CN117285632A - 针对tfpi的单克隆抗体及其用途 - Google Patents
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Abstract
本发明提供针对人TFPI的抗体或其抗原结合片段,还提供了编码所述抗体的核酸分子,用于表达所述抗体的表达载体和宿主细胞,以及所述抗体的生产方法。此外,本发明还提供了包含所述抗体或其抗原结合片段的药物组合物,以及其在制备药物中的用途,所述药物用于预防和/或治疗遗传或获得性凝血因子缺乏患者的凝血疾病的药物中的用途。
Description
技术领域
本发明属于治疗性单克隆抗体领域,更具体地,本发明涉及一种针对组织因子途径抑制物(TFPI)的抗体或其抗原结合片段;还涉及所述抗体在制备预防或治疗遗传或获得性凝血因子缺乏的疾病或事件的药物中的用途。
背景技术
血友病A和B是遗传性凝血功能障碍的出血性疾病,其特征是活性凝血活酶生成障碍,凝血时间延长,终身具有轻微创伤后出血倾向,重症患者没有明显外伤也可发生自发性出血。血友病A的特征是缺失或缺乏凝血因子VIII(FVIII),占血友病总数的80%以上,在男性人群中患病率为1/5000。血友病B的特征是缺失或缺乏凝血因子IX(FIX),其发病率为30000名新生儿中的1名。复发性、自发性和创伤相关出血是重度血友病的特征,典型的出血部位是关节和肌肉,在最低限度治疗下,重症患者每年出血多达30-40次,且会导致不可逆的关节损伤和继发性残疾。目前最常用的治疗方法是因子替代治疗,即补充血友病患者所缺乏的FVIII或FIX。基于目前的治疗方法,预防性治疗需要频繁输注FVIII或FIX,通常每周2到4次,以此减少自发性出血。然而这种治疗方法能有效预防大多数自发性出血,但不能预防外伤性出血,此外治疗的效果受输注频率、剂量以及漏服或延迟给药次数的影响,而剂量和输注频率又受因子的消除半衰期、方案的成本效益和患者可接受性的影响。为了克服因子替代治疗的局限性,提高患者的依从性,减轻患者的负担,需要探索新的治疗方法。
组织因子途径抑制物(tissue factor pathway inhibitor,TFPI)是控制凝血启动阶段的一种体内天然抗凝蛋白,它对组织因子启动的凝血途径具有特异性抑制作用,通过结合TF/FVIIa复合物阻止X因子激活继而抑制凝血功能。当TFPI活性被抗TFPI抗体中和时,凝血过程恢复或放大。TFPI是一种全长由276个氨基酸残基组成的糖蛋白,含K1、K2和K3三个Kunitz结构域,另外还包括2个连接区以及一个富含酸性氨基酸的N末端和一个富含碱性氨基酸的C末端。结构域K1和K2是TFPI发挥抗凝活性的关键部位,K3在该作用中并非必需,但它的存在可以使TFPI更好地抑制凝血。近年来有不少研究表明,K3和C末端可以和肝素、膜表面糖蛋白及多糖结合,另外该区域还与TFPI的抗炎作用有关。TFPI在凝血途径中的抑制作用分两步实现:首先,TFPI通过K2与活化的FⅩ结合,并竞争性地抑制其活性,该过程是一个Ca2+非依赖的可逆性过程;其次,FⅩa/TFPI复合物中的TFPI通过K1与FⅦa/TF复合物中的FⅦa活性部位结合,从而实现对FⅦa/TF复合物的抑制。TFPI抗体作用于TFPI的K-2区域,竞争性阻断FXa与TFPI结合的位点,提升FXa水平,也阻断了TFPI在FXa和Ca2+作用下对TF-FVIIa的抑制作用,导致产生的FXa水平升高并生成凝血酶,通过双重机制提高凝血能力。
抗TFPI抗体可应用于伴有或不伴有FVIII和FIX抑制物的血友病患者,且抗体本身具有更长的半衰期能降低给药频次。针对不同Kunitz结构域的血友病治疗抗体目前已在临床试验中进行了研究,例如,由诺和诺德开发的人源化单克隆抗体Concizumab已进入临床III期研究阶段,由辉瑞制药开发的单克隆抗体Marstacimab已进入临床III期研究阶段,由拜耳开发的BAY-1093884处于临床II期阶段。目前尚没有针对TFPI的上市抗体药物。
发明内容
本发明提供了一种能够特异性结合人TFPI的抗体,编码所述抗体的核酸,包含所述核酸的载体,包含所述载体的宿主细胞,用于生产所述抗体的方法,以及用于预防或治疗遗传或获得性凝血因子缺乏患者的凝血疾病的药物组合物,所述药物组合物包含所述抗体作为活性成分并且能够抑制TFPI从而激活凝血途径。本发明公开的抗人TFPI抗体可以用于治疗或预防血友病。
本发明第一方面,提供一种能够特异性结合TFPI的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含的重链可变区(VH)包含至少一个、两个或三个选自下组的互补决定区(CDR):
(1)HCDR1,其具有如SEQ ID NO:1或7所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(2)HCDR2,其具有如SEQ ID NO:2、8、12或13所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;和
(3)HCDR3,其具有如SEQ ID NO:3或9所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
和/或,其包含的轻链可变区(VL)包含至少一个、两个或三个选自下组的互补决定区(CDR):
(4)LCDR1,其具有如SEQ ID NO:4或10所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(5)LCDR2,其具有如SEQ ID NO:5或11所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;和
(6)LCDR3,其具有如SEQ ID NO:6所示的序列,或者与上述序列相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列。
在某些优选的实施方案中,(1)-(6)任一项中所述的置换为保守置换。
在某些优选的实施方案中,所述重链可变区中含有的HCDR1、HCDR2及HCDR3,和/或所述轻链可变区中含有的LCDR1、LCDR2及LCDR3由Kabat或IMGT编号***定义。实施例3中的表2示例性地给出了鼠源抗体按Kabat或IMGT编号***定义出的CDR氨基酸序列。
在某些优选的实施方案中,所述抗体或其抗原结合片段包含3个VH可变区CDR和3个VL可变区CDR,其选自下组:
(1)其HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:1、2、3、4、5或6所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(2)其HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:7、8、9、10、11或6所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(3)其HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:1、12、3、4、5或6所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(4)其HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:7、13、9、10、11或6所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列。
在某些实施方案中,所述抗体或其抗原结合片段为鼠源的或嵌合的,其重链可变区包含鼠源IgG1、IgG2、IgG3或其变体的重链FR区;和其轻链可变区包含鼠源κ、λ链或其变体的轻链FR区。实施例3中的表3中给出了优选的鼠源抗体的可变区氨基酸序列编号。
在某些优选的实施方案中,所述鼠源或嵌合抗体或其抗原结合片段包含如下的VH和VL序列:VH结构域包含如SEQ ID NO:14所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:15所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列。
在某些实施方案中,所述抗体或其抗原结合片段为人源化的。实施例3给出了人源化策略的基本流程,表2示例性地给出了优选的人源化抗体按Kabat或IMGT编号***定义出的CDR氨基酸序列,表3中给出了优选的人源化抗体的可变区氨基酸序列编号。
