CN114573695A - 抗人b7-h3抗体及其应用 - Google Patents
抗人b7-h3抗体及其应用 Download PDFInfo
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- CN114573695A CN114573695A CN202111459992.0A CN202111459992A CN114573695A CN 114573695 A CN114573695 A CN 114573695A CN 202111459992 A CN202111459992 A CN 202111459992A CN 114573695 A CN114573695 A CN 114573695A
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Abstract
本发明提供了一种抗人B7‑H3单克隆抗体及其应用。以重组人B7‑H3胞外区作为免疫原,通过杂交瘤技术制备鼠源抗人B7‑H3单克隆抗体,鼠源抗人B7‑H3抗体能够结合B7‑H3胞外区的各结构域。在鼠源抗体的基础上构建的人‑鼠嵌合抗体能够特异性结合细胞表面的B7‑H3。通过CDRs移植和CDRs区突变制备的人源化抗体保留了特异性结合人B7‑H3胞外区和细胞膜表面B7‑H3的能力,并且能够由细胞膜表面B7‑H3介导内化。
Description
优先权信息
本申请请求2020年12月2日向中国国家知识产权局提交的、专利申请号为202011398727.1的专利申请的优先权和权益,并且通过参照将其全文并入此处。
技术领域
本发明属于抗体工程领域,具体涉及一种抗人B7-H3单克隆抗体及其应用,特别是涉及一种针对人B7-H3具有高亲和力、与猴B7-H3具有交叉反应、不结合鼠B7-H3的单克隆抗体、嵌合抗体、人源化抗体及应用。
背景技术
B7-H3也称为CD276,是一种I型跨膜蛋白,属于B7-CD28超家族。B7家族分子可提供刺激信号来增强和维持T细胞免疫应答,也可产生抑制信号来限制和减弱T细胞免疫反应。人B7-H3蛋白具有膜结合型和可溶性两种,膜结合型B7-H3蛋白主要分布于肿瘤细胞表面,在细胞内部的细胞核、运输小体和外泌体等也有发现。可溶性B7-H3由蛋白酶从细胞膜上水解下来,肿瘤患者血清中可以检测到高水平的可溶性B7-H3,提示B7-H3可以作为生物标志物(xiec,2016)。抗癌抗体的最新临床和商业成功已引起对基于抗体的治疗剂的极大兴趣。由此,用于治疗癌症的基于B7-H3的抗体治疗剂有待研究。
发明内容
为解决现有技术中抗人B7-H3抗体对膜表面B7-H3亲和力和特异性不足、导致脱靶效应和不良反应的缺陷。本发明提供一种抗人B7-H3单克隆抗体及其应用。以重组人B7-H3胞外区作为免疫原,通过杂交瘤技术制备鼠源抗人B7-H3单克隆抗体,鼠源抗人B7-H3抗体能够结合B7-H3胞外区的各结构域,在鼠源抗体的基础上构建的人-鼠嵌合抗体能够特异性结合细胞表面的B7-H3。通过CDRs移植和CDRs区突变制备的人源化抗体保留了特异性结合人B7-H3胞外区和细胞膜表面B7-H3的能力,并且能够由细胞膜表面B7-H3介导内化。在细胞实验和裸鼠移植瘤动物模型上证实,人源化抗人B7-H3抗体缀合物(ADC)能够特异性杀伤肿瘤细胞。所述抗人B7-H3抗体对人B7-H3胞外区具有小于5E-10的亲和力、能够特异性结合重组细胞和肿瘤细胞表面的B7-H3,在细胞和动物模型中产生了显著的肿瘤杀伤效果、未观察到明显的不良反应,因此具有良好的临床抗肿瘤应用前景。
抗体及其制备方法
根据本发明实施例的一个方面,本发明提供了一种抗人B7-H3抗体或其片段,包括重链可变区和轻链可变区。根据本发明的实施例,所述重链可变区(VH)包括抗原决定区(CDRs)1、2和3,其中,VH CDR1包含与所选VH CDR1氨基酸序列具有至少75%同一性的氨基酸序列;VH CDR2包含与所选VH CDR2氨基酸序列具有至少75%同一性的氨基酸序列;VHCDR3与所选VH CDR3氨基酸序列具有至少75%同一性的氨基酸序列;所述轻链可变区(VL)包括CDRs 1、2和3,其中,VL CDR1包含与所选VL CDR1氨基酸序列具有至少75%同一性的氨基酸序列;VL CDR2包含与所选VL CDR2氨基酸序列具有至少75%同一性的氨基酸序列;VLCDR3与所选VL CDR3氨基酸序列具有至少75%同一性的氨基酸序列;其中,所述所选VHCDRs 1、2和3的氨基酸序列以及所述所选VL CDRs 1、2和3的氨基酸序列选自下列之一:
(1)所述所选VH CDRs 1、2和3的氨基酸序列分别如SEQ ID NO:40、41和42所示,且所述所选VL CDRs 1、2和3的氨基酸序列如SEQ ID NO:43、44和45所示;
(2)所述所选VH CDRs 1、2和3的氨基酸序列分别如SEQ ID NO:46、47和48所示,且所述所选VL CDRs 1、2和3的氨基酸序列如SEQ ID NO:49、50和51所示;
(3)所述所选VH CDRs 1、2和3的氨基酸序列分别如SEQ ID NO:52、53和54所示,且所述所选VL CDRs 1、2和3的氨基酸序列如SEQ ID NO:55、56和57所示。
根据本发明实施例的抗人B7-H3抗体或其片段能特异性结合人B7-H3胞外区和细胞膜表面B7-H3结合位点,并且亲和力强,在一些实施例中,具有小于5E-10的亲和力;并且,抑瘤效果好,毒性小,具有良好的临床应用前景。
另外,根据本发明上述实施例的抗体或抗原结合片段,还可以具有如下附加的技术特征:
根据本发明的实施例,与包含SEQ ID NO:51所示的氨基酸序列的所选VL CDR3具有至少75%同一性的氨基酸序列为QQWSX1X2PLT,其中,X1为S或A,X2为N、A、S或Q。
根据本发明的实施例,所述VH包括与SEQ ID NO:1具有至少75%同一性氨基酸序列,且所述VL包括与SEQ ID NO:2具有至少75%同一性氨基酸序列。
根据本发明的实施例,所述VH包括与SEQ ID NO:3具有至少75%同一性氨基酸序列,且所述VL包括与SEQ ID NO:4具有至少75%同一性氨基酸序列。
根据本发明的实施例,所述VH包括与SEQ ID NO:5具有至少75%同一性氨基酸序列,且所述VL包括与SEQ ID NO:6具有至少75%同一性氨基酸序列。
具体地,所述至少75%同一性可以为至少82%、优选至少85%、更优选至少90%、进一步优选至少91%、92%、93%、94%、95%、96%、97%、98%或甚至99%同一性等大于等于75%的任何百分比的同一性。更具体地,可以是***、删除或替换0、1、2个或多个氨基酸。
进一步说明的是,该抗体或抗原结合片段重链可变区的序列可以是在SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5或SEQ ID NO:6所示的核苷酸序列的基础上进行一个或多个核苷酸的***、删除、突变或修饰等得到的。
根据本发明的实施例,所述VH包括SEQ ID NO:11或17所示的氨基酸序列,所述VL包括SEQ ID NO:12、13、14、15或16所示的氨基酸序列。
根据本发明的实施例,所述VH包括SEQ ID NO:18、21、22或23所示的氨基酸序列,所述VL包括SEQ ID NO:19、20、58、59或60所示的氨基酸序列。
根据本发明的实施例,所述VH包括SEQ ID NO:24、34、35、36或37所示的氨基酸序列,所述VL包括SEQ ID NO:25、26、27、28、29、30、31、32或33所示的氨基酸序列。
根据本发明的实施例,所述抗人B7-H3抗体或其片段能够特异性结合人B7-H3的胞外区,且与人B7-H3胞外区的亲和力常数(KD)小于5E-10。
根据本发明的实施例,所述抗人B7-H3抗体或其片段与猴B7-H3具有交叉反应,与鼠B7-H3则无结合活性。
根据本发明的实施例、所述抗人B7-H3抗体或其片段对猴B7-H3具有弱交叉反应,且对猴B7-H3的结合活性低于对人B7-H3的结合活性。
根据本发明的实施例,所述抗人B7-H3抗体或其片段能够特异性结合至细胞表面的B7-H3,并由B7-H3介导内化至细胞内。
进一步地,根据本发明的又一方面,本发明提供一种抗人B7-H3抗体或其片段。根据本发明的实施例,所述抗人B7-H3抗体或其片段能够特异性结合人B7-H3的胞外区,抗体或其片段与人B7-H3胞外区的亲和力常数(KD)小于5E-10。
根据本发明的实施例,所述抗人B7-H3抗体或其片段与猴B7-H3具有交叉反应,与鼠B7-H3则无结合活性;
根据本发明的实施例,所述抗人B7-H3抗体或其片段对猴B7-H3具有弱交叉反应,且对猴B7-H3的结合活性低于对人B7-H3的结合活性。
根据本发明的实施例,所述抗人B7-H3抗体或其片段能够特异性结合至细胞表面的B7-H3,并由B7-H3介导内化至细胞内。
根据本发明的实施例,所述抗体包括鼠源抗体、兔源抗体、人源抗体、嵌合抗体。
根据本发明的实施例,所述抗人B7-H3抗体或其片段具有选自SEQ ID NO:1、3、5中任一氨基酸序列所示重链可变区的重链CDRs;和/或具有选自SEQ ID NO:2、4、6中任一氨基酸序列所示轻链可变区的轻链CDRs。
根据本发明的实施例,所述抗人B7-H3抗体或其片段具有选自SEQ ID NO:1、3、5中任一氨基酸序列所示的重链可变区;和/或具有选自SEQ ID NO:2、4、6中任一氨基酸序列所示轻链可变区。
根据本发明的实施例,所述抗人B7-H3抗体或其片段具有:
SEQ ID NO:1所示的重链可变区,SEQ ID NO:2所示轻链可变区;
SEQ ID NO:3所示的重链可变区,SEQ ID NO:4所示轻链可变区;或
SEQ ID NO:5所示的重链可变区,SEQ ID NO:6所示轻链可变区。
根据本发明的另一方面,本发明提供了一种抗人B7-H3的人源化抗体或其片段。根据本发明的实施例,所述抗人B7-H3的人源化抗体或其片段,其是在前文所述抗人B7-H3抗体或其片段的基础上,通过CDRs移植获得的人源化抗体或其片段。
根据本发明的实施例,所述抗人B7-H3的人源化抗体或其片段具有:
SEQ ID NO:11、17任一序列所示的重链可变区或其中的重链CDR1-3;
SEQ ID NO:12、13、14、15、16任一序列所示的轻链可变区或其中的轻链CDRs1、2和3。
根据本发明的实施例,所述抗人B7-H3的人源化抗体或其片段具有:
SEQ ID NO:18、21、22、23任一序列所示的重链可变区或其中的重链CDRs1、2和3;
SEQ ID NO:19、20、58、59或60任一序列所示的轻链可变区或其中的轻链CDR1-3。
根据本发明的实施例,所述抗人B7-H3的人源化抗体或其片段具有:
SEQ ID NO:24、34、35、36、37任一序列所示的重链可变区或其中的重链CDRs1、2和3;
SEQ ID NO:25、26、27、28、29、30、31、32、33任一序列所示的轻链可变区或其中的轻链CDRs1、2和3。
根据本发明的另一方面,本发明提供了一种制备抗人B7-H3的人源化抗体或其片段的方法。根据本发明的实施例,在非人源B7-H3抗体或其片段的基础上,利用CDRs移植技术实现重链可变区的人源化和/或轻链可变区的人源化,以便获得前述抗人B7-H3抗体或其片段。
根据本发明实施例的制备抗人B7-H3的人源化抗体或其片段的方法,将非人源单克隆抗体以基因克隆及DNA重组技术等进行人源化改造,经改造后与人的靶点结合,重新表达的抗体,其大部分氨基酸序列为人源序列取代,基本保留非人源亲本单克隆抗体的亲和力和特异性,又降低了其异源性,有利应用于人体,例如,本发明实施例的抗体或抗原结合片段经人源化后,可以与人的B7-H3特异性结合。
根据本发明的实施例,非人源B7-H3抗体或其片段为鼠源B7-H3抗体或其片段。
根据本发明的实施例,所述利用CDRs移植技术实现重链可变区的人源化的步骤包括:
(1)利用非人源B7-H3抗体或其片段的重链可变区序列进行同源比对,选择相似的人源抗体重链模板;
(2)将所述非人源B7-H3抗体或其片段的的VH CDRs 1、2和3移植到人源抗体重链模板中;
(3)根据VH CDR3的序列选择J区序列,实现重链可变区的人源化,获得前述抗人B7-H3抗体或其片段。
根据本发明的实施例,所述利用CDRs移植技术实现轻链可变区的人源化的步骤包括:
(1)利用非人源B7-H3抗体或其片段的轻链可变区序列进行同源比对,选择相似的人源抗体轻链模板;
(2)将所述非人源B7-H3抗体或其片段的VL CDRs 1-3移植到人源抗体轻链模板中;
(3)根据所述VL CDR3的序列选择JK区序列,实现轻链可变区的人源化,获得前述抗人B7-H3抗体或其片段。
根据本发明的另一方面,本发明提供了一种制备抗人B7-H3的人源化抗体或其片段的方法。根据本发明的实施例,所述制备抗人B7-H3的人源化抗体或其片段的方法包括:在前述非人源B7-H3抗体或其片段的基础上,利用CDRs移植技术实现重链可变区的人源化和/或轻链可变区的人源化,以便获得前述抗人B7-H3抗体或其片段。
根据本发明的实施例,前述利用CDRs移植技术实现重链可变区的人源化的步骤包括:
(1)利用前述非人源B7-H3抗体或其片段的重链可变区序列进行同源比对,选择最相似的人源抗体重链模板;
(2)将所述非人源B7-H3抗体或其片段的VH CDRs1、2和3移植到人源抗体重链模板中;
(3)根据VH CDR3的序列选择J区序列,实现重链可变区的人源化,获得前述抗人B7-H3抗体或其片段。
根据本发明的实施例,前述利用CDRs移植技术实现轻链可变区的人源化的步骤包括:
(1)利用前述非人源B7-H3抗体或其片段的轻链可变区序列进行同源比对,选择相似的人源抗体轻链模板;
