CN112601760A - 与c-met特异性结合的抗体及其用途 - Google Patents
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- CN112601760A CN112601760A CN201980036982.0A CN201980036982A CN112601760A CN 112601760 A CN112601760 A CN 112601760A CN 201980036982 A CN201980036982 A CN 201980036982A CN 112601760 A CN112601760 A CN 112601760A
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Abstract
本发明涉及一种与人和小鼠c‑Met具有交叉反应性的抗c‑Met抗体及其用途,并且更具体地涉及:一种抗c‑Met抗体或其抗原结合片段;一种包含所述抗体或其抗原结合片段的双特异性抗体或抗体‑药物缀合物;一种包含所述双特异性抗体或抗体‑药物缀合物的用于预防或治疗癌症的药物组合物;一种编码所述抗体或其抗原结合片段的核酸;一种包含所述核酸的载体和宿主细胞;一种通过使用所述载体和宿主细胞来制备抗c‑Met抗体或其抗原结合片段的方法;以及一种含有所述抗c‑Met抗体或其抗原结合片段以及另一种癌症治疗剂的共给予的癌症治疗组合物。根据本发明的与c‑Met结合的抗体及其抗原结合片段可以以高亲和力与人和小鼠c‑Met结合,并且因此可以通过使用小鼠肿瘤模型在功效评价中鉴定更准确的临床前结果。根据本发明的与c‑Met结合的抗体及其抗原结合片段可以有效地用于预防或治疗目标癌症。
Description
技术领域
本发明涉及一种与人和小鼠c-Met交联的抗c-Met抗体及其用途,并且更具体地涉及一种抗c-Met抗体或其抗原结合片段;一种包含所述抗体或其抗原结合片段的双特异性抗体或抗体-药物缀合物;一种含有所述双特异性抗体或抗体-药物缀合物的用于预防或治疗癌症的药物组合物;一种编码所述抗体或其抗原结合片段的核酸;一种包含所述核酸的载体和宿主细胞;一种使用所述载体和宿主细胞产生抗c-Met抗体或其抗原结合片段的方法;以及一种用于治疗癌症的共给予组合物,所述共给予组合物含有所述抗c-Met抗体或其抗原结合片段以及另外的癌症治疗剂。
背景技术
多种生长因子(如肝细胞生长因子(HGF)、表皮生长因子(EGF)、血管内皮生长因子(VEGF)和成纤维细胞生长因子(FGF))与细胞表面上的受体酪氨酸激酶(RTK)相互作用,以诱导必需和重要的细胞生理调节(如细胞生长、分化、血管生成和组织再生)以及细胞生成(细胞发生)。当这些生长因子和受体在生理原因(如突变、过表达和自激活)方面失调时,它们会导致异常的细胞生长或分化,从而引发并促进癌症进展(Lemmon M.A.和SchlessingerJ.,Cell 141:1117-1134,2010)。
MET(met原癌基因;c-Met)蛋白被称为原癌基因,其表达肝细胞生长因子(HGF)/扩散因子(SF)受体(Dean M.等人,Nature 318:385-388,1985,Gherardi等人,Nat.Rev.Cancer 12:89-103,2012)与唯一已知的配体HGF相互作用以诱导间充质上皮转化(MET),并促进癌细胞的生长、渗透和转移。c-Met被认为是有效的抗癌靶标,因为它还参与了多种机制(如生成、转移、侵袭和血管生成),而与HGF(各种肿瘤发展中的配体)无关。在此背景下,正在积极研究c-Met抑制剂,如化学药物和单克隆抗体(Comoglio PM等人,Nat.Rev.Drug.Discov.7:504-516,2008)。
针对抗癌靶标c-Met的拮抗抗体的开发是基于抑制c-Met的典型抗癌疗法策略。已经报道抗c-Met抗体抑制配体HGF与c-Met之间的相互作用,或通过消化(分解)使c-Met失活。例如,被开发为抗c-Met抗体的OA-5D5(单臂拮抗抗体)是一种激动剂,其已被开发成这样的抗体,所述抗体经修饰以便不具有诱导c-Met二聚化的副作用(Martens T等人,Clin.Cancer Res.15:6144-6152,2006),并且已经开发了DN30以诱导c-Met本身的失活,从而消除其功能并诱导对肿瘤形成的抑制。(Petrelli A等人,PNAS.103:5090-5095,2006)。然而,单臂拮抗剂抗体当单独使用时具有不足的肿瘤抑制作用,但当与化学疗法组合使用时则展现出显著的治疗作用,并且发现使c-Met失活的抗体具有如下缺点,即与配体的竞争性较低和具有作为激动剂的部分作用。因此,仍然需要开发抑制人c-Met功能的治疗性抗体。
为了开发抗癌靶抗体,不仅有必要使用小鼠肿瘤模型评价体外功效,而且还有必要使用小鼠肿瘤模型评价体内临床前功效。特别地,相应抗体的治疗功效主要基于临床前结果(如减小肿瘤大小和增加存活天数的能力)来确定,所述临床前结果可以在使用小鼠肿瘤模型评价功效时检测到。通过注射过表达抗癌靶标的人源癌细胞来构建在当时使用的小鼠肿瘤模型。临床前结果与在确定抗体的治疗效果时的临床结果之间将具有低相关性的可能性很高,这不仅是由于来自注射的人肿瘤细胞的干扰,而且也是由于来自小鼠中实际肿瘤微环境中混合的小鼠源细胞的干扰(Talmadge J.E.等人,Am.J.Pathol.170:793-804,2007)。因此,抑制人源抗癌靶标的抗体、其与抑制小鼠源抗癌靶标或配体的抗体的组合治疗、或对人/小鼠异种抗癌靶标具有特异性的抗体在肿瘤模型中可以展现出更准确的临床前治疗结果。例如,据报道,抑制肿瘤中血管生成的抗Dll4(δ样配体4)抗体通过在小鼠肿瘤模型中针对小鼠Dll4的抗体和针对人Dll4的抗体的组合治疗显著减小了肿瘤的大小(HoeyT.等人,Cell Stem Cell.5:168-177,2009)。此外,在靶向血管内皮生长因子2(VEGFR-2)或血管内皮生长因子(VEGF)的抗体的情况下,与人/小鼠异种抗癌靶标交叉反应的抗体也在小鼠肿瘤模型中展现出高肿瘤抑制作用,这表明需要开发交叉反应性抗体(Huang J.等人,Cytotechnology 62:61-71,2010;Liang W-C等人,J.Biol.Chem.281:951-961,2006)。
如上所述,关于人源或小鼠源的肝细胞生长因子的自分泌/旁分泌作用,仅抑制c-Met功能的抗c-Met抗体对小鼠c-Met受体没有抑制作用。出于该原因,很难评价小鼠肿瘤模型中的临床前功效和作用。人c-Met(P08581,UniProtKB/Swiss-Prot)由1,390个氨基酸组成,而小鼠c-Met(P16056,UniProtKB/Swiss-Prot)由1,379个氨基酸组成,因此人c-Met和小鼠c-Met在它们之间具有89%或更高的高序列同源性(Chan AML等人,Oncogene.2:593-599,1988)。肝细胞生长因子(一种配体)也在人与小鼠之间具有90%或更高的极高序列同源性(Tashiro K等人,PNAS.87:3200-3204,1990),并且配体和受体起作用的典型位点是Sema结构域,因此开发和应用交叉反应性抗体的可能性很高。因此,需要开发与人/小鼠c-Met交叉反应的抗体,所述抗体可通过抑制抗体肿瘤微环境中癌症特异性配体受体对人/小鼠c-Met的作用而在小鼠肿瘤模型中展现出有效的临床前研究结果。
在此技术背景下,本发明人使用亲和力成熟化方法开发了一种改进的抗体,所述抗体具有与人和小鼠c-Met交联的能力以及改进的与c-Met结合的能力,从而完成了本发明。
提供了在该背景技术部分中公开的信息仅是为了更好地理解本发明的背景技术,并且因此它可以不包含形成对本领域技术人员而言已经清楚的现有技术的信息。
发明内容
因此,已根据上述问题而做出本发明,并且本发明的一个目的是提供一种与c-Met特异性结合的抗c-Met抗体或其抗原结合片段。
本发明的另一个目的是提供一种包含所述抗c-Met抗体或其抗原结合片段的双特异性抗体或抗体-药物缀合物。
本发明的另一个目的是提供一种用于预防或治疗癌症的药物组合物,所述药物组合物含有所述抗c-Met抗体或其抗原结合片段和/或所述双特异性抗体或抗体-药物缀合物;以及一种使用所述药物组合物治疗癌症的方法。
本发明的另一个目的是提供一种编码抗c-Met抗体或其抗原结合片段的核酸;一种含有所述核酸的载体和宿主细胞;以及一种使用所述载体和宿主细胞产生抗c-Met抗体或其抗原结合片段的方法。
本发明的另一个目的是提供一种用于治疗癌症的共给予组合物,所述共给予组合物含有抗c-Met抗体或其抗原结合片段以及另外的癌症治疗剂;以及一种使用所述共给予组合物治疗癌症的方法。
本发明的另一个目的是提供所述抗体或其抗原结合片段或所述双特异性抗体或抗体-药物缀合物用于治疗癌症的用途。
本发明的另一个目的是提供所述抗体或其抗原结合片段或所述双特异性抗体或抗体-药物缀合物用于制备癌症治疗剂的用途。
根据本发明的一个方面,上述和其他目的可以通过提供抗c-Met抗体或其抗原结合片段来实现,所述抗体或其抗原结合片段包含:重链可变区,所述重链可变区含有具有SEQ ID NO:1或27的氨基酸序列的重链CDR1、具有选自SEQ ID NO:2和28至31的氨基酸序列的重链CDR2、和具有选自SEQ ID NO:3、32和33的氨基酸序列的重链CDR3;以及轻链可变区,所述轻链可变区含有具有选自SEQ ID NO:4、34和35的氨基酸序列的轻链CDR1、具有选自SEQ ID NO:5、36和37的氨基酸序列的轻链CDR2、和具有选自SEQ ID NO:6、38和39的氨基酸序列的轻链CDR3。
根据本发明的另一方面,提供了一种包含所述抗c-Met抗体或其抗原结合片段的双特异性抗体或抗体-药物缀合物。
根据本发明的另一方面,提供了一种用于预防或治疗癌症的药物组合物,所述药物组合物含有所述抗c-Met抗体或其抗原结合片段和/或所述双特异性抗体或抗体-药物缀合物;以及一种使用所述药物组合物治疗癌症的方法。
根据本发明的另一方面,提供了一种编码所述抗c-Met抗体或其抗原结合片段的核酸;一种含有所述核酸的载体和宿主细胞;以及一种使用所述载体和宿主细胞产生抗c-Met抗体或其抗原结合片段的方法。
根据本发明的另一方面,提供了一种用于治疗癌症的共给予组合物,所述共给予组合物含有所述抗c-Met抗体或其抗原结合片段以及另外的癌症治疗剂;以及一种使用所述共给予组合物治疗癌症的方法。
根据本发明的另一方面,提供了一种治疗癌症的方法,所述方法包括给予共给予组合物,所述共给予组合物含有所述抗体或其抗原结合片段或所述双特异性抗体或抗体-药物缀合物。
根据本发明的另一方面,提供了所述抗体或其抗原结合片段、或所述双特异性抗体或抗体-药物缀合物用于治疗癌症的用途;以及所述抗体或其抗原结合片段、或所述双特异性抗体或抗体-药物缀合物用于制备癌症治疗剂的用途。
附图说明
图1示出了亲本抗体(1F12)的重链可变区序列和CDR/骨架分类。
图2示出了亲本抗体(1F12)的轻链可变区序列和CDR/骨架分类。
图3是抗c-Met抗体的突变体文库的设计。
图4示出了用于构建抗c-Met抗体的突变体文库的引物序列。
图5示出了抗c-Met抗体亲和力变体的CDR序列。
图6示出了16种抗c-Met抗体亲和力变体的激动剂活性的分析结果。
图7示出了抗c-Met抗体的亲和力的分析结果。
图8示出了胃癌细胞系中的生长抑制模式的分析结果。
图9示出了单独的抗c-Met抗体以及抗c-Met抗体与免疫治疗剂的组合在结肠癌细胞系中的功效的分析结果。
图10示出了抗c-Met抗体与放射疗法的组合在结肠癌细胞系中的功效的分析结果。
图11示出了皮下结肠癌植入动物模型中免疫细胞分布的分析结果。
图12示出了在皮下结肠癌植入动物模型中给予抗c-Met抗体后肿瘤细胞中PD-L1表达的变化。
具体实施方式
除非另外定义,否则本文所用的所有技术和科学术语的含义与由本发明所涉及领域中的技术人员所理解的含义相同。一般来说,本文所用的命名法在本领域中是熟知的,并且是通常使用的。
