CN110392697A - 对nectin-4具有特异性的抗体及其用途 - Google Patents
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Abstract
本发明涉及新的抗体抗nectin‑4。Nectin‑4是在几种癌症中过表达的肿瘤相关抗原,特别是分别在30%、49%和86%的乳腺癌、卵巢癌和肺癌中,它们是预后不良的肿瘤。治疗仍然难以实现。这就是本发明人开发基于对nectin‑4具有特异性的抗体(称为14A5.2mab)的新靶向疗法的原因。实际上,发明人因为以下而选择该抗体:其固有的预防性抗转移性质,并且还用于治疗局部原发性和转移性癌症。此外,14A5.2mab可用于治疗对ASG‑22ME(来自Astellas公司)具有耐药性的癌症。因此,本发明涉及14A5.2mab及其用途。
Description
技术领域
本发明涉及对nectin-4具有特异性的抗体及其用途。
背景技术
Nectin-4是属于nectin蛋白质家族的表面分子,所述家族包含4个成员。Nectin是细胞粘附分子,其在发育和成年期间对于上皮细胞、内皮细胞、免疫细胞和神经细胞的各种生物过程(例如极性、增殖、分化和迁移)起关键作用。它们涉及人类的几种病理过程。它们是脊髓灰质炎病毒、单纯疱疹病毒和麻疹病毒的主要受体。编码Nectin-1(PVRL1)或Nectin-4(PVRL4)的基因中的突变导致与其他异常相关的外胚层发育异常综合征。Nectin-4在胎儿发育期间表达。在成人组织中,其表达比家族其他成员的表达更受限制。Nectin-4是主要在预后不良的肿瘤上的肿瘤相关抗原,分别占乳腺癌、卵巢癌和肺癌的30%、49%和86%。在相应的正常组织中未检测到其表达。在乳腺肿瘤中,Nectin-4主要在三阴性癌中表达。在患有这些癌症的患者的血清中,检测到可溶形式的Nectin-4与不良预后相关。血清Nectin-4水平在转移性进展期间增加,且在治疗后减少。这些结果表明,Nectin-4可以成为治疗癌症的可靠靶点。因此,现有技术已经描述了几种抗Nectin-4抗体。特别地,Enfortumab Vedotin(ASG-22ME)是靶向Nectin-4的抗体-药物偶联物(ADC),并且目前在进行用于治疗实体瘤患者的临床研究。
发明简述
本发明涉及对nectin-4具有特异性的抗体及其用途。具体地,本发明由权利要求所限定。
发明详述
本发明涉及对Nectin-4具有特异性的抗体(特别是单克隆抗体)及其用途。特别地,本发明提供了衍生自14A5.2抗体(也称为14A5.2 mab)的抗体。实际上,发明人因为其固有的抗转移性质而选择该抗体。此外,他们表明,14A5.2以相似的亲和力识别与Ha22-2抗体(也称为ASG-22ME,来自Astellas公司)识别的表位不同的表位。14A5.2可用于预防转移性疾病和/或用于治疗局部原发性或转移性癌症。此外,14A5.2可用于治疗对ASG-22ME具有耐药性的癌症。
如本文所用,术语“Nectin-4”具有其在本领域中的一般含义,并且包括人Nectin-4,特别是人Nectin-4的天然序列多肽、同种型、嵌合多肽、所有同源物、片段和前体。天然Nectin-4的氨基酸序列包括NCBI参考序列:NP_112178.2。
根据本发明,14A5.2 mab的VH区由SEQ ID NO:1的序列组成。因此,14A5.2 mab的H-CDR1由SEQ ID NO:1中第31位氨基酸残基至第35位氨基酸残基的序列限定。因此,14A5.2mab的H-CDR2由SEQ ID NO:1中第50位氨基酸残基至第66位氨基酸残基的序列限定。因此,14A5.2 mab的H-CDR3由SEQ ID NO:1中第99位氨基酸残基至第104位氨基酸残基的序列限定。
SEQ ID NO:1:14A5.2 mab的VH区
FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4
EVLLQQSGPELVKPGASVKIPCKASGYTFTDYTMDWVKQSHGKSLEWIGDINPNNDVTMYNEKFKGRATLTVDKSSSTAYMEVRSLTSEDTAVYYCVRGRGFAYWGQGTLVTVSA
根据本发明,14A5.2 mab抗体的VL区由SEQ ID NO:2的序列组成。因此,14A5.2mab的L-CDR1由SEQ ID NO:2中第24位氨基酸残基至第38位氨基酸残基的序列限定。因此,14A5.2 mab的L-CDR2由SEQ ID NO:2中第54位氨基酸残基至第60位氨基酸残基的序列限定。因此,14A5.2 mab的L-CDR3由SEQ ID NO:2中第93位氨基酸残基至第101位氨基酸残基的序列限定。
SEQ ID NO:2:14A5.2 mab抗体的VL区
FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4
DIVLTQSPASLIVSLGQRATISCRASQSVSTSSNSYMHWYQQKPGQPPKLLIRFASNLESGVPARFSGSGSGTYFTLNIHPVEEEDSATYYCQHSWEIPYTFGGGTKLEIK
如本文所用,术语“抗体”或“免疫球蛋白”具有相同的含义,且将在本发明中同等使用。如本文所用,术语“抗体”是指免疫球蛋白分子和免疫球蛋白分子的免疫活性部分,即,含有免疫特异性结合抗原的抗原结合位点的分子。因此,术语抗体不仅包括完整抗体分子,还包括抗体片段以及抗体和抗体片段的变体(包括衍生物)。在天然抗体中,两条重链通过二硫键相互连接,并且每条重链通过二硫键与轻链连接。有两种类型的轻链,lambda(1)和kappa(κ)。有五种主要的重链类别(或同种型),其决定抗体分子的功能活性:IgM、IgD、IgG、IgA和IgE。每条链含有不同的序列结构域。轻链包括两个结构域,可变结构域(VL)和恒定结构域(CL)。重链包括四个结构域,可变结构域(VH)和三个恒定结构域(CH1、CH2和CH3,统称为CH)。轻链(VL)和重链(VH)的可变区决定了对抗原的结合识别和特异性。轻链(CL)和重链(CH)的恒定区结构域赋予重要的生物学特性,例如抗体链结合、分泌、经胎盘移动、补体结合和与Fc受体(FcR)结合。Fv片段是免疫球蛋白的Fab片段的N-末端部分,并且由一条轻链和一条重链的可变部分组成。抗体的特异性在于抗体结合位点和抗原决定簇之间的结构互补性。抗体结合位点由主要来自高变区或互补决定区(CDR)的残基组成。偶尔,来自非高变区或框架区(FR)的残基可参与抗体结合位点或影响整个结构域的结构并因此影响结合位点。互补决定区或CDR是指一起定义天然免疫球蛋白结合位点的天然Fv区的结合亲和力和特异性的氨基酸序列。免疫球蛋白的轻链和重链各自具有三个CDR,分别称为L-CDR1、L-CDR2、L-CDR3和H-CDR1、H-CDR2、H-CDR3。因此,抗原结合位点通常包括六个CDR,其包含来自重链和轻链V区的每一个的CDR组。框架区(FR)是指插入CDR之间的氨基酸序列。在一个实施方案中,本发明的抗体是单克隆抗体。
在本发明的上下文中,本发明抗体的氨基酸残基根据IMGT编号系统编号。已定义IMGT独特编号以比较可变结构域,无论抗原受体、链类型或物种为何(Lefranc M.-P.,"Unique database numbering system for immunogenetic analysis"Immunology Today,18,509(1997);Lefranc M.-P.,"The IMGT unique numbering for Immunoglobulins,Tcell receptors and Ig-like domains"The Immunologist,7,132-136(1999).;Lefranc,M.-P.,Pommié,C.,Ruiz,M.,Giudicelli,V.,Foulquier,E.,Truong,L.,Thouvenin-Contet,V.and Lefranc,G.,"IMGT unique numbering for immunoglobulin and T cellreceptor variable domains and Ig superfamily V-like domains"Dev.Comp.Immunol.,27,55-77(2003))。在IMGT独特编号中,保守氨基酸总是具有相同的位置,例如半胱氨酸23、色氨酸41、疏水氨基酸89、半胱氨酸104、苯丙氨酸或色氨酸118。IMGT独特编号提供以下的标准化划界:框架区(FR1-IMGT:位置1-26,FR2-IMGT:39-55,FR3-IMGT:66-104和FR4-IMGT:118-128)和互补决定区:CDR1-IMGT:27-38,CDR2-IMGT:56-65和CDR3-IMGT:105-117。如果CDR3-IMGT长度小于13个氨基酸,则以111、112、110、113、109等的顺序从环的顶部产生空位。如果CDR3-IMGT长度超过13个氨基酸,则在CDR3-IMGT环顶部的位置111和112之间以112.1、111.1、112.2、111.2、112.3、111.3等的顺序产生额外的位置(http://www.imgt.org/IMGTScientificChart/Nomenclature/IMGT-FRCDRdefinition.html)。
如本文所用,术语“特异性”是指抗体可检测地结合抗原(例如Nectin-4)上呈递的表位,同时与非Nectin-4蛋白质或结构(例如,在癌细胞或其他细胞类型上呈递的其他蛋白质)具有相对较少的可检测的反应性的能力。如本文其他地方所述,使用例如Biacore仪器通过结合或竞争性结合测定可以相对测定特异性。特异性可以通过例如与其他无关分子的非特异性结合相比,与特异性抗原结合的约10:1、约20:1、约50:1、约100:1、10,000:1或更高比例的亲和力/亲合力来表现(在这种情况下,特异性抗原是Nectin-4)。
如本文所用,术语“亲和力”是指抗体与表位结合的强度。抗体的亲和力由解离常数Kd给出,定义为[Ab]x[Ag]/[Ab-Ag],其中[Ab-Ag]是抗体-抗原复合物的摩尔浓度,[Ab]是未结合抗体的摩尔浓度,[Ag]是未结合抗原的摩尔浓度。亲和常数Ka定义为1/Kd。测定mAb亲和力的优选方法可参见Harlow等,Antibodies:A Laboratory Manual,Cold SpringHarbor Laboratory Press,Cold Spring Harbor,N.Y.,1988),Coligan等,eds.,CurrentProtocols in Immunology,Greene Publishing Assoc.and Wiley Interscience,N.Y.,(1992,1993),和Muller,Meth.Enzymol.92:589-601(1983),其通过引用整体并入本文。本领域熟知的用于测定mAb亲和力的优选标准方法是使用Biacore仪器。
如本文所用,术语“单克隆抗体”、“单克隆Ab”、“单克隆抗体组合物”、“mAb”等是指单分子组合物的抗体分子的制剂。单克隆抗体组合物显示对特定表位的单一结合特异性和亲和力。
本发明的抗体通过本领域已知的任何技术产生,例如但不限于单独或组合的任何化学、生物学、遗传学或酶学技术。通常,已知所需序列的氨基酸序列的情况下,本领域技术人员可通过产生多肽的标准技术容易地产生所述抗体。例如,可以使用公知的固相方法合成它们,优选使用可商购的肽合成装置(例如由Applied Biosystems,Foster City,California制造的那种)并按照制造商的说明书。或者,可以通过本领域熟知的重组DNA技术合成本发明的抗体。例如,在将编码抗体的DNA序列整合入表达载体并将这些载体引入将表达所需抗体的合适的真核或原核宿主中后,可以获得作为DNA表达产物的抗体,之后可以使用已知技术分离它们。
在一个实施方案中,本发明的单克隆抗体是嵌合抗体,特别是嵌合小鼠/人抗体。
根据本发明,术语“嵌合抗体”是指包含非人抗体的VH结构域和VL结构域,以及人抗体的CH结构域和CL结构域的抗体。
在一些实施方案中,本发明的人嵌合抗体可以通过以下产生:获得编码如前所述的VL和VH结构域的核酸序列,通过将它们插入具有编码人抗体CH和人抗体CL的基因的用于动物细胞的表达载体来构建人嵌合抗体表达载体,通过将表达载体引入动物细胞来表达编码序列。作为人嵌合抗体的CH结构域,可以是属于人免疫球蛋白的任何区域,但IgG类的那些是合适的,并且也可以使用属于IgG类的任何一个亚类,例如IgG1、IgG2、IgG3和IgG4。另外,作为人嵌合抗体的CL,可以是属于Ig的任何区域,也可以使用κ类或λ类的那些。产生嵌合抗体的方法涉及常规重组DNA,且基因转染技术是本领域熟知的(参见Morrison SL等人(1984)和专利文献US5,202,238;和US5,204,244)。
在另一个实施方案中,本发明的单克隆抗体是人源化抗体。特别地,在所述人源化抗体中,可变结构域包含人受体框架区,和当存在时任选的人恒定结构域,和非人供体CDR,例如小鼠CDR。
在另一个实施方案中,基于相同的人源化方法,本发明的单克隆抗体是犬源化或灵长类化的。
根据本发明,术语“人源化抗体”是指具有来自人抗体的可变区框架和恒定区但保留先前非人抗体的CDR的抗体。
本发明的人源化抗体可以通过以下来制备:如前所述获得编码CDR结构域的核酸序列,通过将它们插入用于动物细胞的表达载体来构建人源化抗体表达载体,所述动物细胞具有编码(i)与人抗体相同的重链恒定区和(ii)与人抗体相同的轻链恒定区的基因,和通过将表达载体引入动物细胞来表达基因。人源化抗体表达载体可以是以下任一类型:编码抗体重链的基因和编码抗体轻链的基因存在于不同的载体上,或两个基因存在于相同载体上(串联型)。就构建人源化抗体表达载体的容易性、引入动物细胞的容易性和动物细胞中抗体H链和L链的表达水平之间的平衡而言,优选串联型的人源化抗体表达载体。串联型人源化抗体表达载体的实例包括pKANTEX93(WO 97/10354)、pEE18等。基于常规重组DNA和基因转染技术产生人源化抗体的方法是本领域熟知的(参见例如,Riechmann L.等1988;Neuberger MS.等1985)。可以使用本领域已知的多种技术将抗体人源化,包括例如CDR-移植(EP 239,400;PCT公开WO91/09967;美国专利号5,225,539;5,530,101;和5,585,089)、镶饰(veneering)或表面重塑(resurfacing)(EP 592,106;EP 519,596;Padlan EA(1991);Studnicka GM等(1994);Roguska MA等(1994))和链替换(美国专利号5,565,332)。用于制备此类抗体的一般重组DNA技术也是已知的(参见欧洲专利申请EP 125023和国际专利申请WO 96/02576)。
在一个实施方案中,本发明的抗体是选自下组的抗原结合片段:Fab、F(ab)'2、单结构域抗体、ScFv、Sc(Fv)2、双抗体、三抗体、四抗体、单抗体(unibody)、微抗体、巨抗体、小型模块化免疫药物(SMIP)、作为分离的互补决定区(CDR)的由模拟抗体高变区的氨基酸残基组成的最小识别单元、和包含VL或VH链或由其组成的片段、以及与SEQ ID NO:1或SEQ IDNO:2具有至少70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99或100%同一性氨基酸序列。
在一些实施方案中,本发明的抗体是具有重链和轻链的抗体,所述重链包含i)14A5.2 mab的H-CDR1,ii)14A5.2 mab的H-CDR2和iii)14A5.2 mab的H-CDR3,所述轻链包含i)14A5.2 mab的L-CDR1,ii)14A5.2 mab的L-CDR2和iii)14A5.2 mab的L-CDR3。
在一些实施方案中,本发明的抗体是具有与SEQ ID NO:1具有至少70%同一性的重链和与SEQ ID NO:2具有至少70%同一性的轻链的抗体。
在一些实施方案中,本发明的抗体是具有与SEQ ID NO:1相同的重链和与SEQ IDNO:2相同的轻链的抗体。