(2)将前述非人源B7-H3抗体或其片段的VL CDRs1、2和3移植到人源抗体轻链模板中;
(3)根据所述VL CDR3的序列选择JK区序列,实现轻链可变区的人源化,获得前述抗人B7-H3抗体或其片段。
根据本发明的实施例,所述制备抗人B7-H3的人源化抗体或其片段的方法:在所述CDRs移植后,还包括对人源化抗体进行亲和力成熟、CDR序列点突变改造和/或化学修饰。
抗体的应用
根据本发明的另一方面,本发明提供了一种融合分子。根据本发明的实施例,所述融合分子包括
(1)第一活性元件,所述第一活性元件为包括前述抗人B7-H3抗体或其片段的第一靶向部分;
(2)一个或多个第二活性元件,所述第二活性元件包括效应子元件和/或第二靶向部分;
其中,所述第一活性元件与第二活性元件通过键或接头连接;所述一个或多个第二活性元件可以相同或不同。
根据本发明的另一方面,本发明提供了一种多核苷酸。根据本发明的实施例,所述多核苷酸编码前述抗人B7-H3抗体或其片段或前述融合分子。由此,由该核酸编码的多肽可以与B7-H3特异性结合。
根据本发明的另一方面,本发明提供了一种核酸构建体。根据本发明的实施例,所述核酸构建体包含本发明前文所述的多核苷酸。
根据本发明的另一方面,本发明提供了一种宿主细胞。根据本发明的实施例,所述宿主细胞包含本发明前文所述的多核苷酸或核酸构建体。
根据本发明的另一方面,本发明提供了一种缀合物。根据本发明的实施例,所述缀合物包括第一活性元件,所述第一活性元件为包括前述抗人B7-H3抗体或其片段的第一靶向部分。
根据本发明的实施例,所述缀合物还包括至少一个第二活性元件,所述第一活性元件和第二活性元件共价连接,所述第二活性元件包括一种或多种效应子部分。
根据本发明的实施例,所述效应子部分为小分子药物缀合物,所述小分子药物缀合物选自以下(1)~(3)组中一种或多种的效应分子或其衍生物:
(1)微管蛋白抑制剂类小分子化合物:美登素衍生物、一甲基澳瑞他汀E(Monomethyl auristatin E)、一甲基澳瑞他汀F(Monomethylauristatin F)、一甲基海兔毒素10(Monomethyl Dolastatin 10)、Tubulysin类衍生物、念珠藻素(Cryptophycin)类衍生物和他托布林(Taltobulin);
(2)拓扑异构酶抑制剂类小分子化合物:阿霉素代谢产物PNU-159682及其衍生物、伊立替康代谢产物SN38衍生物和依喜替康;
(3)DNA结合剂类小分子化合物:PBD类衍生物和duocarmycin类衍生物。
根据本发明的另一方面,本发明提供了一种组合物。根据本发明的实施例,所述组合物包含前文所述抗人B7-H3抗体或其片段、前文所述融合分子、前文所述多核苷酸、前文所述核酸构建体、前文所述宿主细胞,或前文所述缀合物;以及可选的药学上可接受的辅料。由此,该组合物为可以与B7-H3特异性结合,并且特异性强,药效佳。
根据本发明的另一方面,本发明提供了一种制备抗人B7-H3抗体或其片段的方法。根据本发明的实施例,所述制备抗人B7-H3抗体或其片段的方法包括:
(1)在合适的条件下,培养前文所述的宿主细胞;
(2)分离回收抗人B7-H3单克隆抗体或其片段、抗人B7-H3嵌合抗体或其片段、或者人源化抗人B7-H3抗体或其片段。
由此,本发明实施例的方法制备得到的抗体能特异性结合人B7-H3,并且特异性强。
根据本发明的另一方面,本发明提供前述抗人B7-H3抗体或其片段、前述融合分子、前述多核苷酸、前述核酸构建体、前述宿主细胞,前述缀合物和前述组合物在制备B7-H3过表达相关疾病诊断试剂中的用途。
根据本发明的另一方面,本发明提供前述抗人B7-H3抗体或其片段、前述融合分子、前述多核苷酸、前述核酸构建体、前述宿主细胞,前述缀合物和前述组合物在制备治疗B7-H3过表达相关疾病药物中的用途。
根据本发明的实施例,所述B7-H3过表达相关疾病为实体瘤类癌症。
根据本发明的实施例,所述实体瘤类癌症包括:胃癌、结直肠癌、肝癌、胰腺癌、食管癌、非小细胞癌、***癌、卵巢癌、神经母细胞瘤、横纹肌肉瘤、骨肉瘤、尤文肉瘤、肾母细胞瘤和促***增生性小圆细胞瘤。
本发明实施例的抗人B7-H3抗体或其片段能够特异性杀伤肿瘤细胞,特异性结合重组细胞和肿瘤细胞表面的B7-H3,在细胞和动物模型中产生了显著的肿瘤杀伤效果、未观察到明显的不良反应,解决现有技术中抗人B7-H3抗体对膜表面B7-H3亲和力和特异性不足、导致脱靶效应和不良反应的缺陷。
为更好理解本发明,首先定义一些术语。其他定义则贯穿具体实施方式部分而列出。
术语“B7-H3”,即B7同源物3(B7 Homolog 3),B7-H3存在两个亚型2Ig-B7-H3和4Ig-B7-H3。2001年,Chapoval等在NCBI数据库以及人类科学基因组中查阅了所有已知的B7家族成员的胞外区。在来源于人树突状细胞的cDNA文库中发现了一种B7样分子,并在人肿瘤细胞株THP-1和树突状细胞文库中用RT-PCR方法验证了这个核酸序列,B7-H3基因编码316aa的蛋白,该蛋白具有信号肽、一个免疫球蛋白样可变区(IgV)和恒定区(IgC)、一个跨膜区、一个含45aa的胞质尾区。Steinberger等通过建立人DC细胞的单克隆抗体识别了一个分子,其在体外从单核细胞被诱导分化为DC细胞,反转录病毒表达克隆发现,这个分子是B7-H3,这个分子为含有4个免疫球蛋白样区域的I型跨膜蛋白,将其命名为4Ig-B7-H3,通过RT-PCR和Western blot证实4Ig-B7-H3是B7-3最普遍的存在形式,人B7-H3基因定位于第15号染色体上,4Ig-B7-H3可能由编码B7-H3-IgV和B7-H3-IgC外显子的基因座复制产生。
术语“特异性结合”是指,两分子间的非随机的结合反应,如抗体和其所针对的抗原之间的反应。术语“免疫结合”是指发生在抗体分子和抗原(对于该抗原而言抗体为特异性的)之间的特异性结合反应。免疫结合相互作用的强度或亲和力可以相互作用的平衡解离常数(KD)表示,其中KD值越小,表示亲和力越高。两分子间的的免疫结合性质可使用本领域中公知的方法定量。一种方法涉及测量抗原结合位点/抗原复合物形成和解离的速度。指特定抗体-抗原相互作用的“结合速率常数”(Ka或Kon)和“解离速率常数”(Kd或Koff)两者都可通过浓度及缔合和解离的实际速率而计算得出,参见Malmqvist M,1993,Nature,361:186-187。Kd/Ka的比率等于解离常数KD,参见Davies DR等,1990,Annual Rev Biochem.,59:439-473。可用任何有效的方法测量KD、Ka和Kd值。在优选的实施方案中,用生物发光干涉测量法来测量解离常数。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。
本文中的术语“抗体”意在包括全长抗体及其任何抗原结合片段(即,抗原结合部分)或单链。全长抗体是包含至少两条重(H)链和两条轻(L)链的糖蛋白,重链和轻链由二硫键连接。各重链由重链可变区(简称VH)和重链恒定区构成。重链恒定区由三个结构域构成,即CH1、CH2和CH3。各轻链由轻链可变区(简称VL)和轻链恒定区构成。轻链恒定区由一个结构域CL构成。VH和VL区还可以划分为称作互补决定区(CDR)的高变区,其由较为保守的框架区(FR)区分隔开。各VH和VL由三个CDR以及四个FR构成,从氨基端到羧基端以FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4的顺序排布。重链和轻链的可变区包含与抗原相互作用的结合域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合,包括多种免疫***细胞(例如,效应细胞)和传统补体***的第一组分(C1q)。
术语“单克隆抗体”或“单抗”或“单克隆抗体组成”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。
本文中的术语,抗体的“抗原结合片段”(或简称为抗体片段),是指抗体的保持有特异结合抗原能力的一个或多个片段。已证实,抗体的抗原结合功能可以通过全长抗体的片段来实施。包含在抗体的“抗原结合部分”中的结合片段的例子包括(i)Fab片段,由VL、VH、CL和CH1构成的单价片段;(ii)F(ab′)2片段,包含铰链区二硫桥连接的两个Fab片段的二价片段;(iii)由VH和CH1构成的Fd片段;(iv)由抗体单臂VL和VH构成的Fv片段;(v)由VH构成的dAb片段(Ward et al.,(1989)Nature 341:544-546);(vi)分离的互补决定区(CDR);以及(vii)纳米抗体,一种包含单可变结构域和两个恒定结构域的重链可变区。此外,尽管Fv片段的两个结构域VL和VH由不同的基因编码,它们可以通过重组法经由使两者成为单蛋白链的合成接头而连接,其中VL和VH区配对形成单价分子(称为单链Fc(scFv);参见例如Bird et al.,(1988)Science 242:423-426;and Huston et al.,(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。这些单链抗体也意在包括在术语涵义中。这些抗体片段可以通过本领域技术人员已知的常用技术而得到,且片段可以通过与完整抗体相同的方式进行功能筛选。
本发明的抗原结合片段包括能够特异性结合抗原分子的那些。抗体结合片段的实例包括例如但不限于Fab、Fab'、F(ab')2、Fv片段、单链Fv(scFv)片段和单结构域片段。
Fab片段含有轻链的恒定结构域和重链的第一恒定结构域(CH1)。Fab'片段与Fab片段的不同之处在于在重链CH1结构域的羧基末端处的少数残基的添加,包括来自抗体铰链区的一个或多个半胱氨酸。通过切割在F(ab')2胃蛋白酶消化产物的铰链半胱氨酸处的二硫键产生Fab'片段。抗体片段的另外化学偶联是本领域普通技术人员已知的。Fab和F(ab')2片段缺乏完整抗体的片段可结晶(Fc)区,从动物的循环中更快速地清除,并且可能具有比完整抗体更少的非特异性组织结合(参见例如,Wahl等人,1983,J.Nucl.Med.24:316)。
如本领域通常理解的,“Fc”区是不包含抗原特异性结合区的抗体的片段可结晶恒定区。在IgG、IgA和IgD抗体同种型中,Fc区由两个相同的蛋白质片段组成,衍生自抗体的两条重链的第二和第三恒定结构域(分别为CH2和CH3结构域)。IgM和IgE Fc区在每条多肽链中含有三个重链恒定结构域(CH2、CH3和CH4结构域)。
术语“人源化抗体”,人源化抗体主要指鼠源单克隆抗体以基因克隆及DNA重组技术改造,重新表达的抗体,其大部分氨基酸序列为人源序列取代,基本保留亲本鼠单克隆抗体的亲和力和特异性,又降低了其异源性。
术语“嵌合抗体”是指重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而链的剩余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,以及此类抗体的片段,只要它们展现出期望的生物学活性(美国专利No.4,816,567;Morrison SL,Proc.Natl.Acad.Sci.USA,81:6851-6855,1984)。例如,术语“嵌合抗体”可包括这样的抗体(例如人鼠嵌合抗体),其中抗体的重链和轻链可变区来自第一抗体(例如鼠源抗体),而抗体的重链和轻链恒定区来自第二抗体(例如人抗体)。
术语“重链”,重链(heavy chain,H链)大小约为轻链的2倍,含450~550个氨基酸残基,分子量约为55或75kD。每条H链含有4~5个链内二硫键所组成的环肽。不同的H链由于氨基酸组成的排列顺序、二硫键的数目和位置、含的种类和数量不同,其抗原性也不相同,根据H链抗原性的差异可将其分为5类:μ链、γ链、α链、δ链和ε链,不同H链与L链(κ或λ链)组成完整免疫球蛋白的分子分别称之为IgM、IgG、IgA、IgD和IgE。γ、α和δ链上含有4个肽,μ和ε链含有5个环肽。
术语“轻链”,轻链(light chain,L)指在免疫球蛋白单体分子中相对于重链而论,在分子量上较小的多肽链。每条轻链近氨基末端(N端)1/2区域内的氨基酸组成序列多变处为轻链可变区(VL),是Ig分子与抗原结合部位的一个组成部分。其余1/2区域内的氨基酸组成及排列顺序相对稳定处为轻链恒定区(CL)。由于轻链恒定区内氨基酸序列存在某些差异,故轻链有k和λ两型。
术语“种系”,又称胚系(germline),抗体形成细胞具有编码Ig分子的全部基因(即有限数量的C基因和未知数量的V基因,它是通过长期进化形成并通过生殖细胞从亲代传给子代,人免疫球蛋白的重链基因由V-D-J-C基因片段编码而成;轻链基因由V-J-C基因片段编码而成,基因片段的个数不等。人重链基因定位于第14号染色体长臂,跨度约1,100kb,由V、D、J和C四种基因片段组成,包含约95个Va基因片段(分VHl~VH7七个家族,其中功能性基因片段65个、27个D基因片段、6个JH基因片段和9个CH基因片段。Va基因片段位于上游,D基因片段位于VH和JH基因簇之间,JH基因位于DH下游,与下游C基因区相隔7Kb左右,CH基因成簇(cluster)排列,跨度约200kb,P和S基因紧位于JH基因片段下游,C8下游依次是Cγ、Cα和Cε。人轻链基因分为λ和x基因,分别定位于第22号染色体长臂和第2号染色体短臂。功能性VK基因片段约40个,Vc基因片段后是5个功能性J和1个Cκ;Vλ基因片段约30个,4个Jλ基因片段和4个Cλ基因片段。
术语“EC50”,又叫半最大效应浓度,是指引起50%最大效应的抗体浓度。
