CN114437216A - 抗Siglec-15抗体及其在制备药物中的应用 - Google Patents
抗Siglec-15抗体及其在制备药物中的应用 Download PDFInfo
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Abstract
本发明涉及生物制药领域,具体涉及一种抗Siglec‑15抗体或其抗原结合片段、编码本发明抗Siglec‑15抗体或其抗原结合片段的核酸序列、包含该核酸序列的表达载体、包含该表达载体的宿主细胞、包含本发明抗Siglec‑15抗体或其抗原结合片段的组合物、双特异性抗体或本发明抗Siglec‑15抗体或其抗原结合片段与治疗剂连接的免疫连接物,以及本发明Siglec‑15抗体或其抗原结合片段在制备用于治疗癌症的药物中的用途。本发明Siglec‑15抗体或其抗原结合片段可与Siglec‑15结合,用于治疗与Siglec‑15相关的疾病。
Description
技术领域
本发明涉及生物制药领域,具体涉及一种抗Siglec-15抗体或其抗原结合片段、编码本发明抗Siglec-15抗体或其抗原结合片段的核酸序列、包含该核酸序列的表达载体、包含该表达载体的宿主细胞、包含本发明抗Siglec-15抗体或其抗原结合片段的组合物、双特异性抗体或本发明抗Siglec-15抗体或其抗原结合片段与治疗剂连接的免疫连接物,以及本发明Siglec-15抗体或其抗原结合片段在制备治疗癌症的药物中的用途。
背景技术
癌症已成为危害人类健康的重要杀手。由于人口老龄化、工业化、城市化进程的加剧,生活方式的改变等原因,中国癌症的发病数和死亡数仍持续增加,癌症负担已不容忽视。癌症的发生发展是遗传和环境相互作用的结果,由正常组织中单一细胞基因突变恶性转化所造成的不受控的细胞增殖所引发。治疗癌症需在患者可承受的副作用下杀死或去除所有肿瘤细胞。随着手术,放化疗,靶向治疗等技术的发展,不少肿瘤患者的生存期有所延长,由于肿瘤的转移及其异质性,多数患者产生耐药或复发,并最终死亡。
近十年来,出现了以免疫检查点PD-1/PD-L1抑制剂为代表的一种新的免疫治疗方法,这些策略主要针对肿瘤免疫逃逸机制。当PD-1/PD-L1通路在肿瘤微环境中被激活时,效应T细胞的抗肿瘤免疫反应被抑制。阻断这一途径的治疗可有效改善多种肿瘤类型的抗肿瘤免疫反应。随着PD-1/PD-L1抗体药物的上市,肿瘤免疫治疗成为新兴的治疗范式,相较于放化疗与靶向治疗,PD-1/PD-L1抗体药物可使一部分病人获得长期缓解。免疫系统具有巨大的潜力,其能特异性识别并攻击肿瘤细胞而不对正常组织造成毒副作用。此外,免疫系统的记忆能力能防止肿瘤的复发。然而,PD-1/PD-L1抗体药物仅在20%-30%的患者中有效,如何使更多的患者从肿瘤免疫治疗中获益是目前急需解决的问题。这需要寻找新的免疫检查点治疗靶点进行药物开发。
唾液酸结合性免疫球蛋白样凝集素(sialic acid-binding immunoglobulin-like lectin,Siglec)家族是一类经典的免疫球蛋白样凝集素,可通过识别含有唾液酸的糖链结构,介导细胞与细胞或病原体间的相互作用,在固有免疫和适应性免疫中发挥重要的调控作用。目前已发现15种人源和9种鼠源的Siglec分子,Siglec特异性表达于髓系细胞和免疫细胞表面。Siglec家族蛋白为Ⅰ型跨膜蛋白,具有免疫球蛋白超家族结构域,不同的家族成员胞外部分有数量不等的“C2-set”免疫球蛋白样结构域,“C2-set”结构域与免疫球蛋白恒定区具有很高的序列及折叠相似性。胞外末端免疫球蛋白结构域与抗体可变区具有较高的相似性,称为“V-set”结构域,另外还具有跨膜区和胞内段。大多数Siglec胞内段含有免疫受体酪氨酸抑制基序(immunoreceptor tyrosine-based inhibitiory motifs,ITIMs),从而发挥免疫抑制功能。
Siglec-15为在进化中高度保守的Siglec家族成员,其胞外区有两个免疫球蛋白样结构域,“C2-set”结构域和“V-set”结构域,跨膜区包含一个与12kDa的信号衔接分子DNAX活化蛋白(DAP12)相互作用起到关键作用的赖氨酸残基(Lys274,人Siglec-15),Siglec-15和DAP12的相互作用是通过跨膜区的离子键作用。DAP12具有非常短的胞外结构域(<20个氨基酸),跨膜区包含一个天冬氨酸残基(Asp50,人DAP12),胞内区有一个ITAM(immunoreceptor tyrosine-based activating motif),通过ITAM招募SYK使其磷酸化,以传递信号。
早期针对Siglec-15的研究主要集中在破骨细胞相关疾病领域。Hiruma等人报导了通过使用抗Siglec-15的多抗,抑制了RAW264.7小鼠巨噬细胞系(常作为破骨细胞前体模型)、小鼠骨髓巨噬细胞和人破骨细胞前体向破骨细胞的分化。Ishida-Kitagawa等人证明了Siglec-15与DAP12相互作用及SYK信号转导,以及Siglec-15与唾液酸化的配体的相互作用对破骨细胞分化是至关重要的。这些体外研究结果很快在转基因小鼠体内得到验证。Hiruma等人报导,Siglec15缺失小鼠表现出小梁骨轻度的骨硬化(增加的骨量)和尿脱氧吡啶啉(骨吸收的系统性标志)减少,表明破骨细胞活力降低。Takahata团队使用另外的Siglec15缺失小鼠品系也证明上述结果。
近期研究发现Siglec-15表达于肿瘤相关巨噬细胞上,由M-CSF(一种诱导巨噬细胞选择性活化/极化的细胞因子)诱导。共培养sialyl-Tn+肿瘤细胞株和M-CSF诱导的人巨噬细胞或Siglec-15+髓系细胞,提高了髓系细胞TGF-β(一种促进癌细胞上皮-间质转化和转移的多效细胞因子)的产生,其依赖于DAP12和SYK。这些结果表明Siglec-15可能在肿瘤微环境中具有重要的作用。
2019年3月5日,自然医学杂志刊登了陈列平教授团队的新发现:Siglec-15为肿瘤免疫微环境中新的免疫抑制检查点分子且可成为潜在的肿瘤免疫治疗靶点。研究发现,表达于肿瘤细胞或肿瘤相关巨噬细胞表面的Siglec-15能与T细胞表面受体相互作用,抑制T细胞肿瘤杀伤活性。Siglec-15能诱导单核细胞分化为特异性髓细胞,该类细胞抑制T细胞功能促进肿瘤生长。而更进一步进行体外实验发现敲除Siglec-15的小鼠的肿瘤生长降低,且使用Siglec-15单抗治疗后,可以抑制小鼠肿瘤生长。此外,PD-L1和Siglec-15的表达是互斥的,这就预示着Siglec-15的抗体有可能在抗PD-1/PD-L1免疫治疗无响应的患者身上是有效的。以上结果提示Siglec-15是又一个在肿瘤微环境中参与免疫逃逸的分子,且有作为治疗靶标的潜力。
目前本领域对肿瘤疗法仍存在着未被满足的需求。
发明内容
为克服现有技术中缺乏治疗siglec-15相关疾病的药物的缺陷,本发明提供了抗Siglec-15抗体及其在制备药物中的应用。抗Siglec-15抗体与Siglec-15蛋白结合并表现出许多优良特性,包括例如与Siglec-15蛋白高亲和力结合。此外,本发明的抗体可逆转Siglec-15诱导的PBMC增殖抑制和抑制Siglec-15蛋白介导的单核细胞增殖,从而调控免疫应答。因此,本发明还涉及使用抗Siglec-15抗体或其抗原结合片段调控免疫应答的方法。本发明还提供了抗Siglec-15抗体或其抗原结合片段在制备治疗Siglec-15相关疾病的药物或制备治疗肿瘤的药物中的应用。
本发明的第一方面提供结合Siglec-15的分离的抗体及其抗原结合片段。在一些实施方案中,本发明抗Siglec-15抗体或其抗原结合片段包括选自以下组的一个或多个CDR(抗体互补决定区)序列:SEQ ID NO:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、81。
在另外的实施方案中,包括选自以下组的一个或多个重链CDR序列:SEQ ID NO:1、2、3、4、5、11、12、13、17、18、19、20、25、26、27、28、29、35、36、37,和/或,选自以下组的一个或多个轻链CDR序列:SEQ ID NO:6、7、8、9、10、14、15、16、21、22、23、24、30、31、32、33、34、38、39、40、81。
在一些实施方案中,本发明抗Siglec-15抗体或其抗原结合片段包括重链可变区,其包含HCDR1、HCDR2和HCDR3序列,和/或轻链可变区,其包含LCDR1、LCDR2和LCDR3序列,其中:
(a)所述重链可变区HCDR1序列包含选自SEQ ID NO:1、11、17、25、35及其保守修饰的氨基酸序列;所述重链可变区HCDR2序列包含选自SEQ ID NO:2、3、4、12、18、19、26、27、28、36及其保守修饰的氨基酸序列;所述重链可变区HCDR3序列包含选自SEQ ID NO:5、13、20、29、37及其保守修饰的氨基酸序列;
(b)所述轻链可变区LCDR1序列包含选自SEQ ID NO:6、7、14、21、30、31、38、81及其保守修饰的氨基酸序列;所述轻链可变区LCDR2序列包含选自SEQ ID NO:8、9、15、22、23、32、33、39及其保守修饰的氨基酸序列;所述轻链可变区LCDR3序列包含选自SEQ ID NO:10、16、24、34、40及其保守修饰的氨基酸序列;
(c)所述抗体或其抗原结合片段与Siglec-15特异性结合。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中,重链可变区包括选自以下组的CDR序列:SEQ IDNO:1、2、3、4和5,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:6、7、8、9、10和81。
在另一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中,重链可变区包括选自以下组的CDR序列:SEQID NO:11、12和13,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:14、15和16。
在另一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中,重链可变区包括选自以下组的CDR序列:SEQID NO:17、18、19和20,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:21、22、23和24。
在另一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中,重链可变区包括选自以下组的CDR序列:SEQID NO:25、26、27、28和29,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:30、31、32、33和34。
在另一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中,重链可变区包括选自以下组的CDR序列:SEQID NO:35、36和37,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:38、39和40。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,重链可变区包括HCDR1、HCDR2和HCDR3,轻链可变区包括LCDR1、LCDR2和LCDR3,其中,重链可变区HCDR1序列如SEQ ID NO:1所示,HCDR2序列选自SEQ ID NO:2、3和4,HCDR3序列如SEQ ID NO:5所示,轻链可变区LCDR1序列选自SEQ ID NO:6、7和81,LCDR2序列选自SEQ ID NO:8和9,LCDR3序列如SEQ ID NO:10所示。
在另一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,重链可变区包括HCDR1、HCDR2和HCDR3,轻链可变区包括LCDR1、LCDR2和LCDR3,其中,重链可变区HCDR1序列如SEQ ID NO:11所示,HCDR2序列如SEQ ID NO:12所示,HCDR3序列如SEQ ID NO:13所示,轻链可变区LCDR1序列如SEQ IDNO:14所示,LCDR2序列如SEQ ID NO:15所示,LCDR3序列如SEQ ID NO:16所示。
在另一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,重链可变区包括HCDR1、HCDR2和HCDR3,轻链可变区包括LCDR1、LCDR2和LCDR3,其中,重链可变区HCDR1序列如SEQ ID NO:17所示,HCDR2序列选自SEQ ID NO:18和19所示,HCDR3序列如SEQ ID NO:20所示,轻链可变区LCDR1序列如SEQID NO:21所示,LCDR2序列选自SEQ ID NO:22和23,LCDR3序列如SEQ ID NO:24所示。
在另一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,重链可变区包括HCDR1、HCDR2和HCDR3,轻链可变区包括LCDR1、LCDR2和LCDR3,其中,重链可变区HCDR1序列如SEQ ID NO:25所示,HCDR2序列选自SEQ ID NO:26、27和28,HCDR3序列如SEQ ID NO:29所示,轻链可变区LCDR1序列选自SEQ ID NO:30和31,LCDR2序列选自SEQ ID NO:32和33,LCDR3序列如SEQ ID NO:34所示。
在另一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,重链可变区包括HCDR1、HCDR2和HCDR3,轻链可变区包括LCDR1、LCDR2和LCDR3,其中,重链可变区HCDR1序列如SEQ ID NO:35所示,HCDR2序列如SEQ ID NO:36所示,HCDR3序列如SEQ ID NO:37所示,轻链可变区LCDR1序列如SEQ IDNO:38所示,LCDR2序列如SEQ ID NO:39所示,LCDR3序列如SEQ ID NO:40所示。
本发明所述抗体或其抗原结合片段可为鼠源抗体、嵌合抗体、人源化抗体、全人源抗体或其片段,优选为全人源抗体、人源化抗体或其片段。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:重链可变区SEQ ID NO:41或其变体;和/或包含SEQ ID NO:42或其变体的轻链可变区。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:重链可变区SEQ ID NO:43或其变体;和/或包含SEQ ID NO:44或其变体的轻链可变区。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:重链可变区SEQ ID NO:45或其变体;和/或包含SEQ ID NO:46或其变体的轻链可变区。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:重链可变区SEQ ID NO:47或其变体;和/或包含SEQ ID NO:48或其变体的轻链可变区。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:重链可变区SEQ ID NO:49或其变体;和/或包含SEQ ID NO:50或其变体的轻链可变区。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:包含具有与SEQ ID NO:41至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或包含具有与SEQ ID NO:42至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的轻链可变区。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:包含具有与SEQ ID NO:43至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或包含具有与SEQ ID NO:44至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的轻链可变区。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:包含具有与SEQ ID NO:45至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或包含具有与SEQ ID NO:46至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的轻链可变区。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:包含具有与SEQ ID NO:47至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或包含具有与SEQ ID NO:48至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的轻链可变区。
