CN113527483B - 抗人神经生长因子的抗体 - Google Patents
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- CN113527483B CN113527483B CN202010313548.7A CN202010313548A CN113527483B CN 113527483 B CN113527483 B CN 113527483B CN 202010313548 A CN202010313548 A CN 202010313548A CN 113527483 B CN113527483 B CN 113527483B
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Abstract
本发明涉及特异性结合NGF的中和性抗体或其抗原结合片段,以及产生这种抗体的制备方法。本发明还涉及所述抗体在治疗与NGF相关的疾病或病症,尤其在缓解或改善个体疼痛中的应用。
Description
技术领域
本申请涉及抗体领域,具体地,本申请涉及特异性结合NGF的抗体,其制备方法及用途。
背景技术
神经生长因子(NGF)是最早发现的神经营养蛋白(神经营养因子),广泛分布于脑、神经节、虹膜、心脏、脾、胎盘等组织及成纤维细胞、平滑肌、骨骼肌、胶质细胞、雪旺氏细胞等。NGF是神经营养素(NT)中的一员,所述神经营养素是一组进一步包括脑源性神经营养因子(BDNF)、NT-3、NT-4、NT-5的结构相关蛋白。(Wyman等,Gene Therapy(1999),6:1648-1660)。NGF的活性通过两种不同的膜结合受体(酪氨酸激酶A(TrkA)受体及p75受体)介导,所述p75受体在结构上与肿瘤坏死因子受体家族其它成员相关(Chao,等人,Science 232:518-521,1986)。
NGF介导多种疾病或病症例如疼痛(RICHARDS,N.Br J Anaesth(2013),111(1):46-51)、关节炎、胶原血管病、脱髓鞘病、气道炎症性疾病(Hoyle,Cytokine Growth FactorRev(2003),14:551-8.;Lommatzsch,M.Ann NY Acad Sci(2003),992:241-9.)、神经系统疾病、代谢性疾病(如糖尿病)(Yasuda,H.Prog Neurobiol(2003),69(4):229-85.)、病毒感染相关疾病(Garaci,E.PNAS(2003),100(15)8927-8932)、心律失常(W004/032852)、牛皮癣和癌症(Nakagawara,A.Cancer Lett(2001),169(2):107-14.)。
外周组织炎症或神经损伤是导致病理生理性疼痛的成因。NGF能够发挥调节周围神经元和中枢神经元的功能作用,已经证实NGF可与体内的疼痛信号转导系统相互作用,且在对许多物种进行局部或全身施用时会造成痛觉过敏(Sarchielli,ExpertRev.Neurotherapeutics(2004),4(1):115-127.)。
疼痛是一种基于从周围环境接受并由神经系统传递和解释的信号的感知(Millan,Prog.Neurobiol(1999).57:1-164),严重的疼痛影响人类的生活质量,对社会造成了巨大的经济负担。治疗疼痛是临床和社会最常见的诉求之一。但是,治疗疼痛仅部分有效,而且这些治疗中有许多本身会产生诸多不良反应。例如阿片类,具有较好的镇痛作用,但它们同时也是肾脏毒素,剂量高时往往会导致胃肠刺激、溃疡、出血和精神错乱,且长期使用阿片类与伴随出现药物耐受性和依赖性。
由于疼痛领域巨大的临床需求和市场空间。开发新的针对疼痛通路靶点的药物来治疗疼痛十分重要和迫切。近年来由于对NGF在急、慢性疼痛及痛觉过敏中作用的认识不断增强,抗NGF拮抗剂成为疼痛治疗研究的新热点。已报道了诸多鼠源及人源化抗NGF抗体,并且有部分抗NGF的抗体药物临床试验数据显示了积极的结果,然而所述鼠源抗NGF抗体、人源化抗NGF抗体存在免疫原性等问题。
因此,本领域仍需要可以用于预防或者治疗与NGF相关的疾病的组合物或者方法,例如是可以用于预防或者治疗与疼痛相关的那些疾病或者病症的组合物和方法,本申请满足了所述需求。
发明内容
本发明提供了一种新的能够以高亲和力特异性结合NGF的抗体或其抗原结合片段,尤其是特异性结合人NGF的抗体或其抗原结合片段。在优选的实施方案中,本发明提供的抗NGF抗体是人抗体,其可以与非人NGF(包括非人灵长类NGF和/或小鼠NGF)产生交叉反应。在另一个实施方案中,本发明所述的特异性地结合人NGF的人抗体或其抗原结合片段是中和NGF的中和抗体。
一方面,本发明提供了特异性结合人NGF的人抗体或其抗原结合片段,且与神经营养素-3(NT-3)、神经营养素-4(NT-4)、脑源性神经营养因子(BDNF)发生交叉反应。这些抗体的特征是以高亲和力和高特异性与NGF结合,并能够中和NGF的活性。
在一个具体的实施方案中,所述抗NGF抗体及其抗原片段包含选自表I所示抗体的VH区序列的一个、两个或三个CDR(优选三个CDR)。在另一些实施方案中,本发明抗体包含选自表I所示抗体的VL区序列的一个、两个或三个CDR(优选三个CDR)。在一些实施方案中,本发明抗体包含表I所示抗体的6个CDR区序列。在一个优选实施方案中,抗体的CDR序列是表II所示的CDR序列。
在一些实施方案中,本发明的抗NGF抗体或其抗原结合片段包含A)重链互补决定区(CDR):(i)CDR1,其包含SEQ ID NO:1的氨基酸序列,或相对于所述序列含有一个或多个且不超过5个氨基酸的氨基酸取代(例如保守性取代)、缺失或插入的序列,(ii)CDR2,其包含SEQ ID NO:2的氨基酸序列,或相对于所述序列含有一个或多个且不超过3个氨基酸的氨基酸取代(例如保守性取代)、缺失或插入的序列,(iii)CDR3,其包含SEQ ID NO:3的氨基酸序列,或相对于所述序列含有一个或多个且不超过5个氨基酸的氨基酸取代(例如保守性取代)、缺失或插入的所述序列,和B)轻链互补决定区(CDR):(i)CDR1,其包含SEQ ID NO:4的氨基酸序列,或相对于所述序列含有一个或多个且不超过5个氨基酸的氨基酸取代(例如保守性取代)、缺失或插入的序列,(ii)CDR2,其包含SEQ ID NO:5的氨基酸序列,或相对于所述序列含有一个或多个且不超过2个氨基酸的氨基酸取代(例如保守性取代)、缺失或插入的序列,(iii)CDR3,其包含SEQ ID NO:6所示的氨基酸序列,或相对于所述序列含有一个或多个且不超过5个氨基酸的氨基酸取代(例如保守性取代)、缺失或插入的序列,其中包含修饰CDR的抗NGF抗体仍然具有结合NGF的能力。
在一些实施方案中,本发明的抗NGF抗体或其抗原结合片段包含A)重链互补决定区(CDR):(i)CDR1,其由SEQ ID NO:1的氨基酸序列组成,(ii)CDR2,其由SEQ ID NO:2的氨基酸序列组成,(iii)CDR3,其由SEQ ID NO:3的氨基酸序列组成,和B)轻链互补决定区(CDR):(i)CDR1,其由SEQ ID NO:4的氨基酸序列组成,(ii)CDR2,其由SEQ ID NO:5的氨基酸序列组成,(iii)CDR3,其由SEQ ID NO:6所示的氨基酸序列组成。
