CN116554324A - 一种特异性识别4-1bb的抗体、其制备方法及其用途 - Google Patents
一种特异性识别4-1bb的抗体、其制备方法及其用途 Download PDFInfo
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Abstract
本发明公开了一种靶向4‑1BB的抗体。所述抗体包含重链可变区和轻链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3,所述轻链可变区包含LCDR1、LCDR2和LCDR3,其序列信息详见序列表。本发明制备得到的抗体在亲和力方面有更好的表现、在体内抑制肿瘤生长的效果更好、毒副作用更小。
Description
技术领域
本发明属于抗体领域,具体涉及一种特异性识别4-1BB的抗体、其制备方法及其用途。
背景技术
4-1BB又称为“肿瘤坏死因子受体超家族成员9”(TNFRSF9)、CD137,是在TCR激活后诱导的T细胞共刺激受体(Nam等人,2005,Curr Cancer Drug Targets 5:357-363;Watts等人,2005,Annu Rev Immunol,23:23-68),属于肿瘤坏死因子超家族的跨膜共刺激受体蛋白。4-1BB的配体4-1BBL,是存在于包括B细胞、单核细胞、巨噬细胞和树突状细胞在内的抗原呈递细胞上的一种激动剂分子(Watts等人,2005,《免疫学年评》23:23-68)。4-1BB蛋白发现于1989年,是由4个CRD(半胱氨酸富集结构域)所组成的三聚体细胞膜表面受体,主要通过结合其配体4-1BBL激活T细胞,促进其增殖,参与T细胞介导的各种免疫应答过程。4-1BB蛋白表达于胸腺、淋巴结和脾脏等免疫器官以及CD8+T细胞、调节性T细胞和NK细胞表面,在其他免疫细胞中也有表达。4-1BB介导的胞内信号传递主要是通过TRAF1/2激活下游蛋白激酶,进而调控T细胞中激活增殖相关基因的转录表达。
已有多种模型证明使用各种激动剂(例如激动性抗体、重组4-1BBL蛋白质和4-1BB特异性适体)能够高效激活免疫系统来杀伤肿瘤细胞(Dharmadhikari等人,2016,Oncoimmunology,5(4):e1113367和其中的参考文献)。抗4-1BB抗体通过结合T细胞表面的4-1BB阻断或共存其配体4-1BB-L,激活并提高下游信号通路及其功能。激动性4-1BB抗体Urelumab(BMS-663513)是由百时美施贵宝公司(Bristol-Myers Squibb)开发的一种全人IgG4抗体,其临床评价显示在药效方面表现良好,但受试者的治疗相关不良事件,包括与抗体剂量相关的严重肝毒性(ALT升高)仍有报道(Segal等人,2016,Clin Cancer Res,23(8):1929-1936)。另一个4-1BB弱激动剂抗体Utomilumab(PF-05082566)是由辉瑞公司(Pfizer)开发的全人IgG2抗体,与抗PD-1抗体Pembrolizumab的联合使用尽管不会引起任何剂量限制性毒性,但药效方面显示与单独抗PD-1抗体疗法相当(Tolcher,A.等人,2017,ClinCancer Res,23(18):5349-5357)。
4-1BB抗体的激动作用受不同亚型Fc区的影响,目前在临床试验阶段的抗体是IgG2或IgG4型。与大多数TNFR家族成员一样,4-1BB信号依赖于交联进行激活(Wilson等人,2011,Cancer Cell)。在APC膜上表达的4-1BBL可以诱导受体的多重交联。抗体本身只交联两个4-1BB受体,为了诱导更强的信号,经由其它细胞上表达的FcγRs进一步交联对于4-1BB介导的信号激活极其关键。FcγR介导的交联是由单核细胞、巨噬细胞、DC和潜在的B细胞和其它细胞类型介导的。4-1BB激动性抗体的激动效果可能受到以下的影响:1)诱导交联,引发更强的免疫激活,和2)诱导ADCC,其可能导致对两种效应T细胞(主要是CD8+T细胞和Tregs)的杀伤;1)和2)的净效果将可能取决于表达4-1BB的细胞的分布、靶细胞与表达FcγR的免疫细胞结合的可能性、受体密度和亲和力,以及Teff对ADCC的敏感性与Treg对ADCC的敏感性的差异。IgG4形式的抗体在体内引发由巨噬细胞和单核细胞介导的FcγRI交联,但使NK介导的靶向CD8+T细胞的ADCC效应减到最小。4-1BB抗体的肝脏毒性也与其抗体本身的激动效果有关(Qi X等人,2019,Nat Commun 10:2141),有研究指出,强激动型4-1BB抗体在肝脏中非特性地激活了肝脏浸润的免疫细胞,造成不同程度的肝脏损伤;而弱激动型4-1BB抗体由于其特定的表位,只能在免疫细胞更加富集的肿瘤组织被诱导激活,表现出更低肝脏毒性。
4-1BB激动剂抗体已经显示在狼疮、胶原蛋白诱发的关节炎和实验性自身免疫性脑脊髓炎的动物模型中有良好的改善效果。但是对于患有包括癌症在内适于用4-1BB激动剂治疗的各种疾病的患者,仍需要展现足够安全且有效的新型激动性抗体。
发明内容
针对现有技术中缺乏亲和力更好、毒副作用更小以及在体内抑制肿瘤生长效果更好的抗4-1BB抗体药物,本领域亟需研发新的抗4-1BB抗体药物,以解决现有相关上市药物或临床在研药物在药效方面不能与肝脏毒副作用平衡的局限性。本发明利用全人源天然抗体噬菌体展示文库的方法,筛选到了更有效和安全的4-1BB激动剂。
本发明主要通过以下技术方案解决上述技术问题。
本发明的第一方面涉及一种特异性识别4-1BB的抗体或其抗原结合片段,其包含重链可变区和轻链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3,所述轻链可变区包含LCDR1、LCDR2和LCDR3,其中:
所述HCDR1的氨基酸序列如SEQ ID NO:37所示,所述HCDR2的氨基酸序列如SEQ IDNO:38所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示;或,
所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ IDNO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:40所示。
所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ IDNO:39所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示;或,
所述LCDR1的氨基酸序列如SEQ ID NO:12所示,所述LCDR2的氨基酸序列如SEQ IDNO:13所示,所述LCDR3的氨基酸序列如SEQ ID NO:14所示。
优选地:
SEQ ID NO:37的X1为T,其使抗体较天然野生型的具有更好的效果。
SEQ ID NO:38的X2为G、X3为T和/或X4为Y,这些为天然获得抗体的HCDR2所具有的氨基酸,在这些位点的氨基酸基础上可以进行突变、特别是单突变可以取得比天然抗体更好的效果。
SEQ ID NO:39的X5为G、X6为S、X7为N和/或X8为P,这些为天然获得抗体的LCDR2所具有的氨基酸,在这些位点的氨基酸基础上可以进行突变,特别是单突变、或者双突变例如X5为S且X8为R时可以取得比天然抗体更好的效果。
SEQ ID NO:40的X9为G、X10为G、X11为Y和/或X12为S,这些为天然获得抗体的HCDR3所具有的氨基酸,在这些位点的氨基酸基础上可以进行突变,特别是单突变、或者双突变例如X9为P且X10为V,或者X11为G且X12为Y可以取得比天然抗体更好的效果。
在本发明一更佳实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:1所示,所述HCDR2的氨基酸序列如SEQ ID NO:2所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示。
在本发明另一更佳实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:20所示,所述HCDR2的氨基酸序列如SEQ ID NO:21所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示。
在本发明另一更佳实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:20所示,所述HCDR2的氨基酸序列如SEQ ID NO:22所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示。
在本发明另一更佳实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:20所示,所述HCDR2的氨基酸序列如SEQ ID NO:23所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示。
在本发明另一更佳实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:11所示。
在本发明另一更佳实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:33所示。
在本发明另一更佳实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:34所示。
在本发明另一更佳实施方案中,所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:5所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示。
在本发明另一更佳实施方案中,所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:24所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示。
在本发明另一更佳实施方案中,所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:25所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示。
在本发明另一更佳实施方案中,所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:26所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示。
在本发明另一更佳实施方案中,所述LCDR1的氨基酸序列如SEQ ID NO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQ ID NO:14所示。
在本发明另一更佳实施方案中,所述LCDR1的氨基酸序列如SEQ ID NO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQ ID NO:14所示。