在某些优选的实施方案中,所述人源化抗体或其抗原结合片段包含如下的VH和VL序列:VH结构域包含如SEQ ID NO:16所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:17所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列。
在某些实施方案中,所述抗体包含来源于人免疫球蛋白的重链恒定区和轻链恒定区。
较优选地,所述抗体包含人κ轻链恒定区氨基酸序列(氨基酸序列如SEQ ID NO:18所示)。
较优选地,所述抗体包含选自人IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgD和IgE的重链恒定区;更优选地,包含选自人IgG1、IgG2和IgG4的重链恒定区;并且,所述重链恒定区具有天然序列或与其所源自的天然序列相比具有一个或多个氨基酸的置换、缺失或添加的序列。例如,在一种实施方案中,人源化抗体分子包含野生型人IgG1的重链恒定区(氨基酸序列如SEQ ID NO:19所示)。在另一种实施方案中,人源化抗体分子包括在根据EU编号的M252Y、S254T、T256E和M428L突变的人IgG1的重链恒定区(氨基酸序列如SEQ ID NO:20所示)。在另一种实施方案中,人源化抗体分子包含野生型人IgG2的重链恒定区(氨基酸序列如SEQ ID NO:21所示)。在另一种实施方案中,人源化抗体分子包括在根据EU编号的第228位突变(例如S变为P)的人IgG4(氨基酸序列如SEQ ID NO:22所示)。
在一种示例性的实施方案中,人源化抗体分子的重链氨基酸序列如SEQ ID NO:23所示,和轻链氨基酸序列如SEQ ID NO:24所示。
在上述任何实施方案中,本发明所述抗体或其抗原结合片段能够以10nM或更低的KD结合TFPI,较优选地,以1nM或更低的KD结合TFPI;较优选地,以100pM或更低的KD结合TFPI;更优选地,以10pM或更低的KD结合TFPI。
本发明的第二方面,提供了编码上述抗体或其抗原结合片段的DNA分子。
本发明的第三方面,提供了包含上述DNA分子的载体。
本发明的第四方面,提供了包含上述载体的宿主细胞;所述宿主细胞包含原核细胞、酵母或哺乳动物细胞,如CHO细胞、NS0细胞或其它哺乳动物细胞,优选为CHO细胞。
本发明的第五方面,提供了一种药物组合物,所述组合物包含上述抗体或其抗原结合片段以及可药用赋形剂、载体或稀释剂。
本发明的第六方面,还提供了制备本发明所述抗体或其抗原结合片段的方法,其包括:(a)获得抗体或其抗原结合片段的基因,构建抗体或其抗原结合片段的表达载体;(b)通过基因工程方法将上述表达载体转染到宿主细胞中;(c)在允许产生所述抗体或其抗原结合片段的条件下培养上述宿主细胞;(d)分离、纯化产生的所述抗体或其抗原结合片段。
其中,步骤(a)中所述表达载体选自质粒、细菌和病毒中的一种或多种,优选地,所述表达载体为pcDNA3.1;
其中,步骤(b)通过基因工程方法将所构建的载体转染入宿主细胞中,所述宿主细胞包括原核细胞、酵母或哺乳动物细胞,如CHO细胞、NS0细胞或其它哺乳动物细胞,优选为CHO细胞。
其中,步骤(d)通过常规的免疫球蛋白纯化方法,包含蛋白质A亲和层析和离子交换方法分离、纯化所述抗体或其抗原结合片段。
本发明的第七方面,提供了所述抗体或其抗原结合片段在制备预防或治疗遗传或获得性凝血因子缺乏的疾病或事件的药物中的用途。例如,本发明提供的抗体或其抗原结合片段可用来阻止TFPI和FXa之间的相互影响,或防止TFPI依赖的TF/FVIIa活性抑制。此外,人单克隆抗体还可以用来恢复TF/FVIIa驱动的FXa生成,以避开FVIII或FIX依赖的FXa扩增不足。进一步的,所述疾病包括血友病A和血友病B,还包括在血友病患者的自发出血事件,创伤性出血事件,或手术预防、围手术期处理或手术治疗中发生的出血事件。
本发明的其他方面,提供一种用于预防或治疗遗传或获得性凝血因子缺乏的疾病或事件的方法,所述方法包括施用有效量的本发明所述抗体或其抗原结合片段,或本发明所述的药物组合物。
缩写及术语定义
在本文中使用以下缩写:
CDR Complementarity-Determining Region,免疫球蛋白可变区中的互补决定区,用Kabat、IMGT、Chothia或AbM编号***界定(参见术语“超变区”或“CDR区”或“互补决定区”)。
EC50 产生50%功效或结合的浓度
ELISA 酶联免疫吸附测定
FR 抗体框架区(Framework),将CDR区排除在外的免疫球蛋白可变区
HRP 辣根过氧化物酶
IC50 产生50%抑制的浓度
IgG 免疫球蛋白G
Kabat 由Elvin A Kabat倡导的免疫球蛋白氨基酸序列比对及编号***。
PCR 聚合酶链式反应
V区 在不同抗体之间序列可变的IgG链区段。其延伸到轻链的109位Kabat残基和重链的第113位残基。
KD 平衡解离常数
ka 结合速率常数
kd 解离速率常数
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的细胞培养、生物化学、核酸化学、免疫学实验室等操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
术语“组织因子途径抑制剂”或“TFPI”指由细胞天然表达的人TFPI的任何变体、同种型和物种同系物。
术语“EU编号***”(EU Numbering System or Scheme):Eu是指上个世纪60年代末(1968-1969),Gerald M Edelman等人分离纯化得到第一个人IgG1免疫球蛋白,命名为Eu,测定了其氨基酸序列并为其编号(Edelman GM et al,1969,Proc Natl Acad USA,63:78-85)。其它的免疫球蛋白的重链恒定区与Eu进行氨基酸序列比对,对应氨基酸位置就是Eu编号。Eu编号***主要针对的是免疫球蛋白重链恒定区,包括CH1,CH2,CH3和铰链区。
术语“Kabat编号***”(Kabat Numbering System or Scheme):1979年,Kabat等人首先提出了标准化的人免疫球蛋白可变区的编号方案(Kabat EA,Wu TT,Bilofsky H,Sequences ofImmunoglobulin Chains:Tabulation and Analysis of Amino AcidSequences of Precursors,V-regions,C-regions,J-Chain andβ2-Microglobulins.1979.Department of Health,Education,and Welfare,Public HealthService,National Institutes of Health)。在“免疫学相关蛋白质序列”一书中(KabatEA,Wu TT,Perry HM,Gottesman KS,Foeller C.1991.Sequences of Proteins ofImmunological Interest,5th edition.Bethesda,MD:US Department of Health andHuman Services,National Institutes for Health),Kabat等人对抗体轻链和重链的氨基酸序列进行了比对并编号。他们发现这些被分析序列表现出可变的长度,缺省和***的氨基酸或氨基酸片段只能出现在特定的位置。有趣的是,***点多位于CDR内部,但也可能出现在在框架区的某些位置。在Kabat编号方案中,轻链可变区编号到109位置,重链可变区编号到113位置,轻重链的***氨基酸通过字母识别并注释(例如,27a,27b...)。所有Lambda轻链不包含位置10残基,而Lambda和Kappa轻链由两个不同的基因编码,位于不同的染色体上。Lambda和Kappa轻链可以通过它们的恒定区氨基酸序列的不同来区分。与EU编号***只针对重链恒定区不同,Kabat编号***的编号范围覆盖全长免疫球蛋白序列,包括免疫球蛋白轻链和重链的可变区和恒定区。
