CN116419928A - Fcα受体结合抗体 - Google Patents
Fcα受体结合抗体 Download PDFInfo
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- CN116419928A CN116419928A CN202180075236.XA CN202180075236A CN116419928A CN 116419928 A CN116419928 A CN 116419928A CN 202180075236 A CN202180075236 A CN 202180075236A CN 116419928 A CN116419928 A CN 116419928A
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Abstract
本发明涉及增大对人类Fcα受体的结合力的抗体以及将利用其的抗体作用机制最大化的技术,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段通过以IgG形态与效应(effector)细胞,尤其是与在哺乳动物中占最多比例的中性粒细胞的Fcα受体结合来克服现有IgA抗体的缺点并在多种抗体治疗剂中使效应子功能最大化,从而具有使抗体的作用机制(抗体依赖性细胞介导的细胞毒性作用(ADCC)及抗体依赖性细胞吞噬作用(ADCP))最大化的效果,因此可以将利用其的多种Fc‑融合蛋白治疗剂有效用作效应子功能得到提高的药品。
Description
技术领域
本发明涉及增大对人类Fcα受体的结合力的抗体以及将利用其的抗体作用机制最大化的技术。
背景技术
抗体提供体液免疫系统与细胞免疫系统之间的桥梁,抗体的Fab区域识别抗原,与之相反,Fc部分通过所有免疫活性细胞与有差别地表达的Fc受体(FcR)结合。通过由多元抗原/抗体复合体引起的受体的交联,触发靶向细胞的脱粒化、细胞裂解、或吞噬作用及细胞因子-编码基因的转录-激活(Deo,Y.M.et al.,Immunol.Today 18(3):127-135(1997))。抗体通过使抗体Fc区域上的Fc受体结合部位与细胞上的Fc受体(FcR)结合来通过Fc区域与细胞结合。对于免疫球蛋白的Fc区域的受体,在触发单核细胞、巨噬细胞及多形核细胞的许多防御功能方面具有重要作用。这些细胞上对于免疫球蛋白的受体(Fc受体或FcR)被广泛地研究,查明产生对这些受体的单克隆抗体来其在治疗上有效。当抗体与细胞表面上的Fc受体结合时,不仅在包括抗体-包被粒子的吞噬及破坏、免疫复合物的消除、由杀伤细胞引起的抗体-包被靶向细胞的裂解(称为抗体依赖性细胞介导的细胞毒性或ADCC)、炎症介质的释放、胎盘移动及免疫球蛋白生成的控制在内的多方面具有重要作用,而且还触发多种生物学反应。
存在对包括IgG(免疫球蛋白G)(γ受体)、IgE(免疫球蛋白E)(ε受体)、IgA(免疫球蛋白A)(α受体)及IgM(免疫球蛋白M)(μ受体)在内的不同种类的抗体具有特异性的几种Fc受体。其中,IgA受体(Fcα受体或CD89)可以增进效应(effector)细胞的功能。当配体与Fcα受体结合时,触发白细胞及保有Fcα受体的细胞株的抗体依赖性细胞吞噬作用(antibody-dependent cellular phagocytosis,ADCP)和抗体依赖性细胞介导的细胞毒性作用(antibody dependent cellular cytotoxicity,ADCC)。并且,Fcα受体可以通过与对效应细胞上的IgG的受体协同来强化对靶向细胞的抗体依赖细胞吞噬作用。通过抗体Fc区域介导的效应子功能(effector function)可以分为两种:(1)抗体与抗原结合后启动的效应子功能(这样的功能包括例如与补体连续扩增反应相关的或Fc受体(FcR)-保有细胞);以及(2)与抗原结合分开启动的效应子功能(这样的功能赋予例如通过穿胞作用(transcytosis)横穿细胞屏障的能力以及在循环中的持续性)。例如,当补体的Cl成分与抗体结合时,激活补体系统。补体的激活在细胞病原体的调理素化及裂解中起到重要作用。而且,补体的激活还可以刺激炎症反应,与自身免疫过敏症相关。如上所述,Fcα受体或CD89为与IgA的Fc部分结合的受体(Kerr、M.A.1990、Biochem.J.271:285-296),总是主要在包括多形核白细胞(PMN)、单核细胞、巨噬细胞、中性粒细胞及嗜酸性粒细胞在内的细胞毒性免疫效应细胞上表达(Morton、H.C.、et al.、1996、Critical Reviews in Immunology 16:423)。并且,据报告,Fcα受体在淋巴细胞亚群中表达(Morton、H.C.、et al.、1996、CriticalReviews in Immunology16:423),也在肾小球血管系膜细胞(mesangial cell)上表达(Gomez-Guerrero、C.、et al.、1996、J.Immunol.156:4369-4376)。人类Fcα受体的α链多被糖基化,是属于也包含对于IgG及IgE的受体的Ig超级基因组的I型跨膜分子。位于19号染色体上的一个基因编码FcαRIα链的以多种方式剪接(splicing)的多数同型(55kDa至110kDa,Morton、H.C.、et al.、1996、Critical Reviews in Immunology 16:423)。查明骨髓细胞性Fcα受体与在Fcα受体信号传递中起作用的FcRγ链关联(Morton、H.C.et al.1995、J.Biol.Chem.270:29781;Pfefferkorn、L.C.、et al.1995、J.Immunol.153:3228-3236;Saito、K.et al.、1995、J.Allergy Clin.Immunol.96:1152)。Fcα受体与结合有抗原的IgA1与IgA2以及单体IgA1与IgA2结合(Mazangera、R.L.et al.、1990、Biochem.J.272:159-165),这是因为,与FcγR及FcεRI分别被IgG及IgE饱和的方法相同,上述受体在生物体内被单体IgA抗原饱和。骨髓效应细胞上的Fcα受体与综合性IgA、IgA免疫复合物或者与对配体结合结构域内部或外部的表位具有特异性的mAb的交叉结合刺激脱粒化、过氧化物释放、炎性细胞因子的分泌、胞吞作用(endocytosis)及抗体依赖细胞吞噬作用(Patty,C.,A.Herbelin,A.Lihuen,J.F.Bach,and R.C.Monteiro,1995,Immunology 86:1-5;Stewart,W.W.,R.L.MazYegera,L.Shen,and M.A.Kerr,1994,J.Leucocyte Biology 56:481-487;Stewart,W.W.,and M.A.Kerr,1990,Immunology 71:328-334;Shen,L.,1992,J.LeukocyteBiology 51:373-378)。通过Fcα受体触发的这些生理学反应可以在黏膜表面上的第一线体液防御中发挥重要作用(Morton,H.C.,M.van Egmond,and J.G.J.van de Winkel,1996,Critical Reviews in Immunology 16:423)。
另一方面,多数研究结果认为Fc受体依赖机制是对肿瘤的细胞毒性抗体作用的实质原因,表明对肿瘤的最适抗体优先与激活的Fc受体结合(Clynes,R.A.,et al.,NatureMedicine 6(4):443-446(2000);Kalergis,A.M.,and Ravetch,J.V.,J.Exp.Med.195(12):1653-1659(2002年6月)。除抗体依赖性细胞介导的细胞毒性作用以外,种种成功的抗癌单克隆抗体通过激活细胞信号传递级联或阻断与生长因子的接近来诱导调节细胞存活、增殖或细胞凋亡的Fc-独立的直接信号传递机制(Selenko,N.,et al.,J Clin.Immunol.22(3):124-130(2002))。例如,确认到当使用利妥昔单抗处理CD20+B细胞时,诱导Mab-诱导的细胞凋亡(apoptosis)以及诱导补体介导的细胞裂解和抗体依赖性细胞介导的细胞毒性作用(Selenko,N.,et al.,J.Clin.Immunol.22(3):124-130(2002))。并且,淋巴瘤细胞的利妥昔单抗诱导的细胞凋亡不仅杀死细胞,还促进由抗原呈递树突状细胞(DC)引起的淋巴瘤细胞诱导的肽的吸收剂交叉呈递,诱导树突状细胞的成熟,从而产生特异性细胞毒性T淋巴细胞(CTL)。
Fc受体存在对包括IgG(γ受体)、IgE(ε受体)、IgA(α受体)及IgM(μ受体)在内的不同种类的抗体具有特异性的几种。其中,IgA受体(Fcα受体或CD89)可以增进效应(effector)细胞的功能。当配体与Fcα受体结合时,触发白细胞及保有Fcα受体的细胞株的抗体依赖性细胞吞噬作用(antibody-dependent cellular phagocytosis,ADCP)和抗体依赖性细胞介导的细胞毒性作用(antibody dependent cellular cytotoxicity,ADCC)。并且,Fcα受体可以通过与对效应细胞上的IgG的受体协同来强化对靶向细胞的抗体依赖细胞吞噬作用。通过抗体Fc区域介导的效应子功能(effector function)可以分为两种:(1)抗体与抗原结合后启动的效应子功能(这样的功能包括例如与补体连续扩增反应相关的或Fc(FcR)受体-保有细胞);以及(2)与抗原结合分开启动的效应子功能(这样的功能赋予例如通过穿胞作用(transcytosis)横穿细胞屏障的能力以及在循环中的持续性)。例如,当补体的Cl成分与抗体结合时,激活补体系统。补体的激活在细胞病原体的调理素化及裂解中起到重要作用。而且,补体的激活还可以刺激炎症反应,与自身免疫过敏症相关。如上所述,Fcα受体或CD89为与IgA的Fc部分结合的受体(Kerr,M.A.1990,Biochem.J.271:285-296),总是主要在包括多形核白细胞(PMN)、单核细胞、巨噬细胞、中性粒细胞及嗜酸性粒细胞在内的细胞毒性免疫效应细胞上表达(Morton,H.C.,etal.,1996,Critical Reviews inImmunology 16:423)。并且,据报告,Fcα受体在淋巴细胞亚群中表达(Morton,H.C.,etal.,1996,Critical Reviews in Immunology 16:423),也在肾小球血管系膜细胞(mesangial cell)上表达(Gomez-Guerrero,C.,et al.,1996,J.Immunol.156:4369-4376)。人类Fcα受体的α链多被糖基化,是属于也包含对于IgG及IgE的受体的Ig超级基因组的I型跨膜分子。位于19号染色体上的一个基因编码FcαRIα链的以多种方式剪接(splicing)的多数同型(55kDa至110kDa,Morton,H.C.,et al.,1996,Critical Reviewsin Immunology 16:423)。查明骨髓细胞性Fcα受体与在Fcα受体信号传递中起作用的FcRγ链关联(Morton,H.C.et al.1995,J.Biol.Chem.270:29781;Pfefferkorn,L.C.,etal.1995,J.Immunol.153:3228-3236;Saito,K.et al.,1995,J.AllergyClin.Immunol.96:1152)。Fcα受体与结合有抗原的IgA1与IgA2以及单体IgA1与IgA2结合(Mazangera,R.L.et al.,1990,Biochem.J.272:159-165),这是因为,与FcγR及FcεRI分别被IgG及IgE饱和的方法相同,上述受体在生物体内被单体IgA抗原饱和。骨髓效应细胞上的Fcα受体与综合性IgA、IgA免疫复合物的结合或者与对配体结合结构域内部或外部的表位具有特异性的mAb的交叉结合刺激脱粒化、过氧化物释放、炎性细胞因子的分泌、胞吞作用(endocytosis)及抗体依赖细胞吞噬作用(Patty,C.,A.Herbelin,A.Lihuen,J.F.Bach,andR.C.Monteiro,1995,Immunology 86:1-5;Stewart,W.W.,R.L.MazYegera,L.Shen,andM.A.Kerr,1994,J.Leucocyte Biology56:481-487;Stewart,W.W.,and M.A.Kerr,1990,Immunology 71:328-334;Shen,L.,1992,J.Leukocyte Biology 51:373-378)。通过Fcα受体触发的这些生理学反应可以在黏膜表面上的第一线体液防御中发挥重要作用(Morton,H.C.,M.van Egmond,and J.G.J.van de Winkel,1996,Critical Reviews inImmunology16:423)。
然而,哺乳动物中占有最高比例的这种利用白细胞的效应子功能的IgA不仅存在二聚体形态,还因复杂的糖基化、补充(tailpiece)等原因显出比IgG显著低的生产性,因无法与已知与体内的抗体再利用(recycle)相关的FcRn结合而具有比半衰期为3周的IgG短的1周的半衰期的非常大的缺点。
发明内容
技术问题
本发明的目的在于,为了改善IgA抗体生产性降低且半衰期短的缺点,使治疗用蛋白质药品的效应子功能最大化,提供与Fcα受体结合的新型IgG抗体或其具有免疫活性的片段,为了将上述抗体用作治疗用抗体而提出多种形态的双抗体或多抗体平台。
技术方案
为了实现上述目的,本发明提供对Fcα受体具有特异性的抗体或其具有免疫活性的片段。
并且,本发明提供双特异性或多特异性抗体。
并且,本发明提供编码上述抗体的分离的核酸分子、包含其的载体及由上述载体转化的宿主细胞。
并且,本发明提供包含双特异性或多特异性抗体作为有效成分的药物组合物。
并且,本发明提供制备对Fcα受体具有特异性的抗体或其具有免疫活性的片段的方法。
同时,本发明提供制备双特异性或多特异性抗体的方法。
发明的效果
本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段通过以IgG形态与效应(effector)细胞,尤其是与在哺乳动物中占最多比例的中性粒细胞的Fcα受体结合来克服现有IgA抗体的缺点并在多种抗体治疗剂中使效应子功能最大化,从而聚有使抗体的作用机制(抗体依赖性细胞介导的细胞毒性作用及抗体依赖性细胞吞噬作用(ADCP))最大化的效果,因此可以将利用其的多种Fc-融合蛋白治疗剂有效用作效应子功能得到提高的药品。
附图说明
图1示出制备的二聚体Fcα受体-细胞外结构域(ECD)抗原蛋白、四聚体Fcα受体-细胞外结构域抗原蛋白的载体以及它们的十二烷基磺酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)分析结果的图。
图2为示出利用流式细胞仪的抗体探索示意图的图。
图3为示出对Fcα受体-细胞外结构域显出很高结合亲和度的6种scFv人类抗体变异体氨基酸序列分析结果的图。
图4为6种scFv抗体变异体的Fcα受体结合力的分析结果。
图5为示出分别包含6种scFv抗体变异体的IgG(JS9、JS19、JS30、JS40、JS41及JS48)的载体以及在表达及纯化后的十二烷基磺酸钠-聚丙烯酰胺凝胶电泳照片的图。
图6为确认分别包含6种scFv抗体变异体的IgG抗体(JS9、JS19、JS30、JS40、JS41及JS48)的抗原结合力的图。
图7为示出通过超高速探索系统发掘的对Fcα受体-细胞外结构域显出增加的亲和度的3种新型scFv人类抗体变异体的氨基酸序列分析结果的图。
图8为示出通过流式细胞仪分析增加对Fcα受体-细胞外结构域的结合力的3种新型scFv抗体变异体JS116、JS144及JS140对Fcα受体-细胞外结构域的结合力的结果的图。
图9为示出用于将增加对Fcα受体-细胞外结构域的结合力的3种新型scFv抗体变异体制备为IgG形态的动物细胞表达载体以及在将其在动物细胞中表达及纯化后通过十二烷基磺酸钠-聚丙烯酰胺凝胶电泳来确认的图。
图10为示出通过酶联免疫吸附测定(ELISA)确认制备为IgG形态的增加对Fcα受体-细胞外结构域的结合力的3种抗体对Fcα受体-细胞外结构域的结合力的结果的图。
图11为示出用于制备具有JS40的重链可变区(VH)且具有JS48的轻链可变区(VL)的JS40-1抗体及具有JS48的重链可变区且具有JS40的轻链可变区的JS48-1抗体的动物细胞表达载体以及将其在动物细胞中表达及纯化后通过十二烷基磺酸钠-聚丙烯酰胺凝胶电泳来确认的图。
图12为示出通过酶联免疫吸附测定确认对JS40-1抗体及JS48-1抗体对Fcα受体-细胞外结构域的结合力的结果的图。
图13为示出利用IgG抗体JS40及JS48与曲妥珠单抗制备的与2种抗原(Fcα受体及Her-2)结合的双抗体(8种)的表达载体的图。
图14为示出动物细胞表达及纯化的8种双抗体的十二烷基磺酸钠-聚丙烯酰胺凝胶电泳照片。
图15为确认双抗体对2种抗原的结合力的图:[A]部分及[B]部分:对Fcα受体的结合力;[C]部分及[D]部分:对Her-2的结合力。
具体实施方式