在本发明另一更佳实施方案中,所述LCDR1的氨基酸序列如SEQ ID NO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQ ID NO:14所示。
本发明中所述抗体或其抗原结合片段的框架区较佳地为人源或者鼠源框架区,更佳地为人源框架区。
所述重链可变区的氨基酸序列优选包含或由下列序列组成:SEQ ID NO:7、SEQ IDNO:15、SEQ ID NO:27、SEQ ID NO:29、SEQ ID NO:31、SEQ ID NO:35或者SEQ ID NO:36所示的氨基酸序列或其变体。
所述轻链可变区的氨基酸序列优选包含或由下列序列组成:SEQ ID NO:8、SEQ IDNO:16、SEQ ID NO:28、SEQ ID NO:30或者SEQ ID NO:32所示的氨基酸序列或其变体。
在以上所述优选实施方案中,所述变体至少保留突变前序列的功能,且所述变体与其所源自的序列相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的序列同一性。
在本发明一具体实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:1所示,所述HCDR2的氨基酸序列如SEQ ID NO:2所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示,所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:5所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示。
在本发明另一具体实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:20所示,所述HCDR2的氨基酸序列如SEQ ID NO:21所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示,所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:24所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示。
在本发明另一具体实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:20所示,所述HCDR2的氨基酸序列如SEQ ID NO:22所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示,所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:25所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示。
在本发明另一具体实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:20所示,所述HCDR2的氨基酸序列如SEQ ID NO:23所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示,所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:26所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示。
在本发明另一具体实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:11所示,所述LCDR1的氨基酸序列如SEQ ID NO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQ ID NO:14所示。
在本发明另一具体实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:33所示,所述LCDR1的氨基酸序列如SEQ ID NO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQ ID NO:14所示。
在本发明另一具体实施方案中,所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:34所示,所述LCDR1的氨基酸序列如SEQ ID NO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQ ID NO:14所示。
在本发明一最佳实施方案中,所述重链可变区包含或由下列序列组成:SEQ IDNO:7所示的氨基酸序列或其变体,且所述轻链可变区包含或由下列序列组成SEQ ID NO:8所示的氨基酸序列或其变体。
在本发明另一最佳实施方案中,所述重链可变区包含或由下列序列组成:SEQ IDNO:27所示的氨基酸序列或其变体,且所述轻链可变区包含或由下列序列组成:SEQ ID NO:28所示的氨基酸序列或其变体。
在本发明另一最佳实施方案中,所述重链可变区包含或由下列序列组成:SEQ IDNO:29所示的氨基酸序列或其变体,且所述轻链可变区包含或由下列序列组成:SEQ ID NO:30所示的氨基酸序列或其变体。
在本发明另一最佳实施方案中,所述重链可变区包含或由下列序列组成:SEQ IDNO:31所示的氨基酸序列或其变体,且所述轻链可变区包含或由下列序列组成:SEQ ID NO:32所示的氨基酸序列或其变体。
在本发明另一最佳实施方案中,所述重链可变区包含或由下列序列组成:SEQ IDNO:15所示的氨基酸序列或其变体,且所述轻链可变区包含或由下列序列组成:SEQ ID NO:16所示的氨基酸序列或其变体。
在本发明另一最佳实施方案中,所述重链可变区的氨基酸序列包含或由下列序列组成:SEQ ID NO:35所示或其变体,且所述轻链可变区包含或由下列序列组成:SEQ ID NO:16所示的氨基酸序列或其变体。
在本发明另一最佳实施方案中,所述重链可变区包含或由下列序列组成:SEQ IDNO:36所示的氨基酸序列或其变体,且所述轻链可变区包含或由下列序列组成:SEQ ID NO:16所示的氨基酸序列或其变体。
在以上所述最佳实施方案中,所述变体至少保留突变前序列的功能,且所述变体与其所源自的序列相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的序列同一性。
在本发明中,所述“变体”指的是抗体的CDR区域确定、仅重链/轻链可变区的框架区的序列可变。
在本发明中,“互补决定区”或“CDR区”或“CDR”是抗体可变结构域中在序列上高变并且形成在结构上确定的环(“超变环”)和/或含有抗原接触残基(“抗原接触点”)的区域。CDR主要负责与抗原表位结合,从N-端开始顺序编号依次包括CDR1、CDR2和CDR3。
在本发明中,CDR的氨基酸序列均是按照AbM定义规则所示出的(本发明的权利要求中也是按照AbM定义规则所示出的序列)。但是,本领域人员公知,在本领域中可以通过多种方法来定义抗体的CDR,例如基于抗体的三维结构和CDR环的拓扑学的Chothia(Chothia等人.(1989)Nature 342:877-883,Al-Lazikani等人,Standard conformations for thecanonical structures of immunoglobulins,Journal of Molecular Biology,273,927-948(1997)),基于抗体序列可变性的Kabat(Kabat等人,Sequences of Proteins ofImmunological Interest,第4版,U.S.Department of Health and Human Services,National Institutes of Health(1987)),AbM(University of Bath),Contact(University College London),国际ImMunoGeneTics database(IMGT)(万维网imgt.cines.fr/),以及基于利用大量晶体结构的近邻传播聚类(affinity propagationclustering)的North CDR定义。本领域技术人员应当理解的是,除非另有规定,否则术语给定抗体或其区(例如可变区)的“CDR”及“互补决定区”应理解为涵盖如通过本发明描述的上述已知方案中的任何一种界定的互补决定区。虽然本发明的权利要求中请求保护的范围是基于AbM定义规则所示出的序列,但是根据其他CDR的定义规则所对应的氨基酸序列也应当落在本发明的保护范围中。
抗体CDR定义方法
其中,Laa-Lbb可以指从抗体轻链的N端开始,第aa位至第bb位的氨基酸序列;Haa-Hbb可以指从抗体重链的N端开始,第aa位至第bb位的氨基酸序列。例如,L24-L34可以指从抗体轻链N端开始,按照Chothia编码规则的从第24位至第34位的氨基酸序列;H26-H32可以指从抗体重链N端开始,按照Chothia编码规则的从第26位至第32位的氨基酸序列。
因此,在涉及用本发明定义的具体CDR序列限定抗体时,所述抗体的范围还涵盖了这样的抗体,其可变区序列包含所述的具体CDR序列,但是由于应用了不同的方案(例如不同的指派系统规则或组合)而导致其所声称的CDR边界与本发明所定义的具体CDR边界不同。
本发明所述的抗体优选还包含抗体重链恒定区和抗体轻链恒定区;较佳地,所述重链恒定区源自人源抗体重链或其变体,如人IgG4 SP Fc的重链恒定区;所述轻链恒定区源自人源抗体的κ链或者λ链或其变体。
在本发明的优选实施方案中,所述重链恒定区的氨基酸序列如SEQ ID NO:17所示;所述κ链的氨基酸序列如SEQ ID NO:18所示;所述λ链的氨基酸序列如SEQ ID NO:19所示。
在本发明中,术语“抗体”指免疫球蛋白或其片段,其通过至少一个抗原结合位点特异性结合抗原表位。术语“抗体”包括多特异性抗体(例如双特异性抗体)、全人源抗体、非人抗体、人源化抗体、嵌合抗体、单域抗体以及抗原结合片段。抗体可以是合成的(例如通过化学偶联或生物偶联产生的)、酶促处理得到的或重组产生的。本文所提供的抗体包括任何免疫球蛋白类型(例如,IgG、IgM、IgD、IgE、IgA和IgY)、任何类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类(例如,IgG2a和IgG2b)。
本发明中所述抗体可为全长抗体、Fab、Fab’、F(ab’)2、或多特异性抗体,或由上述抗体制得的单克隆抗体。