术语“抗体”通常指具有免疫球蛋白一类功能的蛋白质结合分子。抗体的典型实例是免疫球蛋白,以及其衍生物或功能片段,只要其显示所需的结合特异性即可。用于制备抗体的技术是本领域熟知的。“抗体”包括不同类的天然免疫球蛋白(例如IgA、IgG、IgM、IgD和IgE)和亚类(如IgG1、lgG2、IgA1、IgA2等)。“抗体”还包括非天然免疫球蛋白,包括例如单链抗体,嵌合抗体(例如,人源化鼠抗体)和异源偶联抗体(例如,双特异性抗体),以及其抗原结合片段(例如,Fab',F(ab')2,Fab,Fv和rIgG)。还可参见,例如,Pierce Catalog andHandbook,1994-1995(Pierce Chemical Co,Rockford,Ill);Kuby J,Immunology,3rd Ed,WH Freeman&Co,New York,1997。抗体可以结合至一种抗原,称为“单特异性”;或结合至两种不同的抗原,称为“双特异性”;或结合至多于一种的不同的抗原,称为“多特异性”。抗体可以是单价、二价或多价的,即抗体可以一次结合至一个、两个或多个抗原分子。抗体“单价地”结合至某特定蛋白质,即一分子的抗体仅结合至一分子的蛋白质,但是该抗体也可以结合到不同的蛋白质。当抗体仅结合至两种不同蛋白质的每一种分子时,该抗体为“单价地”结合至每一种蛋白质,并且该抗体是“双特异性的”且“单价地”结合至两种不同蛋白质的每一种。抗体可以是“单体的”,即其包含单个多肽链。抗体可包含多个多肽链(“多聚体的”)或可包含两个(“二聚体的”)、三个(“三聚体的”)或四个(“四聚体的”)多肽链。若抗体为多聚体的,则该抗体可以是同源多聚体(homomulitmer),即抗体包含多于一分子的仅一种多肽链,包括同源二聚体、同源三聚体或同源四聚体。可选的,多聚体抗体可以是异源多聚体,即抗体包含多于一种不同的多肽链,包括异源二聚体、异源三聚体或异源四聚体。
术语“单克隆抗体(mAb)”指获自基本均一抗体群体的抗体,例如除了可能少量存在的突变如天然产生的突变外,群体包含的单独抗体是相同的。因此,定语“单克隆”表示所述抗体特征为不是离散抗体的混合物。单克隆抗体由本领域技术人员所知晓的方法产生,例如通过将骨髓瘤细胞和免疫脾细胞融合制备杂合的抗体产生细胞。通过杂交瘤培养来合成,不会被其它免疫球蛋白污染。单克隆抗体也可以用如重组技术、噬菌体展示技术、合成技术,或其它现有技术得到。
术语“完整抗体”是指由两条抗体重链和两条抗体轻链组成的抗体。“完整抗体重链”是在N-端到C-端方向上由抗体重链可变结构域(VH)、抗体恒定重链结构域1(CH1)、抗体铰链区(HR)、抗体重链恒定结构域2(CH2)和抗体重链恒定结构域3(CH3)组成,缩写为VH-CH1-HR-CH2-CH3;并且在IgE亚类的抗体的情形中,任选地还包括抗体重链恒定结构域4(CH4)。优选地“完整抗体重链”是在N-端到C-端方向上由VH、CH1、HR、CH2和CH3组成的多肽。“完整抗体轻链”是在N-端到C-端方向上由抗体轻链可变结构域(VL)和抗体轻链恒定结构域(CL)组成的多肽,缩写为VL-CL。所述抗体轻链恒定结构域(CL)可以是κ(kappa)或λ(lambda)。完整抗体链通过在CL结构域和CH1结构域之间(即轻链和重链之间)的多肽间二硫键和完整抗体重链的铰链区之间的多肽间二硫键连接在一起。典型的完整抗体的实例是天然抗体如IgG(例如,IgG1和IgG2)、IgM、IgA、IgD和IgE。
术语“抗体片段”或“抗原结合片段”是指保留与抗原特异性结合能力的抗体的抗原结合片段及抗体类似物,其通常包括至少部分母体抗体(Parental Antibody)的抗原结合区或可变区。抗体片段保留母体抗体的至少某些结合特异性。通常,当用摩尔单位(KD)来表示活性时,抗体片段保留至少10%的母体结合活性。优选地,抗体片段保留至少20%、50%、70%、80%、90%、95%或100%的母体抗体对靶标的结合亲和力。抗体片段包括但不限于:Fab片段、Fab'片段、F(ab')2片段、Fv片段、Fd片段、互补决定区(CDR)片段、二硫键稳定性蛋白(dsFv)等;线性抗体(Linear Antibody)、单链抗体(例如scFv单抗体)、单抗体(Unibody,技术来自Genmab)、二价单链抗体、单链噬菌体抗体、单域抗体(Single DomainAntibody)(例如VH结构域抗体)、结构域抗体(Domantis,技术来自Domantis)、纳米抗体(nanobodies,技术来自Ablynx);由抗体片段形成的多特异性抗体(例如三链抗体、四链抗体等);和工程改造抗体如嵌合抗体(Chimeric Antibody)(例如人源化鼠抗体)、异缀合抗体(Heteroconjugate Antibody)等。这些抗体片段用本领域技术人员已知的常规技术获得,并用与完整抗体相同的方法对这些片段的实用性进行筛选。
术语“单链Fv抗体”(或“scFv抗体”)是指包含抗体的VH和VL结构域的抗体片段,是通过接头(linker)连接的重链可变区(VH)和轻链可变区(VL)的重组蛋白,接头使得这两个结构域相交联以形成抗原结合位点,接头序列一般由柔性肽组成,例如但不限于G2(GGGGS)3。scFv的大小一般是一个完整抗体的1/6。单链抗体优选是由一个核苷酸链编码的一条氨基酸链序列。对于scFv综述,可参见Pluckthun A,1994.Antibodies fromEscherichia coli,in The Pharmacology of Monoclonal Antibodies,Vol 113,Rosenberg M and Moore GP(EDs.),Springer-Verlag,New York,pp 269-315。还可参见国际专利申请公开号WO 88/01649和美国专利第4946778号和第5260203号。
术语“VL结构域”是指免疫球蛋白轻链的氨基末端可变区结构域。
术语“VH结构域”是指免疫球蛋白重链的氨基末端可变区结构域。
术语“铰链区”包括重链分子的将CH1结构域连接至CH2结构域的那一部分。该铰链区包含约25个残基并且是柔性的,从而使两个N-末端抗原结合区独立地移动。铰链区可分为三个不同的结构域:上部、中部、和下部铰链结构域(Roux KH et al,1998,J Immunol,161:4083-4090)。
术语“Fv区”包含来自重链和轻链二者的可变区,但缺少恒定区,是包含完整抗原识别和结合位点的最小片段。
术语“重链恒定区”包括来自免疫球蛋白重链的氨基酸序列。包含重链恒定区的多肽至少包含以下一种:CH1结构域、铰链(例如,上部铰链区、中间铰链区,和/或下部铰链区)结构域,CH2结构域、CH3结构域或其变体或片段。例如,本申请中使用的抗原结合多肽可包含具有CH1结构域的多肽链;具有CH1结构域、至少一部分的铰链结构域和CH2结构域的多肽;具有CH1结构域和CH3结构域的多肽链;具有CH1结构域、至少一部分铰链结构域和CH3结构域的多肽链,或者具有CH1结构域,至少一部分铰链结构,CH2结构域,和CH3结构域的多肽链。在另一个实施例中,本申请的多肽包括具有CH3结构域的多肽链。另外,在本申请中使用的抗体可能缺少至少一部分CH2结构域(例如,所有的或一部分的CH2结构域)。如上文所述,但本技术领域的普通技术人员应理解,重链恒定区可能会被修改,使得它们在氨基酸序列上与天然存在的免疫球蛋白分子不同。
术语“轻链恒定区”包括来自抗体轻链的氨基酸序列。优选地,所述轻链恒定区包括恒定kappa结构域和恒定lambda结构域中的至少一个。
术语“Fc区”或“Fc片段”是指免疫球蛋白重链的C端区,其含有铰链区的至少一部分、CH2结构域和CH3结构域,其介导免疫球蛋白与宿主组织或因子的结合,包括与位于免疫***的各种细胞(例如,效应细胞)上的Fc受体结合或与经典补体***的第一组分(C1q)结合。Fc区包括天然序列Fc区和变异Fc区。
通常,人IgG重链Fc区为自其Cys 226或Pro 230位置的氨基酸残基至羧基末端的区段,但其边界可能有变化。Fc区的C末端赖氨酸(残基447,依照EU编号***)可以存在或可以不存在。Fc还可以指独立存在的,或在包含Fc的蛋白多肽的情况下的这一区域,例如“包含Fc区的结合蛋白”,还称为“Fc融合蛋白”(例如,抗体或免疫粘合素)。本发明的抗体中天然序列Fc区来自包括哺乳动物(例如人)的IgG1、IgG2(IgG2A,IgG2B)、IgG3和IgG4。在某些实施方案中,相对于哺乳动物Fc多肽氨基酸序列,两条Fc多肽链的氨基酸序列中每100个氨基酸中具有10个左右氨基酸的单一氨基酸的置换、***和/或缺失。在一些实施方案中,上述Fc区氨基酸差异可以是延长半衰期的Fc改变、增加FcRn结合的改变、增强Fcγ受体(FcγR)结合的改变和/或增强ADCC、ADCP和/或CDC的改变。