以下,参照附图通过本发明的示例详细说明本发明。但是,下述示例仅用于例示本发明,而非以此来限制本发明,对于本发明所属技术领域的普通技术人员熟知的技术或结构的具体说明若判断为会不必要地混淆本发明的要旨,则将省略其详细说明。本发明可以在随附的发明要求保护范围的记载内容及由此解释的同等范畴内进行多种变形及应用。
并且,本说明书中使用的术语(terminology)为适当表达本发明的优选实施例而使用,可以随使用人员、运用人员的意图或本发明所属技术领域的惯例等的不同而不同。因此,应基于本说明书全文的内容来给上述术语下定义。在说明书全文中,当提及某结构要素“包含”某结构要素时,若无特别反对的记载,则表示还可以包含其他结构要素,而不是排除其他结构要素。
在本说明书全文中,不仅对天然存在的氨基酸使用单字母或三字母的代码,对于其他氨基酸还使用Aib(α-氨基异丁酸)、Sar(N-甲基甘氨酸(N-methylglycine))等通常可接受的三字母代码。并且,本发明中以简称提及的氨基酸还根据IUPAC-IUB命名法来记载:丙氨酸:A,精氨酸:R,天冬酰胺:N,天冬氨酸:D,半胱氨酸:C,谷氨酸:E,谷氨酰胺:Q,甘氨酸:G,组氨酸:H,异亮氨酸:I,亮氨酸:L,赖氨酸:K,蛋氨酸:M,苯丙氨酸:F,脯氨酸:P,丝氨酸:S,苏氨酸:T,色氨酸:W,酪氨酸:Y,缬氨酸:V。
在本发明的一实施方式中,本发明涉及对Fcα受体具有特异性的抗体或其具有免疫活性的片段。
在一实例中,上述抗体可以为IgG,具有免疫活性的片段可以为选自由Fab、Fd、Fab'、dAb、F(ab')、F(ab')2、scFv(单链可变片段(single chain fragment variable))、Fv、单链抗体、Fv二聚体、互补决定区片段、人源化抗体、嵌合抗体及双特异抗体(diabody)组成的组中的任一种,更优选地,可以为scFv。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段包含:(a)VH结构域,包含CDRH(互补决定区重链(Complementarity determining regionsHeavy chain))1、CDRH2以及CDRH3,上述CDRH1包含选自由序列1至序列3的氨基酸序列组成的组中的任一种,上述CDRH2包含选自由序列4至序列7的氨基酸序列组成的组中的任一种,上述CDRH3包含选自由序列8至序列15的氨基酸序列组成的组中的任一种;和/或(b)VL结构域,包含CDRL(互补决定区轻链(Complementarity determining regions Light chain))1、CDRL2以及CDRL3,上述CDRL1包含选自由序列16至序列21的氨基酸序列组成的组中的任一种,上述CDRL2包含选自由序列22至序列27的氨基酸序列组成的组中的任一种,上述CDRL3包含选自由序列28至序列32的氨基酸序列组成的组中的任一种。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段包含:(a)VH结构域,包含FR1、FR2、FR3以及FR4,上述FR1包含选自由序列33至序列36的氨基酸序列组成的组中的任一种,上述FR2包含选自由序列37至序列41的氨基酸序列组成的组中的任一种,上述FR3包含选自由序列42至序列44的氨基酸序列组成的组中的任一种,上述FR4包含序列45或序列46的氨基酸序列;和/或(b)VL结构域,包含FR1、FR2、FR3以及FR4,上述FR1包含选自由序列47至序列52的氨基酸序列组成的组中的任一种,上述FR2包含选自由序列53至序列56的氨基酸序列组成的组中的任一种,上述FR3包含选自由序列57至序列63的氨基酸序列组成的组中的任一种,上述FR4包含选自由序列64至序列67的氨基酸序列组成的组中的任一种。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS40,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列33的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列37的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列11的氨基酸序列,上述FR4包含序列46的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列47的氨基酸序列,上述CDRL1包含序列16的氨基酸序列,上述FR2包含序列53的氨基酸序列、上述CDRL2包含序列24的氨基酸序列,上述FR3包含序列57的氨基酸序列,上述CDRL3包含序列28的氨基酸序列,上述FR4包含序列64的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS48,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列34的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列37的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列11的氨基酸序列,上述FR4包含序列46的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列49的氨基酸序列,上述CDRL1包含序列17的氨基酸序列,上述FR2包含序列54的氨基酸序列、上述CDRL2包含序列23的氨基酸序列,上述FR3包含序列59的氨基酸序列,上述CDRL3包含序列30的氨基酸序列,上述FR4包含序列65的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS116,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列33的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列37的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列8的氨基酸序列,上述FR4包含序列45的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列47的氨基酸序列,上述CDRL1包含序列16的氨基酸序列,上述FR2包含序列53的氨基酸序列、上述CDRL2包含序列22的氨基酸序列,上述FR3包含序列57的氨基酸序列,上述CDRL3包含序列28的氨基酸序列,上述FR4包含序列64的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS144,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列33的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列37的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列9的氨基酸序列,上述FR4包含序列45的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列47的氨基酸序列,上述CDRL1包含序列16的氨基酸序列,上述FR2包含序列53的氨基酸序列、上述CDRL2包含序列22的氨基酸序列,上述FR3包含序列57的氨基酸序列,上述CDRL3包含序列28的氨基酸序列,上述FR4包含序列64的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS140,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列34的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列38的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列10的氨基酸序列,上述FR4包含序列46的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列48的氨基酸序列,上述CDRL1包含序列17的氨基酸序列,上述FR2包含序列54的氨基酸序列、上述CDRL2包含序列23的氨基酸序列,上述FR3包含序列58的氨基酸序列,上述CDRL3包含序列29的氨基酸序列,上述FR4包含序列65的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS40-1,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列34的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列37的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列11的氨基酸序列,上述FR4包含序列46的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列49的氨基酸序列,上述CDRL1包含序列16的氨基酸序列,上述FR2包含序列54的氨基酸序列、上述CDRL2包含序列24的氨基酸序列,上述FR3包含序列59的氨基酸序列,上述CDRL3包含序列28的氨基酸序列,上述FR4包含序列65的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS40-1,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列33的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列37的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列11的氨基酸序列,上述FR4包含序列45的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列47的氨基酸序列,上述CDRL1包含序列17的氨基酸序列,上述FR2包含序列53的氨基酸序列、上述CDRL2包含序列23的氨基酸序列,上述FR3包含序列57的氨基酸序列,上述CDRL3包含序列30的氨基酸序列,上述FR4包含序列64的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS9,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列35的氨基酸序列,上述CDRH1包含序列2的氨基酸序列,上述FR2包含序列39的氨基酸序列,上述CDRH2包含序列6的氨基酸序列,上述FR3包含序列43的氨基酸序列,上述CDRH3包含序列23的氨基酸序列,上述FR4包含序列46的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列50的氨基酸序列,上述CDRL1包含序列18的氨基酸序列,上述FR2包含序列55的氨基酸序列、上述CDRL2包含序列25的氨基酸序列,上述FR3包含序列60的氨基酸序列,上述CDRL3包含序列31的氨基酸序列,上述FR4包含序列66的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS19,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列33的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列41的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列15的氨基酸序列,上述FR4包含序列46的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列52的氨基酸序列,上述CDRL1包含序列21的氨基酸序列,上述FR2包含序列56的氨基酸序列、上述CDRL2包含序列27的氨基酸序列,上述FR3包含序列63的氨基酸序列,上述CDRL3包含序列32的氨基酸序列,上述FR4包含序列67的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS30,上述JS40包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列36的氨基酸序列,上述CDRH1包含序列3的氨基酸序列,上述FR2包含序列40的氨基酸序列,上述CDRH2包含序列7的氨基酸序列,上述FR3包含序列44的氨基酸序列,上述CDRH3包含序列13的氨基酸序列,上述FR4包含序列46的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列51的氨基酸序列,上述CDRL1包含序列19的氨基酸序列,上述FR2包含序列54的氨基酸序列、上述CDRL2包含序列26的氨基酸序列,上述FR3包含序列61的氨基酸序列,上述CDRL3包含序列30的氨基酸序列,上述FR4包含序列65的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以为JS41,上述JS41包含V结构域,上述V结构域包含:(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列36的氨基酸序列,上述CDRH1包含序列3的氨基酸序列,上述FR2包含序列40的氨基酸序列,上述CDRH2包含序列7的氨基酸序列,上述FR3包含序列44的氨基酸序列,上述CDRH3包含序列14的氨基酸序列,上述FR4包含序列46的氨基酸序列;和/或(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列51的氨基酸序列,上述CDRL1包含序列20的氨基酸序列,上述FR2包含序列54的氨基酸序列、上述CDRL2包含序列23的氨基酸序列,上述FR3包含序列62的氨基酸序列,上述CDRL3包含序列30的氨基酸序列,上述FR4包含序列65的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以包含:包含序列68的氨基酸序列的CL、包含序列69的氨基酸序列的CH1、包含序列70的氨基酸序列的CH2或包含序列71的氨基酸序列的CH3序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以与Fcα受体的细胞外结构域(Extra Cellular Domain,ECD)特异性结合,Fcα受体的细胞外结构域可以包含序列72的氨基酸序列。
在一实例中,本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段可以增加效应子作用,可以增加白细胞及保有CD89-的细胞株的细胞吞噬作用(antibody-dependent cellular phagocytosis、ADCP)或抗体依赖性细胞介导的细胞毒性作用(antibody dependent cellular cytotoxicity,ADCC)。
在本发明中,术语“Fcα受体”可以与IgA受体或CD89混用。
上述抗体不仅包括全(whole)抗体形态,还包括抗体分子的功能性片段。全抗体为具有两个全长的轻链(light chain)及两个全长的重链(heavy chain)的结构,各个轻链通过二硫键(disulfide bond)与重链连接。抗体分子的功能性片段是指保有抗原结合功能的片段,抗体片段的例包括:(a)由轻链的可变区(VL)、重链的可变区(VH)、轻链的恒定区(CL)及重链的第一恒定区(CH1)组成的Fab片段;(b)由VH及CH1结构域组成的Fd片段;(c)由单抗的VL及VH结构域组成的Fv片段;(d)由VH结构域组成的dAb片段(Ward ES et al.,Nature341:544-546(1989));(e)分离的CDR区域;(f)包含两个连接的Fab片段的作为二价片段的F(ab')2片段;(g)VH结构域与VL结构域通过肽接头结合来形成抗原结合部位的单链Fv分子(scFv);(h)特异性单链Fv二聚体(PCT/US92/09965);以及(i)作为通过基因融合制备的多价或多特异性片段的双特异抗体(diabody)(WO94/13804)等。
本发明的抗体或其具有免疫活性的片段可以选自由动物来源抗体、嵌合抗体、人源化抗体、人类抗体及它们的具有免疫活性的片段组成的组中。上述抗体可以通过重组或合成来生产。
通过使被免疫动物免疫所希望的抗原来生产的动物来源抗体通常在以治疗目的向人类给药后会引起免疫排斥反应,为了抑制这样的免疫排斥反应而开发了嵌合抗体(chimeric antibody)。嵌合抗体利用遗传工程学方法将成为抗-同型(anti-isotype)反应的原因的动物来源抗体的恒定区取代为人类抗体的恒定区。与动物来源抗体相比,嵌合抗体在抗-同型反应中得到了相当部分的改善,但仍在可变区存在动物来源的氨基酸,因此,仍具有潜在的有关抗独特型(anti-idiotypic)反应的副作用。人源化抗体(humanizedantibody)正是为改善这样的副作用而开发的。这是通过将嵌合抗体的可变区中与抗原的结合中起到重要作用的CDR(互补决定区(complementaritiy determining regions))部位移植到人类抗体骨架(framework)中来制备的。