本发明中,术语“全长抗体”可互换地用来指包含由二硫键相互连接的至少两条重链(HC)和两条轻链(LC)的糖蛋白。每条重链由重链可变区(本发明中缩写为VH)和重链恒定区组成。重链恒定区由3个结构域CH1、CH2和CH3组成。每条轻链由轻链可变区(本发明中缩写为VL)和轻链恒定区(本发明中缩写为CL)组成。轻链恒定区由一个结构域CL组成。哺乳动物重链分类为α、δ、ε、γ和μ。哺乳动物轻链分类为λ或κ。包含α、δ、ε、γ和μ重链的免疫球蛋白分类为免疫球蛋白(Ig)A、IgD、IgE、IgG和IgM。完全抗体形成“Y”形状。Y的茎由两条重链的第二和第三恒定区(并且对于IgE和IgM,第四恒定区)结合在一起组成,并且二硫键(链间)在铰链中形成。重链γ、α和δ具有由三个串联(成一行)Ig结构域构成的恒定区,和用于增加柔性的铰链区;重链μ和ε具有由四个免疫球蛋白结构域构成的恒定区。第二和第三恒定区分别称为“CH2结构域”和“CH3结构域”。Y的每个臂包括结合到单个轻链的可变和恒定区的单个重链的可变区和第一恒定区。轻链和重链的可变区负责抗原结合。本发明中,“Fab片段”由一条轻链和一条重链的CH1及可变区组成。Fab分子的重链不能与另一个重链分子形成二硫键。“Fc”区含有包含抗体的CH2和CH3结构域的两个重链片段。两个重链片段由两个或多个二硫键并通过CH3结构域的疏水作用保持在一起。“Fab’片段”含有一条轻链和包含VH结构域和CH1结构域以及CH1和CH2结构域之间区域的一条重链的部分,由此可在两个Fab’片段的两条重链之间形成链间二硫键以形成F(ab’)2分子。“F(ab’)2片段”含有两条轻链和两条包含CH1和CH2结构域之间的恒定区的部分的重链,由此在两条重链间形成链间二硫键。因此F(ab’)2片段由通过两条重链间的二硫键保持在一起的两个Fab’片段组成。术语“Fv”意指向抗体的单臂的VL和VH结构域组成的抗体片段,但缺少恒定区。
术语“多特异性抗体”按其最广义使用,涵盖具有多表位特异性的抗体。这些多特异性抗体包括但不限于:包含重链可变区(VH)和轻链可变区(VL)的抗体,其中该VH-VL单元具有多表位特异性;具有两个或多个VL和VH区的抗体,每个VH-VL单元与不同的靶点或同一个靶点的不同表位结合;具有两个或更多个单可变区的抗体,每个单可变区与不同的靶点或同一个靶点的不同的表位结合;全长抗体、抗体片段、双特异性抗体(diabodies)、和三抗体(triabodies)、共价或非共价连接在一起的抗体片段等。
本发明的抗体包括单克隆抗体。本发明所述的单克隆抗体或mAb或Ab,指由单一的克隆细胞株得到的抗体,所述的细胞株不限于真核的,原核的或噬菌体的克隆细胞株。
本发明的第二方面涉及一种分离的核酸,其编码如本发明第一方面所述的靶向4-1BB的抗体。
本发明的第三方面涉及一种重组表达载体,其包含如本发明第二方面所述的分离的核酸。优选地,所述重组表达载体为质粒、粘粒、噬菌体或病毒载体,所述病毒载体优选逆转录病毒载体、慢病毒载体、腺病毒载体或腺相关病毒载体。
本发明的第四方面涉及一种转化体,其在宿主细胞中包含本发明第三方面所述的重组表达载体;优选地,所述宿主细胞是原核的或真核的,更优选的选自酵母细胞、哺乳动物细胞(例如HEK293细胞或CHO细胞)或适用于制备抗体的其它细胞。一旦已经制备了用于表达的表达载体或DNA序列,则可以将表达载体转染或引入适宜的宿主细胞中。多种技术可以用来实现这个目的,例如,原生质体融合、磷酸钙沉淀、电穿孔、逆转录病毒的转导、病毒转染、基因枪、基于脂质的转染或其他常规技术。在原生质体融合的情况下,将细胞在培养基中培育并且筛选适宜的活性。用于培养所产生的转染细胞和用于回收产生的抗体分子的方法和条件是本领域技术人员已知的并且可以基于本说明书和现有技术已知的方法,根据使用的特定表达载体和哺乳动物宿主细胞变动或优化。另外,可以通过引入允许选择已转染的宿主细胞的一个或多个标记物,选出已经稳定将DNA掺入至其染色体中的细胞。标记物可以例如向营养缺陷型宿主提供原养型、杀生物抗性(例如,抗生素)或重金属(如铜)抗性等。可选择标记基因可以与待表达的DNA序列直接连接或通过共转化引入相同的细胞中。也可能需要额外元件以便最佳合成mRNA。这些元件可以包括剪接信号,以及转录启动子、增强子和终止信号。
本发明的第五方面涉及一种靶向4-1BB的抗体的制备方法,其包含培养如第四方面所述的转化体,从培养物中获得靶向4-1BB的抗体。
本发明的第六方面涉及一种药物组合物,其包含如第一方面所述的靶向4-1BB的抗体,以及药学上可接受的载体;
较佳地,所述药物组合物还含有由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的群组中的一种或多种。
在一些实施方案中,本发明的药物组合物或药物制剂包含合适的药学上可接受的载体例如药用辅料,如本领域中已知的药用载体、药用赋形剂,包括缓冲剂。如本发明所用,“药学上可接受的载体”或“药用载体”包括生理上相容的任何和全部溶剂、分散介质、等渗剂和吸收延迟剂等。适用于本发明的药用载体可以是无菌液体,如水和油,包括那些石油、动物、植物或合成来源的,如花生油、大豆油、矿物油、芝麻油等。当静脉内施用药物组合物时,水是优选的载体。还可以将盐水溶液和水性右旋糖以及甘油溶液用作液体载体,特别是用于可注射溶液。合适的赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石、氯化钠、干燥的脱脂乳、甘油、丙烯、二醇、水、乙醇等。对于赋形剂的使用及其用途,亦参见“Handbook of PharmaceuticalExcipients”,第五版,R.C.Rowe,P.J.Seskey和S.C.Owen,Pharmaceutical Press,London,Chicago。若期望的话,所述组合物还可以含有少量的润湿剂或乳化剂,或pH缓冲剂。这些组合物可以采用溶液、悬浮液、乳剂、片剂、丸剂、胶囊剂、粉末、持续释放配制剂等的形式。口服配制剂可以包含标准药用载体和/或赋形剂,如药用级甘露醇、乳糖、淀粉、硬脂酸镁、糖精。可以通过将具有所需纯度的本发明的抗体与一种或多种任选的药用辅料(Remington’s PharmaceuticalSciences,第16版,Osol,A.编(1980))混合来制备包含本发明所述的药物制剂或药物组合物,优选地以冻干制剂或水溶液的形式。本发明的药物组合物或制剂还可以包含超过一种活性成分,所述活性成分是被治疗的特定适应症所需的,优选具有不会不利地彼此影响的互补活性的那些活性成分。例如,理想的是还提供其它抗感染活性成分,例如其它抗体、抗感染活性剂、小分子药物或免疫调节剂等。所述活性成分以对于目的用途有效的量合适地组合存在。可制备持续释放制剂。持续释放制剂的合适实例包括含有本发明的抗体的固体疏水聚合物的半渗透基质,所述基质呈成形物品,例如薄膜或微囊形式。
本发明的第七方面涉及本发明第一方面所述的靶向4-1BB的抗体和/或第六方面所述的药物组合物在制备诊断、预防和/或治疗肿瘤的药物中的应用。可选地,所述肿瘤选自:结肠癌、胰腺癌、小细胞肺癌、非小细胞肺癌、肾细胞癌、头颈癌和甲状腺癌。
本发明的第八方面涉及试剂盒,其包括如第一方面所述的靶向4-1BB的抗体或如第六方面所述的药物组合物;
较佳地,所述试剂盒还包括(i)施用抗体或药物组合物的装置;和/或(ii)使用说明。
本发明的第九方面涉及一种套装药盒,其包含药盒A和药盒B,其中:
所述药盒A含有如第一方面所述的靶向4-1BB的抗体和/或如第六方面所述的药物组合物;
所述药盒B含有其他抗肿瘤抗体或者包含所述其他抗肿瘤抗体的药物组合物,和/或由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的群组中的一种或多种。
此外,本发明中所用的其它术语的解释具体如下。
如本领域已知,在本发明中可交换使用的“多核苷酸”或“核酸”是指任何长度的核苷酸链,并且包括DNA和RNA。核苷酸可以是脱氧核糖核苷酸、核糖核苷酸、修饰的核苷酸或碱基、和/或它们的类似物、或者能够通过DNA或RNA聚合酶掺入链的任何底物。
如下进行序列之间序列同一性的计算。为确定两个氨基酸序列或两个核酸序列的同一性百分数,将所述序列出于最佳比较目的比对(例如,可以为了最佳比对而在第一和第二氨基酸序列或核酸序列之一或二者中引入空位或可以为比较目的而抛弃非同源序列)。在一个优选实施方案中,为比较目的,所比对的参考序列的长度是至少30%、优选地至少40%、更优选地至少50%、60%和甚至更优选地至少70%、80%、90%、100%的参考序列长度。随后比较在对应氨基酸位置或核苷酸位置处的氨基酸残基或核苷酸。当第一序列中的位置由第二序列中对应位置处的相同氨基酸残基或核苷酸占据时,则所述分子在这个位置处是相同的。可以利用数学算法实现两个序列间的序列比较和同一性百分数的计算。在一个优选实施方案中,使用已经集成至GCG软件包的GAP程序中的Needlema和Wunsch((1970)J.Mol.Biol.48:444-453)算法(在http://www.gcg.com可获得),使用Blossum 62矩阵或PAM250矩阵和空位权重16、14、12、10、8、6或4和长度权重1、2、3、4、5或6,确定两个氨基酸序列之间的同一性百分数。在又一个优选的实施方案中,使用GCG软件包中的GAP程序(在http://www.gcg.com可获得),使用NWSgapdna.CMP矩阵和空位权重40、50、60、70或80和长度权重1、2、3、4、5或6,确定两个核苷酸序列之间的同一性百分数。特别优选的参数集合(和除非另外说明否则应当使用的一个参数集合)是采用空位罚分12、空位延伸罚分4和移码空位罚分5的Blossum 62评分矩阵。还可以使用PAM120加权余数表、空位长度罚分12、空位罚分4,利用已经并入ALIGN程序(2.0版)的E.Meyers和W.Miller算法,((1989)CABIOS,4:11-17)确定两个氨基酸序列或核苷酸序列之间的同一性百分数。额外地或备选地,可以进一步使用本发明所述的核酸序列和蛋白质序列作为“查询序列”以针对公共数据库执行检索,以例如鉴定其他家族成员序列或相关序列。
如本发明所用,“载体”表示构建体,其能够将一种或多种所关注的基因或序列递送入宿主细胞并且优选在宿主细胞中表达所述基因或序列。载体的实例包括但不限于病毒载体、裸DNA或RNA表达载体、质粒、粘粒或噬菌体载体、与阳离子凝聚剂相关的DNA或RNA表达载体、包囊化于脂质体中的DNA或RNA表达载体以及某些真核细胞,例如生产细胞。
在本发明中术语“宿主细胞”可包括已经引入外源性核酸的细胞,包括这些细胞的子代。宿主细胞包括“转化子”和“转化的细胞”,其包括原代转化细胞以及由此来源的子代,而不考虑传代次数。子代在核酸含量上与亲代细胞可能不完全相同,但可能含有突变。本发明包括与在初始转化的细胞中筛选或选择的细胞具有相同功能或生物学活性的突变子代。
在一些实施方案中,氨基酸突变可以是氨基酸的添加、缺失或取代,例如,氨基酸突变是保守氨基酸取代。在一些实施方案中,氨基酸突变不发生在CDR区中。
在本发明的一些实施方案中,本发明所述的氨基酸突变包括氨基酸的取代、插入或缺失。在一些实施方案中,本发明所述的氨基酸突变为氨基酸取代,优选地保守取代。保守取代是指一个氨基酸经相同类别内的另一氨基酸取代,例如一个酸性氨基酸经另一酸性氨基酸取代,一个碱性氨基酸经另一碱性氨基酸取代,或一个中性氨基酸经另一中性氨基酸取代。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