在一个实施方案中,本发明提供结合Siglec-15的分离的抗体或其抗原结合片段,其包含:包含具有与SEQ ID NO:49至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或包含具有与SEQ ID NO:50至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的轻链可变区。
本发明的第二方面提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,该人源化抗体包含在SEQ ID NO:41所示序列的选自以下的一个或多个位点处引入突变的重链可变区:M3、K19、S40、E42、R44、P61、T65、S77、T78、S84、S88、M93、V97、P117和/或S120位点,和/或在SEQ ID NO:42所示序列的选自以下的一个或多个位点处引入突变的轻链可变区:V3、L4、A9、A12、V13、L15、Q17、A19、S22、K24、D32、Q46、P47、E59、I62、A64、N78、H80、P81、V82、E83、E84、A87、A104和/或L110。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包含在SEQ ID NO:41所示序列的选自以下的一个或多个位点处引入突变的重链可变区:M3Q、K19R、S40A、E42G、R44G、P61A、T65K、S77N、T78S、S84N、S88A、M93V、V97A、P117Q和/或S120T,和/或,在SEQ ID NO:42所示序列的选自以下的一个或多个位点处引入突变的轻链可变区:V3Q、L4M、A9S、A12S、V13A、L15V、Q17D、A19V、S22T、K24R、D32E、Q46K、P47A、E59Q、I62V、A64S、N78T、H80S、P81S、V82L、E83Q、E84P、A87F、A104Q和/或L110I。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和/或轻链可变区,其中,重链可变区序列选自SEQ ID NO:51、53、55和57,轻链可变区选自SEQ ID NO:52、54、56、58和82。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,该人源化抗体包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ IDNO:51所示序列或其变体,轻链可变区序列包括SEQ ID NO:52所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:53所示序列或其变体,轻链可变区序列包括SEQ ID NO:54所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:55所示序列或其变体,轻链可变区序列包括SEQ ID NO:56所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:57所示序列或其变体,轻链可变区序列包括SEQ ID NO:58所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:53所示序列或其变体,轻链可变区序列包括SEQ ID NO:56所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:53所示序列或其变体,轻链可变区序列包括SEQ ID NO:58所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:53所示序列或其变体,轻链可变区序列包括SEQ ID NO:82所示序列或其变体。
本发明的第三方面提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包含在SEQ ID NO:45所示序列的选自以下的一个或多个位点处引入突变的重链可变区:E1、Q5、L11、V12、R13、L20、T23、K38、R40、T41、E42、A61、P62、K67、A68、A72、S76、N77、L81、H82、T85、T87、V97和/或S113位点,和/或,在SEQ ID NO:46所示序列的选自以下的一个或多个位点处引入突变的轻链可变区:S8、F12、A18、Y36、L41、P43、K45、V47、T58、D74、G78、N81、I82、P84和/或V89位点。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包含在SEQ ID NO:45所示序列的选自以下的一个或多个位点处引入突变的重链可变区:E1Q、Q5V、L11V、V12K、R13K、L20V、T23K、K38R、R40A、T41P、E42G、A61S、P62Q、K67R、A68V、A72R、S76T或S76A、N77S、L81M、H82E、T85S、T87R、V97A和/或S113T位点,和/或在SEQID NO:46所示序列的选自以下的一个或多个位点处引入突变的轻链可变区:S8P、F12A、A18V、Y36H、L41E、P43G、K45R、V47L、T58K、D74E、G78T、N81S、I82L、P84S和/或V89D位点。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和/或轻链可变区,其中,重链可变区序列选自SEQ ID NO:59、61、63和65,轻链可变区选自SEQ ID NO:60、62、64和66。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:59所示序列或其变体,轻链可变区序列包括SEQ ID NO:60所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:61所示序列或其变体,轻链可变区序列包括SEQ ID NO:62所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:63所示序列或其变体,轻链可变区序列包括SEQ ID NO:64所示序列或其变体。
本发明的第四方面提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包含在SEQ ID NO:47所示序列的选自以下的一个或多个位点处引入突变的重链可变区:E1、Q5、P9、V10、L11、V12、M20、E23、K38、S40、K43、S44、N61、K67、A68、L70、V72、S76、N84、T87、S91和/或S119位点,和/或在SEQ ID NO:48所示序列的选自以下的一个或多个位点处引入突变的轻链可变区:V3、L4、A9、A12、V13、L15、Q17、A19、S22、R43、R46、P47、E59、I62、A64、R72、D80、P81、V82、E83、A84、D85、V87、A104和/或L110位点。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包含在SEQ ID NO:47所示序列的选自以下的一个或多个位点处引入突变的重链可变区:E1Q、Q5V、P9A、V10E、L11V、V12K、M20V、E23K、K38R、S40A、K43Q、S44G、N61A、K67R、A68V、L70M、V72R、S76T、N84S、T87R、S91T和/或S119T位点,和/或在SEQ ID NO:48所示序列的选自以下的一个或多个位点处引入突变的轻链可变区:V3Q、L4M、A9S、A12S、V13A、L15V、Q17D、A19V、S22T、R43K、R46K、P47A、E59Q、I62V、A64S、R72G、D80S、P81S、V82L、E83Q、A84P、D85E、V87F、A104Q和/或L110I位点。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和/或轻链可变区,其中,重链可变区序列选自SEQ ID NO:67、69、71和73,轻链可变区选自SEQ ID NO:68、70、72和74。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:67所示序列或其变体,轻链可变区序列包括SEQ ID NO:68所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:69所示序列或其变体,轻链可变区序列包括SEQ ID NO:70所示序列或其变体。
在一个实施方案中,本发明提供结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包括重链可变区和轻链可变区,其中,重链可变区序列包括SEQ ID NO:71所示序列或其变体,轻链可变区序列包括SEQ ID NO:72所示序列或其变体。
在上述任何实施方案中,本发明抗体或其抗原结合片段的变体可包含一个、两个或三个保守修饰的氨基酸取代。
在上述任何实施方案中,本发明“大写英文字母+数字”表示该数字位置的氨基酸残基,“大写英文字母1+数字+大写英文字母2”,表示该数字位置的氨基酸残基由某一氨基酸替换为另一氨基酸残基,例如,“E1”代表氨基酸编号为1位置的氨基酸残基为谷氨酸,“E1Q”代表氨基酸编号为1位置的谷氨酸被替换为谷氨酰胺,“Q5”代表氨基酸编号为5位置的氨基酸残基为谷氨酰胺,“Q5V”代表氨基酸编号为5位置的谷氨酰胺被替换为缬氨酸,
在上述任何实施方案中,本发明抗体或其抗原结合片段可包含:人重链恒定区或其变体,其中所述变体包含至多20个保守修饰的氨基酸取代;和/或人轻链恒定区或其变体,其中所述变体包含至多20个保守修饰的氨基酸取代。在一些实施方案中,所述变体可包含至多10个保守修饰的氨基酸取代。在一些实施方案中,所述变体可包含至多5个保守修饰的氨基酸取代。在一些实施方案中,所述变体可包含至多3个保守修饰的氨基酸取代。在上述任何实施方案中,人重链恒定区或其变体可以是IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM或IgD恒定区或其变体,优选IgG1或IgG4恒定区或其变体。
本发明抗体或其抗原结合片段中氨基酸残基的编号方式为Kabat的EU索引的编号方式。
在上述任何实施方案中,本发明抗体或或其抗原结合片段可以以930pM或更低的KD结合Siglec-15。在另一个实施方案中,抗体或其抗原结合片段可以以614pM或更低的KD结合Siglec-15。在另一个实施方案中,抗体或其抗原结合片段可以以325pM或更低的KD结合Siglec-15。在另一个实施方案中,抗体或其抗原结合片段可以以202pM或更低的KD结合Siglec-15。在另一个实施方案中,抗体或其抗原结合片段可以以109pM或更低的KD结合Siglec-15。在另一个实施方案中,抗体或其抗原结合片段可以以85.6pM或更低的KD结合Siglec-15。在另一个实施方案中,抗体或其抗原结合片段可以以80.6pM或更低的KD结合Siglec-15。在另一个实施方案中,抗体或其抗原结合片段可以以72.4pM或更低的KD结合Siglec-15。在另一个实施方案中,抗体或其抗原结合片段可以以68.3pM或更低的KD结合Siglec-15。
可用任何有效的方法测量KD值。在优选的实施方案中,用生物发光干涉测量法(例如,实施例2中所述的ForteBio Octet法)来测量解离常数。在其它优选的实施方案中,可用表面等离子共振技术(例如Biacore)或Kinexa来测量解离常数。
在一些实施方案中,本发明抗体抗原结合片段包括但不限于为Fab、Fab’、F(ab’)2、Fv、或scFv、sdFv(disulfide-linked Fv)的抗体片段。
本发明中,Fab片段,由VL、VH、CL和CH1结构域组成的单价片段;F(ab’)2片段,包含通过铰链区二硫桥连接的两个Fab片段的二价片段;Fd片段,由VH和CH1结构域组成;Fv片段,由抗体单臂的VL和VH结构域组成;scFv片段,VL和VH区配对形成的单价分子。
在一些实施方案中,本发明抗Siglec-15抗体或其抗原结合片段可以与人Siglec-15结合。在另一些实施方案中,本发明抗Siglec-15抗体或其抗原结合片段可以与猴Siglec-15结合。在另一些实施方案中,本发明抗Siglec-15抗体或其抗原结合片段可以与鼠Siglec-15结合。
在一些实施方案中,本发明抗Siglec-15抗体或其抗原结合片段与Siglec-15结合的表位相同或不同。
在一些实施方案中,本发明抗体片段为双特异性抗体。
本发明的第五方面还包括包含上述结合Siglec-15的抗体或其抗原结合片段中的任一种的双特异性抗体。
本发明的第六方面还包括编码本发明抗Siglec-15抗体及其抗原结合片段的核酸序列。
本发明的第七方面还包括包含编码本发明抗体或其抗原结合片段的核酸序列的表达载体。
本发明的第八方面还包括包含第七方面所述表达载体的宿主细胞。
此外,本发明的第九方面还包括制备本发明抗体或或其抗原结合片段的方法,该方法包括:(a)在使所述核酸序列表达的条件下在培养基中培养包含编码本发明抗体或其抗原结合片段的核酸的宿主细胞,由此产生包含轻链和重链可变区的多肽;和(b)从所述宿主细胞或培养基回收多肽。
本发明的第十方面还包括包含与可药用载体或稀释剂组合的本发明抗体或其抗原结合片段的组合物。
本发明的第十一方面还包括包含与治疗剂(例如细菌毒素或放射性毒素)连接的本发明抗Siglec-15抗体或其抗原结合片段的免疫连接物。细胞毒剂的非限制性实例包括:泰素(taxol)、细胞松弛素B(cytochalasin B)、丝裂霉素(mitomycin)、依托泊苷(etoposide)和长春新碱(vincristine)或其它抗代谢物、烷化剂、抗生素和抗有丝分裂药。本发明的第十二方面还包括本发明第一方面所述抗Siglec-15抗体或其抗原结合片段、第十方面所述的组合物、第十一方面所述的免疫连接物、第五方面所述的双特异性抗体在制备治疗Siglec-15相关疾病的药物中的应用。
或,本发明第一方面所述抗Siglec-15抗体或其抗原结合片段、第十方面所述的组合物、第十一方面所述的免疫连接物、第五方面所述的双特异性抗体用于治疗Siglec-15相关疾病。
或,一种治疗Siglec-15相关疾病的方法,其包括向有需要的受试者施用本发明第一方面所述抗Siglec-15抗体或其抗原结合片段、第十方面所述的组合物、第十一方面所述的免疫连接物或第五方面所述的双特异性抗体。
本发明所述Siglec-15相关疾病包括但不限于癌症或骨病相关疾病。所述癌症或骨病相关疾病可以是Siglec-15阳性癌症和骨病;
所述癌症包括但不限于白血病、黑色素瘤、头颈癌、胶质母细胞瘤细胞、乳腺癌、卵巢癌、胃癌、尿路上皮癌、胃食管癌、食道癌、子宫内膜癌、结肠癌、肝癌、肺癌或膀胱癌;其中所述白血病包括急性淋巴细胞性白血病(Acute lymphocytic leukemia,ALL)、急性骨髓性白血病(Acute myelogenous leukemia,AML)、慢性淋巴细胞性白血病(Chroniclymphocytic leukemia,CLL)、慢性骨髓性白血病(Chronic myelogenous leukemia,CML);
所述骨病包括但不限于骨质疏松症、骨丢失、骨关节炎、骨软化症等。
本发明还包括本发明抗Siglec-15抗体或其抗原结合片段在用于制备逆转Siglec-15-hFc介导的PBMC增殖抑制药物中的用途。
本发明还包括本发明抗Siglec-15抗体或其抗原结合片段在用于制备抑制Siglec-15蛋白介导的单核细胞增殖的药物中的用途。
本发明还包括本发明抗Siglec-15抗体或其抗原结合片段在用于制备抑制Siglec-15蛋白介导的单核细胞存活的药物中的用途。
本发明还包括本发明抗Siglec-15抗体或其抗原结合片段在用于制备调控免疫应答的药物中的用途。
本发明的第十三方面还包括本发明第一方面所述抗Siglec-15抗体或其抗原结合片段、第十方面所述的组合物、第十一方面所述的免疫连接物、第五方面所述的双特异性抗体在制备抑制肿瘤细胞生长的药物中的用途。
或,本发明第一方面所述抗Siglec-15抗体或其抗原结合片段、第十方面所述的组合物、第十一方面所述的免疫连接物、第五方面所述的双特异性抗体用于抑制肿瘤细胞生长。
或,一种抑制肿瘤细胞生长的方法,其包括向有需要的受试者施用本发明第一方面所述抗Siglec-15抗体或其抗原结合片段、第十方面所述的组合物、第十一方面所述的免疫连接物或第五方面所述的双特异性抗体。
在一些实施方案中,抗Siglec-15抗体或其抗原结合片段可与第二治疗剂或治疗形式组合。
在一个实施方案中,用抗Siglec-15抗体或其抗原结合片段的治疗可与化疗组合。
在一个实施方案中,用抗Siglec-15抗体或其抗原结合片段治疗可与放疗组合。
在一些实施方案中,抗Siglec-15抗体或其抗原结合片段可与用于治疗癌症的另一种治疗性抗体联合。
本发明的积极进步效果在于:
本发明获得一种新的与Siglec-15具有高亲和力的抗体或抗原结合片段、其制备方法、含其的组合物或免疫连接物或双特异性抗体,本发明获得抗Siglec-15抗体或其抗原结合片段具有调控免疫应答的方法,并且具有治疗肿瘤的作用。