用于制备人源化抗体的CDR移植(grafting)技术中最重要的在于选择能够最好地接受动物来源抗体的CDR部位的最优化的人类抗体,为此要灵活使用数据库的运用、结晶结构(crystal structure)的分析以及分子建模技术等。然而,由于即使向最优化的人类抗体骨架移植动物来源抗体的CDR部位也存在位于动物来源抗体骨骼中的给抗原结合带来影响的氨基酸的情况,抗原结合力得不到保护的情况仍占相当数量,因此,可以说用于复原抗原结合力的进一步的抗体工程学技术的应用仍是必需的。
上述抗体或其具有免疫活性的片段可以为从生物体中分离的(生物体内部存在)或非自然生成的(non-naturally occurring),例如,可以通过合成或重组来生产。
本发明的“抗体”是指免疫系统内通过抗原的刺激产生的物质,其种类不受特别限制,可以通过自然或非自然(例如合成或重组)来获得。抗体无论在生物体外还是在生物体内都很稳定且半衰期长,因此有利于大量表达及生产。并且,抗体本质上具有二聚体(dimer)结构,因此亲和力(avidity)很高。完全的抗体为具有两个全长(full length)的轻链及两个全长的重链的结构,各个轻链通过二硫键与重链连接。抗体的恒定区分为重链恒定区与轻链恒定区,重链恒定区有伽马(γ)、缪(μ)、阿尔法(α)、德尔塔(δ)及伊普西龙(ε)型,亚型有伽马1(γ1)、伽马2(γ2)、伽马3(γ3)、伽马4(γ4)、阿尔法1(α1)及阿尔法2(α2)。轻链的恒定区有卡帕(κ)及兰布达(λ)型。
在本发明中,术语“重链”解释为包括全长重链及其片段,所述重链包含含有具有用于赋予抗原特异性的充分可变区序列的氨基酸序列的可变区结构域VH与三个恒定区结构域CH1、CH2及CH3以及铰链的全长重链以及其片段的含义。并且,术语“轻链”解释为包括全长轻链及其片段,所述全长轻链包含含有具有用于赋予抗原特异性的充分可变区序列的氨基酸序列的可变区结构域VL与恒定区结构域CL。
在本发明中,术语“可变区(variable region)或可变部位(variable domain)”是指在执行与抗原的特异性结合功能的同时在序列上显出许多变异的抗体分子的部分,可变区中存在作为互补决定区的CDR1、CDR2及CDR3。在上述CDR之间存在骨架区(frameworkregion,FR)部分,起到支撑CDR环的作用。上述“互补决定区”为与抗原的识别相关的环形状的部位,随着该部位序列的变化来决定抗体对抗原的特异性。
本发明使用的术语“scFv(单链可变片段)”是指通过基因重组只表达抗体的可变区来制备的单链抗体,是指使用短的肽链连接抗体的重链可变区与轻链可变区的单链形态的抗体。若文脉上没有其他明示或者文脉上没有其他的解释,则上述术语“scFv”包括抗原结合片段等scFv片段。这对本发明所属技术领域的普通技术人员来说是显而易见的。
在本发明中,术语“互补决定区(complementarity determining region,CDR)”是指免疫球蛋白的重链及轻链的超变区(hypervariable region)的氨基酸序列。重链及轻链各可以包含三个CDR(CDRH1、CDRH2、CDRH3及CDRL1、CDRL2、CDRL3)。上述CDR可以在抗体与抗原或抗原结合部位的结合中提供重要的接触残基。
在本发明中,术语“特异性结合”或“特异性识别”与本发明所属技术领域中通常的含义相同,是指抗原与抗体通过特异性相互作用发生免疫学反应。
在本发明中,术语“抗原结合片段”为相对于免疫球蛋白整体结构的片段,是指包含抗原能够结合的部分的多肽的一部分。例如,可以为scFv、(scFv)2、scFv-Fc、Fab、Fab'或F(ab')2,但不限定于此。在上述抗原结合片段中,Fab为具有轻链与重链的可变区以及轻链的恒定区与重链的第一个恒定区(CH1)的结构,具有一个抗原结合部位。Fab'与Fab的不同在于,在重链CH1结构域的C-末端具有包含一个以上的半胱氨酸残基的铰链区(hingeregion)。F(ab')2抗体是通过Fab'的铰链区的半胱氨酸残基通过形成二硫键来生成的。Fv为只具有重链可变区及轻链可变部位的最小的抗体片段,生成Fv片段的重组技术在本发明所属技术领域中是广为人知的。双重链Fv(two-chain Fv)通过非共价键连接重链可变部位与轻链可变部位,单链Fv(single-chain Fv)通常可以通过肽接头以共价键连接重链的可变区与单链的可变区,或者直接在C-末端连接,从而形成与双重链Fv等二聚体相同的结构。上述接头可以为由1个至100个或2个至50个任意氨基酸形成的肽接头,适当的序列是本发明所属技术领域中公知的。上述抗原结合片段可以利用蛋白水解酶来获得(例如,使用木瓜蛋白酶有限切割全抗体可以获得Fab,利用胃蛋白酶切割可以获得F(ab')2片段),可以通过基因重组激素来制备。
本发明中的术语“铰链区”为抗体的重链中包含的区域,存在于CH1与CH2区之间,是指提供抗体内抗原结合部位的柔软性(flexibility)功能的区域。例如,上述铰链可以源自人类抗体,具体地,可以源自IgA、IgE或IgG,例如,可以源自IgG1、IgG2、IgG3或IgG4。
在本发明的一实施方式中,本发明涉及双特异性或多特异性抗体,包含本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段以及与Fcα受体以外的靶抗原结合的部分。
在一实例中,与靶抗原结合的部分可以包含抗体或其具有免疫活性的片段,具有免疫活性的片段可以为选自由Fab、Fd、Fab'、dAb、F(ab')、F(ab’)2、scFv、Fv、单链抗体、Fv二聚体、互补决定区片段、人源化抗体、嵌合抗体及双特异抗体组成的组中的任一种,更优先地,可以为scFv或Fab。
在一实例中,靶抗原可以为选自由17-1A抗原、GD3神经节苷脂R24、EGFRvⅢ、PSMA、PSCA、HLA-DR、EpCAM、MUC1核心蛋白、异常糖基化MUC1、含有ED-B结构域的异型纤连蛋白、HER2/neu、癌胚抗原(CEA)、胃泌素释放肽(GRP)受体抗原、粘蛋白(mucine)抗原、表皮生长因子受体(EGF-R)、HER3、HER4、MAGE抗原、SART抗原、MUC1抗原、c-erb-2抗原、TAG 72、碳酸酐酶IX(carbonic anhydrase IX)、α胎蛋白(alpha-fetoprotein)、对A3、A33抗体具有特异性的抗原抗原、Ba 733、BrE3-抗原、CA125、CDl、CD1a、CD3、CD5、CDl5、CD16、CD19、CD20、CD21、CD22、CD23、CD25、CD30、CD33、CD38、CD40、CD45、CD52、CD74、CD79a、CD80、CD138、结肠特异性抗原-p(CSAp)、CSAp、EGP-1、EGP-2、Ep-CAM、FIt-1、Flt-3、叶酸盐受体(folatereceptor)、HLA-DR、人绒毛膜促性腺激素(HCG)及其亚单位、低氧诱导因子(HIF-I)、Ia、IL-2、IL-6、IL-8、胰岛素样生长因子-1(IGF-1)、KC4-抗原、KS-1-抗原、KSl-4、Le-Y、巨噬细胞移动抑制因子(MIF)、MAGE、MUCl、MUC2、MUC3、MUC4、NCA66、NCA95、NCA90、PAM-4抗体特异性抗原、胎盘生长因子、p53、前列腺酸性磷酸酶(prostatic acid phosphatase)、PSA、RS5、SlOO、TAC、生腱蛋白(tenascin)、TRAIL受体、Tn抗原、TF(Thomson-Friedenreich)抗原、肿瘤坏死抗原、VEGF、ED-B纤连蛋白(fibronectin)、血管生成标志物(angiogenesismarker)、肿瘤基因标志物(oncogene marker)或肿瘤基因产物组成的组中的一种以上,肿瘤基因可以为细胞凋亡(Apoptosis)相关基因、转录因子(Trnscription Factor)基因、转移(Metastasis)相关基因、血管生成(Angiogenesis)相关基因或酪氨酸激酶(Tyrosine-Kinase)基因。
在一实例中,上述细胞凋亡相关基因可以为ABL1、AKT1、AKT2、BARD1、BAX、BCL11B、BCL2、BCL2A1、BCL2L1、BCL2L12、BCL3、BCL6、BIRC2、BIRC3、BIRC5、BRAF、CARD11、CAV1、CBL、CDC25A、CDKN1A、CFLAR、CNR2、CTNNB1、CUL4A、DAXX、DDIT3、E2F1、E2F3、E2F5、ESPL1、FOXO1、HDAC1、HSPA5、IGF1R、IGF2、JUN、JUNB、JUND、MALT1、MAP3K7、MCL1、MDM2、MDM4、MYB、MYC、NFKB2、NPM1、NTRK1、PAK1、PAX3、PML、PRKCA、PRKCE、PTK2B、RAF1、RHOA、TGFB1、TNFRSF1B、TP73、TRAF6、YWHAG、YWHAQ或YWHAZ;上述转录因子基因可以为AR、ARID3A、ASCL1、ATF1、ATF3、BCL11A、BCL11B、BCL3、BCL6、CDC5L、CDX2、CREB1、CUX1、DDIT3、DLX5、E2F1、E2F3、E2F5、ELF4、ELK1、ELK3、EN2、ERG、ETS1、ETS2、ETV1、ETV3、ETV4、ETV6、FEV、FEZF1、FLI1、FOS、FOSL1、FOXA1、FOXG1、FOXM1、FOXO1、FOXP1、FOXQ1、GATA1、GATA6、GFI1、GFI1B、GLI1、GLI2、GLI3、HES6、HHEX、HLF、HMGA1、HMGA2、HOXA1、HOXA9、HOXD13、HOXD9、ID1、ID2、IKZF1、IRF2、IRF4、JUN、JUNB、JUND、KAT6A、KDM2A、KDM5B、KLF2、KLF4、KLF5、KLF6、KLF8、KMT2A、LEF1、LHX1、LMX1B、MAF、MAFA、MAFB、MBD1、MECOM、MEF2C、MEIS1、MITF、MYB、MYC、MYCL、MYCN、NANOG、NCOA3、NFIB、NFKB2、NKX2-1、OTX2、PATZ1、PAX2、PAX3、PAX4、PAX8、PBX1、PBX2、PITX2、PLAG1、PLAGL2、PPARG、PPP1R13L、PRDM10、PRDM13、PRDM14、PRDM15、PRDM16、PRDM6、PRDM8、PRDM9、RARA、REL、RERE、RUNX1、RUNX3、SALL4、SATB1、SFPQ、SIX1、SNAI1、SOX2、SOX4、SPI1、SREBF1、STAT3、TAF1、TAL1、TAL2、TBX2、TBX3、TCF3、TFCP2、TFE3、THRA、TLX1、TP63、TP73、TWIST1、WT1、YBX1、YY1、ZBTB16、ZBTB7A、ZIC2、ZNF217或ZNF268;上述转移相关基因可以为AKT1、AKT2、AR、CBL、CDH1、CRK、CSF1、CTNNB1、CTTN、CXCR4、EGFR、FGFR1、FLT3、FYN、GLI1、ILK、ITGA3、JAK2、MET、PDGFRB、PLXNB1、PRKCI、PTCH1、PTPN11、RAC1、RHOA、RHOC、ROCK1、SMO、SNAI1、SRC、TCF3或WT1;上述血管生成相关基因可以为BRAF、CAV1、CTGF、EGFR、ERBB2、ETS1、FGF4、FGF6、FGFR1、FGFR3、FGFR4、ID1、NRAS、PDGFB、PDGFRA、PDGFRB或SPARC;上述酪氨酸激酶基因可以为ABL1、ABL2、ALK、AXL、BLK、EGFR、EPHA2、ERBB2、ERBB3、ERBB4、FES、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT3、FYN、ITK、JAK1、JAK2、KIT、LCK、MERTK、MET、MST1R、NTRK1、NTRK3、PDGFRA、PDGFRB、PTK2B、PTK7、RET、ROS1、SRC、SYK、TEC或YES1。
在一实例中,肿瘤基因可以为SEPTIN9、ACOD1、ACTN4、ADAM28、ADAM9、ADGRF1、ADRBK2、AFF1、AFF3、AGAP2、AGFG1、AGRN、AHCYL1、AHI1、AIMP2、AKAP13、AKAP9、AKIRIN2、AKTIP、ALDH1A1、ALL1、ANIB1、ANP32C、ANP32D、AQP1、ARAF、ARHGEF1、ARHGEF2、ARHGEF5、ASPSCR1、AURKA、BAALC、BAIAP2L1、BANP、BCAR4、BCKDHB、BCL9、BCL9L、BCR、BMI1、BMP7、BOC、BRD4、BRF2、CABIN1、CAMK1D、CAPG、CBFB、CBLB、CBLL1、CBX7、CBX8、CCDC28A、CCDC6、CCNB1、CCNB2、CCND1、CCNE1、CCNL1、CD24、CDC25C、CDC6、CDH17、CDK1、CDK14、CDK4、CDK5R2、CDK6、CDK8、CDKN1B、CDKN3、CDON、CEACAM6、CENPW、CHD1L、CHIC1、CHL1、CKS1B、CMC4、CNTN2、COPS3、COPS5、CRKL、CRLF2、CROT、CRTC1、CRYAB、CSF1R、CSF3、CSF3R、CSNK2A1、CSNK2A2、CT45A1、CTBP2、CTNND2、CTSZ、CUL7、CXCL1、CXCL2、CXCL3、CYGB、CYP24A1、DCD、DCUN1D1DDB2、DDHD2、DDX6、DEK、DIS3、DNPH1、DPPA2、DPPA4、DSG3、DUSP12、DUSP26、ECHS1、ECT2、EEF1A1、EEF1A2、EEF1D、EIF3E、EIF3I、EIF4E、EIF5A2、ELAVL1、ELL、EML4、EMSY、ENTPD5、EPCAM、EPS8、ERAS、ERGIC1、ERVW-1、EVI2A、EVI5、EWSR1、EZH2、FAM189B、FAM72A、FAM83D、FASN、FDPS、FGF10、FGF3、FGF5、FGF8、FR1OP、FHL2、FIP1L1、FNDC3B、FRAT1、FUBP1、FUS、FZD2、GAB2、GAEC1、GALNT10、GALR2、GLO1、GMNN、GNA12、GNA13、GNAI2、GNAQ、GNAS、GOLPH3、GOPC、GPAT4、GPM6A、GPM6B、GPR132、GREM1、GRM1、GSK3A、GSM1、H19、HAS1、HAX1、HDGFRP2、HMGN5、HNRNPA1、HOTAIR、HOTTIP、HOXA-AS2、HRAS、HSPA1A、HSPA4、HSPB1、HULC、IDH1、IFNG、IGF2BP1、IKBKE、IL7R、INPPL1、INTS1、INTS2、INTS3、INTS4、INTS5、INTS7、INTS8、IRS2、IST1、JUP、KDM4C、KIAA0101、KIAA1524、KIF14、KRAS、KSR2、LAMTOR5、LAPTM4B、LCN2、LDHB、LETMD1、LIN28A、LIN28B、LMO1、LMO2、LMO3、LMO4、LSM1、LUADT1、MACC1、MACROD1、MAGEA11、MALAT1、MAML2、MAP3K8、MAPRE1、MAS1、MCC、MCF2、MCF2L、MCTS1、MEFV、MFHAS1、MFNG、MIEN1、MINA、MKL2、MLANA、MLLT1、MLLT11、MLLT3、MLLT4、MMP12、MMS22L、MN1、MNAT1、MOS、MPL、MPST、MRAS、MRE11A、MSI1、MTCP1、MTDH、MTOR、MUC1、MUC4、MUM1、MYD88、NAAA、NANOGP8、NBPF12、NCOA4、NEAT1、NECTIN4、NEDD4、NEDD9、NET1、NINL、NME1、NOTCH1、NOTCH4、NOV、NSD1、NUAK2、NUP214、NUP98、NUTM1、OLR1、PA2G4、PADI2、PAK7、PARK7、PARM1、PBK、PCAT1、PCAT5、PDGFA、PDZK1IP1、PELP1、PFN1P3、PIGU、PIK3CA、PIK3R1、PIM1、PIM2、PIM3、PIR、PIWIL1、PLAC8、PLK1、PPM1D、PPP1R10、PPP1R14A、PPP2R1A、PRAME、PRDM12、PRMT5、PSIP1、PSMD10、PTCH2、PTMA、PTP4A1、PTP4A2、PTP4A3、PTTG1、PTTG1IP、PTTG2、PVT1、RAB11A、RAB18、RAB22A、RAB23、RAB8A、RALGDS、RAP1A、RASSF1、RBM14、RBM15、RBM3、RBMY1A1、RFC3、RGL4、RGR、RHO、RING1、RINT1、RIT1、RNF43、RPL23、RRAS、RRAS2、RSF1、RUNX1T1、S100A4、S100A7、S100A8、SAG、SART3、SBSN、SEA、SEC62、SERTAD1、SERTAD2、SERTAD3、SET、SETBP1、SETDB1、SGK1、SIRT1、SIRT6、SKI、SKIL、SKP2、SLC12A5、SLC3A2、SMR3B、SMURF1、SNCG、SNORA59A、SNORA80E、SPAG9、SPATA4、SPRY2、SQSTM1、SRSF1、SRSF2、SRSF3、SRSF6、SS18、SSX1、SSX2、SSX2B、STIL、STMN1、STRA6、STYK1、SUZ12、SWAP70、SYT1、TAC1、TACSTD2、TAF15、TALDO1、TAZ、TBC1D1、TBC1D15、TBC1D3、TBC1D3C、TBC1D7、TCL1A、TCL1B、TCL6、TCP1、TFG、TGM3、TINCR、TKTL1、TLE1、TMEM140、TMPOP2、TMPRSS2、TNS4、TPD52、TPR、TRE17、TREH、TRIB1、TRIB2、TRIM28、TRIM32、TRIM8、TRIO、TRIP6、TSPAN1、TSPY1、TXN、TYMS、TYRP1、UBE2C、UBE3C、UCA1、UCHL1、UHRF1、URI1、USP22、USP4、USP6、VAV1、VAV2、VAV3、VIM、WAPL、WHSC1、WHSC1L1、WISP1、WNT1、WNT10A、WNT10B、WNT2、WNT3、WNT5A、WWTR1、XCL1、XIAP、YAP1、YEATS4、YY1AP1、ZEB1-AS1、ZFAND4、ZFAS1、ZMYM2、ZNF703或ZNHIT6。