相比于对照抗体Ag10131,本发明的抗体在亲和力方面有更好的表现,除此之外,其在体内抑制肿瘤生长方面的效果也优于对照抗体Ag10131。相比于对照抗体Urelumab,本发明的抗体毒副作用更小。
附图说明
图1显示了候选抗体与抗原蛋白hu4-1BB-His的结合活性。
图2显示了候选抗体与人4-1BB过表达细胞hu4-1BB-CHO的结合活性。
图3A-3B显示了候选抗体与抗原蛋白Mus4-1BB-hFc的结合活性;其中图3A显示了抗体99-2-17与Mus4-1BB-hFc的结合活性,图3B显示了抗体99-2-35与Mus4-1BB-hFc的结合活性。
图4显示了候选抗体阻断4-1BB和受体4-1BBL结合的阻断活性。
图5显示了候选抗体介导的T细胞激活活性。
图6A-6D显示了候选抗体的抗肿瘤功效;其中6A为荷瘤小鼠实验周期内的肿瘤体积统计结果,图6B为荷瘤小鼠实验周期内的小鼠体重统计结果,图6C为实验终止后每组肿瘤实物照片:第1行为阴性对照PBS处理组、第2行为阳性对照Ag10131给药组、第3行为99-2-17给药组、第4行为99-2-35给药组,图6D为实验终止后每组小鼠肿瘤重量统计结果。
图7A-7B显示了母本分子和亲和力成熟改造后分子与抗原蛋白hu4-1BB-His的结合活性;其中图7A为抗体99-2-17以及亲和力成熟抗体17-5、17-10、17-11与抗原蛋白hu4-1BB-His的结合活性,图7B为抗体99-2-35以及亲和力成熟抗体35-5、35-8与抗原蛋白hu4-1BB-His的结合活性。
图8A-8B显示了在没有形成Crosslinking效应时,亲和力成熟抗体和母本抗体激活4-1BB信号通路的活性;其中图8A为抗体99-2-17、17-5、17-10和17-11在没有交联效应的情况下激活人4-1BB信号通路的活性,图8B为抗体99-2-35、35-5和35-8在没有交联效应的情况下激活人4-1BB信号通路的活性。
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:原材料制备和鉴定
1.1 4-1BB抗原蛋白的制备
在人4-1BB的胞外结构域(Uniprot:Q07011的24-186位)基因片段的C端融合人IgG1 Fc片段或His标签,然后通过同源重组的方法构建至真核表达载体pcDNA3.4(Invitrogen)载体。将构建好的各抗原蛋白的表达载体分别转化到大肠杆菌SS320中,37℃过夜培养,利用无毒质粒提取试剂盒(OMEGA,D6950-01)进行质粒提取,得到无内毒素的各质粒以供真核表达使用。
将所得的质粒采用ExpiCHO瞬转表达系统(Thermo Fisher,A29133)进行表达。在转染5-7天后,将细胞表达上清于15000g高速离心10min,所得Fc标签蛋白表达上清用MabSelectSuRe LX(GE,17547403)进行亲和纯化,然后用100mM乙酸钠(pH3.0)洗脱目的蛋白,接着用1M Tris-HCl中和;所得His标签蛋白表达上清用Ni Smart Beads 6FF(常州天地人和生物科技有限公司,SA036050)进行亲和纯化,然后用梯度浓度的咪唑缓冲液洗脱目的蛋白。洗脱下来的各蛋白分别通过超滤浓缩管(Millipore,UFC901096)置换至PBS缓冲液中。最后获得抗原蛋白hu4-1BB-hFc和hu4-1BB-His。
基于同样的方法制得鼠源4-1BB(Uniprot:P20334的24-187位)的Fc标签抗原蛋白(Mus4-1BB-hFc)。
1.2阳性对照抗体的制备
本申请使用的阳性对照抗体为抗4-1BB抗体Ag10058、Ag10131和Urelumab,其中Ag10058(重链和轻链的SEQ ID NO分别为41和42)和Ag10131(重链和轻链的SEQ ID NO分别为43和44)根据专利US20190055314所披露的序列合成,Urelumab(重链和轻链的SEQ ID NO分别为45和46)根据专利US7288638B2所披露的序列合成。通过分子克隆方法分别构建包含对照抗体重链基因的质粒和轻链基因的质粒。其余步骤参考实施例1.1。
1.3 4-1BB-Fc和4-1BB-His抗原蛋白的生物素化
使用EZ-LinkTMSulfo-NHS-LC-生物素化试剂盒(EZ-LinkTMSulfo-NHS-LC-Biotinylation Kit,Thermo Fisher,货号:21435),将计算量的EZ-Link Sulfo-NHS-LC-生物素标记到至hu4-1BB-hFc抗原蛋白上。通过生物素定量试剂盒(Thermo Fisher,28005)测量生物素标记的hu4-1BB-hFc抗原蛋白(文中也称为生物素化的hu4-1BB-hFc)的数量。
通过针对Ag10058和Ag10131的ELISA测定法验证了生物素化的hu4-1BB-hFc的免疫原性。与hu4-1BB-hFc对Ag10058和Ag10131的结合相比较,生物素化的hu4-1BB-hFc显示出与这两种抗4-1BB抗体的相似结合。
采用类似的方法制备生物素化的hu4-1BB-His。
1.4 hu4-1BB-CHO细胞株制备
将人4-1BB(Uniprot编号Q07011)的DNA序列构建至pLVX-puro质粒(Clontech,Cat#632164)上。然后,将所得到的质粒通过电转化至CHO-K细胞(Thermo Fisher)中。通过2μg/mL的嘌呤霉素加压筛选,长出的单细胞克隆使用常规FACS方法检测。
1.5 Jurkat NF-κB荧光素酶报告基因稳转细胞株制备
首先将载体pGL4.32[Luc2p/NF-κB-RE/Hygro]质粒(Promega,货号E8491)通过电转仪(Invitrogen,NeonTM Transfection System,MP922947)电转化至Jurkat细胞(TIB-152TM)中。电转化后,将所得到的细胞分别转移至含有体积百分比为10%FBS(Gibco,15140-141)且不含抗生素的RPMI 1640培养基(Hyclone,SH30243.01)中,然后将细胞接种入6孔板细胞培养皿中培养48小时,接着以平均1500个/孔的密度将细胞分装至96孔细胞培养板中,加入终浓度为500μg/mL的潮霉素B(源培,S160J7)进行筛选,2-3周左右观察细胞株克隆生长情况,并挑取形成克隆的细胞株转移至24孔板中,待细胞培养扩大后,取部分克隆转移至96孔白底板中(Corning,3610),进行佛波酯(使用浓度10ng/mL)和离子霉素(使用浓度1nM)刺激,37℃、5%CO2培养箱中培养6h后加入:Bright-Lite底物(Vazyme,DD1204-03),在酶标仪(Molecular Devices:Spectramax i3x)读取信号值后评价不同克隆NF-κB的表达水平从而获得高表达NF-κB基因的Jurkat细胞系。对于NF-κB表达水平较高的Jurkat NF-κB荧光素酶报告基因稳转细胞克隆进行冻存备用。
1.6 Jurkat 4-1BB/NF-κB荧光素酶报告基因细胞株构建
将人4-1BB(Uniprot编号Q07011)的DNA序列构建至pLVX-Puro表达载体(Clontech,632164)。通过化转的方法导入大肠杆菌。挑取大肠杆菌单克隆后测序得到正确的质粒克隆,进行质粒抽提并再次测序确认。使用Gibco的RPMI 1640无血清培养基(货号:11875085)培养实施例1.5制备的Jurkat NF-κB细胞,电转前一天,将细胞传代至2×105个/mL,次日使用Invitrogen的电转试剂盒(货号:MPK10096)和电转仪(货号:MP922947)将构建好的质粒转入Jurkat NF-κB荧光素酶报告基因稳转细胞株细胞中。将电转后的细胞移至RPMI 1640培养基中,放置于37℃细胞培养箱中培养48h。将电转后的Jurkat细胞按1000个/孔铺到96孔板中,加入终浓度2μg/mL的嘌呤霉素,放置于37℃二氧化碳培养箱中培养,14天后补充加入2μg/mL的嘌呤霉素的RPMI 1640培养基。克隆挑选、细胞扩培和FACS鉴定:挑取96孔板中长出的单细胞克隆,转移至24孔培养板中继续扩大培养,之后通过FACS鉴定稳转成功的细胞株。
实施例2:人源噬菌体展示重组抗体文库的构建及筛选
在本实施例中,人源噬菌体展示重组抗体文库的构建及筛选方法参考专利CN112250763B实施例2。
最终得到对4-1BB抗原具有亲和活性的候选分子。以克隆号对候选抗体进行命名,候选抗体的CDR区氨基酸序列见表1,采用AbM定义CDR的方式,确定互补决定区序列。
表1候选抗体CDR区域的氨基酸序列
实施例3:候选抗体的构建、表达和纯化
3.1质粒构建
将筛选获得的单克隆99-2-17和99-2-35的Fab序列中的VH与人IgG4 SP Fc的重链恒定区(SEQ ID NO:17)的编码序列连接构建获得抗体的重链编码序列。根据筛选出的单克隆99-2-17和99-2-35所带的轻链类型,确定构建全长轻链的类型,99-2-17的Fab序列中的VL与人轻链恒定区(CL)的λ型(SEQ ID NO:18)编码序列连接构建,99-2-35的Fab序列中的VL与人轻链恒定区(CL)的κ型(SEQ ID NO:19)编码序列连接构建,分别获得抗体的轻链编码序列。将获得的编码抗体重链和抗体轻链的核苷酸序列分别构建至真核表达载体质粒pcDNA3.4(Invitrogen)上,将构建好的载体转化到大肠杆菌SS320中,37℃培养,利用无内毒素质粒提取试剂盒(OMEGA,D6950-01)进行质粒提取,得到无内毒素的抗体质粒以供真核表达使用。
3.2抗体的表达和纯化
候选抗体通过ExpiCHO瞬转表达系统(Thermo Fisher,A29133)表达,具体方法如下:转染当天,确认细胞密度为7×106至1×107个/mL左右,细胞存活率>98%,此时用37℃预温的新鲜ExpiCHO表达培养基将细胞调整到终浓度为6×106个/mL。用4℃预冷的OptiPROTMSFM稀释目的质粒(向1mL所述培养基中加入1μg质粒),同时用OptiPROTMSFM稀释ExpiFectamineTMCHO,再将两者等体积混合并轻轻吹打混匀制备成ExpiFectamineTMCHO/质粒DNA混合液,室温孵育1-5min,缓慢加入到准备好的细胞悬液中并同时轻轻摇晃,最后置于细胞培养摇床中,在37℃、8%CO2条件下培养。
在转染后18-22h,向培养液中添加ExpiCHOTMEnhancer和ExpiCHOTMFeed,摇瓶放置于32℃摇床和5%CO2条件下继续培养。在转染后的第5天,添加相同体积的ExpiCHOTMFeed,缓慢加入的同时轻轻混匀细胞混悬液。在转染7天后,将表达有目的蛋白的细胞培养上清于15000g高速离心10min,所得上清用MabSelect SuRe LX(GE,17547403)进行亲和纯化,然后用100mM乙酸钠(pH3.0)洗脱目的蛋白,接着用1M Tris-HCl中和,最后通过超滤浓缩管(Millipore,UFC901096)将所得蛋白换液至PBS缓冲液中。
实施例4:候选抗体的抗原结合活性鉴定
在本实施例中,基于ELISA方法检测了候选抗体与人4-1BB抗原蛋白hu4-1BB-His的亲和效果,还基于FACS方法检测了候选抗体与人4-1BB过表达细胞hu4-1BB-CHO的结合能力。