术语“载体”、“核酸构建体”是指能够运输与其连接的另一种核酸的核酸分子。一种类型的载体是“质粒”,其是指其中可以连接另外的DNA区段的环状双链DNA环。另一种类型的载体是病毒载体,其中额外的DNA区段可以连接到病毒基因组中。某些载体能够在它们被导入的宿主细胞中自主复制(例如,具有细菌复制起点和游离型哺乳动物载体的细菌载体)。其他载体(例如非附加型哺乳动物载体)可以在导入宿主细胞后整合到宿主细胞的基因组中,并由此与宿主基因组一起复制。此外,某些载体能够指导它们有效连接的基因的表达。这种载体在本文中被称为“重组表达载体”(或简称为“表达载体”)。通常,在重组DNA技术中有用的表达载体通常以质粒的形式存在。然而,也包括其他形式的表达载体,如病毒载体(例如,复制缺陷型逆转录病毒,腺病毒和腺伴随病毒),其起到等同的功能。
术语“核酸分子”旨在包括DNA分子和RNA分子。核酸分子可以是单链或双链的,并且可以是cDNA。
术语“多肽”是指包含至少两个连续连接的氨基酸残基的链,对链的长度没有上限。蛋白质中的一个或多个氨基酸残基可含有修饰,例如但不限于糖基化,磷酸化或二硫键。“蛋白质”可以包含一种或多种多肽。
术语“宿主细胞”在其中载体可以增殖并且其DNA可以表达的细胞,所述细胞可以是原核细胞或者真核细胞。该术语还包括受试宿主细胞的任何后代。应理解,并不是所有的后代都与亲本细胞相同,因为在复制过程中可能会发生突变,这类后代被包括在内。
术语“癌症”和“肿瘤”是指或描述哺乳动物的其中细胞群体的特征在于细胞生长不受调控的生理病状。癌症的实例包括但不限于癌瘤、淋巴瘤、胚细胞瘤、肉瘤、白血病、良性或恶性肿瘤。所述癌症的更特定实例包括鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞状癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、成胶质细胞瘤、子***、卵巢癌、肝癌(liver cancer)、膀胱癌、肝细胞瘤、乳癌、结肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、肝癌、***癌、阴门癌、甲状腺癌、脑癌、肝癌(hepatic carcinoma)和各种类型的头颈部癌、I型或II型神经纤维瘤病。所述癌症的其它实例包括具有疗法抗性、难治性或转移性的那些。
术语“抗体药物偶联物”,简称“缀合物”,由抗体、连接子和药物组成,所述连接子是可断裂连接子组合或不可断裂连接子。抗体是球状蛋白,含有一系列氨基酸位点可用于偶联药物-连接子。由于其三级和四级结构,只有溶剂可及的氨基酸可供偶联。事实上,高收率的偶联通常发生在赖氨酸残基的ε-氨基基团或半胱氨酸残基的巯基基团上。抗体蛋白表面的大量赖氨酸侧链导致大量的位点可供药物偶联,从而导致生成的抗体药物偶联物是混合物,含有不同的药物偶联数量(药物/抗体比值,DAR)和偶联位点。本发明提供的偶联产品,尽管仍然是混合物,但与传统方式偶联得到的抗体药物偶联物相比,其DAR分布范围很窄。其平均DAR值接近4,接近最佳抗体药物偶联物平均DAR值(2-4)范围。此外,偶联产品极少不含有裸抗(DAR=0),这一组分对细胞毒杀不起作用。同时,偶联产品也不含有重度偶联产品(DAR=8),这一组分在体内的清除速度很快,相对于低DAR的组分而言。因此,本发明提供的抗体药物偶联物产品非均一性得到很大的改善。
本发明中组成抗体药物偶联物的抗体最好保持其原有野生状态时的抗原结合能力。因此,本发明中的抗体能够,最好专一性地,与抗原结合。为了开发可用于癌症诊断与治疗的有效的细胞水平目标物,研究人员力图找寻跨膜或其他肿瘤相关多肽。这些目标物能够特异性地表达在一种或多种癌症细胞表面,而在一种或多种非癌细胞表面表达很少或不表达。通常,相对于非癌细胞表面而言,这样的肿瘤相关多肽在癌细胞表面更加过度表达。确认这样的肿瘤相关因子,可大大提高基于抗体治疗癌症的专一靶向特性。
本发明所述抗体具有较高的抗B7-H3结合能力,亲和力常数KD值小于5E-10M。人源化抗B7-H3抗体hz9B11、hz10B4、hz17A3可以特异性结合人B7-H3蛋白,其亲和力(KD)分别为2.19E-10M、1.42E-10M、1.77E-10M,而对照抗体MGC-018、Enoblituzumab亲和力(KD)分别为5.97E-10M、9.50E-10M。为其良好的药效提供了分子依据。
本发明抗体具有良好的生物学活性。hz9B11、hz10B4、hz17A3可以有效的结合细胞表面的重组人B7-H3,其半数有效结合浓度(EC50)值分别为0.08277ug/ml,0.1183ug/ml,0.04407ug/ml,优于对照抗体Enoblituzumab(EC50 0.1906ug/ml),hz9B11、hz17A3与对照抗体MGC-018(EC50 0.05649ug/ml)相近。且hz9B11、hz10B4、hz17A3有良好的内化能力。
本发明抗体具有良好的体内药效(小鼠)。A431裸鼠皮下移植瘤模型中,抗B7H-3-ADC抗体hz10B4-M药效优于对照抗体MGC-018、Enoblituzumab,hz17A3-M药效优于对照抗体Enoblituzumab,而hz9B11-M表现一定药效趋势,药效弱于hz10B4和hz17A3,且未观察到ADC小分子MMAE的明显的毒性作用,各实验组动物体重平稳增长,与对照无明显差别。
附图说明
通过阅读下文优选实施方式的详细描述,各种其他的优点和益处对于本领域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的,而并不认为是对本发明的限制。而且在整个附图中,用相同的参考符号表示相同的部件。在附图中:
图1:ELISA检测杂交瘤上清与B7-H3抗原的结合情况;
图2:ELISA检测抗人B7-H3嵌合抗体与不同B7-H3重组蛋白结构域的结合;
图3:FACS检测抗人B7-H3嵌合抗体与293/hB7-H3细胞表面B7H3的结合图;
图4:FACS检测抗人B7-H3嵌合抗体与A431细胞表面B7H3的结合图;
图5:人源化抗体与重组人B7-H3结合的ELISA曲线图;
图6:人源化抗体与重组猴B7-H3结合的ELISA曲线图;
图7:人源化抗体与小鼠重组B7-H3结合的ELISA曲线图;
图8A:hz10B4对人B7-H3胞外区重组蛋白亲和力分析;
图8B:hz17A3对人B7-H3胞外区重组蛋白亲和力分析;
图8C:hz9B11对人B7-H3胞外区重组蛋白亲和力分析;
图8D:MGC-018对人B7-H3胞外区重组蛋白亲和力分析;
图8E:Enoblituzumab对人B7-H3胞外区重组蛋白亲和力分析;
图9:FACS检测抗人B7-H3人源化抗体与SKVO3细胞的结合图;
图10:细胞表面B7-H3介导的抗人B7-H3人源化抗体的内化率;
图11:ADC药物标记的抗人B7-H3抗体对A431细胞的杀伤活性检测;
图12:ADC药物标记的抗人B7-H3抗体对SKVO3细胞的杀伤活性检测;
图13:A431裸鼠皮下移植瘤模型小鼠肿瘤体积变化曲线;
图14:A431裸鼠皮下移植瘤模型小鼠重量变化曲线。
具体实施方式
下面将参照附图更详细地描述本公开的示例性实施方式。虽然附图中显示了本公开的示例性实施方式,然而应当理解,可以以各种形式实现本公开而不应被这里阐述的实施方式所限制。相反,提供这些实施方式是为了能够更透彻地理解本公开,并且能够将本公开的范围完整的传达给本领域的技术人员。
实施例1:抗人B7-H3抗体杂交瘤细胞制备与筛选
1.1杂交瘤制备
免疫:采用人B7-H3胞外区重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-461aa)免疫Balb/c小鼠,用包被人B7-H3-his重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-461aa)的96孔酶标板以ELISA法检测血清滴度;达到融合要求的小鼠用于下一步的细胞融合。
细胞融合及杂交瘤制备:选取滴度达到要求的小鼠,进行冲击免疫,3天后无菌取小鼠脾脏,制备B淋巴细胞悬液,与SP2/0骨髓瘤细胞融合。融合后的细胞用HAT培养基重悬后,分装96孔细胞培养板。置37℃,5%CO2培养箱内培养。
1.2阳性杂交瘤结合筛选
融合后10-14天,以人B7-H3-his胞外区重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-461aa)(20ng/ml)包被酶标板,4℃,过夜;PBS洗三次后,用4%脱脂奶粉-PBS封闭,室温,1hr;用PBS洗三遍,加入杂交瘤克隆培养上清,室温,1hr。设以下对照:(1)阳性对照(PC):免疫后小鼠血清(用PBS 1:1000稀释);(2)阴性对照(NC):免疫前小鼠血清(用PBS 1:1000稀释)。经PBST(0.05%Tween-PBS)洗三遍,PBS洗两遍,加入HRP-羊抗小鼠IgG(Fcγ),37℃,0.5hr;再经PBST(0.05%Tween20-PBS)洗3遍,加入TMB显色液,避光显色15-30min,加入ELISA终止液,终止反应;酶标仪读A450值。按从高到低原则选择读值高的前16个克隆隔天取克隆培养上清进行二次ELISA确认,最终选择445(9B11),485(10B4)和870(17A3)号作为候选克隆进行序列克隆,ELISA结果见图1。
实施例2:鼠源抗人B7-H3抗体的序列测定
将分泌抗人B7-H3抗体的杂交瘤克隆细胞9B11、10B4和17A3扩大培养后,按照TRIzol试剂盒(Cat:15596026,Invitrogen)说明书步骤提取细胞总RNA;利用M-MuLV反转录酶(Cat:M0253S,NEB)将杂交瘤细胞总RNA反转录成cDNA;使用简并引物和Phusion试剂盒(Cat:E0553L,NEB)扩增抗体轻链可变区IgVL(κ)和重链可变区VH序列;利用胶回收试剂盒(Cat:AP-GX-250,Axygen)纯化PCR扩增产物;按照T载体克隆试剂盒(Cat:ZC205,庄盟生物)说明书将扩增PCR产物连接至T载体并转化大肠杆菌感受态细胞,菌株扩增、抽提质粒后进行DNA测序获得单克隆抗体可变区序列。测序结果显示9B11鼠抗体重链可变区氨基酸序列见SEQ ID NO:1,9B11鼠抗体轻链可变区氨基酸序列见SEQ ID NO:2;10B4鼠抗体重链可变区氨基酸序列见SEQ ID NO:3,10B4鼠抗体轻链可变区氨基酸序列见SEQ ID NO:4;17A3鼠抗体重链可变区氨基酸序列见SEQ ID NO:5;17A3鼠抗体轻链可变区氨基酸序列见SEQ IDNO:6。
实施例3:抗人B7-H3嵌合抗体及对照抗体的制备
将对照抗体Enoblituzumab和MGC-018轻重链序列进行全合成,将轻重链序列分别克隆至真核瞬时表达载体中,获得对照抗体轻链和重链表达质粒,转入大肠杆菌扩增,分离获得大量含对照抗体轻链和重链的质粒,利用这些质粒,并根据转染试剂293fectin(Cat:12347019,Gibco)的操作说明,分别将对照抗体的轻、重链质粒转入HEK293细胞中重组表达。细胞转染后5-6天,取培养上清,利用ProA亲和层析柱对表达上清进行纯化,获得对照抗体。其中,对照抗体Enoblituzumab氨基酸序列来源于WHO Drug Information(Vol.30,No.4,2016),重链氨基酸序列见SEQ ID NO:7,轻链氨基酸序列见SEQ ID NO:8;对照抗体MGC-018氨基酸序列来源于专利WO2017180813,重链氨基酸序列见序列9,轻链氨基酸序列见SEQ ID NO:10。
将克隆获得的9B11、10B4和17A3鼠源抗体轻链可变区和重链可变区基因通过PCR引入酶切位点,分别克隆至装有人-kappa轻链恒定区和人IgG1重链恒定区编码基因上游的真核瞬时表达载体中,获得人-鼠嵌合轻链(pKN019-ch9B11L、pKN019-ch10B4L、pKN019-ch17A3L)和人-鼠嵌合重链(pKN025-ch9B11H、pKN025-ch10B4H、pKN025-ch17A3H)表达质粒,转入大肠杆菌扩增,分离获得大量含人-鼠嵌合抗体轻链和重链的质粒,利用该质粒,并根据转染试剂293fectin(Cat:12347019,Gibco)的操作说明,将9B11、10B4和17A3嵌合抗体的轻、重链质粒分别转入HEK293细胞中重组表达。细胞转染后5-6天,取培养上清,利用ProA亲和层析柱对表达上清进行纯化,获得的9B11、10B4和17A3嵌合抗体(ch9B11、ch10B4、ch17A3)。
实施例4:嵌合抗体亲和力分析
利用Fortebio公司的Octet QKe system仪器,采用抗人抗体Fc段的捕获抗体(AHC)生物探针捕获抗体Fc段的方法测定抗体亲和力。测定时将ch9B11、ch10B4、ch17A3嵌合抗体及对照抗体Enoblituzumab,用PBS缓冲液稀释至4μg/ml,流经AHC探针(Cat:18-0015,PALL)表面,时间为120s。人B7-H3胞外区重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-461aa,C-His标签)(60nM)作为流动相,结合时间为300s,解离时间为300s。实验完毕,扣除空白对照响应值,用软件进行1:1Langmuir结合模式拟合,计算抗原抗体结合的动力学常数。动力学常数如下表1所示,表1的结果表明所有克隆均克隆正确,且均能与人B7-H3重组蛋白结合。
表1.嵌合抗体与人B7-H3重组蛋白的亲和力测定结果
实施例5:ELISA检测嵌合抗体与不同B7-H3重组蛋白及不同结构域的结合