在一实例中,靶抗原可以为细胞表面抗原或自身抗原,细胞表面抗原可以为选自由CEA、ED-B纤连蛋白、CD20、CD22、CDl9、EGFR、IGFlR、VEFGRl/Flt-1、VEGFR2/KDR、VEGRF3/Flt-4、HER2/neu、CD30、CD33、CD3、CD16、CD64、CD89、CD2、腺病毒纤维旋钮、PfMSP-1、HN/NDV、EpCAM/17-lA、hTR、IL-2R/Tac、CAl9-9、MUCl、HLA II类抗原、GD2、G250、TAG-72、PSMA、CEACAM6、HMWMAA、CD40、Ml3外壳蛋白及GPIIb/IIIa组成的组中的一种以上。
在本发明的一实施方式中,本发明涉及编码本发明的抗体或其具有免疫活性的片段、本发明的双特异性或多特异性抗体的分离的核酸分子、包含其的载体以及由其转化的宿主细胞。
本发明的核酸分子可以为分离的或重组的,不仅包括单股及双股形态的脱氧核糖核酸(DNA)及核糖核酸(RNA),还包括与对应的互补序列。在分离的核酸为从天然生成的源头分离的核酸的情况下,核酸为从分离的个体的基因组中存在的周边遗传序列中分离的核酸。在从模板上通过酶或化学方法合成的核酸,例如聚合酶链式反应(PCR)产物、互补脱氧核糖核酸(cDNA)分子或寡核苷酸的情况下,通过这样的过程产生的核酸可以理解为分离的核酸分子。分离的核酸分子示出单独的片段形态或更大的核算结构物的核酸分子。当核酸与其他核酸序列以功能关系配制时,形成“可操作地连接”。例如,当前序列或分泌前导序列(leader)的脱氧核糖核酸表达为分泌多肽前的形态的前蛋白(preprotein)时,与多肽的脱氧核糖核酸可操作地连接,当给多肽序列的转录带来影响时,启动子或增强子与编码序列可操作地连接,或者当核糖体接合部分以促进翻译的方式配置时,与编码序列可操作地连接。通常,“可操作地连接”是指连接的脱氧核糖核酸序列以相邻的方式设置,在分泌前导序列的情况下,是指相邻来存在于相同的阅读框架内。但增强子没有必要相邻来设置。连接可以在便利的限制酶部位通过结扎来实现。若不存在这样的部位,则可以根据通常的方法使用合成寡核苷酸衔接头或接头。
编码本发明的抗体或其具有免疫活性的片段、本发明的双特异性或多特异性抗体的分离的核酸分子由于密码子的简并性(degeneracy)或考虑到为表达上述抗体而在生物体内偏好的密码子,可以在不改变从编码区域表达的抗体的氨基酸序列的范围内进行多种变形,在除编码区域以外的其他部分,也可以在不给基因的表达带来影响的范围内进行多种变形或修饰,本发明所属技术领域的普通技术人员应该理解的是,这些变形基因也包括在本发明的范围内。即,本发明的核酸分子可以通过取代、缺失、插入编码具有与之同等活性的蛋白质的一个以上核酸碱基或者它们的组合来变异,这些也包括在本发明的范围内。这样的核酸分子的序列可以为单链或双链,可以为脱氧核糖核酸分子或核糖核酸(mRNA)。
本发明的编码本发明的抗体或其具有免疫活性的片段、本发明的双特异性或多特异性抗体的分离的核酸分子可以插入到用于蛋白质表达的表达载体中。表达载体包括与通常的调节或控制控制(regulatory)序列、筛选标志物、任意的融合配偶体和/或额外要素可操作地连接的蛋白质,即,具有功能关系的蛋白质。在适当的状态下,可以通过培养由核酸转化的宿主细胞来诱导蛋白质表达的方法,优选地,可以通过培养含有编码本发明的抗体或其具有免疫活性的片段、本发明的双特异性或多特异性抗体的分离的核酸分子的表达载体来诱导蛋白质表达的方法来生产本发明的抗体或其具有免疫活性的片段或者本发明的双特异性或多特异性抗体。可以使用包括哺乳动物细胞、细菌、昆虫细胞以及酵母菌在内的多种宿主细胞,但不限定于此。向宿主细胞导入外源性核算的方法是本发明所属技术领域中公知的,根据使用的宿主细胞的不同而不同。优选地,可以使用因生产成本低廉而利用价值高的大肠杆菌作为宿主细胞来生产。
本发明的载体包括质粒载体、粘粒载体、噬菌体载体及病毒载体,但不限定于此。适当的载体除启动子、操纵基因、启动子、终止子、聚腺苷酸化信号及增强子等调节元素以外还包含用于膜靶向化或分泌的信号序列或前导序列,可以根据目的多种多样地调节。载体的启动子可以为结构性或诱导性。上述信号序列在宿主为大肠杆菌属(Escherichiasp.)菌的情况下,可以使用PhoA信号序列、OmpA信号序列等,在宿主为芽孢杆菌属(Bacillus sp.)菌的情况下,可以使用α-淀粉酶信号序列、枯草杆菌蛋白酶信号序列等,在宿主为酵母菌(yeast)的情况下,可以使用MFα信号序列、SUC2信号序列等,在宿主为动物细胞的情况下,可以使用胰岛素信号序列、α干扰素信号序列、抗体分子信号序列等,但不限定于此。并且,载体还可以包含用于选择含有载体的宿主细胞的选择标记,在可复制表达载体的情况下,包含复制源。
在本发明中,术语“载体”是指为了向能够复制核酸序列的细胞导入而能够插入核酸序列的转运体。核酸序列可以为外源性(exogenous)或异种(heterologous)的。载体可以为质粒、粘粒及病毒(例如噬菌体),但不限定于此。本发明所属技术领域的普通技术人员可以通过标准的重组技术构建载体(Maniatis,et al.,Molecular Cloning,A LaboratoryManual,Cold Spring Harbor Press,Cold Spring Harbor,N.Y.,1988;及Ausubel etal.,In:Current Protocols in Molecular Biology,John、Wiley&Sons,Inc,NY,1994等)。
在一实例中,在制备上述载体时,可以根据所要生产上述抗体的宿主细胞的种类适当选择启动子(promoter)、终止子(terminator)、增强子(enhancer)等表达调节序列以及用于膜靶向化或分泌的序列等,可以根据目的多种多样地调节。
在本发明中,术语“表达载体”是指包含编码所要转录的基因产物中的至少一部分的核酸序列的载体。在一部分情况下,此后核糖核酸分子翻译为蛋白质、多肽或肽。表达载体可以包含多种调节序列。除调节转录及翻译的调节序列以外,载体及表达载体还可以包含提供其他功能的核酸序列。
在本发明中,术语“宿主细胞”包括真核生物及原核生物,是指可以复制上述载体的或者可以通过载体表达编码的基因的任意可转化的生物。宿主细胞可以通过上述载体转染(transfected)或转化(transformed),这是指外源性的核酸分子向宿主细胞内转运或导入的过程。
在一实例中,上述宿主细胞可以为细菌或动物细胞,动物细胞株可以为CHO细胞、HEK细胞或NSO细胞,细菌可以为大肠杆菌。
在本发明的一实施方式中,本发明涉及包含本发明的抗体或其具有免疫活性的片段及包含与Fcα受体以外的靶抗原结合的部分的双特异性或多特异性抗体作为有效成分的用于预防或治疗选自由癌症、自身免疫疾病、退行性神经疾病(neurodegerativedisease)、阿尔茨海默病、代谢疾病(metabolic disease)、心血管疾病(cardiovasculardisease)、动脉粥样硬化症(atherosclerosis)、器官移植排斥反应、由真菌、病毒、细菌或寄生虫引起的疾病或症状组成的组中的疾病或疾患的药物组合物。
在一实例中,上述癌症可以为选自由脑肿瘤、黑色素瘤、骨髓瘤、非小细胞肺癌、口腔癌、肝癌、胃癌、结肠癌、乳腺癌、肺癌、骨癌、胰腺癌、皮肤癌、头部或颈部癌、宫颈癌、卵巢癌、大肠癌、小肠癌、直肠癌、输卵管癌、肛周癌、子宫内膜癌、阴道癌、外阴癌、霍奇金病(Hodgkin's disease)、食管癌、淋巴癌、膀胱癌、胆囊癌、内分泌腺癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉芽肿、尿道癌、阴茎癌、前列腺癌、慢性或剂型白血病、淋巴细胞淋巴瘤、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤、原发性中枢神经系统淋巴瘤、脊髓肿瘤、脑干神经胶质瘤及脑垂体腺瘤组成的组中的任一种。
在本发明中,术语“预防”是指通过给药本发明的组合物来抑制或延迟疾病或疾患的发病、扩散及复发的所有行为。
本发明中使用的术语“治疗”是指通过给药本发明的组合物来使疾病或疾患以及由它们引起的并发症的症状好转或痊愈的所有行为。本发明所属技术领域的普通技术人员可以参照大韩医学协会等发布的资料知道本申请的组合物具有效果的疾病的正确标准,可以由此来判断改善、提高及治疗的程度。
本发明中与“有效成分”结合使用的术语“治疗上有效的量”是指在疾病或疾患的预防或治疗中有效的量,本发明的组合物的治疗上有效的量可以根据例如给药方法、目标部位、患者的状态等多种因素的不同而不同。因此,在人体中使用时,给药量应同时考虑安全性及有效性来确定适当量。也可以由通过动物实验确定的有效量来推算在人类中使用的量。在确定有效的量时需要考虑的事项记述在例如Hardman and Limbird,eds.,Goodmanand Gilman's The Pharmacological Basis of Therapeutics,10th ed.(2001),Pergamon Press;及E.W.Martin ed.,Remington's Pharmaceutical Sciences,18th ed.(1990),Mack PublishingCo.中。
以药学上有效的量给药本发明的药物组合物。本发明中使用的术语“医学上有效的量”是指以医学治疗中可接受的收益/风险比例来治疗疾病的充分且不引起副作用的量,有效剂量水平可以根据包括患者的健康状态、疾病或疾患的种类、疾病或疾患的严重程度、药物的活性、对药物的敏感度、给药方法、给药时间、给药途径及代谢比例、治疗期间、联合或同时使用的药物在内的要素以及其他医学领域中公知的因素来确定。本发明的组合物可以作为单独的治疗剂给药,或者与其他治疗剂联合来给药,可以与现有的治疗剂依次或同时给药,可以单次给药或分为多次给药,重点在于,考虑所有上述因素后以无副作用的最少的量来获得最大的效果的量来给药,这可以通过本发明所属技术领域的普通技术人员轻易确定。
本发明的药物组合物可以包含生物学制剂中通常使用的载体、稀释剂、赋形剂或它们两种以上的组合。本发明中使用的术语“药学上可接受的”是指对暴露在上述组合无中的细胞或人体显出无毒性的特性。上述载体只要是能够将组合物转运到生物体内的就不受特别限制,可以添加例如Merck Index,13thed.,Merck&Co.Inc.中记载的化合物、生理盐水、灭菌水、林格氏液、缓冲生理盐水、葡萄糖溶液、麦芽糊精溶液、甘油、乙醇及混合这些成分中的一种成分以上来使用,还可以根据需要加入抗氧化剂、缓冲液、静菌剂等其他通常的添加剂。并且,还可以加入稀释剂、分散剂、表面活性剂、结合剂及润滑剂来配制为水溶液、悬混液等注射用剂型、丸剂、胶囊剂、糖浆或片剂。还可以利用本发明所属技术领域中的适当方法或Remington's Pharmaceutical Science(Mack PublishingCompany,Easton PA,18th,1990)中提供的方法根据各个疾病或成分优选地配制。
在一实例中,上述药物组合物可以为选自由口服剂型、外用剂、栓剂、灭菌注射溶液及喷雾剂组成的组中的一种以上剂型,更优选地,可以为口服剂型或注射剂型。
本发明中使用的术语“给药”是指通过任意适当的方法向个体或患者提供固定的物质,根据目的方法通过胃肠外给药(例如以静脉、皮下、腹腔内或病灶注射剂型来应用)或口服给药,给药量的范围根据患者的体重、年龄、性别、健康状态、饮食、给药时间、给药方法、代谢率及疾病的严重程度的不同而多种多样。本发明组合物的用于口服给药的药物制剂有悬混剂、内溶液剂、乳剂、糖浆剂等,除通常使用的作为单纯稀释剂的水、液体石蜡以外,还可以包含多种赋形剂,例如湿润剂、甜味剂、芳香剂、保存剂等。用于胃肠外给药的制剂包括灭菌的水溶液、非水性溶剂、悬混剂、有机、冷冻干燥制剂、栓剂等。本发明的药物组合物还可以通过能够使活性物质向靶向细胞移动的任意装置来给药。优选的给药方式及制剂为静脉注射剂、皮下注射剂、皮内注射及、肌肉注射剂、点滴注射剂等。注射剂可以利用生理盐水、林格氏液等水性溶剂以及植物油、高级脂肪酸酯(例如油酸乙酯等)、醇类(例如乙醇、苯甲醇、丙二醇、甘油等)等非水性溶剂来制备,可以包含用于防变质的稳定剂(例如抗坏血酸、亚硫酸钠、焦亚硫酸钠、丁基羟基茴香醚(BHA)、生育酚、乙二胺四乙酸(EDTA)等)、乳化剂、用于调节pH的缓冲剂、防止微生物繁殖的保存剂(例如硝酸苯汞、硫柳汞、苯扎氯铵、苯酚、甲酚、苯甲醇等)等药学载体。
本发明中使用的术语“个体”是指实质发生上述疾病或可能发生上述疾病的包括人类在内的猴、牛、马、羊、猪、鸡、火鸡、鹌鹑、猫、狗、大鼠、蝙蝠、小鼠、兔或豚鼠的所等所有动物,“检体”是指从它们分离的飞沫、痰液、全血、血浆、血清、尿液或唾液。
本发明的药物组合物还可以包含药剂学上可接受的添加剂,在此情况下,药剂学上可接受的添加剂可以使用淀粉、明胶化淀粉、微晶纤维素、乳糖、聚维酮、胶体二氧化硅、磷酸钙、乳糖、甘露醇、麦芽糖、阿拉伯胶、预糊化淀粉、玉米淀粉、粉末纤维素、羟丙基纤维素、欧巴代、羟基乙酸淀粉钠、棕榈酸铅、合成硅酸铝、硬脂酸、硬脂酸镁、硬脂酸铝、硬脂酸钙、白糖、葡萄糖、山梨糖醇及滑石粉等。优选地,相对于上述组合物,本发明的药剂学上可接受的添加剂可以包含0.1重量份至90重量份,但不限定于此。
在本发明的一实施方式中,本发明涉及提供有关选自由癌症、自身免疫疾病、退行性神经疾病、阿尔茨海默病、代谢疾病、心血管疾病、动脉粥样硬化症、器官移植排斥反应、由真菌、病毒、细菌或寄生虫引起的疾病或症状组成的组中的疾病或疾患的诊断信息的方法,包括:使从检体分离的试样与本发明的双特异性或多特异性抗体接触来形成抗原-抗体复合物的步骤;以及检测出上述复合物的步骤。
在本发明的一实施方式中,本发明涉及制备对Fcα受体具有特异性的抗体或其具有免疫活性的片段的方法,包括:培养由包含编码本发明的抗体或其具有免疫活性的片段的分离的核酸分子的载体转化的宿主细胞的步骤;以及从宿主细胞培养物中回收抗体或其具有免疫活性的片段的步骤。
在本发明的一实施方式中,本发明涉及制备与Fcα受体及Fcα受体以外的靶抗原结合的双特异性或多特异性抗体的方法,包括培养由包含编码本发明的双特异性或多特异性抗体的分离的核酸分子的载体转化的宿主细胞的步骤;以及从宿主细胞培养物中回收抗体或其具有免疫活性的片段的步骤。
在本发明的一实施方式中,本发明涉及将本发明的对Fcα受体具有特异性的抗体或其具有免疫活性的片段用于抗体治疗剂的制备中的用途。
在本发明的一实施方式中,本发明涉及将本发明的双特异性或多特异性抗体用于选自由癌症、自身免疫疾病、退行性神经疾病、阿尔茨海默病、代谢疾病、心血管疾病、动脉粥样硬化症、器官移植排斥反应、由真菌、病毒、细菌或寄生虫引起的疾病或症状组成的疾病或疾患的预防或治疗的用途。
在本发明的一实施方式中,本发明涉及癌症的治疗方法,包括以药学上有效的量向患有癌症的个体给药本发明的双特异性或多特异性抗体的步骤。
通过下述实施例更为详细地说明本发明。但下述实施例仅用于使本发明的内容具体化,而非用来限制本发明。
实施例1.利用Fcα受体制备抗原
为了发掘通过与Fcα受体结合来具有效应子功能(effector function)的IgG,将Fcα受体的细胞外结构域(Extra Cellular Domain、ECD)准备为抗原。并且,为了制备适合利用流式细胞仪筛选抗体的抗原,制备了用于生产融合(fusion)谷胱甘肽巯基转移酶(GST,Glutathione-S-transferase)标签的二聚体(dimeric)形态及融合链霉亲和素(Streptavidin)标签的四聚体(tetrameric)形态的抗原的动物细胞表达用载体(图1)。然后,利用聚乙烯亚胺(PEI)(波利赛斯公司(Polyscience),23966)转染到以2×106cells/ml的密度培养一天的Expi293F细胞。然后,在震荡培养起中以37℃、125rpm及8%CO2的条件培养7天后,通过离心分离只取上清液。使用25x磷酸盐缓冲溶液(PBS)使上清液平衡后,利用瓶顶过滤器通过0.2μm的过滤器(默克密理博公司(Merck Millipore))过滤。向过滤的培养液中分别加入1ml的GSH树脂(resin)及Ni-NTA树脂并在4℃的温度下搅拌16小时后,通过柱回收树脂后使用5ml的磷酸盐缓冲溶液洗涤后,使用4ml的pH8.0的50mM的Tris-HCl及10mM的还原的谷胱甘肽(西格玛公司(SIGMA))与250mM的咪唑洗脱。通过离心过滤装置3K(Centrifugal filter units 3K)(默克密理博公司)使用磷酸盐缓冲溶液更换缓冲液后,通过十二烷基磺酸钠-聚丙烯酰胺凝胶电泳分析分别纯化的两种抗原蛋白(谷胱甘肽巯基转移酶(GST)-细胞外结构域及链霉亲和素-细胞外结构域)的大小与纯度(图1)。
