CN117362433A - 分离的抗原结合蛋白及其用途 - Google Patents
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Abstract
本申请涉及一种能够特异性结合LILRB4蛋白的分离的抗原结合蛋白。本申请还提供了包含所述分离的抗原结合蛋白的多肽、融合蛋白、药物分子、编码所述分离的抗原结合蛋白的核酸、包含所述分离的抗原结合蛋白的载体、包含所述核酸或所述载体的细胞、制备所述分离的抗原结合蛋白的方法以及所述分离的抗原结合蛋白的用途。
Description
技术领域
本申请涉及生物医药领域,具体的涉及一种靶向LILRB4的抗原结合蛋白及其用途。
背景技术
白细胞免疫球蛋白样受体B4(LILRB4)是白细胞Ig样受体(LILRs)的成员,在生理条件下,LILRB4通过在T细胞和浆细胞等多种免疫细胞上的表达,在免疫系统的功能中起着非常重要的作用。在病理条件下,LILRB4通过多种信号通路影响各种疾病的进程,如肿瘤和白血病的转化和浸润。LILRB4的差异表达存在于多种免疫系统疾病中,如川崎病、系统性红斑狼疮(SLE)和败血症,最近的研究表明LILRB4在精神疾病中也起作用。鉴于LILRB4在免疫系统中的重要作用及其在多种疾病中的差异表达,使其成为多种疾病潜在的治疗靶点。
基于LILRB4的治疗潜能,仍需开发多种能够特异性结合LILRB4的抗体。
发明内容
一方面,本申请提供了一种分离的抗原结合蛋白,其具有下述性质中的一种或多种:1)能够特异性识别白细胞免疫球蛋白样受体B4(LILRB4);2)能够以2×10-7M或更低的KD值与LILRB4蛋白相结合;3)能够阻断LILRB4/APOE结合的活性;4)能够刺激CD8+T细胞的活化;5)能够抑制人单核白血病细胞THP-1的迁移;6)能够抑制肿瘤细胞的生长和/或转移;7)能够阻断LILRB4与Fibronectin的结合。
在某些实施方式中,所述LILRB4为人LILRB4。
在某些实施方式中,所述分离的抗原结合蛋白包含抗体重链可变区VH中的至少一个CDR,且所述VH包含SEQ ID NO:81、SEQ ID NO:33和SEQ ID NO:22中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含HCDR3,所述HCDR3包含SEQ IDNO:83或SEQ ID NO:29所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含HCDR3,且所述HCDR3包含SEQID NO:3、SEQ ID NO:20和SEQ ID NO:29中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含HCDR2,所述HCDR2包含SEQ IDNO:2或SEQ ID NO:28所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含HCDR1,所述HCDR1包含SEQ IDNO:69所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含HCDR1,所述HCDR1包含SEQ IDNO:1或SEQ ID NO:27所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含HCDR1,HCDR2和HCDR3,所述HCDR1,HCDR2和HCDR3包含选自下组的氨基酸序列:
(1)所述HCDR1包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2包含SEQ ID NO:2所示的氨基酸序列,且所述HCDR3包含SEQ ID NO:3所示的氨基酸序列;
(2)所述HCDR1包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2包含SEQ ID NO:2所示的氨基酸序列,且所述HCDR3包含SEQ ID NO:20所示的氨基酸序列;以及
(3)所述HCDR1包含SEQ ID NO:27所示的氨基酸序列,所述HCDR2包含SEQ ID NO:28所示的氨基酸序列,且所述HCDR3包含SEQ ID NO:29所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含H-FR1,所述H-FR1的C端与所述HCDR1的N端直接或间接相连,且所述H-FR1包含SEQ ID NO:73所示的氨基酸序列。
在某些实施方式中,所述H-FR1包含SEQ ID NO:4、SEQ ID NO:17、SEQ ID NO:30和SEQ ID NO:41中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含H-FR2,所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO:74所示的氨基酸序列。
在某些实施方式中,所述H-FR2包含SEQ ID NO:5、SEQ ID NO:31、SEQ ID NO:42和SEQ ID NO:53中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含H-FR3,所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO:75所示的氨基酸序列。
在某些实施方式中,所述H-FR3包含SEQ ID NO:6、SEQ ID NO:18、SEQ ID NO:21、SEQ ID NO:32、SEQ ID NO:43、SEQ ID NO:54和SEQ ID NO:57中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含H-FR4,所述H-FR4的N端与所述HCDR3的C端直接或间接相连,且所述H-FR4包含SEQ ID NO:76所示的氨基酸序列。
在某些实施方式中,所述H-FR4包含SEQ ID NO:7或SEQ ID NO:44所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含H-FR1,H-FR2,H-FR3和H-FR4,所述H-FR1,H-FR2,H-FR3和H-FR4包含选自下组的氨基酸序列:
(1)所述H-FR1包含SEQ ID NO:4所示的氨基酸序列,所述H-FR2包含SEQ ID NO:5所示的氨基酸序列,所述H-FR3包含SEQ ID NO:6所示的氨基酸序列,且所述H-FR4包含SEQID NO:7所示的氨基酸序列;
(2)所述H-FR1包含SEQ ID NO:17所示的氨基酸序列,所述H-FR2包含SEQ ID NO:5所示的氨基酸序列,所述H-FR3包含SEQ ID NO:18所示的氨基酸序列,且所述H-FR4包含SEQID NO:7所示的氨基酸序列;
(3)所述H-FR1包含SEQ ID NO:4所示的氨基酸序列,所述H-FR2包含SEQ ID NO:5所示的氨基酸序列,所述H-FR3包含SEQ ID NO:21所示的氨基酸序列,且所述H-FR4包含SEQID NO:7所示的氨基酸序列;
(4)所述H-FR1包含SEQ ID NO:30所示的氨基酸序列,所述H-FR2包含SEQ ID NO:31所示的氨基酸序列,所述H-FR3包含SEQ ID NO:32所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:7所示的氨基酸序列;
(5)所述H-FR1包含SEQ ID NO:41所示的氨基酸序列,所述H-FR2包含SEQ ID NO:42所示的氨基酸序列,所述H-FR3包含SEQ ID NO:43所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:44所示的氨基酸序列;
(6)所述H-FR1包含SEQ ID NO:41所示的氨基酸序列,所述H-FR2包含SEQ ID NO:53所示的氨基酸序列,所述H-FR3包含SEQ ID NO:54所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:44所示的氨基酸序列;
(7)所述H-FR1包含SEQ ID NO:41所示的氨基酸序列,所述H-FR2包含SEQ ID NO:53所示的氨基酸序列,所述H-FR3包含SEQ ID NO:57所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:44所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含VH,所述VH包含SEQ ID NO:81、SEQ ID NO:33和SEQ ID NO:22中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白所述VH包含SEQ ID NO:8、SEQ IDNO:19、SEQ ID NO:22、SEQ ID NO:33、SEQ ID NO:45、SEQ ID NO:55和SEQ ID NO:58中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含抗体重链恒定区,所述抗体重链恒定区源自IgG重链恒定区。
在某些实施方式中,所述抗体重链恒定区源自人IgG重链恒定区。
在某些实施方式中,所述抗体重链恒定区源自人IgG1重链恒定区或人IgG4重链恒定区。
在某些实施方式中,所述抗体重链恒定区包含SEQ ID NO:63所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含抗体重链,且所述抗体重链包含SEQ ID NO:46、SEQ ID NO:56、SEQ ID NO:59、SEQ ID NO:86、SEQ ID NO:88、SEQ ID NO:89和SEQ ID NO:91中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含抗体轻链可变区VL中的至少一个CDR,所述VL包含SEQ ID NO:82或SEQ ID NO:40所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含LCDR3,所述LCDR3包含SEQ IDNO:72所示的氨基酸序列。
在某些实施方式中,所述LCDR3包含SEQ ID NO:11、SEQ ID NO:24和SEQ ID NO:36中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含LCDR2,所述LCDR2包含SEQ IDNO:71所示的氨基酸序列。
在某些实施方式中,所述LCDR2包含SEQ ID NO:10或SEQ ID NO:35所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含LCDR1,所述LCDR1包含SEQ IDNO:70或SEQ ID NO:34所示的氨基酸序列。
在某些实施方式中,所述LCDR1包含SEQ ID NO:9、SEQ ID NO:23和SEQ ID NO:34中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含LCDR1,LCDR2和LCDR3,所述LCDR1,LCDR2和LCDR3包含选自下组的氨基酸序列:
(1)所述LCDR1包含SEQ ID NO:9所示的氨基酸序列,所述LCDR2包含SEQ ID NO:10所示的氨基酸序列,且所述LCDR3包含SEQ ID NO:11所示的氨基酸序列;
(2)所述LCDR1包含SEQ ID NO:23所示的氨基酸序列,所述LCDR2包含SEQ ID NO:10所示的氨基酸序列,且所述LCDR3包含SEQ ID NO:24所示的氨基酸序列;以及
(3)所述LCDR1包含SEQ ID NO:34所示的氨基酸序列,所述LCDR2包含SEQ ID NO:35所示的氨基酸序列,且所述LCDR3包含SEQ ID NO:36所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含L-FR1,所述L-FR1的C端与所述LCDR1的N端直接或间接相连,且所述L-FR1包含SEQ ID NO:77所示的氨基酸序列。
在某些实施方式中,所述L-FR1包含SEQ ID NO:12、SEQ ID NO:25、SEQ ID NO:37和SEQ ID NO:47中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含L-FR2,所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO:78所示的氨基酸序列。
在某些实施方式中,所述L-FR2包含SEQ ID NO:13、SEQ ID NO:38和SEQ ID NO:48中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含L-FR3,所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO:79所示的氨基酸序列。
在某些实施方式中,所述L-FR3包含SEQ ID NO:14、SEQ ID NO:39、SEQ ID NO:49和SEQ ID NO:60中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含L-FR4,所述L-FR4的N端与所述LCDR3的C端直接或间接相连,且所述L-FR4包含SEQ ID NO:80所示的氨基酸序列。
在某些实施方式中,所述L-FR4包含SEQ ID NO:15或SEQ ID NO:50所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含L-FR1,L-FR2,L-FR3和L-FR4,所述L-FR1,L-FR2,L-FR3和L-FR4包含选自下组的氨基酸序列:
(1)所述L-FR1包含SEQ ID NO:12所示的氨基酸序列,所述L-FR2包含SEQ ID NO:13所示的氨基酸序列,所述L-FR3包含SEQ ID NO:14所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:15所示的氨基酸序列;
(2)所述L-FR1包含SEQ ID NO:25所示的氨基酸序列,所述L-FR2包含SEQ ID NO:13所示的氨基酸序列,所述L-FR3包含SEQ ID NO:14所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:15所示的氨基酸序列;
(3)所述L-FR1包含SEQ ID NO:37所示的氨基酸序列,所述L-FR2包含SEQ ID NO:38所示的氨基酸序列,所述L-FR3包含SEQ ID NO:39所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:15所示的氨基酸序列;
(4)所述L-FR1包含SEQ ID NO:47所示的氨基酸序列,所述L-FR2包含SEQ ID NO:48所示的氨基酸序列,所述L-FR3包含SEQ ID NO:49所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:50所示的氨基酸序列;以及
(5)所述L-FR1包含SEQ ID NO:47所示的氨基酸序列,所述L-FR2包含SEQ ID NO:48所示的氨基酸序列,所述L-FR3包含SEQ ID NO:60所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:50所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含VL,所述VL包含SEQ ID NO:82或SEQ ID NO:40所示的氨基酸序列。
在某些实施方式中,所述VL包含SEQ ID NO:16、SEQ ID NO:26、SEQ ID NO:40、SEQID NO:51和SEQ ID NO:61中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含抗体轻链恒定区,且所述抗体轻链恒定区包含人Igκ恒定区。
在某些实施方式中,所述抗体轻链恒定区包含SEQ ID NO:64所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含抗体轻链,且所述抗体轻链包含SEQ ID NO:52、SEQ ID NO:62、SEQ ID NO:87、SEQ ID NO:90和SEQ ID NO:92中任一项所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含HCDR1,HCDR2,HCDR3,LCDR1,LCDR2和LCDR3,所述HCDR1,HCDR2,HCDR3,LCDR1,LCDR2和LCDR3包含选自下组的氨基酸序列:
(1)所述HCDR1包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2包含SEQ ID NO:2所示的氨基酸序列,所述HCDR3包含SEQ ID NO:3所示的氨基酸序列,所述LCDR1包含SEQ IDNO:9所示的氨基酸序列,所述LCDR2包含SEQ ID NO:10所示的氨基酸序列,所述LCDR3包含SEQ ID NO:11所示的氨基酸序列;
(2)所述HCDR1包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2包含SEQ ID NO:2所示的氨基酸序列,所述HCDR3包含SEQ ID NO:20所示的氨基酸序列,所述LCDR1包含SEQID NO:23所示的氨基酸序列,所述LCDR2包含SEQ ID NO:10所示的氨基酸序列,所述LCDR3包含SEQ ID NO:24所示的氨基酸序列;以及
(3)所述HCDR1包含SEQ ID NO:27所示的氨基酸序列,所述HCDR2包含SEQ ID NO:28所示的氨基酸序列,所述HCDR3包含SEQ ID NO:29所示的氨基酸序列,所述LCDR1包含SEQID NO:34所示的氨基酸序列,所述LCDR2包含SEQ ID NO:35所示的氨基酸序列,所述LCDR3包含SEQ ID NO:36所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包括VH和VL,所述VH和VL包含选自下组的氨基酸序列:
(1)所述VH包含SEQ ID NO:8所示的氨基酸序列,所述VL包含SEQ ID NO:16所示的氨基酸序列;
(2)所述VH包含SEQ ID NO:19所示的氨基酸序列,所述VL包含SEQ ID NO:16所示的氨基酸序列;
(3)所述VH包含SEQ ID NO:22所示的氨基酸序列,所述VL包含SEQ ID NO:26所示的氨基酸序列;
(4)所述VH包含SEQ ID NO:33所示的氨基酸序列,所述VL包含SEQ ID NO:40所示的氨基酸序列;
(5)所述VH包含SEQ ID NO:45所示的氨基酸序列,所述VL包含SEQ ID NO:51所示的氨基酸序列;
(6)所述VH包含SEQ ID NO:55所示的氨基酸序列,所述VL包含SEQ ID NO:51所示的氨基酸序列;
(7)所述VH包含SEQ ID NO:58所示的氨基酸序列,所述VL包含SEQ ID NO:51所示的氨基酸序列;以及
(8)所述VH包含SEQ ID NO:45所示的氨基酸序列,所述VL包含SEQ ID NO:61所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白抗体重链和抗体轻链,所述抗体重链和抗体轻链包含选自下组的氨基酸序列:
(1)所述抗体重链包含SEQ ID NO:86所示的氨基酸序列,且所述抗体轻链包含SEQID NO:87所示的氨基酸序列;
(2)所述抗体重链包含SEQ ID NO:88所示的氨基酸序列,且所述抗体轻链包含SEQID NO:87所示的氨基酸序列;
(3)所述抗体重链包含SEQ ID NO:89所示的氨基酸序列,且所述抗体轻链包含SEQID NO:90所示的氨基酸序列;
(4)所述抗体重链包含SEQ ID NO:91所示的氨基酸序列,且所述抗体轻链包含SEQID NO:92所示的氨基酸序列;
(5)所述抗体重链包含SEQ ID NO:46所示的氨基酸序列,且所述抗体轻链包含SEQID NO:52所示的氨基酸序列;
(6)所述抗体重链包含SEQ ID NO:56所示的氨基酸序列,且所述抗体轻链包含SEQID NO:52所示的氨基酸序列;
(7)所述抗体重链包含SEQ ID NO:59所示的氨基酸序列,且所述抗体轻链包含SEQID NO:52所示的氨基酸序列;以及
(8)所述抗体重链包含SEQ ID NO:46所示的氨基酸序列,且所述抗体轻链包含SEQID NO:62所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包括抗体或其抗原结合片段。
在某些实施方式中,所述抗体选自下组:单克隆抗体、单链抗体、嵌合抗体、多特异性抗体、人源化抗体和全人源抗体。
在某些实施方式中,所述抗原结合片段选自下组:Fab、Fab’、F(ab)2、Fv、F(ab’)2、scFv、di-scFv和dAb片段。
另一方面,本申请提供了多肽,其包含所述分离的抗原结合蛋白。
另一方面,本申请提供了融合蛋白,其包含所述分离的抗原结合蛋白。
另一方面,本申请提供了药物分子,其包含所述分离的抗原结合蛋白。
另一方面,本申请提供了分离的一种或多种核酸分子,其编码所述分离的抗原结合蛋白。
另一方面,本申请提供了载体,其包含所述核酸分子。
另一方面,本申请提供了细胞,其包含所述核酸分子或所述载体。
另一方面,本申请提供了药物组合物,其包含所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体和/或所述细胞,以及任选地药学上可接受的载剂。
在某些实施方式中,所述药物组合物进一步包括选自下组的一种或多种药物:蒽环类拓扑异构酶抑制剂、柔红霉素、阿糖胞苷核苷代谢抑制剂、联合柔红霉素、阿糖胞苷、柔红霉素和阿糖胞苷脂质体注射液、Vyxeos、全反式维甲酸(ATRA)、砷、三氧化二砷、组胺盐酸盐、二盐酸组胺(Ceplene)、白细胞介素-2、白细胞介素2(Proleukin)、吉妥珠单抗奥唑米(Mylotarg)、氯法拉滨、法呢基转移酶抑制剂、地西他滨、IDH1抑制剂、IDH2抑制剂、恩西地平、Idhifa、IDO抑制剂、epacadostat、铂络合物的衍生物、奥沙利铂,激酶抑制剂、酪氨酸激酶抑制剂、PI3激酶抑制剂,BTK抑制剂Ibrutinib,PD-1抗体、PD-L1抗体、抗CTLA-4抗体、LAG3抗体、ICOS抗体,TIGIT抗体、TIM3抗体、结合肿瘤抗原的抗体、结合T细胞表面标记的抗体、结合细胞或NK细胞表面标志物的抗体、烷基化剂、亚硝基脲剂、抗代谢药物、抗肿瘤抗生素、来源于植物的生物碱、拓扑异构酶抑制剂、激素治疗药物、激素拮抗剂、芳香酶抑制剂和P-糖蛋白抑制剂。
另一方面,本申请提供了制备所述分离的抗原结合蛋白的方法,所述方法包括在使得所述的分离的抗原结合蛋白表达的条件下,培养所述的细胞。
另一方面,本申请提供了所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体、所述细胞、和/或所述药物组合物在制备药物中的用途,所述药物用于预防和/或治疗疾病和/或病症,所述疾病和/或病症包括与LILRB4信号传导相关的疾病或病症。
在某些实施方式中,所述疾病和/或病症包括肿瘤。
在某些实施方式中,所述肿瘤包括实体瘤和/或血液瘤。
在某些实施方式中,所述药物与选自下组的一种或多种药物联合使用:蒽环类拓扑异构酶抑制剂、柔红霉素、阿糖胞苷核苷代谢抑制剂、联合柔红霉素、阿糖胞苷、柔红霉素和阿糖胞苷脂质体注射液、Vyxeos、全反式维甲酸(ATRA)、砷、三氧化二砷、组胺盐酸盐、二盐酸组胺(Ceplene)、白细胞介素-2、白细胞介素2(Proleukin)、吉妥珠单抗奥唑米(Mylotarg)、氯法拉滨、法呢基转移酶抑制剂、地西他滨、IDH1抑制剂、IDH2抑制剂、恩西地平、Idhifa、IDO抑制剂、epacadostat、铂络合物的衍生物、奥沙利铂,激酶抑制剂、酪氨酸激酶抑制剂、PI3激酶抑制剂,BTK抑制剂Ibrutinib,PD-1抗体、PD-L1抗体、抗CTLA-4抗体、LAG3抗体、ICOS抗体,TIGIT抗体、TIM3抗体、结合肿瘤抗原的抗体,结合T细胞表面标记的抗体、结合细胞或NK细胞表面标志物的抗体、烷基化剂、亚硝基脲剂、抗代谢药物、抗肿瘤抗生素、来源于植物的生物碱、拓扑异构酶抑制剂、激素治疗药物、激素拮抗剂、芳香酶抑制剂和P-糖蛋白抑制剂。
在某些实施方式中,所述与LILRB4信号传导相关的疾病或病症包括免疫系统疾病和/或恶性血液疾病。
在某些实施方式中,所述免疫系统疾病选自下组中的一种或多种:川崎病、系统性红斑狼疮(SLE)、败血症。
在某些实施方式中,所述实体瘤选自下组中的一种或多种:乳腺癌,黑色素瘤,结肠癌,肺癌,肾癌和胰腺癌。
在某些实施方式中,所述恶性血液疾病选自下组中的一种或多种:骨髓发育不良综合症、骨髓增生性肿瘤、慢性粒单核细胞白血病(CMML)、慢性髓细胞白血病,或急性髓细胞白血病(AML)、急性早幼粒细胞白血病(APL)或M3 AML、急性粒单核细胞白血病或M4 AML、急性单核细胞白血病或M5 AML、急性骨髓母细胞白血病,以及真性红细胞增多症。
另一方面,本申请提供了所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体、所述细胞、和/或所述药物组合物,其用于预防和/或治疗疾病和/或病症,所述疾病和/或病症包括与LILRB4信号传导相关的疾病或病症。
在某些实施方式中,所述疾病和/或病症包括肿瘤。
在某些实施方式中,所述肿瘤包括实体瘤和/或血液瘤。
在某些实施方式中,所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体、所述细胞、和/或所述药物组合物与选自下组的一种或多种药物联合使用:蒽环类拓扑异构酶抑制剂、柔红霉素、阿糖胞苷核苷代谢抑制剂、联合柔红霉素、阿糖胞苷、柔红霉素和阿糖胞苷脂质体注射液、Vyxeos、全反式维甲酸(ATRA)、砷、三氧化二砷、组胺盐酸盐、二盐酸组胺(Ceplene)、白细胞介素-2、白细胞介素2(Proleukin)、吉妥珠单抗奥唑米(Mylotarg)、氯法拉滨、法呢基转移酶抑制剂、地西他滨、IDH1抑制剂、IDH2抑制剂、恩西地平、Idhifa、IDO抑制剂、epacadostat、铂络合物的衍生物、奥沙利铂,激酶抑制剂、酪氨酸激酶抑制剂、PI3激酶抑制剂,BTK抑制剂Ibrutinib,PD-1抗体、PD-L1抗体、抗CTLA-4抗体、LAG3抗体、ICOS抗体,TIGIT抗体、TIM3抗体、结合肿瘤抗原的抗体,结合T细胞表面标记的抗体、结合细胞或NK细胞表面标志物的抗体、烷基化剂、亚硝基脲剂、抗代谢药物、抗肿瘤抗生素、来源于植物的生物碱、拓扑异构酶抑制剂、激素治疗药物、激素拮抗剂、芳香酶抑制剂和P-糖蛋白抑制剂。