在一些实施方案中,本发明的抗体是包含以下的抗体:
-重连,其包含i)与14A5.2 mab的H-CDR1具有至少90%同一性的H-CDR1,ii)与14A5.2 mab的H-CDR2具有至少90%同一性的H-CDR2,和iii)与14A5.2 mab的H-CDR3具有至少90%同一性的H-CDR3,和
-轻链,其包含i)与14A5.2 mab的L-CDR1具有至少90%同一性的L-CDR1,ii)与14A5.2 mab的L-CDR2具有至少90%同一性的L-CDR2,和iii)与14A5.2 mab的L-CDR3具有至少90%同一性的L-CDR3,
其中,
-14A5.2 mab的H-CDR1由SEQ ID NO:1中第31位氨基酸残基至第35位氨基酸残基的序列限定;
-14A5.2 mab的H-CDR2由SEQ ID NO:1中第50位氨基酸残基至第66位氨基酸残基的序列限定;
-14A5.2 mab的H-CDR3由SEQ ID NO:1中第99位氨基酸残基至第104位氨基酸残基的序列限定。
-14A5.2 mab的L-CDR1由SEQ ID NO:2中第24位氨基酸残基至第38位氨基酸残基的序列限定;
-14A5.2 mab的L-CDR2由SEQ ID NO:2中第54位氨基酸残基至第60位氨基酸残基的序列限定;
-14A5.2 mab的L-CDR3由SEQ ID NO:2中第93位氨基酸残基至第101位氨基酸残基的序列限定。
如本文所用,术语抗体的“抗原结合片段”是指完整抗体的一个或多个片段,其保留特异性结合给定抗原(例如nectin-4)的能力。抗体的抗原结合功能可以通过完整抗体的片段进行。术语抗体的抗原结合片段涵盖的结合片段的实例包括Fab片段,由VL、VH、CL和CH1结构域组成的单价片段;Fab'片段,由VL、VH、CL、CH1结构域和铰链区组成的单价片段;F(ab')2片段,包含通过铰链区的二硫键连接的两个Fab'片段的二价片段;由抗体单臂的VH结构域组成的Fd片段;单结构域抗体(sdAb)片段(Ward等,1989 Nature 341:544-546),其由VH结构域或VL结构域组成;和分离的互补决定区(CDR)。此外,虽然Fv片段的两个结构域VL和VH由不同的基因编码,但可以使用重组方法通过人工肽接头将它们连接,所述接头使得它们能够作为其中VL和VH区配对形成单价分子的单个蛋白质链制备(称为单链Fv(ScFv);参见例如Bird等,1989 Science 242:423-426;和Huston等,1988proc.Natl.Acad.Sci.85:5879-5883)。“dsFv”是通过二硫键稳定的VH::VL异二聚体。二价和多价抗体片段可以通过单价scFv的结合自发形成,或可以通过肽接头偶联单价scFv产生,例如二价sc(Fv)2。此类单链抗体包括一个或多个抗原结合部分或抗体片段。使用本领域技术人员已知的常规技术获得这些抗体片段,并以与完整抗体相同的方式筛选片段的效用。单抗体是另一种缺乏IgG4抗体铰链区的抗体片段。铰链区的缺失导致分子基本上是传统IgG4抗体的一半大小并且具有单价结合区而不是IgG4抗体的二价结合区。抗原结合片段可以整合入单结构域抗体、SMIP、巨抗体、微抗体、胞内抗体、双抗体、三抗体和四抗体中(参见,例如,Hollinger和Hudson,2005,Nature Biotechnology,23,9,1126-1136)。术语“双抗体”、“三抗体”或“四抗体”是指具有多价抗原结合位点(2、3或4)的小抗体片段,该片段包含在相同多肽链(VH-VL)中与轻链可变结构域(VL)连接的重链可变结构域(VH)。通过使用太短而不允许相同链上的两个结构域之间配对的接头,该结构域被迫与另一条链的互补结构域配对并产生两个抗原结合位点。抗原结合片段可以整合入包含一对串联的Fv区段(VH-CH1-VH-CH1)的单链分子中,所述串联的Fv区段与互补的轻链多肽一起形成一对抗原结合区(Zapata等,1995 Protein Eng.8(10);1057-1062和美国专利号5,641,870))。
本发明的Fab可以通过用蛋白酶(木瓜蛋白酶)处理与[抗原]特异性反应的抗体而获得。此外,可以通过以下来生产Fab:将编码抗体Fab的DNA插入用于原核表达系统或用于真核表达系统的载体,并将载体引入原核生物或真核生物(视情况而定)以表达Fab。
本发明的F(ab')2可以通过用蛋白酶(胃蛋白酶)处理与[抗原]特异性反应的抗体而获得。此外,F(ab')2可以通过用硫醚键或二硫键结合下述Fab'来制备。
本发明的Fab'可以通过用还原剂二硫苏糖醇处理与[抗原]特异性反应的F(ab')2而获得。此外,可以通过以下来生产Fab':将编码抗体的Fab'片段的DNA插入原核生物的表达载体或真核生物的表达载体中,并将载体引入原核生物或真核生物(视情况而定)以进行表达。
可以通过以下来生产本发明的scFv:获得如前所述编码VH和VL结构域的cDNA,构建编码scFv的DNA,将DNA插入原核生物的表达载体或真核生物的表达载体,然后将表达载体引入原核生物或真核生物(视情况而定)以表达scFv。为制备人源化scFv片段,可以使用称为CDR移植的公知技术,其涉及从供体scFv片段选择互补决定区(CDR),并将它们移植到已知三维结构的人scFv片段框架上(参见例如,WO98/45322、WO87/02671、US5,859,205、US5,585,089、US4,816,567、EP0173494)。
结构域抗体(dAb)是抗体的最小功能性结合单元-分子量约为13kDa-且对应于抗体的重链(VH)或轻链(VL)的可变区。结构域抗体及其制备方法的更多细节可发现于US 6,291,158;6,582,915;6,593,081;6,172,197和6,696,245;US 2004/0110941;EP 1433846,0368684和0616640;WO 2005/035572、2004/101790、2004/081026、2004/058821、2004/003019和2003/002609,其每一个通过引用整体并入本文。
单抗体是另一种基于去除IgG4抗体的铰链区的抗体片段技术。铰链区的缺失导致分子基本上是传统IgG4抗体的一半大小并且具有单价结合区而不是IgG4抗体的二价结合区。此外,由于单抗体较小,它们在较大实体瘤中显示更好的分布,具有潜在有利的功效。可以参考其全文通过引用并入本文的WO 2007/059782获得单抗体的更多细节。
核酸序列、载体和宿主细胞
因此,本发明的进一步目的涉及编码本发明抗体的核酸分子。更具体地,核酸分子编码本发明抗体的重链或轻链。
通常,所述核酸是DNA或RNA分子,其可以包含于任何合适的载体,例如质粒、粘粒、附加体、人工染色体、噬菌体或病毒载体。如本文所用,术语“载体”、“克隆载体”和“表达载体”是指可以将DNA或RNA序列(例如外源基因)引入宿主细胞,以转化宿主并促进引入序列的表达(例如转录和翻译)的介质。因此,本发明的另一个目的涉及包含本发明核酸的载体。此类载体可包含调控元件,例如启动子、增强子、终止子等,以在施用于受试者时引起或指导所述抗体的表达。用于动物细胞的表达载体的启动子和增强子的实例包括SV40的早期启动子和增强子(Mizukami T等1987)、Moloney小鼠白血病病毒的LTR启动子和增强子(Kuwana Y等1987)、免疫球蛋白H链的启动子(Mason JO等1985)和增强子(Gillies SD等1983)等。可以使用用于动物细胞的任何表达载体,只要可以插入并且表达编码人抗体C区的基因。合适载体的实例包括pAGE107(Miyaji H等1990)、pAGE103(Mizukami T等1987)、pHSG274(Brady G等1984)、pKCR(O'Hare K等1981)、pSG1βd2-4(Miyaji H等1990)等。质粒的其他实例包括含有复制起点的复制质粒,或整合质粒,例如pUC、pcDNA、pBR等。病毒载体的其他实例包括腺病毒、逆转录病毒、疱疹病毒和AAV载体。此类重组病毒可通过本领域已知的技术产生,例如通过转染包装细胞或通过用辅助质粒或病毒进行瞬时转染。病毒包装细胞的典型实例包括PA317细胞、PsiCRIP细胞、GPenv+细胞、293细胞等。用于产生这种复制缺陷型重组病毒的详细方案可以在例如WO 95/14785、WO 96/22378、US 5,882,877、US 6,013,516、US 4,861,719、US 5,278,056和WO 94/19478中找到。
本发明的进一步方面涉及通过根据本发明的核酸和/或载体转染、感染或转化的宿主细胞。
如本文所用,术语“转化”是指将“外源”(即外部或细胞外)基因、DNA或RNA序列引入宿主细胞,使得宿主细胞将表达引入的基因或序列以产生所需的物质,通常是由引入的基因或序列编码的蛋白质或酶。接受并表达引入的DNA或RNA的宿主细胞被“转化”。
本发明的核酸可用于在合适的表达系统中生产本发明的抗体。术语“表达系统”是指在合适条件下的宿主细胞和相容载体,例如,其用于表达由载体携带并引入宿主细胞的外源DNA编码的蛋白质。常见的表达系统包括大肠杆菌宿主细胞和质粒载体、昆虫宿主细胞和杆状病毒载体,以及哺乳动物宿主细胞和载体。宿主细胞的其他实例包括但不限于原核细胞(例如细菌)和真核细胞(例如酵母细胞、哺乳动物细胞、昆虫细胞、植物细胞等)。具体实例包括大肠杆菌、克鲁维酵母或酵母菌、哺乳动物细胞系(例如Vero细胞、CHO细胞、3T3细胞、COS细胞等)以及原代或已建立的哺乳动物细胞培养物(例如,由淋巴母细胞、成纤维细胞、胚胎细胞、上皮细胞、神经细胞、脂肪细胞等产生)。实例还包括小鼠SP2/0-Ag14细胞(ATCC CRL1581)、小鼠P3X63-Ag8.653细胞(ATCC CRL1580)、其中二氢叶酸还原酶基因(下文称为“DHFR基因”)有缺陷的CHO细胞(Urlaub G等;1980)、大鼠YB2/3HL.P2.G11.16Ag.20细胞(ATCC CRL1662,以下称为“YB2/0细胞”)等。本发明还涉及用于生产表达根据本发明的抗体的重组宿主细胞的方法,所述方法包括以下步骤:(i)将如上所述的重组核酸或载体体外或离体引入感受态宿主细胞,(ii)体外或离体培养获得的重组宿主细胞,和(iii)任选地,选择表达和/或分泌所述抗体的细胞。这些重组宿主细胞可用于生产本发明的抗体。
通过常规免疫球蛋白纯化方法,例如蛋白A-Sepharose、羟磷灰石层析、凝胶电泳、透析或亲和层析适当地从培养基分离本发明的抗体。
功能性变体
因此,本发明提供包含14A5.2 mab的VL区、VH区的功能性变体的抗体。在本发明单克隆抗体的上下文中,所用的VL或VH的功能性变体仍然允许抗体保留亲本抗体(即14A5.2mab)的至少相当大比例(至少约50%、60%、70%、80%、90%、95%或更多)的亲和力/亲合力和/或特异性/选择性,并且在某些情况下,本发明的这种单克隆抗体可能具有比亲本Ab更高的亲和力、选择性和/或特异性。这种变体可以通过多种亲和力成熟方案获得,包括突变CDR(Yang等,J.Mol.Biol.,254,392-403,1995)、链替换(Marks等,Bio/Technology,10,779-783,1992)、使用大肠杆菌的突变菌株(Low等,J.Mol.Biol.,250,359-368,1996)、DNA改组(Patten等,Curr.Opin.Biotechnol.,8,724-733,1997)、噬菌体展示(Thompson等,J.Mol.Biol.,256,77-88,1996)和有性PCR(Crameri等,Nature,391,288-291,1998)。Vaughan等(以上)讨论了这种亲和力成熟的方法。这种功能性变体通常保留显著的与亲本Ab的序列同一性。CDR变体的序列可能通过大多数保守性替换与亲本抗体序列的CDR序列不同,例如变体中至少约35%、约50%或更多、约60%或更多、约70%或更多、约75%或更多、约80%或更多、约85%或更多、约90%或更多(例如,约65%-95%,例如约92%、93%或94%)的替换是保守性氨基酸残基替代。CDR变体的序列可能通过大多数保守性替换与亲本抗体序列的CDR序列不同,例如变体中至少10个,例如至少9个、8个、7个、6个、5个、4个、3个、2个或1个替换是保守性氨基酸残基替代。在本发明上下文中,保守性替换可以定义为如下所反映的氨基酸类别内的替换:
脂族残基I、L、V和M。
环烯基相关残基F、H、W和Y。
疏水性残基A、C、F、G、H、I、L、M、R、T、V、W和Y。
带负电荷的残基D和E。
极性残基C、D、E、H、K、N、Q、R、S和T。
带正电荷的残基H、K和R。
小残基A、C、D、G、N、P、S、T和V。
非常小的残基A、G和S。
涉及转角的残基A、C、D、E、G、H、K、N,Q、R、S、P和涉及形成的残基T。
柔性残基Q、T、K、S、G、P、D、E和R。
更多的保守性替换分组包括:缬氨酸-亮氨酸-异亮氨酸、苯丙氨酸-酪氨酸、赖氨酸-精氨酸、丙氨酸-缬氨酸和天冬酰胺-谷氨酰胺。与[Ab名称]的CDR相比,变体CDR基本上保留了在亲水(hydropathic)/亲水性质和残基重量/大小方面的保守性。本领域通常理解亲水氨基酸指数在赋予蛋白质相互作用的生物学功能方面的重要性。已经接受的是,氨基酸的相对亲水特性有助于所得蛋白质的二级结构,这又限定了蛋白质与其他分子(例如酶、底物、受体、DNA、抗体、抗原等)的相互作用。根据它们的疏水性和电荷特征,为每种氨基酸指定了亲水指数,它们是:异亮氨酸(+4.5);缬氨酸(+4.2);亮氨酸(+3.8);苯丙氨酸(+2.8);半胱氨酸/胱氨酸(+2.5);蛋氨酸(+1.9);丙氨酸(+1.8);甘氨酸(-0.4);苏氨酸(-0.7);丝氨酸(-0.8);色氨酸(-0.9);酪氨酸(-1.3);脯氨酸(-1.6);组氨酸(-3.2);谷氨酸(-3.5);谷氨酰胺(-3.5);天冬氨酸(-3.5);天冬酰胺(-3.5);赖氨酸(-3.9)和精氨酸(-4.5)。类似残基的保留也可以或替代地通过相似性得分来测量,如使用BLAST程序来测定(例如,可通过NCBI获得的BLAST 2.2.8,使用标准设置BLOSUM62,Open Gap=11和ExtendedGap=1)。合适的变体通常表现出与亲本肽至少约70%的同一性。根据本发明,第一氨基酸序列与第二氨基酸序列具有至少70%同一性是指第一序列与第二氨基酸序列具有70;71;72;73;74;75;76;77;78;79;80;81;82;83;84;85;86;87;88;89;90;91;92;93;94;95;96;97;98;99或100%同一性。根据本发明,第一氨基酸序列与第二氨基酸序列具有至少90%同一性是指第一序列与第二氨基酸序列具有90;91;92;93;94;95;96;97;98;99或100%同一性。
在一些实施方案中,本发明的抗体是具有重链和轻链的抗体,所述重链包含i)14A5.2 mab的H-CDR1,ii)14A5.2 mab的H-CDR2和iii)14A5.2 mab的H-CDR3,所述轻链包含i)14A5.2 mab的L-CDR1,ii)14A5.2 mab的L-CDR2和iii)14A5.2 mab的L-CDR3。
在一些实施方案中,本发明的抗体是具有重链和轻链的抗体,所述重链与SEQ IDNO:1具有至少70;71;72;73;74;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,所述轻链与SEQ ID NO:2具有至少70;71;72;73;74;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。
在一些实施方案中,本发明的抗体是具有与SEQ ID NO:1相同的重链和与SEQ IDNO:2相同的轻链的抗体。
在一个具体的实施方案中,上述抗体与本发明抗体(即,具有SEQ ID NO:1和2的VH和VL的抗体)结合相同的抗原且具有相同的性质。
与本发明抗体竞争的抗体
在另一个方面,本发明提供与本发明抗体竞争结合Nectin-4的抗体。