为了提高抗体功效,需要应用抗体工程化技术。其中,亲和力成熟化使抗体对抗原的亲和力成熟。亲和力成熟化是指通过将随机突变引入抗体基因中来提高抗体对抗原的结合亲和力的方法,并且对于开发新型有效治疗和诊断抗体药物非常有用。对于体外亲和力成熟化,通常使用三种途径。这些途径包括易错PCR、使用简并寡核苷酸的靶残基随机化以及链改组。可被选择作为靶残基的部分是互补决定区(CDR)、特别是CDR-H3和CDR-L3,它们倾向于主导抗体-抗原相互作用并且因此是随机化的逻辑靶标。通过改变抗体基因的靶CDR区中的氨基酸,提高抗体的结合亲和力。据报道,该方法通过改变AKA(与肿瘤相关糖蛋白72结合的人源化抗体)的CDR-H3中的氨基酸,将结合亲和力提高了高达22倍(Hong等人,J.Biol.Chem.2006,281,6985-6992),并且据报道针对乙型肝炎病毒抗原开发的抗体也将结合亲和力提高了高达6倍(Hong等人,J.Microbiol.2007,45,528-533)。
在一方面,本发明涉及一种抗c-Met抗体或其抗原结合片段,优选包含以下的抗c-Met抗体或其抗原结合片段:重链可变区,所述重链可变区含有具有SEQ ID NO:1或27的氨基酸序列的重链CDR1、具有选自SEQ ID NO:2和28至31的氨基酸序列的重链CDR2、和具有选自SEQ ID NO:3、32和33的氨基酸序列的重链CDR3;以及轻链可变区,所述轻链可变区含有具有选自SEQ ID NO:4、34和35的氨基酸序列的轻链CDR1、具有选自SEQ ID NO:5、36和37的氨基酸序列的轻链CDR2和具有选自SEQ ID NO:6、38和39的氨基酸序列的轻链CDR3。
根据本发明,如下与c-met结合的抗体或其抗原结合片段也落入根据本发明的抗c-Met抗体或其抗原结合片段的范围内,所述与c-met结合的抗体或其抗原结合片段包含重链可变区,所述重链可变区具有如下序列,所述序列与具有SEQ ID NO:1或27的氨基酸序列的重链CDR1、具有选自SEQ ID NO:2和28至31的氨基酸序列的重链CDR2、和具有选自SEQ IDNO:3、32和33的氨基酸序列的重链CDR3具有至少80%序列同源性、优选至少90%序列同源性、以及更优选99%序列同源性;并且具有与根据本发明的c-Met相同的特征。
根据本发明,如下抗体或其抗原结合片段也落入根据本发明的抗c-Met抗体或其抗原结合片段的范围内,所述抗体或其抗原结合片段包含轻链可变区,所述轻链可变区具有如下序列,所述序列与具有选自SEQ ID NO:4、34和35的氨基酸序列的轻链CDR1、具有选自SEQ ID NO:5、36和37的氨基酸序列的轻链CDR2、和具有选自SEQ ID NO:6、38和39的氨基酸序列的轻链CDR3具有至少80%序列同源性、优选至少90%序列同源性、以及更优选99%序列同源性;并且具有与根据本发明的c-Met相同的特征。
根据本发明,所述抗c-Met抗体或其抗原结合片段可以包含重链可变区,所述重链可变区含有选自SEQ ID NO:40和42至48的氨基酸序列;以及轻链可变区,所述轻链可变区选自SEQ ID NO:41和49至54。
同时,如下抗体或其抗原结合片段也落入根据本发明的抗c-Met抗体或其抗原结合片段的范围内,所述抗体或其抗原结合片段具有如下序列,所述序列与包含选自SEQ IDNO:40和42至48的氨基酸序列的重链可变区具有至少80%序列同源性、优选至少90%序列同源性、以及更优选99%序列同源性;并且具有与根据本发明的c-Met相同的特征。
同时,如下抗体或其抗原结合片段也落入根据本发明的抗c-Met抗体或其抗原结合片段的范围内,所述抗体或其抗原结合片段包含轻链可变区,所述轻链可变区具有如下序列,所述序列与包含选自SEQ ID NO:41和49至54的氨基酸序列的轻链可变区具有至少80%序列同源性、优选至少90%序列同源性、以及并且更优选99%序列同源性;并且具有与根据本发明的c-Met相同的特征。
另外,根据本发明的抗c-Met抗体或其抗原结合片段还包含这样的抗体或其抗原结合片段,其中根据本发明的抗c-Met抗体或其抗原结合片段中的氨基酸序列的一部分通过保守取代被取代。
如本文所用,术语“保守取代”是指多肽的修饰,所述修饰包括用具有相似的生化特性但不会引起所述多肽的生物学或生化功能损失的氨基酸取代一个或多个氨基酸。术语“保守氨基酸取代”是指氨基酸残基被与其具有相似侧链的氨基酸残基取代。具有相似侧链的氨基酸残基的种类是本领域中已定义且熟知的。这些种类包括具有碱性侧链的氨基酸(例如赖氨酸、精氨酸、组氨酸)、具有酸性侧链的氨基酸(例如天冬氨酸、谷氨酸)、具有不带电荷的极性侧链的氨基酸(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、具有非极性侧链的氨基酸(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、具有β-分支侧链的氨基酸(例如苏氨酸、缬氨酸、异亮氨酸)以及具有芳香族侧链的氨基酸(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。预期本发明的抗体具有保守的氨基酸取代并且仍然有活性。
如本文所用,术语“c-Met特异性抗体”是指与c-Met结合并抑制c-Met的生物学活性的抗体,并且其可以与“抗c-Met抗体”互换使用。
如本文所用,术语“抗c-Met抗体”包括多克隆抗体和单克隆抗体两者,但是优选地是单克隆抗体,并且可以具有完整的全抗体形式。全抗体具有含有两条全长轻链和两条全长重链的结构,并且具有包含恒定区的结构,并且每条轻链通过二硫键与重链连接。
根据本发明的抗c-Met抗体的全抗体包括IgA、IgD、IgE、IgM和IgG形式,并且IgG包括亚型IgG1、IgG2、IgG3和IgG4。
根据本发明的抗c-Met抗体优选地是选自人抗体文库的全人抗体,但不限于此。
如本文所用,根据本发明的抗c-Met抗体的术语“抗原结合片段”是指这样的片段,所述片段具有与抗c-Met抗体的抗原(即,c-Met)结合的功能,包括Fab、Fab'、F(ab')2、scFv、(scFv)2、scFv-Fc、Fv等,并且在本文中与具有相同含义的“抗体片段”可互换使用。
Fab是指这样的结构,所述结构包括重链和轻链各自的可变结构域、轻链的恒定结构域以及重链的第一恒定结构域(CH1),每个Fab具有一个抗原结合位点。Fab'与Fab的不同之处在于,它还包括在重链CH1结构域的C末端含有至少一个半胱氨酸残基的铰链区。F(ab’)2抗体是由Fab'铰链区中的半胱氨酸残基之间的二硫键产生。
Fv(可变片段)是仅具有重链可变结构域和轻链可变结构域的最小抗体片段。两链Fv(dsFv,二硫键稳定化Fv)是这样的片段,在所述片段中重链的可变结构域和轻链的可变结构域通过二硫键连接;并且单链Fv(scFv)是这样的片段,在所述片段中重链的可变区和轻链的可变区通常经由肽接头通过共价键连接。此类抗体片段可以使用蛋白酶获得(例如,可以通过用木瓜蛋白酶切割全抗体来获得,并且F(ab′)2片段可以通过用胃蛋白酶切割全抗体来获得),并且可以使用遗传重组技术(例如,使用一对引物通过PCR(聚合酶链反应)来扩增作为模板的编码抗体的重链或其可变区的DNA以及编码轻链或其可变区的DNA,并且扩增编码肽接头的DNA和两端分别与重链或其可变区和轻链或其可变区连接的一对引物的组合)来制备。
如本文所用,术语“重链”涵盖全长重链及其片段二者,所述全长重链包含可变结构域(VH)和三个恒定结构域(CH1、CH2和CH3),所述可变结构域含有具有足以赋予针对抗原的特异性的可变区序列的氨基酸序列。如本文所用,术语“轻链”涵盖全长轻链和其片段二者,所述全长轻链包含:可变结构域(VL),其含有氨基酸序列,所述氨基酸序列的可变区序列足以赋予针对抗原的特异性;和恒定结构域(CL)。
如本文所用,术语“互补决定区”(CDR)是指免疫球蛋白重链和轻链的高变区的氨基酸序列(Kabat等人,Sequences of Proteins of Immunological Interest,第4版,U.S.Department of Health and Human Services,National Institutes of Health(1987))。重链(CDRH1、CDRH2和CDRH3)和轻链(CDRL1、CDRL2和CDRL3)各自含有三个CDR。CDR提供了使抗体与抗原或表位结合所需的接触残基。
根据本发明,抗c-Met抗体或其抗原结合片段可以具有与人c-Met特异性结合的能力。优选地,抗c-Met抗体或其抗原结合片段可以具有与人c-Met和小鼠c-Met交联的能力,但是本发明不限于此。
在另一方面,本发明涉及一种抗体-药物缀合物(ADC),所述抗体-药物缀合物包含彼此缀合的药物和抗c-Met抗体或其抗原结合片段。
抗体-药物缀合物(ADC)要求抗癌药物应与抗体稳定地结合,直到将抗癌药物递送至靶癌细胞。被递送至靶标的药物应从抗体释放,从而诱导靶细胞死亡。为此目的,药物应与抗体稳定地结合,并且应在从靶细胞释放时具有足够的细胞毒性以诱导靶细胞死亡。
根据本发明,抗c-Met抗体或其抗原结合片段与包括药物例如抗癌剂的细胞毒性物质彼此结合(例如,通过共价键、肽键等),并且因此,可以用作缀合物或融合蛋白(当细胞毒性物质和/或标记物质(标记物)是蛋白质时)。细胞毒性物质可以是对癌细胞特别是实体癌细胞有毒性的任何物质,并且可以包括选自放射性同位素、细胞毒性化合物(小分子)、细胞毒性蛋白和抗癌药物的至少一者,但是本发明不限于此。所述细胞毒性蛋白可以是选自蓖麻毒蛋白、皂草素、白树毒素、苦瓜毒蛋白、debouganin、白喉毒素、假单胞菌毒素等的至少一种,但本发明不限于此。放射性同位素可以包括选自131I、188Rh和90Y的至少一种,但本发明不限于此。细胞毒性化合物可以包括选自倍癌霉素(duocarmycin)、一甲基阿里他汀E(MMAE)、一甲基阿里他汀F(MMAF)、N2’-二乙酰-N2'-(3-巯基-1-氧代丙基)美登素(DM1)、PBD(吡咯并苯二氮卓类)二聚体等的至少一种,但不限于此。
根据本发明,抗体-药物缀合物可以根据本领域熟知的方法获得。
根据本发明,抗体-药物缀合物的特征可在于抗体或其抗原结合片段通过接头与药物结合。
根据本发明,接头可以是可切割的接头或不可切割的接头。
接头是用于将抗c-Met抗体与药物连接的手段。例如,接头允许药物在细胞内条件下以可切割的形式从抗体释放,即通过在细胞内环境中切割接头来释放。
接头可以是肽接头,其可以被存在于细胞内环境中(例如在溶酶体或内体中)的切割剂切割,并且可以被细胞内肽酶或蛋白酶(如溶酶体或内体蛋白酶)切割。通常,肽接头具有至少两个氨基酸的长度。切割剂可以包括组织蛋白酶B、组织蛋白酶D和纤溶酶,它们水解肽以将药物释放到靶细胞中。肽接头可以被在癌症组织中强表达的硫醇依赖性蛋白酶组织蛋白酶-B切割,并且可以是例如Phe-Leu或Gly-Phe-Leu-Gly接头。另外,肽接头可以是例如Val-Cit接头或Phe-Lys接头,其可以被细胞内蛋白酶切割。
根据本发明,可切割的接头对pH敏感,并且在一定pH值下可能对水解敏感。通常,pH敏感的接头是可以在酸性条件下水解的接头。可以在溶酶体中水解的酸不稳定性接头的例子可以包括腙、半卡巴腙、硫代半卡巴腙、顺式乌头酰胺、原酸酯、乙缩醛、缩酮等。
所述接头也可以在还原条件下切割,并且可以是例如二硫键接头。可以使用N-琥珀酰亚胺基-S-乙酰硫代乙酸酯(SATA)、N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯(SPDP)、N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丁酸酯(SPDB)和N-琥珀酰亚胺基-氧羰基-α-甲基-α-(2-吡啶基-二硫代)甲苯(SMPT)形成各种二硫键。