在一些实施方案中,本发明的抗NGF抗体或其抗原结合片段包含重链可变区VH,其包含与SEQ ID NO:7的氨基酸序列具有至少75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性或者更高同一性的氨基酸序列或由所述序列组成,包含所述VH的抗NGF抗体具有结合NGF的能力。在一些实施方案中,本发明的抗NGF抗体或其抗原结合片段包含重链可变区VH,其包含表II所示抗体的3个重链可变区CDR,且与SEQ ID NO:7的氨基酸序列具有至少75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性,包含所述VH的抗NGF抗体具有结合NGF的能力。在一些实施方案中,抗NGF抗体的重链可变区VH包含与SEQ ID NO:7的氨基酸序列相比具有一个或多个取代(例如保守性取代)、插入或缺失的氨基酸序列,包含所述VH的抗NGF抗体具有结合NGF的能力。
在一些实施方案中,本发明的抗NGF抗体或其抗原结合片段包含轻链可变区VL,其包含与SEQ ID NO:8的氨基酸序列具有至少75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性或者更高同一性的氨基酸序列或由所述序列组成,包含所述VL的抗NGF抗体具有结合NGF的能力。在一些实施方案中,本发明的抗NGF抗体或其抗原结合片段包含轻链可变区VL,其包含表II所示抗体的轻链可变区的3个CDR,且与SEQ ID NO:8的氨基酸序列具有至少75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性,包含所述VL的抗NGF抗体具有结合NGF的能力。在一些实施方案中,抗NGF抗体的轻链可变区VL包含与SEQ ID NO:8的氨基酸序列相比具有一个或多个取代(例如保守性取代)、插入或缺失的氨基酸序列,包含所述VH的抗NGF抗体具有结合NGF的能力。
在一些实施方案中,本发明的抗NGF抗体或其抗原结合片段包含重链可变区(VH)和轻链可变区(VL),其中:
1)重链可变区VH包含与SEQ ID NO:7的氨基酸序列具有至少75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性或者更高同一性的氨基酸序列或由所述序列组成;轻链可变区VL包含与SEQ ID NO:8所示的氨基酸序列具有至少75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性或者更高同一性的氨基酸序列或由所述序列组成,或者
2)重链可变区VH包含表II所示重链可变区CDR,且与SEQ ID NO:7的氨基酸序列具有至少75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性;轻链可变区VL包含表II所示轻链可变区的CDR,且与SEQ ID NO:8的氨基酸序列具有至少75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性,包含所述VH和VL的抗NGF抗体具有结合NGF的能力,或
3)重链可变区VH包含与SEQ ID NO:7的氨基酸序列相比具有一个或多个取代(例如保守性取代)、插入或缺失的氨基酸序列;轻链可变区VL包含与SEQ ID NO:8的氨基酸序列相比具有一个或多个取代(例如保守性取代)、插入或缺失的氨基酸序列,包含所述VH和VL的抗NGF抗体具有结合NGF的能力。
在优选的实施方案中,本发明提供抗NGF抗体或其抗原结合片段,其中重链可变区VH包含SEQ ID NO:7所示的氨基酸序列或由其组成;轻链可变区VL包含SEQ ID NO:8所示的氨基酸序列或由其组成。
在一些实施方案中,所述抗NGF抗体或其抗原结合片段还包含来自人抗体胚系共有序列的重链和/或轻链恒定区序列。所述的轻链恒定区优选是人源的κ(CK)或λ(Cλ)链恒定区。重链恒定区可以是γ、μ、α、δ、或ε链,在一些实施方案中,所述的重链恒定区是人源的IgG1、IgG2、IgG3、IgG4、IgA1、IgA2、IgM、IgD和IgE同型。每个重链、轻链类型由具有本领域熟知的序列的特定恒定区来表征。
在一些实施方案中,所述的恒定区优选是人IgG恒定区,例如是人IgG1、IgG2、IgG3或者IgG4同型的恒定区。在一些实施方案中,所述重链和/或轻链恒定区例如在Sequencesof Proteins of Immunological Interest,NIH Publication No.91-3242中记载,本发明中可应用其中任一种。
在优选的实施方案中,本发明提供抗NGF抗体或其抗原结合片段,其中重链恒定区序是人IgG2恒定区,重链恒定区序列包含SEQ ID NO:9所示的氨基酸序列或由其组成;在另一个实施方案中,所述抗体的重链恒定区序也可以是人IgG4恒定区,重链恒定区序列包含SEQ ID NO:10所示的氨基酸序列或由其组成;在一个实施方案中,所述抗体的轻链恒定区包含SEQ ID NO:11所示的氨基酸序列或由其组成。
应当理解,也可以使用这些恒定区结构域的序列变体,例如包含一个或多个氨基酸修饰,其中氨基酸位点是应Kabat等人的(1991)EU索引系统标识。
在一些实施例中,为了防止所述抗体的糖基化,例如在人IgG恒定区进行修饰,这种修饰可以是N297A或N297Q(Sazinsky,PNAS(2008),105(51):20167-20172)。
在一些实施例中,为了改变Fc受体相互作用,例如在人IgG恒定区进行修,这种修饰可以是L234A和/或L235E或L235A。
在一些实施例中,为了延长半衰期,例如在人IgG恒定区进行修饰,这种修饰可以是R435H。
在一些实施例中,为了防止或减少链交换,例如在人IgG恒定区进行修饰,这种修饰可以是S228P(Angal,S.Mol Immunol(1993),30:105-108)
在一些实施例中,为了增强FcRn结合,例如在人IgG恒定区进行修饰,这种修饰可以是M252Y、S254T、T256E(DallAcqua等人,J.Biol.Chem(2006),281(33):23514-23524;Zalevsky等人,Nature Biotech(2010),28(2):157-159)、M428L或N434S。
在一些实施例中,为了改变抗体依赖性细胞毒作用(ADCC),和/或补体依赖性细胞毒作用(CDC),例如在人IgG恒定区进行修饰,这种修饰是已知的(包括但不限于:Natsume等人,Cancer Res(2008),68(10):3863-72;Idusogie等人,J.Immunol(2001),166(4):2571-5;Moore等人mAbs(2010,2(2):181-189;Lazar等人,PNAS(2006),103(11):4005-4010;Shields等人J.Biol.Chem.(2001),276(9):6591-6604;Stavenhagen Cancer Res(2007),67(18):8882-8890;Alegre等人,J.Immunol(1992)148:3461-3468.;Kaneko,Niwa等人Biodrugs(2011),25(1):1-11.)。