如本文所用,在抗体结合预定抗原或表位的上下文中,术语“结合”通常是指当例如在BIAcore 3000仪器中通过表面等离子体共振(SPR)技术,使用可溶形式的抗原作为配体并且抗体作为分析物进行测定时,结合的亲和力对应于约10-7M或更低、例如约10-8M或更低、例如约10-9M或更低、约10-10M或更低,或约10-11M或甚至更低的KD。(GE Healthcare,Piscaataway,NJ)是多种表面等离子体共振测定形式之一,其常规用于单克隆抗体的表位区组。通常,抗体结合预定抗原的亲和力的KD比结合与预定抗原不相同也不紧密相关的非特异性抗原(例如BSA、酪蛋白)的KD低至少十倍、例如低至少100倍、例如低至少1,000倍、例如低至少10,000倍、例如低至少100,000倍。当抗体的KD非常低(即,抗体具有高亲和力)时,其结合抗原的KD通常比非特异性抗原的KD低至少10,000倍。如果这种结合是不可检测的(例如,在BIAcore 3000仪器中使用等离子体共振(SPR)技术,使用可溶形式的抗原作为配体并且抗体作为分析物),或这种结合比检测到的该抗体和具有不同化学结构或氨基酸序列的抗原或表位的结合低100倍、500倍、1000倍或1000倍以上,则称该抗体基本上不结合抗原或表位。
可以基于它们在标准Nectin-4结合测定中与本发明其他抗体的交叉竞争(例如,以统计学上显著的方式竞争性抑制结合)的能力来鉴定另外的抗体。测试抗体抑制本发明抗体与Nectin-4结合的能力表明测试抗体可以与该抗体竞争结合Nectin-4;根据非限制性理论,这种抗体可以与其竞争的抗体结合Nectin-4上相同或相关(例如,结构上相似或空间上接近)的表位。因此,本发明的另一方面提供与本文公开的抗体结合相同抗原并与之竞争的抗体。如本文所用,当在等摩尔浓度的竞争抗体存在下,竞争抗体抑制本发明的抗体或抗原结合片段与nectin-4的结合超过50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、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%时,则抗体“竞争”结合。
在其他实施方案中,本发明的抗体或抗原结合片段结合Nectin-4的一个或多个表位。在一些实施方案中,本发明抗体或抗原结合片段结合的表位是线性表位。在其他实施方案中,本发明抗体或抗原结合片段结合的表位是非线性构象表位。
可以通过本领域已知的任何方法测定本发明抗体的特异性结合。对于表位结合可使用许多不同的竞争性结合测定形式。可以使用的免疫测定包括但不限于使用诸如蛋白质印迹、放射免疫测定、ELISA、“夹心”免疫测定、免疫沉淀测定、沉淀素测定、凝胶扩散沉淀素测定、免疫放射测定、荧光免疫测定、蛋白质A免疫测定和补体固定测定等技术的竞争测定系统。此类测定是常规的并且是本领域熟知的(参见例如Ausubel等,eds,1994 CurrentProtocols in Molecular Biology,Vol.1,John Wiley&sons,Inc.,New York)。
抗体工程化
本发明的工程化抗体包括其中对VH和/或VL内的框架残基进行修饰,以例如改善抗体性质的抗体。通常,进行这样的框架修饰以降低抗体的免疫原性。例如,一种方法是将一个或多个框架残基“回复突变”到相应的种系序列。更具体地,已经历体细胞突变的抗体可以含有与衍生抗体的种系序列不同的框架残基。可以通过将抗体框架序列与衍生抗体的种系序列进行比较来鉴定这些残基。为了使框架区序列恢复其种系构型,可以通过例如定点诱变或PCR介导的诱变将体细胞突变“回复突变”至种系序列。这种“回复突变”抗体也涵盖在本发明中。另一种类型的框架修饰涉及突变框架区内或甚至一个或多个CDR区内的一个或多个残基,以去除T细胞表位,从而降低抗体的潜在免疫原性。该方法也称为“去免疫化”,并且在Carr等的美国专利公开号20030153043中进一步详细描述。
在一些实施方案中,修饰抗体的糖基化。例如,可以改变糖基化以在增加抗体对抗原的亲和力。这种碳水化合物修饰可以通过例如改变抗体序列内的一个或多个糖基化位点来实现。例如,可以进行一个或多个氨基酸替换,其导致消除一个或多个可变区框架糖基化位点,从而消除该位点的糖基化。这种糖基化可以增加抗体对抗原的亲和力。该方法在Carr等的美国专利号5,714,350和6,350,861中进一步详细描述。
在一些实施方案中,对位于第一CDR(CDR1)内及其附近的聚集“热点”中的氨基酸进行一些突变以降低抗体对聚集的易感性(参见Joseph M.Perchiacca et al.,Proteins2011;79:2637–2647)。
本发明的抗体可以是任何同种型。同种型的选择通常由期望的效应子功能来指导。IgG1和IgG3是介导例如ADCC或CDC的效应子功能的同种型,而IgG2和IgG4不介导或以较低的方式介导。可以使用人轻链恒定区中的任一个,κ或λ。如果需要,可以通过已知方法转换本发明的单克隆抗体的类别。通常,类别转换技术可用于将一个IgG亚类转换成另一个,例如从IgG1转变为IgG2。因此,为各种治疗用途,本发明单克隆抗体的效应子功能可以通过同种型转换为例如IgG1、IgG2、IgG3、IgG4、IgD、IgA、IgE或IgM抗体来改变。
在一些实施方案中,本发明的抗体是全长抗体。在一些实施方案中,全长抗体是IgG1抗体。在一些实施方案中,全长抗体是IgG3抗体。
在一些实施方案中,本发明的抗体是非IgG2/4类型的抗体,例如IgG1或IgG3,其被突变使得介导效应子功能(例如ADCC)的能力被降低或甚至被消除。这种突变已经描述于例如Dall'Acqua WF等,J Immunol.177(2):1129-1138(2006)和Hezareh M,J Virol.75(24):12161-12168(2001)。
在一些实施方案中,修饰CH1的铰链区从而改变(例如,增加或减少)铰链区中的半胱氨酸残基的数量。该方法在Bodmer等的美国专利号5,677,425中进一步描述。例如,改变CH1铰链区中的半胱氨酸残基的数量以促进轻链和重链的组装,或提高或降低抗体的稳定性。
在一些实施方案中,通过将至少一个氨基酸残基替换为不同的氨基酸残基来改变Fc区,从而改变抗体的效应子功能。例如,可用将一个或多个氨基酸替换为不同的氨基酸残基,使得抗体对效应子配体具有不同的亲和力,但保留亲本抗体的抗原结合能力。改变其亲和力的效应子配体可以是例如Fc受体或补体的C1组分。该方法在Winter等的美国专利号5,624,821和5,648,260中进一步详细描述。
在一些实施方案中,可以将选自氨基酸残基的一个或多个氨基酸替换为不同的氨基酸残基,使得抗体具有改变的C1q结合和/或降低的或消除的补体依赖性细胞毒性(CDC)。该方法在Idusogie等的美国专利号6,194,551中进一步详细描述。
在一些实施方案中,改变一个或多个氨基酸残基从而改变抗体固定补体的能力。该方法在Bodmer等的PCT公开WO94/29351中进一步详细描述。
在一些实施方案中,修饰Fc区以增加抗体介导抗体依赖性细胞毒性(ADCC)的能力和/或通过修饰一个或多个氨基酸增加抗体对Fc受体的亲和力。该方法在Presta的PCT公开WO 00/42072中进一步描述。此外,已经定位了人IgG1上对FcγRI、FcγRII、FcγRIII和FcRn的结合位点,并且已经描述了具有改进结合的变体(参见R.L.等,2001J.Biol.Chen.276:6591-6604,WO2010106180)。
术语“抗体依赖性细胞介导的细胞毒性”或“ADCC”是本领域熟知的术语,是指细胞介导的以下反应:表达Fc受体(FcR)的非特异性细胞毒性细胞识别靶细胞上结合的抗体,并随后引起靶细胞裂解。介导ADCC的非特异性细胞毒性细胞包括自然杀伤(NK)细胞、巨噬细胞、单核细胞、嗜中性粒细胞和嗜酸性粒细胞。
“效应子功能”是指可归因于抗体Fc区的那些生物活性,其随抗体同种型而变化。抗体效应子功能的实例包括:C1q结合和补体依赖性细胞毒性(CDC);Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬;细胞表面受体(例如B细胞受体)下调和B细胞激活。
另外或可替代地,可以制备具有改变的糖基化类型的抗体,例如具有减少量的岩藻糖基残基或不具有岩藻糖基残基的低岩藻糖基化或非岩藻糖基化抗体,或具有增加的二等分GlcNac结构的抗体。已经证明这种改变的糖基化模式增加抗体的ADCC能力。这种碳水化合物修饰可以通过例如在具有改变的糖基化机制的宿主细胞中表达抗体来实现。具有改变的糖基化机制的细胞已在本领域中描述,并且可用作其中表达本发明的重组抗体的宿主细胞,从而产生具有改变的糖基化的抗体。例如Hang等的EP1,176,195描述了具有功能性破坏的FUT8基因(其编码岩藻糖基转移酶)的细胞系,使得在这种细胞系中表达的抗体表现出低岩藻糖基化或缺乏岩藻糖基残基。因此,在一些实施方案中,本发明的单克隆抗体可以通过在表现出低岩藻糖基化或非岩藻糖基化模式的细胞系(例如,编码岩藻糖基转移酶的FUT8基因表达缺陷的哺乳动物细胞系)中重组表达来产生。Presta的PCT公开WO 03/035835描述了变体CHO细胞系(Lecl3细胞),其将岩藻糖连接至与Asn(297)连接的碳水化合物的能力降低,还导致在该宿主细胞中表达的抗体的低岩藻糖基化(参见Shields,R.L.等,2002J.Biol.Chem.277:26733-26740)。Umana等的PCT公开WO 99/54342描述了工程化以表达糖蛋白修饰的糖基转移酶(例如,β(1,4)-N乙酰葡糖胺基转移酶III(GnTIII))的细胞系,使得在该工程化细胞系中表达的抗体表现出增加的二等分GlcNac结构,其导致抗体的ADCC活性增加(也参见Umana等,1999 Nat.Biotech.17:176-180)。Eureka Therapeutics进一步描述了基因工程化CHO哺乳动物细胞,其能够产生不含岩藻糖残基的具有改变的哺乳动物糖基化模式的抗体(http://www.eurekainc.com/a&boutus/companyoverview.html)。或者,本发明的单克隆抗体可以在工程化用于哺乳动物样糖基化模式且能够产生缺乏岩藻糖作为糖基化模式的抗体的酵母或丝状真菌中产生(参见例如EP1297172B1)。
在另一个实施方案中,修饰抗体以增加其生物半衰期。各种方法都是可能的。例如,如Ward的美国专利No.6,277,375中所述,可以引入一种或多种下列突变:T252L、T254S、T256F。或者,为了增加生物半衰期,如Presta等的美国专利号5,869,046和6,121,022所述,可以改变抗体的CH1或CL区,以包含取自IgG的Fc区的CH2结构域的两个环的补救受体结合表位。US2005/0014934A1(Hinton等)描述了具有增加的半衰期和改进的与新生儿Fc受体(FcRn,负责将母体IgG转移至胎儿)的结合的抗体(Guyer等,J.Immunol.117:587(1976)和Kim等,J.immunol.24:249(1994))。那些抗体包含具有一个或多个替换的Fc区,所述替换改进Fc区与FcRn的结合。此类Fc变体包括在一个或多个Fc区残基处具有替换的那些:238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434,例如,Fc区残基434的替换(美国专利号7,371,826)。
本发明预期的本发明抗体的另一种修饰是聚乙二醇化。可以将抗体聚乙二醇化以例如增加抗体的生物(例如血清)半衰期。为了使抗体聚乙二醇化,通常在其中一个或多个PEG基团与抗体或抗体片段连接的条件下,将抗体或其片段与聚乙二醇(PEG),例如PEG的反应性酯或醛衍生物反应。聚乙二醇化可以通过与反应性PEG分子(或类似的反应性水溶性聚合物)的酰化反应或烷基化反应来进行。如本文所用,术语“聚乙二醇”旨在涵盖用于衍生其他蛋白质的PEG的任何形式,例如单(C1-C10)烷氧基-或芳氧基-聚乙二醇或聚乙二醇-马来酰亚胺。在一些实施方案中,待聚乙二醇化的抗体是无糖基化的抗体。使蛋白质聚乙二醇化的方法是本领域已知的,并且可以应用于本发明的抗体。参见例如Nishimura等的EP0154316和Ishikawa等的EP0401384。
本发明预期的抗体的另一种修饰是将至少本发明抗体的抗原结合区与血清蛋白(例如人血清白蛋白)或其片段偶联或蛋白融合,以增加所得分子的半衰期。例如Balance等的EP0322094描述了这种方法。另一种可能性是将至少本发明抗体的抗原结合区与能够结合血清蛋白(例如人血清白蛋白)的蛋白质融合,以增加所得分子的半衰期。如Nygren等的EP0486525描述了这种方法。
聚唾液酸化是另一种技术,它使用天然聚合物聚唾液酸(PSA)来延长治疗性肽和蛋白质的活性寿命并提高稳定性。PSA是唾液酸(糖)的聚合物。当用于递送蛋白质和治疗性肽药物时,聚唾液酸在偶联时提供保护性微环境。这增加了治疗性蛋白质在循环中的活性寿命,并防止其被免疫系统识别。PSA聚合物天然存在于人体中。它被某些细菌所采用,这些细菌已经进化了数百万年以用它来涂覆它们的细胞壁。然后,这些天然的聚唾液酸化细菌凭借分子模拟能够阻止身体的防御系统。PSA,大自然的终极秘密技术,可以很容易地从这些细菌中大量生产并具有预定的物理特性。即使与蛋白质偶联,细菌PSA也是完全无免疫原性的,因为它在化学上与人体中的PSA相同。
另一种技术包括使用与抗体连接的羟乙基淀粉(“HES”)衍生物。HES是一种来自蜡质玉米淀粉的改性天然聚合物,可以通过机体的酶代谢。通常施用HES溶液以替代不足的血液体积并改进血液的流变学特性。抗体的羟乙基化能够通过增加分子的稳定性以及通过降低肾清除率来延长循环半衰期,从而导致生物活性增加。通过改变不同的参数,例如HES的分子量,可以定制多种HES抗体偶联物。
在另一个实施方案中,突变抗体的Fc铰链区以降低抗体的生物半衰期。更具体地,将一个或多个氨基酸突变引入Fc-铰链片段的CH2-CH3结构域界面区,使得抗体相对于天然Fc-铰链结构域的SpA结合具有受损的葡萄球菌蛋白A(SpA)结合。该方法在Ward等的美国专利号6,165,745中进一步详细描述。
在本发明的某些实施方案中,已经将抗体工程化以除去脱酰胺作用的位点。已知脱酰胺作用导致肽或蛋白质的结构和功能变化。脱酰胺作用可导致生物活性降低,以及蛋白质药物的药代动力学和抗原性的改变(Anal Chem.2005 Mar 1;77(5):1432-9)。
在本发明的某些实施方案中,已经将抗体工程化以增加pI并改进其药物样特性。蛋白质的pI是分子整体生物物理特性的关键决定因素。已知具有低pI的抗体溶解性较差、稳定性较差且易于聚集。此外,纯化具有低pI的抗体是具有挑战性的,并且尤其在用于临床使用的放大期间可能是有问题的。增加本发明抗Nectin-4抗体或其片段的pI改进它们的溶解度,使得抗体能够以更高的浓度(>100mg/ml)配制。高浓度(例如>100mg/ml)的抗体的配制提供了能够通过玻璃体内注射向患者的眼睛施用更高剂量的抗体的优点,这反过来可以减少给药频率,这是治疗慢性病包括心血管疾病的重要优点。更高的pI还可以增加IgG形式抗体的FcRn介导的再循环,从而使药物在体内持续更长的持续时间,需要更少的注射。最后,由于更高的pI导致更长的保质期和体内生物活性,抗体的总体稳定性显著提高。优选地,pI大于或等于8.2。
糖基化修饰还可通过添加唾液酸化聚糖诱导抗体的增强的抗炎特性。向Fc聚糖中添加末端唾液酸可降低FcγR结合,并通过获得新的结合活性将IgG抗体转化为抗炎介质(参见Robert M.Anthony等,J Clin Immunol(2010)30(Suppl 1):S9–S14;Kai-Ting C等,Antibodies 2013,2,392-414)。
抗体模拟物
在一些实施方案中,所公开的重链和轻链、可变区结构域和CDR可用于制备含有可以特异性结合Nectin-4的抗原结合区的多肽。例如,可以将14A5.2 mab的CDR共价或非共价地整合入分子(例如多肽)以制备免疫粘附物。免疫粘附物可以将CDR作为较大多肽链的一部分整合,可以将CDR共价连接至另一条多肽链,或者可以非共价地整合CDR。CDR使得免疫粘附物能够特异性结合特定的目标抗原(例如,nectin-4或其表位)。
术语“多肽”和“蛋白质”在本文中可互换使用,是指氨基酸残基的聚合物。该术语适用于其中一个或多个氨基酸残基是相应天然存在的氨基酸的人工化学模拟物的氨基酸聚合物,以及天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。除非另有说明,否则特定多肽序列也隐含地包括其保守修饰变体。