实施例2.利用超高速探索系统筛选人类抗体
为了使用于利用流式细胞仪的筛选,在上述实施例中准备的抗原蛋白中融合链霉亲和素的抗原蛋白中标记Alexa488荧光分子。然后,利用本发明人构建的细菌显示的scFv抗体文库来筛选与Fcα受体的细胞外结构域结合的人类抗体。具体地,在25ml的包含2%的葡萄糖40μg/ml的氯霉素(chloramphenicol)的TB培养基中以37℃、250rpm的条件培养1ml的文库细胞4小时后,将培养的细胞以1∶100的比例在100ml的包含40μg/ml的氯霉素的TB培养基中培养至OD600=0.5后,在25℃及250rpm的条件下冷却(cooling)20分钟后,加入1mM的异丙基-β-D-硫代半乳糖苷(IPTG)在25℃及250rpm的条件下诱导(Induction)5小时来以OD600=8为标准获得(harvest)蛋白质过表达的大肠杆菌。为了将细胞制备为适合利用流式细胞仪的筛选的原生质球(spheroplasts)形态,使用1ml的10Mm的Tris-HCl(pH8.0)使细胞再悬浮并洗涤2次来去除培养基后,在1ml的STE(0.5M的葡萄糖(sucrose)、10Mm的Tris-HCl及10Mm的乙二胺四乙酸(pH8.0))溶液中以37℃的温度旋转30分钟通过施加渗透压冲击(osmotic shock)的方法来去除细胞外膜。然后在混合1ml的溶液(Solution)A及20μl的50mg/ml的溶菌酶溶液(lysozyme solution)的溶液中以37℃的温度旋转15分钟来去除肽聚糖(peptidoglycan)层并使用1ml的磷酸盐缓冲溶液洗涤后,将300μl放入700μl的磷酸盐缓冲溶液与200nM(以单体(monomer)为基准)的Fcα受体-细胞外结构域-链霉亲和素-Alexa488探针后,在常温下旋转1小时来在原生质球中标记荧光探针。然后,利用流式细胞仪回收因抗原结合力增加而显出高的荧光的克隆,在回收的克隆中通过聚合酶链式反应扩增scFv基因,重复培养、表达诱导、去除细胞外膜及肽聚糖层的原生质球化(spheroplasting)过程、抗原标记及通过流式细胞分析的选择性设门(gating)来筛选对Fcα受体-细胞外结构域示出高亲和度的原生质球的过程。在利用流式细胞仪的筛选过程及用于提高筛选纯度(purity)的再筛选过程后,通过浓缩过程、通过聚合酶链式反应扩增来确保筛选的scFv变异体基因的过程、亚克隆过程以及转化过程后,为了扩增(enrich)所希望的克隆进行下一轮的筛选过程(图2)。通过这样反复的多轮(round)的探索过程获得与Fcα受体-细胞外结构域的结合力优秀的scFv变异体克隆。
实施例3.确认Fcα受体结合抗体变异体的基因序列
为了确认上述实施例2中获得的scFv变异体克隆的基因序列,通过双脱氧测序法(Sanger sequencing)分析脱氧核糖核酸碱基序列,通过分析筛选到6种具有抗体序列的scFv抗体变异体JS9、JS19、JS30、JS40、JS41及JS48(图3)。并且,确认了上述6种scFv变异体的VH及VL氨基酸序列、各变异体的VH的FR1、CDRH1、FR2、CDRH2、FR3、CDRH3及FR4的氨基酸序列以及VL的FR1、CDRL1、FR2、CDRL2、FR3、CDRL3及FR4的氨基酸序列(表1)
表1
实施例4.分析对Fcα受体细胞外结构域的结合力
为了确认上述实施例3中筛选的6种scFv抗体变异体对Fcα受体细胞外结构域的结合力,进行利用流式细胞仪的结合力分析。为此,以上述实施例中使用的方式将各变异体和用作对照组的Fc(野生型)制备为原生质球。将50nM浓度的Fcα受体-细胞外结构域-链霉亲和素-Alexa488抗原与准备的原生质球结合后,在常温下培养1小时。然后,为了去除非特异性结合,使用磷酸盐缓冲溶液洗涤两次后利用流式细胞仪分析对Fcα受体细胞外结构域的结合力。结果,与作为对照组的IgG_Fc及IgA_Fc相比,6种scFv变异体示出显著增加的荧光信号(图4),通过此检验了与Fcα受体细胞外结构域结合的scFv抗体变异体。
实施例5.生产及纯化包含scFv变异体的抗体IgG
为了确认上述实施例3中筛选的6种scFv抗体变异体是否在IgG形态中也具有与Fcα受体的结合力,在分别制备6种scFv的重链及轻链表达载体后,先在100ml的Freestyle293表达(expression)培养液(赛默飞世尔公司(Gibco),12338-018)中以1∶1的比例混合各变异体的重链基因与轻链基因后,以聚乙烯亚胺∶变异体基因=4∶1的比例混合后在常温下放置20分钟后向之前以2×106cells/ml的密度传代培养的Expi293F细胞转染。然后,在振荡培养仪中以37℃、125rpm及8%的CO2的条件培养7天后离心分离来只取上清液。使用25x磷酸盐缓冲溶液(PBS)使上清液平衡后,利用瓶顶过滤器通过0.2μm的过滤器(默克密理博公司)过滤。向过滤的培养液中分别加入500μl的蛋白A(Protein A)树脂(resin)并在4℃的温度下搅拌16小时后,通过柱回收树脂后使用5ml的磷酸盐缓冲溶液洗涤后,使用3ml的pH2.7的100mM甘氨酸(glycine)缓冲液洗脱后,利用1M的Tris-HCl pH8.0来中和。通过离心过滤装置3K(Centrifugal filter units 3K)(默克密理博公司)使用磷酸盐缓冲溶液更换缓冲液后,通过十二烷基磺酸钠-聚丙烯酰胺凝胶电泳分析分别包含6种scFv抗体变异体的IgG(JS9、JS19、JS30、JS40、JS41及JS48)的大小与纯度(图5)。
实施例6.分析包含scFv变异体的抗体对Fcα受体的结合力
为了测定上述实施例5中制备的包含scFv变异体的抗体JS9、JS19、JS30、JS40、JS41及JS48对Fcα受体的结合力,进行了酶联免疫吸附测定实验。具体地,在4℃的温度下在96孔平地聚苯乙烯高粘合(Flat Bottom Polystyrene High Bind)酶标板(科士达公司(costar))各固定50μl的4μg/ml的在pH9.6的0.05M的碳酸钠(Na2CO3)溶液内融合链霉亲和素标签的四聚体形态的Fcα受体(抗原)16小时后,使用100μl的4%的脱脂牛奶(GenomicBase公司)(包含在0.05%的磷酸盐吐温缓冲溶液(PBST)中,pH6.0/pH7.4)在常温下封闭2小时。使用180μl的0.05%的磷酸盐吐温缓冲溶液洗涤4次后,将使用1%的脱脂牛奶(包含在0.05%的磷酸盐吐温缓冲溶液中)连续稀释的抗体JS9、JS19、JS30、JS40、JS41及JS48向各孔中分注50μl来在常温下反应1小时。经过洗涤过程后,使各抗体在常温下与50μl的抗人IgG(H+L)-HRP偶联物(杰克逊免疫研究公司(Jackson Immunoresearch))在常温下反应1小时后洗涤。然后,各加入50μl的1-Step Ultra TMB-酶联免疫吸附测定底物溶液(1-Step Ultra TMB-ELISA Substrate Solution)(赛默飞世尔公司(Thermo FisherScientific))来显色后,加入50μl的2M的硫酸(H2SO4)终止反应后,使用Epoch微孔板分光光度计(Epoch Microplate Spectrophotometer)(伯腾公司(BioTek))分析各抗体对作为抗原的Fcα受体的结合力(图6)。
实施例7.利用超高速探索系统筛选提高与Fcα受体细胞外结构域的结合力的人类抗体
已确认对Fcα受体的结合力的两种抗体(JS40及JS48)作为母抗体来设计用于提高与Fcα受体的结合力的实验。为此,通过易错聚合酶链式反应(Error prone PCR)使用以scFv为显示窗口(display)的JS40及JS48抗体制作含有0.2%的随机突变的文库。并且,利用作为在一抗的发掘中使用的抗原的Fcα受体-细胞外结构域-链霉亲和素-Alexa488探针(probe)与细菌显示的人scFv抗体易错(Error-prone)文库来筛选与Fcα受体结合的人类抗体。在25ml的包含2%的葡萄糖及40μg/ml的氯霉素的TB培养基中以37℃、250rpm的条件培养1ml的文库细胞4小时后。将培养的细胞以1∶100的比例在100ml的包含40μg/ml的氯霉素的TB培养基中培养至OD600=0.5后,在25℃及250rpm的条件下冷却20分钟后,加入1mM的异丙基-β-D-硫代半乳糖苷在25℃及250rpm的条件下诱导5小时来以OD600=8为标准获得蛋白质过表达的大肠杆菌。为了将细胞制备为适合利用流式细胞仪的筛选的原生质球形态,使用1ml的10Mm的Tris-HCl(pH8.0)使细胞再悬浮并洗涤2次来去除残留培养基后,在1ml的STE(0.5M的葡萄糖、10Mm的Tris-HCl及10Mm的乙二胺四乙酸(pH8.0))溶液中以37℃的温度旋转30分钟通过施加渗透压冲击的方法来去除细胞外膜。然后在混合1ml的溶液A及20μl的50mg/ml的溶菌酶溶液的溶液中以37℃的温度旋转15分钟来去除肽聚糖层并使用1ml的磷酸盐缓冲溶液洗涤后,将300μl放入700μl的磷酸盐缓冲溶液与200nM的Fcα受体-细胞外结构域-链霉亲和素-Alexa488探针(以单体为基准)后在常温下旋转1小时来在原生质球中标记荧光探针。然后,利用流式细胞仪回收因抗原结合力增加而显出高的荧光的克隆(图2),在回收的克隆中通过聚合酶链式反应扩增scFv基因后,重复上述培养、表达诱导、去除细胞外膜及肽聚糖层的原生质球化过程、抗原标记及通过流式细胞分析的选择性设门来筛选对Fcα受体-细胞外结构域示出高亲和度的原生质球的过程。在利用流式细胞仪的筛选过程及用于提高筛选纯度的再筛选过程后,通过浓缩过程、通过聚合酶链式反应扩增来确保筛选的scFv变异体基因的过程、亚克隆过程以及转化(transformation)过程后,为了扩增所希望的克隆进行下一轮的筛选过程。通过这样反复的多轮探索过程获得与Fcα受体细胞外结构域的结合力得到提高的新型scFv变异体克隆。
实施例8.确认增加对Fcα受体的结合力的抗体变异体的基因序列
为了确认上述实施例7中确保的scFv变异体克隆的基因序列,通过双脱氧测序法分析脱氧核糖核酸碱基序列(表1)。通过分析筛选到具有抗体序列的3种scFv抗体变异体JS116、JS144及JS140(图7)。
实施例9.分析增加对Fcα受体的结合力的抗体变异体对细胞外结构域的结合力
为了确认筛选的3种scFv抗体变异体JS116、JS144及JS140对Fcα受体细胞外结构域的结合力,利用流式细胞仪分析结合力。为此,以上述实施例7中使用的方式将各变异体和用作对照组的Fc(野生型)制备为原生质球。将50nM浓度的筛选中使用的Fcα受体-细胞外结构域-链霉亲和素-Alexa488抗原与准备的原生质球结合后,在常温下培养1小时。然后,为了去除非特异性结合,使用磷酸盐缓冲溶液洗涤两次后利用流式细胞仪分析对Fcα受体细胞外结构域的结合力。
结果,3种scFv变异体JS116、JS144及JS140都显出比作为对照组的先前的JS40或JS48增加的荧光信号(图8),通过此确认到本发明中发掘的scFv抗体变异体为增加与Fcα受体细胞外结构域的结合力的变异体。
实施例10.生产及纯化增加对Fcα受体细胞外结构域的结合力的3种scFv变异体
为了确认上述实施例中筛选的3种scFv变异体JS116、JS144及JS140在IgG形态下是否也增加与Fcα受体的结合力,在分别制备3种scFv的重链及轻链表达载体后,先在100ml的Freestyle 293表达培养液(赛默飞世尔公司,12338-018)中以1∶1的比例混合各变异体的重链基因与轻链基因后,以聚乙烯亚胺∶变异体基因=4∶1的比例混合后在常温下放置20分钟后向之前以2×106cells/ml的密度传代培养的Expi293F细胞转染。然后,在振荡培养仪中以37℃、125rpm及8%的CO2的条件培养7天后离心分离来只取上清液。使用25x磷酸盐缓冲溶液使上清液平衡后,利用瓶顶过滤器通过0.2μm的过滤器(默克密理博公司)过滤。向过滤的培养液中分别加入500μl的蛋白A(Protein A)树脂并在4℃的温度下搅拌16小时后,通过柱回收树脂后使用5ml的磷酸盐缓冲溶液洗涤后,使用3ml的pH2.7的100mM甘氨酸缓冲液洗脱后,利用1M的Tris-HCl pH8.0来中和。通过离心过滤装置3K(默克密理博公司)使用磷酸盐缓冲溶液更换缓冲液后,通过十二烷基磺酸钠-聚丙烯酰胺凝胶电泳分析分别包含3种scFv抗体变异体的IgG的大小与纯度(图9)。
实施例11.分析增加对Fcα受体的结合力的抗体的结合力
为了确认上述实施例10中制备的抗体在蛋白质上对Fcα受体的结合力,进行酶联免疫吸附测定实验。具体地,在4℃的温度下在96孔平地聚苯乙烯高粘合酶标板(科士达公司)各固定50μl的4μg/ml的在pH9.6的0.05M的碳酸钠溶液内融合链霉亲和素标签的四聚体形态的Fcα受体(抗原)16小时后,使用100μl的4%的脱脂牛奶(GenomicBase公司)(包含在0.05%的磷酸盐吐温缓冲溶液(PBST)中,pH6.0/pH7.4)在常温下封闭2小时。使用180μl的0.05%的磷酸盐吐温缓冲溶液洗涤4次后,将使用1%的脱脂牛奶(包含在0.05%的磷酸盐吐温缓冲溶液中)连续稀释的上述实施例10中以包含3种scFv变异体的方式制备的3种抗体(JS116、JS144及JS140)与作为对照组的先前的2种抗体(JS40及JS48)向各孔中分注50μl来在常温下反应1小时。经过洗涤过程后,使各抗体在常温下与50μl的抗人IgG(H+L)-HRP偶联物(杰克逊免疫研究公司)在常温下反应1小时后洗涤。然后,各加入50μl的1-Step UltraTMB-酶联免疫吸附测定底物溶液(赛默飞世尔公司)来显色后,加入50μl的2M的硫酸终止反应后,使用Epoch微孔板分光光度计(伯腾公司)分析各抗体对作为抗原的Fcα受体的结合力(图10)。
实施例12.生产及纯化JS40及JS48的重链可变区和轻链可变区被取代的抗体
在上述实施例6中发掘的6种抗体中,确认到虽然在蛋白质上与Fcα受体示出最高结合力的两种抗体JS40及JS48的重链可变区的序列非常相似,但VL的序列确完全不同,于是制备了将用作母抗体的JS40及JS48的重链可变区及轻链可变区相互取代来包含在IgG形态的抗体(表1)。为此,分别制备具有JS40的重链可变区并具有JS48的轻链可变区的JS40-1抗体及具有JS48的重链可变区并具有JS40的轻链可变区的JS48-1抗体的scFv的重链及轻链表达载体后,先在100ml的Freestyle 293表达培养液(赛默飞世尔公司,12338-018)中以1∶1的比例混合各变异体的重链基因与轻链基因后,以聚乙烯亚胺∶变异体基因=4∶1的比例混合后在常温下放置20分钟后向之前以2×106cells/ml的密度传代培养的Expi293F细胞转染。然后,在振荡培养仪中以37℃、125rpm及8%的CO2的条件培养7天后离心分离来只取上清液。使用25x磷酸盐缓冲溶液使上清液平衡后,利用瓶顶过滤器通过0.2μm的过滤器(默克密理博公司)过滤。向过滤的培养液中分别加入500μl的蛋白A(Protein A)树脂并在4℃的温度下搅拌16小时后,通过柱回收树脂后使用5ml的磷酸盐缓冲溶液洗涤后,使用3ml的pH2.7的100mM甘氨酸缓冲液洗脱后,利用1M的Tris-HCl pH8.0来中和。通过离心过滤装置3K(默克密理博公司)使用磷酸盐缓冲溶液更换缓冲液后,通过十二烷基磺酸钠-聚丙烯酰胺凝胶电泳分析纯化的2种分别包含JS40-1及JS48-1的IgG的大小与纯度(图11)。
实施例13.分析JS40-1及JS48-1抗体对Fcα受体的结合力
为了确认上述实施例12中制备的JS40-1及JS48-1在但白纸上对Fcα受体的结合力,进行了酶联免疫吸附测定实验。具体地,在4℃的温度下在96孔平地聚苯乙烯高粘合酶标板(科士达公司)各固定50μl的4μg/ml的在pH9.6的0.05M的碳酸钠溶液内融合链霉亲和素标签的四聚体形态的Fcα受体(抗原)16小时后,使用100μl的4%的脱脂牛奶(GenomicBase公司)(包含在0.05%的磷酸盐吐温缓冲溶液中,pH6.0/pH7.4)在常温下封闭2小时。使用180μl的0.05%的磷酸盐吐温缓冲溶液洗涤4次后,将使用1%的脱脂牛奶(包含在0.05%的磷酸盐吐温缓冲溶液中)连续稀释的上述实施例12中制备的2种抗体(JS40-1及JS48-1)与作为对照组的先前的2种抗体(JS40及JS48)向各孔中分株50μl来在常温下反应1小时。经过洗涤过程后,使各抗体在常温下与50μl的抗人IgG(H+L)-HRP偶联物(杰克逊免疫研究公司)在常温下反应1小时后洗涤。然后,各加入50μl的1-Step Ultra TMB-酶联免疫吸附测定底物溶液(赛默飞世尔公司)来显色后,加入50μl的2M的硫酸终止反应后,使用Epoch微孔板分光光度计(伯腾公司)分析各抗体对作为抗原的Fcα受体的结合力(图12)。
实施例14.生产及纯化双抗体
