a示出对照hIgG4以及人源化抗体hu5G11-hIgG1和hu5G11-hIgG4的结合。图3b示出对照hIgG4以及人源化抗体hu13C5-hIgG1和hu13C5-hIgG4的结合。
.图4a-c是示出如通过ELISA测量的在一定抗体浓度范围内杂交瘤抗PD-L1抗体对PD-1/PD-L1相互作用的阻断的一组图。图4a示出与对照mIgG1相比,杂交瘤抗体13C5-mIgG(m13C5)、8C6-mIgG(m8C6)、5G9-mIgG(m5G9)和4A8-mIgG(m4A8)对PD-1/PD-L1结合的阻断。图4b示出与对照mIgG1相比,杂交瘤抗体5G11-mIgG(m5G11)、7B4-mIgG(m7B4)、4D1-mIgG(m4D1)和8H4-mIgG(m8H4)对PD-1/PD-L1结合的阻断。图4c示出与对照mIgG1相比,杂交瘤抗体8H3-mIgG(m8H3)和15F1-mIgG(m15F1)对PD-1/PD-L1结合的阻断。
图5a-c是示出如通过ELISA测量的在一定抗体浓度范围内嵌合抗PD-L1抗体对PD-1/PD-L1相互作用的阻断的一组图。图5a示出与对照hIgG4相比,嵌合抗体ch5G11 hIgG4和ch5G11 hIgG1对PD-1/PD-L1结合的阻断。图5b示出与对照hIgG4相比,嵌合抗体ch8C6-hIgG4对PD-1/PD-L1结合的阻断。图5c示出与对照hIgG4相比,嵌合抗体ch8H4-hIgG4、ch13C5-hIgG1和ch13C5-hIgG4对PD-1/PD-L1结合的阻断。
图6a-b是示出如通过ELISA测量的在一定抗体浓度范围内人源化抗PD-L1抗体对PD-1/PD-L1相互作用的阻断的一组图。图6a示出对照hIgG4以及人源化抗体5G11-hIgG1和5G11-hIgG4对PD-1/PD-L1结合的阻断。图6b示出对照hIgG4以及人源化抗体13C5-hIgG1和13C5-hIgG4对PD-1/PD-L1结合的阻断。
图7a和7b示出如通过FACS测量的在一定抗体浓度范围内杂交瘤抗PD-L1抗体与PD-L1的结合。图7a示出与对照抗体mIgG1相比,杂交瘤抗体4A8、15F1、4D1、13C5、8H4和8H3的结合(如通过平均荧光强度测量的)。图7b示出与对照抗体mIgG1相比,杂交瘤抗体5G11、8C6、5G9或7B4的结合(如通过平均荧光强度测量的)。
图8示出如通过FACS测量的在一定抗体浓度范围内嵌合抗PD-L1抗体与PD-L1的结合。示出对照抗体hIgG4以及嵌合抗体ch13C5-hIgG1、ch5G11-hIgG1和ch5G11-hIgG4的结合。
图9示出如通过FACS测量的在一定抗体浓度范围内人源化抗PD-L1抗体与PD-L1的结合。示出对照抗体hIgG4以及人源化抗体hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1和hu5G11-hIgG4的结合。
.图10a和10b示出如通过FACS测量的在一定抗体浓度范围内杂交瘤抗PD-L1抗体对PD-1/PD-L1相互作用的阻断。图10a示出对照抗体mIgG1以及杂交瘤抗体m4D1、m5G11、m13C5、m7B4和m8H4对PD-1/PD-L1结合的阻断。图10b示出对照抗体mIgG1以及杂交瘤抗体m4A8、m5G9、m8C6、m8H3和m15F1对PD-1/PD-L1结合的阻断。
图11示出如通过FACS测量的在对照抗体hIgG4或嵌合抗PD-L1抗体ch8C6-hIgG4、ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4或ch8H4-hIgG4的一定浓度范围内对PD-1/PD-L1相互作用的阻断。
图12示出如通过FACS测量的在对照抗体hIgG4或人源化抗体hu 13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4的一定浓度范围内对PD-1/PD-L1相互作用的阻断。
图13a是示出在MLR中响应于不同浓度的杂交瘤抗PD-L1抗体的IL-2(pg/mL)产生的图。图13b是示出在MLR中响应于不同浓度的杂交瘤抗PD-L1抗体的IFNγ(pg/mL)产生的图。对于图13a和13b,测试的抗体从左到右是对照mIgG1、m8C6、m4D1、m5G11、m7B4、m8H4、m5G9、m13C5、m8H3和m15F1。也包括仅T细胞和/或仅DC的孔作为阴性对照。如图13a和13b的x轴所示,每种抗体在20μg/mL、2μg/mL、0.2μg/mL、0.02μg/mL和0.002μg/mL下进行测试。
图14a是示出在MLR中响应于不同浓度的嵌合抗PD-L1抗体的IL-2(pg/mL)产生的图。图14b是示出在MLR中响应于不同浓度的嵌合抗PD-L1抗体的IFNγ(pg/mL)产生的图。对于图14a和14b,测试的抗体从左到右是对照hIgG4、嵌合8C6-hIgG4、嵌合8H4-hIgG4、嵌合5G11-hIgG4和嵌合13C5-hIgG1。如图14a和14b的x轴所示,每种抗体在20μg/mL、2μg/mL、0.2μg/mL、0.02μg/mL和0.002μg/mL下进行测试。
图15a是示出在MLR中响应于不同浓度的嵌合人源化抗PD-L1抗体的IL-2(pg/mL)产生的图。图15b是示出在MLR中响应于不同浓度的嵌合人源化抗PD-L1抗体的IFNγ(pg/mL)产生的图。对于图15a和15b,测试的抗体从左到右是对照hIgG4、hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1和hu5G11-hIgG4。如图15a和15b的x轴所示,每种抗体在20μg/mL、2μg/mL、0.2μg/mL、0.02μg/mL和0.002μg/mL下进行测试。
图16示出在具有CD4+CD25+Treg细胞、CD4+CD25-T细胞和树突细胞的同种异体MLR中嵌合(ch)或人源化(hu)抗PD-L1抗体对Treg介导的IFNγ产生(pg/mL)抑制的影响。测试的抗体从左到右是对照hIgG4、ch13C5-hIgG1、ch13C5-hIgG4、hu13C5-hIgG1、hu13C5-hIgG4、ch5G11-hIgG1、ch5G11-hIgG4、hu5G11-hIgG1和hu5G11-hIgG4。
图17示出在人源化抗PD-L1抗体(hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4)、同种型对照(hIgG4)抗体存在下或在无抗体存在下响应于用自体DC和抗CD3抗体的共刺激的T细胞的IFN-γ产生(pg/mL)。
图18a和18b示出如通过IFN-γ产生(pg/mL)测量的人源化抗PD-L1抗体对由破伤风毒素召回的记忆T细胞应答的影响。在以下浓度下测试阴性对照hIgG4或人源化抗体hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4:20μg/mL、2μg/mL、0.2μg/mL、0.02μg/mL和0.002μg/mL。
详述
PD1/PDL1相互作用通过募集干扰TCR信号传导的SHP1和SHP2磷酸酶来抑制T细胞受体信号传导(Chemnitz等(2004)J.Immunol.17:945–954)。PD-L1不仅可以通过抑制PD1表达免疫效应子来促进肿瘤进展,而且还可以调节一些传染病中的细胞介导的免疫(Mueller等(2010)J.Clin.Invest.120:2508–2515)。此外,同种异体效应T细胞应答易受移植物排斥中的PD-1途径调节的影响(Lee等(2003)J.Immunol.171:6929–6935)。因此,PD-1与PD-L1的相互作用在T细胞活化、耐受和免疫介导的组织损伤中发挥重要且各种各样的免疫调节作用。然而,通过阻断PD-1与PD-L1的局部结合可以逆转相互作用(Iwai等(2002)Proc.Nat’l.Acad Sci.USA 99:12293-7;Brown等(2003)J.Immunol.170:1257-66)。
已经发现PD-1由于其在保护肿瘤细胞免受有效的免疫破坏方面的作用而与癌症生长和发展相关。已经揭示PD-1的配体PD-L1在许多小鼠和人肿瘤上具有显著表达,假定所述配体介导免疫逃避(Iwai,Y.等,Proc.Natl.Acad.Sci.USA.99:12293-12297(2002);Strome S.E.等,Cancer Res.,63:6501-6505(2003);Dong等(2002)Nat.Med.8:787-9)。在人中,在如通过免疫组织化学评估的许多原发性肿瘤活组织检查中发现了PD-1(在肿瘤浸润淋巴细胞上)和/或PD-L1(在肿瘤细胞上)的表达。此类组织包括肺、肝、卵巢、子宫颈、皮肤、结肠、神经胶质瘤、膀胱、乳腺、肾、食道、胃、口腔鳞状细胞、膀胱上皮细胞和胰腺的癌症以及头颈部的肿瘤(Brown J.A.等,J.Immunol.170:1257-1266(2003);Dong H.等,Nat.Med.8:793-800(2002);Wintterle等,Cancer Res.63:7462-7467(2003);Strome S.E.等,Cancer Res.,63:6501-6505(2003);Thompson R.H.等,Cancer Res.66:3381-5(2006);Thompson等,Clin.Cancer Res.13:1757-61(2007);Nomi T.等,Clin.Cancer Res.13:2151-7.(2007))。更显著地,肿瘤细胞上的PD-1配体表达与跨越多种肿瘤类型的癌症患者的不良预后相关(综述于OkaZaki和Honjo,Int.Immunol.19:813-824(2007))。
尽管PD-1和PD-L1之间的相互作用导致肿瘤浸润淋巴细胞的减少、T细胞受体介导的增殖的减少以及癌性细胞的免疫逃避(Dong等(2003)J.Mol.Med.81:281-7;Blank等(2005)Cancer Immunol.Immunother.54:3 07-3 14;Konishi等(2004)Clin.CancerRes.10:5094-100),但是阻断PD-1/PD-L1相互作用因此显示出增强肿瘤特异性T细胞免疫性并有助于免疫系统对肿瘤细胞的清除。在侵袭性胰腺癌的鼠类模型中,例如,Nomi T.等(Clin.Cancer Res.13:2151-2157,2007)证明了PD-1/PD-L1阻断的治疗功效。施用PD-1或针对PD-L1的抗体显著抑制肿瘤生长。抗体阻断有效地促进肿瘤反应性CD8+T细胞浸润到肿瘤中,从而使得抗肿瘤效应子(包括IFN-γ、粒酶B和穿孔素)上调。另外,作者表明PDL1/PD-1阻断可以有效地与化学疗法组合以产生协同效应。在另一研究中,使用小鼠中的鳞状细胞癌的模型,PD-1或PD-L1的抗体阻断显著抑制肿瘤生长(Tsushima F.等,Oral Oncol.42:268-274(2006))。
此外,当与肿瘤特异性CTL克隆共培养时,用PD-L1转染鼠类肥大细胞瘤系导致肿瘤细胞裂解减少。当添加抗PD-L1 mAb时,裂解恢复(Iwai Y.等,Proc.Natl.Acad.Sci.USA.99:12293-12297(2002))。在体内,阻断PD1/PD-L1相互作用显示增加过继性T细胞转移疗法在小鼠肿瘤模型中的功效(Strome S.E.等,Cancer Res.63:6501-6505(2003))。对于PD-1在癌症治疗中的作用的另外证据来自用PD-1敲除小鼠进行的实验。表达PD-L1的骨髓瘤细胞仅在野生型动物中生长(导致肿瘤生长和相关动物死亡),而不在PD-1缺陷小鼠中生长(Iwai Y.,等,Proc.Natl.Acad.Sci.USA.99:12293-12297(2002))。在人的研究中,R.M.Wong等(Int.Immunol.19:1223-1234(2007))表明在使用疫苗抗原和来自疫苗接种个体的细胞的离体刺激测定中使用完整的人抗PD-1抗体的PD-1阻断增加了肿瘤特异性CD8+T细胞(CTL)的绝对数目。在类似的研究中,PD-L1的抗体阻断使得肿瘤相关抗原特异性细胞毒性T细胞的细胞溶解活性增强并使得肿瘤特异性TH细胞的细胞因子产生增加(Blank C.等,Int.J.Cancer 119:317-327(2006))同一作者表明,当与抗CTLA-4阻断组合使用时,PD-L1阻断增加体外的肿瘤特异性T细胞应答。总之,PD-1/PD-L1途径是开发用于癌症治疗的抗体治疗剂的靶标。抗PD-L1抗体也可用于慢性病毒感染中。急性病毒感染后产生的记忆CD8+T细胞是高度功能性的,并且构成保护性免疫的重要组分。相反,慢性感染通常以病毒特异性T细胞应答的不同程度的功能损伤(衰竭)为特征,并且此缺陷是宿主不能消除继续存在的病原体的主要原因。尽管功能性效应T细胞最初在感染的早期阶段产生,但是它们在慢性感染过程中逐渐失去功能。Barber等(Barber等,Nature 439:682-687(2006))表明用LCMV的实验室品系感染的小鼠患有慢性感染,导致血液和其他组织中产生高水平的病毒。这些小鼠最初产生了强烈的T细胞应答,但是最终在T细胞衰竭后死于感染。作者发现,通过注射阻断PD-1与PD-L1之间的相互作用的抗体,可以逆转慢性感染小鼠中效应T细胞的数量下降和功能衰退。
在一方面,本发明提供了结合程序性死亡配体1(PD-L1)的抗体或其抗原结合片段。在一个实施方案中,抗体或其片段结合人PD-L1。在另一个实施方案中,抗体或其片段结合人PD-L1并结合食蟹猴(cynomolgous)PD-L1。在另一个实施方案中,抗体或其片段阻断PD-L1与其在T细胞上的受体PD-1的相互作用。在一方面,本发明提供了制备和使用抗PD-L1抗体或其片段的方法,以及包含抗PD-L1抗体或其片段的组合物,所述组合物包括药物组合物。
如本文所用,术语“抗体”是指具有至少一个抗原结合结构域的结合蛋白。本发明的抗体和其片段可以是整个抗体或其任何片段。因此,本发明的抗体和片段包括单克隆抗体或其片段和抗体变体或其片段,以及免疫缀合物。抗体片段的实例包括Fab片段、Fab'片段、F(ab)'片段、Fv片段、分离的CDR区、单链Fv分子(scFv)和本领域已知的其他抗体片段。抗体和其片段还可以包括重组多肽、融合蛋白和双特异性抗体。本文公开的抗PD-L1抗体和其片段可以是IgG1、IgG2、IgG3或IgG4同种型。术语“同种型”是指由重链恒定区基因编码的抗体种类。在一个实施方案中,本文公开的抗PD-L1抗体和其片段是IgG1或IgG4同种型。本发明的PD-L1抗体和其片段可以衍生自任何物种,其包括但不限于小鼠、大鼠、兔、灵长类动物、美洲驼和人。PD-L1抗体和其片段可以是嵌合抗体、人源化抗体或完整的人抗体。在一个实施方案中,抗PD-L1抗体是由源自小鼠的杂交瘤细胞系产生的抗体。因此,在一个实施方案中,抗PD-L1抗体是鼠类抗体。在另一个实施方案中,抗PD-L1抗体是嵌合抗体。在另一个实施方案中,嵌合抗体是小鼠-人嵌合抗体。在另一个实施方案中,抗体是人源化抗体。在另一个实施方案中,抗体衍生自鼠类抗体并且是人源化的。
“嵌合抗体”是下述抗体:所述抗体具有衍生自一种物种的重链可变区的至少一部分和轻链可变区的至少一部分;以及衍生自另一物种的恒定区的至少一部分。例如,在一个实施方案中,嵌合抗体可以包含鼠类可变区和人恒定区。
“人源化抗体”是下述抗体:所述抗体含有衍生自非人抗体的互补决定区(CDR);和衍生自人抗体的框架区以及恒定区。例如,本文提供的抗PD-L1抗体可以包含衍生自一种或多种鼠类抗体的CDR以及人框架区和恒定区。因此,在一个实施方案中,本文提供的人源化抗体与所述抗体的CDR所衍生自的鼠类抗体结合PD-L1上的相同表位。本文提供了示例性人源化抗体。包含本文提供的重链CDR和轻链CDR的另外的抗PD-L1抗体或其变体可以使用任何人框架序列产生,并且也包括在本发明中。在一个实施方案中,适用于在本发明中使用的框架序列包括在结构上与本文提供的框架序列类似的那些框架序列。可以在框架区中进行另外修饰以改进本文提供的抗体的特性。此类另外的框架修饰可以包括化学修饰;点突变以降低免疫原性或去除T细胞表位;或使突变回复为原始种系序列中的残基。在一些实施方案中,此类修饰包括对应于本文示例的突变的那些修饰,包括对种系序列的回复突变。例如,在一个实施方案中,本文提供的人源化抗体的VH和/或VL的人框架区中的一个或多个氨基酸被回复突变为亲本鼠类抗体中对应的氨基酸。例如,对于人源化5G11和人源化13C5的VH和VL,上述模板人抗体的框架氨基酸的几个位点被回复突变为小鼠5G11和13C5抗体中对应的氨基酸序列。在一个实施方案中,轻链可变区的位置53和/或60和/或67处的氨基酸被回复突变为在小鼠5G11或13C5轻链可变区中的所述位置处发现的对应的氨基酸。在另一个实施方案中,重链可变区的位置24和/或28和/或30和/或49和/或73和/或83和/或94处的氨基酸被回复突变为在小鼠5G11或13C5重链可变区中的所述位置处发现的对应的氨基酸。在一个实施方案中,人源化5G11抗体包含轻链可变区,其中在位置60处的氨基酸从Ser(S)突变为Asp(D),并且在位置67处的氨基酸从Ser(S)突变为Tyr(Y);以及重链可变区,其中在位置24处的氨基酸从Phe(F)突变为Val(V),在位置49处的氨基酸从Ala(A)突变为Gly(G),在位置73处的氨基酸从Thr(T)突变为Asn(N),并且在位置83处的氨基酸从Thr(T)突变为Asn(N)。在一个实施方案中,人源化13C5抗体包含轻链可变区,其中在位置53处的氨基酸从Tyr(Y)突变为Lys(K);以及重链可变区,其中在位置28处的氨基酸从Thr(T)突变为Ile(I),在位置30处的氨基酸从Ser(S)突变为Arg(R),在位置49处的氨基酸从Ser(S)突变为Ala(A),并且在位置94处的氨基酸从Tyr(Y)突变为Asp(D)。另外的或另选的回复突变可以在本文提供的人源化抗体的框架区中进行以改进抗体的特性。本发明还包括下述人源化抗体,所述人源化抗体结合PD-L1并且包含对应于本文所述的相对于任何合适的框架序列的示例性修饰的框架修饰,以及以其他方式改进抗体特性的其他框架修饰。