根据本发明,药物和/或药物接头可以通过抗体的赖氨酸随机缀合,或者可以通过当二硫键链还原时暴露的半胱氨酸缀合。在一些情况下,可以通过存在于基因工程化标签(例如肽或蛋白质)中的半胱氨酸来缀合药物-接头。基因工程化标签,例如肽或蛋白质,可以包括可以被例如类异戊二烯转移酶识别的氨基酸基序。肽或蛋白质通过间隔单元的共价键在肽或蛋白质的羧基末端具有缺失或在肽或蛋白质的羧基(C)末端具有添加。肽或蛋白质可以与氨基酸基序直接共价键合,或者可以通过与间隔单元的共价键与氨基酸基序连接。氨基酸间隔单元包括1至20个氨基酸,并且在它们之中优选为甘氨酸单元。
接头可以包括以多个拷贝存在于溶酶体中的β-葡萄糖醛酸苷接头,或被在一些肿瘤细胞中过表达的β-葡萄糖醛酸酶识别和水解。与肽接头不同,此接头具有由于其高亲水性而与具有高疏水性的药物结合时增加抗体-药物组合物的溶解性的优点。
就此而言,根据本发明,可以使用在韩国专利公开号2015-0137015中披露的β-葡萄糖醛酸苷接头,例如包含自毁式基团的β-葡萄糖醛酸苷接头。
另外,所述接头可以是例如不可切割的接头,并且所述药物能够仅通过水解抗体以产生例如氨基酸-接头-药物复合物的单个步骤而被释放。这种类型的接头可以是硫醚基或马来酰亚胺基己酰基,并且可以在血液中保持稳定。
根据本发明,药物可以是化学治疗剂、毒素、微小RNA(miRNA)、siRNA,shRNA或放射性同位素。可以将药物(作为具有药理作用的药剂)与抗体缀合。
化学治疗剂可以是细胞毒性剂或免疫抑制剂。特定地,化学治疗剂可以包括微管蛋白抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂、或能够用作DNA嵌入剂的化学治疗剂。化学治疗剂还可以包括免疫调节化合物、抗癌剂、抗病毒剂、抗细菌剂、抗真菌剂、驱虫剂或它们的组合。
例如,药物可以包括选自以下的至少一种:美登木素生物碱(maytansinoid)、阿里他汀、氨基蝶呤、放线菌素、博来霉素、沙利度胺、喜树碱、N8-乙酰基亚精胺、1-(2-氯乙基)-1,2-二甲基磺酰肼、埃斯培拉霉素(esperamycin)、依托泊苷、6-巯基嘌呤、尾海兔素、单端孢菌素、卡奇霉素、紫杉醇(taxol)、紫杉烷、紫杉醇(paclitaxel)、多西他赛、甲氨蝶呤、长春新碱、长春碱、多柔比星、美法仑、苯丁酸氮芥、杜卡霉素、L-天冬酰胺酶、巯基嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、环磷酰胺、异环磷酰胺、亚硝基脲、顺铂、卡铂、丝裂霉素(丝裂霉素A、丝裂霉素C)、达卡巴嗪、丙卡巴肼、拓扑替康、氮芥、环磷酰胺、5-氟尿嘧啶、二氯乙基亚硝基脲(CNU)、伊立替康、喜树碱、伊达比星、道诺霉素、更生霉素、普卡霉素、天冬酰胺酶、长春瑞滨、苯丁酸氮芥、美法仑、卡莫司汀、洛莫司汀、白消安、苏消安、达卡巴嗪、替尼泊苷、拓扑替康、9-氨基喜树碱、克雷斯托、三甲曲沙、霉酚酸、噻唑呋林、利巴韦林、5-乙炔基-1-β-D核糖呋喃糖基咪唑-4-甲酰胺(EICAR)、羟基脲、去铁胺、氟尿苷、多西氟尿啶、雷替曲塞、阿糖胞苷(ara C)、胞嘧啶阿拉伯糖苷、氟达拉滨、他莫昔芬、雷洛昔芬、甲地孕酮、戈舍瑞林、乙酸亮丙瑞林、氟他胺、比卡鲁胺、EB1089、CB1093、KH1060、维替泊芬、酞菁、光敏剂Pe4、脱甲氧基竹红菌素A、干扰素-α、干扰素-γ、肿瘤坏死因子、吉西他滨、万珂(velcade)、revamid、洛伐他汀、1-甲基-4-苯基吡啶鎓、星形孢菌素、放线菌素D、更生霉素、博来霉素A2、博来霉素B2、培洛霉素、表柔比星、吡柔比星、佐柔比星、米托蒽醌、维拉帕米和毒胡萝卜素、核酸酶和源自细菌或植物和动物的毒素,但不限于此。
根据本发明,药物可以具有选自以下的至少一种亲核基团:胺、硫醇、羟基、酰肼、肟、肼、硫代半卡巴腙、肼甲酸酯和芳基酰肼基团,所述亲核基团可以与接头上的亲电子基团和接头试剂反应形成共价键。
在另一方面中,本发明涉及一种双特异性抗体,所述双特异性抗体包含所述抗c-Met抗体或其抗原结合片段。
双特异性抗体是指这样的抗体,其中在抗体的两个臂中,一个臂包含根据本发明的抗c-Met抗体或其抗原结合片段,并且另一个臂包含对除c-Met以外的抗原(优选癌症相关抗原或免疫检查点蛋白抗原)有特异性的抗体、或与免疫效应细胞相关抗原特异性结合的抗体或它们的抗原结合片段。
除根据本发明的双特异性抗体中包含的抗c-Met抗体以外的抗体所结合的抗原优选地选自癌症相关抗原或免疫检查点蛋白抗原,包括HGF、EGFR、EGFRvIII、Her2、Her3、IGF-1R、VEGF、VEGFR-1、VEGFR-2、VEGFR-3、Ang2、Dll4、NRP1、FGFR、FGFR2、FGFR3、c-Kit、MUC1、MUC16、CD20、CD22、CD27、CD30、CD33、CD40、CD52、CD70、CD79、DDL3、叶酸R1、连接素4、Trop2、gpNMB、Axl、BCMA、PD-1、PD-L1、PD-L2、CTLA4、BTLA、4-1BB、ICOS、GITR、OX40、VISTA、TIM-3、LAG-3、KIR、B7.1、B7.2、B7-H2、B7-H3、B7-H4、B7-H6、B7-H7、EphA2、EphA4、EphB2、E-选择素、EpCam、CEA、PSMA、PSA和c-MET,并且优选地选自免疫效应细胞相关抗原,包括TCR/CD3、CD16(FcγRIIIa)、CD44、CD56、CD69、CD64(FcγRI)、CD89、CD11b/CD18(CR3)等,但本发明不限于此。
在另一方面,本发明涉及一种用于预防和/或治疗癌症的药物组合物,所述药物组合物包含所述抗c-Met抗体或其抗原结合片段。
在另一方面,本发明涉及一种用于预防和/或治疗癌症的药物组合物,所述药物组合物包含所述双特异性抗体或抗体-药物缀合物。
根据本发明,癌症可能与c-Met的表达或过表达相关。
根据本发明,术语“癌症”和“肿瘤”以相同的含义使用,并且是指或意指以不受控制的细胞生长/增殖为特征的哺乳动物的生理学病症。
根据本发明,抗c-Met抗体由于抑制强抗c-Met结合以及因而由此引起的c-Met功能而抑制来源于各种癌的癌细胞的生长,并且抑制c-Met的磷酸化和下游信号转导物,从而抑制c-Met信号传导和血管生成。因此,本发明的抗体对于预防和治疗癌症非常有效。
可以用本发明的组合物治疗的癌症或癌不受特别限制,并且包括实体癌和血癌。此类癌症的例子包括但不限于乳腺癌、结肠癌、肺癌、胃癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、脑癌、子宫癌、鼻咽癌、喉癌、结肠癌、卵巢癌、直肠癌、结直肠癌、阴道癌、小肠癌、内分泌癌、甲状腺癌、甲状旁腺癌、输尿管癌、尿道癌、前列腺癌、支气管癌、膀胱癌、肾癌和骨髓癌。所述癌症可以是原发性癌症或转移性癌症。更优选地,可通过所述药物组合物预防或治疗的癌症可以是表达c-Met的癌症。
根据本发明,所述药物组合物可用于使用放射的组合疗法中。
在另一方面,本发明涉及一种预防和/或治疗c-Met相关疾病的方法,所述方法包括向需要针对c-Met相关疾病的预防或治疗性治疗的患者给予治疗有效量的所述抗c-Met抗体或其抗原结合片段和/或所述双特异性抗体或抗体-药物缀合物。预防和/或治疗所述疾病的方法还可以包括在给予前鉴定需要针对所述疾病的预防或治疗性治疗的患者。
根据本发明,治疗方法包括给予含有所述抗c-Met抗体或其抗原结合片段的药物组合物以及执行辐照。
可以以2Gy至10Gy的剂量施加辐照,但不限于此。
在本发明的方法中,辐照的次数、辐照之间的时间间隔以及药物组合物的给予可以根据本发明的方法而变化,但是优选地,辐照可以与药物组合物的给予同时进行,或者可以在药物组合物的给予后10至20天进行,但不限于此。
在另一方面,本发明涉及所述抗体或其抗原结合片段、或所述双特异性抗体或抗体-药物缀合物用于治疗癌症的用途。
在另一方面,本发明涉及所述抗体或其抗原结合片段、或所述双特异性抗体或抗体-药物缀合物用于制备癌症治疗剂的用途。
在根据本发明的药物组合物、治疗方法和用途中,抗c-Met抗体或其抗原结合片段作为活性成分单独提供,或与细胞毒性物质(如抗癌剂)组合给予,或以与毒性物质缀合的抗体-药物缀合物(ADC)的形式提供。
根据本发明的抗c-Met抗体或其抗原结合片段以及含有所述抗c-Met抗体或其抗原结合片段的药物组合物可以与常规治疗剂组合使用。也就是说,根据本发明的抗c-Met抗体或其抗原结合片段和含有所述抗c-Met抗体或其抗原结合片段的药物组合物可以与常规抗癌剂同时或依次给予。
根据本发明,药物组合物可以包含治疗有效量的抗c-Met抗体或其抗原结合片段以及药学上可接受的载体。
术语“药学上可接受的载体”是指可以添加到活性成分中以帮助配制或稳定药物而不会造成对患者明显有害的毒性效应的物质。所述药学上可接受的载体可以包括配制品中常用的药学上可接受的载体,并且可包括但不限于:乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等。
除了上述成分之外,根据本发明的药物组合物还可以包含润滑剂、润湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。合适的药学上可接受的载体和配制品在《雷明顿药物科学(Remington's Pharmaceutical Science)》(第19版,1995)中详细描述。
本发明的药物组合物可以肠胃外给予,例如通过静脉内注射、皮下注射、肌内注射或腹膜内注射。
根据本发明的药物组合物的适合剂量可以根据以下因素发生变化,诸如配制方法、给予方法、以及患者的年龄、体重、性别、病理状况、饮食、给予时间、给予途径、排泄率和反应性,并且具有普通技术的全科医生可以容易确定并开出对所需治疗或预防有效的剂量。在本发明的优选实施方案中,根据本发明的药物组合物的日剂量可以在0.0001mg/kg至100mg/kg的范围内。术语“药物有效量”可以指足以预防或治疗癌症的量。
根据本发明所属领域的技术人员可易于实施的方法,可以将根据本发明的药物组合物制备成单位剂型,或者可以通过以下方式来制备:通过使用了药学上可接受的载体和/或赋形剂的配制,并入到多剂量容器中。在此,配制品可以是在油或水性介质中的溶液、悬浮液或乳液的形式,或者可以是提取物、粉末、栓剂、颗粒、片剂或胶囊的形式。组合物还可以含有分散剂或稳定剂。
在另一方面中,本发明涉及一种编码根据本发明的抗c-Met抗体的核酸。如本文所用,核酸可以存在于细胞或细胞裂解物中,或者可以按部分纯化的形式或按基本上纯的形式存在。当通过包括例如碱/SDS处理、CsCl显带、柱色谱、琼脂糖凝胶电泳和本领域熟知的其他方法的标准技术从其他细胞组分或其他污染物(例如从其他细胞的核酸或蛋白质)中纯化时,核酸可以是“分离的”或“基本上变成纯的”。本发明的核酸可以是例如DNA或RNA,并且可以包括或可以不包括内含子序列。
根据本发明,编码抗c-Met抗体的核酸可以包含选自SEQ ID NO:55至69的序列。特别地,编码根据本发明的抗体的重链的多核苷酸序列由SEQ ID NO:55或57至63表示,和/或编码根据本发明的抗体的轻链的多核苷酸序列由SEQ ID NO:56或64至69表示。
在另一方面,本发明涉及一种包含所述核酸的重组表达载体。为了表达根据本发明的抗c-Met抗体或其抗原结合片段,可以通过标准分子生物学技术(例如,使用表达所需抗体的杂交瘤进行PCR扩增或cDNA克隆)制备编码部分或全长轻链或重链的DNA,并且可以将DNA“可操作地连接”至转录和翻译控制序列并插入表达载体中。
如本文所用,术语“可操作地连接”可以意指将编码抗体的基因连接到载体中,使得载体内的转录和翻译控制序列起到调节抗体基因的转录和翻译的预期功能。选择表达载体和表达控制序列,以使其与用于表达的宿主细胞相容。将抗体的轻链基因和抗体的重链基因插入分开的载体中,或将两种基因插入同一个表达载体中。通过标准方法将抗体插入表达载体中(例如,将抗体基因片段和载体上的互补限制性酶切位点连接,或当不存在限制性酶切位点时进行平端连接)。在一些情况下,重组表达载体可以编码促进宿主细胞分泌抗体链的信号肽。可以将抗体链基因克隆到载体中,使得信号肽根据框架与抗体链基因的氨基末端结合。信号肽可以是免疫球蛋白信号肽或异源信号肽(即,源自除免疫球蛋白以外的蛋白质的信号肽)。另外,重组表达载体具有控制序列,所述控制序列控制宿主细胞中抗体链基因的表达。术语“控制序列”可以包括控制抗体链基因的转录或翻译的启动子、增强子、和其他表达控制元件(例如,聚腺苷酸化信号)。本领域技术人员将理解,可以通过选择不同的控制序列来改变表达载体的设计,所述控制序列的选择取决于多种因素,例如要转化的宿主细胞的选择和蛋白质的表达水平。