将人B7-H3-his胞外区重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-461aa)、人B7-H3 IgV1-IgV2-his胞外区重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-362aa)、人B7-H3IgV1-IgC1-his胞外区重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-238aa)、人B7-H3 IgC2-mFc胞外区重组蛋白(序列号:UniProtKB-Q5ZPR3,363aa-456aa)、猴B7-H3-his胞外区重组蛋白(序列号:XP_005560056.1,1aa-465aa),浓度0.2μg/mL,100μl,4℃包被过夜,用5%BSA于37℃恒温培养箱封闭60min。PBST洗板4次;加入ch9B11、ch10B4、ch17A3和对照抗体Enoblituzumab以及同型对照抗体(NC)0.5μg/mL,100μl,37℃恒温培养箱反应60min后。PBST洗板4次;然后加入1:5000稀释的HRP-anti-human Fc(Cat:109-035-098,JacksonImmuno Research),反应45min,加入TMB(Cat:ME142,北京泰天河生物)底物显色15min,2MHCl终止后读板。以630nm为参比波长,读取并记录波长450nm下孔板的吸光度值A450nm-630nm。
通过ELISA检测,ch9B11、ch10B4、ch17A3和对照抗体Enoblituzumab与人B7-H3各种结构域重组蛋白和猴B7-H3胞外区重组蛋白都有结合(图2),其中ch10B4与猴B7H3的结合活性明显弱于其他抗体,仅为弱交叉结合,而几个抗体与B7H3-IgC2的结合均略弱于其他结构域,其中ch9B11最明显。
实施例6:FACS检测抗人B7-H3嵌合抗体与293细胞表面人B7-H3重组蛋白的结合
瞬时表达人B7-H3的293细胞株的构建:将HEK293细胞按6*105cells/ml的密度接入摇瓶中,体积10ml,置于37℃,5%CO2的振摇培养箱中130rpm振摇培养24h。将编码全长人B7-H3(序列号:UniProtKB-Q5ZPR3,1aa-534aa)表达质粒与293fectin(Cat:12347019,Gibco)按1:1.2的比例分别在0.5mL Opti-MEM(Cat:11058021,Gibco)培养基中静置5min后,二者混匀室温静置15min,然后加入到HEK293细胞中。置于37℃,5%CO2的振摇培养箱中130rpm振摇培养48h,293/hB7-H3细胞用于FACS检测。
将重组表达人B7-H3的293细胞(293/hB7-H3)悬液分别与嵌合抗体(ch9B11、ch10B4、ch17A3)(浓度为1μg/mL,0.1μg/mL,0.01μg/mL)在37℃孵育30min,设以下对照:(1)阳性对照(PC):对照抗体Enoblituzumab;(2)阴性对照(NC):同型对照抗体。以PBS洗涤细胞3次后,加入1:200稀释的羊抗人IgG-FITC(Cat:F9512,Sigma)并孵育30min。PBS洗涤细胞3次后通过流式细胞仪(型号B49007AD,SNAW31211,BECKMAN COULTER)检测细胞的平均荧光强度(MFI)以检测嵌合抗体与293细胞表面的人B7-H3结合能力。通过FACS检测,ch9B11、ch10B4、ch17A3均能和293细胞表面的人B7-H3重组蛋白结合,且结合能力优于对照抗体Enoblituzumab(图3)。
实施例7:FACS检测抗人B7-H3嵌合抗体与A431(人皮肤鳞癌细胞)的结合
将天然表达人B7-H3的A431细胞悬液分别与嵌合抗体(ch9B11、ch10B4、ch17A3)(浓度为10μg/mL,3倍梯度稀释,11个浓度)在37℃孵育30min,设以下对照:(1)阳性对照(PC):对照抗体Enoblituzumab;(2)阴性对照(NC):同型对照抗体。以PBS洗涤细胞3次后,加入1:200稀释的羊抗人IgG-FITC(Cat:F9512,Sigma)并孵育30min。PBS洗涤细胞3次后通过流式细胞仪(型号B49007AD,SNAW31211,BECKMAN COULTER)检测细胞的平均荧光强度(MFI)以检测嵌合抗体与A431细胞表面的B7-H3结合能力。通过FACS检测,ch9B11、ch10B4、ch17A3均能和A431细胞表面的B7-H3结合,且结合能力优于对照抗体Enoblituzumab,其对应的半数有效结合浓度EC50值见表2,结合图见图4。
表2.FACS检测抗人B7-H3嵌合抗体与A431细胞结合的EC50
ch9B11 | ch17A3 | ch10B4 | Enoblituzumab | |
EC50(μg/ml) | 0.1366 | 0.1008 | 0.2028 | 0.3744 |
实施例8:抗人B7-H3单克隆抗体的人源化及突变设计
8.1鼠源单克隆抗体9B11的人源化
(1)CDR移植
首先对鼠源抗体重链序列进行综合分析,确定抗体与抗原结合的抗原互补决定簇(CDR)区域及支撑抗体保守三维构象的框架区(framework)。随后根据同源性比对结果,选择最相似人源抗体template VH1(1-03)为基础模板,结合全序列blast结果,进行CDR移植,根据CDR3序列(STTTATFYWYFDV,SEQ ID NO:42)情况,选择JH6(wgqgtTvtvss)为J区序列,进行CDR移植,实现了9B11重链可变区(VH)在Framework区的人源化。同理,选择VK III(A27)和VKVI(A26)为基础模板,结合全序列blast结果,进行CDR移植,根据CDR3序列(QQSHSWPYT,SEQ ID NO:45)情况,选择JK2(FGQGTKLEIK)为JK区序列,实现了轻链Framework区的人源化。9B11抗体CDR移植(CDR Grafted)的人源化重链可变区hz9B11_VH1氨基酸序列见序列11;人源化轻链可变区hz9B11_VL1氨基酸序列见序列12,人源化轻链可变区hz9B11_VL2氨基酸序列见序列13。
(2)CDR区突变设计
根据鼠源9B11序列特点,对CDR移植的人源化轻重链可变区序列进行突变设计,突变位点见下表3。
表3. 9B11人源化序列设计
注:数字代表突变的氨基酸位置,数字前的字母代表突变前的氨基酸残基,数字后的字母代表突变后的氨基酸残基,例如Y49K表示将49位氨基酸由Y突变为K
8.2鼠源单克隆抗体10B4的人源化
(1)CDR移植
首先对鼠源抗体重链序列进行综合分析,确定抗体与抗原结合的抗原互补决定簇(CDR)区域及支撑抗体保守三维构象的框架区(framework)。随后根据同源性比对结果,选择VH1(1-03)为基础模板,结合全序列blast结果,进行CDR移植,根据CDR3序列(KGKDYFDWYFDV,SEQ ID NO:48)情况,选择JH6(WGQGTTVTVSS)为J区序列,进行CDR移植,实现了10B4重链可变区(VH)在Framework区的人源化。根据同源性比对结果,选择最相似人源抗体template VK I(O12)为基础模板,结合全序列blast结果,进行CDR移植,根据CDR3序列(QQWSSNPLT,SEQ ID NO:51)情况,选择JK4(FGGGTKVEIK)为JK区序列,实现了轻链Framework区的人源化。10B4抗体CDR移植(CDR Grafted)的人源化重链可变区hz10B4_VH1氨基酸序列见SEQ ID NO:18;轻链可变区hz10B4_VL1氨基酸序列见SEQ ID NO:19。
(2)CDR区突变设计
根据鼠源10B4序列特点,对CDR移植的人源化轻重链可变区序列进行突变设计,突变位点见下表4。
表4. 10B4人源化序列设计
注:数字代表突变的氨基酸位置,数字前的字母代表突变前的氨基酸残基,数字后的字母代表突变后的氨基酸残基,例如M4L表示将hz10B4轻链可变区第4位氨基酸由M突变为L。
8.3鼠源单克隆抗体17A3的人源化
(1)CDR移植
首先对鼠源抗体重链序列进行综合分析,确定抗体与抗原结合的抗原互补决定簇(CDR)区域及支撑抗体保守三维构象的框架区(framework)。随后根据同源性比对结果,选择最相似人源抗体template VH1(1-02)为基础模板,结合全序列blast结果,进行CDR移植,根据CDR3序列(GITAVVGTRYYAMDY)情况,选择JH4(WGQGTLVTVSS)为J区序列,进行CDR移植,实现了17A3重链可变区(VH)在Framework区的人源化。根据同源性比对结果,选择VK III(A27)和VKVI(A26)为基础模板,结合全序列blast结果,进行CDR移植,根据CDR3序列(QQSYSWPLT)情况,选择JK4(FGGGTKVEIK)为JK区序列,实现了轻链Framework区的人源化。17A3抗体CDR移植(CDR Grafted)的人源化重链可变区hz17A3_VH1氨基酸序列见SEQ IDNO:24;人源化轻链可变区hz17A3_VL1氨基酸序列见SEQ ID NO:25,人源化轻链可变区hz17A3_VL2氨基酸序列见SEQ ID NO:26。
(2)CDR区突变设计
根据鼠源17A3序列特点,对CDR移植的人源化轻重链可变区序列进行突变设计,突变位点见下表5。
表5. 17A3人源化序列设计
注:数字代表突变的氨基酸位置,数字前的字母代表突变前的氨基酸残基,数字后的字母代表突变后的氨基酸残基,例如Y49K表示将hz17A3轻链可变区第49位氨基酸Y突变为K。
实施例9:抗人B7-H3人源化单克隆抗体的重组表达
将人源化设计的hz9B11、hz10B4、hz17A3抗体轻重链可变区(hz9B11_VL1、hz9B11_VL2、hz9B11_VH1、hz10B4_VL1、hz10B4_VH1、hz17A3_VL1、hz17A3_VL2、hz17A3_VH1)序列进行全合成,将人源化的重链可变区通过酶切克隆入真核瞬时表达载体pKN041的人IgG1的重链恒定区编码基因的上游,重链恒定区氨基酸序列见SEQ ID NO:38;将人源化的轻链可变区通过酶切克隆入真核瞬时表达载体pKN019的人轻链Cκ的编码基因的上游,轻链恒定区氨基酸序列见SEQ ID NO:39,构建人源化hz9B11、hz10B4、hz17A3抗体的轻、重链表达载体;并根据突变设计,利用StarMut基因定点突变试剂盒(GenStar,Cat:T111-01),分别在轻链和重链表达质粒上进行定点突变,转入大肠杆菌扩增,获得hz9B11、hz10B4、hz17A3抗体轻、重链突变表达质粒;并根据转染试剂293fectin(Cat:12347019,Gibco)的操作说明,将hz9B11、hz10B4、hz17A3人源化抗体的轻、重链质粒进行组合,同时转入HEK293细胞中重组表达,组合信息如表6-8所示。细胞转染后5-6天,取培养上清,利用ProA亲和层析柱对表达上清进行纯化,获得的人源化抗体,利用Fortebio公司的Octet QKe system仪器,采用抗人抗体Fc段的捕获抗体(AHC)生物探针捕获抗体Fc段的方法测定抗体亲和力。测定时将hz9B11、hz10B4、hz17A3抗体及嵌合抗体用PBS缓冲液稀释至4ug/mL,流经AHC探针(Cat:18-0015,PALL)表面,时间为300S。人B7-H3-His重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-461aa)作为流动相,B7-H3-His重组蛋白浓度为60nM。结合时间为100s,解离时间为300s。实验完毕,扣除空白对照响应值,用软件进行1:1Langmuir结合模式拟合,计算抗原抗体结合的动力学常数。人源化hz9B11、hz10B4、hz17A3及其突变抗体的轻、重链组合及亲和力常数KD值分别如表6-8所示。
表6-8中突变体抗体亲和力测定结果显示,多个位点突变后抗体的亲和力发生较大改变。后续研究中选择其中组合hz9B11-6,该组合抗体亲和力(KD)为1.55E-10M,命名为hz9B11;选择其中组合hz10B4-7,该组合抗体亲和力(KD)为1.61E-10M,命名为hz10B4;选择其中组合hz17A3-14,该组合抗体亲和力(KD)为3.01E-10M,命名为hz17A3,进行功能验证。
表6.hz9B11轻、重链组合及亲和力常数KD值
表7.hz10B4轻、重链组合及亲和力常数KD值
表8.hz17A3轻、重链组合及亲和力常数KD值
实施例10:ELISA检测抗B7-H3人源化抗体与B7-H3结合的种属特异性研究
将人B7-H3-his胞外区重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-461aa)、食蟹猴B7-H3-his重组蛋白(Cat:90806-C08H,义翘神州)、小鼠B7-H3-his重组蛋白(Cat:CM83,义翘神州),4℃包被过夜,包被浓度1μg/mL;PBS洗板3次后,加入5%BSA PBS,37℃封闭60min,PBST洗板3次;加入不同稀释倍数的hz10B4(起始浓度为10μg/mL,3倍梯度依次稀释12个浓度),hz17A3(起始浓度为3μg/mL,3倍梯度依次稀释12个浓度),hz9B11(起始浓度为10μg/mL,3倍梯度依次稀释12个浓度),Enoblituzumab(起始浓度为10μg/mL,3倍梯度依次稀释12个浓度),MGC-018(起始浓度为10μg/mL,3倍梯度依次稀释12个浓度),37℃孵育60min,PBST洗板4次;加入1:5000稀释的HRP-anti-human Fc(Cat:109-035-098,Jackson ImmunoResearch),37℃孵育30min,PBST洗板4次;加入TMB底物显色,37℃孵育10min后,加入2MHCl终止反应;以630nm为参比波长,读取并记录波长450nm下孔板的吸光度A450nm-630nm。