附图说明
图1为抗Siglec-15嵌合抗体与293T-hu-S15的结合曲线以及EC50值。
图2A为嵌合抗体21F6C6对Siglec-15蛋白诱导的PBMC增殖抑制的逆转曲线图及EC50值。
图2B为嵌合抗体75E1F2对Siglec-15蛋白诱导的PBMC增殖抑制的逆转曲线图及EC50值。
图2C为嵌合抗体174C11C9对Siglec-15蛋白诱导的PBMC增殖抑制的逆转曲线图及EC50值。
图2D为嵌合抗体124B11F6对Siglec-15蛋白诱导的PBMC增殖抑制的逆转曲线图及EC50值。
图2E为嵌合抗体255C12B10对Siglec-15蛋白诱导的PBMC增殖抑制的逆转曲线图及EC50值。
图3为抗Siglec-15嵌合抗体抑制Siglec-15蛋白介导的单核细胞增殖。
图4A为21F6C6嵌合抗体重链可变区人源化设计图。
图4B为21F6C6嵌合抗体轻链可变区人源化设计图。
图4C为124B11F6嵌合抗体重链可变区人源化设计图。
图4D为124B11F6嵌合抗体轻链可变区人源化设计图。
图4E为174C11C9嵌合抗体重链可变区人源化设计图。
图4F为174C11C9嵌合抗体轻链可变区人源化设计图。
图5A为人源化抗体21F6C6-hH1L1、21F6C6-hH2L2逆转Siglec-15蛋白介导的PBMC增殖抑制的百分比曲线图以及EC50值。
图5B为人源化抗体21F6C6-hH2L3、21F6C6-hH3L3逆转Siglec-15蛋白介导的PBMC增殖抑制的百分比曲线图以及EC50值。
图5C为人源化抗体21F6C6-hH2L4、21F6C6-hH4L4逆转Siglec-15蛋白介导的PBMC增殖抑制的百分比曲线图以及EC50值。
图5D为人源化抗体124B11F6-hH1L1、124B11F6-hH2L2、124B11F6-hH3L3逆转Siglec-15蛋白介导的PBMC增殖抑制的百分比曲线图以及EC50值。
图5E为人源化抗体174C11C9-hH1L1、174C11C9-hH2L2、174C11C9-hH3L3逆转Siglec-15蛋白介导的PBMC增殖抑制的百分比曲线图以及EC50值。
图6为抗Siglec-15人源化抗体抑制Siglec-15蛋白介导的单核细胞增殖图。
图7为MC38-hSiglec15肿瘤模型中对照组和治疗组小鼠肿瘤体积的生长曲线。
图8为MC38-hSiglec15肿瘤模型中对照组和治疗组随着治疗时间的体重变化曲线。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1、Siglec-15抗原及检测用蛋白的制备
以UniProt Sialic acid-binding Ig-like lectin 15Isoform 1的人Siglec-15胞外区域(F20-F263)作为模板,获得编码本发明抗原及检测用蛋白的基因序列,与抗体重链Fc片段(如人IgG1)或者His标签重组,经HEK293或者Expi293细胞表达纯化,获得本发明抗原及检测用蛋白,蛋白生产厂家为北京百普赛斯生物科技股份有限公司,货号分别为SG5-H5253(Fc标签)和SG5-H52H3(His标签),其中人Siglec-15胞外区域序列如SEQ ID NO:75所示,其中1-19为氨基酸残基为信号肽序列,40-158位氨基酸残基为“V-set”结构域,168-251位氨基酸残基为“C2-set”结构域;人Siglec-15全长胞外区域与人IgG1 Fc片段连接得到的重组蛋白(简称hS15-hFc)序列如SEQ ID NO:76所示,其中,1-244位氨基酸残基为Siglec-15全长胞外区域序列,253-483位氨基酸残基为人IgG1 Fc序列;Siglec-15第一结构域(Domain 1,包含“V-set”结构域)与人IgG1 Fc连接得到的重组蛋白(简称hS15-D1-hFc)序列如SEQ ID NO:77所示,其中1-4位氨基酸残基为信号肽序列,5-152位氨基酸残基为Siglec-15第一结构域(其中25-143位氨基酸残基为Siglec-15“V-set”结构域序列),153-159位氨基酸残基为连接子(Linker)序列,160-390位氨基酸残基为人IgG1 Fc序列;人Siglec-15全长胞外区域与His标签序列连接得到的蛋白序列如SEQ ID NO:78所示,其中1-244位氨基酸残基为人Siglec-15全长胞外区域序列,253-262位氨基酸残基为His标签序列。检测用小鼠和食蟹猴Siglec-15蛋白为商业化产品,购买自北京百普赛斯生物科技股份有限公司,货号分别为SG5-M52H7和SG5-C52H6。食蟹猴Siglec-15全长胞外区域与His标签序列连接得到的蛋白序列如SEQ ID NO:79所示,其中1-244位氨基酸残基为猴Siglec-15全长胞外区域序列,253-262位氨基酸残基为His标签序列。小鼠Siglec-15全长胞外区域与His标签序列连接得到的蛋白序列如SEQ ID NO:80所示,其中1-239位氨基酸残基为鼠Siglec-15全长胞外区域序列,248-257位氨基酸残基为His标签序列。
实施例2、抗人Siglec-15杂交瘤单克隆抗体的制备
用经佐剂乳化的hS15-hFc免疫15只小鼠(5只C57bl/6,5只balb/c,5只SJL),2周后用hS15-hFc或者hS15-D1-hFc免疫。取血清进行ELISA实验来评估抗血清滴度。选择血清滴度较高的小鼠进行脾细胞融合。最后一次加强免疫3天后取脾脏细胞进行融合,采用电融合的方式共进行5轮融合,每个融合后获得的杂交瘤细胞铺50块96孔板。对杂交瘤上清进行结合活性实验筛选出阳性克隆,并进一步进行亚克隆。通过结合活性实验和体外免疫细胞功能实验筛选出阳性克隆进行测序。
结果:通过结合活性实验和体外免疫细胞功能实验筛选得到5个阳性杂交瘤克隆,分别为21F6C6、75E1F2、124B11F6、174C11C9和255C12B10,5个杂交瘤克隆的重链可变区和轻链可变区序列分别如下所示。
21F6C6:
重链可变区序列(SEQ ID NO:41):
EVMLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQSPEKRLEWVATISSGGSLIYYPDSVTGRFTISRDNAKSTLYLQMSSLRSEDTAMYYCVRHGYYYGDSTLYYAMDYWGPGTSVTVSS
上述下划线序列分别为HCDR1、HCDR2和HCDR3,氨基酸序列分别如SEQ ID NO:1、2和5所示。SEQ ID NO:3和4均为在SEQ ID NO:2上进行了1或2个氨基酸替换获得。
轻链可变区序列(SEQ ID NO:42):
DIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEAPLTFGAGTKLELK
上述下划线序列分别为LCDR1、LCDR2和LCDR3,氨基酸序列分别如SEQ ID NO:6、8和10所示。SEQ ID NO:7和9分别为在SEQ ID NO:6和8上进行了1个氨基酸替换获得。
75E1F2:
重链可变区序列(SEQ ID NO:43):
EVQLVESGGGSVKPGGSLKLSCAASGFTFSDYGMHWVRQAPEKGLEWITYISSGSSIIDYSDTVKGRFTISRDNAKDTLFLQMTSLRSEDTAIYYCVRREDHYAMDYWGQGTSVTVSS
上述下划线序列分别为HCDR1、HCDR2和HCDR3,氨基酸序列分别如SEQ ID NO:11、12和13所示。
轻链可变区序列(SEQ ID NO:44):
DIVMTQSHKFLSTSVGDRVSITCKASQDVYTAVAWFQQKPGQSPKLLFYSASYRFTGVPDRFNGSGSGTDFTLTITSMQAEDLAVYYCQQHYSTPWTFGGGTKLEIK
上述下划线序列分别LCDR1、LCDR2和LCDR3,氨基酸序列分别如SEQ ID NO:14、15和16所示。
124B11F6:
重链可变区序列(SEQ ID NO:45):
EVQLQQSGAELVRPGASVKLSCTASVFNIKDYYMHWVKQRTEQGLEWIGRIDPEDDKTKYAPKFQGKATITADTSSNTAYLHLSTLTSEDTAVYYCVRGWLGYIMDFWGQGTSVTVSS
上述下划线序列分别为HCDR1、HCDR2和HCDR3,氨基酸序列分别如SEQ ID NO:17、18和20所示。SEQ ID NO:19为在SEQ ID NO:18上进行了2个氨基酸替换获得。
轻链可变区序列(SEQ ID NO:46):
QLVLTQSSSASFSLGASAKLTCTLSSQHSTYTIDWYQQQPLKPPKYVMELKEDGSHSTGDGIPDRFSGSSSGADRYLGISNIQPEDEAVYICGVGATIKEQFVYVFGGGTKVTVL
上述下划线序列分别为LCDR1、LCDR2和LCDR3,氨基酸序列分别如SEQ ID NO:21、22和24所示。SEQ ID NO:23为在SEQ ID NO:22上进行了1个氨基酸替换获得。
174C11C9:
重链可变区序列(SEQ ID NO:47):
EVQLQQSGPVLVKPGASVKMSCEASGYIFTDYYMNWVKQSPGKSLEWIGVFNPYSGGISYNQKFKGKATLTVDTSSSTAYMELNSLTSEDSAVYYCARDYYYLSSHGFYALDYWGQGTSVTVSS
上述下划线序列分别为HCDR1、HCDR2和HCDR3,氨基酸序列分别如SEQ ID NO:25、26和29所示。SEQ ID NO:27和28均为在SEQ ID NO:26上进行了1或2个氨基酸替换获得。轻链可变区序列(SEQ ID NO:48):
DIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFIHWYQQRPGRPPKLLMYRASNLESGIPARFSGSGSRTDFTLTIDPVEADDVATYYCQQSNEDPLTFGAGTKLELK
上述下划线序列分别为LCDR1、LCDR2和LCDR3,氨基酸序列分别如SEQ ID NO:30、32和34所示。SEQ ID NO:31和33分别为在SEQ ID NO:30和32上进行了1个氨基酸替换获得。
255C12B10:
重链可变区序列(SEQ ID NO:49):
EVQLQQSGPELVKPGASVKMSCKASGYTFTGYNMNWVKQSHGKSLEWIGYINPNNGGTRYNQKFKGKATLTINKSSSTAYMELRSLTSEDSAVYYCARDYGIDYWGQGTTLTVSS
上述下划线序列分别为HCDR1、HCDR2和HCDR3,氨基酸序列分别如SEQ ID NO:35、36和37所示。
轻链可变区序列(SEQ ID NO:50):
EIQMTQSPSSMSASLGDRITITCQATQDIVKNLNWYQQKPGKPPSFLIYYATELAEGVPSRFSGSGSGSDYSLTISNLESEDFADYYCLQFYEFPYTFGGGTKLEIK
上述下划线序列分别为LCDR1、LCDR2和LCDR3,氨基酸序列分别如SEQ ID NO:38、39和40所示。
注:上述序列中,下划线序列分别为重链可变区或轻链可变区的CDR1、CDR2和CDR3,被3个CDR序列隔开的依次为重链可变区或轻链可变区的4个框架区序列FWR1、FWR2、FWR3、FWR4。抗体具体的CDR序列及其编号如下表1所示。
表1抗体的CDR序列信息
实施例3、抗人Siglec-15抗体与不同种属来源Siglec-15蛋白的结合
将杂交瘤筛选获得的抗体可变区与人IgG1(N297A)恒定区合成嵌合抗体,分别命名为21F6C6、75E1F2、124B11F6、174C11C9和255C12B10嵌合抗体。不同种属来源Siglec-15蛋白与嵌合抗体进行结合活性实验,人/小鼠/食蟹猴种属来源Siglec-15蛋白来源于北京百普赛斯生物科技股份有限公司。抗原包被0.5μg/ml,抗体从1μg/ml梯度稀释后与抗原进行孵育,二抗使用辣根过氧化物酶标记的Anti-Human IgG抗体,加入底物后读取OD450值。
结果:5个抗Siglec-15嵌合抗体均与人Siglec-15和食蟹猴Siglec-15有结合活性,其中源于124B11F6、174C11C9和255C12B10杂交瘤的嵌合抗体与鼠Siglec-15有结合活性。表2所示为抗Siglec-15嵌合抗体与不同种属的Siglec-15抗原结合的EC50值。
表2抗Siglec-15嵌合抗体与不同种属的Siglec-15抗原结合的EC50值
实施例4、抗人Siglec-15抗体与表达人Siglec-15的细胞的结合
过表达人Siglec-15的HEK293T细胞系购买自康源博创(HEK293T-hu-S15细胞系,货号KC-1314),纯化的抗Siglec-15嵌合抗体以100nM梯度稀释与HEK293T-hu-S15细胞系4℃孵育30分钟,抗人IgG(Fc特异性)-FITC(货号:F9512)二抗添加到样品中孵育30分钟随后通过流式细胞术进行分析。
结果:5个抗Siglec-15嵌合抗体均与HEK293T-hu-S15细胞系结合。图1是抗Siglec-15嵌合抗体与HEK293T-hu-S15的结合曲线以及EC50值。
实施例5、重组抗体对Siglec-15蛋白亲和力评估
使用Biacore8K进行亲和力分析,CM5芯片固定抗人Fc抗体用来捕获待测抗体,将待测抗体原液样品稀释至5μg/mL,并以10μL/min的流速依次注入到实验通道约500RU。被分析物为Human Siglec-15,His Tag(Cat.No.SG5-H52H3),将稀释后的人Siglec-15蛋白依次以30μL/min的流速注入到实验通道与参比通道,结合时间为150s,解离时间为700s。使用Biacore 8K分析软件计算每个抗体的KD值。
结果:表3是抗Siglec-15嵌合抗体与Siglec-15蛋白亲和力分析结果。
表3抗Siglec-15嵌合抗体与Siglec-15蛋白亲和力分析结果
抗体名称 | ka(1/Ms) | kd(1/s) | KD(M) |
21F6C6嵌合抗体 | 3.95E+06 | 1.87E-04 | 4.73E-11 |
174C11C9嵌合抗体 | 1.21E+06 | 3.70E-04 | 3.05E-10 |
75E1F2嵌合抗体 | 8.41E+05 | 7.82E-04 | 9.30E-10 |
124B11F6嵌合抗体 | 1.02E+05 | 1.46E-07 | 1.43E-12 |
255C12B10嵌合抗体 | 2.96E+05 | 1.58E-04 | 5.36E-10 |
实施例6、嵌合抗体表位鉴定
使用Octet RED96e(ForteBio)仪器对待测抗体进行表位竞争实验。使用HIS1K生物传感器捕获Human Siglec-15,His Tag(Cat.No.SG5-H52H3)(5μg/mL),与第一抗体(100nM)结合180s,在生物传感器上将Human Siglec-15,His Tag(抗原)-第一抗体与第二抗体(100nM)结合90s,使用Octet RED96e(ForteBio)分析软件分析数据。
结果:表4是抗Siglec-15嵌合抗体互相竞争参数,60%-100%表示完全不竞争,表明抗原表位不一致或部分一致;20%-60%表示部分竞争,表明抗原表位部分一致;<20%表示完全竞争,表明抗原表位一致。
表4抗Siglec-15嵌合抗体互相竞争参数
注释:涂阴影单元格代表自反应对照结果。
实施例7、抗Siglec-15嵌合抗体可以逆转Siglec-15蛋白介导的PBMC增殖抑制
复苏冻存的外周血单核细胞(PBMC),梯度稀释抗Siglec-15嵌合抗体与hS15-hFc蛋白(0.5μg/ml)37℃孵育30分钟后,加入1×105个PBMC细胞,以及可溶的OKT3(0.5ng/ml,eBioscience),培养3天后,加入celltiterglo(Promega),读取荧光值来评价细胞增殖情况。
结果:5个抗Siglec-15嵌合抗体均可以逆转hS15-hFc介导的PBMC增殖抑制,图2A-E为抗体21F6C6、75E1F2、174C11C9、124B11F6和255C12B10回复抑制的百分比曲线图以及EC50值。
实施例8、抗Siglec-15嵌合抗体可以抑制Siglec-15蛋白介导的单核细胞存活
复苏从人PBMC中分离得到的冻存CD14+单核细胞,不同浓度的抗Siglec-15嵌合抗体和hS15-hFc蛋白37℃孵育30分钟后,加入1×105个CD14+单核细胞。培养6天后,向培养板中加入XTT(Roche,货号11465015001),培养2小时后,读取OD450-OD690来测量细胞活力。
结果:图3所示hS15-hFc蛋白可以诱导CD14+单核细胞存活并增殖,抗Siglec-15嵌合抗体可以梯度抑制Siglec-15蛋白介导的单核细胞增殖。
实施例9、抗Siglec-15抗体人源化
将嵌合抗体21F6C6、124B11F6和174C11C9进行人源化设计,分别提供四条重链和四条轻链,见下表5。
表5嵌合抗体的人源化设计
结果:21F6C6人源化序列设计见图4A和图4B,124B11F6人源化序列设计见图4C和图4D,174C11C9人源化序列设计见图4E和图4F。其中灰色底纹部分是鼠源序列,加粗倾斜部分是CDR区序列,黑色底纹部分是人源化后序列,其余部分为原始人源序列。图4A~4F中,人源化抗体的缩写“hu”与表5的“h”代表相同的意思,可以互换使用;以此类推到本发明中。