为了利用与Fcα受体结合的抗体制备使中性粒细胞的效应子功能最大化的治疗用抗体,将上述实施例中与Fcα受体的结合力高的JS40抗体及JS48抗体分别制备为双抗体形态。具体地,分别将JS40、JS48与以Her-2为靶向的曲妥珠单抗(Trastuzumab)以scFv及Fab形态制备为在Fc中导入旋钮(Knob)(T366W)及孔(Hole)(T366S、L368A、Y407V)的4种双抗体JSB-40-1(JS40 Fab+曲妥珠单抗的scFv)、JSB-48-1(JS48 Fab+曲妥珠单抗的scFv)、JSB-40-2(JS40 scFv+曲妥珠单抗的Fab)及JSB-48-2(JS48 scFv+曲妥珠单抗的Fab),为了制备JS40、JS48与曲妥珠单抗在各抗体的Fc末端以scFv形态连接的4种双抗体JSC-40-1(JS40IgG+曲妥珠单抗scFv)、JSC-48-1(JS48IgG+曲妥珠单抗scFv)、JSC-40-2(曲妥珠单抗IgG+JS40 scFv)及JSC-48-2(曲妥珠单抗IgG+JS48 scFv),分别制备了8种抗体的重链及轻链表达载体(图13)。然后,通过十二烷基磺酸钠-聚丙烯酰胺凝胶电泳分析以与上述实施例相同方式表达及纯化的抗体JSB-40-1、JSB-40-2、JSB-48-1、JSB-48-2、anti-Cκresin、JSC-40-1、JSC-40-2、JSC-48-1及JSC-48-2的大小与纯度(图14)。
实施例15.分析双抗体对两种抗原的结合力
为了测定上述实施例14中制备的双抗体对两种抗原Fcα受体及Her-2的结合力,以与前面实验相同的条件进行酶联免疫吸附测定分析。具体地,将上述双抗体连续稀释来反应后洗涤后,使50μl的蛋白质(Protein)L-HRP偶联物(金斯瑞公司(GenScript))与各抗体在常温下反应1小时后洗涤。然后,各加入50μl的1-Step Ultra TMB-酶联免疫吸附测定底物溶液(赛默飞世尔公司)来显色后,加入50μl的2M的硫酸终止反应后,使用Epoch微孔板分光光度计(伯腾公司)分析各抗体对作为抗原的Fcα受体的结合力。结果,双抗体均显出对Her-2抗原及Fcα受体的优秀的结合力,虽然多种双抗体设计(format)在结合力上存在差异,但都与两种抗原特异性结合(图15)。
SEQUENCE LISTING
<110> 高丽大学校产学协力团
<120> Fc ALPHA受体结合抗体
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<213> 人工序列
<220>
<223> CDRH3-JS9
<400> 12
Ala Thr Glu Ala Arg Gly Leu Ala His
1 5
<210> 13
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CDRH3-JS30
<400> 13
Val Thr Tyr Ser Ala Ser Asp Ala Ala Phe Asp Ser
1 5 10
<210> 14
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CDRH3-JS41
<400> 14
Val Thr Tyr Ser Ala Tyr Asp Ala Ala Phe Asp Ser
1 5 10
<210> 15
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CDRH3-JS19
<400> 15
Val Lys Val Pro Ser Pro Ala Pro Met Gln Gly Pro Asp His
1 5 10
<210> 16
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL1-JS116, JS144, JS40-1, JS40
<400> 16
Gln Gly Ile Ser Asn Tyr Leu Ala Trp Phe
1 5 10
<210> 17
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL1-JS140, JS48-1, JS48
<400> 17
Gln Ser Ile Ser Thr Tyr Leu Asn Trp Tyr
1 5 10
<210> 18
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL1-JS9
<400> 18
Lys Leu Gly Glu Arg Tyr Ala Cys Trp Tyr
1 5 10
<210> 19
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL1-JS30
<400> 19
Gln Ser Ile Ser Thr Cys Leu Asn Trp Tyr
1 5 10
<210> 20
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL1-JS41
<400> 20
Gln Ser Ile Ser Thr Tyr Leu Ser Trp Tyr
1 5 10
<210> 21
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CDRL1-JS19
<400> 21
Ser Ser Asn Ile Gly Ser Asn Thr Val Asn Arg Tyr
1 5 10
<210> 22
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL2-JS116, JS144
<400> 22
Ala Ala Ser Ser Leu Gln Gly Gly Val Pro
1 5 10
<210> 23
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL2-JS140, JS48-1, JS41, JS48
<400> 23
Gly Ala Ser Asn Leu Gln Ser Gly Val Ser
1 5 10
<210> 24
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL2-JS40-1, JS40
<400> 24
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
1 5 10
<210> 25
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDRL2-JS9
<400> 25
Gln Asp Thr Lys Arg Pro Ser Gly Ile
1 5
<210> 26
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL2-JS30
<400> 26
Gly Ala Ser Ile Leu Gln Ser Gly Val Ser
1 5 10
<210> 27
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDRL2-JS19
<400> 27
Ser Asp Asn Gln Arg Pro Ser Gly Val Pro
1 5 10
<210> 28
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDRL3-JS116, JS144, JS40-1, JS40
<400> 28
Gln Gln Tyr His Ser Tyr Pro Leu Thr
1 5
<210> 29
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDRL3-JS140
<400> 29
Gln Gln Gly Asn Asn Val Pro Leu Thr
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDRL3-JS48-1, JS30, JS41, JS48
<400> 30
Gln Gln Gly Asn Ser Val Pro Leu Thr
1 5
<210> 31
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDRL3-JS9
<400> 31
Gln Ala Trp Asp Ser Ser Thr Val Val
1 5
<210> 32
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDRL3-JS19
<400> 32
Ala Val Trp Asp Asp Ser Leu Asn Gly Pro Gly Tyr Val
1 5 10
<210> 33
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> VH-FR1-JS116, JS144, JS48-1, JS40, JS19
<400> 33
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ala Cys Ala Gly Ser
20 25
<210> 34
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> VH-FR1-JS140, JS40-1, JS48
<400> 34
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Thr Cys Ala Gly Ser
20 25
<210> 35
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> VH-FR1-JS9
<400> 35
Glu Val Gln Leu Val Gly Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 36
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> VH-FR1-JS30, JS41
<400> 36
Glu Val Gln Leu Val Glu Ser Gly Pro Gly Gln Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Ser
20 25
<210> 37
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> VH-FR2-JS116, JS144, JS40-1, JS48-1, JS40, JS48
<400> 37
Met Ala Trp Val Arg Leu Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10 15
Gly
<210> 38
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> VH-FR2-JS140
<400> 38
Met Ala Trp Val Arg Leu Ala Pro Gly Glu Gly Leu Glu Trp Val Ser
1 5 10 15
Gly
<210> 39
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> VH-FR2-JS9
<400> 39
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10 15
Ser
<210> 40
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> VH-FR2-JS30, JS41
<400> 40
Trp Gly Trp Val Arg Gln Pro Pro Gly Glu Gly Leu Glu Trp Ile Gly
1 5 10 15
Glu
<210> 41
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> VH-FR2-JS19
<400> 41
Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10 15
Gly
<210> 42
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> VH-FR3-JS116, JS144, JS140, JS40-1, JS48-1, JS19, JS40, JS48
<400> 42
Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
1 5 10 15
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
20 25 30
Thr Ala Val Tyr Tyr Cys
35
<210> 43
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> VH-FR3-JS9
<400> 43
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ala Arg Asp Asn
1 5 10 15
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
20 25 30
Thr Ala Val Tyr Tyr Cys
35
<210> 44
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> VH-FR3-JS30, JS41
<400> 44
Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Met Ser Met Asp Thr
1 5 10 15
Ser Lys Asn Gln Leu Ser Leu Lys Leu Thr Gly Val Thr Ala Val Asp
20 25 30
Thr Ala Val Tyr Tyr Cys
35
<210> 45
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VH-FR4-JS116, JS144, JS48-1
<400> 45
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 46
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VH-FR4-JS140, JS40-1, JS9, JS30, JS41, JS19, JS40, JS48
<400> 46
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 47
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> VL-FR1-JS116, JS144, JS48-1, JS40
<400> 47
Asp Val Val Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
20 25
<210> 48
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> VL-FR1-JS140
<400> 48
Glu Thr Thr Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Arg Ala Ser
20 25
<210> 49
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> VL-FR1-JS40-1, JS48
<400> 49
Glu Thr Thr 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
20 25
<210> 50
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> VL-FR1-JS9
<400> 50
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly His
20 25
<210> 51
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> VL-FR1-JS30, JS41
<400> 51
Glu Thr Thr Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Ile Thr Ile Thr Cys Arg Ala Ser
20 25
<210> 52
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> VL-FR1-JS19
<400> 52
Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser
20 25
<210> 53
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL-FR2-JS116, JS144, JS48-1, JS40
<400> 53
Gln Gln Lys Pro Gly Lys Val Pro Lys Arg Leu Ile Tyr