在一些实施方案中,将本发明的抗原结合片段移植到选自以下的基于非免疫球蛋白的抗体(也称为抗体模拟物)中:affibody、affilin、affitin、adnectin、atrimer、evasin、DARPin、anticalin、avimer、fynomer和versabody。
术语“抗体模拟物”意指能够模拟抗体结合抗原的能力,但不限于天然抗体结构的分子。此类抗体模拟物的实例包括但不限于Adnectin、Affibody、DARPin、Anticalin、Avimer和versabody,它们都采用结合结构,虽然它们模拟传统的抗体结合,但是通过不同的机制产生并起作用。可以基于诸如纤连蛋白III型(Fn3)的多肽将抗体的抗原结合片段移植到支架中(参见美国专利号6,703,199,其描述了纤连蛋白多肽单体)。Affibody在本领域中是公知的,并且是指基于58个氨基酸残基的蛋白质结构域的亲和蛋白质,其衍生自葡萄球菌蛋白质A的IgG结合结构域之一。DARPin(设计的锚蛋白重复蛋白质)是本领域熟知的,并且是指为利用非抗体蛋白的结合能力而开发的抗体模拟DRP(设计的重复蛋白)技术。Anticalin是本领域熟知的并且是指另一种抗体模拟技术,其中结合特异性来自脂笼蛋白。Anticalin也可以是双靶向蛋白(称为Duocalin)的形式。Avimer是本领域熟知的并且是指另一种抗体模拟技术,Avimer衍生自含有天然A结构域的蛋白质。Versabody在是本领域熟知的并且是指另一种抗体模拟技术,它们是具有>15%半胱氨酸的3-5kDa的小蛋白质,其形成高密度二硫键支架,代替典型蛋白质具有的疏水核心。这种抗体模拟物可以包含在支架中。术语“支架”是指具有定制功能和特征的用于工程化新产品的多肽平台。
在一个方面,本发明涉及使用其上可以移植本发明CDR的非免疫球蛋白支架产生基于非免疫球蛋白的抗体(也称为抗体模拟物)。可以使用已知的或未来的非免疫球蛋白框架和支架,只要它们包含对靶蛋白Nectin-4具有特异性的结合区。
纤连蛋白支架基于纤连蛋白III型结构域(例如,III型纤连蛋白的第10个模块(10Fn3结构域))。纤连蛋白III型结构域具有分布在两个β折叠之间的7或8个β链,其本身彼此包裹以形成蛋白质的核心,还包含将β链彼此连接的环(类似于CDR),并且是溶剂暴露的。在β折叠夹层的每个边缘处存在至少三个这样的环,其中边缘是垂直于β链方向的蛋白质的边界(参见US 6,818,418)。这些基于纤连蛋白的支架不是免疫球蛋白,尽管总体折叠与包含骆驼和美洲驼IgG的完整抗原识别单元的最小功能性抗体片段(重链可变区)密切相关。由于这种结构,非免疫球蛋白抗体模拟抗原结合特性,其性质和亲和力与抗体相似。这些支架可用于体外的环随机化和改组策略,其类似于体内的抗体亲和力成熟的过程。这些基于纤连蛋白的分子可以用作支架,其中可以使用标准克隆技术将分子的环区替换为本发明的CDR。
Ankyrin技术基于使用具有Ankyrin衍生的重复模块的蛋白质作为携带可以用于结合不同靶标的可变区的支架。Ankyrin重复模块是33个氨基酸的多肽,由两个反向平行的α-螺旋和β-转角组成。可变区的结合主要通过使用核糖体展示来优化。
Avimer衍生自含有天然A结构域的蛋白质,例如LRP-1。这些结构域本质上用于蛋白质-蛋白质相互作用,并且在人类中超过250种蛋白质在结构上基于通过氨基酸接头连接的“A-结构域”单体(2-10)。可以使用例如美国专利申请公开号20040175756;20050053973;20050048512和20060008844中描述的方法产生可以结合靶标抗原的Avimer。
Affibody亲和配体是小而简单的蛋白质,由基于蛋白A的IgG结合结构域之一的支架的三螺旋束组成。蛋白A是来自金黄色葡萄球菌(Staphylococcus aureus)的表面蛋白。该支架结构域由58个氨基酸组成,其中13个被随机化以产生具有大量配体变体的affibody文库(参见例如US 5,831,012)。Affibody分子模拟抗体,它们的分子量为6kDa。尽管其尺寸小,但是affibody分子的结合位点与抗体的结合位点相似。
Anticalin是由Pieris ProteoLab AG公司开发的产品。它们衍生自脂笼蛋白,脂笼蛋白是一种广泛的小而强大的蛋白质,通常参与化学敏感的或不溶的化合物的生理运输或储存。人组织或体液中存在几种天然脂笼蛋白。蛋白质结构让人想起免疫球蛋白,在刚性框架之上具有高变环。然而,与抗体或其重组片段相反,脂笼蛋白由具有160-180个氨基酸残基的多肽单链组成,仅略微大于单个免疫球蛋白结构域。构成结合口袋的四个环组显示出明显的结构可塑性并且容许各种侧链。因此,结合位点可以在专有过程中重新成形,以便以高亲和力和特异性识别不同形状的规定的靶标分子。脂笼蛋白家族的一种蛋白质,大菜粉蝶(Pieris Brassicae)的bilin结合蛋白(BBP)已被用于通过诱变四个环组来开发anticalin。描述anticalin的专利申请的一个实例是PCT公开号WO 199916873。
Affilin分子是小的非免疫球蛋白蛋白质,其被设计用于针对蛋白质和小分子的特异性亲和力。可以从两个文库非常快速地选择新的affilin分子,每个文库基于不同的人源支架蛋白。Affilin分子与免疫球蛋白蛋白质没有任何结构同源性。目前,使用两种affilin支架,其中一种是γ晶体(一种人结构性眼晶状体蛋白质),另一种是“泛素”超家族蛋白质。两种人支架都非常小,显示出高温稳定性并且几乎抵抗pH变化和变性剂。这种高稳定性主要是由于蛋白质的β折叠结构扩大。“泛素样”蛋白的实例描述于WO2004106368。
Versabody具有高度可溶性,可配制成高浓度。Versabody具有极佳的热稳定性,可提供延长的保质期。关于Versabody的其他信息可以在US 2007/0191272中找到,其通过引用整体并入本文。
以上对抗体片段和模拟技术的描述并不全面。多种其他技术,包括基于替代的基于多肽的技术(例如Qui等,Nature Biotechnology,25(8)921-929(2007)中概述的互补决定区的融合)以及基于核酸的技术(例如US 5,789,157;5864026;5712375;5763566;6013443;6376474;6613526;6114120;6261774和6,387,620中描述的RNA适配子技术,所有这些都通过引用结合到本文中)可以用于本发明的上下文中。
CAR-T细胞
本发明还提供了嵌合抗原受体(CAR),其包含本发明抗体的抗原结合结构域。通常,所述嵌合抗原受体包含本发明抗体的至少一个VH和/或VL序列。本发明的嵌合抗原受体还包含细胞外铰链结构域、跨膜结构域和细胞内T细胞信号传导结构域。
如本文所用,术语“嵌合抗原受体”或“CAR”具有其在本领域中的一般含义,是指人工构建的杂合蛋白或多肽,其含有与T细胞信号传导结构域连接的抗体(例如,scFv)的抗原结合结构域。CAR的特征包括利用单克隆抗体的抗原结合特性,以非MHC限制性方式将T细胞特异性和反应性重新定向到选定靶标的能力。非MHC限制性抗原识别为表达CAR的T细胞提供不依赖于抗原加工而识别抗原的能力,从而绕过肿瘤逃逸的主要机制。此外,当在T细胞中表达时,CAR有利地不与内源性T细胞受体(TCR)α和β链二聚化。
在一些实施方案中,本发明提供了包含抗原结合结构域的CAR,所述抗原结合结构域包含14A5.2 mab的单链可变片段(scFv),或由其组成或基本上由其组成。在一些实施方案中,抗原结合结构域包含接头肽。接头肽可位于轻链可变区和重链可变区之间。
在一些实施方案中,CAR包含细胞外铰链结构域、跨膜结构域和选自CD28、4-1BB和CD3ζ细胞内结构域的细胞内T细胞信号传导结构域。CD28是T细胞共刺激中重要的T细胞标志物。4-1BB向T细胞传递有效的共刺激信号,促进T淋巴细胞的分化并增强其长期存活。CD3ζ与TCR结合产生信号,并含有基于免疫受体酪氨酸的活化基序(ITAM)。
在一些实施方案中,本发明的嵌合抗原受体可以是糖基化的、酰胺化的、羧化的、磷酸化的、酯化的、N-酰化的、通过例如二硫桥环化的,或转化成酸加成盐和/或任选地二聚化或聚合。
本发明还提供编码本发明的嵌合抗原受体的核酸。在一些实施方案中,如上所述将核酸整合入载体。
本发明还提供了宿主细胞,其包含编码本发明的嵌合抗原受体的核酸。尽管宿主细胞可以是任何细胞类型,可以源自任何类型的组织,并且可以是任何发育阶段,宿主细胞是例如从外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)中分离的T细胞。在一些实施方案中,T细胞可以是任何T细胞,例如培养的T细胞,例如原代T细胞,或来自培养的T细胞系的T细胞,例如Jurkat、SupT1等,或从哺乳动物获得的T细胞。如果从哺乳动物获得,T细胞可以从许多来源获得,包括但不限于血液、骨髓、淋巴结、胸腺或其他组织或液体。也可以富集或纯化T细胞。T细胞可以是任何类型的T细胞,并且可以是任何发育阶段,包括但不限于CD4+/CD8+双阳性T细胞、CD4+辅助T细胞例如Th2细胞、CD8+T细胞(例如细胞毒性T细胞)、肿瘤浸润细胞、记忆T细胞、初始T细胞等。T细胞可以是CD8+T细胞或CD4+T细胞。
根据已知技术或基于本公开内容对本领域技术人员显而易见的其变体,如上所述制备的那些T细胞群可用于的过继性免疫疗法的方法和组合物。参见例如,Gruenberg等的美国专利申请公开号2003/0170238;还参见Rosenberg的美国专利号4,690,915。癌症的过继性免疫疗法是指其中向携带肿瘤的宿主施用具有抗肿瘤反应性的免疫细胞的治疗方法,目的是细胞直接或间接介导已形成的肿瘤的消退。淋巴细胞,特别是T淋巴细胞的输注属于这一类。目前,大多数过继性免疫疗法是使用患者自身免疫细胞进行治疗的自体淋巴细胞疗法(ALT)。这些疗法涉及处理患者自身的淋巴细胞,以增强免疫细胞介导的反应或识别机体内的特定抗原或外来物质,包括癌细胞。通过移除患者的淋巴细胞并将这些细胞体外暴露于生物制剂和药物以激活细胞的免疫功能来完成治疗。一旦自体细胞被激活,将这些离体的活化细胞重新输入患者体内以增强免疫系统,从而治疗癌症。在一些实施方案中,通过首先从其培养基中收获细胞,然后将细胞洗涤并以治疗有效量浓缩在适于施用的介质和容器系统(“药学上可接受的”载体)中来配制细胞。合适的输注介质可以是任何等渗介质制剂,通常是生理盐水、Normosol R(Abbott)或Plasma-Lyte A(Baxter),但也可以使用5%葡萄糖水溶液或林格氏乳酸盐。输注介质可以补充有人血清白蛋白。组合物中细胞的治疗有效量取决于具有所需特异性的T细胞的相对代表性、接受者的年龄和体重、靶向病症的严重程度和靶向Ag的免疫原性。这些细胞量可低至约103/kg,优选5×103/kg;高达107/kg,优选108/kg。细胞数量将取决于组合物的最终用途,其中包含的细胞类型也是如此。例如,如果需要对特定Ag具有特异性的细胞,那么该群体将含有大于70%,通常大于80%、85%和90-95%的此类细胞。对于本文提供的用途,细胞的体积通常为1升或更小,可以是500ml或更少,甚至250ml或100ml或更少。临床相关数量的免疫细胞可以分摊到累积等于或超过所需细胞总量的多次输注中。
具体地,本发明的细胞特别适用于治疗癌症。因此,本发明的另一个目的涉及治疗有需要的受试者中的癌症的方法,包括向受试者施用治疗有效量的本发明的细胞群。
多特异性抗体
在一些实施方案中,本发明提供多特异性抗体,其包含来自上文所述的本发明分子的抗体的第一抗原结合位点和至少一个第二抗原结合位点。
在一些实施方案中,第二抗原结合位点用于募集杀伤机制,例如通过结合人效应子细胞上的抗原作为BiTE(双特异性T细胞接合者)抗体(其是针对靶抗原的双特异性scFv2)和US7235641中描述的T细胞上的CD3,或通过结合细胞毒剂或第二治疗剂。如本文所用,术语“效应子细胞”是指免疫细胞,其参与免疫应答的效应子阶段(与免疫应答的认知和激活阶段相反)。示例性免疫细胞包括髓样或淋巴来源细胞,例如淋巴细胞(例如B细胞和T细胞,包括细胞溶解性T细胞(CTL))、杀伤细胞、天然杀伤细胞、巨噬细胞、单核细胞、肥大细胞和粒细胞,例如中性粒细胞、嗜酸性粒细胞和嗜碱性粒细胞。一些效应子细胞表达特异性Fc受体(FcR)并执行特异性免疫功能。在一些实施方案中,效应子细胞能够诱导ADCC,例如天然杀伤细胞。例如,表达FcR的单核细胞、巨噬细胞参与靶细胞的特异性杀伤并将抗原呈递给免疫系统的其他组分。在一些实施方案中,效应子细胞可以吞噬靶抗原或靶细胞。效应子细胞上特定FcR的表达可以通过体液因子如细胞因子来调节。效应子细胞可以吞噬靶抗原或吞噬或裂解靶细胞。合适的细胞毒剂和第二治疗剂在下面举例说明,包括毒素(如放射性标记的肽)、化疗剂和前药。
在一些实施方案中,第二抗原结合位点结合人B细胞上的抗原,例如CD19、CD20、CD21、CD22、CD23、CD46、CD80、CD138和HLA-DR。
在一些实施方案中,第二抗原结合位点结合组织特异性抗原,促进双特异性抗体定位于特定组织。
在一些实施方案中,第二抗原结合位点结合位于与表达Nectin-4的细胞相同类型的细胞上的抗原,通常是肿瘤相关抗原(TAA),但具有不同于第一抗原结合位点的结合特异性。此类多特异性或双特异性抗体可增强肿瘤细胞结合的特异性和/或参与多种效应子途径。示例性TAA包括癌胚抗原(CEA)、前列腺特异性抗原(PSA)、RAGE(肾抗原)、甲胎蛋白、CAMEL(黑素瘤上CTL识别的抗原)、CT抗原(如MAGE-B5、-B6、-C2、-C3和D;Mage-12;CT10;NY-ESO-1、SSX-2、GAGE、BAGE、MAGE和SAGE)、粘蛋白抗原(如MUC1、粘蛋白-CA125等)、神经节苷脂抗原、酪氨酸酶、gp75、c-Met、Marti、MelanA、MUM-1、MUM-2、MUM-3、HLA-B7、Ep-CAM或癌相关整联蛋白,如α5β3整联蛋白。或者,第二抗原结合位点结合[抗原]的不同表位。或者,第二抗原结合位点可结合血管生成因子或其他癌症相关生长因子,例如血管内皮生长因子、成纤维细胞生长因子、表皮生长因子、血管生成素或任何这些的受体,特别是与癌症进展相关的受体。
在一些实施方案中,第二抗原结合位点来自本发明的第二抗体或ADC,例如本发明的抗体。
本发明的多特异性抗体分子的示例性形式包括但不限于(i)通过化学异源偶联交联的两种抗体,一种对[抗原]具有特异性,另一种对第二抗原具有特异性;(ii)包含两个不同抗原结合区的单个抗体;(iii)单链抗体,其包含两个不同的抗原结合区,例如通过额外的肽接头串联连接的两个scFv;(iv)双可变结构域抗体(DVD-Ig),其中每条轻链和重链包含通过短肽键串联的两个可变结构域(Wu等,Generation and Characterization of aDual Variable Domain Immunoglobulin(DVD-IgTM)Molecule,In:Antibody Engineering,Springer Berlin Heidelberg(2010));(v)化学连接的双特异性(Fab')2片段;(vi)Tandab,其是两个单链双抗体的融合物,产生对于每种靶抗原具有两个结合位点的四价双特异性抗体;(vii)flexibody,它是scFv与双抗体的组合,产生多价分子;(viii)一种所谓的“对接和锁定”分子,基于蛋白激酶A中的“二聚化和对接结构域”,当应用于Fab时,其可以产生由与不同Fab片段连接的两个相同Fab片段组成的三价双特异性结合蛋白;(ix)所谓的Scorpion分子,其包含例如与人Fab臂的两个末端融合的两个scFv;和(x)双抗体。双特异性抗体的另一种示例性形式是具有互补CH3结构域以强制异二聚化的IgG样分子。这些分子可以使用已知技术制备,例如称为Triomab/Quadroma(Trion Pharma/Fresenius Biotech)、Knob-into-Hole(Genentech)、CrossMAb(Roche)和静电匹配(Amgen)、LUZ-Y(Genentech)、链交换工程域体(SEEDbody)(EMD Serono)、Biclonic(Merus)和DuoBody(Genmab A/S)的技术。