实施例10、人源化抗体对Siglec-15蛋白亲和力评估
对21F6C6、124B11F6和174C11C9人源化序列进行了不同组合表达(表6)。对21F6C6-hH2L4的LCDR1进行了点突变,获得人源化抗体21F6C6-hH2L4V,去除了异构化翻译后修饰位点,其轻链可变区序列为SEQ ID NO:82(21F6C6-hH2L4V),LCDR1序列见SEQ IDNO:81(21F6C6-hH2L4V)。
使用Biacore进行亲和力分析,CM5芯片固定抗人Fc抗体用来捕获待测抗体,被分析物为Siglec-15蛋白。(方法同实施例6)
结果:表6是人源化抗体与Siglec-15蛋白亲和力分析结果。
表6人源化抗体与Siglec-15蛋白亲和力分析结果
其中,21F6C6-mHL代表鼠抗可变区与hIgG1构成的嵌合抗体21F6C6(174C11C9-mHL和124B11F6-mHL以此类推),21F6C6-hH1L1代表图4A中人源化设计的huVH1与图4B中huVL1分别与hIgG1重链恒定区以及Kappa轻链恒定区重组得到的人源化抗体。124B11F6-hH1L1代表图4C中人源化设计的huVH1与图4D中huVL1分别与hIgG1恒定区以及Lambda-C2轻链恒定区重组得到的人源化抗体。174C11C9-hH2L2代表图4E中人源化设计的huVH2与图4F中huVL2分别与hIgG1恒定区以及Kappa轻链恒定区重组得到的人源化抗体。其他以此类推。
实施例11、人源化抗体可以逆转Siglec-15介导的PBMC增殖抑制
复苏冻存的外周血单核细胞(PBMC),梯度稀释抗Siglec-15人源化抗体与hS15-hFc蛋白(1μg/ml)37℃孵育30分钟后,加入1×105个PBMC细胞,以及可溶的OKT3(5ng/ml,eBioscience),培养3天后,加入celltiterglo(Promega),读取荧光值来评价细胞增殖情况。
结果:抗Siglec-15人源化抗体可以逆转hS15-hFc介导的PBMC增殖抑制,图5A-E为抗体回复抑制的百分比曲线图以及EC50值。
实施例12、抗Siglec-15人源化抗体可以抑制Siglec-15介导的单核细胞存活
复苏从人PBMC中分离得到的冻存CD14+单核细胞,抗Siglec-15人源化抗体(10μg/ml)和hS15-hFc(2μg/ml)蛋白37℃孵育30分钟后,加入1×105个CD14+单核细胞。培养5天后,向培养板中加入celltiterglo(Promega),读取荧光值来测量细胞活力。
结果:图6所示抗Siglec-15人源化抗体可以抑制Siglec-15蛋白介导的单核细胞增殖。
实施例13、抗Siglec-15人源化抗体在HuCELL肿瘤模型中的抗肿瘤药效评价
实验动物为SIGLEC15人源化的C57BL/6J小鼠(C57BL/6J-SIGLEC15HuGEMM),雌性,6~8周(肿瘤接种时的小鼠周龄),体重18-24g(分组时小鼠的体重),共50只(根据小鼠体重和肿瘤大小各选择32只荷瘤鼠随机进行分组)。小鼠购自上海南方模式动物中心(SMOC),动物合格证编号:20190002004257。饲养环境:SPF级。
鼠源MC38-hSiglec15细胞(Clone#6,细胞编号ECL-00260)培养在含有10%胎牛血清的DMEM培养基中。收集指数生长期的MC38-hSiglec15细胞用于接种,用PBS重悬细胞,每只小鼠按照5×106细胞/100μL在背部右侧肩胛处进行皮下接种。C57BL/6J-SIGLEC15HuGEMM小鼠皮下接种MC38-hSiglec15肿瘤细胞,建立同种移植结肠癌细胞肿瘤模型。对照组为hIgG1 isotype同型对照,治疗组分别为21F6C6-hH2L4V(10mg/kg),174C11C9-hH2L2(10mg/kg),每组8只小鼠;对照组和给药组全部按照腹腔注射给药,根据肿瘤抑制率(TGI)进行疗效评价。
21F6C6-hH2L4V:
重链可变区序列(SEQ ID NO:53):
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVATISSGGSLIYYADSVTGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCVRHGYYYGDSTLYYAMDYWGQGTTVTVSS
上述下划线序列分别为HCDR1、HCDR2和HCDR3,氨基酸序列分别如SEQ ID NO:1、3和5所示。
轻链可变区序列(SEQ ID NO:82):
DIQMTQSPSSLSASVGDRVTITCRASQSVDYEGDSYMNWYQQKPGKAPKLLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEAPLTFGQGTKLEIK
上述下划线序列分别为LCDR1、LCDR2和LCDR3,氨基酸序列分别如SEQ ID NO:81、9和10所示。
174C11C9-hH2L2:
重链可变区序列(SEQ ID NO:69):
QVQLVQSGAEVKKPGASVKVSCKASGYIFTDYYMNWVRQAPGQGLEWIGVFNPYSGGISYNQKFKGRVTLTVDTSTSTAYMELSSLRSEDTAVYYCARDYYYLSSHGFYALDYWGQGTTVTVSS
上述下划线序列分别为HCDR1、HCDR2和HCDR3,氨基酸序列分别如SEQ ID NO:25、26和29所示。
轻链可变区序列(SEQ ID NO:70):
DIQLTQSPSSLSASVGDRVTITCRASESVDSYGNSFIHWYQQKPGKAPKLLMYRASNLESGIPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPLTFGQGTKLEIK
上述下划线序列分别为LCDR1、LCDR2和LCDR3,氨基酸序列分别如SEQ ID NO:30、32和34所示。
肿瘤体积计算公式:肿瘤体积(mm3)=1/2×(a×b2)(其中a表示长径,b表示短径)。实验中使用StudyDirectorTM(版本号3.1.399.19,供应商StudylogSystem,Inc.,S.SanFrancisco,CA,USA)软件收集数据,包括肿瘤的长短径的测量和动物体重的称量。肿瘤抑制率,TGI(%),计算公式如下:TGI%=100×(1-ΔT/ΔC)。(ΔT和ΔC分别为治疗组和对照组在某一特定时间点的平均肿瘤体积(MTVt)-分组时的平均肿瘤体积(MTV1))。
所有的统计分析和图形绘制都在R语言环境中进行(3.3.1版)。非特别说明的情况下,所有检验均为双尾检验,P值小于0.05时被认为具有统计显著性
实验结果:
通过对小鼠在给药后第38天肿瘤平均体积分析,hIgG1 isotype(10mg/kg)对照组小鼠在给药后第38天右肿瘤平均体积为1134mm3,21F6C6-hH2L4V(10mg/kg)治疗组在给药后第6天肿瘤开始消失,治疗后第13天所有小鼠被治愈,直到第38天7只小鼠肿瘤体积均一直保持为0mm3,另有一只小鼠肿瘤复发,整体肿瘤抑制率TGI为107%,相较于对照组在抗肿瘤作用上具有统计学上的显著性差异(P<0.005);174C11C9-hH2L2(10mg/kg)治疗组在给药后第6天肿瘤开始消失,治疗后第13天所有小鼠被治愈,直到第38天所有小鼠肿瘤体积均为0mm3,肿瘤抑制率TGI为108%,相较于对照组在抗肿瘤作用上具有统计学上的显著性差异(P<0.005)。对照组和治疗组肿瘤生长情况见图7。对照组和治疗组随着治疗时间的体重变化曲线见图8。本次研究结果表明,与阴性对照hIgG1 isotype(10mg/kg)相比,21F6C6-hH2L4V(10mg/kg)和174C11C9-hH2L2(10mg/kg)单独治疗后在MC38-hSiglec15肿瘤模型上取得显著的抗肿瘤效果(P<0.005),小鼠基本被治愈,肿瘤消失延长观察后,基本无肿瘤复发。
SEQUENCE LISTING
<110> 上海津曼特生物科技有限公司
<120> 抗Siglec-15抗体及其在制备药物中的应用
<130>
<160> 82
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6 HCDR1
<400> 1
Ser Tyr Ala Met Ser
1 5
<210> 2
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6 HCDR2
<400> 2
Thr Ile Ser Ser Gly Gly Ser Leu Ile Tyr Tyr Pro Asp Ser Val Thr
1 5 10 15
Gly
<210> 3
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVH2 HCDR2
<400> 3
Thr Ile Ser Ser Gly Gly Ser Leu Ile Tyr Tyr Ala Asp Ser Val Thr
1 5 10 15
Gly
<210> 4
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVH3/hVH4 HCDR2
<400> 4
Thr Ile Ser Ser Gly Gly Ser Leu Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 5
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6 HCDR3
<400> 5
His Gly Tyr Tyr Tyr Gly Asp Ser Thr Leu Tyr Tyr Ala Met Asp Tyr
1 5 10 15
<210> 6
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6 LCDR1
<400> 6
Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn
1 5 10 15
<210> 7
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVL1~4 LCDR1
<400> 7
Arg Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn
1 5 10 15
<210> 8
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6 LCDR2
<400> 8
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 9
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVL4 LCDR2
<400> 9
Ala Ala Ser Asn Leu Gln Ser
1 5
<210> 10
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6 LCDR3
<400> 10
Gln Gln Ser Asn Glu Ala Pro Leu Thr
1 5
<210> 11
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 75E1F2 HCDR1
<400> 11
Asp Tyr Gly Met His
1 5
<210> 12
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 75E1F2 HCDR2
<400> 12
Tyr Ile Ser Ser Gly Ser Ser Ile Ile Asp Tyr Ser Asp Thr Val Lys
1 5 10 15
Gly
<210> 13
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 75E1F2 HCDR3
<400> 13
Arg Glu Asp His Tyr Ala Met Asp Tyr
1 5
<210> 14
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 75E1F2 LCDR1
<400> 14
Lys Ala Ser Gln Asp Val Tyr Thr Ala Val Ala
1 5 10
<210> 15
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 75E1F2 LCDR2
<400> 15
Ser Ala Ser Tyr Arg Phe Thr
1 5
<210> 16
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 75E1F2 LCDR3
<400> 16
Gln Gln His Tyr Ser Thr Pro Trp Thr
1 5
<210> 17
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6 HCDR1
<400> 17
Asp Tyr Tyr Met His
1 5
<210> 18
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6 HCDR2
<400> 18
Arg Ile Asp Pro Glu Asp Asp Lys Thr Lys Tyr Ala Pro Lys Phe Gln
1 5 10 15
Gly
<210> 19
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVH4 HCDR2
<400> 19
Arg Ile Asp Pro Glu Asp Asp Lys Thr Lys Tyr Ser Gln Lys Phe Gln
1 5 10 15
Gly
<210> 20
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6 HCDR3
<400> 20
Gly Trp Leu Gly Tyr Ile Met Asp Phe
1 5
<210> 21
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6 LCDR1
<400> 21
Thr Leu Ser Ser Gln His Ser Thr Tyr Thr Ile Asp
1 5 10
<210> 22
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6 LCDR2
<400> 22
Leu Lys Glu Asp Gly Ser His Ser Thr Gly Asp
1 5 10
<210> 23
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVL3~4 LCDR2
<400> 23
Leu Lys Glu Asp Gly Ser His Ser Lys Gly Asp
1 5 10
<210> 24
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6 LCDR3
<400> 24
Gly Val Gly Ala Thr Ile Lys Glu Gln Phe Val Tyr Val
1 5 10
<210> 25
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9 HCDR1
<400> 25
Asp Tyr Tyr Met Asn
1 5
<210> 26
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9 HCDR2
<400> 26
Val Phe Asn Pro Tyr Ser Gly Gly Ile Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 27
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVH3 HCDR2
<400> 27
Val Phe Asn Pro Tyr Ser Gly Gly Ile Ser Tyr Ala Gln Lys Phe Lys
1 5 10 15
Gly
<210> 28
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVH4 HCDR2
<400> 28
Val Phe Asn Pro Tyr Ser Gly Gly Ile Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 29
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9 HCDR3
<400> 29
Asp Tyr Tyr Tyr Leu Ser Ser His Gly Phe Tyr Ala Leu Asp Tyr
1 5 10 15