1 5 10
<210> 54
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL-FR2-JS140, JS40-1, JS30, JS41, JS48
<400> 54
Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile Tyr
1 5 10
<210> 55
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL-FR2-JS9
<400> 55
Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
1 5 10
<210> 56
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VL-FR2-JS19
<400> 56
Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr
1 5 10
<210> 57
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> VL-FR3-JS116, JS144, JS48-1, JS40
<400> 57
Ser Arg Phe Arg Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile
1 5 10 15
Ser Cys Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25
<210> 58
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> VL-FR3-JS140
<400> 58
Ser Gln Phe Ser Gly Arg Gly Pro Gly Ala Asp Phe Thr Leu Thr Ile
1 5 10 15
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25
<210> 59
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> VL-FR3-JS40-1, JS48
<400> 59
Ser Gln Phe Ser Gly Arg Gly Pro Gly Thr Asp Phe Thr Leu Thr Ile
1 5 10 15
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25
<210> 60
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> VL-FR3-JS9
<400> 60
Pro Glu Arg Phe Ser Gly Ser Asn Thr Gly Asn Thr Ala Thr Leu Thr
1 5 10 15
Ile Thr Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 61
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> VL-FR3-JS30
<400> 61
Ser Gln Phe Ser Gly Ser Gly Pro Gly Thr Asp Phe Thr Leu Thr Ile
1 5 10 15
Gly Ser Leu Gln Pro Glu Gly Phe Ala Thr Tyr Tyr Cys
20 25
<210> 62
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> VL-FR3-JS41
<400> 62
Ser Gln Phe Arg Gly Ser Gly Pro Gly Thr Asp Phe Thr Leu Thr Ile
1 5 10 15
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25
<210> 63
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> VL-FR3-JS19
<400> 63
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
1 5 10 15
Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25
<210> 64
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL-FR4-JS116, JS144, JS48-1, JS40
<400> 64
Phe Gly Gly Gly Thr Lys Leu Ser Val Leu Gly
1 5 10
<210> 65
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL-FR4-JS140, JS40-1, JS30, JS41, JS48
<400> 65
Phe Gly Gly Gly Thr Lys Val Asp Ile Lys Arg
1 5 10
<210> 66
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL-FR4-JS9
<400> 66
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
1 5 10
<210> 67
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> VL-FR4-JS19
<400> 67
Phe Gly Thr Gly Thr Lys Val Glu Ile Lys Arg
1 5 10
<210> 68
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> CL
<400> 68
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
1 5 10 15
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
20 25 30
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
35 40 45
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
50 55 60
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
65 70 75 80
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
85 90 95
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 69
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> CH1
<400> 69
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val
<210> 70
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> CH2
<400> 70
Glu Pro Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
20 25 30
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
35 40 45
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
50 55 60
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
65 70 75 80
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
85 90 95
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
100 105 110
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
115 120 125
<210> 71
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> CH3
<400> 71
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
1 5 10 15
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 72
<211> 206
<212> PRT
<213> 人类(Homo sapiens)
<400> 72
Gln Glu Gly Asp Phe Pro Met Pro Phe Ile Ser Ala Lys Ser Ser Pro
1 5 10 15
Val Ile Pro Leu Asp Gly Ser Val Lys Ile Gln Cys Gln Ala Ile Arg
20 25 30
Glu Ala Tyr Leu Thr Gln Leu Met Ile Ile Lys Asn Ser Thr Tyr Arg
35 40 45
Glu Ile Gly Arg Arg Leu Lys Phe Trp Asn Glu Thr Asp Pro Glu Phe
50 55 60
Val Ile Asp His Met Asp Ala Asn Lys Ala Gly Arg Tyr Gln Cys Gln
65 70 75 80
Tyr Arg Ile Gly His Tyr Arg Phe Arg Tyr Ser Asp Thr Leu Glu Leu
85 90 95
Val Val Thr Gly Leu Tyr Gly Lys Pro Phe Leu Ser Ala Asp Arg Gly
100 105 110
Leu Val Leu Met Pro Gly Glu Asn Ile Ser Leu Thr Cys Ser Ser Ala
115 120 125
His Ile Pro Phe Asp Arg Phe Ser Leu Ala Lys Glu Gly Glu Leu Ser
130 135 140
Leu Pro Gln His Gln Ser Gly Glu His Pro Ala Asn Phe Ser Leu Gly
145 150 155 160
Pro Val Asp Leu Asn Val Ser Gly Ile Tyr Arg Cys Tyr Gly Trp Tyr
165 170 175
Asn Arg Ser Pro Tyr Leu Trp Ser Phe Pro Ser Asn Ala Leu Glu Leu
180 185 190
Val Val Thr Asp Ser Ile His Gln Asp Tyr Thr Thr Gln Asn
195 200 205
Claims (30)
1.一种对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含选自由序列1至序列3的氨基酸序列组成的组中的任一种,上述CDRH2包含选自由序列4至序列7的氨基酸序列组成的组中的任一种,上述CDRH3包含选自由序列8至序列15的氨基酸序列组成的组中的任一种;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含选自由序列16至序列21的氨基酸序列组成的组中的任一种,上述CDRL2包含选自由序列22至序列27的氨基酸序列组成的组中的任一种,上述CDRL3包含选自由序列28至序列32的氨基酸序列组成的组中的任一种。
2.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,包含:
(a)VH结构域,包含FR1、FR2、FR3以及FR4,上述FR1包含选自由序列33至序列36的氨基酸序列组成的组中的任一种,上述FR2包含选自由序列37至序列41的氨基酸序列组成的组中的任一种,上述FR3包含选自由序列42至序列44的氨基酸序列组成的组中的任一种,上述FR4包含序列45或序列46的氨基酸序列;和/或
(b)VL结构域,包含FR1、FR2、FR3以及FR4,上述FR1包含选自由序列47至序列52的氨基酸序列组成的组中的任一种,上述FR2包含选自由序列53至序列56的氨基酸序列组成的组中的任一种,上述FR3包含选自由序列57至序列63的氨基酸序列组成的组中的任一种,上述FR4包含选自由序列64至序列67的氨基酸序列组成的组中的任一种。
3.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含序列1的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述CDRH3包含序列11的氨基酸序列;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含序列16的氨基酸序列,上述CDRL2包含序列24的氨基酸序列,上述CDRL3包含序列28的氨基酸序列。
4.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含序列1的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述CDRH3包含序列11的氨基酸序列;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含序列17的氨基酸序列,上述CDRL2包含序列23的氨基酸序列,上述CDRL3包含序列30的氨基酸序列。
5.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含序列1的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述CDRH3包含序列8的氨基酸序列;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含序列16的氨基酸序列,上述CDRL2包含序列22的氨基酸序列,上述CDRL3包含序列28的氨基酸序列。
6.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含序列1的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述CDRH3包含序列9的氨基酸序列;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含序列16的氨基酸序列,上述CDRL2包含序列22的氨基酸序列,上述CDRL3包含序列28的氨基酸序列。
7.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含序列1的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述CDRH3包含序列10的氨基酸序列;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含序列17的氨基酸序列,上述CDRL2包含序列23的氨基酸序列,上述CDRL3包含序列29的氨基酸序列。
8.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,包含:
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列34的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列37的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列11的氨基酸序列,上述FR4包含序列46的氨基酸序列;和/或
(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列49的氨基酸序列,上述CDRL1包含序列16的氨基酸序列,上述FR2包含序列54的氨基酸序列、上述CDRL2包含序列24的氨基酸序列,上述FR3包含序列59的氨基酸序列,上述CDRL3包含序列28的氨基酸序列,上述FR4包含序列65的氨基酸序列。
9.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含FR1、CDRH1、FR2、CDRH2、FR3、CDRH3以及FR4,上述FR1包含序列33的氨基酸序列,上述CDRH1包含序列1的氨基酸序列,上述FR2包含序列37的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述FR3包含序列42的氨基酸序列,上述CDRH3包含序列11的氨基酸序列,上述FR4包含序列45的氨基酸序列;和/或