如本文所用,术语“衍生的”当用于指相对于参考抗体或其他结合蛋白的分子或多肽时,意指能够与参考抗体或其他结合蛋白特异性地结合相同表位的分子或多肽。
本文公开的抗体和其抗原结合片段对PD-L1是特异性的。在一个实施方案中,抗体或和其片段对PD-L1是特异性的。在一个实施方案中,本文提供的抗体和片段结合人或灵长类动物PD-L1,但不结合来自任何其他哺乳动物的PD-L1。在另一个实施方案中,抗体或和其片段不结合小鼠PD-L1。术语“人PD-L1”、“hPD-L1”和“huPD-L1”等在本文中可互换使用,并且是指人PD-L1和人PD-L1的变体或同种型。“特异于”意指抗体和其片段以比任何其他靶标更大的亲和力结合PD-L1。如本文所用,术语“EC50”是指有效浓度,抗体的50%最大应答。如本文所用,术语“IC50”是指抑制浓度,抗体的50%最大应答。EC50和IC50两者均可以通过ELISA或FACS分析或本领域已知的任何其他方法进行测量。
在一个实施方案中,抗PD1抗体和其片段或变体对PD-L1具有下述结合亲和力(KD):在约0.001nM至约100nM、约0.002nM至约50nM、约0.005nM至约5nM、约0.01nM至约1nM或约0.05nM至约0.1nM的范围内。在一个实施方案中,抗体和其片段对PD-L1具有下述结合亲和力(KD):约50nM或更小、约25nM或更小、约20nM或更小、约15nM或更小、约10nM或更小、约8nM或更小、约6nM或更小、约5nM或更小、约4nM或更小、约3nM或更小、约2nM或更小、约1nM或更小、约0.9nM或更小、约0.8nM或更小、约0.7nM或更小、约0.6nM或更小、约0.5nM或更小、约0.4nM或更小、约0.3nM或更小、约0.2nM或更小、约0.1nM或更小、约0.09nM或更小、约0.08nM或更小、约0.07nM或更小、约0.06nM或更小、约0.05nM或更小、约0.04nM或更小、约0.03nM或更小、约0.02nM或更小、约0.01nM或更小、约0.009nM或更小、约0.008nM或更小、约0.007nM或更小、约0.006nM或更小、约0.005nM或更小、约0.004nM或更小、约0.003nM或更小、约0.002nM或更小、或约0.001nM或更小。在一个实施方案中,抗体和其片段对PD-L1具有下述结合亲和力(KD):约10nM、约9nM、约8nM、约7nM、约6nM、约5nM、约4nM、约3nM、约2nM、约1nM、约0.9nM、约0.8nM、约0.7nM、约0.6nM、约0.5nM、约0.4nM、约0.3nM、约0.2nM、约0.1nM、约0.09nM、约0.08nM、约0.07nM、约0.06nM、约0.05nM、约0.04nM、约0.03nM、约0.02nM、约0.01nM、约0.009nM、约0.008nM、约0.007nM、约0.006nM、约0.005nM、约0.004nM、约0.003nM、约0.002nM、或约0.001nM。
在一个实施方案中,本文提供的抗体和片段包含轻链和重链,所述轻链和重链的每个包含三个CDR区。本发明的PD-L1抗体的示例性重链CDR序列(HCDR1、HCDR2和HCDR3)提供于下表1中。本发明的PD-L1抗体的示例性轻链CDR序列(LCDR1、LCDR2和LCDR3)提供于下表2中。本发明的PD-L1抗体的示例性可变区以及全长重链序列和轻链序列提供于下表3中。
表1.重链CDR序列
表2.轻链CDR序列
表3.重链可变区和轻链可变区以及全长重链氨基酸序列和全长轻链氨基酸序列
在一个实施方案中,本发明提供了包含抗体13C5、5G9、5G11、8C6、7B4、4D1、4A8、8H4、8H3和/或15F1的轻链CDR和重链CDR的抗PD-L1抗体。本领域技术人员将理解,本文提供的抗体的重链CDR和轻链CDR可以独立地进行选择或混合和匹配,以形成包含来自本文提供的抗体的任何重链CDR1、CDR2和CDR3;以及任何轻链CDR1、CDR2和CDR3的抗体或其结合片段。因此,本发明提供了包含以下项的抗PD-L1抗体:重链CDR1,其包含选自由SEQ ID NO:81、87、93、99、105、111、117、123、129和135组成的组的氨基酸序列;重链CDR2,其包含选自由SEQ ID NO:82、88、94、100、106、112、118、124、130和136组成的组的氨基酸序列;重链CDR3,其包含选自由SEQ ID NO:83、89、95、101、107、113、119、125、131和137组成的组的氨基酸序列;轻链CDR1,其包含选自由SEQ ID NO:84、90、96、102、108、114、120、126、132和138组成的组的氨基酸序列;轻链CDR2,其包含选自由SEQ ID NO:85、91、97、103、109、115、121、127、133和139组成的组的氨基酸序列;以及轻链CDR3,其包含选自由SEQ ID NO:86、92、98、104、110、116、122、128、134和140组成的组的氨基酸序列。在一个实施方案中,本发明提供了包含重链CDR区和轻链CDR区的抗PD-L1抗体,所述重链CDR区和轻链CDR区包含与本文提供的对应的轻链CDR1、CDR2或CDR3或重链CDR1、CDR2或CDR3具有至少75%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的同源性的氨基酸序列。在一个实施方案中,本发明提供了包含重链CDR区和轻链CDR区的抗PD-L1抗体,所述重链CDR区和轻链CDR区包含相对于本文提供的对应的轻链CDR1、CDR2或CDR3或重链CDR1、CDR2或CDR3具有1、2、3、4、5或6个氨基酸取代、缺失或插入的氨基酸序列。
在一个实施方案中,本发明提供了抗PD-L1抗体,其包含选自由13C5、5G9、5G11、8C6、7B4、4D1、4A8、8H4、8H3和/或15F1组成的组的抗体的可变重链和选自由13C5、5G9、5G11、8C6、7B4、4D1、4A8、8H4、8H3和/或15F1组成的组的的抗体的可变轻链。在一个实施方案中,本文提供的抗体和片段包含含有下述氨基酸序列的重链可变区:所述氨基酸序列与选自由SEQ ID NO:2、6、10、14、18、22、26、30、34、38、42和46组成的组的重链可变区具有至少75%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的同源性。在一个实施方案中,本文提供的抗体和片段包含含有根据SEQ ID NO:2、6、10、14、18、22、26、30、34、38、42、46或其变体的氨基酸序列的重链可变区,其中所述变体包含1、2、3、4、5、6、7、8、9或10个氨基酸取代或缺失或其组合。在另一个实施方案中,氨基酸取代为保守取代。
在一个实施方案中,本文提供的抗体和片段包含含有下述氨基酸序列的轻链可变区:所述氨基酸序列与选自由SEQ ID NO:4、8、12、16、20、24、28、32、36、40、44或48组成的组的轻链可变区具有至少75%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的同源性。在一个实施方案中,本文提供的抗体和片段包含含有根据SEQ ID NO:4、8、12、16、20、24、28、32、36、40、44、48或其变体的氨基酸序列的轻链可变区,其中所述变体包含1、2、3、4、5、6、7、8、9、10或更多个氨基酸取代、插入或缺失或其组合。在另一个实施方案中,氨基酸取代为保守取代。
本文公开的在CDR或可变轻链区或可变重链区具有一个或多个氨基酸取代、插入、缺失或其组合的抗PD-L1抗体保留了不具有氨基酸取代、插入或缺失的对应的抗PD-L1抗体的生物活性。因此,本文提供的变体抗PD-L1抗体保留与PD-L1的结合。如本文所用,同源性百分比是指两个参考序列共有的相同氨基酸序列的数目除以氨基酸位置的总数,乘以100。
在一些实施方案中,本文提供的抗PD-L1抗体包含保守的氨基酸取代。本领域技术人员将认识到,保守的氨基酸取代是用具有类似结构或化学特性(例如像类似的侧链)的另一氨基酸取代一个氨基酸。示例性保守取代在本领域中例如,在Watson等,MolecularBiology of the Gene,The Bengamin/Cummings Publication Company,第4版(1987)中进行了描述。
技术人员将理解,可变轻链和可变重链可以独立地选自本文提供的抗体或与本文提供的抗体混合和匹配。因此,本发明提供了抗PD-L1抗体,其包含重链可变区,所述重链可变区与选自由SEQ ID NO:2、6、10、14、18、22、26、30、34、38、42和46组成的组的氨基酸序列具有至少80%的同源性;以及轻链可变区,所述轻链可变区与选自由SEQ ID NO:4、8、12、16、20、24、28、32、36、40、44和48组成的组的氨基酸序列具有至少80%的同源性。
在一个实施方案中,本发明提供与本文公开的任何示例性抗体结合相同表位的抗体。因此,在一个实施方案中,本发明提供了与本文提供的示例性抗体竞争结合PD-L1的抗体。
本文提供的抗PD-L1抗体和其片段还可以包含Fc区修饰以改变效应子功能。Fc修饰可以是氨基酸插入、缺失或取代,或者可以是化学修饰。例如,可以进行Fc区修饰以增加或减少补体结合、增加或减少抗体依赖性细胞毒性,或者增加或减少抗体的半衰期。一些Fc修饰增加或减少抗体对Fcγ受体(诸如FcγRI、FcγRII、FcγRIII或FcRn)的亲和力。各种Fc修饰已经在本领域中,例如,在Shields等,J Biol.Chem 276;6591(2001);Tai等Blood119;2074(2012);Spiekermann等J Exp.Med 196;303(2002);Moore等mAbs 2:2;181(2010);Medzihradsky Methods in Molecular Biology446;293(2008);Mannan等DrugMetabolism and Disposition35;86(2007);和Idusogie等J Immunol 164;4178(2000)中描述。在一些实施方案中,改变了Fc区糖基化模式。在其他实施方案中,通过聚乙二醇化(例如,通过使抗体或其片段与聚乙二醇(PEG)反应来修饰Fc区。
在一个实施方案中,本文提供的抗体或其片段是免疫缀合物,所述免疫缀合物包含抗PD-L1抗体或其片段,并且还包含选自包括另外的治疗剂、细胞毒性剂、免疫粘附分子和显像剂的组的试剂。在一些实施方案中,显像剂选自由放射性标记、酶、荧光标记、发光标记、生物发光标记、磁性标记和生物素组成的组。在一些实施方案中,显像剂是选自由以下组成的组的放射性标记:3H、14C、35S、62Cu、64Cu、89Zr、90Y、99Tc、111In、125I、131I、177Lu、166Ho和153Sm。在一些实施方案中,治疗剂或细胞毒性剂选自包括以下的组:化学治疗剂、免疫抑制剂、免疫刺激剂、抗代谢物、烷化剂、抗生素、生长因子、细胞因子、抗血管生成剂、抗有丝分裂剂、蒽环霉素、毒素和细胞凋亡剂。在一些实施方案中,结合蛋白直接与试剂缀合。在其他实施方案中,结合蛋白通过接头与试剂缀合。合适的接头包括但不限于本文公开的氨基酸和多肽接头。接头可以是可裂解的或不可裂解的。
在一个实施方案中,本发明提供对PD-L1和至少一种其他抗原或表位具有特异性的双特异性或多特异性抗体。可以使用本文提供的结合测定或本领域已知的任何其他结合测定来测试本文提供的抗PD-L1抗体和其片段与PD-L1的结合。
除非另外说明,否则本发明的实践采用本领域熟知的并且在以下中描述的常规分子生物学、细胞生物学、生物化学和免疫学技术:例如,Methods in Molecular Biology,Humana Press;Molecular Cloning:A Laboratory Manual,第二版(Sambrook等,1989);Current Protocols in Immunology(J.E.Coligan等编,1991);Immunobiology(C.A.Janeway和P.Travers,1997);Antibodies(P.Finch,1997);Antibodies:a practicalapproach(D.Catty.编,IRL Press,1988-1989);Monoclonal antibodies:a practicalapproach(P.Shepherd和C.Dean编,Oxford University Press,2000);Phage display:alaboratory manual(C.Barbas III等Cold Spring Harbor Laboratory Press,2001);以及Using antibodies:a laboratory manual(E.Harlow and D.Lane(Cold Spring HarborLaboratory Press,1999)。
在一方面,本发明提供了用于治疗受试者的响应于增强、刺激或引发免疫应答的疾病或病状的方法。如本文所用,术语“治疗(treatment或treating)”是指治疗性治疗以及防范性或预防性措施。需要治疗的受试者包括那些已经患有疾病或病状的受试者,以及可能患疾病或病状并且其目的是预防、延迟或减弱疾病或病状的受试者。如本文所用,术语“受试者”表示哺乳动物,诸如啮齿动物、猫科动物、犬科动物和灵长类动物。优选地,根据本发明的受试者是人。
如本文所用,术语“治疗有效量”是指向受试者提供治疗性和/或预防性益处所必需的化合物或组合物的量。
在一方面,抗体和其抗原结合片段可用于治疗实体肿瘤或非实体肿瘤。因此,在一方面,本发明提供了用于治疗癌症的方法。如本文所用,“癌症”是指哺乳动物中特征通常在于不受调控的细胞生长的生理病状。癌症的实例包括但不限于癌、淋巴瘤、胚细胞瘤、肉瘤(包括脂肪肉瘤、骨原性肉瘤、血管肉瘤、内皮肉瘤、平滑肌肉瘤、脊索瘤、淋巴管肉瘤、淋巴管内皮肉瘤、横纹肌肉瘤、纤维肉瘤、粘液肉瘤、软骨肉瘤)、神经内分泌肿瘤、间皮瘤、滑膜瘤、神经鞘瘤(schwanoma)、脑膜瘤、腺癌、黑色素瘤和白血病或淋巴恶性肿瘤。此类癌症的更具体的实例包括鳞状细胞癌(例如上皮鳞状细胞癌)、霍奇金淋巴瘤;非霍奇金淋巴瘤(伯基特淋巴瘤、小淋巴细胞性淋巴瘤/慢性淋巴细胞性白血病、蕈样真菌病、套细胞淋巴瘤、滤泡性淋巴瘤、弥漫性大B细胞性淋巴瘤、边缘区淋巴瘤、毛细胞白血病和淋巴浆细胞性白血病)、淋巴细胞前体细胞的肿瘤(包括B细胞急性淋巴母细胞性白血病/淋巴瘤和T细胞急性淋巴母细胞性白血病/淋巴瘤)、胸腺瘤、成熟T细胞和NK细胞的肿瘤(包括外周T细胞性白血病、成人T细胞性白血病/T细胞性淋巴瘤和大颗粒淋巴细胞性白血病)、朗格汉斯细胞组织细胞增生症、骨髓瘤诸如急性骨髓性白血病(包括成熟的AML、未分化的AML、急性早幼粒细胞性白血病、急性髓单核细胞性白血病和急性单核细胞性白血病)、骨髓增生异常综合征和慢性骨髓增生性病症(包括慢性骨髓性白血病、B细胞急性淋巴细胞性白血病/淋巴瘤、T细胞急性淋巴细胞性白血病/淋巴瘤)、肺癌(lung cancer)(包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞状细胞癌小细胞肺癌)、腹膜癌、肝细胞癌、胃癌(gastric or stomachcancer)(包括胃肠癌)、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、直肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌(kidney or renalcancer)、前列腺癌、外阴癌、甲状腺癌、肝癌(hepatic carcinoma)、肛门癌、阴茎癌、睾丸癌、食道癌、胆道肿瘤、尤因氏肿瘤、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝癌(hepatoma)、胆管癌、绒膜癌、精原细胞瘤、胚胎性癌、维尔姆斯瘤、睾丸肿瘤、肺癌(lung carcinoma)、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑色素瘤、成神经细胞瘤、成视网膜细胞瘤、白血病、淋巴瘤、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症、骨髓增生异常疾病、重链疾病、神经内分泌肿瘤、神经鞘瘤和其他癌,以及头颈癌。