在一些实施方案中,通过受控的Fab臂交换获得或可获得双特异性抗体,通常使用DuoBody技术。WO2008119353和WO2011111717(都是Genmab A/S)已经描述了通过受控的Fab臂交换产生双特异性抗体的体外方法。在WO 2008119353中描述的一种示例性方法中,在还原条件下孵育时,通过两种均包含IgG4样CH3区域的单特异性抗体之间的“Fab-臂”或“半分子”交换(交换重链和连接的轻链)形成双特异性抗体。所得产物是具有两个Fab臂的双特异性抗体,所述Fab臂可包含不同的序列。在WO 2011131746中描述的另一个示例性方法中,通过包括以下步骤的方法制备本发明的双特异性抗体,其中第一和第二抗体中的至少一种是本发明的抗体:a)提供包含免疫球蛋白的Fc区的第一抗体,所述Fc区包含第一CH3区;b)提供包含免疫球蛋白的Fc区的第二抗体,所述Fc区包含第二CH3区;其中所述第一和第二CH3区的序列不同,并且使得所述第一和第二CH3区之间的异源二聚体相互作用强于所述第一和第二CH3区的每个同源二聚体相互作用;c)在还原条件下将所述第一抗体与所述第二抗体一起孵育;和d)获得所述双特异性抗体,其中所述第一抗体是本发明的抗体,所述第二抗体具有不同的结合特异性,反之亦然。还原条件可以例如通过添加例如选自2-巯基乙胺、二硫苏糖醇和三(2-羧乙基)膦的还原剂来提供。步骤d)可以进一步包括将条件恢复为非还原或较少还原,例如通过去除还原剂,例如通过脱盐。优选地,第一和第二CH3区的序列不同,仅包含少数相当保守的不对称突变,使得所述第一和第二CH3区之间的异源二聚体相互作用强于所述第一和第二CH3区的每个同源二聚体相互作用。关于这些相互作用及其如何实现它们的更多细节在WO 2011131746中提供,其通过引用整体并入本文。以下是这种不对称突变的组合的示例性实施方案,任选地其中一个或两个Fc区是IgG1同种型。
在一些实施方案中,第一Fc区在选自以下的位置处具有氨基酸取代:366、368、370、399、405、407和409,并且第二Fc区在选自以下的位置处具有氨基酸取代:366、368、370、399、405、407和409,并且其中第一和第二Fc区的取代不在相同位置。
在一些实施方案中,第一Fc区在第405位具有氨基酸取代,并且所述第二Fc区在选自以下的位置处具有氨基酸取代:366、368、370、399、407和409,任选地409。
在一些实施方案中,第一Fc区在第409位具有氨基酸取代,并且所述第二Fc区在选自以下的位置处具有氨基酸取代:366、368、370、399、405和407,任选地405或368。
在一些实施方案中,第一和第二Fc区都是IgG1同种型,第一Fc区在第405位具有Leu,第二Fc区在第409位具有Arg。
免疫偶联物
可以将本发明的抗体与可检测标记偶联以形成抗Nectin-4免疫偶联物。合适的可检测标记包括,例如放射性同位素、荧光标记、化学发光标记、酶标记、生物发光标记或胶体金。制备和检测这种可检测标记的免疫偶联物的方法是本领域普通技术人员所熟知的,并在下面更详细地描述。可检测标记可以是通过放射自显影检测的放射性同位素。对本发明目的特别有用的同位素是3H、125I、131I、35S和14C。
可以用荧光化合物标记抗Nectin-4免疫偶联物。通过将免疫偶联物暴露于适当波长的光并检测所得荧光来确定荧光标记的抗体的存在。荧光标记化合物包括异硫氰酸荧光素、罗丹明、藻红蛋白、藻蓝蛋白、别藻蓝蛋白、邻苯二甲醛和荧光胺。
或者,可以通过将抗体与化学发光化合物偶联来可检测地标记抗Nectin-4免疫偶联物。通过检测在化学反应过程中产生的发光的存在来确定化学发光标记的免疫偶联物的存在。化学发光标记化合物的实例包括鲁米诺、异鲁米诺、芳族吖啶酯、咪唑、吖啶盐和草酸酯。
类似地,可以使用生物发光化合物来标记本发明的抗nectin-4免疫偶联物。生物发光是在生物系统中发现的一种化学发光,其中催化蛋白质提高化学发光反应的效率。通过检测发光的存在来确定生物发光蛋白的存在。可用于标记的生物发光化合物包括荧光素、荧光素酶和水母发光蛋白。
或者,可以通过将抗[抗原]的抗体与酶连接来可检测地标记抗Nectin-4免疫偶联物。当在合适的底物存在下孵育抗Nectin-4-酶偶联物时,酶部分与底物反应产生化学部分,其可以例如通过分光光度、荧光或视觉方法检测。可用于可检测地标记多特异性免疫偶联物的酶的实例包括β-半乳糖苷酶、葡萄糖氧化酶、过氧化物酶和碱性磷酸酶。
本领域技术人员将知道可以根据本发明使用的其他合适的标记。标志物部分与抗Nectin-4单克隆抗体的结合可以使用本领域已知的标准技术完成。这方面的典型方法描述于Kennedy等,Clin.Chim.Acta 70:1,1976;Schurs等,Clin.Chim.Acta 81:1,1977;Shih等,Int'l J.Cancer 46:1101,1990;Stein等,Cancer Res.50:1330,1990和Coligan,supra。
此外,通过使用与抗生物素蛋白、链霉亲和生物素偶联的抗Nectin-4单克隆抗体,可以增强免疫化学检测的便利性和多样性(参见例如Wilchek等(eds.),“Avidin-BiotinTechnology,”Methods In Enzymology(Vol.184)(Academic Press 1990);Bayer等,“Immunochemical Applications of Avidin-Biotin Technology,”in Methods InMolecular Biology(Vol.10)149-162(Manson,ed.,The Humana Press,Inc.1992))。
进行免疫测定的方法是公认的(参见例如Cook and Self,“MonoclonalAntibodies in Diagnostic Immunoassays,”in Monoclonal Antibodies:Production,Engineering,and Clinical Application 180-208(Ritter and Ladyman,eds.,Cambridge University Press 1995);Perry,“The Role of Monoclonal Antibodies inthe Advancement of Immunoassay Technology,”in Monoclonal Antibodies:Principles and Applications 107-120(Birch and Lennox,eds.,Wiley-Liss,Inc.1995);Diamandis,Immunoassay(Academic Press,Inc.1996))。
在一些实施方案中,本发明的抗体与治疗部分即药物偶联。治疗部分可以是例如细胞毒素、化学治疗剂、细胞因子、免疫抑制剂、免疫刺激剂、裂解肽或放射性同位素。此类偶联物在本文中称为“抗体-药物偶联物”或“ADC”。
在一些实施方案中,抗体与细胞毒性部分偶联。细胞毒性部分可以例如选自以下:紫杉醇;细胞松弛素B;短杆菌肽D;溴化乙锭;吐根碱;丝裂霉素;依托泊苷;替尼泊苷;长春新碱;长春碱;秋水仙碱;多柔比星;柔红霉素;二羟基蒽二酮;微管蛋白抑制剂如美登素或其类似物或衍生物;抗有丝分裂剂如单甲基奥瑞他汀E或F或其类似物或衍生物;海兔毒素10或15或其类似物;伊立替康或其类似物;米托蒽醌;光辉霉素;放线菌素D;1-脱氢睾酮;糖皮质激素;普鲁卡因;丁卡因;利多卡因;普萘洛尔;嘌呤霉素;卡奇霉素或其类似物或衍生物;抗代谢物,如甲氨喋呤、6巯基嘌呤、6硫鸟嘌呤、阿糖胞苷、氟达拉滨、5氟尿嘧啶、氨烯咪胺、羟基脲、天冬酰胺酶、吉西他滨或克拉屈滨;烷化剂,如二氯甲基二乙胺、硫代嘌呤、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲佐菌素、达卡巴嗪(DTIC)、丙卡巴嗪、丝裂霉素C;铂类衍生物,如顺铂或卡铂;多卡霉素A、多卡霉素SA、雷切霉素(CC-1065)或其类似物或衍生物;抗生素,如放线菌素、博来霉素、柔红霉素、多柔比星、伊达比星、光霉素、丝裂霉素、米托蒽醌、普力霉素、安定霉素(AMC);吡咯并[2,1-c][1,4]-苯并二氮杂卓(PDB);白喉毒素及相关分子如白喉A链及其活性片段和杂合分子、蓖麻毒素如蓖麻毒素A或去糖基化蓖麻毒素A链毒素、霍乱毒素、志贺样毒素如SLT I、SLT II、SLT IIV、LT毒素、C3毒素、志贺毒素、百日咳毒素、破伤风毒素、大豆Bowman-Birk蛋白酶抑制剂、假单胞菌外毒素、阿罗林、皂草素、蒴莲根毒素、胶凝蛋白、相思豆毒素A链、蒴莲根毒素A链、α-八叠球菌素(alpha-sarcin)、油桐(Aleurites fordii)蛋白、石竹素蛋白、美洲商陆蛋白如PAPI、PAPII和PAP-S、苦瓜(momordica charantia)抑制剂、泻果素、巴豆毒素、肥阜草(sapaonaria officinalis)抑制剂、白树毒素、米托菌素(mitogellin)、局限曲菌素、酚霉素和依诺霉素毒素;核糖核酸酶(RNase);DNase I、葡萄球菌内毒素A;商陆抗病毒蛋白;白喉毒素和假单胞菌内毒素。
在一些实施方案中,抗体与核酸或核酸相关分子偶联。在一个这种实施方案中,偶联的核酸是细胞毒性核糖核酸酶(RNase)或脱氧核糖核酸酶(例如DNase I)、反义核酸、抑制性RNA分子(例如siRNA分子)或免疫刺激性核酸(例如含免疫刺激性CpG基序的DNA分子)。在一些实施方案中,抗体与适体或核酶偶联。
在一些实施方案中,抗体例如作为融合蛋白与裂解肽(例如CLIP、马加宁2、蜂毒肽、天蚕素和P18)偶联。
在一些实施方案中,抗体与细胞因子(例如IL-2、IL-4、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、IL-18、IL-23、IL-24、IL-27、IL-28a、IL-28b、IL-29、KGF、IFNa、IFN3、IFNy、GM-CSF、CD40L、Flt3配体、干细胞因子、安西司亭和TNFa)偶联。
在一些实施方案中,抗体与放射性同位素或含放射性同位素的螯合物偶联。例如,抗体可以与允许抗体与放射性同位素络合的螯合剂接头(例如DOTA、DTPA或噻西坦)偶联。抗体还可以或可选地包含一个或多个放射性标记的氨基酸或其他放射性标记的分子或与之偶联。放射性同位素的非限制性实例包括3H、14C、15N、35S、90Y、99Tc、125I、131I、186Re、213Bi、225Ac和227Th。为了治疗目的,可以使用发射β或α颗粒辐射的放射性同位素,例如131I、90Y、211At、212Bi、67Cu、186Re、188Re和212Pb。
在某些实施方案中,抗体-药物偶联物包含抗微管蛋白剂。抗微管蛋白剂的实例包括,例如紫杉烷(例如(紫杉醇)、(多西他赛))、T67(Tularik)、长春花类烷(例如长春新碱、长春碱、长春地辛和长春瑞滨)和多拉司他汀(例如奥瑞他汀E、AFP、MMAF、MMAE、AEB、AEVB)。其他抗微管蛋白剂包括,例如浆果赤霉素衍生物、紫杉烷类似物(例如埃博霉素A和B)、诺可达唑、秋水仙碱和colcimid、雌莫司汀、隐藻菌素、头孢噻吩、美登木素生物碱、考布他汀、圆皮海绵内酯和软珊瑚醇。在一些实施方案中,细胞毒剂是美登木素生物碱,另一组抗微管蛋白剂。例如,在具体的实施方案中,美登木素生物碱是美登素或DM-1(ImmunoGen,Inc.;还参见Chari等,Cancer Res.52:127-131,1992)。
在其他实施方案中,细胞毒剂是抗代谢物。抗代谢物可以是,例如嘌呤拮抗剂(例如硫唑嘌呤或霉酚酸酯)、二氢叶酸还原酶抑制剂(例如甲氨蝶呤)、阿昔洛韦、更昔韦洛、齐多夫定、阿糖腺苷、利巴韦林、叠氮胸苷、胞苷阿拉伯糖苷、金刚烷胺、双脱氧尿苷、碘脱氧尿苷、膦甲酸(poscarnet)或三氟胸苷。
在其他实施方案中,抗Nectin-4抗体与前药转化酶偶联。可以使用已知方法将前药转化酶与抗体重组融合或与其化学偶联。示例性的前药转化酶是羧肽酶G2、β-葡糖醛酸糖苷酶、青霉素-V-酰胺酶、青霉素-G-酰胺酶、β-内酰胺酶、β-葡糖苷酶、硝基还原酶和羧肽酶A。
用作治疗部分的其他分子可以是吡咯并苯并二氮杂二聚体(PBD)。
在一个具体实施方案中,抗体是嵌合抗体,其具有与SEQ ID NO:1相同的重链和与SEQ ID NO:2相同的轻链并与MMAE偶联。
在另一个具体实施方案中,抗体是嵌合抗体,其具有与SEQ ID NO:1相同的重链和与SEQ ID NO:2相同的轻链并与吡咯并苯并二氮杂二聚体(PBD)偶联。
通常,抗体-药物偶联化合物包含药物单元和抗体单元之间的接头单元。在一些实施方案中,接头在细胞内条件下是可切割的,使得在细胞内环境中切割接头从抗体释放药物单元。在其他实施方案中,接头单元不可切割,并且例如通过降解抗体释放药物。
在一些实施方案中,接头可被存在于细胞内环境(例如,在溶酶体或内涵体或胞膜窖内)中的切割剂切割。接头可以是例如被细胞内肽酶或蛋白酶切割的肽基接头,包括但不限于溶酶体或内涵体蛋白酶。在一些实施方案中,肽基接头的长度为至少两个氨基酸或至少三个氨基酸。切割剂可包括组织蛋白酶B和D以及纤溶酶,已知所有这些都能水解二肽药物衍生物,导致活性药物在靶细胞内释放(参见例如,Dubowchik和Walker1999,Pharm.Therapeutics 83:67-123)。
最典型的是可被表达191P4D12的细胞中存在的酶切割的肽基接头。这种接头的实例描述于例如美国专利号6,214,345,出于所有目的其整体通过引用并入本文。在一个具体实施方案中,可被细胞内蛋白酶切割的肽基接头是Val-Cit接头或Phe-Lys接头(参见例如,美国专利号6,214,345,其描述了用Val-Cit接头合成多柔比星)。使用细胞内蛋白水解释放治疗剂的一个优点是试剂在偶联时通常效力减弱,并且偶联物的血清稳定性通常很高。
在其他实施方案中,可切割接头是pH敏感的,即在某些pH值下对水解敏感。
通常,pH敏感性接头在酸性条件下可水解。例如,可以使用在溶酶体中可水解的酸不稳定接头(例如腙、缩氨基脲、缩氨基硫脲、顺式乌头酰胺、原酸酯、缩醛、缩酮等)(参见,例如,美国专利号5,122,368;5,824,805;5,622,929;Dubowchik和Walker,1999,Pharm.Therapeutics 83:67-123;Neville et al.,1989,Biol.Chem.264:14653-14661)。这种接头在中性pH条件下相对稳定,例如血液中的接头,但在低于pH 5.5或5.0(溶酶体的近似pH)下不稳定。在某些实施方案中,可水解的接头是硫醚接头(例如,通过酰基腙键与治疗剂连接的硫醚(参见,例如,美国专利号5,622,929)。
在其他实施方案中,接头可在还原条件下切割(例如,二硫化物接头)。本领域已知多种二硫化物接头,包括例如可使用以下形成的那些:SATA(N-琥珀酰亚胺基-S-乙酰硫代乙酸酯)、SPDP(N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯)、SPDB(N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丁酸酯)和SMPT(N-琥珀酰亚胺基-氧基羰基-α-甲基-α-(2-吡啶基-二硫代)甲苯)、SPDB和SMPT。(参见例如,Thorpe等,1987,Cancer Res.47:5924-5931;Wawrzynczak等,In Immunoconjugates:Antibody Conjugates in Radioimagery andTherapy of Cancer(C.W.Vogel ed.,Oxford U.Press,1987.See also U.S.Pat.No.4,880,935)。
在其他具体实施方案中,接头是丙二酸酯接头(Johnson等,1995,AnticancerRes.15:1387-93)、马来酰亚胺基苯甲酰基接头(Lau等,1995,Bioorg-Med-Chem.3(10):1299-1304),或3'-N-酰胺类似物(Lau等,1995,Bioorg-Med-Chem.3(10):1305-12)。
在其他实施方案中,接头单元不可切割,并且药物通过降解抗体释放。