在另一方面,本发明涉及一种包含所述核酸或所述载体的宿主细胞。根据本发明的宿主细胞优选选自动物细胞、植物细胞、酵母、大肠杆菌(Escherichia coli)和昆虫细胞,但不限于此。
更特别地,根据本发明的宿主细胞可以是原核细胞,例如大肠杆菌(Escherichiacoli)、枯草芽孢杆菌(Bacillus subtilis)、链霉菌属物种(Streptomyces sp.)、假单胞菌属物种(Pseudomonas sp.)、奇异变形杆菌(Proteus mirabilis)或葡萄球菌属物种(Staphylococcus sp.)。宿主细胞可以是选自真菌(例如曲霉属物种(Aspergillus sp.))、酵母(例如巴斯德毕赤酵母(Pichia pastoris)、酿酒酵母(Saccharomyces cerevisiae)、裂殖酵母属物种(Schizosaccharomyces sp.)、和粗糙脉孢菌(Neurospora crassa))的真核细胞、其他较低级的真核细胞以及较高级的真核细胞(如源自昆虫的细胞)。
宿主细胞也可以源自植物或哺乳动物。优选地,有用的宿主细胞可以包括但不限于猴肾细胞(COS7)、NSO细胞、SP2/0细胞、中国仓鼠卵巢(CHO)细胞、W138、幼仓鼠肾(BHK)细胞、MDCK、骨髓瘤细胞系、HuT 78细胞、HEK293细胞等。特别优选地,有用的宿主细胞是CHO细胞。
核酸或载体被转染到宿主细胞中。可以使用通常用于将外来核酸(DNA或RNA)引入原核或真核宿主细胞中的各种技术来进行“转染”,所述技术例如为电泳、磷酸钙沉淀、DEAE-葡聚糖转染或脂质转染。各种表达宿主/载体组合可以用于表达根据本发明的抗c-met抗体。用于真核宿主的合适的表达载体包含,例如,但不限于源自SV40、牛乳头瘤病毒、腺病毒、腺相关病毒、巨细胞病毒和逆转录病毒的表达控制序列。可以用于细菌宿主的表达载体包括从大肠杆菌(Escherichia coli)(E.coli)获得的细菌质粒(例如pET、pRSET、pBluescript、pGEX2T、pUC载体、col E1、pCR1、pBR322、pMB9及其衍生物)、具有广泛宿主范围的质粒(例如RP4)、由多种噬菌体λ衍生物(例如λgt10、λgt11和NM989)例示的噬菌体DNA、以及其他DNA噬菌体(例如M13和丝状单链DNA噬菌体)。可用于酵母细胞的表达载体包括2μ质粒及其衍生物。可用于昆虫细胞的载体是pVL 941。
在另一方面,本发明涉及一种产生根据本发明的抗c-Met抗体或其抗原结合片段的方法,所述方法包括培养宿主细胞以表达根据本发明的抗c-Met抗体或其抗原结合片段。
当将能够表达抗c-Met抗体或其抗原结合片段的重组表达载体引入哺乳动物宿主细胞中时,可以通过以下方式产生抗体:将宿主细胞培养足够长的时间段以使所述抗体在宿主细胞中表达,更优选地培养足够长的时间段以使抗体分泌到培养基中。
在一些情况下,可以将表达的抗体与宿主细胞分离并纯化至同质。抗体的分离或纯化可以使用用于常规蛋白质的分离和纯化方法(例如色谱)进行。这样的色谱可以包括例如涉及蛋白A柱或蛋白G柱的亲和色谱、离子交换色谱、或疏水色谱。可以通过结合过滤、超滤、盐析、透析等进行色谱来分离和纯化抗体。
根据本发明的抗c-Met抗体或其抗原结合片段以及含有所述抗c-Met抗体或其抗原结合片段的药物组合物可以与常规治疗剂组合使用。
在另一方面,本发明涉及一种用于治疗癌症的共给予组合物,所述共给予组合物含有抗c-Met抗体或其抗原结合片段以及另外的癌症治疗剂;以及一种使用所述共给予组合物治疗癌症的方法。
其他癌症治疗剂是指除可用于癌症治疗的根据本发明的抗c-Met抗体或其抗原结合片段以外的所有治疗剂。根据本发明,癌症治疗剂可以是免疫检查点抑制剂,但不限于此。
人类免疫系统具有免疫筛选系统以抑制由T细胞过度增殖引起的超免疫反应。该免疫筛选系统被称为“免疫检查点”,并且所述免疫检查点中所涉及的蛋白质被称为“免疫检查点蛋白”。本质上,免疫检查点执行抑制由T细胞过度活化和/或过度增殖引起的超免疫应答的功能,但是癌细胞通过利用这些免疫检查点来阻止T细胞攻击自身并避免免疫系统的攻击,从而最终导致癌症进展。
在本领域中已经知道,可以使用这种免疫检查点的抑制剂来治疗诸如癌症的疾病,并且靶向免疫检查点蛋白的抗体药物是可商购的,并且正在开发各种免疫检查点抑制剂。
被开发为免疫检查点抑制剂的第一治疗剂是伊匹单抗(ipilimumab),一种对免疫检查点受体CTLA-4(细胞毒性T淋巴细胞相关抗原4)具有特异性的单克隆抗体,其在转移性恶性黑色素瘤中展现出其作用。随后,正在开发对PD-1(程序性细胞死亡-1)和PD-L1(程序性死亡配体-1)(PD-1的配体)具有特异性的单克隆抗体,并且其典型例子包括纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、阿维鲁单抗(avelumab)、阿特珠单抗(atezolizumab)、度伐单抗(durvalumab)等。PD-1或PD-L1抑制剂在各种肿瘤以及恶性黑色素瘤中均展现出作用。
根据本发明,免疫检查点抑制剂是指免疫检查点抑制剂或检查点抑制剂,并且可以是抗CTLA-4抗体、抗PD-1抗体或抗PD-L1抗体,但不限于此。特别地,有用的免疫检查点抑制剂的例子包括但不限于伊匹单抗、纳武单抗、派姆单抗、阿特珠单抗、阿维鲁单抗和度伐单抗。
根据本发明,癌症可以是乳腺癌、结肠癌、肺癌、胃癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、脑癌、子宫癌、鼻咽癌、喉癌、结肠癌、卵巢癌、直肠癌、结直肠癌、阴道癌、小肠癌、内分泌癌、甲状腺癌、甲状旁腺癌、输尿管癌、尿道癌、前列腺癌、支气管癌、膀胱癌、肾癌或骨髓癌,但不限于此。
术语“组合使用”、“组合的使用”或“共给予”意指抗c-Met抗体或其抗原结合片段和另一种另外的癌症治疗剂可以同时、依序或以相反顺序给予,并且可以以可由本领域技术人员确定的适当有效量的组合给予。
在本发明的一个实施方案中,抗PD-L1抗体和根据本发明的抗c-Met抗体的共给予进一步抑制肿瘤的生长。
用于共给予的组合物包含抗c-Met抗体,并且与之相关的配置与如上所述的用于预防或治疗癌症的组合物中所包含的那些配置相同,使得每种配置的描述同样适用于共给予的组合物。
在下文中,将参考实施例更加详细地描述本发明。然而,对本领域技术人员明显的是,提供这些实施例仅用于举例说明本发明,而不应解释为限制本发明的范围。
实施例1:用于亲和力成熟化的突变体文库的构建
使用噬菌体展示技术选择c-Met靶抗体1F12,并使用定向进化来改进抗体的亲和力。抗体的可变区分为互补决定区(CDR)和骨架区,并且CDR极大地促进了抗原-抗体结合。亲本抗体的重链可变区和轻链可变区如图1和图2所示。基于KABAT编号方法,对抗体的CDR和骨架区进行了划分(表1)。
[表1]
人/小鼠c-Met交叉反应性scFv抗体的重链CDR序列和轻链CDR序列
使用NNK简并密码子在亲本抗体(1F12)的重链和轻链的可变区中存在的总共6个CDR中构建10种突变体文库(1F12-H1mut、1F12-H2-1mut、1F12-H2-2mut、1F12-H3-1mut、1F12-H3-2mut、1F12-L1-1mut、1F12-L1-2mut、1F12-L2mut、1F12-L3-1mut和1F12-L3-2mut)(图3)。使用下表2中所示的引物,使用重叠延伸PCR获得1F12突变体单链可变片段(sfiI-VH-接头-VL-sfiI)的DNA序列,其中用于构建突变体文库的CDR序列是随机化的。
[表2]
引物序列
在此,半胱氨酸存在于重链CDR-H3的VH99和VH100d中(图1),并且这两个位点形成链间二硫键从而稳定CDR-H3结构。因此,将TGT密码子而不是NNK密码子用于这两个位点以保留残基。通过使用sfiI(NEB)限制酶去除插入序列来线性化pComb3X scFv表达载体(OmpA前导序列-sfiI-VH-接头-VL-sfiI-His-HA-琥珀密码子-pIII)。在该线性化载体中,使用T4连接酶(NEB)将sfiI-VH-接头-VL-sfiI(其中将各个CDR的位置通过NNK简并密码子随机化为20个氨基酸)插入线性化载体中以构建突变体文库。
实施例2:具有改进的亲和力的抗体的选择
构建的突变体文库使用TG1大肠杆菌(E.coli)作为宿主细胞,并且具有约3.10×1010个转化体。以噬菌体形式回收这些突变体文库,并且通过应用噬菌体展示技术富集展现出对c-Met的更高结合能力的抗体库,并且通过使用ELISA进行筛选来选择出亲和力变体。首先选择13种具有改进的亲和力的克隆,并且这些克隆是1F12_H35H、1F12_H53D、1F12_H57K、1F12_H58D、1F12_H60N、1F12_H100eH、1F12_H100hR、1F12_L26D、1F12_L27bD、1F12_L50E、1F12_L51D、1F12_L95aR和1F12_L96D。1F12-H35H意指这样的突变,其中基于KABAT编号,1F12重链的位置35处的氨基酸被组氨酸(H)取代,并且1F12_L26D意指这样的突变,其中1F12轻链的位置26处的氨基酸被天冬氨酸取代。对于这13种亲和力改进的突变体抗体,在哺乳动物细胞中构建全长人IgG1产生载体,并且该构建是根据制造商手册使用Expi293表达系统(Gibco)执行的。因此,1F12_H100hR(其中亲本抗体的重链中位置100h处的氨基酸被精氨酸取代的克隆)在重复制备期间不表达所有抗体。获得了1F12的六种重链CDR残基被取代的抗体和六种轻链CDR残基被取代的抗体,并通过组合这些抗体产生了四种另外的抗体(1F12_H2L3、1F12_H2L6、1F12_H3L5、1F12_H6L5)。1F12_H2L3是通过以下方式产生的抗体:将其中重链可变区的位置53处的氨基酸被天冬氨酸取代的重链表达载体与其中轻链可变区的位置50处的氨基酸被谷氨酸取代的轻链表达载体组合(意味着它是用分别在7种类型的重链突变体表达载体和6种类型的轻链突变体表达载体中的第二表达载体和第三表达载体产生的)。总之,在图5中除了1F12_H100hR以外的抗体都可以在哺乳动物细胞中表达和纯化,并用于随后的实验中。
表3中显示了总共17种类型的改进的抗体的CDR序列,并且表4中显示了重链可变区序列和轻链可变区序列。另外,表5中显示了编码每种改进的抗体的多核苷酸序列。
[表3]
重链CDR和轻链CDR的氨基酸序列
[表4]
重链可变区序列和轻链可变区序列
[表5]
用于编码重链可变区和轻链可变区的多核苷酸序列
实施例3:激动剂活性分析
激动剂活性的分析对于c-Met抗体的开发至关重要。一般抗体具有带两个互补位的二价结构,这两个互补位识别呈Y型的靶标。为此,一种c-Met抗体与两种c-Met靶抗原结合,这诱导了c-Met二聚化,从而产生激活下游信号传导途径的激动剂活性。Genentech使用杂交瘤技术开发了一种5D5抗体,但是该抗体与c-Met结合并且展现出与c-Met的配体HGF/SF相似的作用,从而产生了改进信号转导途径的激动剂活性。为了使这种现象最小化,将5D5抗体改进为单臂形式OA-5D5,并且使激动剂活性最小化。