4.1基于ELISA检测候选抗体对抗原蛋白hu4-1BB-His的结合能力
在96孔ELISA板上包被hu4-1BB-His(2μg/mL,30μL/孔),4℃过夜。随后使用含5%牛奶的PBS缓冲液封闭2小时,PBST清洗ELISA板3次后加入梯度稀释的候选抗体和对照抗体Ag10131,37℃孵育1小时后,加入二抗Anti-human-IgG-Fc-HRP(abcam,ab97225),孵育1小时后,PBST洗板3次,加入显色液TMB(SurModics,TMBS-1000-01)显色,根据显色情况加入2MHCl终止反应,通过酶标仪(Molecular Devices,SpecterMax 190)在OD450下读板。
试验结果见图1。结果表明抗体99-2-17和99-2-35的EC50值分别为0.4107μg/mL和0.3505μg/mL,劣于对照抗体Ag10131。
4.2.基于FACS检测候选抗体对hu4-1BB-CHO的结合能力
将hu4-1BB-CHO细胞以1.0×105个/孔接种至96孔板。将100μL稀释的抗4-1BB候选抗体和阳性对照抗体Ag10131分别添加到96孔板中。在4℃孵育30分钟后,洗涤细胞,并添加FITC标记的抗人IgGFcγ(AffiniPure F(ab')2Fragment Goat Anti-Human IgG,Fcγfragment specific,Jackson Immunoresearch,货号:109-006-098)二抗,在4℃孵育30分钟。然后洗涤细胞并通过流式细胞术进行测试。
测试结果见图2,结果显示,99-2-17和99-2-35抗体分子与阳性对照抗体Ag10131均与hu4-1BB-CHO细胞有一定的结合能力,其中99-2-17和99-2-35抗体分子的亲和力优于阳性对照抗体Ag10131。
实施例5:候选抗体种属交叉活性鉴定
本实施例中的种属交叉活性检测是采用实施例1.1制备的鼠4-1BB抗原蛋白Mus4-1BB-hFc进行鉴定的,检测候选抗体结合鼠4-1BB的步骤为:在ELISA板上包被Mus4-1BB-hFc(2μg/mL,30μL/孔),4℃过夜。随后使用含5%牛奶的PBS缓冲液封闭2小时,PBST清洗ELISA板3次后加入梯度稀释的候选抗体和阳性对照抗体Ag10131,37℃孵育1小时后,加入二抗Anti-human-kappa+lambda-HRP(Millipore,AP502P+AP506P),孵育1小时后,PBST洗板3次,加入显色液TMB,根据显色情况加入2M HCl终止反应,通过酶标仪在后OD450下读板。
试验结果见图3A-3B,99-2-17和99-2-35抗体分子均与抗原蛋白Mus4-1BB-hFc结合,显示出了良好的鼠交叉活性。
实施例6:候选抗体的阻断活性鉴定
将hu4-1BB-CHO细胞以1.0×105个/孔接种至96孔板,并将100μL稀释的候选抗体、阳性对照抗体Ag10058或同种型对照(纯化的人IgG4同种型对照抗体(Biolegend,货号403502))添加到96孔板中。在4℃孵育30分钟后,洗涤细胞。将4-1BBL(ACRO Biosystems,货号41L-H5265)按照实施例1所述方式进行生物素化(本文中也称为:4-1BBL-生物素),将4-1BBL-生物素稀释至200ng/mL,并将100μL稀释的4-1BBL-生物素添加至96孔板。在4℃下孵育30分钟后,将细胞洗涤,然后添加100μL PE标记的链霉亲和素(eBioscience,货号12-4317-87),4℃下再孵育30分钟。然后洗涤细胞并通过流式细胞术进行测试。
结果如图4所示,结果显示99-2-17和99-2-35抗体分子在浓度为0.01-20μg/mL时显示出对4-1BB与4-1BBL结合的阻断效果。
实施例7:候选抗体介导的T细胞激活测定
T细胞经过抗4-1BB抗体激活后会大量分泌γ-干扰素(下文中也称“IFN-γ”),在本实施例中通过测试分选的原代T细胞分泌的IFN-γ细胞因子的表达量等来评价候选抗体介导的T细胞激活活性。
使用美天旎分选试剂盒(Miltenyibiotec,130-050-101)体外分选CD3阳性T细胞,在补充有10%FBS的RPMI1640培养基中以1×107个/mL的密度制备细胞。96孔细胞培养板用50μL抗CD3抗体(2μg/mL)单独包被或与50μL待测抗体(99-2-17、99-2-35和Ag10058)(20μg/mL、6μg/mL、2μg/mL、0.7μg/mL、0.2μg/mL和0.08μg/mL)在1×PBS中于4℃混合后过夜,混合之前按同浓度1:1将交联剂(Jackson,109-006-098)与待测抗体预孵育30min。将200μL细胞接种到每个测定孔中并在37℃、5%CO2培养箱中温育4天。在显微镜下观察细胞的生长状态和增殖情况。孵育96小时后,将100μL上清液转移到新的96孔板中进行IFN-γ检测。
结果如图5所示,与对照抗体Ag10058相比,99-2-17和99-2-35抗体分子均以剂量依赖性方式诱导CD3+T细胞中IFN-γ的分泌,进一步说明了候选抗体对T细胞的激活活性。
实施例8:抗4-1BB抗体的体内药效试验
本实施例中,验证了候选抗体和阳性对照抗体在动物体内的抑瘤效果,所使用的肿瘤为小鼠结肠腺癌细胞CT-26。。
6-7周龄雌性Balb/c(维通利华)小鼠(16-18g)饲养在恒温恒湿的独立通风盒内,饲养室温度21-24℃,湿度30-53%。将1×106个CT-26细胞对Balb/c小鼠进行左侧腋窝皮下注射(第0天),待小鼠皮下荷瘤体积达到100-200mm3左右时(第7天),剔除肿瘤体积差异较大的小鼠样本,然后依据肿瘤体积进行随机分组(每组8只小鼠):分别是PBS处理组、99-2-17给药组、99-2-35给药组、Ag10131给药组。以Ag10131 3mg/kg作为标准,其它所有药物均采用等摩尔剂量进行给药,即99-2-17和99-2-35抗体各自3mg/kg。每个星期两次给药,以腹膜内注射(i.p.)的方式给药。随时观察和记录肿瘤长(mm)和宽(mm),计算其肿瘤体积(V),计算方式为:V=(长×宽2)/2,抑瘤率TGI(%)=(1-给药组肿瘤平均体积/PBS处理组肿瘤平均体积)×100%。
抗体抑瘤的结果如图6A-6D所示,结果显示在等摩尔剂量下,抗体99-2-17和99-2-35以及对照抗体Ag10131都表现出一定的激活T细胞抑制肿瘤的效果。并且抗体99-2-17和99-2-35的抑瘤效果与对照抗体相当。
实施例9:抗体亲和力成熟
本实施例中,对抗体99-2-17和99-2-35进行亲和力成熟改造,用于提高抗体亲和力和其他生物学活性。亲和力成熟改造是基于M13噬菌体展示技术,采用codon-based引物(引物合成过程中,单个密码子由NNK组成)引入CDR区突变,构建4个噬菌体展示文库:文库1和文库2为单点组合突变,文库1为CDRL1+CDRL3+CDRH3组合突变,文库2为CDRL2+CDRH1+CDRH2组合突变;文库3和文库4为双点饱和突变,文库3为CDRL3的双点饱和突变,文库4为CDRH3的双点饱和突变。
具体的建库方法:首先合成包含点突变的引物(金唯智生物科技有限公司);其次分别以待改造的抗体(也称母本抗体)99-2-17和99-2-35为PCR扩增模板,扩增CDR区包含设计突变的序列,通过桥连PCR的方法,将包含不同CDR突变的片段进行组合,然后通过双酶切(HindⅢ和NotⅠ)和双粘端连接将点突变抗体连接到噬菌体展示载体中,最后通过电转将带有突变位点的抗体序列转入大肠杆菌SS320中。库容计算、噬菌体文库制备和文库筛选操作过程详见实施例2。
通过亲和力成熟改造,获得了候选抗体17-5、17-10、17-11、35-8、35-5。其中17-5、17-10、17-11为抗体99-2-17亲和力成熟改造后得到,35-8、35-5为抗体99-2-35亲和力成熟改造后得到。采用AbM定义CDR的方式,确定了候选抗体17-5、17-10、17-11、35-8、35-5的互补决定区序列,所述CDR的氨基酸序列如表2所示。
表2亲和力成熟改造后抗体的CDR序列
具体地,SEQ ID NO:20相比SEQ ID NO:1具有H10T突变;
SEQ ID NO:21相比SEQ ID NO:2具有Y10R突变;
SEQ ID NO:22相比SEQ ID NO:2具有T9H突变;
SEQ ID NO:23相比SEQ ID NO:2具有G6R突变;
SEQ ID NO:24相比SEQ ID NO:5具有N4V突变;
SEQ ID NO:25相比SEQ ID NO:5具有S3K突变;
SEQ ID NO:26相比SEQ ID NO:5具有G1S和P6R突变;
SEQ ID NO:27相比SEQ ID NO:7具有H35T和Y59R突变;
SEQ ID NO:28相比SEQ ID NO:8具有N55V突变;
SEQ ID NO:29相比SEQ ID NO:7具有H35T和T58H突变;
SEQ ID NO:30相比SEQ ID NO:8具有S54K突变;
SEQ ID NO:31相比SEQ ID NO:7具有H35T和G55R突变;
SEQ ID NO:32相比SEQ ID NO:8具有G52S和P57R突变;
SEQ ID NO:33相比SEQ ID NO:11具有Y6G和S7Y突变;
SEQ ID NO:34相比SEQ ID NO:11具有G4P和G5V突变;
SEQ ID NO:35相比SEQ ID NO:15具有Y104G和S105Y突变;
SEQ ID NO:36相比SEQ ID NO:15具有G102P和G103V突变。
本发明具体涉及到的序列如表3所示。
表3
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实施例10:亲和力成熟后抗体的抗原结合活性鉴定
使用抗原蛋白hu4-1BB-His包被ELISA板,2μg/mL,30μL每孔,4℃孵育过夜。使用PBST洗板3次后进一步使用含5%脱脂奶粉的PBS缓冲液室温封闭2小时,再使用PBST洗板3次后加入稀释后的待测抗体到ELISA板上,30μL每孔,室温孵育60min,使用PBST洗板3次后加入Anti-human-IgG-Fc-HRP,然后室温孵育60min,PBST洗板3次后加入TMB显色,根据显色情况加入2M硫酸终止反应后使用酶标仪OD450读板。
结果见图7A-7B,结果显示改造后的抗体亲和活性均优于母本抗体,且与阳性对照抗体Ag10131相当。
实施例11:荧光素酶报告基因试验
为了测试亲和力成熟改造后分子在无交联剂的情况下是否具有激活4-1BB信号通路功能,采用实施例1.6制备的Jurkat 4-1BB/NF-κB荧光素酶报告基因细胞株作为材料,检测候选抗体结合4-1BB从而激活下游NF-κB荧光素酶报告基因表达的能力。具体实施方式如下:
使用RPMI 1640培养基梯度稀释候选分子、对照抗体Urelumab(首孔10μg/mL,3倍梯度稀释,8个浓度点),将稀释好的候选抗体及对照抗体每孔50μL加入到96孔板中;将Jurkat 4-1BB/NF-κB荧光素酶报告基因细胞株复苏,将传代2-4次且生长状态良好的细胞用于实验,将细胞用RPMI 1640培养基洗涤重悬,计数后将细胞密度调整为2×106个/mL,以每孔50μL加至有抗体的96孔细胞培养板中,置于37℃细胞培养箱中孵育6h。培养结束后,每孔加入30μL荧光素酶底物Bright-Lite(Vazyme,DD1204-03),震荡5min后检测96孔板荧光值。