通常,接头对细胞外环境基本上不敏感。如本文所用,在接头的上下文中“对细胞外环境基本上不敏感”是指当抗体-药物偶联化合物存在于细胞外环境(例如,在血浆中)时,抗体-药物偶联化合物样品中通常不超过约20%,通常不超过约15%,更通常不超过约10%,甚至更通常不超过约5%,不超过约3%,或不超过约1%的接头被切割。接头是否对细胞外环境基本上不敏感可以通过例如以下来确定:将血浆与抗体-药物偶联化合物一起孵育预定的时间段(例如2、4、8、16或24小时),然后定量血浆中存在的游离药物的量。
用于将分子与抗体偶联的技术是本领域公知的(参见例如,MonoclonalAntibodies And Cancer Therapy(Reisfeld等编辑,Alan R.Liss,Inc.,1985)中的Arnon等,“Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”;Controlled Drug Delivery(Robinson等编辑,Marcel Deiker,Inc.,2nd ed.1987)中的Hellstrom等,“Antibodies For Drug Delivery”;Monoclonal Antibodies'84:Biological And Clinical Applications(Pinchera等编辑,1985)中的Thorpe,“AntibodyCarriers Of Cytotoxic Agents In Cancer Therapy:A Review”;MonoclonalAntibodies For Cancer Detection And Therapy(Baldwin等编辑,Academic Press,1985)中的“Analysis,Results,and Future Prospective of the Therapeutic Use ofRadiolabeled Antibody In Cancer Therapy”;和Thorpe等,1982,Immunol.Rev.62:119-58。还参见例如PCT公开WO 89/12624)。通常,核酸分子分别通过N-羟基琥珀酰亚胺酯或马来酰亚胺官能团与抗体上的赖氨酸或半胱氨酸共价连接。已经报道了使用工程化半胱氨酸或掺入非天然氨基酸的偶联方法可改善偶联物的同质性(Axup,J.Y.,Bajjuri,K.M.,Ritland,M.,Hutchins,B.M.,Kim,C.H.,Kazane,S.A.,Halder,R.,Forsyth,J.S.,Santidrian,A.F.,Stafin,K.等(2012).Synthesis of site-specific antibody-drugconjugates using unnatural amino acids.Proc.Natl.Acad.Sci.USA 109,16101–16106.;Junutula,J.R.,Flagella,K.M.,Graham,R.A.,Parsons,K.L.,Ha,E.,Raab,H.,Bhakta,S.,Nguyen,T.,Dugger,D.L.,Li,G.等(2010).Engineered thio-trastuzumab-DM1conjugate with an improved therapeutic index to target humanepidermalgrowth factor receptor 2-positive breast cancer.Clin.Cancer Res.16,4769–4778.)。Junutula等(2008)开发了称为“THIOMAB”(TDC)的基于半胱氨酸的位点特异性偶联物,据称与常规偶联方法相比显示出改善的治疗指数。已经探索了已掺入抗体中的非天然氨基酸与ADC的偶联;然而,这种方法的普遍性尚未确定(Axup等,2012)。特别地,本领域技术人员还可以设想用以下工程化的含Fc多肽:含有酰基供体谷氨酰胺的标签(例如,含有Gin的肽标签或Q-标签)或通过多肽工程(例如,通过多肽上的氨基酸缺失、插入、取代或突变)使其具有反应性的内源性谷氨酰胺。然后,转谷氨酰胺酶可以与胺供体剂(例如,包含或连接到反应性胺的小分子)共价交联,以形成稳定且均质的工程化的含Fc多肽偶联物群,其中胺供体剂通过含有酰基供体谷氨酰胺的标签或可接近/暴露/反应性内源性谷氨酰胺位点特异性地与含Fc多肽偶联(WO 2012059882)。
诊断和治疗用途
本发明的另一方面涉及本发明的抗-Nectin-4抗体用于诊断和/或监测和/或分期癌症,特别是其中Nectin-4过表达的癌症。
根据本发明,其中Nectin-4过表达的癌症是指在癌细胞表面表达的nectin-4水平高于正常细胞(非肿瘤细胞)表达的Nectin-4水平的癌症。
根据本发明,其中Nectin-4过表达的癌症可以是乳腺癌、卵巢癌、肺癌、尿路上皮癌和胰腺癌。在一个实施方案中,乳腺癌是三阴性乳腺癌。
在一个优选的实施方案中,本发明的抗体可以用可检测的分子或物质标记,例如荧光分子、放射性分子或如上所述的本领域已知的任何其他标记。例如,可以通过本领域已知的任何方法用放射性分子标记本发明的抗体。例如,放射性分子包括但不限于用于闪烁扫描研究的放射性原子,例如I123、I124、In111、Re186、Re188。本发明的抗体还可以用用于核磁共振(NMR)成像(也称为磁共振成像,MRI)的自旋标记物标记,例如碘-123、碘-131、铟-111、氟-19、碳-13、氮-15、氧-17、钆、锰或铁。施用抗体后,检测患者体内抗体的分布。用于检测任何特定标记的分布的方法是本领域技术人员已知的,并且可以使用任何适当的方法。一些非限制性实例包括计算机断层扫描(CT)、位置发射断层扫描(PET)、磁共振成像(MRI)、荧光、化学发光和超声波检查。
通常,所述诊断方法涉及使用从患者获得的生物样品。如本文所用,术语“生物样品”包括从受试者获得的多种样品类型,并且可用于诊断或监测测定。生物样品包括但不限于血液和生物来源的其他液体样品、固体组织样品如活组织检查样品或组织培养物或由其衍生的细胞,及其后代。例如,生物样品包括从疑似患有与Nectin-4过表达相关的癌症(在一个优选的实施方案中,从乳腺癌、卵巢癌、肺癌、尿路上皮癌和胰腺癌)的个体收集的组织样品中获得的细胞。
因此,生物样品包括临床样品、癌症样品、培养细胞、细胞上清液、细胞裂解液、血清、血浆、生物液体和组织样品。
本发明的抗体、片段或免疫偶联物可用于治疗与Nectin-4过表达相关的任何疾病,特别是癌症和转移性癌症。
本发明的抗体可以单独使用或与任何合适的试剂组合使用。
在本文所述的治疗方法的每一个实施方案中,以与寻求治疗的疾病或病症的管理相关的常规方法一致的方式递送抗nectin-4抗体或抗nectin-4抗体-药物偶联物。根据本文的公开内容,在足以预防或治疗疾病或病症的条件下,向需要这种治疗的患者施用有效量的抗体或抗体-药物偶联物一段时间。
如本文所用,术语“治疗”是指预防或预防性治疗以及治愈性或疾病改善性治疗,包括治疗处于患病风险或怀疑患有该疾病的受试者以及生病或被诊断为患有疾病或医学病症的受试者,包括抑制临床复发。可以向患有医学病症或最终可能患有病症的受试者施用治疗,以预防、治愈、延迟病症或复发病症的一种或多种症状的发作、降低病症或复发病症的一种或多种症状的严重程度或缓解病症或复发病症的一种或多种症状,或者为了延长受试者的存活期超过在没有这种治疗的情况下预期的存活期。“治疗方案”是指疾病的治疗模式,例如治疗期间使用的剂量模式。治疗方案可包括诱导方案和维持方案。短语“诱导方案”或“诱导期”是指用于疾病初始治疗的治疗方案(或治疗方案的一部分)。诱导方案的一般目标是在治疗方案的初始阶段向受试者提供高水平的药物。诱导方案可以采用(部分或全部)“加载方案”,其可以包括施用比医生在维持方案期间使用的更大剂量的药物,比医生在维持方案期间更频繁地施用药物,或两者。短语“维持方案”或“维持期”是指用于在治疗疾病期间维持受试者,例如使受试者长期(数月或数年)保持缓解的治疗方案(或治疗方案的一部分)。维持方案可以采用连续治疗(例如以规律的间隔(例如每周、每月、每年等)施用药物)或间歇治疗(例如中断治疗、间歇治疗、复发治疗或实现特定的预定标准[例如疾病表现等]时的治疗)。
如本文所用,术语“治疗有效量”或“有效量”是指在必要的剂量和时间段内有效实现所需治疗结果的量。治疗有效量的本发明抗体可根据诸如以下因素而变化:个体的疾病状态、年龄、性别和体重,以及本发明的抗体在个体中引发所需应答的能力。治疗有效量也是其中治疗有益效果超过抗体或抗体部分的任何毒性或有害作用的量。本发明抗体的有效剂量和剂量方案取决于待治疗的疾病或病症,并且可由本领域技术人员确定。具有本领域普通技术的医生可以容易地确定和开出所需药物组合物的有效量。例如,医生可以以低于实现所需治疗效果所需的水平开始在药物组合物中使用的本发明抗体的剂量,并逐渐增加剂量直至达到所需效果。通常,本发明组合物的合适剂量将是这样:化合物的量是根据特定剂量方案有效产生治疗效果的最低剂量。这种有效剂量通常取决于上述因素。例如,用于治疗用途的治疗有效量可以通过其稳定疾病进展的能力来测量。通常,化合物抑制癌症的能力可以例如在预测人肿瘤功效的动物模型系统中评估。或者,组合物的这种性质可以通过熟练医生已知的体外测定法检查化合物诱导细胞毒性的能力来评估。治疗有效量的治疗化合物可以减小肿瘤大小,或减轻受试者的症状。本领域普通技术人员将能够基于诸如以下因素来测定这样的量:受试者的大小、受试者症状的严重性和所选择的特定组合物或施用途径。本发明抗体的治疗有效量的示例性、非限制性范围是约0.1-100mg/kg、例如约0.1-50mg/kg、例如约0.1-20mg/kg、例如约0.1-10mg/kg、例如约0.5、约0.3、约1、约3mg/kg、约5mg/kg或约8mg/kg。本发明抗体的治疗有效量的示例性、非限制性范围是0.02-100mg/kg、例如约0.02-30mg/kg、例如约0.05-10mg/kg或0.1-3mg/kg,例如约0.5-2mg/kg。可以例如静脉内、肌肉内、腹膜内或皮下施用,例如在靶标位点附近施用。调整上述治疗方法和用途中的剂量方案以提供最佳的所需反应(例如治疗反应)。例如,可以施用单次推注,可以随时间施用几个分开的剂量,或者可以根据治疗情况的紧急程度按比例减少或增加剂量。在一些实施方案中,在治疗期间,例如在预定义的时间点监测治疗功效。在一些实施方案中,可通过疾病区域的可视化或通过本文进一步描述的其他诊断方法监测功效,例如,通过使用例诸如本发明的标记抗体、衍生自本发明抗体的片段或小抗体进行一次或多次PET-CT扫描。如果需要,药物组合物的有效每日剂量可以作为两个、三个、四个、五个、六个或更多个亚剂量(任选地,以单位剂型),在一天中以适当的间隔分开施用。在一些实施方案中,本发明的单克隆抗体通过长时间,例如超过24小时的缓慢连续输注施用,以使任何不希望的副作用最小化。还可以使用每周、每两周或每三周一次的给药期来施用有效剂量的本发明抗体。给药期可以限制在例如8周、12周或直到建立临床进展。作为非限制性实例,在治疗开始后的第1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40天的至少一天,或在第1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20周的至少一周,或其任意组合,每24、12、8、6、4或2小时使用单次或分次剂量,或其任何组合,可以用每日剂量为以下含量的本发明抗体提供根据本发明的治疗:每天约0.1-100mg/kg,例如0.2、0.5、0.9、1.0、1.1、1.5、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、40、45、50、60、70、80、90或100mg/kg。
因此,本发明的一个目的涉及治疗有需要的受试者的癌症和转移性癌症的方法,包括向受试者施用治疗有效量的本发明抗体。
在另一个方面,本发明涉及如本文任何方面或实施方案所定义的本发明的抗体,其用作药物。
在一些实施方案中,受试者患有癌症。因此,本发明的另一个目的涉及治疗有需要的受试者的癌症的方法,包括向受试者施用治疗有效量的本发明抗体。
如本文所用,术语“癌症”具有其在本领域中的一般含义,并且包括但不限于实体瘤和血源性肿瘤。术语癌症包括皮肤、组织、器官、骨、软骨、血液和血管的疾病。术语“癌症”还包括原发性和转移性癌症两者。可以通过本发明的方法和组合物治疗的癌症的实例包括但不限于来自以下的癌细胞:膀胱、血液、骨、骨髓、脑、乳房、结肠、食道、胃肠道、牙龈、头、肾、肝、肺、鼻咽、颈、卵巢、前列腺、皮肤、胃、睾丸、舌或子宫。此外,癌症可具体地为以下组织学类型,但不限于这些:肿瘤,恶性;癌;癌,未分化;巨细胞和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌;移行细胞癌;乳头状移行细胞癌;腺癌;胃泌素瘤,恶性;胆管癌;肝细胞癌;合并的肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤性息肉中的腺癌;腺癌,家族性结肠息肉;实体癌;类癌,恶性;支气管肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸性粒细胞癌;嗜酸性腺癌;嗜碱性粒细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡性腺癌;乳头状和滤泡状腺癌;非包膜性硬化癌;肾上腺皮质癌;子宫内膜样癌;皮肤附属癌;大汗腺癌;皮脂腺癌;耳垢;腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;佩吉特病,乳腺癌;腺泡细胞癌;腺鳞癌;腺癌伴鳞状化生;胸腺瘤,恶性;卵巢间质瘤,恶性;肉瘤,恶性;颗粒细胞瘤,恶性;和母细胞瘤(roblastoma),恶性;Sertoli细胞癌;睾丸间质细胞瘤,恶性;脂质细胞瘤,恶性;副神经节瘤,恶性;乳腺外副神经节瘤,恶性;嗜铬细胞瘤;血管球肉瘤;恶性黑色素瘤;无色素性黑色素瘤;浅表扩散性黑色素瘤;巨大色素痣中的恶性黑色素瘤;上皮样细胞黑色素瘤;蓝色痣,恶性;肉瘤;纤维肉瘤;纤维组织细胞瘤,恶性;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;肺泡横纹肌肉瘤;间质肉瘤;混合瘤,恶性;米勒管混合瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;间叶瘤,恶性;勃勒纳瘤(brenner tumor),恶性;叶状肿瘤,恶性;滑膜肉瘤;间皮瘤,恶性;无性细胞瘤;胚胎癌;畸胎瘤,恶性;卵巢肿瘤,恶性;绒毛膜癌;中肾瘤,恶性;血管肉瘤;血管内皮瘤,恶性;卡波西肉瘤;血管外皮细胞瘤,恶性;淋巴管肉瘤;骨肉瘤;皮质骨肉瘤;软骨肉瘤;软骨母细胞瘤,恶性;间充质软骨肉瘤;骨巨细胞瘤;尤因肉瘤;牙源性肿瘤,恶性;成釉细胞性牙肉瘤;成釉细胞瘤,恶性;成釉细胞纤维肉瘤;松果体,恶性;脊索瘤;胶质瘤,恶性;室管膜瘤;星形细胞瘤;原生质星形细胞瘤;原纤维星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质细胞瘤;少突神经母细胞瘤;原始神经外胚层;小脑肉瘤;神经节细胞母细胞瘤;神经母细胞瘤;视网膜母细胞瘤;嗅神经源性肿瘤;脑膜瘤,恶性;神经纤维肉瘤;神经鞘瘤,恶性;颗粒细胞瘤,恶性;恶性淋巴瘤;霍奇金病;霍奇金淋巴瘤;副肉芽肿;恶性淋巴瘤,小淋巴细胞;恶性淋巴瘤,大细胞,弥漫性;恶性淋巴瘤,滤泡;蕈样真菌病;其他指定的非霍奇金淋巴瘤;恶性组织细胞病;多发性骨髓瘤;肥大细胞肉瘤;免疫增殖性小肠疾病;白血病;淋巴白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓样白血病;嗜碱性粒细胞白血病;嗜酸粒细胞白血病;单核细胞白血病;肥大细胞白血病;巨核母细胞白血病;骨髓肉瘤;和毛细胞白血病。
更具体地,本发明适用于治疗乳腺癌、卵巢癌、肺癌、尿路上皮癌和胰腺癌。在一个实施方案中,乳腺癌是三阴性乳腺癌。
在某些实施方案中,抗nectin-4抗体或抗体-药物偶联物与第二试剂组合用于治疗疾病或病症。当用于治疗癌症时,本发明的抗Nectin-4抗体或抗体-药物偶联物可以与常规癌症疗法(例如手术、放疗、化疗或其组合)组合使用。