(b)VL结构域,包含FR1、CDRL1、FR2、CDRL2、FR3、CDRL3以及FR4,上述FR1包含序列47的氨基酸序列,上述CDRL1包含序列17的氨基酸序列,上述FR2包含序列53的氨基酸序列、上述CDRL2包含序列23的氨基酸序列,上述FR3包含序列57的氨基酸序列,上述CDRL3包含序列30的氨基酸序列,上述FR4包含序列64的氨基酸序列。
10.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含序列2的氨基酸序列,上述CDRH2包含序列6的氨基酸序列,上述CDRH3包含序列12的氨基酸序列;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含序列18的氨基酸序列,上述CDRL2包含序列25的氨基酸序列,上述CDRL3包含序列31的氨基酸序列。
11.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含序列1的氨基酸序列,上述CDRH2包含序列4的氨基酸序列,上述CDRH3包含序列15的氨基酸序列;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含序列21的氨基酸序列,上述CDRL2包含序列27的氨基酸序列,上述CDRL3包含序列32的氨基酸序列。
12.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含序列3的氨基酸序列,上述CDRH2包含序列7的氨基酸序列,上述CDRH3包含序列13的氨基酸序列;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含序列19的氨基酸序列,上述CDRL2包含序列26的氨基酸序列,上述CDRL3包含序列30的氨基酸序列。
13.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,
包含V结构域,
上述V结构域包含:
(a)VH结构域,包含CDRH1、CDRH2以及CDRH3,上述CDRH1包含序列3的氨基酸序列,上述CDRH2包含序列7的氨基酸序列,上述CDRH3包含序列14的氨基酸序列;和/或
(b)VL结构域,包含CDRL1、CDRL2以及CDRL3,上述CDRL1包含序列20的氨基酸序列,上述CDRL2包含序列23的氨基酸序列,上述CDRL3包含序列30的氨基酸序列。
14.根据权利要求1所述的对Fcα受体具有特异性的抗体或其具有免疫活性的片段,其特征在于,具有免疫活性的片段为选自由Fab、Fd、Fab'、dAb、F(ab')、F(ab’)2、scFv、Fv、单链抗体、Fv二聚体、互补决定区片段、人源化抗体、嵌合抗体及双特异抗体组成的组中的任一种。
15.一种双特异性或多特异性抗体,其特征在于,包含权利要求1所述的抗体或其具有免疫活性的片段以及与Fcα受体以外的靶抗原结合的部分。
16.根据权利要求15所述的双特异性或多特异性抗体,其特征在于,与靶抗原结合的部分包含抗体或其具有免疫活性的片段。
17.根据权利要求15所述的双特异性或多特异性抗体,其特征在于,靶抗原为选自由17-1A抗原、GD3神经节苷脂R24、EGFRvⅢ、PSMA、PSCA、HLA-DR、EpCAM、MUC1核心蛋白、异常糖基化MUC1、含有ED-B结构域的异型纤连蛋白、HER2/neu、癌胚抗原、胃泌素释放肽受体抗原、粘蛋白抗原、表皮生长因子受体、HER3、HER4、MAGE抗原、SART抗原、MUC1抗原、c-erb-2抗原、TAG 72、碳酸酐酶IX、α胎蛋白、A3抗体特异性抗原、A33抗体特异性抗原、Ba 733、BrE3-抗原、CA125、CDl、CD1a、CD3、CD5、CDl5、CD16、CD19、CD20、CD21、CD22、CD23、CD25、CD30、CD33、CD38、CD40、CD45、CD52、CD74、CD79a、CD80、CD138、结肠特异性抗原-p、CSAp、EGP-1、EGP-2、Ep-CAM、FIt-1、Flt-3、叶酸盐受体、HLA-DR、人绒毛膜促性腺激素及其亚单位、低氧诱导因子、Ia、IL-2、IL-6、IL-8、胰岛素样生长因子-1、KC4-抗原、KS-1-抗原、KSl-4、Le-Y、巨噬细胞移动抑制因子、MAGE、MUCl、MUC2、MUC3、MUC4、NCA66、NCA95、NCA90、PAM-4抗体特异性抗原、胎盘生长因子、p53、前列腺酸性磷酸酶、PSA、RS5、SlOO、TAC、生腱蛋白、TRAIL受体、Tn抗原、TF抗原、肿瘤坏死抗原、VEGF、ED-B纤连蛋白、血管生成标志物、肿瘤基因标志物或肿瘤基因产物组成的组中的一种以上。
18.根据权利要求17所述的双特异性或多特异性抗体,其特征在于,肿瘤基因为选自由SEPTIN9、ACOD1、ACTN4、ADAM28、ADAM9、ADGRF1、ADRBK2、AFF1、AFF3、AGAP2、AGFG1、AGRN、AHCYL1、AHI1、AIMP2、AKAP13、AKAP9、AKIRIN2、AKTIP、ALDH1A1、ALL1、ANIB1、ANP32C、ANP32D、AQP1、ARAF、ARHGEF1、ARHGEF2、ARHGEF5、ASPSCR1、AURKA、BAALC、BAIAP2L1、BANP、BCAR4、BCKDHB、BCL9、BCL9L、BCR、BMI1、BMP7、BOC、BRD4、BRF2、CABIN1、CAMK1D、CAPG、CBFB、CBLB、CBLL1、CBX7、CBX8、CCDC28A、CCDC6、CCNB1、CCNB2、CCND1、CCNE1、CCNL1、CD24、CDC25C、CDC6、CDH17、CDK1、CDK14、CDK4、CDK5R2、CDK6、CDK8、CDKN1B、CDKN3、CDON、CEACAM6、CENPW、CHD1L、CHIC1、CHL1、CKS1B、CMC4、CNTN2、COPS3、COPS5、CRKL、CRLF2、CROT、CRTC1、CRYAB、CSF1R、CSF3、CSF3R、CSNK2A1、CSNK2A2、CT45A1、CTBP2、CTNND2、CTSZ、CUL7、CXCL1、CXCL2、CXCL3、CYGB、CYP24A1、DCD、DCUN1D1DDB2、DDHD2、DDX6、DEK、DIS3、DNPH1、DPPA2、DPPA4、DSG3、DUSP12、DUSP26、ECHS1、ECT2、EEF1A1、EEF1A2、EEF1D、EIF3E、EIF3I、EIF4E、EIF5A2、ELAVL1、ELL、EML4、EMSY、ENTPD5、EPCAM、EPS8、ERAS、ERGIC1、ERVW-1、EVI2A、EVI5、EWSR1、EZH2、FAM189B、FAM72A、FAM83D、FASN、FDPS、FGF10、FGF3、FGF5、FGF8、FR1OP、FHL2、FIP1L1、FNDC3B、FRAT1、FUBP1、FUS、FZD2、GAB2、GAEC1、GALNT10、GALR2、GLO1、GMNN、GNA12、GNA13、GNAI2、GNAQ、GNAS、GOLPH3、GOPC、GPAT4、GPM6A、GPM6B、GPR132、GREM1、GRM1、GSK3A、GSM1、H19、HAS1、HAX1、HDGFRP2、HMGN5、HNRNPA1、HOTAIR、HOTTIP、HOXA-AS2、HRAS、HSPA1A、HSPA4、HSPB1、HULC、IDH1、IFNG、IGF2BP1、IKBKE、IL7R、INPPL1、INTS1、INTS2、INTS3、INTS4、INTS5、INTS7、INTS8、IRS2、IST1、JUP、KDM4C、KIAA0101、KIAA1524、KIF14、KRAS、KSR2、LAMTOR5、LAPTM4B、LCN2、LDHB、LETMD1、LIN28A、LIN28B、LMO1、LMO2、LMO3、LMO4、LSM1、LUADT1、MACC1、MACROD1、MAGEA11、MALAT1、MAML2、MAP3K8、MAPRE1、MAS1、MCC、MCF2、MCF2L、MCTS1、MEFV、MFHAS1、MFNG、MIEN1、MINA、MKL2、MLANA、MLLT1、MLLT11、MLLT3、MLLT4、MMP12、MMS22L、MN1、MNAT1、MOS、MPL、MPST、MRAS、MRE11A、MSI1、MTCP1、MTDH、MTOR、MUC1、MUC4、MUM1、MYD88、NAAA、NANOGP8、NBPF12、NCOA4、NEAT1、NECTIN4、NEDD4、NEDD9、NET1、NINL、NME1、NOTCH1、NOTCH4、NOV、NSD1、NUAK2、NUP214、NUP98、NUTM1、OLR1、PA2G4、PADI2、PAK7、PARK7、PARM1、PBK、PCAT1、PCAT5、PDGFA、PDZK1IP1、PELP1、PFN1P3、PIGU、PIK3CA、PIK3R1、PIM1、PIM2、PIM3、PIR、PIWIL1、PLAC8、PLK1、PPM1D、PPP1R10、PPP1R14A、PPP2R1A、PRAME、PRDM12、PRMT5、PSIP1、PSMD10、PTCH2、PTMA、PTP4A1、PTP4A2、PTP4A3、PTTG1、PTTG1IP、PTTG2、PVT1、RAB11A、RAB18、RAB22A、RAB23、RAB8A、RALGDS、RAP1A、RASSF1、RBM14、RBM15、RBM3、RBMY1A1、RFC3、RGL4、RGR、RHO、RING1、RINT1、RIT1、RNF43、RPL23、RRAS、RRAS2、RSF1、RUNX1T1、S100A4、S100A7、S100A8、SAG、SART3、SBSN、SEA、SEC62、SERTAD1、SERTAD2、SERTAD3、SET、SETBP1、SETDB1、SGK1、SIRT1、SIRT6、SKI、SKIL、SKP2、SLC12A5、SLC3A2、SMR3B、SMURF1、SNCG、SNORA59A、SNORA80E、SPAG9、SPATA4、SPRY2、SQSTM1、SRSF1、SRSF2、SRSF3、SRSF6、SS18、SSX1、SSX2、SSX2B、STIL、STMN1、STRA6、STYK1、SUZ12、SWAP70、SYT1、TAC1、TACSTD2、TAF15、TALDO1、TAZ、TBC1D1、TBC1D15、TBC1D3、TBC1D3C、TBC1D7、TCL1A、TCL1B、TCL6、TCP1、TFG、TGM3、TINCR、TKTL1、TLE1、TMEM140、TMPOP2、TMPRSS2、TNS4、TPD52、TPR、TRE17、TREH、TRIB1、TRIB2、TRIM28、TRIM32、TRIM8、TRIO、TRIP6、TSPAN1、TSPY1、TXN、TYMS、TYRP1、UBE2C、UBE3C、UCA1、UCHL1、UHRF1、URI1、USP22、USP4、USP6、VAV1、VAV2、VAV3、VIM、WAPL、WHSC1、WHSC1L1、WISP1、WNT1、WNT10A、WNT10B、WNT2、WNT3、WNT5A、WWTR1、XCL1、XIAP、YAP1、YEATS4、YY1AP1、ZEB1-AS1、ZFAND4、ZFAS1、ZMYM2、ZNF703及ZNHIT6组成的组中的一种以上。
19.根据权利要求15所述的双特异性或多特异性抗体,其特征在于,靶抗原为细胞表面抗原。
20.根据权利要求19所述的双特异性或多特异性抗体,其特征在于,细胞表面抗原为选自由CEA、ED-B纤连蛋白、CD20、CD22、CDl9、EGFR、IGFlR、VEFGRl/Flt-1、VEGFR2/KDR、VEGRF3/Flt-4、HER2/neu、CD30、CD33、CD3、CD16、CD64、CD89、CD2、腺病毒纤维旋钮、PfMSP-1、HN/NDV、EpCAM/17-lA、hTR、IL-2R/Tac、CAl9-9、MUCl、HLAII类抗原、GD2、G250、TAG-72、PSMA、CEACAM6、HMWMAA、CD40、Ml3外壳蛋白及GPIIb/IIIa组成的组中的一种以上。
21.根据权利要求15所述的双特异性或多特异性抗体,其特征在于,靶抗原为自身抗原。
22.一种分离的核酸分子,其特征在于,编码权利要求1所述的抗体或其具有免疫活性的片段或权利要求15所述的双特异性或多特异性抗体。
23.一种载体,其特征在于,包含权利要求22所述的分离的核酸分子。
24.一种宿主细胞,其特征在于,由权利要求23所述的载体转化。
25.一种用于预防或治疗疾病或疾患的药物组合物,其特征在于,
包含权利要求15所述的双特异性或多特异性抗体作为有效成分,
上述疾病或疾患选自由癌症、自身免疫疾病、退行性神经疾病、阿尔茨海默病、代谢疾病、心血管疾病、动脉粥样硬化症、器官移植排斥反应、由真菌、病毒、细菌或寄生虫引起的疾病或症状组成的组中。
26.一种制备对Fcα受体具有特异性的抗体或其具有免疫活性的片段的方法,其特征在于,包括:
步骤a),培养由包含编码权利要求1所述的抗体或其具有免疫活性的片段的分离的核酸分子的载体转化的宿主细胞;以及
步骤b),从宿主细胞培养物中回收抗体或其具有免疫活性的片段。
27.一种制备与Fcα受体及Fcα受体以外的靶抗原结合的双特异性或多特异性抗体的方法,其特征在于,包括:
步骤a),培养由包含编码权利要求15所述的双特异性或多特异性抗体的分离的核酸分子的载体转化的宿主细胞;以及
步骤b),从宿主细胞培养物中回收抗体或其具有免疫活性的片段。
28.一种对Fcα受体具有特异性的抗体或其具有免疫活性的片段在抗体治疗剂的制备中的用途。
29.一种双特异性或多特异性抗体在疾病或疾患的预防或治疗中的用途,其特征在于,上述疾病或疾患选自由癌症、自身免疫疾病、退行性神经疾病、阿尔茨海默病、代谢疾病、心血管疾病、动脉粥样硬化症、器官移植排斥反应、由真菌、病毒、细菌或寄生虫引起的疾病或症状组成的组中。
30.一种癌症的治疗方法,其特征在于,包括以药学上有效的量向患有癌症的个体给药双特异性或多特异性抗体的步骤。
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US5922845A (en) * | 1996-07-11 | 1999-07-13 | Medarex, Inc. | Therapeutic multispecific compounds comprised of anti-Fcα receptor antibodies |
IL147766A0 (en) * | 1999-07-30 | 2002-08-14 | Medarex Inc | Therapeutic compounds comprised of anti-fc receptor binding agents |
KR100890088B1 (ko) * | 2001-02-12 | 2009-03-24 | 메다렉스, 인코포레이티드 | Fc 알파 수용체(CD89)에 대한 인간 모노클로날 항체 |
US9209965B2 (en) | 2014-01-14 | 2015-12-08 | Microsemi Semiconductor Ulc | Network interface with clock recovery module on line card |
CA3001724A1 (en) * | 2014-10-10 | 2016-04-14 | National Research Council Of Canada | Anti-tau antibody and uses thereof |
-
2021
- 2021-11-03 EP EP21889549.8A patent/EP4242233A1/en active Pending
- 2021-11-03 WO PCT/KR2021/015795 patent/WO2022098084A1/ko unknown
- 2021-11-03 CN CN202180075236.XA patent/CN116419928A/zh active Pending
- 2021-11-03 US US18/035,609 patent/US20230399407A1/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117327703A (zh) * | 2023-11-22 | 2024-01-02 | 青岛大学附属医院 | 一种靶向平滑肌细胞的Agrin-shRNA及其在制备抗动脉粥样硬化的药物中的应用 |
CN117327703B (zh) * | 2023-11-22 | 2024-04-23 | 青岛大学附属医院 | 一种靶向平滑肌细胞的Agrin-shRNA及其在制备抗动脉粥样硬化的药物中的应用 |
Also Published As
Publication number | Publication date |
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EP4242233A1 (en) | 2023-09-13 |
US20230399407A1 (en) | 2023-12-14 |
WO2022098084A1 (ko) | 2022-05-12 |
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