在一个实施方案中,本文提供的抗体和其片段可用于治疗由传染性病原体引起的疾病。传染性病原体包括但不限于细菌、真菌、寄生物和病毒病原体。此类传染性病原体的实例包括以下:葡萄球菌、耐甲氧西林金黄色葡萄球菌、大肠杆菌、链球菌科、奈瑟氏菌科、球菌、肠杆菌科、肠球菌、耐万古霉素肠球菌、隐球菌、组织胞浆菌病、曲霉菌、假单胞菌科、弧菌科、弯曲杆菌、巴斯德氏菌科、博代氏杆菌、弗朗西斯氏菌、布鲁氏菌、军团菌科、拟杆菌科、革兰氏阴性菌、梭菌、棒状杆菌、丙酸杆菌、革兰氏阳性菌、炭疽、放线菌、诺卡氏菌、分枝杆菌、密螺旋体、疏螺旋体、钩端螺旋体、支原体、尿素原体、立克次体、衣原体、念珠菌、系统性真菌病、机会性真菌病、原生动物、线虫、吸虫、绦虫、腺病毒、疱疹病毒(包括、例如、单纯性疱疹病毒和EB病毒以及带状疱疹病毒)、痘病毒、乳多空病毒、肝炎病毒(包括、例如、乙型肝炎病毒和丙型肝炎病毒)、乳头瘤病毒、正粘病毒(包括、例如、甲型流感、乙型流感和丙型流感)、副粘病毒、冠状病毒、小核糖核酸病毒、呼肠孤病毒、披膜病毒、虫媒病毒、布尼亚病毒、弹状病毒、轮状病毒、呼吸道合胞病毒、人类免疫缺陷病毒和逆转录病毒。示例性传染病包括但不限于念珠菌病、念珠菌血症、曲霉菌病、链球菌性肺炎、链球菌性皮肤和口咽病状、革兰氏阴性脓毒症、结核病、单核细胞增多症、流行性感冒、由呼吸道合胞病毒引起的呼吸道疾病、疟疾、血吸虫病和锥虫病。
在一个实施方案中,本文提供的抗体和其片段可用于治疗由T辅助型2(Th2)T细胞介导的疾病,例如像哮喘、过敏反应或移植物抗宿主病。
在一个实施方案中,本文提供的抗体和其片段可用于在有需要的受试者中刺激免疫应答。例如,在一个实施方案中,抗PD-L1抗体和其片段可以与目标抗原一起施用,以便用于引发对所述抗原的免疫应答。目标抗原可以是与病原体(诸如病毒或细菌)相关联的抗原。因此,在一个实施方案中,本发明提供了包含抗PD-L1抗体和抗原的疫苗,其中所述疫苗引发抗原特异性免疫应答。
在一个实施方案中,本文提供的抗PD-L1抗体调节调节T细胞功能。CD4+CD25+调节T细胞是抑制或降低效应T细胞功能的作用的淋巴细胞。术语“调节T细胞”和“Treg”在本文中可互换使用。在一个实施方案中,本文提供的抗PD-L1抗体阻止或逆转调节T细胞对效应T细胞细胞因子产生的抑制作用。例如,在一个实施方案中,本文提供的抗PD-L1抗体恢复与调节T细胞接触的效应T细胞产生IFNγ的能力。
在一个实施方案中,本文公开的抗体和其片段可以通过选自以下的至少一种路径施用至受试者:胃肠外、皮下、肌肉内、静脉内、关节内、支气管内、腹内、囊内、软骨内、腔内、体腔内、小脑内、脑室内、结肠内、宫颈内、胃内、肝内、心肌内、骨内、骨盆内、心包内、腹膜内、胸膜内、前列腺内、肺内、直肠内、肾内、视网膜内、脊柱内、滑膜内、胸腔内、鼓室内、子宫内、膀胱内、玻璃体内、快速注射、结膜下、经阴道、经直肠、经颊、舌下、鼻内、肿瘤内和经皮肤。
在一个实施方案中,本文公开的抗体和其片段可以与一种或多种另外的治疗剂组合施用至有需要的受试者。在一个实施方案中,可以在向受试者施用另外的治疗剂之前、期间和/或之后将抗体和其片段施用至受试者。在一个实施方案中,另外的治疗剂是化学治疗剂、放射治疗剂、细胞因子、抗体或其片段或指示待治疗的疾病的任何其他另外的治疗剂。在一个实施方案中,当一起施用时,无论是同时施用还是依序施用,抗PD-L1抗体和另外的治疗剂均显示出治疗性协同作用。在一个实施方案中,抗PD-L1抗体和另外的治疗剂以单独的制剂施用。在另一个实施方案中,抗PD-L1抗体和另外的治疗剂以相同的制剂施用。在一个实施方案中,本文提供的抗PD-L1抗体和片段增强一种或多种另外的治疗剂的免疫调节作用。在另一个实施方案中,一种或多种另外的治疗剂增强抗PD-L1抗体或其片段的作用。
本发明提供分离的抗体和其抗原结合片段,以及编码所述抗体和片段的核酸,以及包含所述分离的抗体、片段和核酸的组合物。术语“分离的”是指已经从其天然环境中分离的目标化合物(例如,抗体或核酸)。本发明还提供了药物组合物,所述药物组合物包含分离的抗体或其片段,或编码所述抗体或片段的核酸,并且还包含一种或多种药学上可接受的载体。药学上可接受的载体包括,例如,赋形剂、稀释剂、包封材料、填充剂、缓冲剂或其他试剂。
除非另外特别说明,否则单数的使用包括复数。除非另外特别说明,否则词语“一个(a)”或“一个(an)”意指“至少一个”。除非另外说明,否则“或”的使用意指“和/或”。短语“至少一个”的含义等同于短语“一个或多个”的含义。此外,术语“包括(including)”以及其他形式诸如“包括(includes)”和“包括(included)”的使用不是限制性的。此外,除非另外特别说明,否则术语诸如“要素”或“组分”包括包含一个单元的元素或组分以及包含多于一个单元的元素和组分。
尽管为了清楚理解的目的,已经通过举例说明和实施例相当详细地描述了前述发明,但是根据本发明的教义,本领域的普通技术人员将显而易见的是,可另外对本发明进行某些改变和修改而不背离所附权利要求的精神和范围。以下实施例仅以说明方式提供,而并不起限制作用。本领域的技术人员将容易地识别多种非关键性参数,所述参数可发生改变或修改以产生基本上类似的结果。
实施例
实施例1:hPD-L1单克隆抗体的产生
使用hPD-L1-HisTag和hPD-L1-mFc对小鼠的免疫
为了产生针对人PD-L1的抗体,编码与组氨酸标签(hPD-L1-HisTag,SEQ ID NO:143和144)、小鼠Fc(hPD-L1-mFc,SEQ ID NO:145和146)和人Fc标签(hPD-L1-hFc,SEQ IDNO:147和148)融合的hPD-L1的细胞外结构域的开放阅读框的cDNA通过PCR获得,并且分别被亚克隆到表达载体pcDNA3.1(Invitrogen目录号:V-790)中。在freestyle 293细胞中瞬时表达后,用NTA柱(GE healthcare)纯化hPD-L1-HisTag,用蛋白G柱(GE healthcare)纯化hPD-L1-mFc和hPD-L1-hFc。
使用用等体积的弗氏完全/不完全佐剂乳化的重组体hPD-L1-HisTag蛋白(100μg/小鼠)或hPD-L1-mFc每2周皮下免疫BALB/cJ小鼠,持续6周。融合前3天,通过静脉内注射不含佐剂的抗原来加强小鼠。使用PEG Hybri-Max(Sigma Inc.,目录号:7181)将来自免疫小鼠的脾细胞(1×108)与SP2/0骨髓瘤细胞(1.5×107)融合。融合后,将细胞以0.1ml/孔分配到96孔板中,并且在37℃、5%CO2的培养箱中进行孵育。在第1天,通过向每孔添加另外的0.1ml含有血清和HAT加2×甲氨蝶呤的培养基来饲养细胞。在第3天和第7天,用0.1ml新鲜的HT培养基替换来自每个孔的0.1ml培养基。通常在第9-14天之间进行筛选,并且通过ELISA针对与hPD-L1-hFc反应的抗体测试培养物上清液。
为了克隆所选择的杂交瘤细胞,进行四次有限稀释。将杂交瘤细胞培养在含有10%胎牛血清、1%青霉素/链霉素、2%L-谷氨酰胺和1%调整的NaHC03溶液的杜尔贝科氏改良伊格尔培养基(Dulbecco's Modified Eagle's medium)(GIBCO;InvitrogenCorporation,Carlsbad,Calif.)中。然后将所选择的杂交瘤细胞适应于无血清培养基中,并且使用蛋白G柱(GE healthcare)从上清液中纯化抗体。用PBS洗涤后,使用0.1M甘氨酸pH3.0洗脱结合的抗体,然后使用2.0M Tris进行pH中和。将Ultra-15离心浓缩器(Amicon)用于缓冲液交换和抗体浓缩。
实施例2:抗PD-L1抗体cDNA序列克隆和人源化
免疫球蛋白cDNA的克隆
使用通过RNeasy微型试剂盒(Qiagen,目录号:74104)从产生hPD-L1抗体的杂交瘤细胞系中分离的总RNA作为模板来根据制造商的说明书、用II逆转录酶(Life Technology,目录号:18064-14)合成第一链cDNA。然后使用简并小鼠IgG引物在50μl体积的反应混合物中使cDNA产物经受PCR(Kettleborough CA等,European Journal ofImmunology 23:206-211(1993),Strebe N等,Antibody Engineering 1:3-14(2010))。反应在S1000TM热循环仪(Bio-Rad,目录号:184-2000)中进行,进行如下的循环30次:94℃,变性1.5分钟;50℃,退火1分钟;以及72℃,合成1分钟。在第30个循环结束时,将反应混合物在72℃下再温育7分钟以进行延伸。
将PCR混合物在含有0.5μg/ml溴化乙锭的1%琼脂糖/Tris-硼酸盐凝胶中经受电泳。从凝胶上切下具有预期大小(重链和轻链大约450bp)的DNA片段并且对其进行纯化。将3μl纯化的PCR产物克隆到pMD-18T载体(Takara,目录号:D101A)中,并且转化到One TOP10化学感受态大肠杆菌(Invitrogen,目录号:C4040-03)中。通过菌落PCR使用通用M13正向引物和反向引物筛选克隆,并从每个反应中选择10个阳性克隆用于使用M13正向引物和M13反向引物在两个方向上进行DNA测序。
从对应的杂交瘤克隆扩增抗体的重链可变区序列和轻链可变区序列m4A8(SEQ IDNO:25-28)、m4D1(SEQ ID NO:21-24)、m5G9(SEQ ID NO:5-8)、m5G11(SEQ ID NO:9-12)、m8C6(SEQ ID NO:13-16)、m8H3(SEQ ID NO:33-36)、m8H4(SEQ ID NO:29-32)、m7B4(SEQ IDNO:17-20)、m13C5(SEQ ID NO:1-4)和m15F1(SEQ ID NO:37-40)。这些抗体显示出所需的功能,诸如阻断PD-L1与PD-1的结合,以及增强T细胞活化和细胞因子释放。
嵌合5G11和13C5抗体的构建和表达
通过将小鼠VL区的PCR克隆的cDNA分别连接到人κ链恒定区来构建8C6、8H4、5G11和13C5嵌合轻链(分别为SEQ ID NO:52、56、62和68)。通过将小鼠VH区的PCR克隆的cDNA连接到人IgG1和IgG4恒定区来构建8C6、8H4、5G11和13C5嵌合重链(SEQ ID NO:50(8C6-IgG4)、54(8H4-IgG4)、58(5G11-IgG1)、60(5G11-IgG4)、64(13C5-IgG1))。使用设计为向轻链和重链两者添加前导序列的PCR引物修饰小鼠cDNA序列的5'端。
将Freestyle 293细胞(200mL,在106/mL下)用100μg的每种嵌合重链表达质粒和轻链表达质粒进行转染并且将其培养6天。然后用蛋白G柱(GE healthcare)纯化上清液中的嵌合抗体。通过ELISA和Biacore测量嵌合抗体与PD-L1的结合,并且表明嵌合抗体以与鼠类亲本抗体的亲和力相当的亲和力结合PD-L1。
抗体人源化设计
5G11和13C5抗体使用CDR移植方法进行人源化(参见,例如,美国专利号5,225,539)。将鼠类抗体5G11和13C5的轻链可变链序列和重链可变链序列与结构生物信息学研究合作实验室(RCSB)蛋白质数据库(http://www.ncbi.nlm.nih.gov/igblast/igblast.cgi)中可获得的那些相比。基于具有最高序列同源性的VH结构和VL结构分别产生5G11和13C5的模型。
通过搜索国际免疫遗传信息系统网站(http://www.imgt.org/3Dstructure-DB/ cgi/DomainGapAlign.cgi)从与小鼠5G11和13C5抗体具有高序列同源性的人抗体种系中选择用小鼠5G11和13C5抗体的VH和VL中的互补决定区(CDR)嫁接的模板人抗体。对于5G11,所选择的模板人VH是IGHV2-5*10和IGHJ4*01的组合,并且所选择的模板人VL是IGKV1-33*01和IGKJ2*01的组合。对于13C5,所选择的模板人VH是IGHV3-21*04和IGHJ4*01的组合,并且所选择的模板人VL是IGKV7-3*01和IGKJ2*01的组合。
上述模板人抗体的CDR氨基酸序列被杂交瘤(小鼠)5G11(SEQ ID NO:93-98)和13C5(SEQ ID NO:81-86)抗体的CDR取代。用来自小鼠5G11和13C5抗体的VH和VL的必需氨基酸序列嫁接上述模板人抗体VH和VL的框架,以得到功能性人源化抗体。对于5G11和13C5的VH和VL,上述模板人抗体的框架氨基酸的几个位点被回复突变为小鼠5G11和13C5抗体中对应的氨基酸序列。对于人源化5G11抗体的轻链可变区,在位置60处的氨基酸从Ser(S)突变为Asp(D),并且在位置67处的氨基酸从Ser(S)突变为Tyr(Y);并且对于人源化5G11抗体的重链可变区,在位置24处的氨基酸从Phe(F)突变为Val(V),在位置49处的氨基酸从Ala(A)突变为Gly(G),在位置73处的氨基酸从Thr(T)突变为Asn(N),并且在位置83处的氨基酸从Thr(T)突变为Asn(N)。对于人源化13C5的轻链可变区,在位置53处的氨基酸从Tyr(Y)突变为Lys(K);并且对于人源化13C5的重链可变区,在位置28处的氨基酸从Thr(T)突变为Ile(I),在位置30处的氨基酸从Ser(S)突变为Arg(R),在位置49处的氨基酸从Ser(S)突变为Ala(A),并且在位置94处的氨基酸从Tyr(Y)突变为Asp(D)。人源化5G11的VH和VL的氨基酸序列分别作为SEQ ID NO:42和44提供;编码人源化5G11的VH和VL的DNA序列分别作为SEQID NO:41和43提供。人源化13C5的VH和VL的氨基酸序列分别作为SEQ ID NO:46和48提供);编码人源化13C5的VH和VL的DNA序列分别作为SEQ ID NO:45和47提供。
人源化抗体5G11和13C5的完整轻链的氨基酸序列分别作为SEQ ID NO:74和80提供。编码全长人源化5G11和13C5的DNA序列分别作为SEQ ID NO:73和79提供。产生了人源化5G11和13C5抗体的IgG1和IgG4型式。IgG1恒定区携带D265A突变(Clynes R等,NatureMedicine 6:443-446(2000)),而IgG4恒定区具有F234A和L235A双突变(Xu D等,CellularImmunology 200:16-26(2000))。人源化抗体5G11-hIgG1的全长IgG1重链的DNA序列和氨基酸序列分别作为SEQ ID NO:69和70提供。人源化抗体5G11-hIgG4的全长IgG4重链的DNA序列和氨基酸序列分别作为SEQ ID NO:71和72提供。人源化抗体13C5-hIgG1的全长IgG1重链的DNA序列和氨基酸序列分别作为SEQ ID NO:75和76提供。人源化抗体13C5-hIgG4的全长IgG4重链的DNA序列和氨基酸序列分别作为SEQ ID NO:77和78提供。
人源化5G11和13C5抗体的构建和表达
合成编码人源化5G11和13C5抗体轻链和重链的DNA并且将所述DNA克隆到表达载体pcDNA3.1(Invitrogen,目录号:V-790)中。将Freestyle 293细胞(200mL,在106/mL下)用100μg的每种人源化重链表达质粒和轻链表达质粒进行转染并且将其培养6天。然后用蛋白G柱(GE healthcare)纯化上清液中的人源化抗体。