如图8A-8B所示,在无交联剂的情况下,Urelumab显示出比较强的激活4-1BB下游NF-κB荧光素酶报告基因信号活性,而亲和力成熟改造后抗体除17-5、17-10和17-11有较弱的激活能力外,其他抗体如35-8、35-5均无激活能力,结合实施例7中激活T细胞的效果,能够预期本申请制得的抗体在弱激动4-1BB分子的同时,具有比Urelumab相比显著更小的毒副作用。
SEQUENCE LISTING
<110> 三优生物医药(上海)有限公司
<120> 一种特异性识别4-1BB的抗体、其制备方法及其用途
<130> P21019469C
<160> 46
<170> PatentIn version 3.5
<210> 1
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17 HCDR1
<400> 1
Gly Phe Thr Phe Ser Ser Tyr Ala Met His
1 5 10
<210> 2
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17 HCDR2
<400> 2
Ala Ile Ser Ser Asn Gly Gly Ser Thr Tyr
1 5 10
<210> 3
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17、17-5、17-10、17-11 HCDR3
<400> 3
Gly Ser Gly Trp Ser Pro Ile Asp Ala Phe Asp Ile
1 5 10
<210> 4
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17、17-5、17-10、17-11 LCDR1
<400> 4
Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His
1 5 10
<210> 5
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17 LCDR2
<400> 5
Gly Asn Ser Asn Arg Pro Ser
1 5
<210> 6
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17、17-15、17-10、17-11 LCDR3
<400> 6
Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser Gly Ala Val
1 5 10
<210> 7
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17 VH
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ser Ala Ile Ser Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Lys Gly Ser Gly Trp Ser Pro Ile Asp Ala Phe Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 8
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17 VL
<400> 8
Gln Ser Ala Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly Ser Gly Ala Val Phe Gly Gly Gly Thr Gln Leu Thr Val
100 105 110
Leu
<210> 9
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-35、35-5、35-8 HCDR1
<400> 9
Gly Phe Thr Phe Ser Ser Tyr Glu Met Asn
1 5 10
<210> 10
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-35、35-5、35-8 HCDR2
<400> 10
Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
1 5 10
<210> 11
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-35 HCDR3
<400> 11
Asp Phe Asn Gly Gly Tyr Ser Tyr Tyr Pro Ile Ala Phe Asp Ile
1 5 10 15
<210> 12
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-35、35-5、35-8 LCDR1
<400> 12
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 13
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-35、35-5、35-8 LCDR2
<400> 13
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 14
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-35、35-5、35-8 LCDR3
<400> 14
Gln Gln Arg Ser Asn Trp Pro Pro Met Tyr Thr
1 5 10
<210> 15
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-35 VH
<400> 15
Glu Val Gln Leu Leu 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 Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr 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 Asp Phe Asn Gly Gly Tyr Ser Tyr Tyr Pro Ile Ala Phe Asp
100 105 110
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 16
<211> 109
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-35、35-5、35-8 VL
<400> 16
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Met Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 17
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4SP 重链恒定区
<400> 17
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 18
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> CL lambda
<400> 18
Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210> 19
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> CL kappa
<400> 19
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> 20
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-5、17-10、17-11 HCDR1
<400> 20
Gly Phe Thr Phe Ser Ser Tyr Ala Met Thr
1 5 10
<210> 21
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-5 HCDR2
<400> 21
Ala Ile Ser Ser Asn Gly Gly Ser Thr Arg
1 5 10
<210> 22
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-10 HCDR2
<400> 22
Ala Ile Ser Ser Asn Gly Gly Ser His Tyr
1 5 10
<210> 23
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-11 HCDR2
<400> 23
Ala Ile Ser Ser Asn Arg Gly Ser Thr Tyr
1 5 10
<210> 24
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-5 LCDR2
<400> 24
Gly Asn Ser Val Arg Pro Ser
1 5
<210> 25
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-10 LCDR2
<400> 25
Gly Asn Lys Asn Arg Pro Ser
1 5
<210> 26
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-11 LCDR2
<400> 26
Ser Asn Ser Asn Arg Arg Ser
1 5
<210> 27
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-5 VH
<400> 27
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ser Ala Ile Ser Ser Asn Gly Gly Ser Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Lys Gly Ser Gly Trp Ser Pro Ile Asp Ala Phe Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 28
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-5 VL