在一些实施例中,还可以通过T366W修饰、和任选地进一步通过经由在相对的CH3结构域上的S354C和Y349C修饰引入二硫键而诱导异源二聚体化(Carter,Journal ofImmunological Methods(2001),248:7-15.)。
在一些实施方案中,本发明的抗体还涵盖与上文所述的任何抗体竞争结合NGF的抗体、以及与上文所述的任何抗体结合NGF相同表位的抗体。
在一些实施方案中,至少部分的抗NGF抗体的框架序列是人共有框架序列。
在一个实施方案中,本发明的抗NGF抗体是完整抗体,例如IgG1、IgG2、IgG3、IgG4、IgM、IgA和IgE抗体。在另一个实施方案中,本发明的抗NGF抗体仅涵盖其抗原结合部分,例如:Fab、Fab'-SH、Fv、scFv或(Fab')2片段。在一个实施方案中,可以修饰本发明的抗NGF抗体,以实现某种功能,例如消除残余的效应子功能(Glu可消除残余效应子功能(Reddy等,2000))。
在一些实施方案中,本发明的抗NGF抗体是中和性抗体,用于中和NGF。
第二方面,本发明提供了编码以上任何抗NGF抗体或其片段的核酸。在一个实施方案中,提供了包含所述核酸的载体。在一个实施方案中,载体是表达载体。
第三方面,本发明提供了包含所述载体、或者包含所述核酸或抗体的宿主细胞。在一个实施方案中,宿主细胞是真核细胞。在另一个实施方案中,宿主细胞选自哺乳动物细胞或适用于制备抗体或其抗原结合片段的其它细胞,其中所述哺乳动物细胞例如是CHO细胞、HEK293细胞或COS细胞。在另一个实施方案中,宿主细胞是原核细胞,例如大肠杆菌细胞、酵母细胞。
第四方面,本发明提供制备抗NGF抗体或其抗原结合片段的方法,其中所述方法包含在适于表达编码所述抗体或其抗原结合片段的核酸的条件下培养所述宿主细胞,以及任选地分离所述抗体或其抗原结合片段。在某个实施方案中,所述方法还包括从宿主细胞回收抗NGF抗体或其抗原结合片段。
在一个实施方案中,本发明提供由本发明的方法制备的抗NGF抗体或其抗原结合片段。
第五方面,本发明提供了包含本文所述的任何抗NGF抗体或其抗原结合片段的组合物,优选所述组合物为药物组合物。
在一个实施方案中,所述组合物还包含药用载体。在一个实施方案中,组合物中包含的抗NGF抗体及其抗原结合片段偶联至偶联部分。在一个实施方案中,该药物组合物进一步包含药学可接受载剂,赋形剂,或稀释剂。
第六方面,本发明提供了用于治疗与NGF相关的疾病或病症的方法,包括向受试者施用治疗有效量的本发明的抗NGF抗体,或施用本发明的药物组合物。
本发明还涉及用于缓解或改善与NGF介导的疾病或病症相关的症状的方法,包括向受试者给予治疗有效量的本发明的抗NGF抗体,或施用本发明的药物组合物。
在一个具体实施方案中,所述NGF介导的疾病或病症涵括与NGF水平升高或对NGF敏感性提高有关的任何医学疾病或病症,包括但不限于疼痛、关节炎、胶原血管病、脱髓鞘病、气道炎症性疾病、神经系统疾病、代谢性疾病(如糖尿病)、病毒感染相关疾病、心律失常、牛皮癣和癌症。
在一个实施方案中,所述NGF介导的疾病或病症是疼痛相关病症,炎症性疼痛、手术后刀口疼痛、神经性疼痛、骨折疼痛、痛风关节痛、烧伤疼痛、癌症疼痛、复合性局部疼痛综合征、疱疹后神经痛或与镰刀细胞危象有关的疼痛。在一个实施方案中,所述疼痛为病理生理性疼痛。
进一步地,所述方法通过消除、抑制或降低NGF的活性而改善、减轻、抑制或预防任何与NGF相关疾病或病症,或减轻与所述疾病相关的症状,例如疼痛。在一个实施方案中,本发明通过单独施用一种抗NGF拮抗剂,如本发明的抗体或其抗原结合片段来治疗所述与NGF相关的疾病或病症。在另一个实施方案中,本发明公开的治疗方法将抗NGF抗体与第二治疗剂联合施用,以治疗与NGF相关的疾病或病症。所述第二治疗剂选自其他神经营素、止痛剂、抗炎剂、化学治疗剂或免疫治疗剂。
在一个实施方案中,本发明提供了缓解或改善NGF介导的疼痛的方法,包括向受试者施用治疗有效量的本发明的抗NGF抗体,或治疗有效量的药物组合物。
第七方面,本发明提供了检测对象或样品中NGF的方法,所述方法包括:(a)将对象或样品与本文所述的任何抗NGF抗体或其片段接触;和(b)检测抗NGF抗体或其片段和NGF间的复合物的形成。在一个优选实施方案中,本发明的抗NGF抗体及其抗原结合片段还包括可检测的标记。
在一个实施方案中,本发明提供的抗体可用于检测、诊断及监测与改变或异常的NGF表达相关的疾病或病症。
第八方面,本发明涉及本文所述任何抗NGF抗体或其片段在制备用于治疗受试者中与NGF相关疾病或病症的药物或试剂盒中的用途。
在一个实施方案中,本发明提供了包含所述抗NGF抗体的组合物在制备用于用于治疗受试者在与NGF相关的疾病或病症的药物或试剂盒中的用途。
在另一个实施方案中,本发明还涉及本文所述任何抗NGF抗体或其片段,或包含所述抗NGF抗体的组合物在制备用于缓解或改善NGF介导的疼痛的药物中的用途。
在另一个实施方案中,本文的任何抗NGF抗体或其片段,供作为药物使用。
第九方面,本发明提供了一种包含本发明的抗体或者组合物的试剂盒,例如诊断试剂盒,检测试剂盒,治疗试剂盒等。
本发明还涵盖本文所述的任何实施方案的任意组合。本文所述的任何实施方案或其任何组合适用于本文所述的发明的任何和所有抗NGF抗体或其片段、方法和用途。
发明的有益效果
本发明提供了能够特异性识别/结合NGF的人抗体及其抗原结合片段,所述抗体及其抗原结合片段针对NGF具有中和作用,并且对NT-3、NT-4、BDNF发生交叉反应。由于本发明的抗NGF抗体是完全人抗体,因此在治疗与NGF相关的疾病或病症,或者缓解与NGF相关的疼痛的同时,对受试者具有低的免疫原性,从而可以有效避免受试者针对其产生相应的免疫反应,因此降低了与常规抗NGF抗体相关的副作用。
附图说明
图1:样本(Ns006)抗NGF抗体滴度检测结果;
图2:抗体结合活性检测结果;
图3:抗体TRN1028亲和力曲线;
图4:抗体TRN1028抑制TF-1细胞增殖;
图5:单次皮下给药对CFA诱导小鼠炎性疼痛MWT的影响(n=9)。
发明详述
1.1定义
在下文详细描述本发明前,应理解本发明不限于本文中描述的特定方法学、方案和试剂,因为这些可以变化。还应理解本文中使用的术语仅为了描述具体实施方案,而并不意图限制本发明的范围,其仅会由所附权利要求书限制。除非另外定义,本文中使用的所有技术和科学术语与本发明所属领域中普通技术人员通常的理解具有相同的含义。
为了解释本说明书,将使用以下定义,并且只要适当,以单数形式使用的术语也可以包括复数,并且反之亦然。应当理解,本文所用的术语仅是为了描述具体的实施方案,并且不意欲是限制性的。
术语“约”在与数字数值联合使用时意为涵盖具有比指定数字数值小5%的下限和比指定数字数值大5%的上限的范围内的数字数值。
术语“和/或”应理解为意指可选项中的任一项或可选项的两项。
如本文中所用,术语“包含”或“包括”意指包括所述的要素、整数或步骤,但是不排除任意其他要素、整数或步骤。在本文中,当使用术语“包含”或“包括”时,除非另有指明,否则也涵盖由所述及的要素、整数或步骤组成的情形。例如,当提及“包含”某个具体序列的抗体可变区时,也旨在涵盖由该具体序列组成的抗体可变区。
术语“神经生长因子”或“NGF”指所有哺乳动物种类(包括人)的天然序列NGF,此外还涵盖其保持至少部分NGF生物学活性的任何形式,例如NGF突变体、NGF直系同源物、NGF旁系同源物等。