实验结果表明hz10B4,hz17A3,hz9B11及对照抗体Sacituzumab均可以特异性的与重组人、食蟹猴B7H3结合,而与重组小鼠B7H3则无结合活性(图5,6,7),其对应的半数有效结合浓度EC50值见表9。
表9.抗人B7-H3人源化抗体与人、猴、小鼠B7-H3结合检测
EC50(nM) | hz10B4 | hz17A3 | hz9B11 | MGC-018 | Enoblituzumab |
人B7-H3 | 0.1613 | 0.2805 | 0.2187 | 0.1168 | 0.1169 |
猴B7-H3 | 4.058 | 0.1083 | 0.1183 | 0.07819 | 0.1335 |
实施例11:抗B7-H3人源化抗体亲和力分析
利用Fortebio公司的Octet QKe system仪器,采用抗人抗体Fc段的捕获抗体(AHC)生物探针捕获抗体Fc段的方法测定抗体亲和力。测定时将抗体(hz10B4,hz17A3,hz9B11和对照抗体MGC-018,Enoblituzumab)用PBS缓冲液稀释至4ug/mL,流经AHC探针(Cat:18-0015,PALL)表面,时间为120s。人B7-H3-his胞外区重组蛋白(序列号:UniProtKB-Q5ZPR3,1aa-461aa)作为流动相。结合时间为300s,解离时间为300s。实验完毕,扣除空白对照响应值,用软件进行1:1Langmuir结合模式拟合,计算抗原抗体结合的动力学常数。
hz10B4,hz17A3,hz9B11和对照抗体MGC-018,Enoblituzumab与人B7-H3重组蛋白的反应曲线如图8所示,拟合曲线并计算亲和力,hz10B4亲和力(KD)为1.42E-10M,hz17A3亲和力(KD)为1.77E-10M,hz9B11亲和力(KD)为2.19E-10M,MGC-018亲和力(KD)为5.97E-10M,Enoblituzumab亲和力(KD)为9.50E-10M。详细动力学参数如下表10所示。结果表明hz10B4,hz17A3,hz9B11与人B7-H3具有高亲和力,优于对照抗体。
表10.抗人B7-H3人源化抗体与人B7-H3胞外区重组蛋白的亲和力测定结果
实施例12:FACS检测抗人B7-H3人源化抗体与天然表达人B7-H3细胞的结合
将天然表达人B7-H3的人卵巢癌细胞(SKVO3)悬液分别与人源化抗体(hz9B11、hz10B4、hz17A3)(浓度为10μg/mL,3倍梯度稀释,10个浓度)在37℃孵育30min,设以下对照:(1)阳性对照(PC):对照抗体Enoblituzumab和MGC-018;(2)阴性对照(NC):同型对照抗体。以PBS洗涤细胞3次后,加入1:200稀释的羊抗人IgG-FITC(Cat:F9512,Sigma)并孵育30min。PBS洗涤细胞3次后通过流式细胞仪(型号B49007AD,SNAW31211,BECKMAN COULTER)检测细胞的平均荧光强度(MFI)以检测人源化抗体与SKVO3细胞表面的B7-H3结合能力。通过FACS检测,hz9B11、hz10B4、hz17A3均能和SKVO3细胞表面的B7-H3结合,且结合能力优于对照抗体Enoblituzumab,其对应的半数有效结合浓度EC50值见表11,结合图见图9。
表11.FACS检测抗人B7-H3嵌合抗体与A431细胞结合的EC50
实施例13:抗人B7-H3人源化抗体结合细胞表面B7-H3的内化活性
将天然表达人B7-H3的人乳腺癌细胞MBA-MB-468,以3×103cells/孔的密度接种于96孔细胞培养板,培养24小时。用PBS洗涤细胞1次,弃上清。将人源化抗体hz9B11、hz10B4、hz17A3和阳性对照Enoblituzumab,阴性对照:同型对照抗体,用RPMI 1640(含10%FBS)稀释至10μg/mL,加入MBA-MB-468细胞中,一组放37℃电热恒温培养箱,一组放4℃冰箱做为阴性对照;阴性对照孵育1小时后PBS洗涤3次,加入1:200稀释的山羊抗人IgG Fc-FITC二抗,4℃孵育30分钟后,PBS洗涤3次,FACS检测细胞的平均荧光强度(MFI),37℃实验组孵育5h后,加入1:200稀释的山羊抗人IgG Fc-FITC二抗,4℃孵育30分钟PBS洗涤3次,FACS检测细胞的平均荧光强度(MFI)。根据公式计算抗体的内化效率:内化率%=100-(37℃孵育样品的MFI×100/4℃孵育对照样品的MFI)。
实验结果(图10)表明人源化hz9B11、hz10B4、hz17A3和对照抗体Enoblituzumab在37℃条件下都能够被B7-H3介导内吞。
实施例14:ADC药物标记的抗人B7-H3抗体对肿瘤细胞的杀伤活性检测
将天然表达人B7-H3的SKVO3及A431细胞悬液以1×103个/孔的密度接种于96孔细胞培养板,置于37℃5%CO2孵箱中培养过夜后,加入不同浓度的ADC药物MMAE标记的抗B7-H3抗体样本hz9B11-M、hz10B4-M、hz17A3-M和阳性对照Enoblituzumab-M、MGC-018-M以及ADC对照MW14-M(11.1ug/ml,3倍稀释,6个浓度,3个复孔)置于37℃5%CO2孵箱培养,4天后用Cell Counting Kit-8(CCK-8)试剂盒检测ADC标记的抗B7-H3抗体对细胞的杀伤活性。
结果显示(图11,12),各抗B7-H3 ADC抗体均能剂量依赖地杀伤肿瘤细胞,A431细胞上,hz10B4活性略优于hz9B11和hz17A3,与对照抗体MGC-018相当,明显优于Enoblituzumab;SKOV-3上,hz9B11和hz17A3低浓度下表现一定活性优势,明显优于对照抗体,hz10B4与对照抗体MGC-018相当,明显优于Enoblituzumab。
实施例15:抗B7-H3-ADC抗体在A431裸鼠皮下移植瘤模型中的药效学评价
取五周龄、雄性BALB/c裸鼠,皮下接种3×106的A431细胞,待肿瘤生长至100mm3左右时进行随机分组,5只/组,分组及给药剂量、频率如表15,每组每周静脉注射给药两次,共给药4次,给药同时测量瘤体积及裸鼠体重,停药后持续观察2周,当裸鼠体重下降超过15%时,或单只裸鼠瘤体积超过3000mm3或一组裸鼠平均瘤体积超过2000mm3时停止实验,给予裸鼠安乐死。裸鼠分组及给药方案如表12所示,瘤体积及裸鼠体重变化曲线如图13-14所示。
表12.裸小鼠分组及给药方案
组别 | 药物 | 给药剂量 | 给药频率 |
1 | hz10B4-M | 6.25mg/kg | Biw×4 |
2 | hz9B11-M | 6.25mg/kg | Biw×4 |
3 | hz17A3-M | 6.25mg/kg | Biw×4 |
4 | Enoblituzumab-M | 6.25mg/kg | Biw×4 |
5 | MGC-018-M | 6.25mg/kg | Biw×4 |
6 | ADC对照MW14-M | 6.25mg/kg | Biw×4 |
如图13-14所示,A431裸鼠皮下移植瘤模型中,hz10B4抗肿瘤药效效果最佳,与MGC-018基本相当或略好;hz17A3抗肿瘤药效次之,优于Enoblituzumab;而hz9B11表现一定药效趋势,药效弱于hz10B4和hz17A3。各ADC抗体未观察到ADC小分子MMAE的明显的毒性作用,各实验组动物体重平稳增长,与对照无明显差别。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以所述权利要求的保护范围为准。
序列表
<110> 迈威(上海)生物科技股份有限公司
<120> 抗人B7-H3抗体及其应用
<150> 202011398727.1
<151> 2020-12-02
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Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asp Tyr
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Ala Ile His Trp Val Lys Gln Ser His Ala Met Ser Leu Glu Trp Ile
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Gly Ile Ile Asn Thr Tyr Tyr Gly Asn Thr Asn Tyr Asn Gln Lys Phe
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Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
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Met Glu Leu Ala Arg Leu Thr Ser Ala Asp Ser Ala Ile Tyr Tyr Cys
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Ala Arg Ser Thr Thr Thr Ala Thr Phe Tyr Trp Tyr Phe Asp Val Trp
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Gly Ala Gly Thr Thr Val Ser Val Ser Ser
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Asp Ile Val Leu Thr Gln Ser Pro Val Thr Leu Ser Val Thr Pro Gly
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Asp Ser Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Asn Asn Asn
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Leu His Trp Tyr Gln Gln Lys Pro His Glu Ser Pro Arg Leu Leu Ile
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Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Phe Asn Ser Val Glu Thr
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Glu Asp Phe Gly Met Tyr Phe Cys Gln Gln Ser His Ser Trp Pro Tyr
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Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
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Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
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Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
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Ile Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
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Gly Gly Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
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Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
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Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
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Ala Arg Lys Gly Lys Asp Tyr Phe Asp Trp Tyr Phe Asp Val Trp Gly
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Ala Gly Thr Thr Val Thr Val Ser Ser
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Gln Ile Val Leu Thr Gln Ser Pro Thr Ile Met Ser Ala Ser Pro Gly
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Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
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His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