如本文中所使用的,术语“免疫应答”是指,免疫细胞(例如淋巴细胞、抗原呈递细胞、吞噬细胞或粒细胞)以及由免疫细胞或肝脏所产生的可溶性大分子(包括抗体、细胞因子、以及补体)的作用,该作用导致对侵入性病原体、被病原体感染的细胞或组织、癌细胞、或者在自身免疫或病理炎症情况下的正常人类细胞或组织的选择性损害、破坏或将它们从人体中清除。在本发明中,术语“抗原特异性T细胞应答”指由T细胞产生的免疫应答,该应答产生于当该T细胞特异的抗原对该T细胞的刺激之时。由T细胞在抗原特异性刺激时产生的反应的非限制性实例包括T细胞的增殖以及细胞因子(例如IL-2)的产生。
如本文中所使用的,术语“抗体依赖性细胞介导的细胞毒性(ADCC)”是指,一种细胞毒性形式,Ig通过与细胞毒性细胞(例如自然杀伤(NK)细胞、中性粒细胞或巨噬细胞)上存在的Fc受体(FcR)结合,使这些细胞毒性效应细胞特异性结合到抗原附着的靶细胞上,然后通过分泌细胞毒素杀死靶细胞。检测抗体的ADCC活性的方法是本领域已知的,例如可通过测定待测抗体与Fc受体(例如CD16a)之间的结合活性来评价。
如本文中所使用的,术语“补体依赖的细胞毒性(CDC)”是指,通过使补体成分C1q与抗体Fc结合来激活补体级联的细胞毒性形式。检测抗体的CDC活性的方法是本领域已知的,例如可通过测定待测抗体与Fc受体(例如C1q)之间的结合活性来评价。
在IgG、IgA和IgD抗体同种型中,Fc区包含抗体两条重链中的每一条的CH2和CH3恒定结构域;IgM和IgE Fc区包含在每条多肽链中的三个重链恒定结构域(CH2-4结构域)。
术语“人源化抗体”是指经基因工程改造的非人源抗体,其氨基酸序列经修饰以提高与人源抗体的序列的同源性。非人抗体的CDR域外的大部分或全部氨基酸,例如小鼠抗体被来自人免疫球蛋白的相应氨基酸置换,而一个或多个CDR区内的大部分或全部氨基酸未改变。氨基酸的添加,删除,***,替换或修饰是允许的,只要它们不会消除抗体结合特定抗原的能力。“人源化”抗体保留与原始抗体类似的抗原特异性。CDR的来源没有特别限制,可来源于任何动物。例如,可以利用源于小鼠抗体、大鼠抗体、兔抗体或非人灵长类动物(例如,食蟹猴)抗体的CDR区。框架区可以通过搜索IMGT antibody germline database(http://www.imgt.org/3Dstructure-DB/cgi/DomainGapAlign.cgi)获得人类抗体胚系序列,一般选取与被改造的非人源抗体同源度高的人类胚系抗体序列做人源化抗体的框架区。
术语“超变区”或“CDR区”或“互补决定区”是指负责抗原结合的抗体氨基酸残基,是非连续的氨基酸序列。CDR区序列可以由Kabat、Chothia、IMGT(Lefrancet al,2003,DevComparat Immunol,27:55-77)方法来定义或本领域熟知的任何CDR区序列确定方法而鉴定的可变区内的氨基酸残基。例如,超变区包含以下氨基酸残基:来自序列比对所界定的“互补决定区”或“CDR”的氨基酸残基(Kabat编号***),例如,轻链可变结构域的24-34(LCDR1)、50-56(LCDR2)和89-97(LCDR3)位残基和重链可变结构域的31-35(HCDR1)、50-65(HCDR2)和95-102(HCDR3)位残基,参见Kabat et al,1991,Sequences of Proteins ofImmunological Interest,5th Edition,Public Health Service,National Institutesof Health,Bethesda,Md.;和/或来自根据结构来界定的“超变环”(HVL)的残基(Chothia编号***),例如,轻链可变结构域的26-32(LCDR1)、50-52(LCDR2)和91-96(LCDR3)位残基和重链可变结构域的26-32(HCDR1)、53-55(HCDR2)和96-101(HCDR3)位残基,参见Chothia Cand Lesk AM,1987,J Mol Biol,196:901-917;Chothia C et al,1989,Nature,342:878-883。“框架”残基或“FR”残基为除本文定义的超变区残基之外的可变结构域残基。在某些实施方案中,本发明的抗体或其抗原结合片段含有的CDR优选地通过Kabat或IMGT编号***确定。本领域技术人员可以明确地将每种编号***赋予任何可变结构域序列,而不依赖于超出序列本身之外的任何实验数据。例如,给定抗体的Kabat残基编号方式可通过将抗体序列与每种“标准”编号序列对比同源区来确定。基于本文提供的序列编号方案,确定序列表中任何可变区序列的编号完全在本领域技术人员的常规技术范围内。
本文使用的关于核酸(如DNA或RNA)的术语“分离的”,是指分别从其它的以天然来源的大分子存在的DNA或RNA分离的分子。本文使用的术语“分离的”也指通过重组DNA技术生产时基本不含细胞材料,病毒材料或培养基的核酸或多肽,或经化学合成制备时基本不含化学前体或其它化学品。此外,“分离的核酸”是指包括不是天然存在的片段并且不会以天然状态发现的核酸片段。本文中术语“分离的”也用于指从其它细胞蛋白或组织分离的细胞或多肽。分离的多肽是指包括纯化的和重组的多肽。
术语“交叉反应”是指本文所述的抗体结合来自不同物种的抗原的能力。交叉反应性可通过检测在结合测定法(例如,SPR、ELISA)中与纯化抗原的特定反应性,或与生理表达抗原的细胞的结合或以其它方式与生理表达抗原的细胞的功能相互作用来测量。本领域中已知测定结合亲和力的分析的实例包括表面等离子共振(例如,Biacore)或类似技术(例如,Kinexa或Octet)。
术语“免疫结合”和“免疫结合性质”是指一种非共价相互作用,其发生在免疫球蛋白分子和抗原(对于该抗原而言免疫球蛋白为特异性的)之间。免疫结合相互作用的强度或亲和力可以用相互作用的平衡解离常数(KD)表示,其中KD值越小,表示亲和力越高。所选多肽的免疫结合性质可使用本领域中公知的方法测定。一种测定方法涉及测量抗原/抗体复合物形成和解离的速度。“结合速率常数”(Ka或Kon)和“解离速率常数”(Kd或Koff)两者都可通过浓度及缔合和解离的实际速率而计算得出(参见Malmqvist M,1993,Nature,361:186-187)。kd/ka的比率等于平衡解离常数KD(参见Davies DR et al,1990,Annual RevBiochem,59:439-473)。可用任何有效的方法测量KD、ka和kd值。
术语“宿主细胞”指在其中载体可以增殖并且其DNA可以表达的细胞,所述细胞可以是原核细胞或者真核细胞。该术语还包括受试宿主细胞的任何后代。应理解,并不是所有的后代都与亲本细胞相同,因为在复制过程中可能会发生突变,这类后代被包括在内。宿主细胞包含原核细胞、酵母或哺乳动物细胞,如CHO细胞、NS0细胞或其它哺乳动物细胞。
术语“同一性”用于指两个多肽之间或两个核酸之间序列的匹配情况。当两个进行比较的序列中的某个位置都被相同的碱基或氨基酸单体亚单元占据时(例如,两个DNA分子的每一个中的某个位置都被腺嘌呤占据,或两个多肽的每一个中的某个位置都被赖氨酸占据),那么各分子在该位置上是同一的。两个序列之间的“百分数同一性”是由这两个序列共有的匹配位置数目除以进行比较的位置数目×100的函数。例如,如果两个序列的10个位置中有6个匹配,那么这两个序列具有60%的同一性。例如,DNA序列CTGACT和CAGGTT共有50%的同一性(总共6个位置中有3个位置匹配)。通常,在将两个序列比对以产生最大同一性时进行比较。这样的比对可通过计算机程序例如Align程序(DNAstar,Inc.)方便地进行,通过使用Needleman和Wunsch的方法(Needleman SB and Wunsch CD,1970,J Mol Biol,48:443-453)来实现。
术语“突变的”、“突变体”和“突变”分别指与天然核酸或多肽相比(即可以用来定义野生型的参照序列),置换、缺失或***一个或多个核苷酸或氨基酸。
术语“保守修饰”意图指氨基酸修饰不会显著影响或改变含有该氨基酸序列的抗体的结合特征。此类保守修饰包括氨基酸的取代、添加和缺失。修饰可以通过本领域已知的标准技术,例如定点突变和PCR介导的突变引入到本发明的抗体中。保守氨基酸取代指氨基酸残基用具有类似侧链的氨基酸残基替换。本领域中对具有类似侧链的氨基酸残基家族已有详细说明。这些家族包括具有碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(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)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)和芳香侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此,可以用来自同一侧链家族的其它氨基酸残基替换本发明抗体CDR区中的一个或多个氨基酸残基。