测量Akt磷酸化程度,以对亲本抗体1F12和16种亲和力变体的激动剂活性进行定量。特别地,当在96孔细胞培养板中的Caki-1肾细胞癌细胞系在RPMI1640完全培养基(+10%FBS)中达到每孔约70%汇合度时,进行血清饥饿24小时。用亲本抗体和16种亲和力变体处理细胞系,并且将c-Met激动剂抗体5D5、展现出最小激动剂活性的OA-5D5以及c-Met配体HGF/SF(R&D systems)用作对照组。将PBS以与用样品媒介物处理的样品相同的体积进行处理,将抗体以10μg/mL处理,并且将HGF/SF以50ng/L处理。抗体和配体的处理时间为30分钟,并且所述实验一式三份地执行。在用每个样品处理后30分钟立即用1X PBS执行洗涤一次,并使用裂解缓冲液执行细胞裂解。然后,使用Phospho-Akt Sandwich ELISA试剂盒(Cell Signaling Technology)根据制造商手册测量Akt磷酸化,测量每个孔的发光信号,将PBS处理组的值转换为0%并且将HGF/SF处理组的值转换为100%,并且将每种抗体的激动剂活性数字化。c-Met激动剂抗体5D5诱导86.01%的Akt磷酸化,并且展现出与HGF的激动剂活性类似的激动剂活性。经修饰以最小化激动剂活性的OA-5D5(单臂单价抗体)展现出为30.46%的降低的激动剂活性。相比之下,发现1F12亲本抗体的激动剂活性为18.23%,并且下表6(图6)中显示了16种类型的亲和力变体的激动剂活性。
[表6]
对抗体在Caki-1细胞系中的激动剂活性的分析
平均值(%) | 标准偏差 | |
PBS | 0.00 | 3.12 |
1F12 | 18.23 | 2.31 |
1F12_H35H | 17.32 | 6.51 |
1F12_H53D | 24.47 | 0.23 |
1F12_H57K | 26.84 | 6.77 |
1F12_H58D | 21.53 | 4.43 |
1F12_H60N | 27.70 | 7.94 |
1F12_H100eH | 27.46 | 8.59 |
1F12_L26D | 38.06 | 2.31 |
1F12_L27bD | 30.27 | 9.37 |
1F12_L50E | 37.17 | 13.70 |
1F12_L51D | 42.49 | 6.12 |
1F12_L95aR | 29.50 | 2.38 |
1F12_L96D | 21.20 | 14.10 |
1F12_H2L3 | 24.53 | 9.29 |
1F12_H2L6 | 25.97 | 9.34 |
1F12_H3L5 | 18.92 | 4.05 |
1F12_H6L5 | 18.18 | 4.29 |
OA-5D5 | 30.46 | 4.10 |
5D5 | 86.01 | 5.36 |
HGF | 100.00 | 11.41 |
实施例4:亲和力分析
一式三份地执行基于ELISA的亲和力分析。将重组人c-Met(Sino biological)以50ng/孔在96孔ELISA平板(Costar)上于4℃下包被过夜。第二天,用3%脱脂乳溶液执行封闭1小时,然后使用1X PBST(Cell Signaling Technology)执行洗涤三次。将每种抗体从PBS(Gibco)中的200nM稀释1/2,在每个孔中的100μL体积中进行处理,并在室温下静置1小时。在使用1XPBST(Cell Signaling Technology)洗涤三次后,将在3%脱脂乳溶液中以1:10000稀释的抗人Fab-HRP(Thermo Scientific)二抗以100μL的量添加到每个孔中,然后在室温下静置1小时。在使用1X PBST(Cell Signaling Technology)将每个孔洗涤5次后,将每个孔用100μL的TMB溶液(Thermo Scientific)处理,然后当颜色开始变蓝时用100μL的终止溶液(Cell Signaling Technology)处理以终止反应。使用UV/VIS分光光度计测量OD450,并将该值归一化。结果显示,与亲本抗体(1F12)相比,1F12_H2L3、1F12_H2L6、1F12_H3L5和1F12_H6L5克隆的亲和力增加,并且1F12_H3L5克隆展现出最高的亲和力(图7)。
实施例5:对癌细胞生长抑制能力的分析
MKN45是c-Met被扩增的胃癌细胞系,获自JCRB Cell Bank(日本),进行培养并且随后保持在补充有10%FBS的RPMI 1640培养基中。使用奥那妥珠单抗(Onartuzumab)(OA-5D5;单价c-Met抗体,Genentech)作为对照抗体,并基于公开的抗体序列构建抗体表达载体。使用Expi293表达系统(Gibco)执行瞬时表达,通过使用安装在AKTA avant(GE)上的MabSelect SuRe(GE)的亲和色谱法执行纯化,并且通过SE-HPLC分析检测出纯度为98%或更高。通过ELISA和SPR分析确定与文献中报道的结果的相似性。为了分析对细胞生长的抑制活性,将细胞以3,000个细胞/孔的密度接种在96孔测定板(Corning,3610)上含有RPMN1640和10%FBS的完全培养基中,并孵育过夜以使细胞附着于测定板上,去除培养基,并将抗体在完全培养基中从最大100nM稀释1/5,并用100μL的培养基处理。在72小时后,将每个孔用100μL的Cell Titer Glo(Promega)处理,并使用Infinite M200 Pro(TECAN)分析细胞活力。结果显示,1F12_H2L3、1F12_H2L6、1F12_H3L5和1F12_H6L5抗体展现出比未修饰的(亲本)抗体(1F12)和对照抗体奥那妥珠单抗更好的功效,并且确定1F12_H3L5抗体展现出最佳功效(图8)。
实施例6:对动物模型中肿瘤生长抑制能力的评价
为了评价在移植了肿瘤细胞的动物模型中的肿瘤生长抑制能力,将作为小鼠结肠癌肿瘤细胞的MC38细胞移植到小鼠体内以构建肿瘤动物模型,并在给予1F12_H3L5后评价肿瘤生长抑制能力。
以200,000个细胞/100μL的密度制备MC38。此时,使用含有以1:1混合的汉克盐(Hank's Salt,HBSS)溶液(Gibco)和基础基底膜基质(Basal Matrigel,)的溶液。使用1cc注射器(26G)将制备的细胞以100μL移植到7至8周大的雌性C57BL/6小鼠背部右侧的后部中。
1F12_H3L5(20mg/kg,腹膜内)和阿特珠单抗(5mg/kg,腹膜内)的给予是从将MC38细胞系移植到每只小鼠体内后的第5天开始,并且每周进行两次。为了评价共给予时的反应性,在肿瘤移植后的第5天,像单一给予组一样给予1F12_H3L5(20mg/kg,腹膜内)和阿特珠单抗(5mg/kg,腹膜内)。首先给予1F12_H3L5(20mg/kg,腹膜内),然后给予阿特珠单抗(5mg/kg,腹膜内)。通过使用卡尺测量以毫米(mm)为单位的长轴和短轴,并将测量值应用于[(长轴)×(短轴)2×0.5]的计算公式来计算肿瘤大小。
评价结果显示,MC38肿瘤动物模型未展现出1F12_H3L5(20mg/kg,腹膜内),并且阿特珠单抗(5mg/kg,腹膜内)给予组展现出约40%至约50%的肿瘤抑制率。与对照组相比,同一模型中的共给予组(1F12_H3L5+阿特珠单抗)抑制肿瘤形成(肿瘤移植后22天),并且在共给予组中只有一名受试者体内形成了肿瘤,并且肿瘤在其余四名受试者中仍未形成(在实验终止后约43天)。
在MC38肿瘤动物模型中进行的动物测试的结果表明,通过1F12_H3L5和阿特珠单抗(PD-L1抑制剂)(其已知是一种典型的免疫检查点抑制剂)的共给予可以改进1F12_H3L5的治疗功效(图9)。
实施例7:在动物模型中评价对组合疗法与放射疗法的反应性
为了评价在移植了肿瘤细胞的动物模型中的肿瘤生长抑制能力,将作为小鼠结肠癌肿瘤细胞的MC38细胞移植到小鼠体内以创建肿瘤动物模型,并在给予1F12_H3L5后评价肿瘤生长抑制能力。
以200,000个细胞/100μL的密度制备MC38。此时,使用含有以1:1比率混合的汉克盐(HBSS)溶液(Gibco)和基础基底膜基质的溶液。使用1cc注射器(26G)将制备的细胞以100μL的量移植到7至8周大的雌性C57BL/6小鼠背部右侧的后部中。通过使用卡尺测量以毫米(mm)为单位的长轴和短轴,并将测量值应用于[(长轴)×(短轴)2×0.5]的计算公式来计算肿瘤大小。为了进行放射疗法,在肿瘤植入后20天将小鼠麻醉,并使用辐射辐照器以2Gy的单剂量辐照皮下植入的肿瘤。
测试结果显示,在测试结束时,在受辐照组中观察到了约80%的肿瘤生长抑制,并且当1F12_H3L5或阿特珠单抗与辐照一起给予时,发现了约90%的肿瘤生长抑制能力(图10)。
实施例8:对MC38动物模型肿瘤中免疫细胞表达的分析
为了分析诸如用于与免疫检查点抑制剂等共给予的策略的机制,构建MC38动物模型,并且分析免疫细胞在肿瘤组织中的表达。
以200,000个细胞/100μL制备MC38。此时,使用含有以1:1比率混合的汉克盐(HBSS)溶液(Gibco)和基础基底膜基质的溶液。使用1cc注射器(26G)将制备的细胞以100μL的量移植到7至8周大的雌性C57BL/6小鼠背部右侧的后部中。当肿瘤大小达到约800-1,000mm3时,通过尸检获得肿瘤组织,并通过使用分离的肿瘤组织进行RNA测序来执行分析。使用先前在文献中报道的每种主要免疫细胞的基因表达特征进行分析。
MC38肿瘤组织中主要免疫细胞表达的检测结果显示,许多免疫细胞浸润在肿瘤中(图11)。这表明在MC38肿瘤模型中极有可能显现出对免疫检查点抑制剂治疗和肿瘤免疫相关治疗的反应性,并且预期可以根据在随后测试中肿瘤中免疫细胞表达的趋势来预测治疗反应性。
实施例9:对肿瘤中免疫检查点PD-L1的分析
为了检测在给予了1F12_H3L5的小鼠和未给予1F12_H3L5的小鼠的MC38肿瘤细胞中免疫检查点PD-L1的表达的变化,将肿瘤组织分离成单个细胞。通过用作为免疫细胞标记物的CD45和PD-L1对单独细胞进行染色,执行对肿瘤细胞中的PD-L1的分析。为了排除侵入肿瘤细胞的免疫细胞,在不表达CD45的细胞中检测PD-L1的表达。
结果显示,在给予了1F12_H3L5的小鼠受试者中,表达PD-L1的细胞的数量增加大于两倍(图12)。这表明对1F12_H3L5和PD-L1抑制剂的敏感性可能增加。
工业实用性
根据本发明的与c-Met结合的抗体或其抗原结合片段可以以高亲和力与人和小鼠c-Met结合,因此在使用小鼠肿瘤模型的功效评价中展现出更准确的临床前结果。根据本发明的与c-Met结合的抗体或其抗原结合片段可用于预防或治疗目标癌症。
尽管已经详细描述了本发明的具体配置,但本领域技术人员应理解,出于说明目的提供本说明书以阐述优选实施方案,并且不应理解为限制本发明的范围。因此,本发明的实质范围由所附权利要求书及其等同物进行限定。
序列表自由文本
附有电子文件。
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<120> 与C-MET特异性结合的抗体及其用途
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<213> 人工序列
<220>
<223> 引物
<400> 10
aaaggtgaat ccagaggctg caca 24
<210> 11
<211> 75
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 11
gggaaggggc tggagtgggt ctcannkatc nnknnknnkn nknnknnknn ktattacgct 60
gattctgtaa aaggt 75
<210> 12
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 12
tgagacccac tccagcccct tccc 24
<210> 13
<211> 72
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 13
atctcttata gtggtggtag tacannknnk nnknnknnkn nknnknnkcg gttcaccatc 60
tccagagaca at 72
<210> 14
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 14
tgtactacca ccactataag agat 24
<210> 15
<211> 75