<400> 28
Gln Ser Ala Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Val Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly Ser Gly Ala Val Phe Gly Gly Gly Thr Gln Leu Thr Val
100 105 110
Leu
<210> 29
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-10 VH
<400> 29
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ser Ala Ile Ser Ser Asn Gly Gly Ser His Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Lys Gly Ser Gly Trp Ser Pro Ile Asp Ala Phe Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 30
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-10 VL
<400> 30
Gln Ser Ala Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Lys Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly Ser Gly Ala Val Phe Gly Gly Gly Thr Gln Leu Thr Val
100 105 110
Leu
<210> 31
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-11 VH
<400> 31
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ser Ala Ile Ser Ser Asn Arg Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Lys Gly Ser Gly Trp Ser Pro Ile Asp Ala Phe Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 32
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> 17-11 VL
<400> 32
Gln Ser Ala Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Ser Asn Ser Asn Arg Arg Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly Ser Gly Ala Val Phe Gly Gly Gly Thr Gln Leu Thr Val
100 105 110
Leu
<210> 33
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 35-5 HCDR3
<400> 33
Asp Phe Asn Gly Gly Gly Tyr Tyr Tyr Pro Ile Ala Phe Asp Ile
1 5 10 15
<210> 34
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 35-8 HCDR3
<400> 34
Asp Phe Asn Pro Val Tyr Ser Tyr Tyr Pro Ile Ala Phe Asp Ile
1 5 10 15
<210> 35
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> 35-5 VH
<400> 35
Glu Val Gln Leu Leu 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 Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr 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 Asp Phe Asn Gly Gly Gly Tyr Tyr Tyr Pro Ile Ala Phe Asp
100 105 110
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 36
<211> 124
<212> PRT
<213> Artificial Sequence
<220>
<223> 35-8 VH
<400> 36
Glu Val Gln Leu Leu 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 Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr 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 Asp Phe Asn Pro Val Tyr Ser Tyr Tyr Pro Ile Ala Phe Asp
100 105 110
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 37
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17、17-5、17-10、17-11 HCDR1
<220>
<221> VARIANT
<222> (10)..(10)
<223> Xaa为X1,X1为H或T
<400> 37
Gly Phe Thr Phe Ser Ser Tyr Ala Met Xaa
1 5 10
<210> 38
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17、17-5、17-10、17-11 HCDR2
<220>
<221> VARIANT
<222> (6)..(6)
<223> Xaa为X2,X2为G或R
<220>
<221> VARIANT
<222> (9)..(9)
<223> Xaa为X3,X3为T或H
<220>
<221> VARIANT
<222> (10)..(10)
<223> Xaa为X4,X4为Y或R
<400> 38
Ala Ile Ser Ser Asn Xaa Gly Ser Xaa Xaa
1 5 10
<210> 39
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-17、17-15、17-10、17-11 LCDR2
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa为X5,X5为G或S
<220>
<221> VARIANT
<222> (3)..(3)
<223> Xaa为X6,X6为S或K
<220>
<221> VARIANT
<222> (4)..(4)
<223> Xaa为X7,X7为N或V
<220>
<221> VARIANT
<222> (6)..(6)
<223> Xaa为X8,X8为P或R
<400> 39
Xaa Asn Xaa Xaa Arg Xaa Ser
1 5
<210> 40
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> 99-2-35、35-5、35-8 HCDR3
<220>
<221> VARIANT
<222> (4)..(4)
<223> Xaa为X9,X9为G或P
<220>
<221> VARIANT
<222> (5)..(5)
<223> Xaa为X10,X10为G或V
<220>
<221> VARIANT
<222> (6)..(6)
<223> Xaa为X11,X11为Y或G
<220>
<221> VARIANT
<222> (7)..(7)
<223> Xaa为X12,X12为S或Y
<400> 40
Asp Phe Asn Xaa Xaa Xaa Xaa Tyr Tyr Pro Ile Ala Phe Asp Ile
1 5 10 15
<210> 41
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> Ag10058 重链
<400> 41
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 Ser Leu Ser Thr Ser
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala Leu Ile Asp Trp Asp Asp Asp Lys Tyr Tyr Ser Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Gly Ser Asp Thr Val Leu Gly Asp Trp Phe Ala Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
435 440 445
Gly Lys
450
<210> 42
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Ag10058 轻链
<400> 42
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 Ser Pro Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser 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 Gln Gly Tyr Ser Leu Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 43
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> Ag10131 重链
<400> 43
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 Ser Leu Ser Thr Gly
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala Leu Ile Asp Trp Ala Asp Asp Lys Tyr Tyr Ser Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
65 70 75 80