通过Biacore分析测量PD-L1与PD-L1抗体之间的结合动力学,所述Biacore分析在25℃下在Biacore 3000仪器上进行并且以1Hz的数据收集速率进行记录。将多克隆兔抗小鼠IgG(GE,BR-1008-38)用10mM pH 5.0的乙酸钠进行稀释,并且使用胺偶联试剂盒(GE,BR10050)固定到CM5生物传感器芯片的参考流动池和实验流动池上达到约15000RU。在每个循环的开始,将稀释的测试抗体(1.5μg/mL)注射在实验流动池上,持续1分钟以被捕获。PD-L1分析物系列通过以下方式制备:用运行缓冲液将母液稀释至100nM,然后在相同缓冲液中进行2X系列稀释以降至0.78nM。将分析物以30μL/分钟的流速在参考流动池和实验流动池上连续注射3分钟。使运行缓冲液(含有0.05%P20的PBS)以30μL/分钟的流速流过10分钟。在每个循环结束时,以10μL/分钟的流速用10mM pH1.7甘氨酸-HCl缓冲液的3分钟注射来再生生物传感器表面。对于每个分析物样品注射(即每个循环),通过减去同时记录的来自参考表面的响应,然后另外减去来自单一参考的运行缓冲液样品的响应来双重参考从实验生物传感器表面获得的结合响应。通过使用Biaevaluation 4.0软件将整个滴定系列的双重参考的传感图(sensorgram)拟合至Langmuir模型(1:1)来同时测定缔合速率常数和解离速率常数(ka和kd)。通过KD=kd/ka的关系由所确定的速率常数来计算解离常数KD。抗PD-L1抗体与人PD-L1和食蟹猴PD-L1(cyno-PD-L1)的结合亲和力总结在表4中。
表4.抗PD-L1抗体的PD-L1结合亲和力
所选择的抗体 | 抗原 | KD(M) |
m4A8 | 人PD-L1 | 2.33E-9 |
m4D1 | 人PD-L1 | 4.39E-9 |
m5G9 | 人PD-L1 | 4.78E-9 |
m5G11 | 人PD-L1 | 1.90E-10 |
m7B4 | 人PD-L1 | 6.01E-9 |
m8H3 | 人PD-L1 | 6.60E-9 |
m8H4 | 人PD-L1 | 4.56E-9 |
m8C6 | 人PD-L1 | 1.53E-9 |
m13C5 | 人PD-L1 | 1.35E-9 |
m15F1 | 人PD-L1 | 3.59E-9 |
ch5G11 | 人PD-L1 | 2.86E-10 |
ch13C5 | 人PD-L1 | 2.28E-09 |
hu5G11 | 人PD-L1 | 2.25E-10 |
hu13C5 | 人PD-L1 | 1.74E-09 |
hu5G11 | Cyno-PD-L1 | 2.75E-10 |
hu13C5 | Cyno-PD-L1 | 2.43E-09 |
实施例3:抗PD-L1抗体的基于ELISA的结合分析
ELISA结合分析基于人PD-L1-mFc(用于嵌合抗体和人源化抗体检测)和PD-L1-hFc蛋白(用于杂交瘤抗体检测)进行。将96孔板(Costar,目录号:9018)在4℃下用100μL的2μg/mlPD-L1-mFc(Crownbio)的包被缓冲液PBS(Hyclone,目录号:SH30256.01B)包被过夜。抽吸孔,并且通过添加200μL阻断缓冲液(具有1%(w/v)牛血清白蛋白(BSA,Roche,目录号:738328)的PBS)并且在37℃下孵育1小时来封闭非特异性结合位点。用洗涤缓冲液(具有0.05%(v/v)吐温20(Sigma,目录号:P1379)的PBS)洗涤平板三次后,添加100μL/孔的杂交瘤抗PD-L1抗体(图1)、嵌合抗PD-L1抗体(图2)或人源化抗PD-L1抗体(图3)在阻断缓冲液中的1:10连续稀释液(从20μg/mL开始)并且在室温下孵育1小时。洗涤所述平板并用100μL/孔的在阻断缓冲液中的山羊抗小鼠IgG(H+L)(Thermo,目录号:31432)孵育60分钟。洗涤所述平板后,添加100μL/孔的底物溶液TMB(eBioscience,目录号:00-4201-56)并将所述平板在室温下温育2min。添加100μL/孔的停止溶液(2N H2SO4)以停止反应。产生比色信号并且使用Auto Plate SpectraMax Plus(供应商:Moleculer Devices;型号:MNR0643;软件:SoftMaxPro v5.4)在450nm处读取所述比色信号。使用GraphPad Prism 5分析数据,并计算EC50(图1-3;表5-7)。这些数据表明,如通过ELISA测量的,抗PD-L1抗体(杂交瘤、嵌合的和人源化的)结合PD-L1。
表5.抗PD-L1杂交瘤单克隆抗体与PD-L1的基于ELISA的结合EC50
杂交瘤抗体 | m5G11 | m7B4 | m4D1 | m8H4 | m13C5 |
EC50ng/ml | 45.9 | 31.42 | 7.14 | 29.04 | 65.1 |
杂交瘤抗体 | m8C6 | m5G9 | m4A8 | m8H3 | m15F1 |
EC50ng/ml | 18.2 | 31.2 | 57.6 | 48.7 | 48.7 |
表6.抗PD-L1嵌合抗体与PD-L1的基于ELISA的结合EC50
表7.人源化抗PD-L1抗体与PD-L1的基于ELISA的结合EC50
通过阻断生物素化的人PD-L1-mFc与人PD-1-hFc的结合进行基于ELISA的配体阻断分析。将PD-1-hFc抗原(Crownbio)悬浮于PBS缓冲液(2 ug/ml,100 ul/孔)中并在96孔板(Costar,目录号:9018)上在4℃下包被过夜。抽吸孔,并且通过添加200μL阻断缓冲液(具有1%(w/v)牛血清白蛋白(BSA,Roche,目录号:738328)的PBS)并且在37℃下孵育1小时来封闭非特异性结合位点。用洗涤缓冲液(具有0.05%(v/v)吐温20(Sigma,目录号:P1379)的PBS)洗涤平板三次后,添加100μL/孔的杂交瘤抗PD-L1抗体(图4)、嵌合抗PD-L1抗体(图5)或人源化抗PD-L1抗体(图6)在阻断缓冲液中的1:3连续稀释液(从20μg/mL开始)并且在37℃下孵育1小时。然后向每个孔添加100μl PDL-1-mFc-生物素(0.1μg/ml),并在37℃下孵育2h。将所述平板洗涤3次后,添加第二抗体(Avidin HRP eBioscience目录号:E07418-1632,1:500,100μl/孔),并在37℃下孵育0.5小时。洗涤所述平板后,添加100μL/孔的底物溶液TMB(eBioscience,目录号:00-4201-56),并将所述平板在室温下温育3min。添加100μL/孔的停止溶液(2N H2SO4)以停止反应。产生比色信号并且使用Auto Plate SpectraMax Plus(供应商:Moleculer Devices;型号:MNR0643;软件:SoftMax Pro v5.4)在450nm处读取所述比色信号。使用GraphPad Prism 5分析数据,并计算IC50(图4-6;表8-10)。这些数据表明,如通过ELISA测量的,抗PD-L1抗体(杂交瘤、嵌合的和人源化的)可以阻断PD-1与细胞表面上的PD-L1的结合。
表8.抗PD-L1杂交瘤单克隆抗体抑制PD-1与固体表面上的PD-L1的结合的IC50
表9.抗PD-L1嵌合抗体抑制PD-1与固体表面上的PD-L1的结合的IC50
表10.人源化抗PD-L1抗体抑制PD-1与固体表面上的PD-L1的结合的IC50
人源化抗体 | hu5G11-hIgG1 | hu5G11-hIgG4 | hu13C5-hIgG1 | hu13C5-hIgG4 |
IC50(ng/ml) | 793.6 | 822.5 | 1202.6 | 1192.4 |
实施例4:抗PD-L1抗体的基于细胞的结合分析
基于与稳定表达PD-L1的293T细胞系(PD-L1-293T)的结合进行抗PD-L1抗体的细胞结合分析。将2x105个293T-PD-L1细胞添加到96孔培养板的各孔中,并与指示抗体(20μg/ml,1:5的稀释度)在4℃下孵育1h。将细胞用FACS缓冲液洗涤三次后,以100μl/孔将第二抗体(PE山羊抗小鼠:1:200;PE小鼠抗人:1:10)添加到细胞,并在4℃下孵育40min。将细胞用FACS缓冲液洗涤三次并通过FACS阵列进行分析。杂交瘤抗体的结合在图7a和7b中示出。嵌合抗体的结合在图8中示出。人源化抗体的结合在图9中示出。针对杂交瘤抗体、嵌合抗体和人源化抗体的计算的EC50分别示于下表11、12和13中。这些数据表明,如通过FACS分析测量的,抗PD-L1抗体(杂交瘤、嵌合的和人源化的)结合PD-L1。
表11.抗PD-L1杂交瘤单克隆抗体与细胞表面上的PD-L1的EC50
杂交瘤抗体 | m4D1 | m4A8 | m5G11 | m8H4 | m8H3 |
EC50 ng/ml | 36.07 | 67.83 | 35.94 | 43.49 | 50.81 |
杂交瘤抗体 | m8C6 | m9G9 | m7B4 | m13C5 | m15F1 |
EC50ng/ml | 40.97 | 33.7 | 47.41 | 45.29 | 47.8 |
表12.抗PD-L1嵌合抗体与细胞表面上的PD-L1的EC50
嵌合抗体 | ch13C5 hIgG1 | ch5G11 hIgG1 | ch5G11 hIgG4 |
EC50 ng/ml | 75.75 | 58.26 | 89.68 |
表13.人源化抗PD-L1抗体与细胞表面上的PD-L1的EC50
也研究了抗PD-L1抗体对PD-1与细胞表面上的PD-L1的结合的影响。简言之,将PD-L1-293T细胞悬浮于FACS缓冲液(具有3%胎牛血清的PBS)中。将不同浓度的杂交瘤抗PD-L1抗体(图10)、嵌合抗PD-L1抗体(图11)或人源化抗PD-L1抗体(图12)添加到细胞悬浮液中,并在96孔板中在4℃下孵育60分钟。然后将生物素标记的PD-L1蛋白添加到孔并在4℃下孵育60分钟。将细胞用PBS洗涤3次,并与小鼠抗生物素PE(Biolegend,目录号409004)一起孵育。然后通过使用FACS阵列的流式细胞术分析检测细胞相关的荧光。通过染色的平均荧光强度(MFI)来测量抗PD-L1抗体对PD-1与PD-L1-293T的结合的影响。抗PD-L1杂交瘤抗体对PD-1结合的抑制在图10a和10b中示出。抗PD-L1嵌合抗体对PD-1结合的抑制在图11中示出。抗PD-L1人源化抗体对PD-1结合的抑制在图12中示出。针对杂交瘤抗体(表14)、嵌合抗体(表15)和人源化抗体(表16)计算的IC50在下表中示出。这些数据表明,如通过FACS分析测量的,抗PD-L1抗体(杂交瘤、嵌合的和人源化的)可以阻断PD-1与细胞表面上的PD-L1的结合。
表14.抗PD-L1杂交瘤单克隆抗体抑制PD-1与细胞表面上的PD-L1的结合的IC50
杂交瘤抗体 | mIgG1 | m4D1 | m5G11 | m13C5 | m7B4 | m8H4 |
IC50 ng/ml | NA | 27.3 | 16.3 | 28.9 | 38.1 | 30.6 |
杂交瘤抗体 | m4A8 | m5G9 | m8C6 | m8H3 | m15F1 | |
IC50ng/ml | 29.1 | 49.1 | 8.2 | 33.6 | 21.1 |
表15.抗PD-L1嵌合抗体抑制PD-1与细胞表面上的PD-L1的结合的IC50
表16.人源化抗PD-L1抗体抑制PD-1与细胞表面上的PD-L1的结合的IC50
实施例5:抗PD-L1抗体对混合淋巴细胞反应中T细胞活化的影响
采用混合淋巴细胞反应来证明鼠类抗PD-L1抗体(图13a、13b)、嵌合抗PD-L1抗体(图14a、14b)或人源化抗PD-L1抗体(图15a、15b)在阻断淋巴细胞效应细胞中的PD-L1/PD-1途径中的作用。在存在或不存在人源化抗PD-L1抗体的情况下测试测定中的T细胞的IFN-γ和IL-2分泌。
使用CD4+阴性选择分离试剂盒(Mitenyi Biotech,目录号130-091-155)从人PBMC中纯化人CD4+T细胞。未成熟的树突细胞(DC)衍生自使用Mo-DC产生工具盒(Miltenyi,目录号130-093-568)从人PBMC分离的单核细胞。将细胞用Mo-DC分化培养基培养7天,然后用Mo-Dc成熟培养基诱导2天成为成熟DC。为了建立MLR,对于每个反应,添加105个纯化的T细胞和104个同种异体成熟DC细胞,总体积为200μl。测试抗体在如图13a、13b、14a、14b、15a和15b中所示的不同浓度(即20μg/mL、2μg/mL、0.2μg/mL、0.02μg/mL和0.002μg/mL)下进行测定。无抗体或同种型对照抗体被用作阴性对照。将细胞在37℃下培养5天。在第6天,使用IL-2ELISA试剂盒(eBioscience)和hIFN-γELISA试剂盒(R&D,目录号DY285)测量培养基中IFN-γ和IL-2的水平。IL-2分泌的结果在图13a、14a和15a中示出,并且IFN-γ分泌的结果在图13b、14b和15b中示出。研究结果表明,杂交瘤抗PD-L1抗体、嵌合抗PD-L1抗体和人源化抗PD-L1抗体以浓度依赖性方式促进T细胞IFN-γ和IL-2分泌。相反,含有同种型对照抗体的培养物不显示IFN-γ和IL-2分泌的增加。
实施例6:抗PD-L1抗体对T调节细胞的功能的影响
T调节细胞(CD4+、CD25+)是抑制免疫应答的淋巴细胞。在存在或不存在嵌合抗PD-L1抗体或人源化抗PD-L1抗体的情况下测试T调节细胞对MLR中T效应细胞的细胞因子分泌的影响。使用调节T细胞分离试剂盒(Miltenyi Biotec,目录号130-091-301)从PBMC中纯化T调节细胞(CD4+CD25+)。未成熟的树突细胞(DC)衍生自使用Mo-DC产生工具盒(Miltenyi,目录号130-093-568)从人PBMC分离的单核细胞。将细胞用Mo-DC分化培养基培养7天,然后用Mo-Dc成熟培养基诱导2天成为成熟DC。以4:1的CD4+CD25-与T调节细胞比率将T调节细胞添加到含有纯化的CD4+CD25-T细胞和同种异体树突细胞的混合淋巴细胞反应中。例如:向反应添加1x10^5个细胞/孔的CD4+CD25-细胞、1x10^4个细胞/孔的mDC以及0.25x10^5个细胞/孔的CD4+CD25+细胞。将抗体以10μg/ml的浓度添加至每个反应。无抗体或同种型对照抗体被用作阴性对照。将细胞在37℃下培养5天。在第5天,取50μl培养基以检测IL-2和IFN-γ浓度。在用50μl培养基增补每个孔后,将细胞再培养2天,然后通过CTG(Promega,G7573)分析细胞增殖。使用hIFN-γELISA试剂盒(R&D,目录号DY285)和IL-2ELISA试剂盒(eBioscience)测量培养基中IFN-γ和IL-2的水平。如图16所示,嵌合抗PD-L1抗体和人源化抗PD-L1抗体ch-13C5-hIgG1、ch-13C5-hIgG4、hu-13C5-IgG1、hu-13C5-IgG4、ch-5G11-IgG1、ch-5G11-IgG4、hu-5G11-IgG1和hu-5G11-IgG4可以降低Treg细胞对CD4+CD25-T效应细胞的IFN-γ分泌的抑制作用,这表明抗PD-L1抗体可以调节T调节细胞的免疫遏制功能。
实施例7:人源化抗PD-L1抗体对自体T细胞活化的影响
在本实施例中,检查了通过抗PD-L1抗体阻断PD-1/PD-L1途径对T细胞活化的影响。在存在自体单核细胞衍生的树突细胞(DC)的情况下,用1μg/ml可溶性抗CD3抗体(R&D,目录号MAB100)活化纯化的人CD4+T细胞(Mitenyi Biotech,目录号130-091-155)。在存在或不存在滴定的抗PD-L1抗体的情况下活化三天后,收获培养基并且用ELISA测量IFNγ的浓度。结果在图17中示出,并且表明通过人源化抗PD-L1抗体进行的PD-L1阻断增强了T细胞的IFN-γ分泌。
实施例8:通过人源化抗PD-L1抗体增强对破伤风类毒素激发的人T细胞召回应答
为了研究通过用抗PD-L1抗体阻断PD-1/PD-L1途径是否调节抗原特异性T细胞受体触发,采用人T细胞召回测定,使用破伤风类毒素(TT)抗原刺激健康TT免疫的供体血液中预先存在的记忆T细胞。为此,将来自最近[<1年]TT免疫的供体的新鲜PBMC以4x10^5个细胞/孔接种到使用RPMI1640(Invitrogen,cat#A10491-01)的96孔圆底板(costar,目录号3799)中,所述RPMI1640增补有80U/ml青霉素、80g/ml链霉素和30%自体血清,添加有各种浓度的人源化5G11或13C5,并且用0.1ug/ml SEB和1μg/ml TT(Astarte Biologies)刺激所述新鲜PBMC。在37℃、5%CO2下共培养7天后,收获上清液并测量IFN-γ的浓度。图18a和18b提供了使用来自两个单独供体的PBMC的测定结果。研究结果表明,与单独TT抗原相比,用抗PD-L1抗体的PD-L1阻断使得记忆性T细胞的IFN-γ分泌增强。
总之,人源化5G11和13C5抗体在人源化过程中保留了其亲本抗体的功能活性。
序列表
<110> Crown Bioscience, Inc.