在某些实施方式中,所述与LILRB4信号传导相关的疾病或病症包括免疫系统疾病和/或恶性血液疾病。
在某些实施方式中,所述免疫系统疾病选自下组中的一种或多种:川崎病、系统性红斑狼疮(SLE)、败血症。
在某些实施方式中,所述实体瘤选自下组中的一种或多种:乳腺癌,黑色素瘤,结肠癌,肺癌,肾癌和胰腺癌。
在某些实施方式中,所述恶性血液疾病选自下组中的一种或多种:骨髓发育不良综合症、骨髓增生性肿瘤、慢性粒单核细胞白血病(CMML)、慢性髓细胞白血病,或急性髓细胞白血病(AML)、急性早幼粒细胞白血病(APL)或M3 AML、急性粒单核细胞白血病或M4 AML、急性单核细胞白血病或M5 AML、急性骨髓母细胞白血病,以及真性红细胞增多症。
另一方面,本申请提供了一种预防和/或治疗疾病和/或病症的方法,其包括向有需要的受试者施用有效量的所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体、所述细胞、和/或所述药物组合物,所述疾病和/或病症包括与LILRB4信号传导相关的疾病或病症。
在某些实施方式中,所述疾病和/或病症包括肿瘤。
在某些实施方式中,所述肿瘤包括实体瘤和/或血液瘤。
在某些实施方式中,所述方法中,所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体、所述细胞、和/或所述药物组合物与选自下组的一种或多种药物联合使用:蒽环类拓扑异构酶抑制剂、柔红霉素、阿糖胞苷核苷代谢抑制剂、联合柔红霉素、阿糖胞苷、柔红霉素和阿糖胞苷脂质体注射液、Vyxeos、全反式维甲酸(ATRA)、砷、三氧化二砷、组胺盐酸盐、二盐酸组胺(Ceplene)、白细胞介素-2、白细胞介素2(Proleukin)、吉妥珠单抗奥唑米(Mylotarg)、氯法拉滨、法呢基转移酶抑制剂、地西他滨、IDH1抑制剂、IDH2抑制剂、恩西地平、Idhifa、IDO抑制剂、epacadostat、铂络合物的衍生物、奥沙利铂,激酶抑制剂、酪氨酸激酶抑制剂、PI3激酶抑制剂,BTK抑制剂Ibrutinib,PD-1抗体、PD-L1抗体、抗CTLA-4抗体、LAG3抗体、ICOS抗体,TIGIT抗体、TIM3抗体、结合肿瘤抗原的抗体,结合T细胞表面标记的抗体、结合细胞或NK细胞表面标志物的抗体、烷基化剂、亚硝基脲剂、抗代谢药物、抗肿瘤抗生素、来源于植物的生物碱、拓扑异构酶抑制剂、激素治疗药物、激素拮抗剂、芳香酶抑制剂和P-糖蛋白抑制剂。
在某些实施方式中,所述与LILRB4信号传导相关的疾病或病症包括免疫系统疾病和/或恶性血液疾病。
在某些实施方式中,所述免疫系统疾病选自下组中的一种或多种:川崎病、系统性红斑狼疮(SLE)、败血症。
在某些实施方式中,所述实体瘤选自下组中的一种或多种:乳腺癌,黑色素瘤,结肠癌,肺癌,肾癌和胰腺癌。
在某些实施方式中,所述恶性血液疾病选自下组中的一种或多种:骨髓发育不良综合症、骨髓增生性肿瘤、慢性粒单核细胞白血病(CMML)、慢性髓细胞白血病,或急性髓细胞白血病(AML)、急性早幼粒细胞白血病(APL)或M3 AML、急性粒单核细胞白血病或M4 AML、急性单核细胞白血病或M5 AML、急性骨髓母细胞白血病,以及真性红细胞增多症。
另一方面,本申请提供了诊断受试者中与LILRB4蛋白的表达相关的疾病或病况的方法,所述方法包括:使源自所述受试者的样品与所述的分离的抗原结合蛋白接触,以及判断所述样品中能够特异性结合所述分离的抗原结合蛋白的物质的存在和/或含量。
另一方面,本申请提供了检测样品中LILRB4的方法,所述方法包括施用所述分离的抗原结合蛋白。
在某些实施方式中,所述方法为体外和/或离体方法。
另一方面,本申请中提供了检测试剂盒,其包含所述分离的抗原结合蛋白,所述检测试剂盒用于检测样品或受试者中LILRB4蛋白的存在和/或含量。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的附图和说明书中的描述仅仅是示例性的,而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下:
图1显示的是本申请所述分离的抗原结合蛋白与人LILRB4的结合测定。
图2显示的是本申请所述分离的抗原结合蛋白与LILRB家族蛋白结合特异性检测结果。
图3A和图3B显示的是本申请所述分离的抗原结合蛋白阻断LILRB4/APOE结合的活性检测。
图4显示的是本申请所述分离的抗原结合蛋白激活CD8+T细胞的效果检测。
图5显示的是本申请所述分离的抗原结合蛋白对THP-1细胞的迁移抑制作用。
图6显示的是小鼠给药后肿瘤体积增长的趋势图。
图7显示的是施用本申请所述分离的抗原结合蛋白后,在不同组织器官中hCD45+细胞的比例。
图8显示的是本申请所述分离的抗原结合蛋白与LILRB4的结合测定。
图9显示的是本申请所述分离的抗原结合蛋白与THP-1细胞的结合测定。
图10显示的是本申请所述分离的抗原结合蛋白对THP-1细胞的迁移抑制作用。
图11显示的是本申请所述分离的抗原结合蛋白阻断LILRB4/APOE结合的活性检测。
图12显示的是本申请所述分离的抗原结合蛋白在293T-hLILRB4细胞上的ADCC活性。
图13显示的是本申请所述分离的抗原结合蛋白激活CD8+T细胞的效果检测.
图14显示的是小鼠给药后肿瘤体积增长的趋势图。
图15显示的是小鼠给药后肿瘤体积变化的荧光图。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式,熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
以下对本申请做进一步描述:在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
在本申请中,术语“分离的”通常指从天然状态下经人工手段获得的。如果自然界中出现某一种“分离”的物质或成分,那么可能是其所处的天然环境发生了改变,或从天然环境下分离出该物质,或二者情况均有发生。例如,某一活体动物体内天然存在某种未被分离的多聚核苷酸或多肽,而从这种天然状态下分离出来的高纯度的相同的多聚核苷酸或多肽即称之为分离的。术语“分离的”不排除混有人工或合成的物质,也不排除存在不影响物质活性的其它不纯物质。
在本申请中,术语“分离的抗原结合蛋白”通常指从天然状态下经人工手段获得的具有抗原结合能力的蛋白。该“分离的抗原结合蛋白”可以包含结合抗原的部分和任选地,允许抗原结合部分采用促进所述抗原结合部分结合抗原的构象的支架或构架部分。抗原结合蛋白可以包含例如抗体来源的蛋白支架或具有移植的CDR或CDR衍生物的备选蛋白支架或人工支架。此类支架包括,但不限于包含被引入例如以稳定抗原结合蛋白的三维结构的突变的抗体来源的支架以及包含例如生物相容性聚合物的完全合成的支架。参见例如Korndorfer等,2003,Proteins:Structure,Function,andBioinformatics,53(1):121-129(2003);Roque等,Biotechnol.Prog.20:639-654(2004)。此外,肽抗体模拟物("PAMs")以及利用纤连蛋白组分基于抗体模拟物的支架可以用作支架。
在本申请中,术语“KD”(同样地,“KD”或“KD”)通常指“亲和常数”或“平衡解离常数”,并指在滴定测量中在平衡时、或者通过将解离速率常数(kd)除以结合速率常数(ka)所获得的值。使用结合速率常数(ka)、解离速率常数(kd)和平衡解离常数(KD)表示结合蛋白(例如本申请所述的分离的抗原结合蛋白)对抗原(例如LILRB4蛋白)的结合亲和力。确定结合和解离速率常数的方法为本领域熟知。使用基于荧光的技术提供了高灵敏度以及在生理缓冲液中在平衡时检查样品的能力。例如,可以通过Octet测定所述KD值,也可以使用其他实验途径和仪器例如BIAcore(生物分子相互作用分析)测定(例如,可以从BIAcoreInternationalAB,aGEHealthcarecompany,Uppsala,瑞典获得的仪器)。另外,也可以使用可以从SapidyneInstruments(Boise,Idaho)获得的KinExA(动态排阻测定(KineticExclusionAssay))测定所述KD值,或者使用表面等离子共振仪(SPR)测定所述KD值。
在本申请中,术语“LILRB4蛋白”通常是指白细胞免疫球蛋白样受体B4(LILRB4)。在本申请中,该术语涵盖完整的LILRB4及其功能活性片段、变体、同源物、类似物以及衍生物。
在本申请中,术语“特异性结合”或“特异性的”通常指可测量的和可再现的相互作用,比如靶标和抗体之间的结合,可在分子(包括生物分子)的异质群体存在的情况可决定靶标的存在。例如,特异性结合靶标(其可以为表位)的抗体是以比它结合其它靶标更大的亲和性、亲合力、更容易、和/或以更大的持续时间结合该靶标的抗体。在一个实施方案中,抗体结合无关靶标的程度小于抗体对靶标的结合的约10%,如例如通过放射免疫分析(RIA)测量的。例如,在本申请中,所述分离的抗原结合蛋白能够以<2x10-7M或更低的解离常数(KD)与LILRB4蛋白相结合。在某些实施方案中,特异性结合可以包括但不要求排他性地结合。
在本申请中,术语“可变结构域”通常指抗体重链或轻链的氨基末端结构域。重链和轻链的可变结构域可以分别称为“VH”和“VL”(或者分别称为“VH”和“VL”)。这些结构域通常是抗体的变化最大的部分(相对于相同类型的其它抗体),且包含抗原结合位点。
在本申请中,术语“可变”通常指在抗体之间可变结构域的某些区段在序列上存在很大差异的事实。V结构域介导抗原结合并决定特定抗体对其特定抗原的特异性。然而,可变性并非在整个可变结构域范围内均匀分布。相反,它集中在轻链和重链可变结构域中称为高变区(CDR或HVR)的三个区段中。可变结构域的更高度保守的部分称为框架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区,大多数采用β-折叠构型,通过三个CDR连接,其形成环形连接,并且在一些情况下形成β-折叠结构的一部分。每条链中的CDR通过FR区紧密靠近地保持在一起,并且来自另一条链的CDR一同促进抗体的抗原结合位点的形成(参见Kabat et al,Sequences of Immunological Interest,Fifth Edition,NationalInstitute of Health,Bethesda,Md.(1991))。恒定结构域不直接参与抗体与抗原的结合,但显示出各种效应子功能,例如抗体参与抗体依赖性细胞毒性。
在本申请中,术语“抗体”通常指免疫球蛋白或其片段或其衍生物,涵盖包括抗原结合位点的任何多肽,无论其是在体外还是体内产生的。该术语包括但不限于多克隆的、单克隆的、单特异性的、多特异性的、非特异性的、人源化的、单链的、嵌合的、合成的、重组的、杂化的、突变的和移植的抗体。除非另外被术语“完整的”修饰,如在“完整的抗体”中,为了本发明的目的,术语“抗体”也包括抗体片段,比如Fab、F(ab')2、Fv、scFv、Fd、dAb和保持抗原结合功能(例如,特异性结合LILRB4)的其它抗体片段。通常,这样的片段应当包括抗原结合结构域。基本的4链抗体单元是由两个相同的轻(L)链和两个相同的重(H)链组成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元与另外一个称为J链的多肽组成,且含有10个抗原结合位点,而IgA抗体包括2-5个可以与J链相结合聚合形成多价组合的基本4链单元。就IgG而言,4链单元一般为约150,000道尔顿。每个L链通过一个共价二硫键与H链连接,而两个H链通过一个或多个取决于H链同种型的二硫键相互连接。每个H和L链还具有规则间隔的链内二硫化桥键。每个H链在N末端具有可变结构域(VH),对于α和γ链各自继之以三个恒定结构域(CH)、对于μ和ε同种型继之以四个CH结构域。每个L链在N末端具有可变结构域(VL),在其另一端具有恒定结构域。VL与VH对应,且CL与重链的第一恒定结构域(CH1)相对应。特定的氨基酸残基被认为在轻链和重链可变结构域之间形成界面。VH和VL配对一起形成单个抗原结合位点。对于不同类别抗体的结构和性质,参见例如Basic and ClinicalImmunology,8th Edition,Daniel P.Sties,Abba I.Terr and Tristram G.Parsolw(eds),Appleton&Lange,Norwalk,Conn.,1994,第71页和第6章。来自任何脊椎动物物种的L链可以基于其恒定结构域的氨基酸序列被分为两种明显不同的类型中的一种,称为κ和λ。取决于其重链(CH)恒定结构域的氨基酸序列,可以将免疫球蛋白分为不同的类别或同种型。存在五类免疫球蛋白:IgA、IgD、IgE、IgG和IgM,具有分别被命名为α、δ、ε、γ和μ的重链。基于CH序列和功能方面的相对小的差异,将γ和α类进一步分成亚类,例如,人表达下述亚类:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgK1。
在本申请中,术语“CDR”通常指抗体可变结构域的区域,其序列是高度可变的和/或形成结构定义环。通常,抗体包括六个CDR;在VH中三个(HCDR1、HCDR2、HCDR3),和在VL中三个(LCDR1、LCDR2、LCDR3)。在天然抗体中,HCDR3和LCDR3显示所述六个CDR的大多数多样性,并且特别地HCDR3被认为在赋予抗体的精细特异性方面起独特作用。参见,例如Xu etal,Immunity 13:37-45(2000);Johnson and Wu,in Methods in Molecular Biology248:1-25(Lo,ed.,Human Press,Totowa,N.J.,2003)。实际上,仅由重链组成的天然存在的骆驼抗体在缺乏轻链的情况功能正常且稳定。参见,例如,Hamers-Casterman et al.,Nature 363:446-448(1993);Sheriff et al,Nature Struct.Biol.3:733-736(1996)。
在本申请中,术语“FR”通常指抗体可变结构域的更高度保守的部分,其被称为框架区。通常,天然重链和轻链的可变结构域各自包含四个FR区,即在VH中四个(H-FR1,H-FR2,H-FR3,和H-FR4),和在VL中四个(L-FR1,L-FR2,L-FR3,和L-FR4)。例如,本申请所述的分离的抗原结合蛋白的VL可以包括框架区L-FR1,L-FR2,L-FR3,和L-FR4。本申请所述的分离的抗原结合蛋白的VH可以包括框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在本申请中,术语“抗原结合片段”通常指具有特异结合抗原(例如,LILRB4蛋白)能力的一个或多个片段。在本申请中,所述抗原结合片段可以包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
在本申请中,术语“单克隆抗体”或“单抗”或“单克隆抗体组成”通常是指单一分子组成的抗体分子制品。单克隆抗体组成呈现出对于特定表位的单一结合特异性和亲和力。
在本申请中,术语“单链抗体”通常是指包含抗体重链可变区和轻链可变区的分子。例如,所述单链抗体可以由抗体重链可变区和轻链可变区通过连接分子(linker)(例如,连接肽)连接而成。
在本申请中,术语“人源抗体”通常是指可变区框架和CDR区得自人种系免疫球蛋白序列的抗体。此外,如果抗体包含恒定区,其也得自人种系免疫球蛋白序列。本申请的人源抗体可以包含不由人种系免疫球蛋白序列编码的氨基酸残基,例如通过体外随机突变或点突变或通过体内体细胞突变而导入的突变。然而,术语“人源抗体”不包括在人框架序列中插入得自其他哺乳动物物种的CDR序列的抗体。
在本申请中,术语“鼠源抗体”通常是指可变区框架和CDR区得自小鼠种系免疫球蛋白序列的抗体。此外,如果抗体包含恒定区,其也得自小鼠种系免疫球蛋白序列。本申请的鼠源抗体可以包含不由小鼠种系免疫球蛋白序列编码的氨基酸残基,例如通过体外随机突变或点突变或通过体内体细胞突变而导入的突变。然而,术语“鼠源抗体”不包括在小鼠框架序列中插入得自其他哺乳动物物种的CDR序列的抗体。
在本申请中,术语“嵌合抗体”通常是指通过组合非人源遗传物质与人源遗传物质而得来的抗体。或者更笼统地说,嵌合抗体是指组合有一个物种的遗传物质与另一物种遗传物质的抗体。
在本申请中,术语“多特异性抗体”通常是指可以同时识别两个或两个以上抗原或者表位的抗体分子。所述多特异性抗体可以通过化学偶联法、杂交-杂交瘤法、基因工程抗体制备法等方法在真核表达系统或者在原核表达系统中获得。
在本申请中,术语“人源化抗体”通常是指来源于非人物种但其蛋白序列已经被修改以增加其与人天然生成抗体的相似度的抗体。
在本申请中,术语“全人源抗体”通常是指全人抗体,即抗体的恒定区和可变区均来源于人。所述全人源抗体可以通过噬菌体抗体库技术、转基因小鼠制备人源性抗体、核糖体展示技术、EBV转化B细胞克隆技术、单个B细胞克隆等技术来实现。
在本申请中,术语“直接相连”与术语“间接相连”相对,术语“直接相连”通常是指直接连接。例如,所述直接相连可以为物质间没有间隔子而直接相连的情况。所述间隔子可以是连接子。例如,所述连接子可以为肽连接子。术语“间接相连”通常是指物质间不直接相连的情况。例如,所述间接相连可以为通过间隔子而连接的情况。例如,在本申请所述的分离的抗原结合蛋白中,所述L-FR1的C端与所述LCDR1的N端可以直接或间接相连。
在本申请中,术语“多肽”、“肽”和“蛋白”可以互换使用,通常是指氨基酸残基的聚合物。这个术语可用于指一个或多个氨基酸残基是其相应的天然氨基酸的人工合成化学模拟物的氨基酸聚合物,也可用于指天然的氨基酸聚合物,那些含修饰残基的氨基酸聚合物以及非天然的氨基酸聚合物。
在本申请中,术语“融合蛋白”通常是指由两种或更多种多肽构成的蛋白质,它们尽管通常在天然状态下不结合,但是通过它们各自的氨基和羧基末端经肽键而结合在一起以形成一个连续多肽。应理解的是该两种或更多种多肽组分可以直接结合或者通过肽接头/间隔物而间接结合。
在本申请中,术语“药物分子”通常是指具有所需生物学效力的分子。药物可以是预防性或治疗性的。药物分子可以包括不限于:蛋白分子,包括但不限于肽,多肽,蛋白质,包括翻译后修饰的蛋白质、融合蛋白、抗体等;小分子,包括无机或有机化合物;核酸分子,包括但不限于双链或单链DNA、或双链或单链RNA(如反义(分子)、RNAi等)、内含子序列、三螺旋核酸分子和适体;或疫苗。
在本申请中,术语“分离的核酸分子”通常指任何长度的分离形式的核苷酸,脱氧核糖核苷酸或核糖核苷酸,或从其天然环境分离的或人工合成的类似物。
在本申请中,术语“载体”通常指可将编码某蛋白的多聚核苷酸插入其中并使蛋白获得表达的一种核酸运载工具。载体可通过转化、转导或转染宿主细胞,使其携带的遗传物质元件在宿主细胞内表达得以表达。举例来说,载体包括:质粒;噬菌粒;柯斯质粒;人工染色体如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。用作载体的动物病毒种类有逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。一种载体可能含有多种控制表达的元件,包括启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,载体还可含有复制起始位点。载体还有可能包括有协助其进入细胞的成分,如病毒颗粒、脂质体或蛋白外壳,但不仅仅只有这些物质。
在本申请中,术语“细胞”通常指可以是或已经是受试者质粒或载体的接受者的单个细胞、细胞系或细胞培养物,其包括本发明所述的核酸分子或本发明所述的载体。细胞可以包括单个细胞的后代。由于天然、偶然或有意的突变,后代可以不一定与原始母细胞完全相同(在总DNA互补体的形态上或在基因组上)。细胞可包括用本申请所述的载体在体外转染的细胞。细胞可以是细菌细胞(例如,大肠杆菌)、酵母细胞或其它真核细胞,例如COS细胞、中国仓鼠卵巢(CHO)细胞、CHO-K1细胞、LNCAP细胞、HeLa细胞、HEK293细胞、COS-1细胞、NS0细胞、人非小细胞肺癌A549细胞、人皮肤鳞癌A431细胞、肾透明细胞腺癌786-O细胞、人胰腺癌MIAPaCa-2细胞、红白血病K562细胞、急性T细胞白血病Jurkat细胞、人乳腺癌MCF-7细胞、人乳腺癌MDA-MB-231细胞、人乳腺癌MDA-MB-468细胞、人乳腺癌SKBR3细胞、人卵巢癌SKOV3细胞、淋巴瘤U-937细胞、淋巴瘤Raji细胞、人骨髓瘤U266细胞或人多发性骨髓瘤RPMI8226细胞。在某些实施方案中,细胞为哺乳动物细胞。
在本申请中,术语“药物组合物”通常指涉及适合施用于患者、优选人患者的组合物。例如,本申请所述的药物组合物,其可以包含本申请所述的分离的抗原结合蛋白、本申请所述的免疫缀合物、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的细胞,以及任选地药学上可接受的佐剂。此外,所述药物组合物还可以包含一种或多种(药学上有效的)载剂、稳定剂、赋形剂、稀释剂、增溶剂、表面活性剂、乳化剂和/或防腐剂的合适的制剂。组合物的可接受成分在所用剂量和浓度下优选地对接受者无毒。本发明的药物组合物包括但不限于液体、冷冻和冻干组合物。
在本申请中,术语“药学上可接受的载剂”通常指与药物给药相容的任何和所有的溶剂、分散介质、包衣、等渗剂和吸收延迟剂等,通常安全、无毒,且既不是生物学上也非其它方面不合需要的。
在本申请中,术语“受试者”通常指人类或非人类动物,包括但不限于猫、狗、马、猪、奶牛、羊、兔、小鼠、大鼠或猴。
在本申请中,术语“包含”通常是指包括明确指定的特征,但不排除其他要素。
在本申请中,术语“约”通常是指在指定数值以上或以下0.5%-10%的范围内变动,例如在指定数值以上或以下0.5%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、或10%的范围内变动。
发明详述
分离的抗原结合蛋白
抗体的CDR又称互补决定区,是可变区的一部分。该区域的氨基酸残基可以与抗原或抗原表位接触。抗体CDR可以通过多种编码系统来确定,如CCG、Kabat、Chothia、IMGT、AbM、综合考虑Kabat/Chothia等。这些编码系统为本领域内已知,具体可参见,例如,http://www.bioinf.org.uk/abs/index.html#kabatnum。本领域技术人员可以根据抗体的序列和结构,用不同的编码系统确定出CDR区。使用不同的编码系统,CDR区可能存在差别。在本申请中,所述CDR涵盖根据任何CDR划分方式划分得到的CDR序列;也涵盖其变体,所述变体包括所述CDR的氨基酸序列经过取代、缺失和/或添加一个或多个氨基酸。例如1-30个、1-20个或1-10个,又例如1个、2个、3个、4个、5个、6个、7个、8个或9个氨基酸取代、缺失和/或插入;也涵盖其同源物,所述同源物可以为与所述CDR的氨基酸序列具有至少约85%(例如,具有至少约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的氨基酸序列。例如,本申请序列表中所述的分离的抗原结合蛋白的CDR可以使用Kabat确定出来。
一方面,本申请提供了一种分离的抗原结合蛋白,其可包含如SEQ ID NO:81、SEQID NO:33和SEQ ID NO:22中任一项所示的VH中的至少一个CDR;和/或包含如SEQ ID NO:82或SEQ ID NO:40所示的VL中的至少一个CDR。
X1VQLX2QX3GAEX4X5KPGASVKX6SCKASGYTFTSYWMHWVX7QX8PGQGLEWX9GEINPSNGRTNYNEKFKSX10X11TX12TX13DX14SX15STX16YX17X18LX19SLX20SEDX21AVYYCARDRYDEGNAMDYWGQGTX22VTVSS(SEQ ID NO:81)。其中,X1可以是E或Q;X2可以是Q或V;X3可以是P或S;X4可以是L或V;X5可以是K或V;X6可以是L或V;X7可以是K或R;X8可以是A或R;X9可以是I或M;X10可以是K或R;X11可以是A或V;X12可以是L或M;X13可以是R或V;X14可以是K或T;X15可以是S或T;X16可以是A或V;X17可以是M或V;X18可以是E或Q;X19可以是N或S;X20可以是R或T;X21可以是S或T;X22可以是S或T。
DIX1MTX2X3X4SSLSASX5GDRVTIX6CRASQDIX7NYLNWYQQKPX8X9X10X11KLLIYYTSRLHSGVPSRFSGSGSGTX12YX13X14TISX15LX16X17X18DX19ATYX20CQQGX21TLPX22TFGX23GTX24LEIK(SEQ ID NO:82)。其中,X1可以为Q或V;X2可以为H或Q;X3可以为S或T;X4可以为P或T;X5可以为L或V;X6可以为S或T;X7可以为S或T;X8可以为D或G;X9可以为G或K;X10可以为A或T;X11可以为P或V;X12可以为D或E;X13可以为S或T;X14可以为F或L;X15可以为N或S;X16可以为E或Q;X17可以为P或Q;X18可以为D或E;X19可以为F或I;X20可以为F或Y;X21可以为D或N;X22可以为P或R;X23可以为G或Q;X24可以为K或R。
在本申请中,所述VH可包含SEQ ID NO:8、SEQ ID NO:19、SEQ ID NO:22、SEQ IDNO:33、SEQ ID NO:45、SEQ ID NO:55和SEQ ID NO:58中任一项所示的氨基酸序列。
在本申请中,所述VL可包含SEQ ID NO:16、SEQ ID NO:26、SEQ ID NO:40、SEQ IDNO:51和SEQ ID NO:61中任一项所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的HCDR可以通过任何形式划分,只要VH和/或VL与本申请中任一项所示VH和/或VL的氨基酸序列相同,以任何形式划分得到的HCDR都可落入本申请的保护范围内。
例如,使用不同的CDR标记的方法划分VH(SEQ ID NO:8)和/或VL(SEQ ID NO:16)可总结如下表。
Chothia | AbM | Kabat | Contact | IMGT | |
LCDR1 | L24-34 | L24-34 | L24-34 | L30-36 | L27-32 |
LCDR2 | L50-56 | L50-56 | L50-56 | L46-55 | L50-51 |
LCDR3 | L89-97 | L89-97 | L89-97 | L89-96 | L89-97 |
HCDR1 | H26-32 | H26-35 | H31-35 | H30-35 | H26-33 |
HCDR2 | H52-57 | H50-59 | H50-66 | H47-59 | H51-58 |