本发明的抗体或编码本申请抗体的核酸或多核苷酸,可以应用于制备药物组合物或无菌组合物,例如,将抗体与药学上可接受的载体、赋形剂或稳定剂混合。药物组合物可包括一种或组合的(如两种或更多不同的)本发明的抗体。例如,本发明的药物组合物可包含与靶抗原上的不同表位结合的具有互补活性的抗体或抗体片段(或免疫缀合物)的组合。治疗和诊断剂的制剂可通过以例如冻干粉末、浆液、水性溶液或悬浮液的形式与药学可接受的载体、赋形剂或稳定剂混合来制备。术语“药学上可接受的”指当分子本体、分子片段或组合物适当地给予动物或人时,它们不会产生不利的、过敏的或其它不良反应。可作为药学上可接受的载体或其组分的一些物质的具体示例包括糖类(如乳糖)、淀粉、纤维素及其衍生物、植物油、明胶、多元醇(如丙二醇)、海藻酸等。本发明的抗体或编码本申请抗体的核酸或多核苷酸可单独使用,或可与一种或更多种其它治疗剂共同使用,所述治疗剂例如疫苗。
术语“药学上可接受的载体和/或赋形剂和/或稳定剂”,是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂和/或稳定剂,它们在所采用的剂量和浓度对暴露于其的细胞或哺乳动物是无毒的。包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂,稀释剂,维持渗透压的试剂,延迟吸收的试剂,防腐剂。例如,pH调节剂包括但不限于磷酸盐缓冲液。表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80。离子强度增强剂包括但不限于氯化钠。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。维持渗透压的试剂包括但不限于糖、NaCl及其类似物。延迟吸收的试剂包括但不限于单硬脂酸盐和明胶。稀释剂包括但不限于水,水性缓冲液(如缓冲盐水),醇和多元醇(如甘油)等。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如硫柳汞,2-苯氧乙醇,对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。稳定剂具有本领域技术人员通常理解的含义,其能够稳定药物中的活性成分的期望活性,包括但不限于谷氨酸钠,明胶,SPGA,糖类(如山梨醇,甘露醇,淀粉,蔗糖,乳糖,葡聚糖,或葡萄糖),氨基酸(如谷氨酸,甘氨酸),蛋白质(如干燥乳清,白蛋白或酪蛋白)或其降解产物(如乳白蛋白水解物)等。
如本文中所使用的,术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,预防疾病有效量是指,足以预防,阻止,或延迟疾病的发生的量;治疗疾病有效量是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫***的总体状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
通过下列实施例对本发明的实施方案进一步说明,但本领域技术人员应理解,下列附图和实施例仅用于说明本发明,而不是对本发明的进一步限制。
附图说明
图1、抗人TFPI抗体与人TFPI蛋白结合力测定。
图2、抗人TFPI抗体恢复FXa活性的测定。
图3、抗人TFPI抗体中和TFPI的测定。
图4、抗人TFPI抗体结合HUVEC细胞的测定
图5、抗人TFPI抗体中和HUVEC细胞上TFPI的测定。
具体实施方式
现参照下列意在举例说明本发明(而非限定本发明)的实施例来描述本发明。
除非特别指明,本发明中所使用的分子生物学实验方法和免疫检测法,基本上参照J.Sambrook等人,分子克隆:实验室手册,第2版,冷泉港实验室出版社,1989,以及F.M.Ausubel等人,精编分子生物学实验指南,第3版,John Wiley&Sons,Inc.,1995中所述的方法进行;限制性内切酶的使用依照产品制造商推荐的条件。本领域技术人员知晓,实施例以举例方式描述本发明,且不意欲限制本发明所要求保护的范围。
实施例1、抗人TFPI鼠源单克隆抗体的制备
将人TFPI抗原(蛋白序列:NCBI序列号NP_006278.1)50μg/只以完全弗氏佐剂充分乳化后,采用多点免疫方式免疫雄性Balb/C小鼠,免疫周期为三周一次。在第3次免疫后第10天,通过尾静脉取血,ELISA测试血浆抗人TFPI抗体滴度以监测小鼠免疫应答程度,然后在融合前3天,对产生抗人TFPI抗体滴度最高的小鼠加强免疫一次。3天后,处死小鼠并取出该小鼠脾脏与小鼠骨髓瘤Sp2/0细胞株融合。混合2×108个Sp2/0细胞与2×108个脾细胞在50%聚乙二醇(分子量为1450)和5%二甲基亚砜(DMSO)溶液中融合。用Iscove培养基(含有10%胎牛血清,100U/mL青霉素,100μg/mL链霉素,0.1mM次黄嘌呤,0.4μM氨基蝶呤和16μg胸苷)来调整脾脏细胞数至5×105/mL,以0.3mL加入96孔培养板孔内,并置于37℃,5%CO2培养箱内。培养10天后,采用高通量ELISA法分别检测上清中抗体与TFPI高亲和结合的克隆。再将上述单克隆抗体的孔内融合细胞进行亚克隆,进一步筛选获得杂交瘤细胞株#3-71。
在补充10%FCS的RPMI 1640培养基中培养产生特异性抗体的克隆。当细胞密度达到大约5×105个细胞/mL时,用无血清培养基替换该培养基。2至4天后,将培养过的培养基离心,以收集培养物上清液。将蛋白G柱用于纯化抗体。用150mM NaCl透析单克隆抗体洗脱液。通过0.22μm滤器将透析的溶液过滤除菌,以获得待测试的纯化的抗人TFPI鼠源单克隆抗体mAb3-71。
实施例2、TFPI鼠源抗体亲和力测定及动力学研究
采用生物薄膜干涉技术(BLI)对纯化的抗人TFPI鼠源单克隆抗体mAb3-71与人TFPI的结合亲和力常数进行测定,仪器为PALL公司的ForteBio Octet RED&QK***。多通道平行定量分析浓度梯度设定为:3.125、6.25、12.5、25、50和100nM,His标签的人TFPI 10μg/mL偶联Ni-NTA传感器。亲和力测定结果如表1所示,结果显示,鼠源单克隆抗体对人TFPI具有极高的结合亲和力,KD值可达到10-12M数量级。
表1、鼠单抗的亲和力测定结果
抗体 | KD(M) | Ka(1/Ms) | Kd(1/s) |
mAb3-71 | 4.539E-12 | 2.893E+05 | 1.313E-06 |
实施例3、抗人TFPI鼠源抗体的人源化
采用CDR移植方法(CDR grafting)对鼠源抗体进行人源化改造。CDR grafting的基本原理是通过把鼠抗的CDR区移植到人源抗体模板上,同时把稳定CDR构象和对抗原-抗体结合重要的几个或一些关键鼠抗FR区残基,也一并引入到人源抗体模板上(backmutations),从而达到既降低鼠抗的免疫原性又保持鼠抗的亲和力的目的。除了上述CDR grafting操作外,我们还进一步对CDR grafting后的人源化抗体的等电点(PI)、疏水聚集(aggregation)、翻译后修饰(PTM,如糖基化、断裂、异构化位点等)和免疫原性(immunogenicity)四方面进行计算,对于造成这四方面问题的氨基酸进行突变,以便使人源化抗体在临床使用时充分发挥出药效。
抗体人源化的具体流程如下。搜索IMGT网站的人抗体胚系数据库(IMGT humanantibody germline database,http://www.imgt.org/3Dstructure-DB/cgi/DomainGapAlign.cgi),获得与鼠抗具有高相似度的人源抗体模板。用Discovery Studio对鼠抗和人源抗体模板进行CDR区注释,按Kabat或IMGT方案定义出CDR区。用鼠抗的六个CDR区分别替换人源抗体模板的六个CDR区。移植的6个CDR区中的单独每个CDR区可以是按Kabat定义出的氨基酸区域,或按IMGT定义出的氨基酸区域。CDR移植后进行从鼠源抗体到人源化模板FR区的回复突变。稳定抗体CDR区构象和对抗原-抗体结合重要的关键鼠抗FR区氨基酸包括4类氨基酸残基:1)以内埋藏在抗体表面下的氨基酸;2)CDR区/>以内暴露在抗体表面的氨基酸;3)抗体轻链和重链结构域之间的界面氨基酸;和4)稳定抗体CDR区构象的vernier zone residues(Foote J and Winter G,1992,J Mol Biol,224:487-499)。以上4类关键鼠抗FR区残基是通过建立鼠抗三维结构模型确定的。对于与鼠抗序列不一致的人源模板的这4类氨基酸,通过三维结构分析,选择对保持CDR构象和抗原-抗体结合重要的氨基酸,进行从鼠抗到人源模板的氨基酸移植或替换。然后,对4类氨基酸移植后产生的人源化抗体进一步计算等电点、疏水聚集、翻译后修饰和免疫原性,对问题氨基酸进行突变,从而得到最终的人源化抗体序列。