<210> 30
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9 LCDR1
<400> 30
Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Ile His
1 5 10 15
<210> 31
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVL4 LCDR1
<400> 31
Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Thr Phe Ile His
1 5 10 15
<210> 32
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9 LCDR2
<400> 32
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 33
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVL4 LCDR2
<400> 33
Arg Ala Ser Asn Leu Gln Ser
1 5
<210> 34
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9 LCDR3
<400> 34
Gln Gln Ser Asn Glu Asp Pro Leu Thr
1 5
<210> 35
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 255C12B10 HCDR1
<400> 35
Gly Tyr Asn Met Asn
1 5
<210> 36
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 255C12B10 HCDR2
<400> 36
Tyr Ile Asn Pro Asn Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 37
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 255C12B10 HCDR3
<400> 37
Asp Tyr Gly Ile Asp Tyr
1 5
<210> 38
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 255C12B10 LCDR1
<400> 38
Gln Ala Thr Gln Asp Ile Val Lys Asn Leu Asn
1 5 10
<210> 39
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 255C12B10 LCDR2
<400> 39
Tyr Ala Thr Glu Leu Ala Glu
1 5
<210> 40
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 255C12B10 LCDR3
<400> 40
Leu Gln Phe Tyr Glu Phe Pro Tyr Thr
1 5
<210> 41
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6重链可变区
<400> 41
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ser Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Ser Leu Ile Tyr Tyr Pro Asp Ser Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Val Arg His Gly Tyr Tyr Tyr Gly Asp Ser Thr Leu Tyr Tyr Ala Met
100 105 110
Asp Tyr Trp Gly Pro Gly Thr Ser Val Thr Val Ser Ser
115 120 125
<210> 42
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6轻链可变区
<400> 42
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile 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 Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Ala Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 43
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 75E1F2的重链可变区
<400> 43
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Ile
35 40 45
Thr Tyr Ile Ser Ser Gly Ser Ser Ile Ile Asp Tyr Ser Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asp Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Val Arg Arg Glu Asp His Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 44
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 75E1F2的轻链可变区
<400> 44
Asp Ile Val Met Thr Gln Ser His Lys Phe Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Tyr Thr Ala
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Phe
35 40 45
Tyr Ser Ala Ser Tyr Arg Phe Thr Gly Val Pro Asp Arg Phe Asn Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Ser Met Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 45
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6的重链可变区
<400> 45
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Val Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Thr Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Asp Lys Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu His Leu Ser Thr Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Gly Trp Leu Gly Tyr Ile Met Asp Phe Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 46
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6的轻链可变区
<400> 46
Gln Leu Val Leu Thr Gln Ser Ser Ser Ala Ser Phe Ser Leu Gly Ala
1 5 10 15
Ser Ala Lys Leu Thr Cys Thr Leu Ser Ser Gln His Ser Thr Tyr Thr
20 25 30
Ile Asp Trp Tyr Gln Gln Gln Pro Leu Lys Pro Pro Lys Tyr Val Met
35 40 45
Glu Leu Lys Glu Asp Gly Ser His Ser Thr Gly Asp Gly Ile Pro Asp
50 55 60
Arg Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr Leu Gly Ile Ser
65 70 75 80
Asn Ile Gln Pro Glu Asp Glu Ala Val Tyr Ile Cys Gly Val Gly Ala
85 90 95
Thr Ile Lys Glu Gln Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Val
100 105 110
Thr Val Leu
115
<210> 47
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9的重链可变区
<400> 47
Glu Val Gln Leu Gln Gln Ser Gly Pro Val Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Glu Ala Ser Gly Tyr Ile Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Lys Gln Ser Pro Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Phe Asn Pro Tyr Ser Gly Gly Ile Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Tyr Tyr Leu Ser Ser His Gly Phe Tyr Ala Leu Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 48
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9的轻链可变区
<400> 48
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Ile His Trp Tyr Gln Gln Arg Pro Gly Arg Pro Pro
35 40 45
Lys Leu Leu Met Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 49
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> 255C12B10的重链可变区
<400> 49
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ile Asn Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Gly Ile Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 50
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 255C12B10的轻链可变区
<400> 50
Glu Ile Gln Met Thr Gln Ser Pro Ser Ser Met Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Ile Thr Ile Thr Cys Gln Ala Thr Gln Asp Ile Val Lys Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Ser Phe Leu Ile
35 40 45
Tyr Tyr Ala Thr Glu Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Phe Tyr Glu Phe Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 51
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVH1重链可变区
<400> 51
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Ser Leu Ile Tyr Tyr Pro Asp Ser Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg His Gly Tyr Tyr Tyr Gly Asp Ser Thr Leu Tyr Tyr Ala Met
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 52
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVL1轻链可变区
<400> 52
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Val Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 53
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVH2重链可变区
<400> 53
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Ser Leu Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg His Gly Tyr Tyr Tyr Gly Asp Ser Thr Leu Tyr Tyr Ala Met
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 54
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVL2轻链可变区
<400> 54
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Val Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 55
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVH3重链可变区
<400> 55
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Ser Leu Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Gly Tyr Tyr Tyr Gly Asp Ser Thr Leu Tyr Tyr Ala Met
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 56
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVL3轻链可变区
<400> 56
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 57
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVH4重链可变区
<400> 57
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Ser Leu Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Gly Tyr Tyr Tyr Gly Asp Ser Thr Leu Tyr Tyr Ala Met
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 58
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hVL4轻链可变区
<400> 58
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 59
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVH1重链可变区
<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 Val Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Asp Lys Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Gly Trp Leu Gly Tyr Ile Met Asp Phe Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 60