Zha, Jiping
Sun, Ziyong
Qiu, Junzhuan
<120> 抗PD-L1抗体
<130> CRBI-007/01WO
<150> PCT/CN2014/083715
<151> 2014-08-05
<160> 156
<170> PatentIn 3.5 版
<210> 1
<211> 348
<212> DNA
<213> 小鼠属种
<400> 1
gaggtgaagc tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cattttcaga agctatggca tgtcttgggt tcgccagact 120
ccagagaaga ggctggagtg ggtcgcatcc attagtagtg gtggtagcac ctactatcca 180
gacagtgtga agggccgatt caccatctcc agagataatg ccaggaacat cttgtacctg 240
caaatgagca gtctgaggtc tgaggacacg gccatgtatg actgtgcaag aggctatgat 300
tcggggtttg cttattgggg ccaagggact ctggtcactg tctctgaa 348
<210> 2
<211> 116
<212> PRT
<213> 小鼠属种
<400> 2
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Glu
115
<210> 3
<211> 336
<212> DNA
<213> 小鼠属种
<400> 3
gacattgtgc tgacacagtc tcctgcttcc ttagctgttt ctctggggca gagggccacc 60
atctcatgca gggccagcca aagtgtcagt acttctagct ctagttttat gcactggtac 120
caacagaaac caggacagcc acccaaactc ctcatcaagt atgcatccaa cctagaatct 180
ggggtccctg ccaggttcag tggcagtggg tctgggacag acttcaccct caacatccat 240
cctgtggagg aggaggatac tgcaacatat tactgtcagc acagttggga gattccgtac 300
acgttcggag gggggaccaa gctggaaata aaacgg 336
<210> 4
<211> 112
<212> PRT
<213> 小鼠属种
<400> 4
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 5
<211> 348
<212> DNA
<213> 小鼠属种
<400> 5
gaagtaaagt tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cactttcaga agctatggca tgtcttgggt tcgccagact 120
ccagagaaga ggctggagtg ggtcgcatcc attagtagtg gtggtaccac ctactatcca 180
gacagtgtga agggccgatt catcatctcc agagataatg ccaggaacat cctgtacctg 240
caaatgagca gtctgaggtc tgaggacacg gccatgtatt attgtgcaaa aggctatgat 300
tcggggtttg cttactgggg ccaagggact ctggtcattg tctctgca 348
<210> 6
<211> 116
<212> PRT
<213> 小鼠属种
<400> 6
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Ile Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Lys Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Ile Val Ser Ala
115
<210> 7
<211> 333
<212> DNA
<213> 小鼠属种
<400> 7
gacattgtgc tgacacagtc tcctccttcc ttagctgtat ctctggggca gagggccacc 60
atctcatgca gggccagcca aagtgtcagt acatctagtt ctagttatat gcactggtac 120
caacagaaac caggacagcc tcccaaactc ctcatcaagt atgcatccaa cctagaatct 180
ggggtccctg ccaggttcag tggcagtggg tctgggacag acttcaccct caacatccat 240
cctgtggagg aggaggatac tgcaacatat tactgtcagc acagttggga gattccgtac 300
acgttcggag gggggaccaa gctggaaata aaa 333
<210> 8
<211> 111
<212> PRT
<213> 小鼠属种
<400> 8
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Ser Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 9
<211> 348
<212> DNA
<213> 小鼠属种
<400> 9
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact acctatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggaatg gctgggagtg atatggcgtg gtgtaaccac agactataat 180
gcagctttca tgtccagact gaccatcacc aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaagc taatgacaca gccatatatt actgtgccag actgggtttc 300
tatgctatgg actactgggg tcaaggaacc tcagtcaccg tctcctca 348
<210> 10
<211> 116
<212> PRT
<213> 小鼠属种
<400> 10
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser
115
<210> 11
<211> 324
<212> DNA
<213> 小鼠属种
<400> 11
agtattgtga tgacccagac tcccaaattc ctgcttgtat cagcaggaga cagggttacc 60
ataacctgca aggccagtca gagtgtgagt aatgatgtag cttggtacca gcagaagcca 120
gggcagtctc ctaaactgct gatatattat gcagccaatc gctacactgg agtccctgat 180
cgcttcactg gcagtggata tgggacggat ttcactttca ccatcagcat tgtgcaggct 240
gaagacctgg cagtttattt ctgtcagcag gattatacct ctccgtacac gttcggaggg 300
gggaccaagc tggaaataaa acgg 324
<210> 12
<211> 107
<212> PRT
<213> 小鼠属种
<400> 12
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ile Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 13
<211> 348
<212> DNA
<213> 小鼠属种
<400> 13
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact agctatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggagtcac agactataat 180
gcagctttca tatccagact gagcatcagc aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaagc taatgacaca gccatatatt actgtgccag actcggtttc 300
tatgctatgg actactgggg tcaaggaacc tcagtcaccg tctcctca 348
<210> 14
<211> 116
<212> PRT
<213> 小鼠属种
<400> 14
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Val Thr Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser
115
<210> 15
<211> 321
<212> DNA
<213> 小鼠属种
<400> 15
agtattgtga tgacccagac tcccaaattc ctacttgtat cagcaggaga cagggttacc 60
ataacctgca aggccagtca gagtgtgagt aatgatgtag gttggtacca acagaagcca 120
gggcagtctc ctaaactact gatatactat gcatccaatc gctactctgg agtccctgat 180
cgcttcactg gcagtggata tgggacggat ttcactttca ccatcagcac tgtgcaggct 240
gaagacctgg cagtttattt ctgtcaacaa gattatacct ctccgtacac gttcggaggg 300
gggaccaagc tggaaataaa a 321
<210> 16
<211> 107
<212> PRT
<213> 小鼠属种
<400> 16
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 17
<211> 357
<212> DNA
<213> 小鼠属种
<400> 17
gaggtgaagc tgttcgagtc tggaggtggc ctggtgcagc ctggaggatc cctgaaactc 60
tcctgtgtag cctcaggatt cgattttagt acatactgga tgcattgggt ccggcaggct 120
ccagggcaag ggctagaatg gattggacaa attaatccag atagcactac gataaactat 180
gcgccatctc taaaggatag attcatcatc tccagagaca acgccaaaaa tacgctgttc 240
ctgcaaatga gcaaagtgag atctgaggac actgcccttt attactgtgc aaaacccggg 300
gactatggtt acgactttga ctgctggggc caaggcacca ctctcacagt ctcctca 357
<210> 18
<211> 119
<212> PRT
<213> 小鼠属种
<400> 18
Glu Val Lys Leu Phe Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Asp Phe Ser Thr Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Asn Pro Asp Ser Thr Thr Ile Asn Tyr Ala Pro Ser Leu
50 55 60
Lys Asp Arg Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Pro Gly Asp Tyr Gly Tyr Asp Phe Asp Cys Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 19
<211> 339
<212> DNA
<213> 小鼠属种
<400> 19
gatgttttga tgacccaaac tccactctac ctgcctgtca gtcttggaga tcaggcctcc 60
atctcttgca gatctagtca gatcattgta catagtaatg caaacaccta tttagaatgg 120
ttcctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttccg 300
tacacgttcg gaggggggac caagctggaa ataaaacgg 339
<210> 20
<211> 112
<212> PRT
<213> 小鼠属种
<400> 20
Asp Val Leu Met Thr Gln Thr Pro Leu Tyr Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ile Ile Val His Ser
20 25 30
Asn Ala Asn Thr Tyr Leu Glu Trp Phe Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 21
<211> 357
<212> DNA
<213> 小鼠属种
<400> 21
gaggtgcagc ttcaggagtc aggacctagc ctcgtgaaac cttctcagac tctgtccctc 60
acctgttctg tcactggcga ctccatcacc agtggttact ggaactggat ccggaaattc 120
ccagggaata aacttgagta catggggtac ataagctaca gtggtagcac ttactacaat 180
ccatctctca aaagtcgaat ctccatcact cgagacacat ccaagaacca gtactacctg 240
cagttgaatt ctgtgactac tgaggacaca gccacatatt actgtgcaag aagtctacta 300
tggttctcta cggggtttgc ttactggggc caagggactc tggtcactgt ctctgca 357
<210> 22
<211> 119
<212> PRT
<213> 小鼠属种
<400> 22
Glu Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Tyr Leu
65 70 75 80
Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Ser Leu Leu Trp Phe Ser Thr Gly Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 23
<211> 324
<212> DNA
<213> 小鼠属种
<400> 23
caaattgttc tcacccagtc tccagcaatc atgtctgcat ctcctgggga gaaggtcacc 60
ttgacctgca gtgccagctc aagtgtaagt tccagctact tgtactggaa ccagcagaag 120
ccaggatcct cccccaaagt ctggatttat aacacatcca acctggcttc tggagtccct 180
gctcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagcatggag 240
gctgaagatg ctgcctctta tttctgccat cagtggagaa gttacccacc cacgctcggt 300
gctgggacca agctggagct gaaa 324
<210> 24
<211> 108
<212> PRT
<213> 小鼠属种
<400> 24
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Leu Thr Cys Ser Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu Tyr Trp Asn Gln Gln Lys Pro Gly Ser Ser Pro Lys Val Trp
35 40 45
Ile Tyr Asn Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Ser Tyr Phe Cys His Gln Trp Arg Ser Tyr Pro
85 90 95
Pro Thr Leu Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 25
<211> 348
<212> DNA
<213> 小鼠属种
<400> 25
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact agctatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaatcac agactataat 180
gcagctttca aatccagact gagcatcagc aaggacaatt ccaagagcca agttttcttt 240
aagatgaaca gtctgcaagc taatgacaca gccatatatt tctgtgccag actgggtttt 300
tatgctatgg actactgggg tcaaggaacc tcagtcaccg tctcctca 348
<210> 26
<211> 116
<212> PRT
<213> 小鼠属种
<400> 26
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Ile Thr Asp Tyr Asn Ala Ala Phe Lys
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asn Asp Thr Ala Ile Tyr Phe Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser
115
<210> 27
<211> 318
<212> DNA
<213> 小鼠属种
<400> 27
caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60
atgacctgca gtgccaactc aagtgtaagt tacatgcact ggtaccagca gaagtcaggc 120
acttccccca aaagatggat ttatgacaca tccaaactgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagcat gggggctgaa 240
gatgctgcca cttattactg ccagcagtgg agtagtaacc catggacgtt cggtggaggc 300
accaagctgg aaatcaaa 318
<210> 28
<211> 106
<212> PRT
<213> 小鼠属种
<400> 28
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Asn Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Gly Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 29
<211> 348
<212> DNA
<213> 小鼠属种
<400> 29
gaagtgaaac tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cactttcagg agctatggca tgtcttgggc tcgccagatt 120
ccagagaaga ggctggagtg ggtcgcatcc attagtagtg gtggaaccac ctactatcta 180
gggagtgtgc agggccgatt cacaatctcc agagataatg ccaggaacat cctgtacctg 240
caaatgagca gtctgaggtc tgaggacacg gccatgtatt attgtgcaag aggctatgat 300
gcgggatttg cttactgggg ccaagggact ctggtcagtg tctctgaa 348
<210> 30
<211> 116
<212> PRT
<213> 小鼠属种
<400> 30
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Ala Arg Gln Ile Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Leu Gly Ser Val Gln
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Gly Tyr Asp Ala Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Ser Val Ser Glu
115
<210> 31
<211> 333
<212> DNA
<213> 小鼠属种
<400> 31
gacattgtgc tgacacagtc tcctgcttcc ttagctgtat ctctggggca gagggccacc 60
atctcatgca gggccagcca aagtgtcagt acatctagct atagttatat gcactggtac 120
caacagaaac caggacagcc tcccaaactc ctcatcaagt atgcatccaa cctagaatct 180
ggggtccctg ccaggttcag tggcagtggg tctgggacag acttcaccct caacatccat 240
cctgtggagg aggaggatac tgcaacatat tactgtcaga acagttggga gattccgtac 300
acgttcggag gggggaccaa gctggaaata aaa 333
<210> 32
<211> 111
<212> PRT
<213> 小鼠属种
<400> 32
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln Asn Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 33
<211> 351
<212> DNA
<213> 小鼠属种
<400> 33
gaggtgcagc ttcaggagtc aggacctagc ctcgtcaaac cttctcagac tctgtccctc 60
acctgttctg tcactggcga ctccatcacc agtggttact ggacctggat ccggaaattc 120
ccagggaata aacttgaata catgggatac ataagctaca ctggtagcac ttactacaat 180
ccatctctca aaagtcgaat ctccatctct cgagacacat ccaagagcca gtactacctg 240
cagttgaatt ctgtgactac tgaggacaca gccacatatt actgtgcaag acagagggat 300
tggttagggt ttgcttactg gggccaaggg actctggtca ctgtctctgc a 351
<210> 34
<211> 117
<212> PRT
<213> 小鼠属种
<400> 34
Glu Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Thr Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met
35 40 45
Gly Tyr Ile Ser Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ile Ser Ile Ser Arg Asp Thr Ser Lys Ser Gln Tyr Tyr Leu
65 70 75 80
Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Gln Arg Asp Trp Leu Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 35
<211> 339
<212> DNA
<213> 小鼠属种
<400> 35
gatattgtga tgacacagac tccatcctcc ctagctgtgt cacttggaga gaaggttact 60
atgagctgca agtccagtca gagcctttta tatagtagca atcaaaagaa ctccttggcc 120
tggtaccagc agaaaccagg acagtctcct aaactgctga tttactgggc atccaatagg 180
gaatctgggg tccctgatcg cttcacaggc agtagctctg ggacagattt cactctcacc 240
atcagcagtg tgaaggctga agacctggca gtttattact gtcagcaata ttatagctat 300
ccgctcacgt tcggtgctgg gaccaagctg gagctgaaa 339
<210> 36
<211> 113
<212> PRT
<213> 小鼠属种
<400> 36
Asp Ile Val Met Thr Gln Thr Pro Ser Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Asn Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Ser Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 37
<211> 348
<212> DNA
<213> 小鼠属种
<400> 37
gaagagaagc tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cagtttcagt agttatggca tgtcttgggt tcgtcagact 120
ccagagaaga ggctggagtg ggtcgcatcc atcagtagtg gtggtagtat ctactatcca 180
gacagtgtga agggccgatt caccatctcc agagataatg ccaggaacat cctgtacctg 240
caaatgagca gtctgaggtc tgaggacacg gccatgtatt attgtgcaag aggctatgat 300
gcggggtttg ctttctgggg ccaagggaca ctggtcactg cctctgca 348
<210> 38
<211> 116
<212> PRT
<213> 小鼠属种
<400> 38
Glu Glu Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Ile Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Gly Tyr Asp Ala Gly Phe Ala Phe Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Ala Ser Ala
115
<210> 39
<211> 333
<212> DNA
<213> 小鼠属种
<400> 39
gacattgtgc tgacacagtc tcctgcttcc ttagctgtat ctctggggca gagggccacc 60
atctcatgca gggccagcca aagtgtcagt acatctagtt atagttatgt gcactggtac 120
caacagaaac caggacagcc acccaaactc ctcatcaagt atgcatccaa cctagaatct 180
ggggtccctg ccaggttcag tggcagtggg tctgggacag acttcaccct caacatccat 240
cctgtggagg aggaggatac tgcaacatat tactgtcagc acagttggga gattccgtac 300
acgttcggag gggggaccaa gctggaaata aaa 333
<210> 40
<211> 111
<212> PRT
<213> 小鼠属种
<400> 40
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Tyr Ser Tyr Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 41
<211> 348
<212> DNA
<213> 人工序列
<220>
<223> 人源化5G11抗体重链可变区序列
<400> 41
cagatcacac tgaaagaaag cggccctacc ctggtcaagc caactcagac cctgacactg 60
acttgcaccg tgtctgggtt ctctctgagt acatacggag tccactggat caggcagccc 120
cctggcaaag ctctggagtg gctgggagtg atttggcggg gcgtcaccac agactataac 180
gccgctttta tgtcaagact gacaatcact aaggataaca gcaaaaatca ggtggtcctg 240
accatgaaca atatggaccc cgtggatacc gcaacatact attgtgcccg gctggggttc 300
tacgccatgg actattgggg ccaggggact ctggtgaccg tctcgagc 348
<210> 42
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 人源化5G11抗体重链可变区序列
<400> 42
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu
65 70 75 80
Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 43
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 人源化5G11抗体轻链可变区序列
<400> 43
gatatccaga tgactcagtc tccaagcagc ctgtctgcat ctgtggggga cagggtcacc 60
atcacatgca aagcatctca gagtgtgtca aacgatgtcg cctggtacca gcagaagccc 120
ggaaaagctc ctaagctgct gatttactat gccgctaatc ggtacactgg cgtgccagac 180
agattcagcg gatccggata tggaaccgat ttcactttta ccatcagctc cctgcagcca 240
gaggacattg ccacatattt ctgtcagcag gattacacaa gcccctatac ttttggccag 300
gggaccaaac tggaaatcaa g 321
<210> 44
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人源化5G11抗体轻链可变区序列
<400> 44
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 45
<211> 348
<212> DNA
<213> 人工序列
<220>
<223> 人源化13C5抗体重链可变区序列
<400> 45
gaggtgcagc tggtcgagtc aggagggggg ctggtcaagc caggagggtc actgcgactg 60
agctgcgcag cttccgggtt catctttagg tcttatggca tgagttgggt gcgccaggca 120
ccagggaaag gactggagtg ggtcgcttca atcagctccg gaggcagcac ttactatcct 180
gactccgtga agggccggtt caccatttct agagataacg ccaaaaatag tctgtacctg 240
cagatgaact ctctgcgagc agaagacaca gccgtctacg attgtgctag aggatatgac 300
agcggctttg catactgggg ccaggggacc ctggtgacag tctcgagc 348
<210> 46
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 人源化13C5抗体重链可变区序列
<400> 46
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 47
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> 人源化13C5抗体轻链可变区序列
<400> 47
gacattgtgc tgactcagag ccccgcttca ctggcagtgt ctccagggca gcgggcaacc 60
atcacatgca gagcctcaca gagcgtctcc accagctcct ctagtttcat gcactggtac 120
cagcagaagc ccggacagcc ccctaagctg ctgatcaaat atgctagcaa cctggagtcc 180
ggcgtgccag ccaggttctc tggcagtggg tcaggaaccg actttactct gaccattaat 240
cccgtcgaag ccaacgatac agctaattac tattgtcagc attcctggga gatcccttac 300
acatttggcc aggggactaa gctggagatc aag 333
<210> 48
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人源化13C5抗体轻链可变区序列
<400> 48
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 49
<211> 1329
<212> DNA
<213> 人工序列
<220>
<223> 8C6-IgG4 (F234A/L235A)嵌合抗体重链全长序列
<400> 49
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact agctatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggagtcac agactataat 180