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Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
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Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
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Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
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Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Val
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Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr
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Ala Leu His Trp Val Lys Gln Ser His Ala Lys Ser Pro Gln Trp Ile
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Gly Leu Ile Asn Thr Tyr Ser Ser Asn Thr Asn Tyr Asn Gln Lys Phe
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Lys Asp Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
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Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
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Ala Arg Gly Ile Thr Ala Val Val Gly Thr Arg Tyr Tyr Ala Met Asp
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Asn Ile Val Leu Thr Gln Ser Pro Thr Thr Leu Ser Val Thr Pro Gly
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Asp Thr Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
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Lys Tyr Thr Ser Gln Asn Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Thr
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Glu Asp Phe Gly Met Tyr Phe Cys Gln Gln Ser Tyr Ser Trp Pro Leu
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Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala
100 105 110
Pro
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Ala Tyr Ile Ser Ser Asp Ser Ser Ala Ile Tyr Tyr Ala Asp Thr 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 Asp Glu Asp Thr Ala Val Tyr Tyr Cys
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Gly Arg Gly Arg Glu Asn Ile Tyr Tyr Gly Ser Arg Leu Asp Tyr Trp
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Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
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Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
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Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
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Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
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Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
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Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
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His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
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Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Val
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Gly Gly Pro Ser Val Phe Leu Leu Pro Pro Lys Pro Lys Asp Thr Leu
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Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
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His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
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Val His Asn Ala Lys Thr Lys Pro Pro Glu Glu Gln Tyr Asn Ser Thr
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Leu Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
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Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
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Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
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Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
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Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
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Leu Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
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Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
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Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
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Ser Pro Gly Lys
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<210> 8
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
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Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Asn
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Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
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Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Asn Tyr Pro Phe
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Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
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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> 9
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
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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
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Gly Gly Ser Asn Thr Tyr Tyr Pro Asp Ser Leu
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 Asp Gly Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 10
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
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 Ile Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Val
35 40 45
Tyr Asn Thr Lys Thr Leu Pro Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 11
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
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 Asp Tyr
20 25 30
Ala Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Thr Tyr Tyr Gly Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Thr Thr Ala Thr Phe Tyr Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 12