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVL1轻链可变区
<400> 60
Gln Leu Val Leu Thr Gln Ser Pro Ser Ala Ser Phe Ser Leu Gly Ala
1 5 10 15
Ser Ala Lys Leu Thr Cys Thr Leu Ser Ser Gln His Ser Thr Tyr Thr
20 25 30
Ile Asp Trp Tyr Gln Gln Gln Pro Glu Lys Gly Pro Arg Tyr Val Met
35 40 45
Glu Leu Lys Glu Asp Gly Ser His Ser Thr Gly Asp Gly Ile Pro Asp
50 55 60
Arg Phe Ser Gly Ser Ser Ser Gly Ala Glu Arg Tyr Leu Thr Ile Ser
65 70 75 80
Ser Ile Gln Ser Glu Asp Glu Ala Asp Tyr Ile Cys Gly Val Gly Ala
85 90 95
Thr Ile Lys Glu Gln Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Val
100 105 110
Thr Val Leu
115
<210> 61
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVH2重链可变区
<400> 61
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 Val Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Asp Lys Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Gly Trp Leu Gly Tyr Ile Met Asp Phe Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 62
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVL2轻链可变区
<400> 62
Gln Leu Val Leu Thr Gln Ser Pro Ser Ala Ser Ala Ser Leu Gly Ala
1 5 10 15
Ser Val Lys Leu Thr Cys Thr Leu Ser Ser Gln His Ser Thr Tyr Thr
20 25 30
Ile Asp Trp Tyr Gln Gln Gln Pro Glu Lys Gly Pro Arg Tyr Val Met
35 40 45
Glu Leu Lys Glu Asp Gly Ser His Ser Thr Gly Asp Gly Ile Pro Asp
50 55 60
Arg Phe Ser Gly Ser Ser Ser Gly Ala Glu Arg Tyr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ser Glu Asp Glu Ala Asp Tyr Ile Cys Gly Val Gly Ala
85 90 95
Thr Ile Lys Glu Gln Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Val
100 105 110
Thr Val Leu
115
<210> 63
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVH3重链可变区
<400> 63
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 Val Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Asp Lys Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala 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
Val Arg Gly Trp Leu Gly Tyr Ile Met Asp Phe Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 64
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVL3轻链可变区
<400> 64
Gln Leu Val Leu Thr Gln Ser Pro Ser Ala Ser Ala Ser Leu Gly Ala
1 5 10 15
Ser Val Lys Leu Thr Cys Thr Leu Ser Ser Gln His Ser Thr Tyr Thr
20 25 30
Ile Asp Trp Tyr Gln Gln Gln Pro Glu Lys Gly Pro Arg Tyr Leu Met
35 40 45
Glu Leu Lys Glu Asp Gly Ser His Ser Lys Gly Asp Gly Ile Pro Asp
50 55 60
Arg Phe Ser Gly Ser Ser Ser Gly Ala Glu Arg Tyr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ser Glu Asp Glu Ala Asp Tyr Ile Cys Gly Val Gly Ala
85 90 95
Thr Ile Lys Glu Gln Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Val
100 105 110
Thr Val Leu
115
<210> 65
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVH4重链可变区
<400> 65
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 Val Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Asp Lys Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Trp Leu Gly Tyr Ile Met Asp Phe Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 66
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> 124B11F6-hVL4轻链可变区
<400> 66
Gln Leu Val Leu Thr Gln Ser Pro Ser Ala Ser Ala Ser Leu Gly Ala
1 5 10 15
Ser Val Lys Leu Thr Cys Thr Leu Ser Ser Gln His Ser Thr Tyr Thr
20 25 30
Ile Asp Trp His Gln Gln Gln Pro Glu Lys Gly Pro Arg Tyr Leu Met
35 40 45
Glu Leu Lys Glu Asp Gly Ser His Ser Lys Gly Asp Gly Ile Pro Asp
50 55 60
Arg Phe Ser Gly Ser Ser Ser Gly Ala Glu Arg Tyr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ser Glu Asp Glu Ala Asp Tyr Ile Cys Gly Val Gly Ala
85 90 95
Thr Ile Lys Glu Gln Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Val
100 105 110
Thr Val Leu
115
<210> 67
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVH1重链可变区
<400> 67
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 Ile Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Phe Asn Pro Tyr Ser Gly Gly Ile Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Tyr Tyr Leu Ser Ser His Gly Phe Tyr Ala Leu Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 68
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVL1轻链可变区
<400> 68
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Ile His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Met Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Val Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 69
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVH2重链可变区
<400> 69
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 Ile Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Phe Asn Pro Tyr Ser Gly Gly Ile Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Tyr Tyr Leu Ser Ser His Gly Phe Tyr Ala Leu Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 70
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVL2轻链可变区
<400> 70
Asp Ile Gln Leu 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 Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Ile His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Met Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 71
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVH3重链可变区
<400> 71
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 Ile Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Phe Asn Pro Tyr Ser Gly Gly Ile Ser Tyr Ala Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Tyr Tyr Leu Ser Ser His Gly Phe Tyr Ala Leu Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 72
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVL3轻链可变区
<400> 72
Asp Ile Gln Leu 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 Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Ile His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Met Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 73
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVH4重链可变区
<400> 73
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 Ile Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Phe Asn Pro Tyr Ser Gly Gly Ile Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Tyr Tyr Leu Ser Ser His Gly Phe Tyr Ala Leu Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 74
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 174C11C9-hVL4轻链可变区
<400> 74
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr
20 25 30
Gly Asn Thr Phe Ile His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Met Tyr Arg Ala Ser Asn Leu Gln Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 75
<211> 263
<212> PRT
<213> Artificial Sequence
<220>
<223> hSiglec-15胞外区
<400> 75
Met Glu Lys Ser Ile Trp Leu Leu Ala Cys Leu Ala Trp Val Leu Pro
1 5 10 15
Thr Gly Ser Phe Val Arg Thr Lys Ile Asp Thr Thr Glu Asn Leu Leu
20 25 30
Asn Thr Glu Val His Ser Ser Pro Ala Gln Arg Trp Ser Met Gln Val
35 40 45
Pro Pro Glu Val Ser Ala Glu Ala Gly Asp Ala Ala Val Leu Pro Cys
50 55 60
Thr Phe Thr His Pro His Arg His Tyr Asp Gly Pro Leu Thr Ala Ile
65 70 75 80
Trp Arg Ala Gly Glu Pro Tyr Ala Gly Pro Gln Val Phe Arg Cys Ala
85 90 95
Ala Ala Arg Gly Ser Glu Leu Cys Gln Thr Ala Leu Ser Leu His Gly
100 105 110
Arg Phe Arg Leu Leu Gly Asn Pro Arg Arg Asn Asp Leu Ser Leu Arg
115 120 125
Val Glu Arg Leu Ala Leu Ala Asp Asp Arg Arg Tyr Phe Cys Arg Val
130 135 140
Glu Phe Ala Gly Asp Val His Asp Arg Tyr Glu Ser Arg His Gly Val
145 150 155 160
Arg Leu His Val Thr Ala Ala Pro Arg Ile Val Asn Ile Ser Val Leu
165 170 175
Pro Ser Pro Ala His Ala Phe Arg Ala Leu Cys Thr Ala Glu Gly Glu
180 185 190
Pro Pro Pro Ala Leu Ala Trp Ser Gly Pro Ala Leu Gly Asn Ser Leu
195 200 205
Ala Ala Val Arg Ser Pro Arg Glu Gly His Gly His Leu Val Thr Ala