HCDR3 | H99-109 | H99-109 | H99-109 | H97-108 | H97-109 |
例如,使用不同的CDR标记的方法划分VH(SEQ ID NO:19)和/或VL(SEQ ID NO:16)可总结如下表。
Chothia | AbM | Kabat | Contact | IMGT | |
LCDR1 | L24-34 | L24-34 | L24-34 | L30-36 | L27-32 |
LCDR2 | L50-56 | L50-56 | L50-56 | L46-55 | L50-51 |
LCDR3 | L89-97 | L89-97 | L89-97 | L89-96 | L89-97 |
HCDR1 | H26-32 | H26-35 | H31-35 | H30-35 | H26-33 |
HCDR2 | H52-57 | H50-59 | H50-66 | H47-59 | H51-58 |
HCDR3 | H99-109 | H99-109 | H99-109 | H97-108 | H97-109 |
例如,使用不同的CDR标记的方法划分VH(SEQ ID NO:22)和/或VL(SEQ ID NO:26)可总结如下表。
Chothia | AbM | Kabat | Contact | IMGT | |
LCDR1 | L24-34 | L24-34 | L24-34 | L30-36 | L27-32 |
LCDR2 | L50-56 | L50-56 | L50-56 | L46-55 | L50-51 |
LCDR3 | L89-97 | L89-97 | L89-97 | L89-96 | L89-97 |
HCDR1 | H26-32 | H26-35 | H31-35 | H30-35 | H26-33 |
HCDR2 | H52-57 | H50-59 | H50-66 | H47-59 | H51-58 |
HCDR3 | H99-110 | H99-110 | H99-110 | H97-109 | H97-110 |
例如,使用不同的CDR标记的方法划分VH(SEQ ID NO:33)和/或VL(SEQ ID NO:40)可总结如下表。
Chothia | AbM | Kabat | Contact | IMGT | |
LCDR1 | L24-38 | L24-38 | L24-38 | L30-40 | L27-36 |
LCDR2 | L54-60 | L54-60 | L54-60 | L50-59 | L54-55 |
LCDR3 | L93-101 | L93-101 | L93-101 | L93-100 | L93-101 |
HCDR1 | H26-32 | H26-35 | H31-35 | H30-35 | H26-33 |
HCDR2 | H52-59 | H50-61 | H50-68 | H47-61 | H51-60 |
HCDR3 | H101-108 | H101-108 | H101-108 | H99-107 | H99-108 |
其中,Laa-Lbb可以指从抗体轻链可变区的N端开始,第aa位至第bb位的氨基酸序列;Haa-Hbb可以指从抗体重链可变区的N端开始,第aa位至第bb位的氨基酸序列。例如,L24-L34可以指从抗体轻链N端开始,第24位至第34位的氨基酸序列;H26-H35可以指从抗体重链N端开始,第26位至第35位的氨基酸序列。
做为其中一种情况,在本申请的序列表中,所述分离的抗原结合蛋白的CDR序列及框架区(FR)序列通过Kabat编号方式确定。
在本申请中,所述分离的抗原结合蛋白的所述VH可以包含HCDR1、HCDR2和HCDR3。
在本申请中,所述HCDR1可以包含SEQ ID NO:69所示的氨基酸序列。
X1X2WMX3(SEQ ID NO:69)。其中,X1可以为D或S;X2可以为A或Y;X3可以为D或H。
例如,所述HCDR1可包含SEQ ID NO:1或SEQ ID NO:27所示的氨基酸序列。
在本申请中,所述HCDR2可以包含SEQ ID NO:2或SEQ ID NO:28所示的氨基酸序列。
在本申请中,所述HCDR3可以包含SEQ ID NO:83或SEQ ID NO:29所示的氨基酸序列。
[-G][DI][RY]Y[DG][EY][DG][NY]AMDY(SEQ ID NO:83)。其中X1可以不存在或者为G;X2可以为D或I;X3可以为R或Y;X4可以为D或G;X5可以为E或Y;X6可以为D或G;X7可以为N或Y。
在本申请中,所述分离的抗原结合蛋白的HCDR1可包含SEQ ID NO:1或SEQ ID NO:27所示的氨基酸序列,HCDR2可包含SEQ ID NO:2或SEQ ID NO:28所示的氨基酸序列,且HCDR3可包含SEQ ID NO:3、SEQ ID NO:20和SEQ ID NO:29中任一项所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的所述HCDR1可包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2可包含SEQ ID NO:2所示的氨基酸序列,且所述HCDR3可包含SEQ IDNO:3所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的所述HCDR1可包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2可包含SEQ ID NO:2所示的氨基酸序列,且所述HCDR3可包含SEQ IDNO:20所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的所述HCDR1可包含SEQ ID NO:27所示的氨基酸序列,所述HCDR2可包含SEQ ID NO:28所示的氨基酸序列,且所述HCDR3可包含SEQID NO:29所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的所述VL可以包含LCDR1、LCDR2和LCDR3。
在本申请中,所述LCDR1可以包含SEQ ID NO:70或SEQ ID NO:34所示的氨基酸序列。
RASQDIX1NYLN(SEQ ID NO:70)。其中,X1可以为S或T。
例如,所述LCDR1可包含SEQ ID NO:9、SEQ ID NO:23和SEQ ID NO:34中任一项所示的氨基酸序列。
在本申请中,所述LCDR2可以包含SEQ ID NO:71所示的氨基酸序列。
YX1SX2LX3S(SEQ ID NO:71)。其中,X1可以为A或T;X2可以为N或R;X3可以为H或Q。
例如,所述LCDR2可包含SEQ ID NO:10或SEQ ID NO:35所示的氨基酸序列。
在本申请中,所述LCDR3可以包含SEQ ID NO:72所示的氨基酸序列。
QX1X2X3X4X5PX6T(SEQ ID NO:72)。例如,X1可以为H或Q;X2可以为G或S;X3可以为D、N或W;X4可以为E或T;X5可以为I或L;X6可以为P或R。
例如,所述LCDR3可包含SEQ ID NO:11、SEQ ID NO:24和SEQ ID NO:36中任一项所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的LCDR1可包含SEQ ID NO:70或SEQ IDNO:34所示的氨基酸序列,LCDR2可包含SEQ ID NO:71所示的氨基酸序列,且LCDR3可包含SEQ ID NO:72所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的所述LCDR1可包含SEQ ID NO:9所示的氨基酸序列,所述LCDR2可包含SEQ ID NO:10所示的氨基酸序列,且所述LCDR3可包含SEQ IDNO:11所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的所述LCDR1可包含SEQ ID NO:23所示的氨基酸序列,所述LCDR2可包含SEQ ID NO:10所示的氨基酸序列,且所述LCDR3可包含SEQID NO:24所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的所述LCDR1可包含SEQ ID NO:34所示的氨基酸序列,所述LCDR2可包含SEQ ID NO:35所示的氨基酸序列,且所述LCDR3可包含SEQID NO:36所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可包含HCDR1,HCDR2,HCDR3,LCDR1,LCDR2和LCDR3。
在本申请中,所述分离的抗原结合蛋白的HCDR1可包含SEQ ID NO:1或SEQ ID NO:27所示的氨基酸序列,HCDR2可包含SEQ ID NO:2或SEQ ID NO:28所示的氨基酸序列,HCDR3可包含SEQ ID NO:3、SEQ ID NO:20和SEQ ID NO:29中任一项所示的氨基酸序列,LCDR1可包含SEQ ID NO:9、SEQ ID NO:23和SEQ ID NO:34中任一项所示的氨基酸序列,LCDR2可包含SEQ ID NO:10或SEQ ID NO:35所示的氨基酸序列,且LCDR3可包含SEQ ID NO:11、SEQ IDNO:24和SEQ ID NO:36中任一项所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的HCDR1,HCDR2,HCDR3,LCDR1,LCDR2和LCDR3可包含选自下组的氨基酸序列:
(1)所述HCDR1可包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2可包含SEQ IDNO:2所示的氨基酸序列,所述HCDR3可包含SEQ ID NO:3所示的氨基酸序列,所述LCDR1可包含SEQ ID NO:9所示的氨基酸序列,所述LCDR2可包含SEQ ID NO:10所示的氨基酸序列,所述LCDR3可包含SEQ ID NO:11所示的氨基酸序列;
(2)所述HCDR1可包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2可包含SEQ IDNO:2所示的氨基酸序列,所述HCDR3可包含SEQ ID NO:20所示的氨基酸序列,所述LCDR1可包含SEQ ID NO:23所示的氨基酸序列,所述LCDR2可包含SEQ ID NO:10所示的氨基酸序列,所述LCDR3可包含SEQ ID NO:24所示的氨基酸序列;以及
(3)所述HCDR1可包含SEQ ID NO:27所示的氨基酸序列,所述HCDR2可包含SEQ IDNO:28所示的氨基酸序列,所述HCDR3可包含SEQ ID NO:29所示的氨基酸序列,所述LCDR1可包含SEQ ID NO:34所示的氨基酸序列,所述LCDR2可包含SEQ ID NO:35所示的氨基酸序列,所述LCDR3可包含SEQ ID NO:36所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的所述VH可以包含框架区H-FR1,H-FR2,H-FR3,和H-FR4。
在本申请中,所述H-FR1的C末端可以与所述HCDR1的N末端直接或间接相连,且所述H-FR1可以包含SEQ ID NO:73所示的氨基酸序列。
X1VX2LX3X4X5GX6X7X8X9X10PGX11SX12KX13SCX14ASGX15TFX16(SEQ ID NO:73)。其中,X1可以为E或Q;X2可以为K或Q;X3可以为E、V或Q;X4可以为E或Q;X5可以为P或S;X6可以为A或G;X7可以为E或G;X8可以为L或V;X9可以为K或V;X10可以为K或Q;X11可以为A或G;X12可以为M或V;X13可以为L或V;X14可以为A或K;X15可以为F或Y;X16可以为S或T。
例如,所述H-FR1可包含SEQ ID NO:4、SEQ ID NO:17、SEQ ID NO:30和SEQ ID NO:41中任一项所示的氨基酸序列。
在本申请中,所述H-FR2可以位于所述HCDR1与所述HCDR2之间,且所述H-FR2可以包含SEQ ID NO:74所示的氨基酸序列。
WVX1QX2PX3X4GLEWX5X6(SEQ ID NO:74)。其中,X1可以为K或R;X2可以为A、R或S;X3可以为E或G;X4可以为K或Q;X5可以为I、M或V;X6可以为A或G。
例如,所述H-FR2可包含SEQ ID NO:5、SEQ ID NO:31、SEQ ID NO:42和SEQ ID NO:53中任一项所示的氨基酸序列。
在本申请中,所述H-FR3可以位于所述HCDR2与所述HCDR3之间,且所述H-FR3可以包含SEQ ID NO:75所示的氨基酸序列。
X1X2TX3X4X5DX6SX7SX8X9YX10X11X12X13SLX14X15EDX16X17X18YYCX19R(SEQ ID NO:75)。其中,X1可以为K或R;X2可以为A、F或V;X3可以为I、L或M;X4可以为I、S或T;X5可以为R或V;X6可以为D、K或T;X7可以为K、S或T;X8可以为S或T;X9可以为A或V;X10可以为L、M或V;X11可以为E或Q;X12可以为L或M;X13可以为N或S;X14可以为R或T;X15可以为A或S;X16可以为S或T;X17可以为A或G;X18可以为I或V;X19可以为A或T。
例如,所述H-FR3可包含SEQ ID NO:6、SEQ ID NO:18、SEQ ID NO:21、SEQ ID NO:32、SEQ ID NO:43、SEQ ID NO:54和SEQ ID NO:57中任一项所示的氨基酸序列。
在本申请中,所述H-FR4的N末端可以与所述HCDR3的C末端相连,且所述H-FR4可以包含SEQ ID NO:76所示的氨基酸序列。
GQGTX1VTVSS(SEQ ID NO:76)。其中,X1可以为S或T。
例如,所述H-FR4可包含SEQ ID NO:7或SEQ ID NO:44所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的H-FR1可包含SEQ ID NO:73所示的氨基酸序列,H-FR2可包含SEQ ID NO:74所示的氨基酸序列,H-FR3可包含SEQ ID NO:75所示的氨基酸序列,H-FR4可包含SEQ ID NO:76所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的H-FR1,H-FR2,H-FR3和H-FR4可包含如下组所示的氨基酸序列:
(1)所述H-FR1包含SEQ ID NO:4所示的氨基酸序列,所述H-FR2包含SEQ ID NO:5所示的氨基酸序列,所述H-FR3包含SEQ ID NO:6所示的氨基酸序列,且所述H-FR4包含SEQID NO:7所示的氨基酸序列;
(2)所述H-FR1包含SEQ ID NO:17所示的氨基酸序列,所述H-FR2包含SEQ ID NO:5所示的氨基酸序列,所述H-FR3包含SEQ ID NO:18所示的氨基酸序列,且所述H-FR4包含SEQID NO:7所示的氨基酸序列;
(3)所述H-FR1包含SEQ ID NO:4所示的氨基酸序列,所述H-FR2包含SEQ ID NO:5所示的氨基酸序列,所述H-FR3包含SEQ ID NO:21所示的氨基酸序列,且所述H-FR4包含SEQID NO:7所示的氨基酸序列;
(4)所述H-FR1包含SEQ ID NO:30所示的氨基酸序列,所述H-FR2包含SEQ ID NO:31所示的氨基酸序列,所述H-FR3包含SEQ ID NO:32所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:7所示的氨基酸序列;
(5)所述H-FR1包含SEQ ID NO:41所示的氨基酸序列,所述H-FR2包含SEQ ID NO:42所示的氨基酸序列,所述H-FR3包含SEQ ID NO:43所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:44所示的氨基酸序列;
(6)所述H-FR1包含SEQ ID NO:41所示的氨基酸序列,所述H-FR2包含SEQ ID NO:53所示的氨基酸序列,所述H-FR3包含SEQ ID NO:54所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:44所示的氨基酸序列;
(7)所述H-FR1包含SEQ ID NO:41所示的氨基酸序列,所述H-FR2包含SEQ ID NO:53所示的氨基酸序列,所述H-FR3包含SEQ ID NO:57所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:44所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白的VL可以包含框架区L-FR1,L-FR2,L-FR3,和L-FR4。
在本申请中,所述L-FR1的C末端可以与所述LCDR1的N末端直接或间接相连,且所述L-FR1可以包含SEQ ID NO:77所示的氨基酸序列。
DIX1MTX2X3X4X5SLX6X7SX8GX9RX10TIX11C(SEQ ID NO:77)。其中,X1可以为Q或V;X2可以为H或Q;X3可以为S或T;X4可以为P或T;X5可以为A或S;X6可以为A或S;X7可以为A或V;X8可以为L或V;X9可以为D或Q;X10可以为A或V;X11可以为S或T。
例如,所述L-FR1可包含SEQ ID NO:12、SEQ ID NO:25、SEQ ID NO:37和SEQ IDNO:47中任一项所示的氨基酸序列。
在本申请中,所述L-FR2可以位于所述LCDR1与所述LCDR2之间,且所述L-FR2可以包含SEQ ID NO:78所示的氨基酸序列。
WYQQKPX1X2X3X4KLLIX5(SEQ ID NO:78)。其中,X1可以为D或G;X2可以为G、K或Q;X3可以为A、P或T;X4可以为P或V;X5可以为K或Y。
例如,所述L-FR2可包含SEQ ID NO:13、SEQ ID NO:38和SEQ ID NO:48中任一项所示的氨基酸序列。
在本申请中,所述L-FR3可以位于所述LCDR2与所述LCDR3之间,且所述L-FR3可以包含SEQ ID NO:79所示的氨基酸序列。
GVPX1RFSGSGSGTX2X3X4X5X6IX7X8X9X10X11X12DX13ATYX14C(SEQ ID NO:79)。其中,X1可以为A或S;X2可以为D或E;X3可以为F或Y;X4可以为S或T;X5可以为F或L;X6可以为N或T;X7可以为H或S;X8可以为N、P或S;X9可以为L或V;X10可以为E或Q;X11可以为E、P或Q;X12可以为D或E;X13可以为F、I或S;X14可以为F或Y。
例如,所述L-FR3可包含SEQ ID NO:14、SEQ ID NO:39、SEQ ID NO:49和SEQ IDNO:60中任一项所示的氨基酸序列。
在本申请中,所述L-FR4的N末端可以与所述HCDR3的C末端相连,且所述L-FR4可以包含SEQ ID NO:80所示的氨基酸序列。
FGX1GTX2LEIK(SEQ ID NO:80)。其中X1可以为G或Q;X2可以为K或R。
例如,所述L-FR4可包含SEQ ID NO:15或SEQ ID NO:50所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的L-FR1可包含SEQ ID NO:77所示的氨基酸序列,L-FR2可包含SEQ ID NO:78所示的氨基酸序列,L-FR3可包含SEQ ID NO:79所示的氨基酸序列,L-FR4可包含SEQ ID NO:80所示的氨基酸序列。
例如,本申请所述的分离的抗原结合蛋白的H-FR1,H-FR2,H-FR3和H-FR4可包含如下组所示的氨基酸序列:
(1)所述L-FR1包含SEQ ID NO:12所示的氨基酸序列,所述L-FR2包含SEQ ID NO:13所示的氨基酸序列,所述L-FR3包含SEQ ID NO:14所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:15所示的氨基酸序列;
(2)所述L-FR1包含SEQ ID NO:25所示的氨基酸序列,所述L-FR2包含SEQ ID NO:13所示的氨基酸序列,所述L-FR3包含SEQ ID NO:14所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:15所示的氨基酸序列;
(3)所述L-FR1包含SEQ ID NO:37所示的氨基酸序列,所述L-FR2包含SEQ ID NO:38所示的氨基酸序列,所述L-FR3包含SEQ ID NO:39所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:15所示的氨基酸序列;
(4)所述L-FR1包含SEQ ID NO:47所示的氨基酸序列,所述L-FR2包含SEQ ID NO:48所示的氨基酸序列,所述L-FR3包含SEQ ID NO:49所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:50所示的氨基酸序列;以及
(5)所述L-FR1包含SEQ ID NO:47所示的氨基酸序列,所述L-FR2包含SEQ ID NO:48所示的氨基酸序列,所述L-FR3包含SEQ ID NO:60所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:50所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白可包含HCDR1,HCDR2,HCDR3,LCDR1,LCDR2和LCDR3。
例如,所述分离的抗原结合蛋白的所述HCDR1可包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2可包含SEQ ID NO:2所示的氨基酸序列,所述HCDR3可包含SEQ ID NO:3所示的氨基酸序列,所述LCDR1可包含SEQ ID NO:9所示的氨基酸序列,所述LCDR2可包含SEQ IDNO:10所示的氨基酸序列,所述LCDR3可包含SEQ ID NO:11所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述HCDR1可包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2可包含SEQ ID NO:2所示的氨基酸序列,所述HCDR3可包含SEQ ID NO:20所示的氨基酸序列,所述LCDR1可包含SEQ ID NO:23所示的氨基酸序列,所述LCDR2可包含SEQID NO:10所示的氨基酸序列,所述LCDR3可包含SEQ ID NO:24所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述HCDR1可包含SEQ ID NO:27所示的氨基酸序列,所述HCDR2可包含SEQ ID NO:28所示的氨基酸序列,所述HCDR3可包含SEQ ID NO:29所示的氨基酸序列,所述LCDR1可包含SEQ ID NO:34所示的氨基酸序列,所述LCDR2可包含SEQ ID NO:35所示的氨基酸序列,所述LCDR3可包含SEQ ID NO:36所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白可包含抗体轻链可变区VH和抗体重链可变区VL。
在本申请中,所述VH可包含SEQ ID NO:81、SEQ ID NO:33和SEQ ID NO:22中任一项所示的氨基酸序列。例如,所述VH可包含SEQ ID NO:8、SEQ ID NO:19、SEQ ID NO:22、SEQID NO:33、SEQ ID NO:45、SEQ ID NO:55和SEQ ID NO:58中任一项所示的氨基酸序列。
在本申请中,所述VL可包含SEQ ID NO:82或SEQ ID NO:40所示的氨基酸序列。例如,所述VL可包含SEQ ID NO:16、SEQ ID NO:26、SEQ ID NO:40、SEQ ID NO:51和SEQ IDNO:61中任一项所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述VH可包含SEQ ID NO:8所示的氨基酸序列,所述VL可包含SEQ ID NO:16所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述VH可包含SEQ ID NO:19所示的氨基酸序列,所述VL可包含SEQ ID NO:16所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述VH可包含SEQ ID NO:22所示的氨基酸序列,所述VL可包含SEQ ID NO:26所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述VH可包含SEQ ID NO:33所示的氨基酸序列,所述VL可包含SEQ ID NO:40所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述VH可包含SEQ ID NO:45所示的氨基酸序列,所述VL可包含SEQ ID NO:51所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述VH可包含SEQ ID NO:55所示的氨基酸序列,所述VL可包含SEQ ID NO:51所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述VH可包含SEQ ID NO:58所示的氨基酸序列,所述VL可包含SEQ ID NO:51所示的氨基酸序列。
例如,所述分离的抗原结合蛋白的所述VH可包含SEQ ID NO:45所示的氨基酸序列,所述VL可包含SEQ ID NO:61所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG重链恒定区。
在某些实施方式中,所述分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG1重链恒定区。在另一些实施方式中,所述分离的抗原结合蛋白可以包括抗体重链恒定区,且所述抗体重链恒定区可以源自人IgG4重链恒定区。