本发明还提供了治疗应用,其中本发明的抗体与至少一种其他治疗剂组合使用,例如用于治疗癌症和转移性癌症。这种施用可以是同时的、分开的或依次的。对于同时施用,根据需要试剂可以作为一个组合物或作为单独的组合物施用。其他治疗剂通常与待治疗的病症有关。示例性治疗剂包括其他抗癌抗体、细胞毒性剂、化疗剂、抗血管生成剂、抗癌免疫原、细胞周期控制/凋亡调节剂、激素调节剂和下述其他试剂。
在一些实施方案中,本发明的抗体与化疗剂组合使用。术语“化疗剂”是指有效抑制肿瘤生长的化合物。化疗剂的实例包括:烷化剂,例如噻替派和环磷酰胺;烷基磺酸盐,例如白消安、英丙舒凡和哌泊舒凡;氮杂环丙烷,例如苯佐替派、卡波醌、美妥替派和乌瑞替派;乙烯亚胺和甲基蜜胺,包括六甲蜜胺、三乙烯蜜胺、三乙烯磷酰胺、三乙烯硫代磷酰胺和三羟甲基蜜胺;番茄枝内酯类(尤其是布拉他辛和布拉他辛酮);喜树碱(包括合成类似物拓扑替康);苔藓抑素;卡利他汀(callystatin);CC-1065(包括其阿多来新、卡折来新和比折来新合成类似物);隐藻素类(特别是隐藻素1和隐藻素8);多拉司他丁;倍癌霉素(duocarmycin,包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素;水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑素;氮芥,诸如氯丁酸氮芥、萘氮芥、胆磷酰胺、磷雌氮芥、异磷酰胺、双氯乙基甲胺、盐酸氧氮芥、美法仑、新氮芥、苯芥胆甾醇、松龙苯芥、三芥环磷酰胺、尿嘧啶氮芥;硝基脲类,诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀、雷莫司汀;抗生素,诸如烯二炔类抗生素(如加利车霉素,尤其是加利车霉素11和加利车霉素211,参见例如Agnew,Chem.Intl.Ed.Engl.33183-186,1994);蒽环类抗生素,包括达内霉素A(dynemicin A);埃斯波霉素;以及新抑癌菌素发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素类、放线菌素、氨茴霉素、氮丝氨酸、博来霉素类、放线菌素C、卡柔比星(carabicin)、洋红霉素、嗜癌霉素、色霉素类、更生霉素、柔红霉素、地托比星、6-重氮基-5-氧-L-正亮氨酸、阿霉素(包括吗啉阿霉素、氰吗啉阿霉素、2-吡咯啉阿霉素和脱氧阿霉素)、表柔比星、依索比星、依达比星、麻西罗霉素、丝裂霉素、霉酚酸、诺加霉素、橄榄霉素类、培来霉素、泼非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链脲霉素、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢物,诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸、甲氨蝶呤、蝶酰三谷氨酸、曲麦克特;嘌呤类似物,诸如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,诸如安西他滨、氮杂胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、脱氧氟尿苷、依诺他滨、氟尿苷、5-FU;雄激素类,诸如卡鲁睾酮、羟甲雄酮丙酸酯、表硫雄醇、美雄烷、睾内酯;抗肾上腺类,诸如氨鲁米特、曼托坦、曲洛司坦;叶酸补充剂,诸如亚叶酸;醋葡内酯;醛磷酰胺糖苷;氨基酮戊酸;蒽尿嘧啶;氨苯吖啶;贝斯布西(bestrabucil);比生群;依达曲沙;地磷酰胺(defofamine);秋水仙胺;地吖醌;依洛尼塞(eifornithine);依利醋铵;埃博霉素(epothilone);环氧甘醚;硝酸镓;羟脲;蘑菇多糖;氯尼达明;美登木素生物碱类,诸如美登素和美坦西醇类;丙米腙;米托蒽醌;莫匹达谋;二胺硝吖啶(nitraerine);喷司他丁;蛋氨氮芥;吡柔比星;足叶草酸;2-乙基酰肼;甲基苄肼;丙亚胺;根霉素;西作非兰;螺旋锗;细格孢氮杂酸;三亚胺醌;2,2',2"-三氯三乙胺;单端孢菌素类(尤其是T-2毒素、粘液霉素A(verracurin A)、杆孢菌素A和蛇形菌素);乌拉坦;长春地辛;达卡巴嗪;甘露醇氮芥;二溴甘露醇;二溴卫矛醇;哌泊溴烷;加西托星(gacytosine);阿糖胞苷(“Ara-C”);环磷酰胺;硫替哌;类紫杉醇,如紫杉醇(paclitaxel)(Bristol-Myers Squibb Oncology,Princeton,N.J.)和多西他塞(Rhone-Poulenc Rorer,Antony,France);苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂类似物,诸如顺铂和卡铂;长春碱;铂;依托泊苷(VP-16);异磷酰胺;丝裂霉素C;米托蒽醌;长春新碱;长春瑞滨;诺维本;诺安托;替尼泊苷;道诺霉素;氨基蝶呤;希罗达;伊本膦酸盐;CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);视黄酸;卡培他滨;及上述任何的药学上可接受的盐、酸或衍生物。该定义还包括用于调节或抑制激素对肿瘤作用的抗激素剂,例如抗雌激素,包括例如他莫昔芬、雷洛昔芬、抑制4(5)-咪唑的芳香酶、4-羟基他莫昔芬、曲奥昔芬、那洛昔芬、LY117018、奥那斯酮、和托瑞米芬(Fareston);和抗雄激素,如氟他米特、尼鲁米特、比卡米特、亮丙瑞林和戈舍瑞林;以及上述任何的药学上可接受的盐、酸或衍生物。
在一些实施方案中,本发明的抗体与靶向癌症疗法组合使用。靶向癌症疗法是通过干扰参与癌症的生长、进展和扩散的特定分子(“分子靶标”)来阻断癌症的生长和扩散的药物或其他物质。靶向癌症疗法有时称为“分子靶向药”、“分子靶向疗法”、“精准医疗”或类似的名称。在一些实施方案中,靶向疗法是向受试者施用酪氨酸激酶抑制剂。术语“酪氨酸激酶抑制剂”是指作为受体和/或非受体酪氨酸激酶的选择性或非选择性抑制剂的任何一种治疗剂或药物。酪氨酸激酶抑制剂和相关化合物是本领域已知的,且描述于其全文通过引用并入本文的美国专利公开2007/0254295。本领域技术人员将理解,与酪氨酸激酶抑制剂相关的化合物将概括酪氨酸激酶抑制剂的作用,例如,相关化合物将作用于酪氨酸激酶信号传导通路的不同成员,以产生与那个酪氨酸激酶的酪氨酸激酶抑制剂相同的作用。适用于本发明实施方案的方法的酪氨酸激酶抑制剂和相关化合物的实例包括但不限于:达沙替尼(BMS-354825)、PP2、BEZ235、塞卡替尼、吉非替尼(易瑞沙)、舒尼替尼(Sutent;SU11248)、厄洛替尼(特罗凯;OSI-1774)、拉帕替尼(GW572016;GW2016)、卡奈替尼(CI1033)、塞玛昔布(semaxinib,SU5416)、瓦他拉尼(PTK787/ZK222584)、索拉非尼(BAY 43-9006)、伊马替尼(Gleevec;STI571)、来氟米特(SU101)、凡德他尼(Zactima;ZD6474)、MK-2206(8-[4-氨基环丁基)苯基]-9-苯基-1,2,4-三唑并[3,4-f][1,6]萘啶-3(2H)-酮盐酸盐)衍生物、其类似物,及其组合。适用于本发明的另外的酪氨酸激酶抑制剂和相关化合物描述于例如,美国专利公开2007/0254295、美国专利号5,618,829、5,639,757、5,728,868、5,804,396、6,100,254、6,127,374、6,245,759、6,306,874、6,313,138、6,316,444、6,329,380、6,344,459、6,420,382、6,479,512、6,498,165、6,544,988、6,562,818、6,586,423、6,586,424、6,740,665、6,794,393、6,875,767、6,927,293和6,958,340,所有这些的全文都通过引用并入本文。在一些实施方案中,酪氨酸激酶抑制剂是已经口服施用的小分子激酶抑制剂,并且已经是至少一个I期临床试验,更优选至少一个II期临床试验,甚至更优选至少一个III期临床试验的主题,最优选由FDA批准用于至少一种血液或肿瘤适应症。此类抑制剂的实例包括但不限于:吉非替尼、厄洛替尼、拉帕替尼、卡奈替尼、BMS-599626(AC-480)、来那替尼、KRN-633、CEP-11981、伊马替尼、尼罗替尼、达沙替尼、AZM-475271、CP-724714、TAK-165、舒尼替尼、瓦他拉尼、CP-547632、凡德他尼、伯舒替尼、来他替尼、坦度替尼、米哚妥林、恩扎妥林、AEE-788、帕唑帕尼、阿西替尼、Motasenib、OSI-930、西地尼布、KRN-951、多韦替尼、Seliciclib、SNS-032、PD-0332991、MKC-1(Ro-317453;R-440)、索拉非尼、ABT-869、布立尼布(BMS-582664)、SU-14813、替拉替尼、SU-6668、(TSU-68)、L-21649、MLN-8054、AEW-541和PD-0325901。
在一些实施方案中,本发明的抗体与免疫治疗剂组合使用。如本文所用,术语“免疫治疗剂”是指间接或直接增强、刺激或增加机体对癌细胞的免疫应答和/或降低其他抗癌疗法的副作用的化合物、组合物或治疗。因此,免疫疗法是直接或间接刺激或增强免疫系统对癌细胞的应答和/或减轻可能已经由其他抗癌剂引起的副作用的疗法。免疫疗法在本领域中也称为免疫性疗法、生物性疗法、生物反应调节剂疗法和生物疗法。本领域已知的常见免疫治疗剂的实例包括但不限于:细胞因子、癌症疫苗、单克隆抗体和非细胞因子佐剂。或者,免疫治疗性治疗可以包括向受试者施用一定量的免疫细胞(T细胞、NK细胞、树突细胞、B细胞......)。免疫治疗剂可以是非特异性的,即通常增强免疫系统以使人体更有效地对抗癌细胞的生长和/或扩散,或者它们可以是特异性的,即靶向癌细胞本身。免疫治疗方案可以结合使用非特异性和特异性的免疫治疗剂。非特异性免疫治疗剂是刺激或间接改善免疫系统的物质。非特异性免疫治疗剂已被单独用作治疗癌症的主要疗法,以及在主要疗法之外使用,在这种情况下,非特异性免疫治疗剂作为佐剂发挥作用以增强其他疗法(例如癌症疫苗)的有效性。在后一种情况下,非特异性免疫治疗剂也可以发挥作用以减少其他疗法的副作用,例如由某些化疗剂诱导的骨髓抑制。非特异性免疫治疗剂可作用于关键免疫系统细胞并引起次级反应,例如增加细胞因子和免疫球蛋白的产生。或者,试剂本身可包含细胞因子。非特异性免疫治疗剂通常分类为细胞因子或非细胞因子佐剂。已经在癌症治疗中发现许多细胞因子的应用,作为设计为增强免疫系统的一般非特异性免疫疗法,或作为与其他疗法一起提供的佐剂。合适的细胞因子包括但不限于干扰素、白细胞介素和集落刺激因子。本发明预期的干扰素(IFN)包括常见类型的IFN,IFN-α、IFN-β和IFN-γ。IFN可以直接作用于癌细胞,例如,通过减缓它们的生长,促进它们发育成具有更正常行为的细胞和/或增加它们的抗原产生,从而使癌细胞更容易被免疫系统识别并破坏。IFN还可以间接作用于癌细胞,例如,通过减慢血管生成、增强免疫系统和/或刺激自然杀伤(NK)细胞、T细胞和巨噬细胞。重组IFN-α可作为罗扰素(Roche Pharmaceuticals)和甘乐能(ScheringCorporation)商购获得。本发明预期的白细胞介素包括IL-2、IL-4、IL-11和IL-12。市售重组白细胞介素的实例包括(IL-2;Chiron Corporation)和(IL-12;Wyeth Pharmaceuticals)。Zymogenetics,Inc(Seattle,Wash.)目前正在测试重组形式的IL-21,其也预期用于与本发明组合使用。本发明预期的集落刺激因子(CSF)包括粒细胞集落刺激因子(G-CSF或非格司亭)、粒细胞-巨噬细胞集落刺激因子(GM-CSF或沙格司亭)和促红细胞生成素(阿法依伯汀、达比波廷)。用一种或多种生长因子治疗可以帮助刺激经历传统化疗的受试者中新血细胞的产生。因此,用CSF治疗可有助于减少与化疗相关的副作用,并且可允许使用更高剂量的化疗剂。各种重组集落刺激因子可商购获得,例如(G-CSF;Amgen)、Neulasta(培非格司亭;Amgen)、Leukine(GM-CSF;Berlex)、Procrit(促红细胞生成素;Ortho Biotech)、Epogen(促红细胞生成素;Amgen)、Arnesp(促红细胞生成素)。本发明的组合的组合物和组合的施用方法还可以包括“全细胞”和“过继性”免疫治疗方法。例如,此类方法可包括输注或重新输注免疫系统细胞(例如肿瘤浸润淋巴细胞(TIL),例如CC2+和/或CD8+T细胞(例如用肿瘤特异性抗原和/或遗传增强扩增的T细胞)、表达抗体的B细胞或其他产生抗体或呈递抗体的细胞、树突细胞(例如,用DC-扩增剂如GM-CSF和/或Flt3-L培养的树突细胞,和/或肿瘤相关的抗原负载的树突细胞)、抗肿瘤NK细胞、所谓的杂交细胞或其组合。细胞裂解物也可用于这些方法和组合物中。临床试验中可用于这些方面的细胞“疫苗”包括CanvaxinTM、APC-8015(Dendreon)、HSPPC-96(Antigenics)和细胞裂解物。从癌细胞脱落的抗原及其混合物(参见例如Bystryn等,Clinical Cancer Research Vol.7,1882-1887,2001年7月),任选地与佐剂如明矾混合,也可以是这些方法和组合的组合物中的组分。
特别地,本发明的抗体可以与另一种抗体,例如专利申请WO2012047724中所述的抗体Ha22-2(Seattle Genetics)组合使用。
在一些实施方案中,本发明的抗体与放射疗法组合使用。放射疗法可以包括辐射或向患者施用相关的放射性药物。辐射源对于待治疗患者而言可以是外部的或内部的(放射治疗可以是例如外部束放射治疗(EBRT)或近距离放射治疗(BT)的形式)。可用于实施此类方法的放射性元素包括例如镭、铯-137、铱-192、镅-241、金-198、钴-57、铜-67、锝-99、碘-123、碘-131和铟-111。
在一些实施方案中,本发明的抗体与对共刺激分子具有特异性的抗体组合使用。对共刺激分子具有特异性的抗体的实例包括但不限于抗CTLA4抗体(例如伊匹单抗)、抗PD1抗体、抗PDL1抗体、抗TIMP3抗体、抗LAG3抗体、抗B7H3抗体、抗B7H4抗体或抗B7H6抗体。
在一些实施方案中,第二试剂是通过ADCC诱导表达第二试剂结合的抗原的细胞死亡的试剂。在一些实施方案中,所述试剂是抗体(例如IgG1或IgG3同种型),其作用模式涉及向抗体结合的细胞诱导ADCC。NK细胞在诱导ADCC中具有重要作用,并且可以通过使用这种第二试剂将NK细胞增加的反应性引导至靶细胞。在一些实施方案中,第二试剂是对细胞表面抗原(例如膜抗原)具有特异性的抗体。在一些实施方案中,第二抗体对以下具有特异性:如上所述的肿瘤抗原(例如,肿瘤细胞特异性表达的分子),例如CD20、CD52、ErbB2(或HER2/Neu)、CD33、CD22、CD25、MUC-1、CEA、KDR、αVβ3等,特别是淋巴瘤抗原(例如CD20)。因此,本发明还提供增强抗肿瘤抗原的单克隆抗体的抗肿瘤作用的方法。在本发明的方法中,通过依次施用抗一种或多种肿瘤抗原的抗体和本发明的抗体,ADCC功能被特异性增强,其反过来增强靶细胞杀伤。
因此,另一个目的涉及增强有需要的受试者的抗体的NK细胞抗体依赖性细胞毒性(ADCC)的方法,包括向受试者施用抗体,并向受试者施用本发明的抗体。
本发明的另一个目的涉及治疗有需要的受试者的癌症的方法,包括向受试者施用对癌细胞抗原具有选择性的第一抗体,并向受试者施用本发明的抗体。