210 215 220
Glu Leu Pro Ala Leu Thr His Asp Gly Arg Tyr Thr Cys Thr Ala Ala
225 230 235 240
Asn Ser Leu Gly Arg Ser Glu Ala Ser Val Tyr Leu Phe Arg Phe His
245 250 255
Gly Ala Ser Gly Ala Ser Thr
260
<210> 76
<211> 483
<212> PRT
<213> Artificial Sequence
<220>
<223> hS15-hFc蛋白
<400> 76
Phe Val Arg Thr Lys Ile Asp Thr Thr Glu Asn Leu Leu Asn Thr Glu
1 5 10 15
Val His Ser Ser Pro Ala Gln Arg Trp Ser Met Gln Val Pro Pro Glu
20 25 30
Val Ser Ala Glu Ala Gly Asp Ala Ala Val Leu Pro Cys Thr Phe Thr
35 40 45
His Pro His Arg His Tyr Asp Gly Pro Leu Thr Ala Ile Trp Arg Ala
50 55 60
Gly Glu Pro Tyr Ala Gly Pro Gln Val Phe Arg Cys Ala Ala Ala Arg
65 70 75 80
Gly Ser Glu Leu Cys Gln Thr Ala Leu Ser Leu His Gly Arg Phe Arg
85 90 95
Leu Leu Gly Asn Pro Arg Arg Asn Asp Leu Ser Leu Arg Val Glu Arg
100 105 110
Leu Ala Leu Ala Asp Asp Arg Arg Tyr Phe Cys Arg Val Glu Phe Ala
115 120 125
Gly Asp Val His Asp Arg Tyr Glu Ser Arg His Gly Val Arg Leu His
130 135 140
Val Thr Ala Ala Pro Arg Ile Val Asn Ile Ser Val Leu Pro Ser Pro
145 150 155 160
Ala His Ala Phe Arg Ala Leu Cys Thr Ala Glu Gly Glu Pro Pro Pro
165 170 175
Ala Leu Ala Trp Ser Gly Pro Ala Leu Gly Asn Ser Leu Ala Ala Val
180 185 190
Arg Ser Pro Arg Glu Gly His Gly His Leu Val Thr Ala Glu Leu Pro
195 200 205
Ala Leu Thr His Asp Gly Arg Tyr Thr Cys Thr Ala Ala Asn Ser Leu
210 215 220
Gly Arg Ser Glu Ala Ser Val Tyr Leu Phe Arg Phe His Gly Ala Ser
225 230 235 240
Gly Ala Ser Thr Gly Gly Gly Ser Gly Gly Gly Ser Pro Lys Ser Ser
245 250 255
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
260 265 270
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
275 280 285
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
290 295 300
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
305 310 315 320
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
325 330 335
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
340 345 350
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
355 360 365
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
370 375 380
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
385 390 395 400
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
405 410 415
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
420 425 430
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
435 440 445
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
450 455 460
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
465 470 475 480
Pro Gly Lys
<210> 77
<211> 390
<212> PRT
<213> Artificial Sequence
<220>
<223> hS15-D1-hFc
<400> 77
Pro Thr Gly Ser Phe Val Arg Thr Lys Ile Asp Thr Thr Glu Asn Leu
1 5 10 15
Leu Asn Thr Glu Val His Ser Ser Pro Ala Gln Arg Trp Ser Met Gln
20 25 30
Val Pro Pro Glu Val Ser Ala Glu Ala Gly Asp Ala Ala Val Leu Pro
35 40 45
Cys Thr Phe Thr His Pro His Arg His Tyr Asp Gly Pro Leu Thr Ala
50 55 60
Ile Trp Arg Ala Gly Glu Pro Tyr Ala Gly Pro Gln Val Phe Arg Cys
65 70 75 80
Ala Ala Ala Arg Gly Ser Glu Leu Cys Gln Thr Ala Leu Ser Leu His
85 90 95
Gly Arg Phe Arg Leu Leu Gly Asn Pro Arg Arg Asn Asp Leu Ser Leu
100 105 110
Arg Val Glu Arg Leu Ala Leu Ala Asp Asp Arg Arg Tyr Phe Cys Arg
115 120 125
Val Glu Phe Ala Gly Asp Val His Asp Arg Tyr Glu Ser Arg His Gly
130 135 140
Val Arg Leu His Val Thr Ala Ala Asp Ile Glu Gly Arg Met Asp Pro
145 150 155 160
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
165 170 175
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
180 185 190
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
195 200 205
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
210 215 220
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
225 230 235 240
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
245 250 255
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
260 265 270
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
275 280 285
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
290 295 300
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
305 310 315 320
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
325 330 335
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
340 345 350
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
355 360 365
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
370 375 380
Ser Leu Ser Pro Gly Lys
385 390
<210> 78
<211> 262
<212> PRT
<213> Artificial Sequence
<220>
<223> hS15-His蛋白
<400> 78
Phe Val Arg Thr Lys Ile Asp Thr Thr Glu Asn Leu Leu Asn Thr Glu
1 5 10 15
Val His Ser Ser Pro Ala Gln Arg Trp Ser Met Gln Val Pro Pro Glu
20 25 30
Val Ser Ala Glu Ala Gly Asp Ala Ala Val Leu Pro Cys Thr Phe Thr
35 40 45
His Pro His Arg His Tyr Asp Gly Pro Leu Thr Ala Ile Trp Arg Ala
50 55 60
Gly Glu Pro Tyr Ala Gly Pro Gln Val Phe Arg Cys Ala Ala Ala Arg
65 70 75 80
Gly Ser Glu Leu Cys Gln Thr Ala Leu Ser Leu His Gly Arg Phe Arg
85 90 95
Leu Leu Gly Asn Pro Arg Arg Asn Asp Leu Ser Leu Arg Val Glu Arg
100 105 110
Leu Ala Leu Ala Asp Asp Arg Arg Tyr Phe Cys Arg Val Glu Phe Ala
115 120 125
Gly Asp Val His Asp Arg Tyr Glu Ser Arg His Gly Val Arg Leu His
130 135 140
Val Thr Ala Ala Pro Arg Ile Val Asn Ile Ser Val Leu Pro Ser Pro
145 150 155 160
Ala His Ala Phe Arg Ala Leu Cys Thr Ala Glu Gly Glu Pro Pro Pro
165 170 175
Ala Leu Ala Trp Ser Gly Pro Ala Leu Gly Asn Ser Leu Ala Ala Val
180 185 190
Arg Ser Pro Arg Glu Gly His Gly His Leu Val Thr Ala Glu Leu Pro
195 200 205
Ala Leu Thr His Asp Gly Arg Tyr Thr Cys Thr Ala Ala Asn Ser Leu
210 215 220
Gly Arg Ser Glu Ala Ser Val Tyr Leu Phe Arg Phe His Gly Ala Ser
225 230 235 240
Gly Ala Ser Thr Gly Gly Gly Ser Gly Gly Gly Ser His His His His
245 250 255
His His His His His His
260
<210> 79
<211> 262
<212> PRT
<213> Artificial Sequence
<220>
<223> 食蟹猴S15-His蛋白
<400> 79
Phe Val Arg Thr Lys Ile Asp Thr Thr Glu Asn Leu Leu Asn Thr Glu
1 5 10 15
Val His Ser Ser Pro Ala Gln Arg Trp Ser Met Gln Val Pro Ala Glu
20 25 30
Val Ser Ala Ala Ala Gly Asp Ala Ala Val Leu Pro Cys Thr Phe Thr
35 40 45
His Pro His Arg His Tyr Asp Gly Pro Leu Thr Ala Ile Trp Arg Ala
50 55 60
Gly Glu Pro Tyr Ala Gly Pro Gln Val Phe Arg Cys Ala Ala Ala Arg
65 70 75 80
Gly Ser Glu Leu Cys Gln Thr Ala Leu Ser Leu His Gly Arg Phe Arg
85 90 95
Leu Leu Gly Asn Pro Arg Arg Asn Asp Leu Ser Leu Arg Val Glu Arg
100 105 110
Leu Ala Leu Ala Asp Asp Arg Arg Tyr Phe Cys Arg Val Glu Phe Ala
115 120 125
Gly Asp Val His Asp Arg Tyr Glu Ser Arg His Gly Val Arg Leu His
130 135 140
Val Thr Ala Ala Pro Arg Ile Ile Asn Ile Ser Val Leu Pro Gly Pro
145 150 155 160
Ala His Ala Phe Arg Ala Leu Cys Thr Ala Glu Gly Glu Pro Pro Pro
165 170 175
Ala Leu Ala Trp Ser Gly Pro Ala Leu Gly Asn Gly Ser Ala Ala Val
180 185 190
Pro Ser Ser Gly Gln Gly His Gly His Leu Val Thr Ala Glu Leu Pro
195 200 205
Ala Leu Asn His Asp Gly Arg Tyr Thr Cys Thr Ala Ala Asn Ser Leu
210 215 220
Gly Arg Ser Glu Ala Ser Val Tyr Leu Phe Arg Phe His Gly Ala Ser
225 230 235 240
Gly Ala Ser Thr Gly Gly Gly Ser Gly Gly Gly Ser His His His His
245 250 255
His His His His His His
260
<210> 80
<211> 257
<212> PRT
<213> Artificial Sequence
<220>
<223> 小鼠S15-His蛋白
<400> 80
Arg Arg Asp Ala Ser Gly Asp Leu Leu Asn Thr Glu Ala His Ser Ala
1 5 10 15
Pro Ala Gln Arg Trp Ser Met Gln Val Pro Ala Glu Val Asn Ala Glu
20 25 30
Ala Gly Asp Ala Ala Val Leu Pro Cys Thr Phe Thr His Pro His Arg
35 40 45
His Tyr Asp Gly Pro Leu Thr Ala Ile Trp Arg Ser Gly Glu Pro Tyr
50 55 60
Ala Gly Pro Gln Val Phe Arg Cys Thr Ala Ala Pro Gly Ser Glu Leu
65 70 75 80
Cys Gln Thr Ala Leu Ser Leu His Gly Arg Phe Arg Leu Leu Gly Asn
85 90 95
Pro Arg Arg Asn Asp Leu Ser Leu Arg Val Glu Arg Leu Ala Leu Ala
100 105 110