例如,所述抗体重链恒定区可以包含SEQ ID NO:63所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包括抗体轻链恒定区,且所述抗体轻链恒定区可以包括人Igκ恒定区。例如,所述抗体轻链恒定区可以包含SEQ ID NO:64所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包含抗体重链HC,且所述HC可以包含SEQ ID NO:46、SEQ ID NO:56、SEQ ID NO:59、SEQ ID NO:86、SEQ ID NO:88、SEQ ID NO:89和SEQ ID NO:91中任一项所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可以包含抗体轻链LC,且所述LC可以包含SEQ ID NO:52、SEQ ID NO:62、SEQ ID NO:87、SEQ ID NO:90和SEQ ID NO:92中任一项所示的氨基酸序列。
本申请所述的分离的抗原结合蛋白可以包含抗体重链和抗体轻链。
例如,所述抗体重链可包含SEQ ID NO:86所示的氨基酸序列,且所述抗体轻链可包含SEQ ID NO:87所示的氨基酸序列。
例如,所述抗体重链可包含SEQ ID NO:88所示的氨基酸序列,且所述抗体轻链可包含SEQ ID NO:87所示的氨基酸序列。
例如,所述抗体重链可包含SEQ ID NO:89所示的氨基酸序列,且所述抗体轻链可包含SEQ ID NO:90所示的氨基酸序列。
例如,所述抗体重链可包含SEQ ID NO:91所示的氨基酸序列,且所述抗体轻链可包含SEQ ID NO:92所示的氨基酸序列。
例如,所述抗体重链可包含SEQ ID NO:46所示的氨基酸序列,且所述抗体轻链可包含SEQ ID NO:52所示的氨基酸序列。
例如,所述抗体重链可包含SEQ ID NO:56所示的氨基酸序列,且所述抗体轻链可包含SEQ ID NO:52所示的氨基酸序列。
例如,所述抗体重链可包含SEQ ID NO:59所示的氨基酸序列,且所述抗体轻链可包含SEQ ID NO:52所示的氨基酸序列。
例如,所述抗体重链可包含SEQ ID NO:46所示的氨基酸序列,且所述抗体轻链可包含SEQ ID NO:62所示的氨基酸序列。
此外,需要说明的是,本申请所述分离的抗原结合蛋白可以包含与本申请所述的抗原结合蛋白存在一个或多个保守序列修饰的重链和/或轻链序列。所谓“保守序列修饰”是指不会显著影响或改变抗体结合特性的氨基酸修饰。这样的保守修饰包括氨基酸替换、添加和删除。可以通过领域内已知的标准技术,例如点突变和PCR介导的突变,将修饰引入本申请所述分离的抗原结合蛋白中。保守氨基酸替换是氨基酸残基用具有相似侧链的氨基酸残基进行替换。具有相似侧链的氨基酸残基组在领域内已知。这些氨基酸残基组包括具有碱性侧链(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链(例如,天冬氨酸、谷氨酸)、不带电极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。在某些实施方式中,本申请所述分离的抗原结合蛋白的CDR区中的一个或多个氨基酸残基可以用同侧链组的其他氨基酸残基替换。本领域内的技术人员知道,一些保守序列修改不会使抗原结合性消失,具体可以参见,例如,Brummell et al.,(1993)Biochem 32:1180-8;de Wildt et al.,(1997)Prot.Eng.10:835-41;Komissarov et al.,(1997)J.Biol.Chem.272:26864-26870;Hall et al.,(1992)J.Immunol.149:1605-12;Kelley and O'Connell(1993)Biochem.32:6862-35;Adib-Conquy et al.,(1998)Int.Immunol.10:341-6 and Beers et al.,(2000)Clin.Can.Res.6:2835-43。
在本申请中涉及的蛋白质、多肽和/或氨基酸序列,还应理解为至少包含以下的范围:与该所述蛋白质或多肽具备相同或类似功能的变体或同源物。
在本申请中,所述变体可以为,在所述蛋白质和/或所述多肽(例如,本申请所述分离的抗原结合蛋白)的氨基酸序列中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽。例如,所述变体可包含已经通过至少1个,例如1-30个、1-20个或1-10个,又例如1个、2个、3个、4个或5个氨基酸取代、缺失和/或插入而具有氨基酸改变的蛋白质或多肽。所述功能性变体可基本上保持改变(例如取代、缺失或添加)之前的所述蛋白质或所述多肽的生物学特性。例如,所述功能性变体可保持改变之前的所述蛋白质或所述多肽的至少60%,70%,80%,90%,或100%的生物学活性(例如特异性结合LILRB4蛋白的能力)。
在本申请中,所述同源物可以为,与所述蛋白质和/或所述多肽(例如,本申请所述抗体或其抗原结合片段)的氨基酸序列具有至少约80%(例如,具有至少约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
在本申请中,所述同源性通常是指两个或多个序列之间的相似性或关联的程度。可以通过以下方式计算“序列同源性百分比”:将两条待比对的序列在比较窗中进行比较,确定两条序列中存在相同核酸碱基(例如,A、T、C、G、I)或相同氨基酸残基(例如,Ala、Pro、Ser、Thr、Gly、Val、Leu、Ile、Phe、Tyr、Trp、Lys、Arg、His、Asp、Glu、Asn、Gln、Cys和Met)的位置的数目以得到匹配位置的数目,将匹配位置的数目除以比较窗中的总位置数(即,窗大小),并且将结果乘以100,以产生序列同源性百分比。为了确定序列同源性百分数而进行的比对,可以按本领域已知的多种方式实现,例如,使用可公开获得的计算机软件如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以确定用于比对序列的适宜参数,包括为实现正在比较的全长序列范围内或目标序列区域内最大比对所需要的任何算法。所述同源性也可以通过以下的方法测定:FASTA和BLAST。对FASTA算法的描述可以参见W.R.Pearson和D.J.Lipman的“用于生物学序列比较的改进的工具”,美国国家科学院院刊(Proc.Natl.Acad.Sci.),85:2444-2448,1988;和D.J.Lipman和W.R.Pearson的“快速灵敏的蛋白质相似性搜索”,Science,227:1435-1441,1989。对BLAST算法的描述可参见S.Altschul、W.Gish、W.Miller、E.W.Myers和D.Lipman的“一种基本的局部对比(alignment)搜索工具”,分子生物学杂志,215:403-410,1990。
在本申请中,所述分离的抗原结合蛋白可以包括抗体或其抗原结合片段。例如,本申请所述的分离的抗原结合蛋白可以包括但不限于重组抗体、单克隆抗体、人抗体、鼠源抗体、人源化抗体、嵌合抗体、单链抗体、多抗体、Fv片段、scFv片段、Fab片段、Fab'片段、F(ab')2片段和骆驼化单结构域抗体。
在本申请中,所述抗体可以为人源化抗体。换句话说,本申请所述的分离的抗原结合蛋白,其可以为免疫特异性结合至相关抗原(例如人LILRB4)且包含基本上具有人类抗体的氨基酸序列的框架(FR)区及基本上具有非人类抗体的氨基酸序列的互补决定区(CDR)的抗体或其变异体、衍生物、类似物或片段。此处的“基本上”在CDR的情况下是指CDR的氨基酸序列与非人类抗体CDR的氨基酸序列至少80%、优选至少85%、至少90%、至少95%、至少98%或至少99%同一。所述人源化抗体基本上可以包含所有至少一个且通常两个可变域(Fab、Fab′、F(ab′)2、FabC、Fv),其中所有或基本上所有CDR区对应于非人类免疫球蛋白(即抗体)的CDR区且所有或基本上所有框架区为具有人类免疫球蛋白共有序列的框架区。优选地,人源化抗体还包含至少一部分免疫球蛋白恒定区(例如,Fc),通常为人类免疫球蛋白的恒定区。在一些实施例中,人源化抗体含有轻链以及重链的至少可变域。抗体还可包括重链的CH1、铰链、CH2、CH3及CH4区。在一些实施例中,人源化抗体仅含人源化轻链。在一些实施例中,人源化抗体仅含人源化重链。在特定实施例中,人源化抗体仅含轻链和/或人源化重链的人源化可变域。
在本申请中,所述抗原结合片段可以包括Fab,Fab’,F(ab)2、Fv片段、F(ab’)2,scFv,di-scFv和/或dAb。
在本申请中,所述分离的抗原结合蛋白可具有下述性质中的一种或多种:1)能够特异性识别白细胞免疫球蛋白样受体B4(LILRB4);2)能够以2×10-7M或更低的KD值与LILRB4蛋白相结合;3)能够阻断LILRB4/APOE结合的活性;4)能够刺激CD8+T细胞的活化;5)能够抑制人单核白血病细胞THP-1的迁移;6)能够抑制肿瘤细胞的生长和/或转移;7)能够阻断LILRB4与Fibronectin的结合。
在本申请中,所述分离的抗原结合蛋白能够以2×10-7M或更低的KD与LILRB4蛋白相结合。例如,本申请所述的分离的抗原结合蛋白结合人LILRB4蛋白的KD值可以为≤2×10-7M、≤1.5×10-7M、≤1×10-7M、≤9×10-8M、≤8×10-8M、≤7×10-8M、≤6×10-8M、≤5×10- 8M、≤4×10-8M、≤3×10-8M、≤2×10-8M、≤1.5×10-8M、≤1.2×10-8M、≤1.15×10-8M、≤1.1×10-8M、≤1.05×10-8M、≤1×10-8M、≤5×10-9M或≤1×10-9M。
在本申请中,所述KD值还可以通过ELISA、竞争ELISA或BIACORE或KINEXA进行测定。
在本申请中,所述分离的抗原结合蛋白能够特异性结合人LILRB4蛋白。所述特异性结合可以通过FACS测定。
在本申请中,所述LILRB4蛋白可以为人LILRB4蛋白(GenBank登录号:CAG46845.1)。
所述LILRB4蛋白可以包括LILRB4蛋白的变体。例如,所述变体可以为:1)在所述LILRB4蛋白的氨基酸序列中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和2)与所述LILRB4蛋白具有至少约85%(例如,具有至少约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
所述LILRB4蛋白还可以包括LILRB4蛋白的功能活性片段。
多肽、融合蛋白、药物分子、核酸分子、载体、细胞和药物组合物
另一方面,本申请提供了多肽,其包含所述分离的抗原结合蛋白。
另一方面,本申请提供了融合蛋白,其包含所述分离的抗原结合蛋白。
另一方面,本申请提供了药物分子,其包含所述分离的抗原结合蛋白。
另一方面,本申请提供了分离的一种或多种核酸分子,其编码所述分离的抗原结合蛋白。本申请所述的分离的一种或多种核酸分子可以为任何长度的分离形式的核苷酸,脱氧核糖核苷酸或核糖核苷酸,或从其天然环境分离的或人工合成的类似物,但可以编码本申请所述的分离的抗原结合蛋白。
另一方面,本申请还提供了载体,其可以包含本申请所述的核酸分子。所述载体可通过转化、转导或转染宿主细胞,使其携带的遗传物质元件在宿主细胞内表达得以表达。例如,载体可以包括:质粒;噬菌粒;柯斯质粒;人工染色体如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。用作载体的动物病毒种类有逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。又例如,所述载体可以含有多种控制表达的元件,包括启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,所述载体还可以含有复制起始位点。此外,所述载体还可以包括有协助其进入细胞的成分,如病毒颗粒、脂质体或蛋白外壳,但不仅仅只有这些物质。
另一方面,本申请还提供了细胞,其可以包含本申请所述的核酸分子或本申请所述的载体。所述细胞可以包括单个细胞的后代。由于天然、偶然或有意的突变,后代可以不一定与原始母细胞完全相同(在总DNA互补体的形态上或在基因组上)。在某些实施方式中,所述细胞还可以包括用本发明所述的载体在体外转染的细胞。在某些实施方式中,所述细胞可以是细菌细胞(例如,大肠杆菌)、酵母细胞或其它真核细胞。
另一方面,本申请还提供了药物组合物,其可以包含本申请所述的分离的抗原结合蛋白、本申请所述的多肽、本申请所述的融合蛋白、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的细胞,以及任选地药学上可接受的载剂。
在某些实施方案中,所述药物组合物还可以包含一种或多种(药学上有效的)载剂、稳定剂、赋形剂、稀释剂、增溶剂、表面活性剂、乳化剂和/或防腐剂的合适的制剂。组合物的可接受成分在所用剂量和浓度下优选地对接受者无毒。本发明的药物组合物包括但不限于液体、冷冻和冻干组合物。
在某些实施方案中,所述药学上可接受的佐剂可以包括与药物给药相容的任何和所有的溶剂、分散介质、包衣、等渗剂和吸收延迟剂,通常安全、无毒,且既不是生物学上也非其它方面不合需要的。
在某些实施方案中,所述药物组合物可以包含肠胃外、经皮、腔内、动脉内、鞘内和/或鼻内施用或直接注射到组织中。例如,所述药物组合物可以通过输注或注射施用于患者或者受试者。在某些实施方案中,所述药物组合物的施用可以通过不同的方式进行,例如静脉内、腹膜内、皮下、肌肉内、局部或真皮内施用。在某些实施方案中,所述药物组合物可以不间断施用。所述不间断(或连续)施用可以通过患者佩戴的小泵系统来实现,以测量流入患者体内的治疗剂,如WO2015/036583所述。
在本申请中,所述药物组合物可进一步包括选自下组的一种或多种药物:蒽环类拓扑异构酶抑制剂、柔红霉素、阿糖胞苷核苷代谢抑制剂、联合柔红霉素、阿糖胞苷、柔红霉素和阿糖胞苷脂质体注射液、Vyxeos、全反式维甲酸(ATRA)、砷、三氧化二砷、组胺盐酸盐、二盐酸组胺(Ceplene)、白细胞介素-2、白细胞介素2(Proleukin)、吉妥珠单抗奥唑米(Mylotarg)、氯法拉滨、法呢基转移酶抑制剂、地西他滨、IDH1抑制剂、IDH2抑制剂、恩西地平、Idhifa、IDO抑制剂、epacadostat、铂络合物的衍生物、奥沙利铂,激酶抑制剂、酪氨酸激酶抑制剂、PI3激酶抑制剂,BTK抑制剂Ibrutinib,PD-1抗体、PD-L1抗体、抗CTLA-4抗体、LAG3抗体、ICOS抗体,TIGIT抗体、TIM3抗体、结合肿瘤抗原的抗体、结合T细胞表面标记的抗体、结合细胞或NK细胞表面标志物的抗体、烷基化剂、亚硝基脲剂、抗代谢药物、抗肿瘤抗生素、来源于植物的生物碱、拓扑异构酶抑制剂、激素治疗药物、激素拮抗剂、芳香酶抑制剂和P-糖蛋白抑制剂。
制备方法和用途
另一方面,本申请还提供了制备本申请所述的分离的抗原结合蛋白的方法,所述方法可以包括在使得本申请所述的分离的抗原结合蛋白表达的条件下,培养本申请所述的细胞。
另一方面,本申请提供了所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体、所述细胞、和/或所述药物组合物在制备药物中的用途,所述药物用于预防和/或治疗疾病和/或病症。
另一方面,本申请提供了所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体、所述细胞、和/或所述药物组合物,其用于预防和/或治疗疾病和/或病症。
另一方面,本申请提供了一种预防和/或治疗疾病和/或病症的方法,其包括向有需要的受试者施用有效量的所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体、所述细胞、和/或所述药物组合物。
在本申请中,所述施用可以通过不同的方式进行,例如静脉内、瘤内、腹膜内、皮下、肌肉内、局部或真皮内施用。
在本申请中,所述疾病和/或病症可包括与LILRB4信号传导相关的疾病或病症。
在本申请中,所述疾病和/或病症可包括肿瘤。
在本申请中,所述疾病和/或病症可包括LILRB4阳性疾病和/或病症。
在本申请中,所述肿瘤可包括实体瘤和/或血液瘤。
在本申请中,所述与LILRB4信号传导相关的疾病或病症可包括免疫系统疾病和/或恶性血液疾病。
在本申请中,所述免疫系统疾病可选自下组中的一种或多种:川崎病、系统性红斑狼疮(SLE)、败血症。
在本申请中,所述实体瘤可选自下组中的一种或多种:乳腺癌,黑色素瘤,结肠癌,肺癌,肾癌和胰腺癌。
在本申请中,所述恶性血液疾病可选自下组中的一种或多种:骨髓发育不良综合症、骨髓增生性肿瘤、慢性粒单核细胞白血病(CMML)、慢性髓细胞白血病,或急性髓细胞白血病(AML)、急性早幼粒细胞白血病(APL)或M3 AML、急性粒单核细胞白血病或M4 AML、急性单核细胞白血病或M5 AML、急性骨髓母细胞白血病,以及真性红细胞增多症。
在本申请中,所述分离的抗原结合蛋白、所述多肽、所述融合蛋白、所述药物分子、所述核酸分子、所述载体、所述细胞、所述药物组合物和/或所述药物可与选自下组的一种或多种药物联合使用:蒽环类拓扑异构酶抑制剂、柔红霉素、阿糖胞苷核苷代谢抑制剂、联合柔红霉素、阿糖胞苷、柔红霉素和阿糖胞苷脂质体注射液、Vyxeos、全反式维甲酸(ATRA)、砷、三氧化二砷、组胺盐酸盐、二盐酸组胺(Ceplene)、白细胞介素-2、白细胞介素2(Proleukin)、吉妥珠单抗奥唑米(Mylotarg)、氯法拉滨、法呢基转移酶抑制剂、地西他滨、IDH1抑制剂、IDH2抑制剂、恩西地平、Idhifa、IDO抑制剂、epacadostat、铂络合物的衍生物、奥沙利铂,激酶抑制剂、酪氨酸激酶抑制剂、PI3激酶抑制剂,BTK抑制剂Ibrutinib,PD-1抗体、PD-L1抗体、抗CTLA-4抗体、LAG3抗体、ICOS抗体,TIGIT抗体、TIM3抗体、结合肿瘤抗原的抗体,结合T细胞表面标记的抗体、结合细胞或NK细胞表面标志物的抗体、烷基化剂、亚硝基脲剂、抗代谢药物、抗肿瘤抗生素、来源于植物的生物碱、拓扑异构酶抑制剂、激素治疗药物、激素拮抗剂、芳香酶抑制剂和P-糖蛋白抑制剂。
另一方面,本申请提供了根据所述的抗体或其抗原结合片段用于制备诊断剂的用途,其中所述诊断剂用于诊断与LILRB4蛋白的表达相关的疾病或病况。
另一方面,本申请提供了根据所述的分离的抗原结合蛋白,其用于诊断与LILRB4蛋白的表达相关的疾病或病况。
在本申请中,所述诊断剂可以单独使用或者可以与仪器、器具、设备或系统组合使用。在疾病的预防、诊断、治疗监测、预后观察、健康状态评价以及遗传性疾病的预测过程中,可以使用所述诊断剂对人体样本(例如,各种体液、细胞、组织样本等)进行体外检测。所述诊断剂可以选自以下组:试剂、试剂盒、校准品和质控品。
所述体外检测的方法可以选自以下组:Western Blot、ELISA和免疫组化法。例如,所述试剂可以包括能够测量所述LILRB4蛋白表达量的试剂。例如,所述试剂可以选自以下组:用以实施Western Blot的试剂、用以实施ELISA的试剂和用以实施免疫组化法的试剂。
另一方面,本申请中提供了检测试剂盒,其包含所述分离的抗原结合蛋白,所述检测试剂盒用于检测样品中LILRB4蛋白的存在和/或含量。特别地,本申请涉及利用本申请的抗体结合ELISA、免疫组化、蛋白印迹、流式细胞技术等免疫检测方法使用的免疫检测试剂盒。
试剂盒中包括本申请的抗体,用于检测LILRB4相关癌细胞,具体地,免疫检测试剂盒将在适合容器构件中包含本申请的抗体作为结合至LILRB4的第一抗体,以及任选的免疫检测试剂。
在某些实施例中,抗体可预先结合至固体载体,例如柱基质和/或微量滴定板孔。
试剂盒中的免疫检测试剂可呈多种形式中的任一者,包括与给定抗体结合或连接的那些可检测标记。还可以包括与二级结合配体结合或连接的可检测标记。示例性二级配体是对第一抗体具有结合亲和力的那些二级抗体。
适用于本申请试剂盒中的其它免疫检测试剂包括双组分试剂,其包含对第一抗体具有结合亲和力的二级抗体,以及对第二抗体具有结合亲和力的第三抗体,第三抗体连接至可检测标记。如上所述,本领域中已知多种示例性标记且所有此类标记均可结合本公开使用。
试剂盒可进一步包含适当等分的LILRB4组合物,无论标记或未标记,其可用于制备供检测分析用的标准曲线。试剂盒可含有呈完全共轭形式、呈中间物形式的抗体-标记共轭物或由试剂盒的使用者完成共轭的各别部分。试剂盒的组分可封装于水性介质中或以冻干形式封装。
试剂盒的容器构件一般将包括至少一个小瓶、试管、烧瓶、瓶子、注射器,或其中可放入抗体或优选适当等分的抗体的其它容器构件。本公开的试剂盒通常还将包括用于容纳抗体、抗原及任何其它试剂容器的构件,其呈密封形式以供商业销售。此类容器可包括上述小瓶保留于其中的注射成型或吹塑成型塑料容器。
另一方面,本申请提供了一种诊断受试者中与LILRB4蛋白的表达相关的疾病或病况的方法,所述方法包括:使源自所述受试者的样品与所述的分离的抗原结合蛋白接触,以及判断所述样品中能够特异性结合所述分离的抗原结合蛋白的物质的存在和/或含量。
另一方面,本申请提供了一种检测样品或受试者中LILRB4的方法,所述方法包括施用所述的分离的抗原结合蛋白。在本申请中,所述施用可以通过不同的方式进行,例如静脉内、瘤内、腹膜内、皮下、肌肉内、局部或真皮内施用。
本申请还提供了以下实施方案:
1.分离的抗原结合蛋白,其包含抗体重链可变区VH中的至少一个CDR,且所述VH包含SEQ ID NO:81、SEQ ID NO:33和SEQ ID NO:22中任一项所示的氨基酸序列。
2.根据实施方案1所述的分离的抗原结合蛋白,其包含HCDR3,所述HCDR3包含SEQID NO:83或SEQ ID NO:29所示的氨基酸序列。
3.根据实施方案2所述的分离的抗原结合蛋白,其中所述HCDR3包含SEQ ID NO:3、SEQ ID NO:20和SEQ ID NO:29中任一项所示的氨基酸序列。
4.根据实施方案1-3中任一项所述的分离的抗原结合蛋白,其包含HCDR2,所述HCDR2包含SEQ ID NO:2或SEQ ID NO:28所示的氨基酸序列。
5.根据实施方案1-4中任一项所述的分离的抗原结合蛋白,其包含HCDR1,所述HCDR1包含SEQ ID NO:69所示的氨基酸序列。
6.根据实施方案5所述的分离的抗原结合蛋白,其中所述HCDR1包含SEQ ID NO:1或SEQ ID NO:27所示的氨基酸序列。
7.根据实施方案1-6中任一项所述的分离的抗原结合蛋白,其包含HCDR1,HCDR2和HCDR3,所述HCDR1,HCDR2和HCDR3包含选自下组的氨基酸序列:
(1)所述HCDR1包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2包含SEQ ID NO:2所示的氨基酸序列,且所述HCDR3包含SEQ ID NO:3所示的氨基酸序列;
(2)所述HCDR1包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2包含SEQ ID NO:2所示的氨基酸序列,且所述HCDR3包含SEQ ID NO:20所示的氨基酸序列;以及
(3)所述HCDR1包含SEQ ID NO:27所示的氨基酸序列,所述HCDR2包含SEQ ID NO:28所示的氨基酸序列,且所述HCDR3包含SEQ ID NO:29所示的氨基酸序列。
8.根据实施方案1-7中任一项所述的分离的抗原结合蛋白,其包含H-FR1,所述H-FR1的C端与所述HCDR1的N端直接或间接相连,且所述H-FR1包含SEQ ID NO:73所示的氨基酸序列。
9.根据实施方案8所述的分离的抗原结合蛋白,其中所述H-FR1包含SEQ ID NO:4、SEQ ID NO:17、SEQ ID NO:30和SEQ ID NO:41中任一项所示的氨基酸序列。
10.根据实施方案1-9中任一项所述的分离的抗原结合蛋白,其包含H-FR2,所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO:74所示的氨基酸序列。
11.根据实施方案10所述的分离的抗原结合蛋白,其中所述H-FR2包含SEQ ID NO:5、SEQ ID NO:31、SEQ ID NO:42和SEQ ID NO:53中任一项所示的氨基酸序列。
12.根据实施方案1-11中任一项所述的分离的抗原结合蛋白,其包含H-FR3,所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO:75所示的氨基酸序列。
13.根据实施方案12所述的分离的抗原结合蛋白,其中所述H-FR3包含SEQ ID NO:6、SEQ ID NO:18、SEQ ID NO:21、SEQ ID NO:32、SEQ ID NO:43、SEQ ID NO:54和SEQ IDNO:57中任一项所示的氨基酸序列。
14.根据实施方案1-13中任一项所述的分离的抗原结合蛋白,其包含H-FR4,所述H-FR4的N端与所述HCDR3的C端直接或间接相连,且所述H-FR4包含SEQ ID NO:76所示的氨基酸序列。
15.根据实施方案14所述的分离的抗原结合蛋白,其中所述H-FR4包含SEQ ID NO:7或SEQ ID NO:44所示的氨基酸序列。
16.根据实施方案1-15中任一项所述的分离的抗原结合蛋白,其包含H-FR1,H-FR2,H-FR3和H-FR4,所述H-FR1,H-FR2,H-FR3和H-FR4包含选自下组的氨基酸序列:
(1)所述H-FR1包含SEQ ID NO:4所示的氨基酸序列,所述H-FR2包含SEQ ID NO:5所示的氨基酸序列,所述H-FR3包含SEQ ID NO:6所示的氨基酸序列,且所述H-FR4包含SEQID NO:7所示的氨基酸序列;
(2)所述H-FR1包含SEQ ID NO:17所示的氨基酸序列,所述H-FR2包含SEQ ID NO:5所示的氨基酸序列,所述H-FR3包含SEQ ID NO:18所示的氨基酸序列,且所述H-FR4包含SEQID NO:7所示的氨基酸序列;
(3)所述H-FR1包含SEQ ID NO:4所示的氨基酸序列,所述H-FR2包含SEQ ID NO:5所示的氨基酸序列,所述H-FR3包含SEQ ID NO:21所示的氨基酸序列,且所述H-FR4包含SEQID NO:7所示的氨基酸序列;
(4)所述H-FR1包含SEQ ID NO:30所示的氨基酸序列,所述H-FR2包含SEQ ID NO:31所示的氨基酸序列,所述H-FR3包含SEQ ID NO:32所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:7所示的氨基酸序列;
(5)所述H-FR1包含SEQ ID NO:41所示的氨基酸序列,所述H-FR2包含SEQ ID NO:42所示的氨基酸序列,所述H-FR3包含SEQ ID NO:43所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:44所示的氨基酸序列;
(6)所述H-FR1包含SEQ ID NO:41所示的氨基酸序列,所述H-FR2包含SEQ ID NO:53所示的氨基酸序列,所述H-FR3包含SEQ ID NO:54所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:44所示的氨基酸序列;