Tyr Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Gly Ser Asp Thr Val Ile Gly Asp Trp Phe Ala Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
435 440 445
Gly Lys
450
<210> 44
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Ag10131 轻链
<400> 44
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 Ile Gly Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr 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 Gln Gly Tyr Tyr Leu Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 45
<211> 448
<212> PRT
<213> Artificial Sequence
<220>
<223> Urelumab 重链
<400> 45
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Gly Gly Tyr Val Thr Tyr Asn Pro Ser Leu Glu
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Tyr Gly Pro Gly Asn Tyr Asp Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 46
<211> 216
<212> PRT
<213> Artificial Sequence
<220>
<223> Urelumab 轻链
<400> 46
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Ala Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215
Claims (13)
1.一种靶向4-1BB的抗体,其包含重链可变区和/或轻链可变区,所述重链可变区包含HCDR1、HCDR2和HCDR3,所述轻链可变区包含LCDR1、LCDR2和LCDR3,其特征在于,
所述HCDR1的氨基酸序列如SEQ ID NO:37所示,所述HCDR2的氨基酸序列如SEQ ID NO:38所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示,所述LCDR1的氨基酸序列如SEQ IDNO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:39所示,所述LCDR3的氨基酸序列如SEQID NO:6所示;或,
所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:40所示,所述LCDR1的氨基酸序列如SEQ IDNO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQID NO:14所示;优选地,
SEQ ID NO:37的X1为T;
SEQ ID NO:38的X2为G、X3为T和/或X4为Y;
SEQ ID NO:39的X5为G、X6为S、X7为N和/或X8为P,或者X5为S且X8为R;
SEQ ID NO:40的X9为G、X10为G、X11为Y和/或X12为S,或者X9为P且X10为V,或者X11为G且X12为Y。
2.如权利要求1所述的抗体,其特征在于,所述HCDR1的氨基酸序列如SEQ ID NO:1所示,所述HCDR2的氨基酸序列如SEQ ID NO:2所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示,所述LCDR1的氨基酸序列如SEQ ID NO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:5所示,所述LCDR3的氨基酸序列如SEQ ID NO:6所示;或,
所述HCDR1的氨基酸序列如SEQ ID NO:20所示,所述HCDR2的氨基酸序列如SEQ ID NO:21所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示,所述LCDR1的氨基酸序列如SEQ IDNO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:24所示,所述LCDR3的氨基酸序列如SEQID NO:6所示;或
所述HCDR1的氨基酸序列如SEQ ID NO:20所示,所述HCDR2的氨基酸序列如SEQ ID NO:22所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示,所述LCDR1的氨基酸序列如SEQ IDNO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:25所示,所述LCDR3的氨基酸序列如SEQID NO:6所示;或
所述HCDR1的氨基酸序列如SEQ ID NO:20所示,所述HCDR2的氨基酸序列如SEQ ID NO:23所示,所述HCDR3的氨基酸序列如SEQ ID NO:3所示,所述LCDR1的氨基酸序列如SEQ IDNO:4所示,所述LCDR2的氨基酸序列如SEQ ID NO:26所示,所述LCDR3的氨基酸序列如SEQID NO:6所示;或
所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:11所示,所述LCDR1的氨基酸序列如SEQ IDNO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQID NO:14所示;或,
所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:33所示,所述LCDR1的氨基酸序列如SEQ IDNO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQID NO:14所示;或
所述HCDR1的氨基酸序列如SEQ ID NO:9所示,所述HCDR2的氨基酸序列如SEQ ID NO:10所示,所述HCDR3的氨基酸序列如SEQ ID NO:34所示,所述LCDR1的氨基酸序列如SEQ IDNO:12所示,所述LCDR2的氨基酸序列如SEQ ID NO:13所示,所述LCDR3的氨基酸序列如SEQID NO:14所示。
3.如权利要求1或2所述的抗体,其特征在于,所述重链可变区的框架区为人源框架区;和/或,
所述轻链可变区的框架区为人源框架区;
优选地,所述重链可变区包含如SEQ ID NO:7所示的氨基酸序列或其变体,且所述轻链可变区包含如SEQ ID NO:8所示的氨基酸序列或其变体;或
所述重链可变区包含如SEQ ID NO:27所示的氨基酸序列或其变体,且所述轻链可变区包含如SEQ ID NO:28所示的氨基酸序列或其变体;或
所述重链可变区包含如SEQ ID NO:29所示的氨基酸序列或其变体,且所述轻链可变区包含如SEQ ID NO:30所示的氨基酸序列或其变体;或
所述重链可变区包含如SEQ ID NO:31所示的氨基酸序列或其变体,且所述轻链可变区包含如SEQ ID NO:32所示的氨基酸序列或其变体;或
所述重链可变区包含如SEQ ID NO:15所示的氨基酸序列或其变体,且所述轻链可变区包含如SEQ ID NO:16所示的氨基酸序列或其变体;或
所述重链可变区包含如SEQ ID NO:35所示的氨基酸序列或其变体,且所述轻链可变区包含如SEQ ID NO:16所示的氨基酸序列或其变体;或
所述重链可变区包含如SEQ ID NO:36所示的氨基酸序列或其变体,且所述轻链可变区包含如SEQ ID NO:16所示的氨基酸序列或其变体;
且所述变体与其所源自的序列相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的序列同一性。
4.如权利要求3所述的抗体,其特征在于,所述抗体满足以下四项中的一项或多项:
(1)所述抗体为天然抗体,或其变体;
(2)所述抗体为全长抗体、Fab、Fab’、F(ab’)2;
(3)所述抗体为单特异性抗体或多特异性抗体;
(4)所述抗体为由上述抗体制得的单克隆抗体。
5.如权利要求4所述的抗体,其特征在于,当所述抗体为全长抗体时,重链恒定区源自人源抗体的重链或其变体,如人IgG4 SP Fc的重链恒定区;轻链恒定区源自人源抗体的κ链或者λ链或其变体;
优选地,所述重链恒定区的氨基酸序列如SEQ ID NO:17所示;
所述κ链的氨基酸序列如SEQ ID NO:18所示;
所述λ链的氨基酸序列如SEQ ID NO:19所示。
6.一种分离的核酸,其编码如权利要求1~5任一项所述的靶向4-1BB的抗体。
7.一种重组表达载体,其包含如权利要求6所述的分离的核酸;优选地,所述重组表达载体为质粒、粘粒、噬菌体或病毒载体,所述病毒载体优选逆转录病毒载体、慢病毒载体、腺病毒载体或腺相关病毒载体。
8.一种转化体,其包含如权利要求7所述的重组表达载体;优选地,所述转化体的宿主细胞为原核细胞或真核细胞;更优选地,所述真核细胞为酵母细胞或哺乳动物细胞;其中,所述哺乳动物细胞例如为HEK293细胞或CHO细胞。
9.一种靶向4-1BB的抗体的制备方法,其包含以下步骤:
培养如权利要求8所述的转化体,从培养物中获得靶向4-1BB的抗体。
10.一种药物组合物,其包含如权利要求1~5任一项所述的靶向4-1BB的抗体,以及药学上可接受的载体;
较佳地,所述药物组合物还含有由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的群组中的一种或多种。
11.如权利要求1~5任一项所述的靶向4-1BB的抗体,和/或如权利要求10所述的药物组合物在制备诊断、预防和/或治疗肿瘤的药物中的应用;
可选地,所述肿瘤选自:结肠癌、胰腺癌、小细胞肺癌、非小细胞肺癌、肾细胞癌、头颈癌和甲状腺癌。
12.一种试剂盒,其包括如权利要求1~5任一项所述的靶向4-1BB的抗体或如权利要求10所述的药物组合物;
较佳地,所述试剂盒还包括(i)施用抗体或药物组合物的装置;和/或(ii)使用说明。
13.一种套装药盒,其包含药盒A和药盒B,其中:
所述药盒A含有如权利要求1~5任一项所述的靶向4-1BB的抗体和/或如权利要求10所述的药物组合物;
所述药盒B含有其他抗肿瘤抗体或者包含所述其他抗肿瘤抗体的药物组合物,和/或由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的群组中的一种或多种。
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