根据以上方法,以鼠源抗体mAb3-71的CDR为基础构建了人源化抗体,命名为AB8D,上述鼠抗和人源化抗体的可变区所包含的CDR区氨基酸序列如表2所示,重链和轻链可变区氨基酸序列如表3所示。
表2、关于示例性的抗TFPI鼠源和人源化抗体的CDR区序列
表3、鼠源和人源化抗体可变区氨基酸序列
VH氨基酸序列 | VL氨基酸序列 | |
mAb3-71 | SEQ ID NO:14 | SEQ ID NO:15 |
AB8D | SEQ ID NO:16 | SEQ ID NO:17 |
为了获得由两条重链和两条轻链组成的全长抗体序列,可将表3中所示VH和VL序列的与抗体重链恒定区(优选自人IgG1、IgG2或IgG4)和轻链恒定区(优选自人κ轻链,氨基酸序列如SEQ ID NO:18所示)序列采用常规技术进行拼接或组装。优选的,所述重链恒定区为人野生型重链恒定区或其突变体。
在一种示例性的实施方案中,人源化抗体分子包含野生型人IgG1的重链恒定区(氨基酸序列如SEQ ID NO:19所示)。在另一种实施方案中,人源化抗体分子包括在根据EU编号的M252Y、S254T、T256E和M428L突变的人IgG1的重链恒定区(氨基酸序列如SEQ ID NO:20所示)。在另一种实施方案中,人源化抗体分子包含野生型人IgG2的重链恒定区(氨基酸序列如SEQ ID NO:21所示)。或采用修饰的人IgG4恒定区序列,在一种实施方案中,人源化抗体分子包括在根据EU编号的第228位突变(例如S变为P)的人IgG4(氨基酸序列如SEQ IDNO:22所示)。
在一种示例性的实施方案中,人源化抗体分子的重链氨基酸序列如SEQ ID NO:23所示,和轻链氨基酸序列如SEQ ID NO:24所示。
实施例4、抗人TFPI抗体表达载体构建、表达、制备
根据上述实施例中获得的重链和轻链序列,设计编码cDNA***到pcDNA3.1真核表达载体中,构建人源化表达载体。该表达载体质粒含有在哺乳动物细胞中高水平表达所需的巨细胞病毒早期基因启动因子-增强子。同时,载体质粒中含有可选择标记基因,从而在细菌中赋予氨苄青霉素抗性,而在哺乳动物细胞中赋予G418抗性。另外,载体质粒中含有二氢叶酸还原酶(DHFR)基因,在合适的宿主细胞中,能以氨甲喋呤(MTX)共扩增抗体基因和DHFR基因。
将上述已构建的重组表达载体质粒转染入哺乳动物宿主细胞系,以表达人源化抗体。为了稳定高水平的表达,优选的宿主细胞系是DHFR缺陷型的中国仓鼠卵巢(CHO)细胞(参见美国专利No.4,818,679)。优选的转染方法是电穿孔,也可以使用其他方法,包括磷酸钙共沉降,脂转染和原生质融合等。在电穿孔中,用设为300V电场和1050μFd电容的GenePulser(Bio-Rad Laboratories),在比色杯内加入2×107个细胞悬浮在0.8mL的PBS中,并含有20μg的表达载体质粒。转染2天后,加入含有0.2mg/mL G418以及200nM MTX(Sigma)。为了实现较高水平的表达,用受MTX药物抑制的DHFR基因共扩增转染的抗体基因。用极限稀释亚克隆转染子及ELISA方法测定各细胞系的分泌率,选出高水平表达抗体的细胞株。收集抗体的条件培养基,用于测定其体外和体内生物学活性。
实施例5、抗人TFPI抗体的纯化与定性
本实施例中示例性地描述了人源化抗体AB8D的纯化和定性方法。细胞培养上清经过高速低温离心或深层过滤、0.22μm除菌过滤等澄清处理,后续经过protein A亲和、阴离子交换和阳离子交换三步层析进行纯化,具体方法如下:第一步捕获采用protein A亲和层析,平衡液为PBS缓冲液,使用洗脱缓冲液(50mM NaAc-HAc,pH 3.7)进行线性洗脱,加入1M冰醋酸调节蛋白A洗脱产物的pH至3.6-3.8,室温条件孵育60分钟进行病毒灭活,然后加入2M Tris调节pH至5.5中和。中间纯化选择阴离子交换填料Q Bestarose FF去除残留DNA、内毒素、杂质蛋白等,平衡液为50mM NaAc-HAc,pH 5.5。从阴离子介质流穿下来的蛋白,直接结合到阳离子交换介质MonomixHC45-SP,阳离子交换层析平衡液为50mM NaAc-HAc,pH5.5,使用洗脱液(50mM NaAc-HAc,0.2M NaCL,pH 5.5)进行线性洗脱。从阳离子介质洗脱下来的蛋白溶液经过纳滤膜过滤、超滤换液浓缩以及除菌过滤,获得原液。
对原液进行SEC-HPLC纯度分析及SDS-PAGE电泳分析,其中SEC-HPLC结果显示,纯化后抗体的主峰纯度达99%以上。AB8D抗体理论分子量约145KD,在还原条件下,SDS-PAGE电泳显示轻链约25KD,重链大约50KD,与理论值基本符合。
实施例6、抗人TFPI抗体体外生物学功能评价
6.1、抗人TFPI抗体与人TFPI蛋白亲和力测定
人TFPI以0.1μg/mL包被酶标板,每孔100μL,4℃包被过夜。弃去包被溶液,用1%BSA的PBS溶液(PBSB)封闭,每孔200μL,37℃孵育1小时,用含有0.05%Tween-20的PBS溶液(PBST)洗板。然后加入稀释好的一系列浓度的AB8D,每孔100μL,37℃孵育1小时。用含有0.05%PBST洗板,然后加入HRP标记的羊抗人IgG(H+L)(Jackson Laboratory)作为检测抗体,37℃孵育1小时。用0.05%PBST清洗3次,加入TMB,每孔100μL,室温显色5分钟。加入0.2MH2SO4终止反应,每孔50μL。酶标仪在双波长450/620nm处读取吸收值。以OD450 nm-OD620 nm作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行分析,四参数拟合曲线,计算EC50值。如图1所示,AB8D与人TFPI蛋白具有亲和力,EC50为1.65ng/mL。
6.2、FXa活性测定试验
人TFPI用缓冲液1(含有20mM HEPES、150mM NaCl、5mM CaCl2、0.5mg/ml BSA,pH8.0)稀释,浓度为10μg/mL,每孔50μL,加入到96孔平底板中。然后加入稀释好的一系列浓度AB8D,每孔50μL,37℃孵育30分钟。FXa(购自Haematologic Technologies)用缓冲液1稀释,浓度为1μg/mL,每孔50μL,37℃孵育30分钟。将底物S-2765(购自CHROMOGENIX)用缓冲液1稀释至2mM,每孔50μL,反应后于酶标仪读取405nm处吸光度值。再以OD405 nm作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism6进行作图。如图2所示,AB8D能恢复TFPI抑制的FXa的活性,EC50为6.9μg/mL。
6.3、TFPI中和试验:TF/FVIIa/FXa抑制效果测定
TF(Tissue factor,购自北京博尔西科技有限公司)或FVIIa(WHO)用缓冲液1稀释,TF浓度为1.4ng/mL,FVIIa浓度为45IU/mL,每孔分别加25μL,加入到96孔板中,37℃孵育10分钟。然后加入稀释好的一系列浓度AB8D,每孔25μL;人TFPI用缓冲液1稀释,浓度为10μg/mL,每孔25μL,加入到96孔板中,37℃孵育30分钟。FX(购自Haematologic Technologies)用缓冲液1稀释,浓度为44.2μg/mL,每孔25μL,37℃孵育30分钟。加入75mM EDTA,每孔10μL,终止反应。将底物S-2765用缓冲液1稀释至2mM,每孔50μL,反应后于酶标仪读取405nm处吸光度值。以OD 405nm作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行分析,四参数拟合曲线,计算EC50值。如图3所示,分子水平上,AB8D可中和TFPI的抑制作用,呈剂量依赖性恢复TFPI介导的FVIIa/TF抑制的FXa的活性,EC50为3.17μg/mL。
6.4、FACS法检测与HUVECs细胞表达TFPI的结合