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Asn Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser His Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 13
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala
65 70 75 80
Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser His Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 14
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Asn Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser His Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 15
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Asn Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser His Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 16
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Asn Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser His Ser Trp Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 17
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Glu 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 Asp Tyr
20 25 30
Ala Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Thr Tyr Tyr Gly Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Thr Thr Ala Thr Phe Tyr Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 18
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Gly Lys Asp Tyr Phe Asp Trp Tyr Phe Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 19
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 20
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 21
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Glu 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 Glu Tyr
20 25 30
Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Gly Lys Asp Tyr Phe Asp Trp Tyr Phe Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 22
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Glu 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 Glu Tyr
20 25 30
Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ala Ser Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Gly Lys Asp Tyr Phe Asp Trp Tyr Phe Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 23
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Glu 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 Glu Tyr
20 25 30
Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Asn Gln Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Gly Lys Asp Tyr Phe Asp Trp Tyr Phe Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 24
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ala Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Leu Ile Asn Thr Tyr Ser Ser Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Thr Ala Val Val Gly Thr Arg Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 25
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Gln Asn Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 26
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Gln Asn Ile Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala
65 70 75 80
Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 27
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Thr Ser Gln Asn Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 28
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Gln Asn Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 29
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Thr Ser Gln Asn Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 30
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Thr Ser Gln Ser Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 31
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Thr Ser Gln Ser Ile Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 32
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Lys Tyr Thr Ser Gln Asn Ile Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala
65 70 75 80
Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 33
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Gln Asn Ile Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Glu Ala
65 70 75 80
Glu Asp Ala Ala Thr Tyr Phe Cys Gln Gln Ser Tyr Ser Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 34
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
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 Asp Tyr
20 25 30
Ala Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Asn Thr Tyr Ser Ser Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Thr Ala Val Val Gly Thr Arg Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 35
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Glu 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 Asp Tyr
20 25 30
Ala Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Leu Ile Asn Thr Tyr Ser Ser Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Thr Ala Val Val Gly Thr Arg Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 36
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Glu 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 Asp Tyr
20 25 30
Ala Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Leu Ile Ser Thr Tyr Ser Ser Asn Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Thr Ala Val Val Gly Thr Arg Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 37
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Glu 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 Asp Tyr
20 25 30
Ala Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Leu Ile Asn Thr Tyr Ser Ser Ser Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Thr Ala Val Val Gly Thr Arg Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 38
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
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
Arg 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 Glu Glu
225 230 235 240
Met 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> 39
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
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> 40
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Asp Tyr Ala Ile His
1 5
<210> 41