(7)所述H-FR1包含SEQ ID NO:41所示的氨基酸序列,所述H-FR2包含SEQ ID NO:53所示的氨基酸序列,所述H-FR3包含SEQ ID NO:57所示的氨基酸序列,且所述H-FR4包含SEQ ID NO:44所示的氨基酸序列。
17.根据实施方案1-16中任一项所述的分离的抗原结合蛋白,其包含VH,所述VH包含SEQ ID NO:81、SEQ ID NO:33和SEQ ID NO:22中任一项所示的氨基酸序列。
18.根据实施方案1-17中任一项所述的分离的抗原结合蛋白,其中所述VH包含SEQID NO:8、SEQ ID NO:19、SEQ ID NO:22、SEQ ID NO:33、SEQ ID NO:45、SEQ ID NO:55和SEQID NO:58中任一项所示的氨基酸序列。
19.根据实施方案1-18中任一项所述的分离的抗原结合蛋白,其包含抗体重链恒定区,所述抗体重链恒定区源自IgG重链恒定区。
20.根据实施方案19所述的分离的抗原结合蛋白,其中所述抗体重链恒定区源自人IgG重链恒定区。
21.根据实施方案19-20中任一项所述的分离的抗原结合蛋白,其中所述抗体重链恒定区源自人IgG1重链恒定区或人IgG4重链恒定区。
22.根据实施方案19-21中任一项所述的分离的抗原结合蛋白,其中所述抗体重链恒定区包含SEQ ID NO:63所示的氨基酸序列。
23.根据实施方案1-22中任一项所述的分离的抗原结合蛋白,其包含抗体重链,且所述抗体重链包含SEQ ID NO:46、SEQ ID NO:56和SEQ ID NO:59、SEQ ID NO:86、SEQ IDNO:88、SEQ ID NO:89和SEQ ID NO:91中任一项所示的氨基酸序列。
24.根据实施方案1-23中任一项所述的分离的抗原结合蛋白,其包含抗体轻链可变区VL中的至少一个CDR,所述VL包含SEQ ID NO:82或SEQ ID NO:40所示的氨基酸序列。
25.根据实施方案1-24中任一项所述的分离的抗原结合蛋白,其包含LCDR3,所述LCDR3包含SEQ ID NO:72所示的氨基酸序列。
26.根据实施方案25所述的分离的抗原结合蛋白,其中所述LCDR3包含SEQ ID NO:11、SEQ ID NO:24和SEQ ID NO:36中任一项所示的氨基酸序列。
27.根据实施方案1-26中任一项所述的分离的抗原结合蛋白,其包含LCDR2,所述LCDR2包含SEQ ID NO:71所示的氨基酸序列。
28.根据实施方案27所述的分离的抗原结合蛋白,其中所述LCDR2包含SEQ ID NO:10或SEQ ID NO:35所示的氨基酸序列。
29.根据实施方案1-28中任一项所述的分离的抗原结合蛋白,其包含LCDR1,所述LCDR1包含SEQ ID NO:70或SEQ ID NO:34所示的氨基酸序列。
30.根据实施方案29所述的分离的抗原结合蛋白,其中所述LCDR1包含SEQ ID NO:9、SEQ ID NO:23和SEQ ID NO:34中任一项所示的氨基酸序列。
31.根据实施方案1-30中任一项所述的分离的抗原结合蛋白,其包含LCDR1,LCDR2和LCDR3,所述LCDR1,LCDR2和LCDR3包含选自下组的氨基酸序列:
(1)所述LCDR1包含SEQ ID NO:9所示的氨基酸序列,所述LCDR2包含SEQ ID NO:10所示的氨基酸序列,且所述LCDR3包含SEQ ID NO:11所示的氨基酸序列;
(2)所述LCDR1包含SEQ ID NO:23所示的氨基酸序列,所述LCDR2包含SEQ ID NO:10所示的氨基酸序列,且所述LCDR3包含SEQ ID NO:24所示的氨基酸序列;以及
(3)所述LCDR1包含SEQ ID NO:34所示的氨基酸序列,所述LCDR2包含SEQ ID NO:35所示的氨基酸序列,且所述LCDR3包含SEQ ID NO:36所示的氨基酸序列。
32.根据实施方案1-31中任一项所述的分离的抗原结合蛋白,其包含L-FR1,所述L-FR1的C端与所述LCDR1的N端直接或间接相连,且所述L-FR1包含SEQ ID NO:77所示的氨基酸序列。
33.根据实施方案32所述的分离的抗原结合蛋白,其中所述L-FR1包含SEQ ID NO:12、SEQ ID NO:25、SEQ ID NO:37和SEQ ID NO:47中任一项所示的氨基酸序列。
34.根据实施方案1-33中任一项所述的分离的抗原结合蛋白,其包含L-FR2,所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO:78所示的氨基酸序列。
35.根据实施方案34所述的分离的抗原结合蛋白,其中所述L-FR2包含SEQ ID NO:13、SEQ ID NO:38和SEQ ID NO:48中任一项所示的氨基酸序列。
36.根据实施方案1-35中任一项所述的分离的抗原结合蛋白,其包含L-FR3,所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO:79所示的氨基酸序列。
37.根据实施方案36所述的分离的抗原结合蛋白,其中所述L-FR3包含SEQ ID NO:14、SEQ ID NO:39、SEQ ID NO:49和SEQ ID NO:60中任一项所示的氨基酸序列。
38.根据实施方案1-37中任一项所述的分离的抗原结合蛋白,其包含L-FR4,所述L-FR4的N端与所述LCDR3的C端直接或间接相连,且所述L-FR4包含SEQ ID NO:80所示的氨基酸序列。
39.根据实施方案38所述的分离的抗原结合蛋白,其中所述L-FR4包含SEQ ID NO:15或SEQ ID NO:50所示的氨基酸序列。
40.根据实施方案1-39中任一项所述的分离的抗原结合蛋白,其包含L-FR1,L-FR2,L-FR3和L-FR4,所述L-FR1,L-FR2,L-FR3和L-FR4包含选自下组的氨基酸序列:
(1)所述L-FR1包含SEQ ID NO:12所示的氨基酸序列,所述L-FR2包含SEQ ID NO:13所示的氨基酸序列,所述L-FR3包含SEQ ID NO:14所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:15所示的氨基酸序列;
(2)所述L-FR1包含SEQ ID NO:25所示的氨基酸序列,所述L-FR2包含SEQ ID NO:13所示的氨基酸序列,所述L-FR3包含SEQ ID NO:14所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:15所示的氨基酸序列;
(3)所述L-FR1包含SEQ ID NO:37所示的氨基酸序列,所述L-FR2包含SEQ ID NO:38所示的氨基酸序列,所述L-FR3包含SEQ ID NO:39所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:15所示的氨基酸序列;
(4)所述L-FR1包含SEQ ID NO:47所示的氨基酸序列,所述L-FR2包含SEQ ID NO:48所示的氨基酸序列,所述L-FR3包含SEQ ID NO:49所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:50所示的氨基酸序列;以及
(5)所述L-FR1包含SEQ ID NO:47所示的氨基酸序列,所述L-FR2包含SEQ ID NO:48所示的氨基酸序列,所述L-FR3包含SEQ ID NO:60所示的氨基酸序列,且所述L-FR4包含SEQ ID NO:50所示的氨基酸序列。
41.根据实施方案1-40中任一项所述的分离的抗原结合蛋白,其包含VL,所述VL包含SEQ ID NO:82或SEQ ID NO:40所示的氨基酸序列。
42.根据实施方案24-41所述的分离的抗原结合蛋白,其中所述VL包含SEQ ID NO:16、SEQ ID NO:26、SEQ ID NO:40、SEQ ID NO:51和SEQ ID NO:61中任一项所示的氨基酸序列。
43.根据实施方案1-42中任一项所述的分离的抗原结合蛋白,其包含抗体轻链恒定区,且所述抗体轻链恒定区包含人Igκ恒定区。
44.根据实施方案43所述的分离的抗原结合蛋白,其中所述抗体轻链恒定区包含SEQ ID NO:64所示的氨基酸序列。
45.根据实施方案43-44中任一项所述的分离的抗原结合蛋白,其包含抗体轻链,且所述抗体轻链包含SEQ ID NO:52、SEQ ID NO:62、SEQ ID NO:87、SEQ ID NO:90和SEQ IDNO:92中任一项所示的氨基酸序列。
46.根据实施方案1-45中任一项所述的分离的抗原结合蛋白,其包含HCDR1,HCDR2,HCDR3,LCDR1,LCDR2和LCDR3,所述HCDR1,HCDR2,HCDR3,LCDR1,LCDR2和LCDR3包含选自下组的氨基酸序列:
(1)所述HCDR1包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2包含SEQ ID NO:2所示的氨基酸序列,所述HCDR3包含SEQ ID NO:3所示的氨基酸序列,所述LCDR1包含SEQ IDNO:9所示的氨基酸序列,所述LCDR2包含SEQ ID NO:10所示的氨基酸序列,所述LCDR3包含SEQ ID NO:11所示的氨基酸序列;
(2)所述HCDR1包含SEQ ID NO:1所示的氨基酸序列,所述HCDR2包含SEQ ID NO:2所示的氨基酸序列,所述HCDR3包含SEQ ID NO:20所示的氨基酸序列,所述LCDR1包含SEQID NO:23所示的氨基酸序列,所述LCDR2包含SEQ ID NO:10所示的氨基酸序列,所述LCDR3包含SEQ ID NO:24所示的氨基酸序列;以及
(3)所述HCDR1包含SEQ ID NO:27所示的氨基酸序列,所述HCDR2包含SEQ ID NO:28所示的氨基酸序列,所述HCDR3包含SEQ ID NO:29所示的氨基酸序列,所述LCDR1包含SEQID NO:34所示的氨基酸序列,所述LCDR2包含SEQ ID NO:35所示的氨基酸序列,所述LCDR3包含SEQ ID NO:36所示的氨基酸序列。
47.根据实施方案1-46中任一项所述的分离的抗原结合蛋白,其包括VH和VL,所述VH和VL包含选自下组的氨基酸序列:
(1)所述VH包含SEQ ID NO:8所示的氨基酸序列,所述VL包含SEQ ID NO:16所示的氨基酸序列;
(2)所述VH包含SEQ ID NO:19所示的氨基酸序列,所述VL包含SEQ ID NO:16所示的氨基酸序列;
(3)所述VH包含SEQ ID NO:22所示的氨基酸序列,所述VL包含SEQ ID NO:26所示的氨基酸序列;
(4)所述VH包含SEQ ID NO:33所示的氨基酸序列,所述VL包含SEQ ID NO:40所示的氨基酸序列;
(5)所述VH包含SEQ ID NO:45所示的氨基酸序列,所述VL包含SEQ ID NO:51所示的氨基酸序列;
(6)所述VH包含SEQ ID NO:55所示的氨基酸序列,所述VL包含SEQ ID NO:51所示的氨基酸序列;
(7)所述VH包含SEQ ID NO:58所示的氨基酸序列,所述VL包含SEQ ID NO:51所示的氨基酸序列;以及
(8)所述VH包含SEQ ID NO:45所示的氨基酸序列,所述VL包含SEQ ID NO:61所示的氨基酸序列。
48.根据实施方案1-47中任一项所述的分离的抗原结合蛋白,其包含抗体重链和抗体轻链,所述抗体重链和抗体轻链包含选自下组的氨基酸序列:
(1)所述抗体重链包含SEQ ID NO:86所示的氨基酸序列,且所述抗体轻链包含SEQID NO:87所示的氨基酸序列;
(2)所述抗体重链包含SEQ ID NO:88所示的氨基酸序列,且所述抗体轻链包含SEQID NO:87所示的氨基酸序列;
(3)所述抗体重链包含SEQ ID NO:89所示的氨基酸序列,且所述抗体轻链包含SEQID NO:90所示的氨基酸序列;
(4)所述抗体重链包含SEQ ID NO:91所示的氨基酸序列,且所述抗体轻链包含SEQID NO:92所示的氨基酸序列;
(5)所述抗体重链包含SEQ ID NO:46所示的氨基酸序列,且所述抗体轻链包含SEQID NO:52所示的氨基酸序列;
(6)所述抗体重链包含SEQ ID NO:56所示的氨基酸序列,且所述抗体轻链包含SEQID NO:52所示的氨基酸序列;
(7)所述抗体重链包含SEQ ID NO:59所示的氨基酸序列,且所述抗体轻链包含SEQID NO:52所示的氨基酸序列;以及
(8)所述抗体重链包含SEQ ID NO:46所示的氨基酸序列,且所述抗体轻链包含SEQID NO:62所示的氨基酸序列。
49.根据实施方案1-48中任一项所述的分离的抗原结合蛋白,其包括抗体或其抗原结合片段。
50.根据实施方案49所述的分离的抗原结合蛋白,所述抗体选自下组:单克隆抗体、单链抗体、嵌合抗体、多特异性抗体、人源化抗体和全人源抗体。
51.根据实施方案49-50中任一项所述的分离的抗原结合蛋白,所述抗原结合片段选自下组:Fab、Fab’、F(ab)2、Fv、F(ab’)2、scFv、di-scFv和dAb片段。
52.根据实施方案1-51中任一项所述的分离的抗原结合蛋白,其具有下述性质中的一种或多种:
1)能够特异性识别白细胞免疫球蛋白样受体B4(LILRB4);
2)能够以2×10-7M或更低的KD值与LILRB4蛋白相结合;
3)能够阻断LILRB4/APOE结合的活性;
4)能够刺激CD8+T细胞的活化;
5)能够抑制人单核白血病细胞THP-1的迁移;
6)能够抑制肿瘤细胞的生长和/或转移;
7)能够阻断LILRB4与Fibronectin的结合。
53.根据实施方案52所述的分离的抗原结合蛋白,其中所述LILRB4为人LILRB4。
54.多肽,其包含实施方案1-53中任一项所述的分离的抗原结合蛋白。
55.融合蛋白,其包含实施方案1-53中任一项所述的分离的抗原结合蛋白。
56.药物分子,其包含实施方案1-53中任一项所述的分离的抗原结合蛋白。
57.分离的一种或多种核酸分子,其编码实施方案1-53中任一项所述的分离的抗原结合蛋白。
58.载体,其包含实施方案57所述的核酸分子。
59.细胞,其包含实施方案57所述的核酸分子或实施方案58所述的载体。
60.药物组合物,其包含实施方案1-53中任一项所述的分离的抗原结合蛋白、实施方案54所述的多肽、实施方案55所述的融合蛋白、实施方案56所述的药物分子、实施方案57所述的核酸分子、实施方案58所述的载体和/或实施方案59所述的细胞,以及任选地药学上可接受的载剂。
61.根据实施方案60所述的药物组合物,其进一步包括选自下组的一种或多种药物:蒽环类拓扑异构酶抑制剂、柔红霉素、阿糖胞苷核苷代谢抑制剂、联合柔红霉素、阿糖胞苷、柔红霉素和阿糖胞苷脂质体注射液、Vyxeos、全反式维甲酸(ATRA)、砷、三氧化二砷、组胺盐酸盐、二盐酸组胺(Ceplene)、白细胞介素-2、白细胞介素2(Proleukin)、吉妥珠单抗奥唑米(Mylotarg)、氯法拉滨、法呢基转移酶抑制剂、地西他滨、IDH1抑制剂、IDH2抑制剂、恩西地平、Idhifa、IDO抑制剂、epacadostat、铂络合物的衍生物、奥沙利铂,激酶抑制剂、酪氨酸激酶抑制剂、PI3激酶抑制剂,BTK抑制剂Ibrutinib,PD-1抗体、PD-L1抗体、抗CTLA-4抗体、LAG3抗体、ICOS抗体,TIGIT抗体、TIM3抗体、结合肿瘤抗原的抗体、结合T细胞表面标记的抗体、结合细胞或NK细胞表面标志物的抗体、烷基化剂、亚硝基脲剂、抗代谢药物、抗肿瘤抗生素、来源于植物的生物碱、拓扑异构酶抑制剂、激素治疗药物、激素拮抗剂、芳香酶抑制剂和P-糖蛋白抑制剂。
62.制备实施方案1-53中任一项所述的分离的抗原结合蛋白的方法,所述方法包括在使得实施方案1-53中任一项所述的分离的抗原结合蛋白表达的条件下,培养实施方案59所述的细胞。
63.实施方案1-53中任一项所述的分离的抗原结合蛋白、实施方案54所述的多肽、实施方案55所述的融合蛋白、实施方案56所述的药物分子、实施方案57所述的核酸分子、实施方案58所述的载体、实施方案59所述的细胞、和/或实施方案60-61中任一项所述的药物组合物在制备药物中的用途,所述药物用于预防和/或治疗疾病和/或病症,所述疾病和/或病症包括与LILRB4信号传导相关的疾病或病症。
64.根据实施方案63所述的用途,其中所述疾病和/或病症包括肿瘤。
65.根据实施方案64所述的用途,其中所述肿瘤包括实体瘤和/或血液瘤。
66.根据实施方案63-65中任一项所述的用途,其中所述药物与选自下组的一种或多种药物联合使用:蒽环类拓扑异构酶抑制剂、柔红霉素、阿糖胞苷核苷代谢抑制剂、联合柔红霉素、阿糖胞苷、柔红霉素和阿糖胞苷脂质体注射液、Vyxeos、全反式维甲酸(ATRA)、砷、三氧化二砷、组胺盐酸盐、二盐酸组胺(Ceplene)、白细胞介素-2、白细胞介素2(Proleukin)、吉妥珠单抗奥唑米(Mylotarg)、氯法拉滨、法呢基转移酶抑制剂、地西他滨、IDH1抑制剂、IDH2抑制剂、恩西地平、Idhifa、IDO抑制剂、epacadostat、铂络合物的衍生物、奥沙利铂,激酶抑制剂、酪氨酸激酶抑制剂、PI3激酶抑制剂,BTK抑制剂Ibrutinib,PD-1抗体、PD-L1抗体、抗CTLA-4抗体、LAG3抗体、ICOS抗体,TIGIT抗体、TIM3抗体、结合肿瘤抗原的抗体,结合T细胞表面标记的抗体、结合细胞或NK细胞表面标志物的抗体、烷基化剂、亚硝基脲剂、抗代谢药物、抗肿瘤抗生素、来源于植物的生物碱、拓扑异构酶抑制剂、激素治疗药物、激素拮抗剂、芳香酶抑制剂和P-糖蛋白抑制剂。
67.根据实施方案63-66中任一项所述的用途,其中所述与LILRB4信号传导相关的疾病或病症包括免疫系统疾病和/或恶性血液疾病。
68.根据实施方案67所述的用途,其中所述免疫系统疾病选自下组中的一种或多种:川崎病、系统性红斑狼疮(SLE)、败血症。
69.根据实施方案65-68中任一项所述的用途,其中所述实体瘤选自下组中的一种或多种:乳腺癌,黑色素瘤,结肠癌,肺癌,肾癌和胰腺癌。
70.根据实施方案67-69中任一项所述的用途,其中所述恶性血液疾病选自下组中的一种或多种:骨髓发育不良综合症、骨髓增生性肿瘤、慢性粒单核细胞白血病(CMML)、慢性髓细胞白血病,或急性髓细胞白血病(AML)、急性早幼粒细胞白血病(APL)或M3 AML、急性粒单核细胞白血病或M4 AML、急性单核细胞白血病或M5 AML、急性骨髓母细胞白血病,以及真性红细胞增多症。
71.诊断受试者中与LILRB4蛋白的表达相关的疾病或病况的方法,所述方法包括:使源自所述受试者的样品与实施方案1-53中任一项所述的分离的抗原结合蛋白接触,以及判断所述样品中能够特异性结合所述分离的抗原结合蛋白的物质的存在和/或含量。
72.检测样品中LILRB4蛋白的方法,所述方法包括施用实施方案1-53中任一项所述的分离的抗原结合蛋白。
73.根据实施方案72所述的检测方法,其为体外和/或离体方法。
74.检测试剂盒,其包括实施方案1-53中任一项所述的分离的抗原结合蛋白,所述检测试剂盒用于检测样品或受试者中LILRB4蛋白的存在和/或含量。
不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请的抗原结合蛋白、制备方法和用途等,而不用于限制本申请发明的范围。
实施例
实施例1杂交瘤技术筛选单克隆抗体
用人LILRB4蛋白细胞外结构域-人IgG1 Fc融合蛋白(命名为LILRB4-Fc),其中人LILRB4的序列信息参考Q8NHJ6,人IgG1 Fc片段的序列参考AXN93652.1,人LILRB4蛋白细胞外结构域的氨基酸序列如SEQ ID NO:84所示;LILRB4-Fc的氨基酸序列如SEQ ID NO:85所示)常规免疫Balb/c小鼠(北京维通利华实验动物技术有限公司)。
在第0、14和28天,在弗氏完全佐剂(第一次注射)或弗氏不完全佐剂(第二和第三次注射)存在下,用100μg LILRB4-Fc对Balb/c小鼠进行皮下注射。使用常规的杂交瘤技术方案(Salhi等,Biochem.J.2004),将来自于小鼠的脾细胞与小鼠骨髓瘤细胞SP2/0(ATCC)融合。将细胞在含有HAT培养基的板中培养(每个孔105个细胞)用于杂交瘤选择。在12天后,收获上清液,并通过直接酶联免疫吸附测定法(ELISA)筛选对LILRB4具备结合特异性的克隆(阳性克隆)。通过筛选,得到一系列靶向人LILRB4胞外域(ECD)的鼠单克隆抗体。
将获得的鼠单克隆抗体的可变区基因克隆入含有人IgG1恒定区基因的真核表达载体pCMV-163中,构建抗体表达载体,并转染至CHO-S细胞中进行表达,再利用常规的Protein A亲和纯化嵌合抗体,将其命名为1A2-7、3A2-18、3G9-1、5E11-2,嵌合抗体的氨基酸序列见下表,其中CDR序列使用Kabat方式划分。
1A2-7 | 3A2-18 | 3G9-1 | 5E11-2 | |
HCDR1 | SEQ ID NO:1 | SEQ ID NO:1 | SEQ ID NO:1 | SEQ ID NO:27 |
HCDR2 | SEQ ID NO:2 | SEQ ID NO:2 | SEQ ID NO:2 | SEQ ID NO:28 |
HCDR3 | SEQ ID NO:3 | SEQ ID NO:3 | SEQ ID NO:20 | SEQ ID NO:29 |
VH | SEQ ID NO:8 | SEQ ID NO:19 | SEQ ID NO:22 | SEQ ID NO:33 |
LCDR1 | SEQ ID NO:9 | SEQ ID NO:9 | SEQ ID NO:23 | SEQ ID NO:34 |
LCDR2 | SEQ ID NO:10 | SEQ ID NO:10 | SEQ ID NO:10 | SEQ ID NO:35 |
LCDR3 | SEQ ID NO:11 | SEQ ID NO:11 | SEQ ID NO:24 | SEQ ID NO:36 |
VL | SEQ ID NO:16 | SEQ ID NO:16 | SEQ ID NO:26 | SEQ ID NO:40 |
实施例2嵌合抗体与人LILRB4的结合
将LILRB4蛋白(Human LILRB4/CD85k/ILT3 Protein(ECD,His Tag),SinoBiological)包被ELISA板条,37℃2h;PBST洗涤后,加入10%的胎牛血清,37℃封闭1小时;加入不同浓度的嵌合抗体和阳性抗体C84,37℃反应1小时;PBST洗涤后,加入辣根过氧化物酶标记的羊抗人IgG Fc二抗(Goat anti-human IgG Fc antibody,horseradishperoxidase(HRP)conjugate,affinity purified,Invitrogen),37℃反应30分钟;PBST洗涤5次;每孔加入100μL TMB(eBioscience),室温(20±5℃)避光放置2~3min;随后每孔加入100μL 2N H2SO4终止液终止底物反应,酶标仪450nm处读取OD值,分析嵌合抗体与LILRB4的结合能力。
结果如图1所示,嵌合抗体1A2-7、3A2-18、3G9-1、5E11-2与LILRB4的结合能力与阳性抗体C84相似。
实施例3嵌合抗体与人LILRB家族蛋白结合特异性检测
将LILRB家族蛋白LILRB1(Human LILRB1/CD85/ILT2/ILR1 Protein(ECD,HisTag),Sino Biological)、LILRB2(Human LILRB2/ILT4/LIR-2Protein(ECD,His Tag),SinoBiological)、LILRB3(Human LILRB3/LIR3/ILT5/CD85a Protein(ECD,His Tag),SinoBiological)、LILRB4(Human LILRB4/CD85k/ILT3 protein(His Tag),Sino Biological)、LILRB5(Human LILRB5/CD85c/LIR-8Protein(ECD,His Tag),Sino Biological)蛋白分别包被ELISA板条,4℃过夜;PBST洗涤后,加入10%的胎牛血清,37℃封闭1小时;每孔加入10μg/mL的嵌合抗体,37℃反应1小时;PBST洗涤后,加入辣根过氧化物酶标记的羊抗人IgG Fc二抗(Goat anti-human IgG Fc antibody,horseradish peroxidase(HRP)conjugate,affinity purified,Invitrogen),37℃反应30分钟;PBST洗涤5次;每孔加入100μL TMB(eBioscience),室温(20±5℃)避光放置1~2min;随后每孔加入100μL 2N H2SO4终止液终止底物反应,酶标仪450nm处读取OD值,分析嵌合抗体与LILRB1、LILRB2、LILRB3和LILRB5的非特异结合能力。
结果如图2所示,嵌合抗体均与LILRB1、LILRB2、LILRB3和LILRB5无非特异结合。
实施例4嵌合抗体阻断LILRB4/APOE结合的活性检测
利用jurkat-LILRB4-CHO-CD3-APOE报告基因细胞系检测嵌合抗体阻断LILRB4/APOE结合的活性,以128-3(Oncoimmune抗体128-3)为阳性对照。
取对数生长期的APOE/TCR activator/CHO细胞,接种96孔板,37℃培养过夜。次日,弃去上清,PBS洗涤两次后,加入1640培养基稀释好的抗体样品,然后加入对数生长期的LILRB4 effector reporter细胞,放置到37℃培养箱中培养。5小时候将细胞取出,加入bright-Glo荧光素酶,酶标仪读取数值,根据每个孔的数值,利用prism Graphpad软件进行分析。
结果如图3A和图3B所示,嵌合抗体1A2-7和3A2-18能够阻断LILRB4与APOE的结合,其中1A2-7阻断活性优于阳性对照128-3。
实施例5嵌合抗体刺激CD8+T细胞活化
从健康供者全血中提取PBMC,用CD8+T细胞分离试剂盒(CD8+T Cell IsolationKit,Miltenyi)分离得到CD8+T细胞,按5×104个细胞/孔加到96孔板(96-well Clear RoundBottom TC-treated Microplate,Corning);加入T细胞激活磁珠(Human T-Activator CD3/CD28/CD137,GIBCO),置37℃5%CO2培养箱孵育2天;加入终浓度为200μg/mL的嵌合抗体,阳性对照抗体C84,以及同型对照,再按5×104个细胞/孔加入人单核白血病细胞THP-1,置37℃5%CO2培养箱继续孵育5天后,收集上清,用Human IFN-γElisa Kit(ExCell Bio)检测上清中的IFN-γ的水平,评价嵌合抗体在THP-1/CD8+T淋巴细胞共培养实验中活化CD8+T细胞的能力。
结果如图4所示,嵌合抗体1A2-7、3A2-18、3G9-1、5E11-2在THP-1/CD8+T淋巴细胞共培养中活化CD8+T细胞的能力与阳性对照抗体C84相似。