培养HUVEC细胞(人脐静脉内皮细胞系,上海酶研生物科技有限公司),离心收集细胞用1%PBSB重悬,分别调整细胞密度1×106个/mL,每孔100μL,加入96孔U底板中,4℃封闭30分钟。用1%PBSB洗涤细胞1次。然后加入稀释好的一系列浓度的AB8D,每孔100μL,4℃孵育1小时。离心去上清,用1%PBSB清洗2遍,加入稀释好的AF647羊抗人IgG(H+L)抗体(Jackson Immuno Research Inc.,1:400稀释),每孔100μL,4℃避光孵育1小时。离心去上清,1%PBSB洗板两遍,加入1%PBSB重悬细胞,每孔150μL,流式细胞仪检测信号强度。再以平均荧光强度作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行分析,四参数拟合曲线,计算EC50值。如图4所示,AB8D能通过TFPI结合HUVEC,EC50为28.6ng/mL。
6.5、抗人TFPI抗体对HUVEC的TFPI中和作用
当HUVEC细胞融合率达到80%以上且外观状态良好时,弃去培养基,使用无菌磷酸盐缓冲液润洗培养皿。每个培养皿中加入1mL细胞消化液,室温孵育1分钟。每个培养皿中加入2mL含10%胎牛血清的ECM培养基终止细胞消化,重悬细胞。将细胞悬液转移至15mL离心管,800rpm离心5分钟。弃掉上清,加入适量培养基重悬细胞,轻吹混匀。细胞计数:取适量细胞计数,然后将细胞密度调整至5×105个/mL,轻吹混匀,每孔100μL,细胞铺板于96孔板中,置于CO2培养箱中进行过夜培养。第二天,弃掉细胞培养液,用DPBS洗涤2次,加入配制好的TNFα(400ng/mL)和IL-1β(400ng/mL),每孔各25μL;然后加入用缓冲液2(含有25mM HEPES、137mM NaCl、3.5mM KCl,pH7.4)稀释的一系列浓度AB8D,每孔25μL,加入到上述96孔板中,置于CO2培养箱中孵育2小时,缓冲液2作为空白对照。FVIIa用缓冲液3(含有25mM HEPES、137mM NaCl、3.5mM KCl、5mM CaCl2、1mg/ml BSA,pH7.4)稀释,浓度为45IU/mL,每孔25μL,37℃孵育15分钟。FX用缓冲液3稀释,浓度为400nM,每孔25μL,37℃孵育40分钟。取40μL上清液,转移至新的96孔板中,加入75mM EDTA,每孔10μL,终止反应。将底物S-2765用缓冲液3稀释至1.2mM,每孔50μL,反应后于酶标仪读取405nm处吸光度值。再以OD405 nm作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行作图,四参数拟合曲线,计算EC50值。如图5所示,细胞水平上,AB8D可中和HUVEC细胞TFPI,阻断TFPI介导的FVIIa/TF抑制并恢复FXa的活性,EC50为117.3ng/mL。
实施例7、抗人TFPI抗体体内药效学评价
24只雄性普通级新西兰兔(2.0~2.5kg),购买于上海杰思捷实验动物有限公司,按照体重随机分为8组,分别为G1:溶媒对照组、G2:AB8D-10mg/kg组、G3:AB8D-5mg/kg组、G4:AB8D-2.5mg/kg组、G5:溶媒对照组、G6:AB8D-20mg/kg组、G7:AB8D-10mg/kg组、G8:AB8D-5mg/kg组。
各实验组皮下给予相应的溶媒对照或不同浓度的AB8D供试品。G1-G4组和G5-G8组分别在给药后第4天和第7天,经兔耳缘静脉单次注射给予15mg/kg的抗凝血八因子中和抗体(抗FVIII中和抗体)建立血友病模型。各实验组给予抗FVIII中和抗体45min后,使用2%-5%的异氟烷麻醉兔子,将麻醉状态的兔子调整为俯卧位,将一侧前爪放在37℃生理盐水的烧杯中预浸泡,切第三指指甲,造成角质层出血。切割后,将爪子自然垂下伸入37℃生理盐水烧杯中,前爪伸入生理盐水液面下方。记录出血时间的同时利用称重法测量出血量,出血时间超过60min时记录为60min。
如表4和表5所示,在单次给予AB8D4天和7天后,AB8D≥5mg/kg对于血友病模型兔子的角质层出血量和出血时间均具有抑制作用。
表4、单次给药4天后出血量和出血时间(mean±SEM,n=3)
表5、单次给药7天后出血量和出血时间(mean±SEM,n=3)
虽然说明并描述了本发明的优选例,应理解本领域的技术人员可根据本文的教导做出各种改变,这些改变不违背本发明的范围。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可对本发明做各种修改或改动,这些等价形式同样落后于本申请所附权利要求书所限定的范围。
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<110> 安源医药科技(上海)有限公司
<120> 针对TFPI的单克隆抗体及其用途
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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 Asn Phe Gly Thr Gln Thr
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85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
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Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
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Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
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Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
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Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
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Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ser Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 22
<211> 327
<212> PRT
<213> 修饰的人IgG4氨基酸序列()
<400> 22
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
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Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
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Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 23
<211> 446
<212> PRT
<213> AB8D重链氨基酸序列()
<400> 23
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Thr Pro Gly Gln Gly Leu Glu Trp Ile
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Gly Glu Ile Lys Pro Asp Gln Gly Arg Ile Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Thr Arg Ala Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Ser Ser Val Val Asp Val Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
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Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