术语“抗体”在本文中以最广意义使用并且涵盖多种抗体结构物,包括但不限于单克隆抗体、多克隆抗体、多特异性抗体(例如,双特异性抗体)和抗体片段,只要它们显示出所需的抗原结合活性即可。完整抗体通常将包含至少两条全长重链和两条全长轻链,但在某些情况下可包括较少的链,例如骆驼中天然存在的抗体可仅包含重链。
如本文所用,“单克隆抗体”或“mAb”指来源于例如真核生物的、原核生物的或噬菌体克隆的单一拷贝或克隆的抗体,即,除了通常以很少量存在的可能变体抗体(例如,含有天然突变或在单克隆抗体制品的生产过程中产生的变体抗体)以外,构成所述群体的各个抗体是相同的和/或结合相同表位。修饰语“单克隆”表示抗体从基本上同质的抗体群获得的特征,并且不应解释为需要通过任何特定方法产生抗体。单克隆抗体可以例如通过杂交瘤技术、重组技术、噬菌体展示技术、合成技术例如CDR嫁接、或此类或其它本领域已知的技术的组合来产生。
“天然抗体”指具有不同结构的天然存在的免疫球蛋白分子。“天然序列Fc结构域”包含与在自然界中找到的Fc结构域的氨基酸序列相同的氨基酸序列。天然序列人Fc结构域包括例如天然序列人IgG1 Fc结构域(非A和A同种异型);天然序列人IgG2 Fc结构域;天然序列人IgG3 Fc结构域;和天然序列人IgG4 Fc结构域;及其天然存在变体。
“人抗体”指具有这样的氨基酸序列的抗体,所述氨基酸序列对应于这样抗体的氨基酸序列,所述抗体由人或人细胞生成或来源于非人来源,其利用人抗体库或其它人抗体编码序列。人抗体的这种定义明确排除包含非人抗原结合残基的人源化抗体。
术语“中和抗体”是减少或抑制NGF的生物活性,如减少或抑制NGF与一个或多个它的受体(优选是TrkA)的结合的抗体或抗体片段。生物活性的减少可以是部分减少的或是完全减少的。抗体中和NGF的程度称作抗体的中和效力。利用普通技术人员已知的和/或本文所述或所提及的一个或多个测试可确定或测量抗体的中和效力,包括但不限于竞争性结合测定法、直接和间接夹心测定法、免疫沉淀测定及酶联免疫吸附测定(ELISA)。
“抗NGF抗体”是指能结合NGF并抑制NGF生物学活性和/或由NGF信号介导的下游途径的抗体。抗NGF抗体包含阻断、拮抗、抑制或降低(包括显著降低)NGF生物学活性,包括由NGF信号介导的下游途径如受体结合和/或引发对NGF细胞反应的抗体。
在一些实施方案中,本发明还涵盖抗NGF抗体的片段。抗体片段的实例包括但不限于Fv、Fab、Fab′、Fab’-SH,F(ab’)2、双抗体、线性抗体、单链抗体分子(例如scFv);和由抗体片段形成的多特异性抗体。
NGF的“生物学活性”一般是指结合NGF受体和/或活化NGF受体信号途径的能力。例如,生物学活性包括任何一个或多个以下内容:结合NGF受体(如p75和/或TrkA)的能力;促进TrkA受体二聚化和/或TrkA自动磷酸化的能力;活化NGF受体信号途径的能力;促进细胞分化、增殖、存活、生长及其它在细胞生理学中的变化;促进小鼠E13.5三叉神经元存活的能力以及介导疼痛,包括手术后疼痛的能力。
每个重链由一个重链可变区(HCVR或VH)和一个重链恒定区组成。重链恒定区由三个域CH1、CH2和CH3组成。每个轻链由一个轻链可变区(LCVR或VL)和一个轻链恒定区组成。轻链恒定区由一个域CL组成。VH和VL区可进一步分成被称为互补决定区(CDR)的高变区,其中散布着较保守的被称为框架区(FR)的区域。每个VH和VL均由三个CDR和四个FR组成,从氨基端到羧基端按以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。
“互补决定区”或“CDR区”或“CDR”或“高变区”,是抗体可变区中主要负责与抗原表位结合的氨基酸区域。重链和轻链的CDR通常被称作CDR1、CDR2和CDR3,从N-端开始顺序编号。
本领域公知多种用于在一个给定的VH或VL氨基酸序列中确定其CDR序列的方案:Kabat互补决定区(CDR)是基于序列变异性确定的并且是最常用的(Kabat等人,Sequencesof Proteins of Immunological Interest,第5版,Public Health Service,NationalInstitutes of Health,Bethesda,Md.(1991)),而Chothia指的是结构环的位置(Chothia等人,(1987)J.Mol.Biol.196:901-917;Chothia等人(1989)Nature 342:877-883),AbMCDR是Kabat CDR和Chothia结构环之间的折中,并且由Oxford Molecular的AbM抗体建模软件使用,“接触性”(Contact)CDR基于对可获得的复杂晶体结构的分析。根据不同的CDR确定方案,这些CDR中的每一个的残基如下所述。
在一个实施方案中,本发明抗体的CDR是根据Kabat编号系统位于如下Kabat残基位置的CDR序列:
VL中的位置24-34(CDR1)、位置50-56(CDR2)、和位置89-97(CDR3),以及VH中的位置27-35(CDR1)、位置50-65(CDR2)、和位置93-102(CDR3)。
CDR也可以基于与参考CDR序列(例如本发明示例性CDR之任一)具有相同的Kabat编号位置而确定。
与抗体相关的术语“变体”在本文中指,包含已经通过至少1个,例如1-30,或1-20或1-10个,例如1或2或3或4或5个氨基酸取代、缺失和/或插入而具有氨基酸改变的目标抗体区域(例如重链可变区或轻链可变区或重链CDR区或轻链CDR区)的抗体,其中变体基本上保持改变之前的抗体分子的生物学特性。在一方面,本发明涵盖在本文中所述及的任何抗体的变体。在一个实施方案中,抗体变体保持改变前抗体的至少60%,70%,80%,90%,或100%的生物学活性(例如抗原结合能力)。可以理解的,抗体的重链可变区或轻链可变区、或各CDR区可以单独改变或组合改变。在一些实施方案中,在一个或多个或全部三个重链CDR中的氨基酸改变不超过1个、2个、3个、4个、5个、6个、7个、8个、9个或10个。优选地,所述氨基酸改变为氨基酸取代,优选保守取代。
术语“保守取代”是指一个氨基酸经相同类别内的另一氨基酸取代,例如一个酸性氨基酸经另一酸性氨基酸取代,一个碱性氨基酸经另一碱性氨基酸取代,或一个中性氨基酸经另一中性氨基酸取代。示例性的取代如下表所示:
原始残基 | 示例性取代 | 优选保守取代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Asp,Lys;Arg | Gln |
Asp(D) | Glu;Asn | Glu |
Cys(C) | Ser;Ala | Ser |
Gln(Q) | Asn;Glu | Asn |
Glu(E) | Asp;Gln | Asp |
Gly(G) | Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe;正亮氨酸 | Leu |
Leu(L) | 正亮氨酸;Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Trp;Leu;Val;Ile;Ala;Tyr | Tyr |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Val;Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala;正亮氨酸 | Leu |