实施例6嵌合抗体对THP-1细胞迁移的抑制作用
收集血清饥饿24h的人单核白血病细胞THP-1,加入24孔细胞培养板,加入终浓度为10μg/mL的嵌合抗体和阳性对照抗体C84,置37℃5%CO2培养箱孵育1h;取100μL细胞与抗体的混合液加入到Transwell(6.5mmwith 8.0μm Pore PolycarbonateMembrane Insert,Corning)的上室中,并向下室加入700μL的完全培养基,置37℃5%CO2培养箱孵育24h;从下室取100μL溶液加入到白色透明底96孔板(96-well Black/Clear andWhite/Clear Bottom Polystyrene Microplates,Corning)中,加入100μL的细胞活力检测试剂(CellTiter-LumiTM发光法细胞活力检测试剂盒,碧云天),室温避光孵育10min后,用多功能酶标仪检测化学发光的相对荧光强度值,以梯度稀释的THP-1细胞及其对应的相对荧光强度值绘制标准曲线,计算下室的细胞数,分析嵌合抗体对THP-1细胞迁移的抑制作用。
结果如图5所示,嵌合抗体1A2-7、3A2-18、3G9-1抑制THP-1细胞迁移的能力强于阳性对照抗体C84,5E11-2抑制能力与阳性对照抗体C84相似。
实施例7嵌合抗体抑制THP-1在NSG小鼠体内的生长及转移
将PBS重悬的THP1-Luc人单核细胞白血病细胞5×106/0.2mL/只体积尾静脉注射到B-NDG小鼠体内,分组当天根据小鼠成像信号(平均成像信号1.9x107p/s)和体重(平均体重22.4g)将小鼠随机分配到5个实验组中,每组5只,分别为G1(PBS)、G2(1A2-7,10mg/kg)、G3(3A2-18,10mg/kg)、G5(C84,10m/kg)。分组当天(day 0)和分组后day 3进行给药,所有小鼠均为腹腔注射给药。接种细胞后(即分组给药前,day0),给药后day3、7、14、21、25以及结束实验前(day26)使用小动物活体成像仪是对小鼠进行成像,获取成像信号图以及信号强度,观察体内肿瘤生长情况完成观察后,结束实验。给药和观察期间,每周测量两次动物体重,并记录测量值。
实验终点时,对照组(PBS)肿瘤成像信号强度为1.43x109±1.32x108p/s;1A2-7组肿瘤成像信号强度1.27x106±2.35x105p/s,TGITV为101.3%;3A2-18组肿瘤成像信号强度为1.18x106±2.79x105p/s,TGITV为101.3%;C84组肿瘤成像信号强度为3.74x107±1.92x107p/s,TGITV为98.7%。与G1组相比,各组P值均<0.001,表明受试品1A2-7、3A2-18、C84在10mg/kg剂量下对THP1-LUC细胞移植的B-NDG小鼠肿瘤生长有显著抑制作用。
结果如图6所示,嵌合抗体1A2-7和3A2-18能够有效抑制肿瘤的生长,且抑制效果显著优于阳性对照抗体C84。
上述实验终点时,小鼠称重、成像后,安乐死小鼠,绘制实验动物生存曲线;流式细胞检测分析各组小鼠肝脏、肺脏和骨髓中hCD45+细胞的比例(live/dead,hCD45+,mCD45+)。
成瘤模型实验前,流式细胞检测分析表明,THP1-Luc细胞均为hCD45+细胞,细胞中没有mCD45的表达。给药前,本实验中构建的模型小鼠B-NDG小鼠的肺脏、骨髓(BM)和肝脏中均检测到hCD45+细胞。
给药后的流式检测结果显示,与G1对照组比较,各组小鼠肝脏、肺脏和骨髓中hCD45+细胞占比都显著减少,表明受试品C84、1A2-7和3A2-18在10mg/kg剂量下能够明显降低小鼠肝脏、肺脏和骨髓中肿瘤细胞量,能够抑制肿瘤细胞迁移,结果如图7所示。
实施例8抗体人源化
对抗体进行人源化改造,采用标准CDR嫁接方法进行人源化。人类重链和轻链可变序列进行BLAST搜索,并从每个序列中选择3或4个序列作为人源化的受体框架。将重链和轻链CDR1、CDR2和CDR3克隆到3个不同的重链框架(H1-H4)和2个不同的轻链框架(L1-L2)中。然后检测4种不同的抗体组合(详见表1)在CHO-S细胞中的表达水平,抗原结合能力。
人源化抗体名称 | 重链 | 轻链 |
RB4-G1-018 | SEQ ID NO:46 | SEQ ID NO:52 |
RB4-G1-019 | SEQ ID NO:56 | SEQ ID NO:52 |
RB4-G1-020 | SEQ ID NO:59 | SEQ ID NO:52 |
RB4-G1-022 | SEQ ID NO:46 | SEQ ID NO:62 |
实施例9人源化抗体与人LILRB4的结合
将LILRB4蛋白(Human LILRB4/CD85k/ILT3 Protein(ECD,His Tag),SinoBiological)包被ELISA板条,37℃2h;PBST洗涤后,加入10%的胎牛血清,37℃封闭1小时;加入不同浓度的人源化抗体和和阳性抗体128-3,37℃反应1小时;PBST洗涤后,加入辣根过氧化物酶标记的羊抗人IgG Fc二抗(Goat anti-human IgG Fc antibody,horseradishperoxidase(HRP)conjugate,affinity purified,Invitrogen),37℃反应30分钟;PBST洗涤5次;每孔加入100μL TMB(eBioscience),室温(20±5℃)避光放置2~3min;随后每孔加入100μL 2N H2SO4终止液终止底物反应,酶标仪450nm处读取OD值,分析人源化抗体与LILRB4的结合能力。
结果如图8所示,人源化抗体RB4-G1-018、RB4-G1-019、RB4-G1-020、RB4-G1-022与LILRB4的结合能力与阳性对照抗体128-3相似。
实施例10人源化抗体亲和力测定
采用BIACORE 8K生物大分子相互作用仪(GE公司)分析抗体亲和力。使用Series SSensor Chip Protein A芯片(GE公司)捕获待测抗体,待测抗体浓度定为15μg/mL,以10μl/min进样直到RU=500;以LILRB4(北京百普赛斯科技股份有限公司,货号LI4-H52H7,6×His标签,理论分子量为28.2Kda)为流动相,使用6个浓度梯度(介于0.0977nM-200nM),结合时间为180秒;解离时间为300秒。待测抗体亲和力的结果如下所示。
Ligand | Analyte | ka(1/Ms) | kd(1/s) | KD(M) |
RB4-G1-018 | Human LILRB4 | 1.54E+06 | 4.33E-03 | 2.81E-09 |
RB4-G1-019 | Human LILRB4 | 1.24E+06 | 3.43E-03 | 2.77E-09 |
RB4-G1-022 | Human LILRB4 | 1.80E+06 | 4.18E-03 | 2.33E-09 |
RB4-G1-020 | Human LILRB4 | 2.53E+06 | 8.34E-03 | 3.29E-09 |
128-3 | Human LILRB4 | 1.72E+06 | 4.22E-03 | 2.46E-09 |
实施例11人源化抗体与LILRB4阳性细胞结合力测定
收集人单核白血病细胞THP-1,按照每管5×105个细胞加至1.5mL EP管中;加入不同浓度的人源化抗体和阳性对照抗体128-3,冰上避光孵育30min;FACS洗液洗涤后,加入PE荧光标记的羊抗人IgG Fc二抗(Goat Anti-Human IgG Fc Secondary Antibody,Invitrogen),冰上避光孵育30min;FACS洗液洗涤2遍;每管加入400μL 1%多聚甲醛固定液(Solarbio)固定细胞,混匀后上机检测PE荧光的相对荧光强度,分析人源化抗体与LILRB4阳性细胞THP-1的结合能力。
结果如图9所示,人源化抗体结合LILRB4阳性细胞THP-1的活性相似且强于阳性抗体128-3。
实施例12人源化抗体抑制LILRB4+肿瘤迁移
将PBS重悬的THP1-Luc人单核细胞白血病细胞5×106/0.2mL/只体积尾静脉注射到B-NDG小鼠体内。接种当天根据小鼠成像信号(平均成像信号3.6x107p/s)和小鼠体重(平均体重23g)将小鼠随机分配到6个实验组中,每组5只,分别为G1(PBS)、G2(C84,10mg/kg)、G3(RB4-G1-018,10mg/kg)、G4(RB4-G1-019,10mg/kg)、G5(RB4-G1-020,10m/kg)和G6(RB4-G1-022,10mg/kg)。所有小鼠分组当天(day 0)和分组后day 3进行腹腔注射给药。分别在分组给药前(day0),给药后day7、14、21、25和结束实验当天(day28)使用小动物活体成像仪是对小鼠进行成像,获取成像信号图以及信号强度,观察体内肿瘤生长情况。给药和观察期间,每周测量两次动物体重,并记录测量值。
实验终点时,小鼠称重、成像后,安乐死小鼠,绘制实验动物生存曲线;流式细胞检测分析各组小鼠肝脏、肺脏和骨髓中hCD45+细胞的比例(live/dead,hCD45+,mCD45+)。
流式检测结果如图10所示,与G1对照组比较,各组小鼠肝脏、肺脏和骨髓中hCD45+细胞占比都显著减少,表明受试品C84、RB4-G1-018、RB4-G1-019、RB4-G1-020和RB4-G1-022在10mg/kg剂量下能够明显降低小鼠肝脏、肺脏和骨髓中肿瘤细胞量。
实施例13利用jurkat-LILRB4-CHO-CD3-APOE报告基因细胞系检测LILRB4人源化抗体阻断LILRB4/APOE结合的活性
取对数生长期的APOE/TCR activator/CHO细胞,接种96孔板,37℃培养过夜。次日,弃去上清,PBS洗涤两次后,加入1640培养基稀释好的抗体样品,50ul每孔,然后加入对数生长期的LILRB4 effector reporter细胞,放置到37℃培养箱中培养。5小时后将细胞取出,加入bright-Glo荧光素酶,酶标仪读取数值,根据每个孔的数值,利用prism Graphpad软件进行分析。
结果如图11所示,人源化抗体均能阻断APOE与LILRB4的结合,且阻断能力强于阳性对照抗体128-3和C84。
实施例14人源化抗体在293T-hLILRB4细胞上ADCC活性
收集过表达人LILRB4基因的293T-hLILRB4细胞,加到白色透明底96孔板(96-wellBlack/Clear and White/Clear Bottom Polystyrene Microplates,Corning)中;加入不同浓度的人源化抗体和阳性抗体128-3;再加入过表达人FcγRIIIa基因及NFAT荧光报告基因的效应细胞Jurkat-hFcγRⅢa-NFAT,将96孔板置于37℃5%CO2培养箱中培养6h;每孔加入100μL荧光素酶检测试剂(Bright-LumiTM萤火虫萤光素酶报告基因检测试剂盒,碧云天),室温避光孵育10min后,多功能酶标仪检测化学发光的相对荧光强度值,分析人源化抗体在293T-hLILRB4细胞上介导的ADCC活性。
结果如图12所示,人源化抗体RB4-G1-018、RB4-G1-019、RB4-G1-022的ADCC活性相似且强于阳性对照抗体128-3,RB4-G1-020的ADCC活性与阳性对照抗体128-3相似。
实施例15人源化抗体刺激CD8+T细胞活化
从健康供者全血中提取PBMC,用CD8+T细胞分离试剂盒(CD8+T Cell IsolationKit,Miltenyi)分离得到CD8+T细胞,按5×104个细胞/孔加到96孔板(96-well Clear RoundBottom TC-treated Microplate,Corning);加入T细胞激活磁珠(Human T-Activator CD3/CD28/CD137,GIBCO),置37℃5%CO2培养箱孵育2天;加入终浓度为200μg/mL的人源化抗体,阳性抗体128-3,以及同型对照,再按5×104个细胞/孔加入人单核白血病细胞THP-1,置37℃5%CO2培养箱继续孵育5天后,收集上清,用Human TNF-αElisa Kit(ExCell Bio)检测上清中的TNF-α的水平,评价人源化抗体在THP-1/CD8+T淋巴细胞共培养实验中活化CD8+T细胞的能力。
结果如图13所示,人源化抗体RB4-G1-018和RB4-G1-020在THP-1/CD8+T淋巴细胞共培养中活化CD8+T细胞的能力强于阳性抗体128-3。
实施例16LILRB4人源化抗体能够抑制THP1-LUC细胞移植的B-NDG小鼠体内的肿瘤生长
将PBS重悬的THP1-Luc人单核细胞白血病细胞5×106/0.2mL/只体积尾静脉注射到B-NDG小鼠体内。接种当天根据小鼠成像信号(平均成像信号3.6x107p/s)和小鼠体重(平均体重23g)将小鼠随机分配到6个实验组中,每组5只,分别为G1(PBS)、G2(C84,10mg/kg)、G3(RB4-G1-018,10mg/kg)、G4(RB4-G1-019,10mg/kg)、G5(RB4-G1-020,10m/kg)和G6(RB4-G1-022,10mg/kg)。所有小鼠分组当天(day 0)和分组后day 3进行腹腔注射给药。分别在分组给药前(day0),给药后day7、14、21、25和结束实验当天(day28)使用小动物活体成像仪是对小鼠进行成像,获取成像信号图以及信号强度,观察体内肿瘤生长情况。给药和观察期间,每周测量两次动物体重,并记录测量值。
结果显示,分组后第28天,G1组肿瘤成像信号强度为2.54x109±3.87x108p/s;G2组肿瘤成像信号强度1.06x107±4.50x106p/s,TGITV为101.0%;G3组肿瘤成像信号强度为4.24x106±1.71x106p/s,TGITV为101.3%;G4组肿瘤成像信号强度为1.29x106±2.79x105p/s,TGITV为101.4%;G5组肿瘤成像信号强度为5.82x106±2.35x106p/s,TGITV为101.2%;G6组肿瘤成像信号强度为4.08x106±2.63x106p/s,TGITV为101.3%。
结果如图14和图15所示,与G1对照组相比,G2-G6的P值均为0.000,表明受试品C84、RB4-G1-018、RB4-G1-019、RB4-G1-020和RB4-G1-022在10mg/kg剂量下对THP1-LUC肿瘤生长有显著的抑制作用。且RB4-G1-018、RB4-G1-019、RB4-G1-020和RB4-G1-022效果优于C84。
序列表
<110> 杭州尚健生物技术有限公司;尚健单抗(北京)生物技术有限公司
<120> 分离的抗原结合蛋白及其用途
<130> 0070-PA-031
<160> 92
<170> PatentIn version 3.5
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<213> 人工序列(Artificial Sequence)
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<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1HCDR1
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1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 5
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/3G9-1 H-FR2
<400> 5
Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 6
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7 H-FR3
<400> 6
Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
1 5 10 15
Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 7
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/3G9-1/5E11-2 H-FR4
<400> 7
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
1 5 10
<210> 8
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7 VH
<400> 8
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 9
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022 LCDR1
<400> 9
Arg Ala Ser Gln Asp Ile Thr Asn Tyr Leu Asn
1 5 10
<210> 10
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1LCDR2
<400> 10
Tyr Thr Ser Arg Leu His Ser
1 5
<210> 11
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022 LCDR3
<400> 11
Gln Gln Gly Asp Thr Leu Pro Arg Thr
1 5
<210> 12
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18 L-FR1
<400> 12
Asp Ile Val Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys
20
<210> 13
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/3G9-1 L-FR2
<400> 13
Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr
1 5 10 15
<210> 14
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/3G9-1 L-FR3
<400> 14
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser
1 5 10 15
Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys
20 25 30
<210> 15
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/3G9-1/5E11-2 L-FR4
<400> 15
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 16
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18 VL
<400> 16
Asp Ile Val Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 17
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3A2-18 H-FR1
<400> 17
Glu Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 18
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3A2-18 H-FR3
<400> 18
Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Val Gln
1 5 10 15
Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 19
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3A2-18 VH
<400> 19
Glu Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Val Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 20
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3G9-1 HCDR3
<400> 20
Gly Ile Tyr Tyr Gly Tyr Asp Tyr Ala Met Asp Tyr
1 5 10
<210> 21
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3G9-1 H-FR3
<400> 21
Lys Ala Thr Leu Ile Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 22
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3G9-1 VH
<400> 22
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Ile Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Tyr Tyr Gly Tyr Asp Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 23
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3G9-1 LCDR1
<400> 23
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 24
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3G9-1 LCDR3
<400> 24
Gln Gln Gly Asn Thr Leu Pro Pro Thr
1 5
<210> 25
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3G9-1 L-FR1
<400> 25
Asp Ile Gln Met Thr His Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys
20
<210> 26
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3G9-1 VL
<400> 26
Asp Ile Gln Met Thr His Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 27
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 HCDR1
<400> 27
Asp Ala Trp Met Asp
1 5
<210> 28
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 HCDR2
<400> 28
Glu Ile Arg Ser Lys Pro Asn Asn His Ala Thr Tyr Tyr Ala Glu Ser
1 5 10 15
Val Lys Gly
<210> 29
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 HCDR3
<400> 29
Thr Thr Asp Tyr Ser Met Asp Tyr
1 5
<210> 30
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 H-FR1
<400> 30
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
<210> 31
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 H-FR2
<400> 31
Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val Ala
1 5 10
<210> 32
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 H-FR3
<400> 32
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser Val Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Gly Ile Tyr Tyr Cys Thr Arg
20 25 30
<210> 33
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 VH
<400> 33
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala
20 25 30
Trp Met Asp Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Ser Lys Pro Asn Asn His Ala Thr Tyr Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Thr Arg Thr Thr Asp Tyr Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 34
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 LCDR1
<400> 34
Arg Ala Ser Gln Ser Val Ser Ala Ser Ser Tyr Ser Tyr Met His
1 5 10 15
<210> 35
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 LCDR2
<400> 35
Tyr Ala Ser Asn Leu Gln Ser
1 5
<210> 36
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 LCDR3
<400> 36
Gln His Ser Trp Glu Ile Pro Arg Thr
1 5
<210> 37