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 15
gacacggccg tgtattactg tgcgarannk nnkarannkt gtnnknnknn kgcttgttct 60
tatgctaatg gtatg 75
<210> 16
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 16
cgcacagtaa tacacggccg tgtc 24
<210> 17
<211> 69
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 17
gctagtcgtt cttgtcagcg gcctnnktgt nnknnknnkn nknnkatgga cgtctggggc 60
cagggtaca 69
<210> 18
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 18
aggccgctga caagaacgac tagc 24
<210> 19
<211> 66
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 19
gggcagaggg tcaccatctc ttgtnnknnk nnknnknnkn nkattggcaa taattatgtc 60
acctgg 66
<210> 20
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 20
acaagagatg gtgaccctct gccc 24
<210> 21
<211> 69
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 21
tcttgtactg gctcttcatc taatnnknnk nnknnknnkn nknnktggta ccagcagctc 60
ccaggaacg 69
<210> 22
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 22
attagatgaa gagccagtac aaga 24
<210> 23
<211> 69
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 23
acggccccca aactcctcat ctatnnknnk nnknnknnkn nknnkggggt ccctgaccga 60
ttctctggc 69
<210> 24
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 24
atagatgagg agtttggggg ccgt 24
<210> 25
<211> 107
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 25
tggtgctggc cggcctggcc taggaccgtc agcttggtgc ctccgccgaa gacataagca 60
ctcaggctmn nmnnmnnmnn mnnacagtaa taatcagcct catcctc 107
<210> 26
<211> 92
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 26
tggtgctggc cggcctggcc taggaccgtc agcttggtgc ctccgccgaa mnnmnnmnnm 60
nnmnnmnnat aatcccaaga accacagtaa ta 92
<210> 27
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CDRH1
<400> 27
Asn Tyr Ala Met His
1 5
<210> 28
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDRH2
<400> 28
Gly Ile Ser Tyr Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 29
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDRH2
<400> 29
Gly Ile Ser Tyr Ser Gly Gly Ser Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 30
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDRH2
<400> 30
Gly Ile Ser Tyr Ser Gly Gly Ser Thr Asp Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 31
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDRH2
<400> 31
Gly Ile Ser Tyr Ser Gly Gly Ser Thr Tyr Tyr Asn Asp Ser Val Lys
1 5 10 15
Gly
<210> 32
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> CDRH3
<400> 32
Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys His Tyr Ala Asn Gly Met
1 5 10 15
Asp Val
<210> 33
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> CDRH3
<400> 33
Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys Ser Tyr Ala Arg Gly Met
1 5 10 15
Asp Val
<210> 34
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDRL1
<400> 34
Thr Gly Asp Ser Ser Asn Ile Gly Asn Asn Tyr Val Thr
1 5 10
<210> 35
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDRL1
<400> 35
Thr Gly Ser Ser Ser Asp Ile Gly Asn Asn Tyr Val Thr
1 5 10
<210> 36
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDRL2
<400> 36
Glu Asn Asn His Arg Pro Ser
1 5
<210> 37
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDRL2
<400> 37
Tyr Asp Asn His Arg Pro Ser
1 5
<210> 38
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDRL3
<400> 38
Gly Ser Trp Asp Tyr Ser Leu Arg Ala Tyr Val
1 5 10
<210> 39
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDRL3
<400> 39
Gly Ser Trp Asp Tyr Ser Leu Ser Ala Asp Val
1 5 10
<210> 40
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 40
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 Asn Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Ser 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys Ser Tyr Ala Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 41
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 41
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asn Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 42
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 42
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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys Ser Tyr Ala Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 43
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 43
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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Ser Gly Gly Ser Lys 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys Ser Tyr Ala Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 44
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 44
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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Ser Gly Gly Ser Thr Asp 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys Ser Tyr Ala Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 45
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 45
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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Ser Gly Gly Ser Thr Tyr Tyr Asn 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys Ser Tyr Ala Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 46
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 46