在一些实施方案中,抗体变体与亲本抗体在目的抗体序列区域上具有至少80%、90%或95%或99%或更高的氨基酸同一性。
“分离的”抗体是这样的抗体,其已经与其天然环境的组分分离。在一些实施方案中,将抗体纯化至超过95%或99%纯度,如通过例如电泳(例如,SDS-PAGE,等电聚焦(IEF),毛细管电泳)或层析(例如,离子交换或反相HPLC)确定的。对于用于评估抗体纯度的方法的综述,参见,例如,Flatman等,J.Chromatogr.B848:79-87(2007)。
“分离的”核酸是指这样的核酸分子,其已经与其天然环境的组分分离。分离的核酸包括包含在通常包含该核酸分子的细胞中的核酸分子,但是该核酸分子存在于染色体外或在不同于其天然染色体位置的染色体位置处。
术语“载体”当在本文中使用时是指能够增殖与其相连的另一个核酸的核酸分子。该术语包括作为自我复制核酸结构的载体以及结合到已经引入其的宿主细胞的基因组中的载体。一些载体能够指导与其可操作相连的核酸的表达。这样的载体在本文中被称为“表达载体”。
术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可交换地使用且是指其中引入外源核酸的细胞,包括这种细胞的子代。宿主细胞包括“转化体”和“转化的细胞”,其包括初级转化的细胞和来源于其的子代,而不考虑传代的数目。子代在核酸含量上可能与亲本细胞不完全相同,而是可以包含突变。本文中包括与在最初转化的细胞中筛选或选择的具有相同功能或生物学活性的突变体子代。
用于克隆或表达编码抗体的载体的适当宿主细胞包括本文描述的原核或真核细胞。例如,抗体可在细菌中产生,特别当不需要糖基化和Fc效应子功能时。对于抗体片段和多肽在细菌中的表达,见,例如,美国专利号5,648,237,5,789,199和5,840,523,还见Charlton,Methods in Molecular Biology,卷248(B.K.C.Lo,编辑,Humana Press,Totowa,NJ,2003),第245-254页,其描述抗体片段在大肠杆菌中的表达)。在表达后,抗体可以从可溶级分中的细菌细胞糊状物分离,并且可以进一步纯化。
在一个实施方案中,宿主细胞是真核的。在另一个实施方案中,宿主细胞选自酵母细胞、哺乳动物细胞或适用于制备抗体或其抗原结合片段的其它细胞。例如,真核微生物诸如丝状真菌或酵母是关于编码抗体的载体的合适克隆或表达宿主,包括真菌和酵母菌株,其糖基化途径已经进行“人源化”,导致产生具有部分或完全人糖基化模式的抗体。参见Gerngross,Nat.Biotech.22:1409-1414(2004),和Li等,Nat.Biotech.24:210-215(2006)。适于表达糖基化抗体的宿主细胞也衍生自多细胞生物体(无脊椎动物和脊椎动物)。也可以将脊椎动物细胞用作宿主。例如,可以使用被改造以适合于悬浮生长的哺乳动物细胞系。有用哺乳动物宿主细胞系的其它实例是用SV40转化的猴肾CV1系(COS-7);人胚肾系(293或293细胞,如例如Graham等,J.Gen Virol.36:59(1977)中所描述的)等。其它有用的哺乳动物宿主细胞系包括中国仓鼠卵巢(CHO)细胞,包括DHFR-CHO细胞(Urlaub等,Proc.Natl.Acad.Sci.USA 77:216(1980));以及骨髓瘤细胞系如Y0,NS0和Sp2/0。关于适合产生抗体的某些哺乳动物宿主细胞系的综述见例如Yazaki和Wu,Methods in MolecularBiology,卷248(B.K.C.Lo,ed.,Humana Press,Totowa,NJ),第255-268页(2003)。
相对于参比多肽序列的“百分比(%)氨基酸序列同一性”定义为在将所述序列进行比对(并在必要时导入空位)以获取最大百分比序列同一性,且不将任何保守取代视为序列同一性的部分之后,候选序列中的氨基酸残基与参比多肽序列中的相同氨基酸残基的百分比。可使用本领域各种方法进行序列比对以便测定百分比氨基酸序列同一性,例如,使用公众可得到的计算机软件如BLAST、BLAST-2、ALIGN或MEGALIGN(DNASTAR)软件。本领域技术人员可以决定测量比对的适宜参数,包括对所比较的序列全长获得最大比对所需的任何算法。
当在本申请中提到序列同一性的百分比时,若未另外特别指出,这些百分比相对于较长序列的全长计算。相对于较长序列的全长计算适用于核酸序列和多肽序列两者。
“亲和力”或“结合亲和力”指反映结合对的成员(例如抗体与抗原)之间相互作用的固有结合亲和力。分子X对其配偶体Y的亲和力通常可用平衡解离常数(KD)来表述。平衡解离常数是解离速率常数和结合速率常数(分别是kdis和kon)的比值。亲和力可通过本领域知道的常用方法来测量,包括现有技术已知以及本文中所描述的那些。
在本发明的一个实施方案中,本发明的抗NGF抗体与NGF的平衡解离常数(KD)小于等于1×10-7M、小于等于1×10-8M、小于等于1×10-9M、小于等于1×10-10M、小于等于1×10- 11M、小于等于1×10-12M、小于等于1×10-13M等。
“免疫缀合物”指与一种或多种异源分子,包括但不限于载体缀合的抗体。
术语“药物组合物”指这样的制剂,其以允许包含在其中的活性成分的生物学活性有效的形式存在,并且不包含对施用所述制剂的受试者具有不可接受的毒性的另外的成分。
本发明在另一方面提供了包括一种或多种结合NGF或其免疫活性片段的单克隆抗体的药物组合物。应理解,本发明提供的抗NGF抗体或药物组合物可以整合至制剂中合适的运载体、赋形剂和其他试剂以联合给药,从而提供改善的转移、递送、耐受等。
术语“药用载体”指与治疗剂一起施用的稀释剂、佐剂(例如弗氏佐剂(完全和不完全的))、赋形剂或媒介物。
适用于本发明的药用载体可以是常规的,参见“Handbook ofPharmaceuticalExcipients”,第七版,R.C.Rowe,P.J.Seskey和S.C.Owen,PharmaceuticalPress,London,Chicago描述的药物制剂辅料;以及“Remington’SpharmaceuticalSciences”,E.W.Martin,Mack Publishing Co,Easton,PA出版,第21版,2012,描述的适用于药物递送所公开抗体的组合物和制剂。
术语“有效量”指以单一或多次剂量施用后,足以获得或者至少部分获得期望的效果的量或剂量,“治疗有效量”指在治疗的受试者中产生预期效果的量,包括受试者病症的改善(例如,一个或多个症状的改善)和/或症状进展的延迟等。预防疾病的有效量指足以预防、阻止或延迟疾病的发生的量。确定有效量完全在本领域技术人员的能力范围之内,例如治疗有效量取决于涉及的具体疾病;疾病的程度或严重性;个体患者的应答;施用的具体抗体;施用模式;施用制剂的生物利用率特征;选择的给药方案;和任何伴随疗法的使用等。
用于本文时,“治疗”指减缓、中断、阻滞、缓解、停止、降低、或逆转已存在的症状、病症、病况或疾病的进展或严重性。
术语“受试者”或“个体”是灵长类(例如,人和非人灵长类诸如猴)。在某些实施方案中,个体或受试者是人。