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Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 24
<211> 215
<212> PRT
<213> AB8D轻链氨基酸序列()
<400> 24
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp
35 40 45
Ile Ser Gly Thr Ser Ile Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Lys Tyr Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Phe Cys His Gln Trp Ser His Tyr Pro
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
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Claims (17)
1.一种能够特异性结合TFPI的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含的重链可变区(VH)包含至少一个、两个或三个选自下组的互补决定区(CDR):
(1)HCDR1,其具有如SEQ ID NO:1或7所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(2)HCDR2,其具有如SEQ ID NO:2、8、12或13所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;和
(3)HCDR3,其具有如SEQ ID NO:3或9所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
和/或,其包含的轻链可变区(VL)包含至少一个、两个或三个选自下组的互补决定区(CDR):
(4)LCDR1,其具有如SEQ ID NO:4或10所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(5)LCDR2,其具有如SEQ ID NO:5或11所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;和
(6)LCDR3,其具有如SEQ ID NO:6所示的序列,或者与上述序列相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
其中,所述重链可变区含有的CDR和/或轻链可变区含有的CDR由Kabat或IMGT编号***定义;
优选的,(1)-(6)任一项中所述的置换为保守置换。
2.如权利要求1所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包含3个VH可变区CDR和3个VL可变区CDR,其选自下组:
(1)其HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:1、2、3、4、5或6所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(2)其HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:7、8、9、10、11或6所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(3)其HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:1、12、3、4、5或6所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(4)其HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3分别具有如SEQ ID NO:7、13、9、10、11或6所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列。
3.如权利要求2所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段为鼠源的或嵌合的,其重链可变区包含鼠源IgG1、IgG2、IgG3或其变体的重链FR区;和其轻链可变区包含鼠源κ、λ链或其变体的轻链FR区。
4.如权利要求3所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包含如下的VH和VL序列:
VH结构域包含如SEQ ID NO:14所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:15所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列。
5.如权利要求2所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段为人源化的。
6.如权利要求5所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包含如下的VH和VL序列:
VH结构域包含如SEQ ID NO:16所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:17所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列。
7.如权利要求5所述抗体,其特征在于,所述抗体包含来源于人免疫球蛋白的重链恒定区和轻链恒定区;优选地,所述重链恒定区选自人IgG1、IgG2、IgG3和IgG4的重链恒定区;并且,所述重链恒定区具有天然序列或与其所源自的天然序列相比具有一个或多个氨基酸的置换、缺失或添加的序列;和所述轻链恒定区优选如SEQ ID NO:18所示的人κ轻链的恒定区。
8.如权利要求7所述抗体,其特征在于,所述抗体包含的重链恒定区选自下组:
(1)如SEQ ID NO:19所示的野生型人IgG1的重链恒定区;
(2)如SEQ ID NO:20所示的含有M252Y、S254T、T256E和M428L突变的人IgG1的重链恒定区;
(3)如SEQ ID NO:21所示的野生型人IgG2的重链恒定区;
(4)如SEQ ID NO:22所示的含有S228P突变的人IgG4的重链恒定区。
9.如权利要求7所述的抗体,其特征在于,所述抗体其重链具有如SEQ ID NO:23所示的氨基酸序列,和其轻链具有如SEQ ID NO:24所示的氨基酸序列。
10.如权利要求1-9任一项所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段能够以10nM或更低的KD结合TFPI。
11.编码如权利要求1-9任一项所述抗体或其抗原结合片段的DNA分子。
12.包含如权利要求11所述DNA分子的载体。
13.包含如权利要求12所述载体的宿主细胞,所述宿主细胞包含原核细胞、酵母或哺乳动物细胞,优选为CHO细胞。
14.一种药物组合物,所述组合物包含如权利要求1-9任一项所述的抗体或其抗原结合片段以及可药用赋形剂、载体或稀释剂。
15.制备如权利要求1-9任一项所述抗体或其抗原结合片段的方法,其包括:(a)获得抗体或其抗原结合片段的基因,构建抗体或其抗原结合片段的表达载体;(b)通过基因工程方法将上述表达载体转染到宿主细胞中;(c)在允许产生所述抗体或其抗原结合片段的条件下培养上述宿主细胞;(d)分离、纯化产生的所述抗体或其抗原结合片段;
其中,步骤(a)中所述表达载体选自质粒、细菌和病毒中的一种或多种,优选地,所述表达载体为pcDNA3.1载体;
其中,步骤(b)通过基因工程方法将所构建的载体转染入宿主细胞中,所述宿主细胞包含原核细胞、酵母或哺乳动物细胞,优选为CHO细胞;
其中,步骤(d)通过常规的免疫球蛋白纯化方法,包含蛋白质A亲和层析和离子交换方法分离、纯化所述抗体或其抗原结合片段。
16.如权利要求1-9任一项所述抗体或其抗原结合片段在制备预防或治疗遗传或获得性凝血因子缺乏的疾病或事件的药物中的用途。
17.如权利要求1-9任一项所述抗体或其抗原结合片段在制备预防或治疗遗传或获得性凝血因子缺乏的疾病或事件的药物中的用途,其特征在于,所述疾病为血友病。
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