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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Ser 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys His Tyr Ala Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 47
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 47
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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Ser 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys Ser Tyr Ala Arg
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 48
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 48
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 Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Tyr Ser 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Ser Arg Ser Cys Gln Arg Pro Ala Cys Ser Tyr Ala Asn
100 105 110
Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 49
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 49
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Asp Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asn Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 50
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 50
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asp Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asn Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 51
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 51
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Glu Asn Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 52
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 52
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asp Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 53
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 53
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asn Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Arg Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 54
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 54
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asn Asn His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu
85 90 95
Ser Ala Asp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 55
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 55
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc aattatgcta tgcactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaggg atctcttata gtggtggtag tacatattac 180
gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaagctagt 300
cgttcttgtc agcggcctgc ttgttcttat gctaatggta tggacgtctg gggccagggt 360
acactggtca ccgtgagctc a 381
<210> 56
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 56
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgtactg gctcttcatc taatattggc aataattatg tcacctggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat tataataatc atcggccaag cggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tccgaggatg aggctgatta ttactgtggt tcttgggatt atagcctgag tgcttatgtc 300
ttcggcggag gcaccaagct tacggtccta 330
<210> 57
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 57
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc aattatgcta tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaggg atctcttatg atggtggtag tacatattac 180
gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaagctagt 300
cgttcttgtc agcggcctgc ttgttcttat gctaatggta tggacgtctg gggccagggt 360
acactggtca ccgtgagctc a 381
<210> 58
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 58
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc aattatgcta tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaggg atctcttata gtggtggtag taaatattac 180
gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaagctagt 300
cgttcttgtc agcggcctgc ttgttcttat gctaatggta tggacgtctg gggccagggt 360
acactggtca ccgtgagctc a 381
<210> 59
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 59
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc aattatgcta tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaggg atctcttata gtggtggtag tacagattac 180
gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaagctagt 300
cgttcttgtc agcggcctgc ttgttcttat gctaatggta tggacgtctg gggccagggt 360
acactggtca ccgtgagctc a 381
<210> 60
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 60
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc aattatgcta tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaggg atctcttata gtggtggtag tacatattac 180
aatgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaagctagt 300
cgttcttgtc agcggcctgc ttgttcttat gctaatggta tggacgtctg gggccagggt 360
acactggtca ccgtgagctc a 381
<210> 61
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 61
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc aattatgcta tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaggg atctcttata gtggtggtag tacatattac 180
gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaagctagt 300
cgttcttgtc agcggcctgc ttgtcattat gctaatggta tggacgtctg gggccagggt 360
acactggtca ccgtgagctc a 381
<210> 62
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 62
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc aattatgcta tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaggg atctcttata gtggtggtag tacatattac 180
gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaagctagt 300