“缓解”疼痛或疼痛的一种或多种症状表示与不施用抗NGF抗体相比,减轻或改善疼痛的一种或多种症状。“缓解”也包括缩短或减少症状的持续时间。
术语“疼痛”是指任何病因学,包括急性及慢性疼痛以及任何有炎性组分的疼痛。如文中应用的"疼痛"包括疼痛的伤害感受及感觉,并且疼痛可用本领域公知的疼痛分值及其它方法进行客观及主观的评估。
术语“痛觉过敏”指机体对正常伤害性或不愉快刺激产生的增强的疼痛反应。
1.2本发明示例性抗NGF抗体TRN1028的序列
表I:抗体TRN1028的重链可变区序列和轻链可变区序列:
表II:抗体TRN1028的CDR序列:
SEQ ID NO:9:
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:10:
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:11:
GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
实施例
以下实施例进一步说明本发明,然而,应理解实施例以说明而非限定的方式来描述,并且本领域技术人员可以进行多种修改。
除非明确指明相反,否则本发明的实施将采用本领域技术内的常规化学、生物化学、有机化学、分子生物学、微生物学、重组DNA技术、遗传学、免疫学和细胞生物学的方法。这些方法的描述可以参见,例如,Sambrook等人,Molecular Cloning:A LaboratoryManual(第3版,2001);Sambrook等人,Molecular Cloning:A Laboratory Manual(第2版,1989);Maniatis等人,Molecular Cloning:A Laboratory Manual(1982);Ausubel等人,Current Protocols in Molecular Biology(John Wiley和Sons,2008年7月更新);ShortProtocols in Molecular Biology:A Compendium of Methods from Current Protocolsin Molecular Biology,Greene Pub.Associates和Wiley-Interscience;Glover,DNACloning:A Practical Approach,vol.I&II(IRL Press,Oxford,1985);Anand,Techniquesfor the Analysis of Complex Genomes,(Academic Press,New York,1992);Transcription and Translation(B.Hames&S.Higgins,Eds.,1984);Perbal,A PracticalGuide to Molecular Cloning(1984);Harlow和Lane,Antibodies,(Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.,1998)Current Protocols in ImmunologyQ.E.Coligan,A.M.Kruisbeek,D.H.Margulies,E.M.Shevach和W.Strober,eds.,1991);Annual Review of Immunology;以及期刊专著如Advances in Immunology。
举出以下实例是为了向本领域一般技术人员就如何准备和利用本发明的方法和组合物提供一个完整的披露和说明,并非意在限制本发明的保护范围。
实施例1.制备人抗NGF抗体
1)PBMC分离
对患有多种疾病的病人注射鼠神经生长因子(金露捷)联合治疗30天(遵医嘱)后,采集其10mL外周血液于含有肝素的抗凝管中,利用密度离心法分离血浆与PBMC细胞。具体操作如下:取10mL静脉血,400g、22℃离心15min;吸取离心后上清透明血浆层,分装于-80℃冷冻保存;将剩余部分与等量的RPMI1640培养基充分混匀,缓慢加入到含有淋巴细胞分离液Ficoll的无菌离心管内,并保持液面分层完整;2000rpm水平离心20min,用毛细管吸取位于云雾层中的PBMC细胞,置另一无菌离心管中,加入5倍以上体积的RPMI1640培养基,1500rpm离心10min,重复洗涤两次,细胞计数后以1×107/支进行-80℃冻存备用。
2)样本抗NGF抗体滴度检测
将hNGF(Sino Biological)用pH 9.6的磷酸盐包被缓冲液稀释至2μg/mL,按0.1mL/孔加至96孔板,4℃包被过夜,用封闭液37℃封闭2h。将100μL的系列稀释血浆样本作为一抗加入,37℃孵育1h,再加入用HRP标记的羊抗人IgG(1:10000稀释)二抗37℃孵育1h,之后加入100μL/孔的底物显色液TMB,37℃避光放置5min后,用2M硫酸中止反应,读取OD450值。结果(如图1)显示样本Ns006有较高吸光值,表明Ns006样本中的抗NGF抗体滴度较高,并且能与hNGF结合。然后将标记为Ns006样品的PBMC进行流式分选。
3)流式细胞分选仪分选单个浆细胞
根据上述血清学实验结果,通过流式细胞仪(BD,Facs Aria Sorp),从相应标号的样品中PBMC中分选单个浆细胞;设置门控CD3/CD14/CD16/cd235a-CD19+CD20+/-CD38hiCD27hi,从PBMC中分选特异性细胞群。再分选出针对hNGF蛋白特异性的记忆浆细胞细胞群(>3%),挑选单个浆细胞置于96孔PCR板中(每孔20μL单细胞裂解液),使每个孔含有一个浆细胞,-80℃冰箱保存备用。
4)从单个浆细胞中分离抗体可变区基因
先利用恒定区引物(参见CN107760690B中公开的引物信息)与Superscript III反转录酶(Invitrogen,Carlsbad,CA)从实施例1步骤3)中获得的记忆浆细胞中反转录合成cDNA第一条链。再通过下述PCR程序分离抗体基因。
第一轮PCR:50μL体系,加入5μL反转录反应产物、25μL Taq酶Mix、25μM的各亚型重链与轻链抗体恒定区引物。反应条件:
95℃预变性5min;
循环条件:94℃变性30s,55℃退火60s,72℃延伸90s;重复循环35次;
最后72℃延伸7min,反应产物用于第二轮PCR反应。
第二轮PCR:50μL体系,加入3μL第一轮PCR反应产物、25μL Taq酶Mix、20μM的各亚型重链与轻链抗体可变区引物。反应条件:
95℃预变性5min;
循环条件:94℃变性30s,58℃退火60s(或Lambda链64℃退火60s),72℃延伸90s;重复循环35次;
最后用72℃延伸7min。获得的PCR产物用1.2%的琼脂糖凝胶电泳进行鉴定,获得可变区基因,其重链可变区氨基酸序列VH如SEQ ID NO:7所示和其轻链可变区氨基酸序列VL如SEQ ID NO:8所示。
5)重组抗体表达载体的构建、表达及纯化