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 L-FR1
<400> 37
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys
20
<210> 38
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 L-FR2
<400> 38
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Lys
1 5 10 15
<210> 39
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 L-FR3
<400> 39
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Asn Ile His Pro Val Glu Glu Glu Asp Ser Ala Thr Tyr Tyr Cys
20 25 30
<210> 40
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2 VL
<400> 40
Asp Ile Gln Met 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 Ala 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 Gln 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 Ser Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 41
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022 H-FR1
<400> 41
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 42
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-022 H-FR2
<400> 42
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 43
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-022 H-FR3
<400> 43
Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 44
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022 H-FR4
<400> 44
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 45
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-022 VH
<400> 45
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 46
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-022 重链
<400> 46
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 47
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022 L-FR1
<400> 47
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
20
<210> 48
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022 L-FR2
<400> 48
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 49
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-019/RB4-G1-020 L-FR3
<400> 49
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Tyr Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 50
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022 L-FR4
<400> 50
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
1 5 10
<210> 51
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-019/RB4-G1-020 VL
<400> 51
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Thr Leu Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 52
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-018/RB4-G1-019/RB4-G1-020 轻链
<400> 52
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Thr Leu Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Arg 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> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-019/RB4-G1-020 H-FR2
<400> 53
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 54
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-019 H-FR3
<400> 54
Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Val Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 55
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-019 VH
<400> 55
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 56
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-019 重链
<400> 56
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 57
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-020 H-FR3
<400> 57
Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 58
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-020 VH
<400> 58
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 59
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-020 重链
<400> 59
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 60
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-022 L-FR3
<400> 60
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr
1 5 10 15
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
20 25 30
<210> 61
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-022 VL
<400> 61
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Thr Leu Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 62
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> RB4-G1-022 轻链
<400> 62
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Thr Leu Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Arg 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> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重链恒定区
<400> 63
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 64
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 轻链恒定区
<400> 64
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 65
<211> 451
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 128-3: Oncoimmune对照抗体, 重链
<400> 65
Glu Gln Ser Leu Glu Glu Ser Gly Gly Asp Leu Val Thr Pro Gly Ala
1 5 10 15
Ser Leu Thr Leu Thr Cys Lys Ala Ser Gly Ile Asp Phe Ser Asn His
20 25 30
Tyr Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Cys Ile Phe Ser Gly Asp Ser Ala Ser Thr Tyr Tyr Ala Ser
50 55 60
Trp Ala Lys Gly Arg Phe Thr Ile Ser Lys Ser Ser Ser Pro Thr Val
65 70 75 80
Thr Leu Gln Met Thr Ser Leu Thr Ala Ala Asp Thr Ala Thr Tyr Phe
85 90 95
Cys Ala Arg Gly Met Ser Thr Asn Asp Trp Ala Ser Asp Leu Trp Gly
100 105 110
Pro Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 66
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 128-3: Oncoimmune对照抗体, 轻链
<400> 66
Glu Leu Val Met Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Ile Asn Ser Ile
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Arg Pro Lys Leu Leu
35 40 45
Ile Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys
50 55 60
Gly Ser Ala Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Asp Leu Glu
65 70 75 80
Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asp Trp Gly
85 90 95
Asp Val Glu Asn Thr Phe Gly Gly Gly Thr Glu Val 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> 67
<211> 451
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> C84: Oncoimmune对照抗体,重链
<400> 67
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys
85 90 95
Ala Ser Ile Tyr Tyr His Thr Ser Leu Trp Tyr Phe Asp Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 68
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> C84: Oncoimmune对照抗体,轻链
<400> 68
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Arg Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Val 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 Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 69
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 HCDR1通式
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa = Asp或Ser
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Ala或Tyr
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa = Asp或His
<400> 69
Xaa Xaa Trp Met Xaa
1 5
<210> 70
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1LCDR1 通式
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa = Ser或Thr
<400> 70
Arg Ala Ser Gln Asp Ile Xaa Asn Tyr Leu Asn
1 5 10
<210> 71
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 LCDR2通式
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Ala或Thr
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa = Asn或Arg
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = His或Gln
<400> 71
Tyr Xaa Ser Xaa Leu Xaa Ser
1 5
<210> 72
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 LCDR3通式
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = His或Gln
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa = Gly或Ser
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa = Asp、Asn或Trp
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa = Glu或Thr
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = Ile或Leu
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa = Pro或Arg
<400> 72
Gln Xaa Xaa Xaa Xaa Xaa Pro Xaa Thr
1 5
<210> 73
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 H-FR1通式
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa = Glu或Gln
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa = Lys或Gln
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa = Glu、Gln或Val
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = Glu或Gln
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa = Pro或Ser
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa = Ala或Gly
<220>
<221> misc_feature
<222> (10)..(10)
<223> Xaa = Glu或Gly
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa = Leu或Val
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa = Lys或Val
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa = Lys或Gln
<220>
<221> misc_feature
<222> (16)..(16)
<223> Xaa = Ala或Gly
<220>
<221> misc_feature
<222> (18)..(18)
<223> Xaa = Met或Val
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Leu或Val
<220>
<221> misc_feature
<222> (23)..(23)
<223> Xaa = Ala或Lys
<220>
<221> misc_feature
<222> (27)..(27)
<223> Xaa = Phe或Tyr
<220>
<221> misc_feature
<222> (30)..(30)
<223> Xaa = Ser或Thr
<400> 73
Xaa Val Xaa Leu Xaa Xaa Xaa Gly Xaa Xaa Xaa Xaa Xaa Pro Gly Xaa
1 5 10 15
Ser Xaa Lys Xaa Ser Cys Xaa Ala Ser Gly Xaa Thr Phe Xaa
20 25 30
<210> 74
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 H-FR2通式
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa = Lys或Arg
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa = Ala、Arg或Ser
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa = Glu或Gly
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa = Lys或Gln
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa = Ile、Met或Val
<220>
<221> misc_feature
<222> (14)..(14)
<223> Xaa = Ala或Gly
<400> 74
Trp Val Xaa Gln Xaa Pro Xaa Xaa Gly Leu Glu Trp Xaa Xaa
1 5 10
<210> 75
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 H-FR3通式
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa = Lys或Arg
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Ala、Phe或Val
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa = Ile、Leu或Met
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa = Ile、Ser或Thr
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = Arg或Val
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa = Asp、Lys或Thr
<220>
<221> misc_feature
<222> (10)..(10)
<223> Xaa = Lys、Ser或Thr
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa = Ala或Val
<220>
<221> misc_feature
<222> (15)..(15)
<223> Xaa = Leu、Met或Val
<220>
<221> misc_feature
<222> (16)..(16)
<223> Xaa = Glu或Gln
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa = Leu或Met
<220>
<221> misc_feature
<222> (18)..(18)
<223> Xaa = Asn或Ser
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa = Arg或Thr
<220>
<221> misc_feature
<222> (22)..(22)
<223> Xaa = Ala或Ser
<220>
<221> misc_feature
<222> (25)..(25)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (26)..(26)
<223> Xaa = Ala或Gly
<220>
<221> misc_feature
<222> (27)..(27)
<223> Xaa = Ile或Val
<220>
<221> misc_feature
<222> (31)..(31)
<223> Xaa = Ala或Thr
<400> 75
Xaa Xaa Thr Xaa Xaa Xaa Asp Xaa Ser Xaa Ser Xaa Xaa Tyr Xaa Xaa
1 5 10 15
Xaa Xaa Ser Leu Xaa Xaa Glu Asp Xaa Xaa Xaa Tyr Tyr Cys Xaa Arg
20 25 30
<210> 76
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 H-FR4通式
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = Ser或Thr
<400> 76
Trp Gly Gln Gly Thr Xaa Val Thr Val Ser Ser
1 5 10
<210> 77
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 L-FR1通式
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa = Gln或Val
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = His或Gln
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa = Pro或Thr
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa = Ala或Ser
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa = Ala或Ser
<220>
<221> misc_feature
<222> (13)..(13)
<223> Xaa = Ala或Val
<220>
<221> misc_feature
<222> (15)..(15)
<223> Xaa = Leu或Val
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa = Asp或Gln
<220>
<221> misc_feature
<222> (19)..(19)
<223> Xaa = Ala或Val
<220>
<221> misc_feature
<222> (22)..(22)
<223> Xaa = Ser或Thr
<400> 77
Asp Ile Xaa Met Thr Xaa Xaa Xaa Xaa Ser Leu Xaa Xaa Ser Xaa Gly
1 5 10 15