gcagctttca tatccagact gagcatcagc aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaagc taatgacaca gccatatatt actgtgccag actcggtttc 300
tatgctatgg actactgggg tcaaggaacc tcagtcaccg tctcgagcgc ctccaccaag 360
ggacccagcg tgtttcccct ggccccctgt tccagatcca cctccgaaag cacagccgct 420
ctcggctgcc tggtcaagga ttacttccct gagcccgtga cagtctcctg gaatagcggc 480
gctctgacct ccggcgtgca taccttccct gctgtgctgc aatcctccgg actgtacagc 540
ctgagcagcg tggtcaccgt gccttcctcc agcctgggaa ccaaaaccta cacatgcaac 600
gtggaccaca agcccagcaa caccaaagtg gacaagaggg tggagtccaa gtacggaccc 660
ccttgtcctc cctgccctgc tcctgaagcc gctggaggac ctagcgtgtt cctgtttccc 720
cccaagccca aggacaccct catgatctcc aggacccccg aggtgacctg tgtcgtggtg 780
gacgtgagcc aagaggaccc cgaggtgcag ttcaactggt acgtggatgg cgtcgaggtc 840
cataacgcca agaccaagcc tagggaggag cagttcaaca gcacctacag agtggtgagc 900
gtcctgaccg tgctccacca agactggctg aacggcaagg aatacaagtg caaggtctcc 960
aacaagggac tcccttcctc catcgagaag accatcagca aggccaaggg ccagcccaga 1020
gaaccccaag tctacacact gccccccagc caagaggaaa tgaccaagaa ccaggtgagc 1080
ctgacctgcc tggtgaaagg cttctacccc agcgacattg ctgtcgaatg ggagagcaac 1140
ggccaacccg agaacaacta caagaccacc ccccctgtgc tcgacagcga cggctccttc 1200
ttcctctaca gcaggctgac agtggacaag tccaggtggc aagagggcaa tgtcttcagc 1260
tgtagcgtca tgcacgaggc cctccacaac cactacaccc agaagagcct gtccctctcc 1320
ctgggctga 1329
<210> 50
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 8C6-IgG4 (F234A/L235A)嵌合抗体重链全长序列
<400> 50
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Val Thr Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
<210> 51
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> 8C6嵌合抗体轻链全长序列
<400> 51
agtattgtga tgacccagac tcccaaattc ctacttgtat cagcaggaga cagggttacc 60
ataacctgca aggccagtca gagtgtgagt aatgatgtag gttggtacca acagaagcca 120
gggcagtctc ctaaactact gatatactat gcatccaatc gctactctgg agtccctgat 180
cgcttcactg gcagtggata tgggacggat ttcactttca ccatcagcac tgtgcaggct 240
gaagacctgg cagtttattt ctgtcaacaa gattatacct ctccgtacac gttcggaggg 300
gggaccaagc tggaaataaa acgtacggtg gccgcaccaa gcgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagctttaac agaggcgagt gctga 645
<210> 52
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 8C6嵌合抗体轻链全长序列
<400> 52
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 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> 53
<211> 1329
<212> DNA
<213> 人工序列
<220>
<223> 8H4-IgG4 (F234A/L235A)嵌合抗体重链全长序列
<400> 53
gaagtgaaac tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cactttcagg agctatggca tgtcttgggc tcgccagatt 120
ccagagaaga ggctggagtg ggtcgcatcc attagtagtg gtggaaccac ctactatcta 180
gggagtgtgc agggccgatt cacaatctcc agagataatg ccaggaacat cctgtacctg 240
caaatgagca gtctgaggtc tgaggacacg gccatgtatt attgtgcaag aggctatgat 300
gcgggatttg cttactgggg ccaagggact ctggtcagtg tctcgagcgc ctccaccaag 360
ggacccagcg tgtttcccct ggccccctgt tccagatcca cctccgaaag cacagccgct 420
ctcggctgcc tggtcaagga ttacttccct gagcccgtga cagtctcctg gaatagcggc 480
gctctgacct ccggcgtgca taccttccct gctgtgctgc aatcctccgg actgtacagc 540
ctgagcagcg tggtcaccgt gccttcctcc agcctgggaa ccaaaaccta cacatgcaac 600
gtggaccaca agcccagcaa caccaaagtg gacaagaggg tggagtccaa gtacggaccc 660
ccttgtcctc cctgccctgc tcctgaagcc gctggaggac ctagcgtgtt cctgtttccc 720
cccaagccca aggacaccct catgatctcc aggacccccg aggtgacctg tgtcgtggtg 780
gacgtgagcc aagaggaccc cgaggtgcag ttcaactggt acgtggatgg cgtcgaggtc 840
cataacgcca agaccaagcc tagggaggag cagttcaaca gcacctacag agtggtgagc 900
gtcctgaccg tgctccacca agactggctg aacggcaagg aatacaagtg caaggtctcc 960
aacaagggac tcccttcctc catcgagaag accatcagca aggccaaggg ccagcccaga 1020
gaaccccaag tctacacact gccccccagc caagaggaaa tgaccaagaa ccaggtgagc 1080
ctgacctgcc tggtgaaagg cttctacccc agcgacattg ctgtcgaatg ggagagcaac 1140
ggccaacccg agaacaacta caagaccacc ccccctgtgc tcgacagcga cggctccttc 1200
ttcctctaca gcaggctgac agtggacaag tccaggtggc aagagggcaa tgtcttcagc 1260
tgtagcgtca tgcacgaggc cctccacaac cactacaccc agaagagcct gtccctctcc 1320
ctgggctga 1329
<210> 54
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 8H4-IgG4 (F234A/L235A)嵌合抗体重链全长序列
<400> 54
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Ala Arg Gln Ile Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Leu Gly Ser Val Gln
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Gly Tyr Asp Ala Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Ser Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
<210> 55
<211> 657
<212> DNA
<213> 人工序列
<220>
<223> 8H4嵌合抗体轻链全长序列
<400> 55
gacattgtgc tgacacagtc tcctgcttcc ttagctgtat ctctggggca gagggccacc 60
atctcatgca gggccagcca aagtgtcagt acatctagct atagttatat gcactggtac 120
caacagaaac caggacagcc tcccaaactc ctcatcaagt atgcatccaa cctagaatct 180
ggggtccctg ccaggttcag tggcagtggg tctgggacag acttcaccct caacatccat 240
cctgtggagg aggaggatac tgcaacatat tactgtcaga acagttggga gattccgtac 300
acgttcggag gggggaccaa gctggaaata aaacgtacgg tggccgcacc aagcgtcttc 360
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600
acccatcagg gcctgagctc gcccgtcaca aagagcttta acagaggcga gtgctga 657
<210> 56
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> 8H4嵌合抗体轻链全长序列
<400> 56
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln Asn Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 57
<211> 1341
<212> DNA
<213> 人工序列
<220>
<223> 5G11-IgG1 (D265A)嵌合抗体重链全长序列
<400> 57
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact acctatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggaatg gctgggagtg atatggcgtg gtgtaaccac agactataat 180
gcagctttca tgtccagact gaccatcacc aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaagc taatgacaca gccatatatt actgtgccag actgggtttc 300
tatgctatgg actactgggg tcaaggaacc tcagtcaccg tctcgagcgc ctccactaag 360
ggcccatccg tgttccctct ggcaccctcc agcaagagca caagcggagg caccgccgca 420
ctgggctgcc tcgtgaagga ctacttccca gaacccgtga ccgtcagctg gaatagcggc 480
gctctgacca gcggagtcca cactttcccc gcagtgctgc agtccagcgg cctgtacagc 540
ctgagcagcg tggtcactgt gccaagcagc agcctgggca ctcagaccta catctgcaac 600
gtcaaccaca agcccagcaa cacaaaggtg gacaagaagg tcgagcccaa gtcctgcgat 660
aagacccaca cctgccctcc atgtcccgcc cccgagctgc tgggaggacc cagcgtcttc 720
ctgtttcccc ccaagccaaa ggacaccctg atgatcagca ggacccccga agtgacctgc 780
gtcgtggtgg ccgtgagcca cgaagatccc gaggtgaagt tcaactggta cgtggacggc 840
gtggaagtgc acaacgccaa gacaaaaccc agggaggagc agtatgccag cacctacagg 900
gtcgtgagcg tcctgaccgt gctgcaccaa gactggctga acggcaagga gtataagtgc 960
aaggtgagca acaaggcact gcccgccccc atcgagaaga ccatttccaa ggccaagggg 1020
caacctaggg agccacaggt ctacactctg ccccctagca gggacgagct gaccaagaac 1080
caggtctccc tgacttgcct ggtgaagggg ttttatccca gcgacatcgc cgtcgagtgg 1140
gagagcaatg gccagcccga aaacaactac aagaccacac cccctgtgct ggacagcgac 1200
ggcagcttct ttctgtatag caaactgaca gtggataaga gcagatggca gcagggcaac 1260
gtgttctcct gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagtccctg 1320
agcctgtccc ccggaaaatg a 1341
<210> 58
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 5G11-IgG1 (D265A)嵌合抗体重链全长序列
<400> 58
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 Ala Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Ala 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln 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 Pro Gly Lys
435 440 445
<210> 59
<211> 1329
<212> DNA
<213> 人工序列
<220>
<223> 5G11-IgG4 (F234A/L235A)嵌合抗体重链全长序列
<400> 59
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact acctatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggaatg gctgggagtg atatggcgtg gtgtaaccac agactataat 180
gcagctttca tgtccagact gaccatcacc aaggacaatt ccaagagcca agttttcttt 240
aaaatgaaca gtctgcaagc taatgacaca gccatatatt actgtgccag actgggtttc 300
tatgctatgg actactgggg tcaaggaacc tcagtcaccg tctcgagcgc ctccaccaag 360
ggacccagcg tgtttcccct ggccccctgt tccagatcca cctccgaaag cacagccgct 420
ctcggctgcc tggtcaagga ttacttccct gagcccgtga cagtctcctg gaatagcggc 480
gctctgacct ccggcgtgca taccttccct gctgtgctgc aatcctccgg actgtacagc 540
ctgagcagcg tggtcaccgt gccttcctcc agcctgggaa ccaaaaccta cacatgcaac 600
gtggaccaca agcccagcaa caccaaagtg gacaagaggg tggagtccaa gtacggaccc 660
ccttgtcctc cctgccctgc tcctgaagcc gctggaggac ctagcgtgtt cctgtttccc 720
cccaagccca aggacaccct catgatctcc aggacccccg aggtgacctg tgtcgtggtg 780
gacgtgagcc aagaggaccc cgaggtgcag ttcaactggt acgtggatgg cgtcgaggtc 840
cataacgcca agaccaagcc tagggaggag cagttcaaca gcacctacag agtggtgagc 900
gtcctgaccg tgctccacca agactggctg aacggcaagg aatacaagtg caaggtctcc 960
aacaagggac tcccttcctc catcgagaag accatcagca aggccaaggg ccagcccaga 1020
gaaccccaag tctacacact gccccccagc caagaggaaa tgaccaagaa ccaggtgagc 1080
ctgacctgcc tggtgaaagg cttctacccc agcgacattg ctgtcgaatg ggagagcaac 1140
ggccaacccg agaacaacta caagaccacc ccccctgtgc tcgacagcga cggctccttc 1200
ttcctctaca gcaggctgac agtggacaag tccaggtggc aagagggcaa tgtcttcagc 1260
tgtagcgtca tgcacgaggc cctccacaac cactacaccc agaagagcct gtccctctcc 1320
ctgggctga 1329
<210> 60
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 5G11-IgG4 (F234A/L235A)嵌合抗体重链全长序列
<400> 60
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
<210> 61
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> 5G11嵌合抗体轻链全长序列
<400> 61
agtattgtga tgacccagac tcccaaattc ctgcttgtat cagcaggaga cagggttacc 60
ataacctgca aggccagtca gagtgtgagt aatgatgtag cttggtacca gcagaagcca 120
gggcagtctc ctaaactgct gatatattat gcagccaatc gctacactgg agtccctgat 180
cgcttcactg gcagtggata tgggacggat ttcactttca ccatcagcat tgtgcaggct 240
gaagacctgg cagtttattt ctgtcagcag gattatacct ctccgtacac gttcggaggg 300
gggaccaagc tggaaataaa acgtacggtg gccgcaccaa gcgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagctttaac agaggcgagt gctga 645
<210> 62
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 5G11嵌合抗体轻链全长序列
<400> 62
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ile Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 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> 63
<211> 1341
<212> DNA
<213> 人工序列
<220>
<223> 13C5-IgG1 (D265A) 嵌合抗体重链全长序列
<400> 63
gaagtgaagc tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cattttcaga agctatggca tgtcttgggt tcgccagact 120
ccagagaaga ggctggagtg ggtcgcatcc attagtagtg gtggtagcac ctactatcca 180
gacagtgtga agggccgatt caccatctcc agagataatg ccaggaacat cttgtacctg 240
caaatgagca gtctgaggtc tgaggacacg gccatgtatg actgtgcaag aggctatgat 300
tcggggtttg cttattgggg ccaagggact ctggtcactg tctcgagcgc ctccactaag 360
ggcccatccg tgttccctct ggcaccctcc agcaagagca caagcggagg caccgccgca 420
ctgggctgcc tcgtgaagga ctacttccca gaacccgtga ccgtcagctg gaatagcggc 480
gctctgacca gcggagtcca cactttcccc gcagtgctgc agtccagcgg cctgtacagc 540
ctgagcagcg tggtcactgt gccaagcagc agcctgggca ctcagaccta catctgcaac 600
gtcaaccaca agcccagcaa cacaaaggtg gacaagaagg tcgagcccaa gtcctgcgat 660
aagacccaca cctgccctcc atgtcccgcc cccgagctgc tgggaggacc cagcgtcttc 720
ctgtttcccc ccaagccaaa ggacaccctg atgatcagca ggacccccga agtgacctgc 780
gtcgtggtgg ccgtgagcca cgaagatccc gaggtgaagt tcaactggta cgtggacggc 840
gtggaagtgc acaacgccaa gacaaaaccc agggaggagc agtatgccag cacctacagg 900
gtcgtgagcg tcctgaccgt gctgcaccaa gactggctga acggcaagga gtataagtgc 960
aaggtgagca acaaggcact gcccgccccc atcgagaaga ccatttccaa ggccaagggg 1020
caacctaggg agccacaggt ctacactctg ccccctagca gggacgagct gaccaagaac 1080
caggtctccc tgacttgcct ggtgaagggg ttttatccca gcgacatcgc cgtcgagtgg 1140
gagagcaatg gccagcccga aaacaactac aagaccacac cccctgtgct ggacagcgac 1200
ggcagcttct ttctgtatag caaactgaca gtggataaga gcagatggca gcagggcaac 1260
gtgttctcct gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagtccctg 1320
agcctgtccc ccggaaaatg a 1341
<210> 64
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 13C5-IgG1 (D265A) 嵌合抗体重链全长序列
<400> 64
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 Ala Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Ala 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln 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 Pro Gly Lys
435 440 445
<210> 65
<211> 1329
<212> DNA
<213> 人工序列
<220>
<223> 13C5-IgG4 (F234A/L235A)嵌合抗体重链全长序列
<400> 65
gaagtgaagc tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cattttcaga agctatggca tgtcttgggt tcgccagact 120
ccagagaaga ggctggagtg ggtcgcatcc attagtagtg gtggtagcac ctactatcca 180
gacagtgtga agggccgatt caccatctcc agagataatg ccaggaacat cttgtacctg 240
caaatgagca gtctgaggtc tgaggacacg gccatgtatg actgtgcaag aggctatgat 300
tcggggtttg cttattgggg ccaagggact ctggtcactg tctcgagcgc ctccaccaag 360
ggacccagcg tgtttcccct ggccccctgt tccagatcca cctccgaaag cacagccgct 420
ctcggctgcc tggtcaagga ttacttccct gagcccgtga cagtctcctg gaatagcggc 480
gctctgacct ccggcgtgca taccttccct gctgtgctgc aatcctccgg actgtacagc 540
ctgagcagcg tggtcaccgt gccttcctcc agcctgggaa ccaaaaccta cacatgcaac 600
gtggaccaca agcccagcaa caccaaagtg gacaagaggg tggagtccaa gtacggaccc 660
ccttgtcctc cctgccctgc tcctgaagcc gctggaggac ctagcgtgtt cctgtttccc 720
cccaagccca aggacaccct catgatctcc aggacccccg aggtgacctg tgtcgtggtg 780
gacgtgagcc aagaggaccc cgaggtgcag ttcaactggt acgtggatgg cgtcgaggtc 840
cataacgcca agaccaagcc tagggaggag cagttcaaca gcacctacag agtggtgagc 900
gtcctgaccg tgctccacca agactggctg aacggcaagg aatacaagtg caaggtctcc 960
aacaagggac tcccttcctc catcgagaag accatcagca aggccaaggg ccagcccaga 1020
gaaccccaag tctacacact gccccccagc caagaggaaa tgaccaagaa ccaggtgagc 1080
ctgacctgcc tggtgaaagg cttctacccc agcgacattg ctgtcgaatg ggagagcaac 1140
ggccaacccg agaacaacta caagaccacc ccccctgtgc tcgacagcga cggctccttc 1200
ttcctctaca gcaggctgac agtggacaag tccaggtggc aagagggcaa tgtcttcagc 1260
tgtagcgtca tgcacgaggc cctccacaac cactacaccc agaagagcct gtccctctcc 1320
ctgggctga 1329
<210> 66
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 13C5-IgG4 (F234A/L235A)嵌合抗体重链全长序列
<400> 66
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
<210> 67
<211> 663
<212> DNA
<213> 人工序列
<220>
<223> 13C5嵌合抗体轻链全长序列
<400> 67
gacattgtgc tgacacagtc tcctgcttcc ttagctgttt ctctggggca gagggccacc 60
atctcatgca gggccagcca aagtgtcagt acttctagct ctagttttat gcactggtac 120
caacagaaac caggacagcc acccaaactc ctcatcaagt atgcatccaa cctagaatct 180
ggggtccctg ccaggttcag tggcagtggg tctgggacag acttcaccct caacatccat 240
cctgtggagg aggaggatac tgcaacatat tactgtcagc acagttggga gattccgtac 300
acgttcggag gggggaccaa gctggaaata aaacgtacgc gtacggtggc cgcaccaagc 360
gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420
ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480
caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540
ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600
gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gctttaacag aggcgagtgc 660
tga 663
<210> 68
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 13C5嵌合抗体轻链全长序列
<400> 68
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 69
<211> 1341
<212> DNA
<213> 人工序列
<220>
<223> 人源化5G11-IgG1 (D265A)抗体重链全长序列
<400> 69
cagatcacac tgaaagaaag cggccctacc ctggtcaagc caactcagac cctgacactg 60
acttgcaccg tgtctgggtt ctctctgagt acatacggag tccactggat caggcagccc 120
cctggcaaag ctctggagtg gctgggagtg atttggcggg gcgtcaccac agactataac 180
gccgctttta tgtcaagact gacaatcact aaggataaca gcaaaaatca ggtggtcctg 240
accatgaaca atatggaccc cgtggatacc gcaacatact attgtgcccg gctggggttc 300
tacgccatgg actattgggg ccaggggact ctggtgaccg tctcgagcgc ctccactaag 360
ggcccatccg tgttccctct ggcaccctcc agcaagagca caagcggagg caccgccgca 420
ctgggctgcc tcgtgaagga ctacttccca gaacccgtga ccgtcagctg gaatagcggc 480
gctctgacca gcggagtcca cactttcccc gcagtgctgc agtccagcgg cctgtacagc 540
ctgagcagcg tggtcactgt gccaagcagc agcctgggca ctcagaccta catctgcaac 600
gtcaaccaca agcccagcaa cacaaaggtg gacaagaagg tcgagcccaa gtcctgcgat 660
aagacccaca cctgccctcc atgtcccgcc cccgagctgc tgggaggacc cagcgtcttc 720
ctgtttcccc ccaagccaaa ggacaccctg atgatcagca ggacccccga agtgacctgc 780
gtcgtggtgg ccgtgagcca cgaagatccc gaggtgaagt tcaactggta cgtggacggc 840
gtggaagtgc acaacgccaa gacaaaaccc agggaggagc agtataacag cacctacagg 900
gtcgtgagcg tcctgaccgt gctgcaccaa gactggctga acggcaagga gtataagtgc 960
aaggtgagca acaaggcact gcccgccccc atcgagaaga ccatttccaa ggccaagggg 1020
caacctaggg agccacaggt ctacactctg ccccctagca gggacgagct gaccaagaac 1080