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Ile Ile Asn Thr Tyr Tyr Gly Asn Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 42
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Ser Thr Thr Thr Ala Thr Phe Tyr Trp Tyr Phe Asp Val
1 5 10
<210> 43
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Arg Ala Ser Gln Ser Ile Asn Asn Asn Leu His
1 5 10
<210> 44
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Tyr Ala Ser Gln Ser Ile Ser
1 5
<210> 45
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Gln Gln Ser His Ser Trp Pro Tyr Thr
1 5
<210> 46
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Glu Tyr Ile Met His
1 5
<210> 47
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Gly Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 48
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Lys Gly Lys Asp Tyr Phe Asp Trp Tyr Phe Asp Val
1 5 10
<210> 49
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Ser Ala Ser Ser Ser Val Ser Tyr Met His
1 5 10
<210> 50
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 51
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
Gln Gln Trp Ser Ser Asn Pro Leu Thr
1 5
<210> 52
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 52
Asp Tyr Ala Leu His
1 5
<210> 53
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
Leu Ile Asn Thr Tyr Ser Ser Asn Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 54
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 54
Gly Ile Thr Ala Val Val Gly Thr Arg Tyr Tyr Ala Met Asp Tyr
1 5 10 15
<210> 55
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
Arg Ala Ser Gln Ser Ile Ser Asn Asn Leu His
1 5 10
<210> 56
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 56
Tyr Thr Ser Gln Asn Ile Ser
1 5
<210> 57
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 57
Gln Gln Ser Tyr Ser Trp Pro Leu Thr
1 5
<210> 58
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 58
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Ala Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 59
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 59
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ala Ser Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 60
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 60
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Gln Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
Claims (22)
1.一种抗人B7-H3抗体或其片段,其特征在于,包括:
重链可变区,所述重链可变区(VH)包括抗原决定区(CDRs)1、2和3,其中,VHCDR1包含与所选VH CDR1氨基酸序列具有至少75%同一性的氨基酸序列;VH CDR2包含与所选VH CDR2氨基酸序列具有至少75%同一性的氨基酸序列;VH CDR3与所选VHCDR3氨基酸序列具有至少75%同一性的氨基酸序列;
轻链可变区,所述轻链可变区(VL)包括CDRs 1、2和3,其中,VL CDR1包含与所选VLCDR1氨基酸序列具有至少75%同一性的氨基酸序列;VL CDR2包含与所选VLCDR2氨基酸序列具有至少75%同一性的氨基酸序列;VL CDR3与所选VL CDR3氨基酸序列具有至少75%同一性的氨基酸序列;
其中,所述所选VH CDRs 1、2和3的氨基酸序列以及所述所选VL CDRs 1、2和3的氨基酸序列选自下列之一:
(1)所述所选VH CDRs 1、2和3的氨基酸序列分别如SEQ ID NO:40、41和42所示,且所述所选VL CDRs 1、2和3的氨基酸序列如SEQ ID NO:43、44和45所示;
(2)所述所选VH CDRs 1、2和3的氨基酸序列分别如SEQ ID NO:46、47和48所示,且所述所选VL CDRs 1、2和3的氨基酸序列如SEQ ID NO:49、50和51所示;
(3)所述所选VH CDRs 1、2和3的氨基酸序列分别如SEQ ID NO:52、53和54所示,且所述所选VL CDRs 1、2和3的氨基酸序列如SEQ ID NO:55、56和57所示,
任选地,与包含SEQ ID NO:51所示的氨基酸序列的所选VL CDR3具有至少75%同一性的氨基酸序列为QQWSX1X2PLT,其中,X1为S或A,X2为N、A、S或Q。
2.如权利要求1所述抗人B7-H3抗体或其片段,其特征在于,所述VH包括与SEQ IDNO:1具有至少75%同一性氨基酸序列,且所述VL包括与SEQ ID NO:2具有至少75%同一性氨基酸序列,
任选地,所述VH包括与SEQ ID NO:3具有至少75%同一性氨基酸序列,且所述VL包括与SEQ ID NO:4具有至少75%同一性氨基酸序列,
任选地,所述VH包括与SEQ ID NO:5具有至少75%同一性氨基酸序列,且所述VL包括与SEQ ID NO:6具有至少75%同一性氨基酸序列。
3.如权利要求2所述抗人B7-H3抗体或其片段,其特征在于,所述VH包括SEQ IDNO:11或17所示的氨基酸序列,所述VL包括SEQ ID NO:12、13、14、15或16所示的氨基酸序列,
任选地,所述VH包括SEQ ID NO:18、21、22或23所示的氨基酸序列,所述VL包括SEQ IDNO:19、20、58、59或60所示的氨基酸序列,
任选地,所述VH包括SEQ ID NO:24、34、35、36或37所示的氨基酸序列,所述VL包括SEQID NO:25、26、27、28、29、30、31、32或33所示的氨基酸序列。
4.如权利要求1所述抗人B7-H3抗体或其片段,其特征在于,所述抗人B7-H3抗体或其片段能够特异性结合人B7-H3的胞外区,且与人B7-H3胞外区的亲和力常数(KD)小于5E-10。
5.一种制备抗人B7-H3的人源化抗体或其片段的方法,其特征在于,包括:在非人源B7-H3抗体或其片段的基础上,利用CDRs移植技术实现重链可变区的人源化和/或轻链可变区的人源化,以便获得权利要求1-4任一项所述抗人B7-H3抗体或其片段。
6.如权利要求5所述制备抗人B7-H3的人源化抗体或其片段的方法,其特征在于,所述利用CDRs移植技术实现重链可变区的人源化的步骤包括:
(1)利用非人源B7-H3抗体或其片段的重链可变区序列进行同源比对,选择相似的人源抗体重链模板;
(2)将所述非人源B7-H3抗体或其片段的的VH CDRs 1、2和3移植到人源抗体重链模板中;
(3)根据VH CDR3的序列选择J区序列,实现重链可变区的人源化,获得权利要求1-4任一项所述抗人B7-H3抗体或其片段。
7.如权利要求5所述制备抗人B7-H3的人源化抗体或其片段的方法,其特征在于,所述利用CDRs移植技术实现轻链可变区的人源化的步骤包括:
(1)利用非人源B7-H3抗体或其片段的轻链可变区序列进行同源比对,选择相似的人源抗体轻链模板;
(2)将所述非人源B7-H3抗体或其片段的VL CDRs 1-3移植到人源抗体轻链模板中;
(3)根据所述VL CDR3的序列选择JK区序列,实现轻链可变区的人源化,获得权利要求1-4任一项所述抗人B7-H3抗体或其片段。
8.如权利要求5-7中任一项所述制备抗人B7-H3的人源化抗体或其片段的方法,其特征在于,在所述CDRs移植后,还包括对人源化抗体进行亲和力成熟、CDR序列点突变改造和/或化学修饰。
9.一种融合分子,其特征在于,包括
(1)第一活性元件,所述第一活性元件为包括权利要求1-4中任一项所述抗人B7-H3抗体或其片段的第一靶向部分;
(2)一个或多个第二活性元件,所述第二活性元件包括效应子元件和/或第二靶向部分;
其中,所述第一活性元件与第二活性元件通过键或接头连接;所述一个或多个第二活性元件可以相同或不同。
10.一种多核苷酸,其特征在于,所述多核苷酸编码权利要求1-4中任一项所述抗人B7-H3抗体或其片段或权利要求19所述融合分子。
11.构建体,其特征在于,包含权利要求10所述的多核苷酸。
12.宿主细胞,其特征在于,包含权利要求10所述的多核苷酸或权利要求11所述的核酸构建体。
13.一种缀合物,其包括第一活性元件,所述第一活性元件为包括权利要求1-4中任一项所述抗人B7-H3抗体或其片段的第一靶向部分。
14.如权利要求13所述的缀合物,还包括至少一个第二活性元件,所述第一活性元件和第二活性元件共价连接。
15.如权利要求14所述的缀合物,所述第二活性元件包括一种或多种效应子部分。
16.如权利要求15所述的缀合物,其中所述效应子部分为小分子药物缀合物,所述小分子药物缀合物选自以下(1)~(3)组中一种或多种的效应分子或其衍生物:
(1)微管蛋白抑制剂类小分子化合物:美登素衍生物、一甲基澳瑞他汀E(Monomethylauristatin E)、一甲基澳瑞他汀F(Monomethylauristatin F)、一甲基海兔毒素10(MonomethylDolastatin 10)、Tubulysin类衍生物、念珠藻素(Cryptophycin)类衍生物和他托布林(Taltobulin);
(2)拓扑异构酶抑制剂类小分子化合物:阿霉素代谢产物PNU-159682及其衍生物、伊立替康代谢产物SN38衍生物和依喜替康;
(3)DNA结合剂类小分子化合物:PBD类衍生物和duocarmycin类衍生物。
17.一种组合物,其包含;
权利要求1-4中任一项所述抗人B7-H3抗体或其片段、权利要求9所述融合分子、权利要求10所述多核苷酸、权利要求11所述核酸构建体、权利要求12所述宿主细胞,或权利要求13-16中任一项所述缀合物;以及
可选的药学上可接受的辅料。
18.一种制备抗人B7-H3抗体或其片段的方法,包括:
(1)在合适的条件下,培养权利要求12所述的宿主细胞;
(2)分离回收抗人B7-H3单克隆抗体或其片段、抗人B7-H3嵌合抗体或其片段、或者人源化抗人B7-H3抗体或其片段。
19.权利要求1-4中任一项所述抗人B7-H3抗体或其片段、权利要求9所述融合分子、权利要求10所述多核苷酸、权利要求11所述核酸构建体、权利要求12所述宿主细胞,或权利要求13-16中任一项所述缀合物和权利要求17所述组合物在制备B7-H3过表达相关疾病诊断试剂中的用途。
20.权利要求1-4中任一项所述抗人B7-H3抗体或其片段、权利要求9所述融合分子、权利要求10所述多核苷酸、权利要求11所述核酸构建体、权利要求12所述宿主细胞,或权利要求13-16中任一项所述缀合物和权利要求17所述组合物在制备治疗B7-H3过表达相关疾病药物中的用途。
21.如权利要求19或20所述的用途,其特征在于,所述B7-H3过表达相关疾病为实体瘤类癌症。
22.如权利要求21所述的用途,其特征在于,所述实体瘤类癌症包括胃癌、结直肠癌、肝癌、胰腺癌、食管癌、非小细胞癌、***癌、卵巢癌、神经母细胞瘤、横纹肌肉瘤、骨肉瘤、尤文肉瘤、肾母细胞瘤和促***增生性小圆细胞瘤。
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