Xaa Arg Xaa Thr Ile Xaa Cys
20
<210> 78
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 L-FR2通式
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa = Asp或Gly
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa = Gly、Lys或Gln
<220>
<221> misc_feature
<222> (9)..(9)
<223> Xaa = Ala、Pro或Thr
<220>
<221> misc_feature
<222> (10)..(10)
<223> Xaa = Pro或Val
<220>
<221> misc_feature
<222> (15)..(15)
<223> Xaa = Lys或Tyr
<400> 78
Trp Tyr Gln Gln Lys Pro Xaa Xaa Xaa Xaa Lys Leu Leu Ile Xaa
1 5 10 15
<210> 79
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 L-FR3通式
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa = Ala或Ser
<220>
<221> misc_feature
<222> (14)..(14)
<223> Xaa = Asp或Glu
<220>
<221> misc_feature
<222> (15)..(15)
<223> Xaa = Phe或Tyr
<220>
<221> misc_feature
<222> (16)..(16)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa = Phe或Leu
<220>
<221> misc_feature
<222> (18)..(18)
<223> Xaa = Asn或Thr
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = His或Ser
<220>
<221> misc_feature
<222> (21)..(21)
<223> Xaa = Asn、Pro或Ser
<220>
<221> misc_feature
<222> (22)..(22)
<223> Xaa = Leu或Val
<220>
<221> misc_feature
<222> (23)..(23)
<223> Xaa = Glu或Gln
<220>
<221> misc_feature
<222> (24)..(24)
<223> Xaa = Glu、Pro或Gln
<220>
<221> misc_feature
<222> (25)..(25)
<223> Xaa = Asp或Glu
<220>
<221> misc_feature
<222> (27)..(27)
<223> Xaa = Phe、Ile或Ser
<220>
<221> misc_feature
<222> (31)..(31)
<223> Xaa = Phe或Tyr
<400> 79
Gly Val Pro Xaa Arg Phe Ser Gly Ser Gly Ser Gly Thr Xaa Xaa Xaa
1 5 10 15
Xaa Xaa Ile Xaa Xaa Xaa Xaa Xaa Xaa Asp Xaa Ala Thr Tyr Xaa Cys
20 25 30
<210> 80
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1/5E11-2 L-FR4通式
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa = Gly或Gln
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = Lys或Arg
<400> 80
Phe Gly Xaa Gly Thr Xaa Leu Glu Ile Lys
1 5 10
<210> 81
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-019/RB4-G1-018/RB4-G1-022/RB4-G1-020 VH通式
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa = Glu或Gln
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa = Gln或Val
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa = Pro或Ser
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa = Leu或Val
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa = Lys或Val
<220>
<221> misc_feature
<222> (20)..(20)
<223> Xaa = Leu或Val
<220>
<221> misc_feature
<222> (38)..(38)
<223> Xaa = Lys或Arg
<220>
<221> misc_feature
<222> (40)..(40)
<223> Xaa = Ala或Arg
<220>
<221> misc_feature
<222> (48)..(48)
<223> Xaa = Ile或Met
<220>
<221> misc_feature
<222> (67)..(67)
<223> Xaa = Lys或Arg
<220>
<221> misc_feature
<222> (68)..(68)
<223> Xaa = Ala或Val
<220>
<221> misc_feature
<222> (70)..(70)
<223> Xaa = Leu或Met
<220>
<221> misc_feature
<222> (72)..(72)
<223> Xaa = Arg或Val
<220>
<221> misc_feature
<222> (74)..(74)
<223> Xaa = Lys或Thr
<220>
<221> misc_feature
<222> (76)..(76)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (79)..(79)
<223> Xaa = Ala或Val
<220>
<221> misc_feature
<222> (81)..(81)
<223> Xaa = Met或Val
<220>
<221> misc_feature
<222> (82)..(82)
<223> Xaa = Glu或Gln
<220>
<221> misc_feature
<222> (84)..(84)
<223> Xaa = Asn或Ser
<220>
<221> misc_feature
<222> (87)..(87)
<223> Xaa = Arg或Thr
<220>
<221> misc_feature
<222> (91)..(91)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (115)..(115)
<223> Xaa = Ser或Thr
<400> 81
Xaa Val Gln Leu Xaa Gln Xaa Gly Ala Glu Xaa Xaa Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Xaa Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Xaa Gln Xaa Pro Gly Gln Gly Leu Glu Trp Xaa
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Xaa Xaa Thr Xaa Thr Xaa Asp Xaa Ser Xaa Ser Thr Xaa Tyr
65 70 75 80
Xaa Xaa Leu Xaa Ser Leu Xaa Ser Glu Asp Xaa Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Xaa Val Thr Val Ser Ser
115 120
<210> 82
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/3G9-1/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022 VL通式
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa = Gln或Val
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = His或Gln
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa = Pro或Thr
<220>
<221> misc_feature
<222> (15)..(15)
<223> Xaa = Leu或Val
<220>
<221> misc_feature
<222> (22)..(22)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (30)..(30)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (41)..(41)
<223> Xaa = Asp或Gly
<220>
<221> misc_feature
<222> (42)..(42)
<223> Xaa = Gly或Lys
<220>
<221> misc_feature
<222> (43)..(43)
<223> Xaa = Ala或Thr
<220>
<221> misc_feature
<222> (44)..(44)
<223> Xaa = Pro或Val
<220>
<221> misc_feature
<222> (70)..(70)
<223> Xaa = Asp或Glu
<220>
<221> misc_feature
<222> (72)..(72)
<223> Xaa = Ser或Thr
<220>
<221> misc_feature
<222> (73)..(73)
<223> Xaa = Phe或Leu
<220>
<221> misc_feature
<222> (77)..(77)
<223> Xaa = Asn或Ser
<220>
<221> misc_feature
<222> (79)..(79)
<223> Xaa = Glu或Gln
<220>
<221> misc_feature
<222> (80)..(80)
<223> Xaa = Pro或Gln
<220>
<221> misc_feature
<222> (81)..(81)
<223> Xaa = Asp或Glu
<220>
<221> misc_feature
<222> (83)..(83)
<223> Xaa = Phe或Ile
<220>
<221> misc_feature
<222> (87)..(87)
<223> Xaa = Phe或Tyr
<220>
<221> misc_feature
<222> (92)..(92)
<223> Xaa = Asp或Asn
<220>
<221> misc_feature
<222> (96)..(96)
<223> Xaa = Pro或Arg
<220>
<221> misc_feature
<222> (100)..(100)
<223> Xaa = Gly或Gln
<220>
<221> misc_feature
<222> (103)..(103)
<223> Xaa = Lys或Arg
<400> 82
Asp Ile Xaa Met Thr Xaa Xaa Xaa Ser Ser Leu Ser Ala Ser Xaa Gly
1 5 10 15
Asp Arg Val Thr Ile Xaa Cys Arg Ala Ser Gln Asp Ile Xaa Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Xaa Xaa Xaa Xaa Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Xaa Tyr Xaa Xaa Thr Ile Ser Xaa Leu Xaa Xaa
65 70 75 80
Xaa Asp Xaa Ala Thr Tyr Xaa Cys Gln Gln Gly Xaa Thr Leu Pro Xaa
85 90 95
Thr Phe Gly Xaa Gly Thr Xaa Leu Glu Ile Lys
100 105
<210> 83
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18/RB4-G1-018/RB4-G1-019/RB4-G1-020/RB4-G1-022/3G9-1HCDR3通式
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa = Gly或不存在
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa = Asp或Ile
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa = Arg或Tyr
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa = Asp或Gly
<220>
<221> misc_feature
<222> (6)..(6)
<223> Xaa = Glu或Tyr
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa = Asp或Gly
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa = Asn或Tyr
<400> 83
Xaa Xaa Xaa Tyr Xaa Xaa Xaa Xaa Ala Met Asp Tyr
1 5 10
<210> 84
<211> 238
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人LILRB4蛋白细胞外结构域
<400> 84
Gln Ala Gly Pro Leu Pro Lys Pro Thr Leu Trp Ala Glu Pro Gly Ser
1 5 10 15
Val Ile Ser Trp Gly Asn Ser Val Thr Ile Trp Cys Gln Gly Thr Leu
20 25 30
Glu Ala Arg Glu Tyr Arg Leu Asp Lys Glu Glu Ser Pro Ala Pro Trp
35 40 45
Asp Arg Gln Asn Pro Leu Glu Pro Lys Asn Lys Ala Arg Phe Ser Ile
50 55 60
Pro Ser Met Thr Glu Asp Tyr Ala Gly Arg Tyr Arg Cys Tyr Tyr Arg
65 70 75 80
Ser Pro Val Gly Trp Ser Gln Pro Ser Asp Pro Leu Glu Leu Val Met
85 90 95
Thr Gly Ala Tyr Ser Lys Pro Thr Leu Ser Ala Leu Pro Ser Pro Leu
100 105 110
Val Thr Ser Gly Lys Ser Val Thr Leu Leu Cys Gln Ser Arg Ser Pro
115 120 125
Met Asp Thr Phe Leu Leu Ile Lys Glu Arg Ala Ala His Pro Leu Leu
130 135 140
His Leu Arg Ser Glu His Gly Ala Gln Gln His Gln Ala Glu Phe Pro
145 150 155 160
Met Ser Pro Val Thr Ser Val His Gly Gly Thr Tyr Arg Cys Phe Ser
165 170 175
Ser His Gly Phe Ser His Tyr Leu Leu Ser His Pro Ser Asp Pro Leu
180 185 190
Glu Leu Ile Val Ser Gly Ser Leu Glu Asp Pro Arg Pro Ser Pro Thr
195 200 205
Arg Ser Val Ser Thr Ala Ala Gly Pro Glu Asp Gln Pro Leu Met Pro
210 215 220
Thr Gly Ser Val Pro His Ser Gly Leu Arg Arg His Trp Glu
225 230 235
<210> 85
<211> 469
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LILRB4-Fc
<400> 85
Gln Ala Gly Pro Leu Pro Lys Pro Thr Leu Trp Ala Glu Pro Gly Ser
1 5 10 15
Val Ile Ser Trp Gly Asn Ser Val Thr Ile Trp Cys Gln Gly Thr Leu
20 25 30
Glu Ala Arg Glu Tyr Arg Leu Asp Lys Glu Glu Ser Pro Ala Pro Trp
35 40 45
Asp Arg Gln Asn Pro Leu Glu Pro Lys Asn Lys Ala Arg Phe Ser Ile
50 55 60
Pro Ser Met Thr Glu Asp Tyr Ala Gly Arg Tyr Arg Cys Tyr Tyr Arg
65 70 75 80
Ser Pro Val Gly Trp Ser Gln Pro Ser Asp Pro Leu Glu Leu Val Met
85 90 95
Thr Gly Ala Tyr Ser Lys Pro Thr Leu Ser Ala Leu Pro Ser Pro Leu
100 105 110
Val Thr Ser Gly Lys Ser Val Thr Leu Leu Cys Gln Ser Arg Ser Pro
115 120 125
Met Asp Thr Phe Leu Leu Ile Lys Glu Arg Ala Ala His Pro Leu Leu
130 135 140
His Leu Arg Ser Glu His Gly Ala Gln Gln His Gln Ala Glu Phe Pro
145 150 155 160
Met Ser Pro Val Thr Ser Val His Gly Gly Thr Tyr Arg Cys Phe Ser
165 170 175
Ser His Gly Phe Ser His Tyr Leu Leu Ser His Pro Ser Asp Pro Leu
180 185 190
Glu Leu Ile Val Ser Gly Ser Leu Glu Asp Pro Arg Pro Ser Pro Thr
195 200 205
Arg Ser Val Ser Thr Ala Ala Gly Pro Glu Asp Gln Pro Leu Met Pro
210 215 220
Thr Gly Ser Val Pro His Ser Gly Leu Arg Arg His Trp Glu Pro Lys
225 230 235 240
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Lys
465
<210> 86
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7重链
<400> 86
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 87
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1A2-7/3A2-18 轻链
<400> 87
Asp Ile Val Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Arg
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> 88
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3A2-18重链
<400> 88
Glu Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Val Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Tyr Asp Glu Gly Asn Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 89
<211> 451
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3G9-1重链
<400> 89
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Ile Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Tyr Tyr Gly Tyr Asp Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 90
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 3G9-1轻链
<400> 90
Asp Ile Gln Met Thr His Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Pro
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> 91
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2重链
<400> 91
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala
20 25 30
Trp Met Asp Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Ser Lys Pro Asn Asn His Ala Thr Tyr Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Thr Arg Thr Thr Asp Tyr Ser Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 92
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 5E11-2轻链
<400> 92
Asp Ile Gln Met 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 Ala 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 Gln 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 Ser Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Arg 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
Claims (10)
1.分离的抗原结合蛋白,其包含抗体重链可变区VH中的至少一个CDR,且所述VH包含SEQ ID NO:81、SEQ ID NO:33和SEQ ID NO:22中任一项所示的氨基酸序列。
2.多肽,其包含权利要求1所述的分离的抗原结合蛋白。
3.融合蛋白,其包含权利要求1所述的分离的抗原结合蛋白。
4.药物分子,其包含权利要求1所述的分离的抗原结合蛋白。
5.分离的一种或多种核酸分子,其编码权利要求1所述的分离的抗原结合蛋白。
6.载体,其包含权利要求5所述的核酸分子。
7.细胞,其包含权利要求5所述的核酸分子或权利要求6所述的载体。
8.药物组合物,其包含权利要求1所述的分离的抗原结合蛋白、权利要求2所述的多肽、权利要求3所述的融合蛋白、权利要求4所述的药物分子、权利要求5所述的核酸分子、权利要求6所述的载体和/或权利要求7所述的细胞,以及任选地药学上可接受的载剂。
9.权利要求1所述的分离的抗原结合蛋白、权利要求2所述的多肽、权利要求3所述的融合蛋白、权利要求4所述的药物分子、权利要求5所述的核酸分子、权利要求6所述的载体、权利要求7所述的细胞、和/或权利要求8所述的药物组合物在制备药物中的用途,所述药物用于预防和/或治疗疾病和/或病症,所述疾病和/或病症包括与LILRB4信号传导相关的疾病或病症。
10.检测试剂盒,其包括权利要求1所述的分离的抗原结合蛋白,所述检测试剂盒用于检测样品或受试者中LILRB4蛋白的存在和/或含量。
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PCT/CN2023/104012 WO2024002266A1 (zh) | 2022-06-30 | 2023-06-29 | 分离的抗原结合蛋白及其用途 |
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CA2611519A1 (en) * | 2005-06-17 | 2006-12-28 | Tolerx, Inc. | Ilt3 binding molecules and uses therefor |
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