caggtctccc tgacttgcct ggtgaagggg ttttatccca gcgacatcgc cgtcgagtgg 1140
gagagcaatg gccagcccga aaacaactac aagaccacac cccctgtgct ggacagcgac 1200
ggcagcttct ttctgtatag caaactgaca gtggataaga gcagatggca gcagggcaac 1260
gtgttctcct gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagtccctg 1320
agcctgtccc ccggaaaatg a 1341
<210> 70
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 人源化5G11-IgG1 (D265A)抗体重链全长序列
<400> 70
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu
65 70 75 80
Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 Ala Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln 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 Pro Gly Lys
435 440 445
<210> 71
<211> 1329
<212> DNA
<213> 人工序列
<220>
<223> 人源化5G11-IgG4 (F234A/L235A)抗体重链全长序列
<400> 71
cagatcacac tgaaagaaag cggccctacc ctggtcaagc caactcagac cctgacactg 60
acttgcaccg tgtctgggtt ctctctgagt acatacggag tccactggat caggcagccc 120
cctggcaaag ctctggagtg gctgggagtg atttggcggg gcgtcaccac agactataac 180
gccgctttta tgtcaagact gacaatcact aaggataaca gcaaaaatca ggtggtcctg 240
accatgaaca atatggaccc cgtggatacc gcaacatact attgtgcccg gctggggttc 300
tacgccatgg actattgggg ccaggggact ctggtgaccg tctcgagcgc ctccaccaag 360
ggacccagcg tgtttcccct ggccccctgt tccagatcca cctccgaaag cacagccgct 420
ctcggctgcc tggtcaagga ttacttccct gagcccgtga cagtctcctg gaatagcggc 480
gctctgacct ccggcgtgca taccttccct gctgtgctgc aatcctccgg actgtacagc 540
ctgagcagcg tggtcaccgt gccttcctcc agcctgggaa ccaaaaccta cacatgcaac 600
gtggaccaca agcccagcaa caccaaagtg gacaagaggg tggagtccaa gtacggaccc 660
ccttgtcctc cctgccctgc tcctgaagcc gctggaggac ctagcgtgtt cctgtttccc 720
cccaagccca aggacaccct catgatctcc aggacccccg aggtgacctg tgtcgtggtg 780
gacgtgagcc aagaggaccc cgaggtgcag ttcaactggt acgtggatgg cgtcgaggtc 840
cataacgcca agaccaagcc tagggaggag cagttcaaca gcacctacag agtggtgagc 900
gtcctgaccg tgctccacca agactggctg aacggcaagg aatacaagtg caaggtctcc 960
aacaagggac tcccttcctc catcgagaag accatcagca aggccaaggg ccagcccaga 1020
gaaccccaag tctacacact gccccccagc caagaggaaa tgaccaagaa ccaggtgagc 1080
ctgacctgcc tggtgaaagg cttctacccc agcgacattg ctgtcgaatg ggagagcaac 1140
ggccaacccg agaacaacta caagaccacc ccccctgtgc tcgacagcga cggctccttc 1200
ttcctctaca gcaggctgac agtggacaag tccaggtggc aagagggcaa tgtcttcagc 1260
tgtagcgtca tgcacgaggc cctccacaac cactacaccc agaagagcct gtccctctcc 1320
ctgggctga 1329
<210> 72
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 人源化5G11-IgG4 (F234A/L235A)抗体重链全长序列
<400> 72
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu
65 70 75 80
Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
<210> 73
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> 人源化5G11抗体轻链全长序列
<400> 73
gatatccaga tgactcagtc tccaagcagc ctgtctgcat ctgtggggga cagggtcacc 60
atcacatgca aagcatctca gagtgtgtca aacgatgtcg cctggtacca gcagaagccc 120
ggaaaagctc ctaagctgct gatttactat gccgctaatc ggtacactgg cgtgccagac 180
agattcagcg gatccggata tggaaccgat ttcactttta ccatcagctc cctgcagcca 240
gaggacattg ccacatattt ctgtcagcag gattacacaa gcccctatac ttttggccag 300
gggaccaaac tggaaatcaa gcgtacggtg gccgcaccaa gcgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagctttaac agaggcgagt gctga 645
<210> 74
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 人源化5G11抗体轻链全长序列
<400> 74
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 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> 75
<211> 1341
<212> DNA
<213> 人工序列
<220>
<223> 人源化13C5-IgG1 (D265A)抗体重链全长序列
<400> 75
gaggtgcagc tggtcgagtc aggagggggg ctggtcaagc caggagggtc actgcgactg 60
agctgcgcag cttccgggtt catctttagg tcttatggca tgagttgggt gcgccaggca 120
ccagggaaag gactggagtg ggtcgcttca atcagctccg gaggcagcac ttactatcct 180
gactccgtga agggccggtt caccatttct agagataacg ccaaaaatag tctgtacctg 240
cagatgaact ctctgcgagc agaagacaca gccgtctacg attgtgctag aggatatgac 300
agcggctttg catactgggg ccaggggacc ctggtgacag tctcgagcgc ctccactaag 360
ggcccatccg tgttccctct ggcaccctcc agcaagagca caagcggagg caccgccgca 420
ctgggctgcc tcgtgaagga ctacttccca gaacccgtga ccgtcagctg gaatagcggc 480
gctctgacca gcggagtcca cactttcccc gcagtgctgc agtccagcgg cctgtacagc 540
ctgagcagcg tggtcactgt gccaagcagc agcctgggca ctcagaccta catctgcaac 600
gtcaaccaca agcccagcaa cacaaaggtg gacaagaagg tcgagcccaa gtcctgcgat 660
aagacccaca cctgccctcc atgtcccgcc cccgagctgc tgggaggacc cagcgtcttc 720
ctgtttcccc ccaagccaaa ggacaccctg atgatcagca ggacccccga agtgacctgc 780
gtcgtggtgg ccgtgagcca cgaagatccc gaggtgaagt tcaactggta cgtggacggc 840
gtggaagtgc acaacgccaa gacaaaaccc agggaggagc agtataacag cacctacagg 900
gtcgtgagcg tcctgaccgt gctgcaccaa gactggctga acggcaagga gtataagtgc 960
aaggtgagca acaaggcact gcccgccccc atcgagaaga ccatttccaa ggccaagggg 1020
caacctaggg agccacaggt ctacactctg ccccctagca gggacgagct gaccaagaac 1080
caggtctccc tgacttgcct ggtgaagggg ttttatccca gcgacatcgc cgtcgagtgg 1140
gagagcaatg gccagcccga aaacaactac aagaccacac cccctgtgct ggacagcgac 1200
ggcagcttct ttctgtatag caaactgaca gtggataaga gcagatggca gcagggcaac 1260
gtgttctcct gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagtccctg 1320
agcctgtccc ccggaaaatg a 1341
<210> 76
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 人源化13C5-IgG1 (D265A)抗体重链全长序列
<400> 76
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu 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 Ala Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln 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 Pro Gly Lys
435 440 445
<210> 77
<211> 1329
<212> DNA
<213> 人工序列
<220>
<223> 人源化13C5-IgG4 (F234A/L235A)抗体重链全长序列
<400> 77
gaggtgcagc tggtcgagtc aggagggggg ctggtcaagc caggagggtc actgcgactg 60
agctgcgcag cttccgggtt catctttagg tcttatggca tgagttgggt gcgccaggca 120
ccagggaaag gactggagtg ggtcgcttca atcagctccg gaggcagcac ttactatcct 180
gactccgtga agggccggtt caccatttct agagataacg ccaaaaatag tctgtacctg 240
cagatgaact ctctgcgagc agaagacaca gccgtctacg attgtgctag aggatatgac 300
agcggctttg catactgggg ccaggggacc ctggtgacag tctcgagcgc ctccaccaag 360
ggacccagcg tgtttcccct ggccccctgt tccagatcca cctccgaaag cacagccgct 420
ctcggctgcc tggtcaagga ttacttccct gagcccgtga cagtctcctg gaatagcggc 480
gctctgacct ccggcgtgca taccttccct gctgtgctgc aatcctccgg actgtacagc 540
ctgagcagcg tggtcaccgt gccttcctcc agcctgggaa ccaaaaccta cacatgcaac 600
gtggaccaca agcccagcaa caccaaagtg gacaagaggg tggagtccaa gtacggaccc 660
ccttgtcctc cctgccctgc tcctgaagcc gctggaggac ctagcgtgtt cctgtttccc 720
cccaagccca aggacaccct catgatctcc aggacccccg aggtgacctg tgtcgtggtg 780
gacgtgagcc aagaggaccc cgaggtgcag ttcaactggt acgtggatgg cgtcgaggtc 840
cataacgcca agaccaagcc tagggaggag cagttcaaca gcacctacag agtggtgagc 900
gtcctgaccg tgctccacca agactggctg aacggcaagg aatacaagtg caaggtctcc 960
aacaagggac tcccttcctc catcgagaag accatcagca aggccaaggg ccagcccaga 1020
gaaccccaag tctacacact gccccccagc caagaggaaa tgaccaagaa ccaggtgagc 1080
ctgacctgcc tggtgaaagg cttctacccc agcgacattg ctgtcgaatg ggagagcaac 1140
ggccaacccg agaacaacta caagaccacc ccccctgtgc tcgacagcga cggctccttc 1200
ttcctctaca gcaggctgac agtggacaag tccaggtggc aagagggcaa tgtcttcagc 1260
tgtagcgtca tgcacgaggc cctccacaac cactacaccc agaagagcct gtccctctcc 1320
ctgggctga 1329
<210> 78
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 人源化13C5-IgG4 (F234A/L235A)抗体重链全长序列
<400> 78
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
<210> 79
<211> 657
<212> DNA
<213> 人工序列
<220>
<223> 人源化13C5抗体轻链全长序列
<400> 79
gacattgtgc tgactcagag ccccgcttca ctggcagtgt ctccagggca gcgggcaacc 60
atcacatgca gagcctcaca gagcgtctcc accagctcct ctagtttcat gcactggtac 120
cagcagaagc ccggacagcc ccctaagctg ctgatcaaat atgctagcaa cctggagtcc 180
ggcgtgccag ccaggttctc tggcagtggg tcaggaaccg actttactct gaccattaat 240
cccgtcgaag ccaacgatac agctaattac tattgtcagc attcctggga gatcccttac 300
acatttggcc aggggactaa gctggagatc aagcgtacgg tggccgcacc aagcgtcttc 360
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600
acccatcagg gcctgagctc gcccgtcaca aagagcttta acagaggcga gtgctga 657
<210> 80
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> 人源化13C5抗体轻链全长序列
<400> 80
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 81
<211> 5
<212> PRT
<213> 小鼠属种
<400> 81
Ser Tyr Gly Met Ser
1 5
<210> 82
<211> 16
<212> PRT
<213> 小鼠属种
<400> 82
Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys Gly
1 5 10 15
<210> 83
<211> 8
<212> PRT
<213> 小鼠属种
<400> 83
Gly Tyr Asp Ser Gly Phe Ala Tyr
1 5
<210> 84
<211> 15
<212> PRT
<213> 小鼠属种
<400> 84
Arg Ala Ser Gln Ser Val Ser Thr Ser Ser Ser Ser Phe Met His
1 5 10 15
<210> 85
<211> 7
<212> PRT
<213> 小鼠属种
<400> 85
Tyr Ala Ser Asn Leu Glu Ser
1 5
<210> 86
<211> 9
<212> PRT
<213> 小鼠属种
<400> 86
Gln His Ser Trp Glu Ile Pro Tyr Thr
1 5
<210> 87
<211> 5
<212> PRT
<213> 小鼠属种
<400> 87
Ser Tyr Gly Met Ser
1 5
<210> 88
<211> 16
<212> PRT
<213> 小鼠属种
<400> 88
Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys Gly
1 5 10 15
<210> 89
<211> 8
<212> PRT
<213> 小鼠属种
<400> 89
Gly Tyr Asp Ser Gly Phe Ala Tyr
1 5
<210> 90
<211> 15
<212> PRT
<213> 小鼠属种
<400> 90
Arg Ala Ser Gln Ser Val Ser Thr Ser Ser Ser Ser Tyr Met His
1 5 10 15
<210> 91
<211> 7
<212> PRT
<213> 小鼠属种
<400> 91
Tyr Ala Ser Asn Leu Glu Ser
1 5
<210> 92
<211> 9
<212> PRT
<213> 小鼠属种
<400> 92
Gln His Ser Trp Glu Ile Pro Tyr Thr
1 5
<210> 93
<211> 5
<212> PRT
<213> 小鼠属种
<400> 93
Thr Tyr Gly Val His
1 5
<210> 94
<211> 16
<212> PRT
<213> 小鼠属种
<400> 94
Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met Ser
1 5 10 15
<210> 95
<211> 8
<212> PRT
<213> 小鼠属种
<400> 95
Leu Gly Phe Tyr Ala Met Asp Tyr
1 5
<210> 96
<211> 11
<212> PRT
<213> 小鼠属种
<400> 96
Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 97
<211> 7
<212> PRT
<213> 小鼠属种
<400> 97
Tyr Ala Ala Asn Arg Tyr Thr
1 5
<210> 98
<211> 9
<212> PRT
<213> 小鼠属种
<400> 98
Gln Gln Asp Tyr Thr Ser Pro Tyr Thr
1 5
<210> 99
<211> 5
<212> PRT
<213> 小鼠属种
<400> 99
Ser Tyr Gly Val His
1 5
<210> 100
<211> 16
<212> PRT
<213> 小鼠属种
<400> 100
Val Ile Trp Ser Gly Gly Val Thr Asp Tyr Asn Ala Ala Phe Ile Ser
1 5 10 15
<210> 101
<211> 8
<212> PRT
<213> 小鼠属种
<400> 101
Leu Gly Phe Tyr Ala Met Asp Tyr
1 5
<210> 102
<211> 11
<212> PRT
<213> 小鼠属种
<400> 102
Lys Ala Ser Gln Ser Val Ser Asn Asp Val Gly
1 5 10
<210> 103
<211> 7
<212> PRT
<213> 小鼠属种
<400> 103
Tyr Ala Ser Asn Arg Tyr Ser
1 5
<210> 104
<211> 9
<212> PRT
<213> 小鼠属种
<400> 104
Gln Gln Asp Tyr Thr Ser Pro Tyr Thr
1 5
<210> 105
<211> 5
<212> PRT
<213> 小鼠属种
<400> 105
Thr Tyr Trp Met His
1 5
<210> 106
<211> 17
<212> PRT
<213> 小鼠属种
<400> 106
Gln Ile Asn Pro Asp Ser Thr Thr Ile Asn Tyr Ala Pro Ser Leu Lys
1 5 10 15
Asp
<210> 107
<211> 10
<212> PRT
<213> 小鼠属种
<400> 107
Pro Gly Asp Tyr Gly Tyr Asp Phe Asp Cys
1 5 10
<210> 108
<211> 16
<212> PRT
<213> 小鼠属种
<400> 108
Arg Ser Ser Gln Ile Ile Val His Ser Asn Ala Asn Thr Tyr Leu Glu
1 5 10 15
<210> 109
<211> 7
<212> PRT
<213> 小鼠属种
<400> 109
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 110
<211> 9
<212> PRT
<213> 小鼠属种
<400> 110
Phe Gln Gly Ser His Val Pro Tyr Thr
1 5
<210> 111
<211> 5
<212> PRT
<213> 小鼠属种
<400> 111
Ser Gly Tyr Trp Asn
1 5
<210> 112
<211> 16
<212> PRT
<213> 小鼠属种
<400> 112
Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 113
<211> 11
<212> PRT
<213> 小鼠属种
<400> 113
Ser Leu Leu Trp Phe Ser Thr Gly Phe Ala Tyr
1 5 10
<210> 114
<211> 12
<212> PRT
<213> 小鼠属种
<400> 114
Ser Ala Ser Ser Ser Val Ser Ser Ser Tyr Leu Tyr
1 5 10
<210> 115
<211> 7
<212> PRT
<213> 小鼠属种
<400> 115
Asn Thr Ser Asn Leu Ala Ser
1 5
<210> 116
<211> 9
<212> PRT
<213> 小鼠属种
<400> 116
His Gln Trp Arg Ser Tyr Pro Pro Thr
1 5
<210> 117
<211> 5
<212> PRT
<213> 小鼠属种
<400> 117
Ser Tyr Gly Val His
1 5
<210> 118
<211> 16
<212> PRT
<213> 小鼠属种
<400> 118
Val Ile Trp Ser Gly Gly Ile Thr Asp Tyr Asn Ala Ala Phe Lys Ser
1 5 10 15
<210> 119
<211> 8
<212> PRT
<213> 小鼠属种
<400> 119
Leu Gly Phe Tyr Ala Met Asp Tyr
1 5
<210> 120
<211> 10
<212> PRT
<213> 小鼠属种
<400> 120
Ser Ala Asn Ser Ser Val Ser Tyr Met His
1 5 10
<210> 121
<211> 7
<212> PRT
<213> 小鼠属种
<400> 121
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 122
<211> 9
<212> PRT
<213> 小鼠属种
<400> 122
Gln Gln Trp Ser Ser Asn Pro Trp Thr
1 5
<210> 123
<211> 5
<212> PRT
<213> 小鼠属种
<400> 123
Ser Tyr Gly Met Ser
1 5
<210> 124
<211> 16
<212> PRT
<213> 小鼠属种
<400> 124
Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Leu Gly Ser Val Gln Gly
1 5 10 15
<210> 125
<211> 8
<212> PRT
<213> 小鼠属种
<400> 125
Gly Tyr Asp Ala Gly Phe Ala Tyr
1 5
<210> 126
<211> 15
<212> PRT
<213> 小鼠属种
<400> 126
Arg Ala Ser Gln Ser Val Ser Thr Ser Ser Tyr Ser Tyr Met His
1 5 10 15
<210> 127
<211> 7
<212> PRT
<213> 小鼠属种
<400> 127
Tyr Ala Ser Asn Leu Glu Ser
1 5
<210> 128
<211> 9
<212> PRT
<213> 小鼠属种
<400> 128
Gln Asn Ser Trp Glu Ile Pro Tyr Thr
1 5
<210> 129
<211> 5
<212> PRT
<213> 小鼠属种
<400> 129
Ser Gly Tyr Trp Thr
1 5
<210> 130
<211> 16
<212> PRT
<213> 小鼠属种
<400> 130
Tyr Ile Ser Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 131
<211> 9
<212> PRT
<213> 小鼠属种
<400> 131
Gln Arg Asp Trp Leu Gly Phe Ala Tyr
1 5
<210> 132
<211> 17
<212> PRT
<213> 小鼠属种
<400> 132
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Ser Leu
1 5 10 15
Ala
<210> 133
<211> 7
<212> PRT
<213> 小鼠属种
<400> 133
Trp Ala Ser Asn Arg Glu Ser
1 5
<210> 134
<211> 9
<212> PRT
<213> 小鼠属种
<400> 134
Gln Gln Tyr Tyr Ser Tyr Pro Leu Thr
1 5
<210> 135
<211> 5
<212> PRT
<213> 小鼠属种
<400> 135
Ser Tyr Gly Met Ser
1 5
<210> 136
<211> 16
<212> PRT
<213> 小鼠属种
<400> 136
Ser Ile Ser Ser Gly Gly Ser Ile Tyr Tyr Pro Asp Ser Val Lys Gly
1 5 10 15
<210> 137
<211> 8
<212> PRT
<213> 小鼠属种
<400> 137
Gly Tyr Asp Ala Gly Phe Ala Phe
1 5
<210> 138
<211> 15
<212> PRT
<213> 小鼠属种
<400> 138
Arg Ala Ser Gln Ser Val Ser Thr Ser Ser Tyr Ser Tyr Val His
1 5 10 15
<210> 139
<211> 7
<212> PRT
<213> 小鼠属种
<400> 139
Tyr Ala Ser Asn Leu Glu Ser
1 5
<210> 140
<211> 9
<212> PRT
<213> 小鼠属种
<400> 140
Gln His Ser Trp Glu Ile Pro Tyr Thr
1 5
<210> 141
<211> 660
<212> DNA
<213> 智人
<400> 141
tttactgtca cggttcccaa ggacctatat gtggtagagt atggtagcaa tatgacaatt 60
gaatgcaaat tcccagtaga aaaacaatta gacctggctg cactaattgt ctattgggaa 120
atggaggata agaacattat tcaatttgtg catggagagg aagacctgaa ggttcagcat 180
agtagctaca gacagagggc ccggctgttg aaggaccagc tctccctggg aaatgctgca 240
cttcagatca cagatgtgaa attgcaggat gcaggggtgt accgctgcat gatcagctat 300
ggtggtgccg actacaagcg aattactgtg aaagtcaatg ccccatacaa caaaatcaac 360
caaagaattt tggttgtgga tccagtcacc tctgaacatg aactgacatg tcaggctgag 420
ggctacccca aggccgaagt catctggaca agcagtgacc atcaagtcct gagtggtaag 480
accaccacca ccaattccaa gagagaggag aagcttttca atgtgaccag cacactgaga 540
atcaacacaa caactaatga gattttctac tgcactttta ggagattaga tcctgaggaa 600
aaccatacag ctgaattggt catcccagaa ctacctctgg cacatcctcc aaatgaaagg 660
<210> 142
<211> 220
<212> PRT
<213> 智人
<400> 142
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 10 15
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
20 25 30
Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
35 40 45
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg
50 55 60
Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65 70 75 80
Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
85 90 95
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg
210 215 220
<210> 143
<211> 681
<212> DNA
<213> 智人
<400> 143
tttactgtca cggttcccaa ggacctatat gtggtagagt atggtagcaa tatgacaatt 60
gaatgcaaat tcccagtaga aaaacaatta gacctggctg cactaattgt ctattgggaa 120
atggaggata agaacattat tcaatttgtg catggagagg aagacctgaa ggttcagcat 180
agtagctaca gacagagggc ccggctgttg aaggaccagc tctccctggg aaatgctgca 240
cttcagatca cagatgtgaa attgcaggat gcaggggtgt accgctgcat gatcagctat 300
ggtggtgccg actacaagcg aattactgtg aaagtcaatg ccccatacaa caaaatcaac 360
caaagaattt tggttgtgga tccagtcacc tctgaacatg aactgacatg tcaggctgag 420
ggctacccca aggccgaagt catctggaca agcagtgacc atcaagtcct gagtggtaag 480
accaccacca ccaattccaa gagagaggag aagcttttca atgtgaccag cacactgaga 540
atcaacacaa caactaatga gattttctac tgcactttta ggagattaga tcctgaggaa 600
aaccatacag ctgaattggt catcccagaa ctacctctgg cacatcctcc aaatgaaagg 660
catcatcacc accatcacta a 681
<210> 144
<211> 226
<212> PRT
<213> 智人
<400> 144
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 10 15
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
20 25 30
Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
35 40 45
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg
50 55 60
Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65 70 75 80
Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
85 90 95
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg His His His His
210 215 220
His His
225
<210> 145
<211> 1344
<212> DNA
<213> 人工序列
<220>
<223> 人PD-L1-mFc序列
<400> 145
tttactgtca cggttcccaa ggacctatat gtggtagagt atggtagcaa tatgacaatt 60
gaatgcaaat tcccagtaga aaaacaatta gacctggctg cactaattgt ctattgggaa 120
atggaggata agaacattat tcaatttgtg catggagagg aagacctgaa ggttcagcat 180
agtagctaca gacagagggc ccggctgttg aaggaccagc tctccctggg aaatgctgca 240
cttcagatca cagatgtgaa attgcaggat gcaggggtgt accgctgcat gatcagctat 300
ggtggtgccg actacaagcg aattactgtg aaagtcaatg ccccatacaa caaaatcaac 360
caaagaattt tggttgtgga tccagtcacc tctgaacatg aactgacatg tcaggctgag 420
ggctacccca aggccgaagt catctggaca agcagtgacc atcaagtcct gagtggtaag 480
accaccacca ccaattccaa gagagaggag aagcttttca atgtgaccag cacactgaga 540
atcaacacaa caactaatga gattttctac tgcactttta ggagattaga tcctgaggaa 600
aaccatacag ctgaattggt catcccagaa ctacctctgg cacatcctcc aaatgaaagg 660
ggtaccagat ctagaggctg caaaccctgt atctgcacag tgcccgaggt gagctccgtg 720
ttcatctttc cccccaagcc caaggacgtg ctgaccatca cactcacacc caaggtcacc 780
tgcgtggtcg tggacatctc caaggacgac cccgaagtcc agttcagctg gttcgtggac 840
gacgtggagg tgcacaccgc tcagacccaa cccagagagg agcagtttaa ctccaccttc 900
aggtccgtgt ccgagctccc catcatgcac caggactggc tgaatggcaa ggagttcaag 960
tgcagggtga actccgctgc tttccccgcc cccattgaga agaccatctc caagaccaag 1020
ggaaggccca aggcccccca ggtgtacacc attccccctc ccaaggagca gatggccaag 1080
gacaaggtgt ccctgacctg tatgatcacc gacttctttc ccgaggacat caccgtcgaa 1140
tggcagtgga acggccagcc cgccgagaac tataagaaca cccaacccat catggacacc 1200
gacggcagct acttcgtgta tagcaagctc aacgtgcaga agagcaactg ggaagccgga 1260
aataccttca cctgctccgt cctgcacgag ggcctgcaca accaccatac cgaaaagagc 1320
ctgagccaca gccccggaaa gtaa 1344
<210> 146
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 人PD-L1-mFc序列
<400> 146
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 10 15
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
20 25 30
Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
35 40 45
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg
50 55 60
Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65 70 75 80
Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
85 90 95
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Gly Thr Arg Ser
210 215 220
Arg Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
245 250 255
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
260 265 270
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
290 295 300
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
305 310 315 320
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
340 345 350
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
355 360 365
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
370 375 380
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
385 390 395 400
Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
405 410 415
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
420 425 430
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 147
<211> 1374
<212> DNA
<213> 人工序列
<220>
<223> 人PD-L1-hFc序列
<400> 147
tttactgtca cggttcccaa ggacctatat gtggtagagt atggtagcaa tatgacaatt 60
gaatgcaaat tcccagtaga aaaacaatta gacctggctg cactaattgt ctattgggaa 120
atggaggata agaacattat tcaatttgtg catggagagg aagacctgaa ggttcagcat 180
agtagctaca gacagagggc ccggctgttg aaggaccagc tctccctggg aaatgctgca 240
cttcagatca cagatgtgaa attgcaggat gcaggggtgt accgctgcat gatcagctat 300
ggtggtgccg actacaagcg aattactgtg aaagtcaatg ccccatacaa caaaatcaac 360
caaagaattt tggttgtgga tccagtcacc tctgaacatg aactgacatg tcaggctgag 420
ggctacccca aggccgaagt catctggaca agcagtgacc atcaagtcct gagtggtaag 480
accaccacca ccaattccaa gagagaggag aagcttttca atgtgaccag cacactgaga 540
atcaacacaa caactaatga gattttctac tgcactttta ggagattaga tcctgaggaa 600
aaccatacag ctgaattggt catcccagaa ctacctctgg cacatcctcc aaatgaaagg 660
ggtaccagat ctagagagcc caaatcttct gacaaaactc acacatgccc accgtgccca 720
gcacctgaat tcgagggtgc accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 780
ctcatgatct cccggactcc tgaggtcaca tgcgtggtgg tggacgtaag ccacgaagac 840
cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 900
ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 960
caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccaacc 1020
cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 1080
ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgacctg cctggtcaaa 1140
ggcttctatc caagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1200
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 1260
accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 1320
gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa atga 1374
<210> 148
<211> 457
<212> PRT
<213> 人工序列
<220>
<223> 人PD-L1-hFc序列
<400> 148
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 10 15
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
20 25 30
Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
35 40 45
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser Tyr Arg
50 55 60
Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65 70 75 80
Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
85 90 95
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr Cys Thr
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Gly Thr Arg Ser
210 215 220
Arg Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Phe Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Thr Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 149
<211> 681
<212> DNA
<213> 人工序列
<220>
<223> Cyno-PD-L1-HisTag
<400> 149
tttactgtca cggttcccaa ggacctatat gtggtagagt atggcagcaa tatgacaatt 60
gaatgcaaat tcccagtaga aaaacaatta gacctgactt cactaattgt ctattgggaa 120
atggaggata agaacattat tcaatttgtg catggagagg aagacctgaa ggttcagcat 180
agtaactaca gacagagggc ccagctgttg aaggaccagc tctccctggg aaatgctgca 240
cttcggatca cagatgtgaa attgcaggat gcaggggttt accgctgcat gatcagctat 300
ggtggtgccg actacaagcg gattaccgtg aaagtcaatg ctccatacaa caaaatcaac 360
caaagaattt tggttgtcga tccagtcacc tctgaacatg aactaacatg tcaggctgag 420
ggctacccca aggccgaagt catttggaca agcagtgacc atcaagtcct gagtggtaag 480
accaccacca ccaattccaa gagagaggag aagcttttaa atgtgaccag cacactgaga 540
atcaacacaa cagctaatga gattttctac tgcattttta ggagattaga tcctgaggaa 600
aaccatacag ctgaattggt catcccagaa ctacctctgg cgcttcctcc aaatgaaagg 660
catcatcacc accatcacta a 681
<210> 150
<211> 226
<212> PRT
<213> 人工序列
<220>
<223> Cyno-PD-L1-HisTag
<400> 150
Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr Gly Ser
1 5 10 15
Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu Asp Leu
20 25 30
Thr Ser Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile Ile Gln
35 40 45
Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Asn Tyr Arg
50 55 60
Gln Arg Ala Gln Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn Ala Ala
65 70 75 80
Leu Arg Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr Arg Cys
85 90 95
Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val Lys Val
100 105 110
Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val Asp Pro
115 120 125
Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr Pro Lys
130 135 140
Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser Gly Lys
145 150 155 160
Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Leu Asn Val Thr
165 170 175
Ser Thr Leu Arg Ile Asn Thr Thr Ala Asn Glu Ile Phe Tyr Cys Ile
180 185 190
Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu Val Ile
195 200 205
Pro Glu Leu Pro Leu Ala Leu Pro Pro Asn Glu Arg His His His His
210 215 220
His His
225
<210> 151
<211> 450
<212> DNA
<213> 智人
<400> 151
ccaggatggt tcttagactc cccagacagg ccctggaacc cccccacctt ctccccagcc 60
ctgctcgtgg tgaccgaagg ggacaacgcc accttcacct gcagcttctc caacacatcg 120
gagagcttcg tgctaaactg gtaccgcatg agccccagca accagacgga caagctggcc 180
gccttccccg aggaccgcag ccagcccggc caggactgcc gcttccgtgt cacacaactg 240
cccaacgggc gtgacttcca catgagcgtg gtcagggccc ggcgcaatga cagcggcacc 300
tacctctgtg gggccatctc cctggccccc aaggcgcaga tcaaagagag cctgcgggca 360
gagctcaggg tgacagagag aagggcagaa gtgcccacag cccaccccag cccctcaccc 420
aggccagccg gccagttcca aaccctggtg 450
<210> 152
<211> 150
<212> PRT
<213> 智人
<400> 152
Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
1 5 10 15
Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
20 25 30
Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
35 40 45
Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
50 55 60
Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
65 70 75 80
Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
85 90 95
Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
100 105 110
Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
115 120 125
Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
130 135 140
Gln Phe Gln Thr Leu Val
145 150
<210> 153
<211> 1134
<212> DNA
<213> 人工序列
<220>
<223> 人PD-1-mFc序列
<400> 153
ccaggatggt tcttagactc cccagacagg ccctggaacc cccccacctt ctccccagcc 60
ctgctcgtgg tgaccgaagg ggacaacgcc accttcacct gcagcttctc caacacatcg 120
gagagcttcg tgctaaactg gtaccgcatg agccccagca accagacgga caagctggcc 180
gccttccccg aggaccgcag ccagcccggc caggactgcc gcttccgtgt cacacaactg 240
cccaacgggc gtgacttcca catgagcgtg gtcagggccc ggcgcaatga cagcggcacc 300
tacctctgtg gggccatctc cctggccccc aaggcgcaga tcaaagagag cctgcgggca 360
gagctcaggg tgacagagag aagggcagaa gtgcccacag cccaccccag cccctcaccc 420
aggccagccg gccagttcca aaccctggtg ggtaccagat ctagaggctg caaaccctgt 480
atctgcacag tgcccgaggt gagctccgtg ttcatctttc cccccaagcc caaggacgtg 540
ctgaccatca cactcacacc caaggtcacc tgcgtggtcg tggacatctc caaggacgac 600
cccgaagtcc agttcagctg gttcgtggac gacgtggagg tgcacaccgc tcagacccaa 660
cccagagagg agcagtttaa ctccaccttc aggtccgtgt ccgagctccc catcatgcac 720
caggactggc tgaatggcaa ggagttcaag tgcagggtga actccgctgc tttccccgcc 780
cccattgaga agaccatctc caagaccaag ggaaggccca aggcccccca ggtgtacacc 840
attccccctc ccaaggagca gatggccaag gacaaggtgt ccctgacctg tatgatcacc 900
gacttctttc ccgaggacat caccgtcgaa tggcagtgga acggccagcc cgccgagaac 960
tataagaaca cccaacccat catggacacc gacggcagct acttcgtgta tagcaagctc 1020
aacgtgcaga agagcaactg ggaagccgga aataccttca cctgctccgt cctgcacgag 1080
ggcctgcaca accaccatac cgaaaagagc ctgagccaca gccccggaaa gtaa 1134
<210> 154
<211> 377
<212> PRT
<213> 人工序列
<220>
<223> 人PD-1-mFc序列
<400> 154
Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
1 5 10 15
Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
20 25 30
Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
35 40 45
Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
50 55 60
Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
65 70 75 80
Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
85 90 95
Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
100 105 110
Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
115 120 125
Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
130 135 140
Gln Phe Gln Thr Leu Val Gly Thr Arg Ser Arg Gly Cys Lys Pro Cys
145 150 155 160
Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys
165 170 175
Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val
180 185 190
Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe
195 200 205
Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu
210 215 220
Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His
225 230 235 240
Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala
245 250 255
Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg
260 265 270
Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met
275 280 285
Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro
290 295 300
Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn
305 310 315 320
Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val
325 330 335
Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr
340 345 350
Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu
355 360 365
Lys Ser Leu Ser His Ser Pro Gly Lys
370 375
<210> 155
<211> 1164
<212> DNA
<213> 人工序列
<220>
<223> 人PD-1-hFc序列
<400> 155
ccaggatggt tcttagactc cccagacagg ccctggaacc cccccacctt ctccccagcc 60
ctgctcgtgg tgaccgaagg ggacaacgcc accttcacct gcagcttctc caacacatcg 120
gagagcttcg tgctaaactg gtaccgcatg agccccagca accagacgga caagctggcc 180
gccttccccg aggaccgcag ccagcccggc caggactgcc gcttccgtgt cacacaactg 240
cccaacgggc gtgacttcca catgagcgtg gtcagggccc ggcgcaatga cagcggcacc 300
tacctctgtg gggccatctc cctggccccc aaggcgcaga tcaaagagag cctgcgggca 360
gagctcaggg tgacagagag aagggcagaa gtgcccacag cccaccccag cccctcaccc 420
aggccagccg gccagttcca aaccctggtg ggtaccagat ctagagagcc caaatcttct 480
gacaaaactc acacatgccc accgtgccca gcacctgaat tcgagggtgc accgtcagtc 540
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggactcc tgaggtcaca 600
tgcgtggtgg tggacgtaag ccacgaagac cctgaggtca agttcaactg gtacgtggac 660
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 720
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 780
tgcaaggtct ccaacaaagc cctcccaacc cccatcgaga aaaccatctc caaagccaaa 840
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 900
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc caagcgacat cgccgtggag 960
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1020
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1080
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1140
ctctccctgt ctccgggtaa atga 1164
<210> 156
<211> 222
<212> PRT
<213> 人工序列
<220>
<223> 人PD-1-hFc序列
<400> 156
Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
1 5 10 15
Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
20 25 30
Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
35 40 45
Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
50 55 60
Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
65 70 75 80
Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
85 90 95
Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
100 105 110
Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
115 120 125
Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
130 135 140
Gln Phe Gln Thr Leu Val Gly Thr Arg Ser Arg Glu Pro Lys Ser Ser
145 150 155 160
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly
165 170 175
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
180 185 190
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
195 200 205
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
210 215 220
Claims (10)
1.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含以下项:重链CDR1序列,其与选自由SEQ ID NO:81、87、99、105、111、117、123、129和135组成的组的氨基酸序列具有至少80%同源性;重链CDR2序列,其与选自由SEQ ID NO:82、88、94、100、106、112、118、124、130和136组成的组的氨基酸序列具有至少80%同源性;重链CDR3序列,其与选自由SEQ ID NO:83、89、95、101、107、113、119、125、131和137组成的组的氨基酸序列具有至少80%同源性;轻链CDR1序列,其与选自由SEQ ID NO:84、90、96、102、108、114、120、126、132和138组成的组的氨基酸序列具有至少80%同源性;轻链CDR2序列,其与选自由SEQ IDNO:85、91、97、103、109、115、121、127、133和139组成的组的氨基酸序列具有至少80%同源性;以及轻链CDR3序列,其与选自由SEQ ID NO:86、92、98、104、110、116、122、128、134和140组成的组的氨基酸序列具有至少80%同源性。
2.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含重链可变区,所述重链可变区包含与选自由SEQ ID NO:2、6、10、14、18、22、26、30、34、38、42和46组成的组的氨基酸序列具有至少80%同源性的氨基酸序列;以及轻链可变区,所述轻链可变区包含与选自由SEQ ID NO:4、8、12、16、20、24、28、32、36、40、44和48组成的组的氨基酸序列具有至少80%同源性的氨基酸序列。
3.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQ IDNO:42的重链可变区和根据SEQ ID NO:44的轻链可变区。
4.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQ IDNO:46的重链可变区和根据SEQ ID NO:48的轻链可变区。
5.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQ IDNO:70的重链和根据SEQ ID NO:74的轻链。
6.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQ IDNO:72的重链和根据SEQ ID NO:74的轻链。
7.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQ IDNO:76的重链和根据SEQ ID NO:80的轻链。
8.一种结合PD-L1的分离的抗体或其片段,其中所述抗体或其片段包含根据SEQ IDNO:78的重链和根据SEQ ID NO:80的轻链。
9.一种组合物,其包含根据权利要求1-8中任一项所述的抗体或其片段以及药学上可接受的载体。
10.根据权利要求1-8中任一项所述的抗体或其片段在制备用于增加T细胞活化的药物中的用途。
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