Asp Ser Gly Arg Tyr Phe Cys Arg Val Glu Phe Thr Gly Asp Ala His
115 120 125
Asp Arg Tyr Glu Ser Arg His Gly Val Arg Leu Arg Val Thr Ala Ala
130 135 140
Ala Pro Arg Ile Val Asn Ile Ser Val Leu Pro Gly Pro Ala His Ala
145 150 155 160
Phe Arg Ala Leu Cys Thr Ala Glu Gly Glu Pro Pro Pro Ala Leu Ala
165 170 175
Trp Ser Gly Pro Ala Pro Gly Asn Ser Ser Ala Ala Leu Gln Gly Gln
180 185 190
Gly His Gly Tyr Gln Val Thr Ala Glu Leu Pro Ala Leu Thr Arg Asp
195 200 205
Gly Arg Tyr Thr Cys Thr Ala Ala Asn Ser Leu Gly Arg Ala Glu Ala
210 215 220
Ser Val Tyr Leu Phe Arg Phe His Gly Ala Pro Gly Thr Ser Thr Gly
225 230 235 240
Gly Gly Ser Gly Gly Gly Ser His His His His His His His His His
245 250 255
His
<210> 81
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hH2L4V LCDR1
<400> 81
Arg Ala Ser Gln Ser Val Asp Tyr Glu Gly Asp Ser Tyr Met Asn
1 5 10 15
<210> 82
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 21F6C6-hH2L4V 轻链可变区序列
<400> 82
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Tyr Glu
20 25 30
Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Claims (10)
1.一种结合Siglec-15的分离的抗体及其抗原结合片段,其特征在于,所述结合Siglec-15的分离的抗体或其抗原结合片段包括选自以下组的一个或多个CDR序列:SEQ IDNO:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、81;优选地,所述结合Siglec-15的分离的抗体或其抗原结合片段包括选自以下组的一个或多个重链CDR序列:SEQ ID NO:1、2、3、4、5、11、12、13、17、18、19、20、25、26、27、28、29、35、36、37,和/或,选自以下组的一个或多个轻链CDR序列:SEQ ID NO:6、7、8、9、10、14、15、16、21、22、23、24、30、31、32、33、34、38、39、40、81。
2.权利要求1所述的结合Siglec-15的分离的抗体或其抗原结合片段,其特征在于,所述结合Siglec-15的分离的抗体或其抗原结合片段包括重链可变区,其包含HCDR1、HCDR2和HCDR3序列,和/或轻链可变区,其包含LCDR1、LCDR2和LCDR3序列,其中:
(a)所述重链可变区HCDR1序列包含选自SEQ ID NO:1、11、17、25、35及其保守修饰的氨基酸序列;所述重链可变区HCDR2序列包含选自SEQ ID NO:2、3、4、12、18、19、26、27、28、36及其保守修饰的氨基酸序列;所述重链可变区HCDR3序列包含选自SEQ ID NO:5、13、20、29、37及其保守修饰的氨基酸序列;
(b)所述轻链可变区LCDR1序列包含选自SEQ ID NO:6、7、14、21、30、31、38、81及其保守修饰的氨基酸序列;所述轻链可变区LCDR2序列包含选自SEQ ID NO:8、9、15、22、23、32、33、39及其保守修饰的氨基酸序列;所述轻链可变区LCDR3序列包含选自SEQ ID NO:10、16、24、34、40及其保守修饰的氨基酸序列;或,
(a)重链可变区包括选自以下组的CDR序列:SEQ ID NO:1、2、3、4和5,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:6、7、8、9、10和81;或
(b)重链可变区包括选自以下组的CDR序列:SEQ ID NO:11、12和13,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:14、15和16;或
(c)重链可变区包括选自以下组的CDR序列:SEQ ID NO:17、18、19和20,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:21、22、23和24;或
(d)重链可变区包括选自以下组的CDR序列:SEQ ID NO:25、26、27、28和29,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:30、31、32、33和34;或
(e)重链可变区包括选自以下组的CDR序列:SEQ ID NO:35、36和37,轻链可变区包括选自以下组的CDR序列:SEQ ID NO:38、39和40。
3.权利要求1所述的结合Siglec-15的分离的抗体及其抗原结合片段,其特征在于,所述结合Siglec-15的分离的抗体及其抗原结合片段包括重链可变区和/或轻链可变区,重链可变区包括HCDR1、HCDR2和HCDR3,轻链可变区包括LCDR1、LCDR2和LCDR3,其中,
(a)重链可变区HCDR1序列如SEQ ID NO:1所示,HCDR2序列选自SEQ ID NO:2、3和4,HCDR3序列如SEQ ID NO:5所示,轻链可变区LCDR1序列选自SEQ ID NO:6、7和81,LCDR2序列选自SEQ ID NO:8和9,LCDR3序列如SEQ ID NO:10所示;或
(b)重链可变区HCDR1序列如SEQ ID NO:11所示,HCDR2序列如SEQ ID NO:12所示,HCDR3序列如SEQ ID NO:13所示,轻链可变区LCDR1序列如SEQ ID NO:14所示,LCDR2序列如SEQ ID NO:15所示,LCDR3序列如SEQ ID NO:16所示;或
(c)重链可变区HCDR1序列如SEQ ID NO:17所示,HCDR2序列选自SEQ ID NO:18和19所示,HCDR3序列如SEQ ID NO:20所示,轻链可变区LCDR1序列如SEQ ID NO:21所示,LCDR2序列选自SEQ ID NO:22和23,LCDR3序列如SEQ ID NO:24所示;或
(d)重链可变区HCDR1序列如SEQ ID NO:25所示,HCDR2序列选自SEQ ID NO:26、27和28,HCDR3序列如SEQ ID NO:29所示,轻链可变区LCDR1序列选自SEQ ID NO:30和31,LCDR2序列选自SEQ ID NO:32和33,LCDR3序列如SEQ ID NO:34所示;或
(e)重链可变区HCDR1序列如SEQ ID NO:35所示,HCDR2序列如SEQ ID NO:36所示,HCDR3序列如SEQ ID NO:37所示,轻链可变区LCDR1序列如SEQ ID NO:38所示,LCDR2序列如SEQ ID NO:39所示,LCDR3序列如SEQ ID NO:40所示。
4.权利要求1-3任一项所述的结合Siglec-15的分离的抗体及其抗原结合片段,其特征在于,所述结合Siglec-15的分离的抗体及其抗原结合片段可为鼠源抗体、嵌合抗体、人源化抗体、全人源抗体或其片段,优选为人源化抗体或其片段。
5.权利要求1所述的结合Siglec-15的分离的抗体及其抗原结合片段,其特征在于,所述结合Siglec-15的分离的抗体及其抗原结合片段包括:
(a)重链可变区SEQ ID NO:41或与SEQ ID NO:41至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或SEQ ID NO:42或与SEQ ID NO:42至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区的轻链可变区;或
(b)重链可变区SEQ ID NO:43或与SEQ ID NO:43至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或SEQ ID NO:44或与SEQ ID NO:44至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区的轻链可变区;或
(c)重链可变区SEQ ID NO:45或与SEQ ID NO:45至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或SEQ ID NO:46或与SEQ ID NO:46至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区的轻链可变区;或
(d)重链可变区SEQ ID NO:47或与SEQ ID NO:47至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或SEQ ID NO:48或与SEQ ID NO:48至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区的轻链可变区;或
(e)重链可变区SEQ ID NO:49或与SEQ ID NO:49至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区;和/或SEQ ID NO:50或与SEQ ID NO:50至少90%、95%、96%、97%、98%或99%同源性的氨基酸序列的重链可变区的轻链可变区。
6.一种结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包含在SEQ ID NO:41所示序列的选自以下的一个或多个位点处引入突变的重链可变区:M3、K19、S40、E42、R44、P61、T65、S77、T78、S84、S88、M93、V97、P117和/或S120位点,和/或,在SEQ ID NO:42所示序列的选自以下的一个或多个位点处引入突变的轻链可变区:V3、L4、A9、A12、V13、L15、Q17、A19、S22、K24、D32、Q46、P47、E59、I62、A64、N78、H80、P81、V82、E83、E84、A87、A104和/或L110;优选地,该人源化抗体或其抗原结合片段包含在SEQ ID NO:41所示序列的选自以下的一个或多个位点处引入下列突变的重链可变区:M3Q、K19R、S40A、E42G、R44G、P61A、T65K、S77N、T78S、S84N、S88A、M93V、V97A、P117Q和/或S120T,和/或,在SEQ ID NO:42所示序列的选自以下的一个或多个位点处引入下列突变的轻链可变区:V3Q、L4M、A9S、A12S、V13A、L15V、Q17D、A19V、S22T、K24R、D32E、Q46K、P47A、E59Q、I62V、A64S、N78T、H80S、P81S、V82L、E83Q、E84P、A87F、A104Q和/或L110I;更优选地,所述人源化抗体或其抗原结合片段包括重链可变区和/或轻链可变区,其中,重链可变区序列选自SEQ ID NO:51、53、55和57,轻链可变区选自SEQ ID NO:52、54、56、58和82;
进一步更优选地,所述重链可变区如SEQ ID NO:51所示,和/或,所述轻链可变区如SEQID NO:52所示;或,所述重链可变区如SEQ ID NO:53所示,和/或,所述轻链可变区如SEQ IDNO:54所示;或,所述重链可变区如SEQ ID NO:53所示,和/或,所述轻链可变区如SEQ IDNO:56所示;或,所述重链可变区如SEQ ID NO:53所示,和/或,所述轻链可变区如SEQ IDNO:58所示;或,所述重链可变区如SEQ ID NO:53所示,和/或,所述轻链可变区如SEQ IDNO:82所示;或,所述重链可变区如SEQ ID NO:55所示,和/或,所述轻链可变区如SEQ IDNO:56所示;或,所述重链可变区如SEQ ID NO:57所示,和/或,所述轻链可变区如SEQ IDNO:58所示。
7.一种结合Siglec-15的分离的人源化抗体或其抗原结合片段,所述人源化抗体或其抗原结合片段包含在SEQ ID NO:45所示序列的选自以下的一个或多个位点处引入突变的重链可变区:E1、Q5、L11、V12、R13、L20、T23、K38、R40、T41、E42、A61、P62、K67、A68、A72、S76、N77、L81、H82、T85、T87、V97和/或S113位点,和/或,在SEQ ID NO:46所示序列的选自以下的一个或多个位点处引入突变的轻链可变区:S8、F12、A18、Y36、L41、P43、K45、V47、T58、D74、G78、N81、I82、P84和/或V89位点;优选地,所述人源化抗体或其抗原结合片段包含在SEQ IDNO:45所示序列的选自以下的一个或多个位点处引入下列突变的重链可变区:E1Q、Q5V、L11V、V12K、R13K、L20V、T23K、K38R、R40A、T41P、E42G、A61S、P62Q、K67R、A68V、A72R、S76T或S76A、N77S、L81M、H82E、T85S、T87R、V97A和/或S113T位点,和/或,在SEQ ID NO:46所示序列的选自以下的一个或多个位点处引入下列突变的轻链可变区:S8P、F12A、A18V、Y36H、L41E、P43G、K45R、V47L、T58K、D74E、G78T、N81S、I82L、P84S和/或V89D;更优选地,所述结合Siglec-15的分离的人源化抗体或其抗原结合片段,包括重链可变区和/或轻链可变区,其中,重链可变区序列选自SEQ ID NO:59、61、63和65,轻链可变区选自SEQ ID NO:60、62、64和66;
进一步优选地,所述重链可变区如SEQ ID NO:59所示,和/或,所述轻链可变区如SEQID NO:60所示;或,所述重链可变区如SEQ ID NO:61所示,和/或,所述轻链可变区如SEQ IDNO:62所示;或,所述重链可变区如SEQ ID NO:63所示,和/或,所述轻链可变区如SEQ IDNO:64所示。
8.一种结合Siglec-15的分离的人源化抗体或其抗原结合片段,其包含在SEQ ID NO:47所示序列的选自以下的一个或多个位点处引入突变的重链可变区:E1、Q5、P9、V10、L11、V12、M20、E23、K38、S40、K43、S44、N61、K67、A68、L70、V72、S76、N84、T87、S91和/或S119位点,和/或在SEQ ID NO:48所示序列的选自以下的一个或多个位点处引入突变的轻链可变区:V3、L4、A9、A12、V13、L15、Q17、A19、S22、R43、R46、P47、E59、I62、A64、R72、D80、P81、V82、E83、A84、D85、V87、A104和/或L110位点;优选地,所述人源化抗体或其抗原结合片段包含在SEQID NO:47所示序列的选自以下的一个或多个位点处引入下列突变的重链可变区:E1Q、Q5V、P9A、V10E、L11V、V12K、M20V、E23K、K38R、S40A、K43Q、S44G、N61A、K67R、A68V、L70M、V72R、S76T、N84S、T87R、S91T和/或S119T位点,和/或在SEQ ID NO:48所示序列的选自以下的一个或多个位点处引入下列突变的轻链可变区:V3Q、L4M、A9S、A12S、V13A、L15V、Q17D、A19V、S22T、R43K、R46K、P47A、E59Q、I62V、A64S、R72G、D80S、P81S、V82L、E83Q、A84P、D85E、V87F、A104Q和/或L110I;更优选地,所述人源化抗体或其抗原结合片段包括重链可变区和/或轻链可变区,其中,重链可变区序列选自SEQ ID NO:67、69、71和73,轻链可变区选自SEQ IDNO:68、70、72和74;
进一步更优选地,所述重链可变区如SEQ ID NO:67所示,和/或,所述轻链可变区如SEQID NO:68所示;或,所述重链可变区如SEQ ID NO:69所示,和/或,所述轻链可变区如SEQ IDNO:70所示;或,所述重链可变区如SEQ ID NO:71所示,和/或,所述轻链可变区如SEQ IDNO:72所示。
9.权利要求1-8任一项所述的结合Siglec-15的分离的抗体或其抗原结合片段,其特征在于,还包括恒定区或其变体,优选包括IgG1或IgG4恒定区或其变体。
10.编码权利要求1-9任一项所述的结合Siglec-15的分离的抗体及其抗原结合片段的核酸序列。
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