在一个实施例方案中,将上述鉴定得到的抗体可变区基因的PCR产物用常规方法克隆到含有人IgG恒定区的pcDNA3.1+/C-(K)-DYK质粒上,构建人抗NGF抗体的表达载体,然后将表达载体转化大肠杆菌DH5α感受态细菌进行载体扩增,提取载体(重组质粒)。将获得的重组质粒共转染至HEK293细胞,然后按照常规方法培养HEK293细胞并表达所述抗体。收集培养物上清,4000rpm离心1h,利用Protein A亲和层析法对上清液进行纯化。通过SDS-PAGE检验纯化的抗体的表达及纯化情况。SDS-PAGE检测结果表明成功表达了抗体,将所述抗体命名为TRN1028,其相对分子量约180KD,其重链约55KD、轻链约30KD。
实施例2.抗体结合活性检测
通过ELISA试验检测抗体TRN1028与hNGF的结合活性。具体而言,以将2μg/mL的hNGF作为抗原用pH 9.6的碳酸盐缓冲液稀释包被于96孔板中、4℃过夜;封闭液37℃封闭2h。用封闭液倍比稀释抗体TRN1028,10μg/mL起始,3倍稀释12个梯度;然后将各个梯度的抗体TRN1028加入96孔板,后37℃孵育1h。PBST缓冲液洗涤,加入100μ/孔LHRP标记的羊抗人IgG(1:10000),37℃孵育1h。PBST缓冲液洗涤,避光、加入TMB显色液100μL/孔,37℃放置5min,H2SO4终止反应。450nm波长检测,计算、分析结果。在本实验中,将现有技术中公开的具有良好效果的抗NGF抗体Tanezumab(CAS编号880266-57-9,CN 102746399B公开,也称作E3)作为阳性对照。
结果显示(见图2):抗NGF抗体E3结合hNGF的EC50为2.96ng/mL;而本申请的人抗NGF抗体TRN1028与hNGF结合的EC50为1.86ng/mL;表明人抗NGF抗体TRN1028具有强结合活性。
实施例3.抗体的结合亲和力
抗体和抗原决定簇之间的结合力称为抗体亲和力,体现了抗体分子和抗原决定簇结合的能力。在本实施例中,使用表面等离子体共振分析(BIACORE3000)检测抗体TRN1028的抗原结合亲和力。用氨基偶联的方法把抗人IgG(Fc)抗体固定在CM5传感芯片(GE)表面上,捕获抗NGF抗体作为配体,使捕获水平达到400RU左右;不同浓度的hNGF蛋白作为分析物流经检测通道,对抗原与抗体的结合以及对结合的复合物的解离进行实时监测。用BiacoreX100 Evaluation Software(2.0.1)进行动力学分析(计算解离常数(KD))。
结果如图3显示,TRN1028的抗原解离常数低至2.52*10-11M,解离速率为2.63*10-04/s,表明抗体TRN1028与抗原hNGF具有有非常强的结合亲和力。
实施例4.抗体的中和活性
在本实施例中,利用TF-1细胞(人红系白血病细胞)检测抗NGF抗体阻断NGF依赖型TrkA受体介导的细胞增殖活性的能力(Cheva1ier等,Blood(1994),83(6):1479-1485)。NGF能够与TrkA结合,TrkA作为NGF的高亲和力受体,结合NGF后形成二聚体,激活胞内域酪氨酸激酶区,引起相应的酪氨酸磷酸化,从而激活下游信号转导系统,执行调节靶细胞的功能,从而诱导TF-1细胞增殖。
将生长对数期的TF-1细胞(ATCC,CRL-2003TM)置于37℃、5%CO2中饥饿培养24h。用基本培养基配制32ng/mL浓度的hNGF溶液,以每孔25uL的量加入96孔细胞培养板中。再用基本培养基配制6ug/mL浓度的本发明抗体的溶液,并以此作为起始浓度,之后进行3倍稀释获得8个浓度梯度。向96孔板中各加入25uL人抗NGF抗体系列稀释溶液,37℃孵育30min。向96孔板各孔中加入饥饿培养了24h的50uL密度为6×105/mL的TF-1细胞,hNGF的终浓度为8ng/mL、细胞终密度为3×105/mL。继续培养72h后加入MTS试剂,37℃孵育2h,然后进行检测。通过吸光值计算抗体TRN1028的EC50,分析信号对抗体浓度的依懒性,E3抗体作为对照。
结果显示(见图4),抗体TRN1028和对照组的剂量反应曲线为典型的S型剂量-效应反应曲线。计算表明,抗体TRN1028和对照组阻断NGF信号的EC50分别为12.41ng/mL、14.35ng/mL。表明本发明的抗体能够抑制NGF诱导的TF-1细胞的增殖,具有更好的中和活性。
实施例5.抗体与BDNF、NT-3、NT-4的交叉反应
本发明通过ELISA确定抗体TRN1028对其他神经营养因子的交叉反应性。分别以hBDNF、hNT-3、hNT-4(Absin)为抗原,按200ug/孔包被96孔板,4℃过夜;然后用封闭液常温封闭2个小时。以浓度递减的抗体TRN1028(范围是10ug/ml-0ug/ml)按100ul/孔加入,37℃孵育1h。用山羊-抗-人IgG-HRP(1:10000)和底物显色液使TMB来检测抗体TRN1028。双波长450-630nm检测OD值。
结果显示抗体TRN1028均与hBDNF、hNT-3和hNT-4发生结合反应,经计算,其结合EC50分别为1.377ng/mL、3.35ng/mL、1053ng/mL。即本发明的人抗NGF抗体与BDNF、NT-3和NT-4等神经营养因子能够发生交叉反应,具有极强的广谱性。NGF与BDNF、NT-3、NT-4同属于神经营养家族,其在氨基酸序列具有一定的同源性。但是,它们的生物功能存在差异:BDNF在AD、脑缺血损伤、PD、抑郁焦虑等疾病有重要的保护及治疗作用,BDNF可能较NGF与内异症相关疼痛的关系更加密切,BDNF还被发现其在肿瘤的发生发展上表现出作用;NT-3基因可引起皮肤触-压觉感受器明显缺失,NT-3也在先天性神经系统疾病表现出作用;NTs通过神经源性炎症反应或者诱导细胞因子失衡和自身免疫应答,参与了以细胞消亡(应激性秃发)或过度增殖(特应性皮炎、银屑病等)为特征的炎症性皮肤病的发病。TRN1028与BDNF、NT-3和NT-4发生结合反应这一特性,可能在多发性、复发性疾病或癌症疼痛的治疗中提供意想不到的效果。
实施例6.抗体的抗痛觉过敏活性
为了评估抗体TRN1028在调节疼痛方面的作用,进行如下实验。
选取小鼠(C57BL/6N,雄性),用VonFrey(厂家:IITC)纤维测定3次小鼠左后足足底的机械缩足阈(Mechanical Withdrawal Threshold,MWT),取3次平均值为其基础痛阈。次日(第1天),除空白对照组外,其余各组小鼠均于左后足足底皮内注射30μl CFA(3mg/ml)致炎。24h后(第2天),同样方法3次检测小鼠左后足MWT,取平均值为给药前的痛阈值。剔除MWT过大或过小的动物,挑选45只动物根据MWT值平均分成5组(n=9),随后皮下注射PBS或受试物:第1组为空白对照组,给予PBS,第2组为模型对照组,给予PBS,第3、4、5组分别为给予10mg/kg的受试物TRN1028、E3、阴性对照抗体;并测定给药后24h(第3天)、48h(第4天)、72h(第5天)的痛阈,计算给药后的痛阈提高率。
痛阈提高率%=(MWT给药组-MWT模型组)/MWT模型组×100%。
在单次皮下注射给药24h后,TRN1028组、E3组和阴性对照组的小鼠的MWT值没有显著性差异。至给药48h、72h后,E3组、TRN1028组小鼠MWT与模型组比较仍具有统计学的显著性差异(P<0.01~0.001),痛阈提高率均超过20%。而阴性对照组的MWT值虽略高于模型组,但差异无统计学意义(P>0.05)(图5、表1)。因此表明抗体TRN1028在CFA诱导引发的炎症反应具有明显的缓解、治疗疼痛的作用,即本发明的人抗NGF抗体具有抗痛觉过敏活性。