cgttcttgtc agcggcctgc ttgttcttat gctagaggta tggacgtctg gggccagggt 360
acactggtca ccgtgagctc a 381
<210> 63
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> Heavy Chain Variable region
<400> 63
gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc aattatgcta tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaggg atctcttata gtggtggtag tacatattac 180
gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaagctagt 300
cgttcttgtc agcggcctgc ttgttcttat gctaatggta tggacgtctg gggccagggt 360
acactggtca ccgtgagctc a 381
<210> 64
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 64
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgtactg gcgattcatc taatattggc aataattatg tcacctggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat tataataatc atcggccaag cggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tccgaggatg aggctgatta ttactgtggt tcttgggatt atagcctgag tgcttatgtc 300
ttcggcggag gcaccaagct tacggtccta 330
<210> 65
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 65
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgtactg gctcttcatc tgatattggc aataattatg tcacctggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat tataataatc atcggccaag cggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tccgaggatg aggctgatta ttactgtggt tcttgggatt atagcctgag tgcttatgtc 300
ttcggcggag gcaccaagct tacggtccta 330
<210> 66
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 66
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgtactg gctcttcatc taatattggc aataattatg tcacctggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat gaaaataatc atcggccaag cggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tccgaggatg aggctgatta ttactgtggt tcttgggatt atagcctgag tgcttatgtc 300
ttcggcggag gcaccaagct tacggtccta 330
<210> 67
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 67
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgtactg gctcttcatc taatattggc aataattatg tcacctggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat tatgataatc atcggccaag cggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tccgaggatg aggctgatta ttactgtggt tcttgggatt atagcctgag tgcttatgtc 300
ttcggcggag gcaccaagct tacggtccta 330
<210> 68
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 68
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgtactg gctcttcatc taatattggc aataattatg tcacctggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat tataataatc atcggccaag cggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tccgaggatg aggctgatta ttactgtggt tcttgggatt atagcctgag agcttatgtc 300
ttcggcggag gcaccaagct tacggtccta 330
<210> 69
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> Light Chain Variable region
<400> 69
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgtactg gctcttcatc taatattggc aataattatg tcacctggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat tataataatc atcggccaag cggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tccgaggatg aggctgatta ttactgtggt tcttgggatt atagcctgag tgctgatgtc 300
ttcggcggag gcaccaagct tacggtccta 330
Claims (20)
1.一种抗c-Met抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:重链可变区,所述重链可变区含有具有SEQ ID NO:1或27的氨基酸序列的重链CDR1、具有选自SEQ IDNO:2和28至31的氨基酸序列的重链CDR2、和具有选自SEQ ID NO:3、32和33的氨基酸序列的重链CDR3;以及
轻链可变区,所述轻链可变区含有具有选自SEQ ID NO:4、34和35的氨基酸序列的轻链CDR1、具有选自SEQ ID NO:5、36和37的氨基酸序列的轻链CDR2、和具有选自SEQ ID NO:6、38和39的氨基酸序列的轻链CDR3。
2.根据权利要求1所述的抗c-Met抗体或其抗原结合片段,其中所述抗c-Met抗体或其抗原结合片段包含重链可变区,所述重链可变区含有选自SEQ ID NO:40和42至48的氨基酸序列;以及轻链可变区,所述轻链可变区选自SEQ ID NO:41和49至54。
3.根据权利要求1或2所述的抗c-Met抗体或其抗原结合片段,其中所述抗c-Met抗体是单克隆抗体。
4.根据权利要求1或2所述的抗c-Met抗体或其抗原结合片段,其中所述抗原结合片段选自所述抗c-Met抗体的scFv、(scFv)2、scFv-Fc、Fab、Fab'和F(ab')2。
5.根据权利要求1所述的抗c-Met抗体或其抗原结合片段,其中所述抗c-Met抗体或其抗原结合片段与人c-Met和小鼠c-Met交联。
6.一种双特异性抗体或抗体-药物缀合物,所述双特异性抗体或抗体-药物缀合物包含根据权利要求1所述的抗c-Met抗体或其抗原结合片段。
7.一种用于预防或治疗癌症的药物组合物,所述药物组合物包含根据权利要求1所述的抗c-Met抗体或其抗原结合片段作为活性成分。
8.一种用于预防或治疗癌症的药物组合物,所述药物组合物包含根据权利要求6所述的双特异性抗体或抗体-药物缀合物作为活性成分。
9.根据权利要求7或8所述的药物组合物,其中所述癌症是乳腺癌、结肠癌、肺癌、胃癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、脑癌、子宫癌、鼻咽癌、喉癌、结肠癌、卵巢癌、直肠癌、结直肠癌、阴道癌、小肠癌、内分泌癌、甲状腺癌、甲状旁腺癌、输尿管癌、尿道癌、前列腺癌、支气管癌、膀胱癌、肾癌或骨髓癌。
10.根据权利要求7或8所述的药物组合物,其中所述药物组合物用于使用放射的组合疗法。
11.一种核酸,所述核酸编码根据权利要求1所述的抗c-Met抗体或其抗原结合片段。
12.一种重组表达载体,所述重组表达载体包含根据权利要求11所述的核酸。
13.一种使用根据权利要求12所述的重组表达载体转化的宿主细胞。
14.根据权利要求13所述的宿主细胞,其中所述宿主细胞选自动物细胞、植物细胞、酵母、大肠杆菌和昆虫细胞。
15.根据权利要求13所述的宿主细胞,其中所述宿主细胞选自:猴肾细胞(COS7)、NSO细胞、SP2/0细胞、中国仓鼠卵巢(CHO)细胞、W138、幼仓鼠肾(BHK)细胞、MDCK、骨髓瘤细胞系,HuT78细胞、HEK293细胞、枯草芽孢杆菌、链霉菌属物种、假单胞菌属物种、奇异变形杆菌、葡萄球菌属物种、曲霉属物种、巴斯德毕赤酵母、酿酒酵母、裂殖酵母属物种和粗糙脉孢菌。
16.一种产生抗c-Met抗体或其抗原结合片段的方法,所述方法包括培养根据权利要求13至15中任一项所述的宿主细胞。
17.一种用于通过共给予治疗癌症的组合物,所述组合物包含根据权利要求1所述的抗c-Met抗体或其抗原结合片段以及另外的癌症治疗剂。
18.根据权利要求17所述的组合物,其中所述癌症治疗剂是免疫检查点抑制剂。
19.根据权利要求18所述的组合物,其中所述免疫检查点抑制剂是抗CTLA-4抗体、抗PD-1抗体或抗PD-L1抗体。
20.根据权利要求17所述的组合物,其中所述癌症是乳腺癌、结肠癌、肺癌、胃癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、脑癌、子宫癌、鼻咽癌、喉癌、结肠癌、卵巢癌、直肠癌、结直肠癌、阴道癌、小肠癌、内分泌癌、甲状腺癌、甲状旁腺癌、输尿管癌、尿道癌、前列腺癌、支气管癌、膀胱癌、肾癌或骨髓癌。
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KR10-2019-0050780 | 2019-04-30 | ||
PCT/KR2019/005257 WO2019212253A1 (ko) | 2018-05-02 | 2019-05-02 | C-met에 특이적으로 결합하는 항체 및 그의 용도 |
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WO2024131949A1 (zh) * | 2022-12-23 | 2024-06-27 | 苏州宜联生物医药有限公司 | Anti-cMet抗体、抗体药物偶联物及其制备方法和用途 |
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