表1单次皮下注射给药对CFA诱导的炎症反应的痛阈值
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Claims (24)
1.一种特异性地结合人神经生长因子的人抗体或其抗原结合片段,其包含:
(a)包含下述CDR的重链可变区:
CDR1,其序列如SEQ ID NO:1所示;
CDR2,其序列如SEQ ID NO:2所示;
CDR3,其序列如SEQ ID NO:3所示,
(b)包含下述CDR的轻链可变区:
CDR1,其序列如SEQ ID NO:4所示;
CDR2,其序列如SEQ ID NO:5所示;
CDR3,其序列如SEQ ID NO:6所示。
2.权利要求1所述的特异性地结合人神经生长因子的人抗体或其抗原结合片段,其中所述重链可变区选自:
(1)包含权利要求1所述的重链可变区的CDR,且与SEQ ID NO:7具有至少80%同一性的序列;
(2)包含SEQ ID NO:7所示的序列。
3.权利要求1或2所述的特异性地结合人神经生长因子的人抗体或其抗原结合片段,其中所述轻链可变区选自:
(1)包含权利要求1所述的轻链可变区的CDR,且与SEQ ID NO:8具有至少80%同一性的序列;
(2)包含SEQ ID NO:8所示的序列。
4.权利要求1或2所述的特异性地结合人神经生长因子的人抗体或其抗原结合片段,其中所述抗体是人单克隆抗体。
5.权利要求1或2所述的特异性地结合人神经生长因子的人抗体或其抗原结合片段,其中所述抗原结合片段选自Fab、Fab’-SH、Fv、scFv或(Fab’)2片段。
6.权利要求1或2所述的特异性地结合人神经生长因子的人抗体或其抗原结合片段,其包含恒定区序列,其中所述恒定区序列的至少一部分是人共有恒定区序列。
7.权利要求1或2所述的抗体或其抗原结合片段,其中所述抗体的重链恒定区包含SEQID NO:9或SEQ ID NO:10所示的氨基酸序列,轻链恒定区包含SEQ ID NO:11所示的氨基酸序列。
8.编码如权利要求1到7中任何一项所述的特异性地结合人神经生长因子的人抗体或其抗原结合片段的核酸分子。
9.一种包含如权利要求8所述的核酸分子的载体。
10.权利要求9所述的载体,其中所述载体是表达载体。
11.包含权利要求9或10所述载体的宿主细胞。
12.权利要求11所述的宿主细胞,其中所述宿主细胞是原核细胞或真核细胞。
13.权利要求11所述的宿主细胞,其中所述宿主细胞选自大肠杆菌细胞、酵母细胞、哺乳动物细胞或适用于制备抗体或其抗原结合片段的其它细胞。
14.权利要求13所述的宿主细胞,其中所述哺乳动物细胞是CHO细胞、HEK293细胞或COS细胞。
15.一种产生特异性地结合人神经生长因子的人抗体或其抗原结合片段的方法,包括在适于表达编码权利要求1至7中任一项的特异性地结合人神经生长因子的人抗体或其抗原结合片段的核酸的条件下培养权利要求11的宿主细胞。
16.权利要求15所述的方法,其中所述方法包括分离所述特异性地结合人神经生长因子的人抗体或其抗原结合片段的步骤。
17.权利要求15或16的方法,其中所述方法包括收集所产生的抗体或其抗原结合片段的步骤。
18.由权利要求15所述的方法制备的特异性地结合人神经生长因子的人抗体或其抗原结合片段。
19.一种包含如权利要求1-7或18中任何一项所述的抗体或其抗原结合片段以及药学上可接受载体的药物组合物。
20.权利要求1-7或18中任何一项所述的抗体或其抗原结合片段在制备用于减轻、缓解或抑制疼痛的药物中的用途。
21.如权利要求20所述的用途,其中所述疼痛是病理生理性疼痛。
22.权利要求1-7或18任何一项所述的抗体或其抗原结合片段在制备用于与第二治疗剂共治疗应用以减轻或抑制与人神经生长因子相关病症或疾病相关的疼痛的药物中的用途。
23.权利要求22所述的用途,其中所述第二治疗剂选自其他神经营养素、止痛剂、抗炎剂、化学治疗剂或免疫治疗剂。
24.权利要求1-7或18任何一项所述的抗体或其抗原结合片段在制备用于检测样品中人神经生长因子异常表达的检测试剂中的用途。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101827609A (zh) * | 2007-08-10 | 2010-09-08 | 里珍纳龙药品有限公司 | 抗人神经生长因子的高亲和力人抗体 |
EP2364728A1 (en) * | 2003-07-15 | 2011-09-14 | Amgen, Inc | Human anti-NGF neutralizing antibodies as selective NGF pathway inhibitors |
CN102762228A (zh) * | 2009-10-09 | 2012-10-31 | 安姆根有限公司 | 作为选择性ngf途径抑制剂的人抗ngf中和抗体 |
CN104910274A (zh) * | 2015-02-12 | 2015-09-16 | 北京华安科创生物技术有限公司 | 抗人神经生长因子的中和性单克隆抗体12c11及其杂交瘤细胞株 |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2364728A1 (en) * | 2003-07-15 | 2011-09-14 | Amgen, Inc | Human anti-NGF neutralizing antibodies as selective NGF pathway inhibitors |
CN102358903A (zh) * | 2003-07-15 | 2012-02-22 | 安姆根有限公司 | 作为选择性ngf途径抑制剂的人抗ngf中和抗体 |
CN101827609A (zh) * | 2007-08-10 | 2010-09-08 | 里珍纳龙药品有限公司 | 抗人神经生长因子的高亲和力人抗体 |
CN102762228A (zh) * | 2009-10-09 | 2012-10-31 | 安姆根有限公司 | 作为选择性ngf途径抑制剂的人抗ngf中和抗体 |
CN104910274A (zh) * | 2015-02-12 | 2015-09-16 | 北京华安科创生物技术有限公司 | 抗人神经生长因子的中和性单克隆抗体12c11及其杂交瘤细胞株 |
Non-Patent Citations (3)
Title |
---|
Diabetic neuropathy and nerve regeneration;Yasuda,H.等;《Progress in Neurobiology》;第69卷;第229-285页 * |
Preparation and characterization of a high-affinity monoclonal antibody against nerve growth factor;Shuang Liu等;《Protein Expression and Purification》;20211007;第189卷;第1-10页 * |
慢性疼痛神经生理机制的研究进展;陈华伦等;《重庆医学》;20210115;第50卷(第10期);第1777-1781页 * |
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