许多抗体目前在临床上用于治疗癌症,而其他抗体处于临床开发的不同阶段。本发明方法的目标抗体通过ADCC起作用,并且通常对肿瘤细胞具有选择性,尽管本领域技术人员将认识到一些临床上有用的抗体确实作用于非肿瘤细胞,例如CD20。有许多抗原和相应的单克隆抗体用于治疗B细胞恶性肿瘤。一种流行的靶抗原是CD20,其存在于B细胞恶性肿瘤中。利妥昔单抗是针对CD20抗原的嵌合非偶联单克隆抗体。CD20在B细胞活化、增殖和分化中具有重要的功能作用。单克隆抗体阿仑单抗靶向CD52抗原,其用于治疗慢性淋巴细胞白血病。许多抗体靶向CD22,并且最近证明了其与毒素的组合在抗化疗的毛细胞白血病中的功效。靶向CD20的单克隆抗体还包括托西莫单抗和替伊莫单抗。可用于本发明方法的单克隆抗体已用于实体瘤,包括但不限于依决洛单抗和曲妥珠单抗(赫赛汀)。依决洛单抗靶向结肠癌和直肠癌中见到的17-1A抗原,并已被批准在欧洲用于这些适应症。其抗肿瘤作用通过ADCC、CDC和诱导抗个体基因型网络介导。曲妥珠单抗靶向HER-2/neu抗原。这种抗原见于25%至35%的乳腺癌。曲妥珠单抗被认为以多种方式起作用:下调HER-2受体的表达、抑制过表达HER-2蛋白的人肿瘤细胞的增殖、增强免疫募集和针对过表达HER-2蛋白的肿瘤细胞的ADCC,以及下调血管生成因子。阿仑单抗(Campath)用于治疗慢性淋巴细胞白血病;结肠癌和肺癌;吉姆单抗(Mylotarg)可用于治疗急性髓性白血病;替伊莫单抗(Zevalin)可用于治疗非霍奇金淋巴瘤;帕尼单抗(Vectibix)可用于治疗结肠癌。西妥昔单抗(Erbitux)也适用于本发明的方法。该抗体与EGF受体(EGFR)结合,并已用于治疗实体瘤,包括结肠癌和头颈部鳞状细胞癌(SCCHN)。
药物组合物
通常,本发明的抗体以药物组合物的形式向受试者施用,所述药物组合物包含药学上可接受的载体。可用于这些组合物的药学上可接受的载体包括但不限于:离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白例如人血清白蛋白、缓冲物质例如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙烯乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。为了用于向患者施用,将组合物配制成用于向患者施用。本发明的组合物可以通过以下施用:口服、胃肠外、通过吸入喷雾、局部、直肠、经鼻、经颊、阴道或通过植入型药盒。本文使用的包括皮下、静脉内、肌肉内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。本发明组合物的无菌可注射形式可以是水性或油性悬浮液。可以根据本领域已知的技术使用合适的分散剂或润湿剂和悬浮剂配制这些悬浮液。无菌可注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为1,3-丁二醇溶液。可以使用的可接受载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,无菌的固定油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。与天然的药学上可接受的油,例如橄榄油或蓖麻油,尤其是它们的聚氧乙基化形式一样,脂肪酸,例如油酸及其甘油酯衍生物可用于制备注射剂。这些油溶液或悬浮液还可含有长链醇类稀释剂或分散剂,例如羧甲基纤维素或通常用于配制药学上可接受的剂型(包括乳剂和混悬剂)的类似分散剂。通常用于制备药学上可接受的固体、液体或其它剂型的其他常用的表面活性剂,例如Tween、Span和其他乳化剂或生物利用度增强剂也可用于配制目的。本发明的组合物可以以任何口服可接受的剂型口服施用,包括但不限于胶囊、片剂、水性悬浮液或溶液。在口服用片剂的情况下,常用的载体包括乳糖和玉米淀粉。通常还添加润滑剂,例如硬脂酸镁。对于胶囊形式的口服施用,有用的稀释剂包括例如乳糖。当口服使用需要水性悬浮液时,将活性成分与乳化剂和悬浮剂组合。如果需要,还可以加入某些甜味剂、调味剂或着色剂。或者,本发明的组合物可以用于直肠施用的栓剂的形式施用。这些可以通过将试剂与合适的无刺激性赋形剂混合来制备,所述赋形剂在室温下为固体但在直肠温度下为液体,因此将在直肠中融化以释放药物。这种材料包括可可脂、蜂蜡和聚乙二醇。本发明的组合物也可局部施用,特别是当治疗靶标包括局部施用易于接近的区域或器官时,包括眼、皮肤或下肠道疾病。对于这些区域或器官中的每一个,容易制备合适的局部制剂。对于局部应用,组合物可以配制成合适的软膏,其含有悬浮或溶解在一种或多种载体中的活性组分。用于局部施用本发明化合物的载体包括但不限于矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者,可以将组合物配制成合适的洗剂或霜剂,其含有悬浮或溶解在一种或多种药学上可接受的载体中的活性组分。合适的载体包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苯甲醇和水。用于下肠道的局部应用可以以直肠栓剂制剂(参见上文)或以合适的灌肠制剂实现。也可以使用贴剂。本发明的组合物还可以通过鼻气雾剂或吸入施用。这种组合物根据药物制剂领域熟知的技术制备,并且可以使用苯甲醇或其他合适的防腐剂、提高生物利用度的吸收促进剂、碳氟化合物和/或其他常规的增溶剂或分散剂制备为盐水溶液。例如,存在于本发明药物组合物中的抗体可以在100mg(10mL)或500mg(50mL)一次性使用小瓶中以10mg/mL的浓度提供。该产品配制为用于静脉内施用:9.0mg/mL氯化钠、7.35mg/mL柠檬酸钠二水合物、0.7mg/mL聚山梨醇酯80和无菌注射用水。将pH调节至6.5。本发明药物组合物中抗体的示例性合适剂量范围可为约1mg/m2至500mg/m2。然而,应当理解,这些明细是示例性的,并且考虑到必须在临床试验中测定的药物组合物中特定抗体的亲和力和耐受性,可以调整最佳明细和方案。可以制备用于注射(例如,肌肉内静脉注射)的本发明的药物组合物以含有无菌缓冲水(例如对于肌肉内,1ml)和约1ng至约100mg,例如约50ng至约30mg或更优选约5mg至约25mg的本发明的抗肌球蛋白18A抗体。
在某些实施方案中,考虑使用脂质体和/或纳米颗粒将抗体引入宿主细胞中。脂质体和/或纳米颗粒的形成和使用是本领域技术人员已知的。
纳米胶囊通常可以以稳定且可重复的方式包封化合物。为了避免由细胞内聚合物过载引起的副作用,通常使用能够在体内降解的聚合物设计这种超细颗粒(大小约0.1μm)。满足这些要求的可生物降解的聚烷基-氰基丙烯酸酯纳米颗粒预期用于本发明,并且可以容易地制备这些颗粒。
脂质体由磷脂形成,所述磷脂分散在水性介质中并自发形成多层同心双层囊泡(也称为多层囊泡(MLV))。MLV的直径通常为25nm至4μm。超声处理MLV导致形成直径为的小单层囊泡(SUV),其在核心中含有水溶液。脂质体的物理特性取决于pH、离子强度和二价阳离子的存在。
通过以下附图和实施例进一步说明本发明。然而,这些实施例和附图不应以任何方式解释为限制本发明的范围。
附图说明
图1:使用14A5.2单克隆抗体的Nectin-4表达的蛋白质印迹分析。
图2:14A5.2表位的表征。通过使用所示的不同单克隆抗体的ELISA进行竞争分析。14A5.2-HRP抗体与nectin-4的结合被14A5.2本身和mab1抑制,而不被mab2和Ha22-2抑制。
图3:ch14A5.2和Ha22-2对SUM190细胞诱导的细胞毒性。
在该实验中,通过将指定浓度的抗体与蛋白-G-DM1一起孵育来模拟ADC。在第5天测量细胞生长。14A5.2和Ha22.2诱导细胞毒性,具有相似的IC50。功效高于赫赛汀。
图4:ch14A5.2-vc-MMAE和Ha22-2-vc-MMAE对SUM190细胞诱导的细胞毒性。两种ADC(5ng/ml)的IC50相似。
图5:chN41mab-vc-MMAE、N41mab-vc-MMAE、ch14A5.2-vc-MMAE和Ha22-2-vc-MMAEADC对肿瘤生长的影响。用不同ADC(对于所有抗体,间隔6天以2.5mg/kg(交叉)进行2次i.v.注射)进行单次处理后,在NSG小鼠中作为肿瘤原位生长的SUM190细胞显示出消退。
图6:A.由指定浓度的抗体诱导的ADCC。发光对应于靶细胞的凋亡。B.ADCC介导的裂解效率代表测试的每种抗体的最大凋亡水平。
具体实施方式
材料和方法
蛋白质印迹
在100-mm培养皿中的MDA-MB-231wt或nectin-4转染细胞中分析Nectin-4表达,用冰冷的PBS洗涤3次,然后在750μl含有50mM Hepes、pH 7.5、150mM NaCl、1.5mM MgCl2、1mMEGTA、1%Triton X-100和10%甘油的冰冷裂解缓冲液中重悬30分钟。如推荐的那样添加蛋白酶抑制剂混合物(Roche Diagnostics)。将裂解物在SDS样品缓冲液(60mM Tris-HCl、pH6.7、3%SDS、2%(v/v)2-巯基乙醇和5%甘油)中加热,通过8%SDS-PAGE分离,半干转移至聚偏二氟乙烯膜(Immobilon-P,Millipore,Boston,MA,USA),用1μg/ml 14A5.2单克隆抗体探测。用ECL(Pierce)进行可视化。
竞争性测定
通过ELISA进行Mab竞争性测定。如图所示,用nectin4 VCC-Fc将96孔板在+4℃下包被过夜。在各种浓度的4种不同抗nectin-4 mab(mab1、mab2、mab3和Ha22-2mab)存在下,测量过氧化物酶偶联的14A5.2-HRP mab的结合。
ch14A5.2和Ha22-2(也称为来自Astellas公司的ASG-22ME)对SUM190细胞诱导的
细胞毒性
为了分析人源化抗体的作用,在0.65nM蛋白质-G-DM1存在下,将SUM190细胞与指定浓度的抗体一起孵育。使用制造商(Biosource,CA,USA)推荐的alamarBlue染色程序测量细胞生长。该测试包含荧光氧化还原指示剂。荧光强度与细胞代谢减少成比例。通过在第0天在96孔板中孵育3000个细胞/孔来进行实验。在第5天,通过在37℃下孵育1/10体积的alamarBlue溶液2小时来测量AlamarBlue,并在595nm处读取(FLUOstar Optima,BMGLabtech)。
生产ADC
ADC由Concortis(San Diego,CA,USA)生产。由纯化的ch14A5.2单克隆抗体产生偶联物。使用的接头是与单甲基奥瑞他汀-E(MMAE)共价偶联的MC-Val-Cit-PAB-PNP(马来酰亚胺基己酰基-L-缬氨酸-L-瓜氨酸-对氨基苯甲醇对硝基苯基碳酸酯)。选择这种可切割的接头是因为它诱导了强有力的旁观者杀伤。药物抗体比约为4。为了分析ADC的作用,将SUM190细胞与指定浓度的ADC一起孵育。使用制造商(Biosource,CA,USA)推荐的alamarBlue染色程序测量细胞生长。该测试包含荧光氧化还原指示剂。荧光强度与细胞代谢减少成比例。通过在第0天在96孔板中孵育3000个细胞/孔来进行实验。在第5天,通过在37℃下孵育1/10体积的alamarBlue溶液2小时来测量AlamarBlue,并在595nm处读取(FLUOstar Optima,BMG Labtech)。
动物模型
所有实验均与法国动物处理指南一致,并经当地伦理委员会批准(协议编号:01152-01)。NOD/SCID/γc敲除小鼠(NSG)获自Dr.C.River(Margate,UK)。将小鼠圈养在无菌条件下,无限制提供无菌食物和水,并保持12小时光照和12小时黑暗循环。将其中(0.5×106)悬浮在50%无酚红的Matrigel(Becton Dickinson Bioscience)中的SUM190细胞接种在乳腺脂肪垫中。
通过用数字卡尺测量并计算肿瘤体积(长度×宽度2×π/6)来监测肿瘤生长。将所有动物随机分配到处理组,使得每组的平均肿瘤体积为100至200mm3。如各实验中所述进行ADC处理。
抗体依赖性细胞介导的细胞毒性(ADCC)
将SUM190靶细胞(10E5细胞)铺板在96孔白色微孔板上过夜。使用制造商推荐的EasySepTM试剂盒从健康供体中纯化NK细胞。将10E6细胞(比例E:T=10)与指定浓度的抗体一起孵育4小时。使用Promega的Caspase-Glo发光试剂盒测量胱天蛋白酶-3/-7活化。孵育30分钟后测量发光(FLUOstar Optima,BMG Labtech)。
结果
本文提供的14A5.2单克隆抗体是根据严格标准(如特异性、表位作图和抗肿瘤活性)选择一系列抗nectin-4单克隆抗体所得。这对于在临床中使用是至关重要的,即,以最小的副作用优化抗肿瘤活性。
蛋白质印迹
在一系列抗nectin-4单克隆抗体中,14A5.2在转染的细胞中检测到独特的72kDa条带,而在用空载体转染的细胞中没有检测到(图1)。该m.w.对应于如前所述的nectin-4单体(Reymond等,JBC,2001)。MDAMB231wt细胞表达nectin-1、nectin-2和nectin-3。这表明14A5.2对nectin-4具有高度特异性,并且不检测其他nectin成员或其他不相关的蛋白质。通过FACS分析获得了类似的结果。
竞争性测定
在一系列抗nectin-4单克隆抗体中,我们筛选了与Ha22-2结合不同表位的抗体。14A5.2在nectin-4的IgV远端结构域中的表位与Ha22-2不同。如图2所示,Ha22-2与14A5.2没有竞争结合。Mab1是抗nectin-4阳性对照(与14A5.2竞争结合)。Mab2是抗nectin-4阴性对照(不与14A5.2竞争结合)。
在一系列抗nectin-4单克隆抗体中,我们筛选了具有强结合亲和力的单克隆抗体。将嵌合形式的14A5.2的结合与Ha22-2进行比较,通过FACS分析(20ng/ml)显示相似的亲和力(数据未显示)。
ch14A5.2和Ha22-2对SUM190细胞诱导的细胞毒性
该结果(图3)表明,在蛋白质-G-DM1存在下,ch14A5.2(IC50=6ng/ml)和Ha22.2(IC50=5ng/ml)的细胞毒性相似。在相同条件下,我们注意到曲妥珠单抗的IC50为100ng/ml。
生产ADC
该结果(图4)表明ch14A5.2-MMAE和Ha22.2-MMAE具有相似的细胞毒性。IC50为5ng/ml。
体内实验
在用SUM190细胞系异种移植的免疫受损的NSG小鼠中测试我们的ADC的活性。用连续两次i.v.剂量的chN41-vc-MMAE、ch14A5.2-vc-MMAE和Ha22.2-vc-MMAE抗体处理小鼠(图5)。CD30-vc-MMAE用作无关对照。这些剂量对小鼠无毒。两种ADC均诱导快速(4天)且显著的肿瘤消退,并且ch14A5.2与chN41(本发明人的另一种抗nectin-4抗体)相比效果更优异(持续时间持续长达20天)。
此外,图5的结果显示,在小鼠模型(免疫系统的活化)中,嵌合14A5.2抗体(ch14A5.2-vc-MMAE)的功效与其中Fc起作用的完全鼠抗体N41(N41-vc-MMAE)相同。因此,即使在NGS(使用的小鼠模型)中,吞噬作用或调理作用仍然是可能的。我们可以得出结论,如果14A5.2具有在小鼠模型中起作用的Fc(与ch14A5.2相反),则该抗体将具有比N41抗体更好的功效。
在体内抑制原发部位的转移性进展
用表达Nectin-4的荧光素酶阳性MDA-MB-231细胞原位异种移植小鼠。35天后测量原发肿瘤的体积。每周用10mg/kg裸14A5.2mabi.v.处理小鼠。通过生物发光测定被杀死小鼠的肺和肝脏。显示肺和肝脏的定量。通过35天的发光分析观察到,用两次连续i.v.的与MMAE偶联的14A5.2mab剂量处理原位异种移植诱导了所有转移性病变的快速减少和消失(数据未显示)。
ADCC测定
进行包括14A5.2抗体的不同抗体的ADCC活性分析。14A5.2的ADCC活性与N41抗体相似,但在IC50方面比Ha22好4倍(图6A)。14A5.2和N41抗体的裂解效率比Ha22好2倍(图6B)。曲妥珠单抗/赫赛汀和利妥昔单抗分别用作阳性和阴性对照。
结论
实现的不同测试表明,抗体14A5.2在ADC中优于N41,在ADCC中优于Ha22。因此,14A5.2抗体是测试的最好抗体(表1)。
表1:测试的不同抗体的效果
参考文献
在整个申请中,各种参考文献描述了本发明所属领域的现有技术。这些参考文献的公开内容通过引用结合到本公开中。
Claims (15)
1.一种具有重链和轻链的抗体,其中所述重链包含i)14A5.2mab的H-CDR1,ii)14A5.2mab的H-CDR2和iii)14A5.2 mab的H-CDR3,所述轻链包含i)14A5.2 mab的L-CDR1,ii)14A5.2 mab的L-CDR2和iii)14A5.2 mab的L-CDR3,其中:
-14A5.2 mab的H-CDR1由SEQ ID NO:1中第31位氨基酸残基至第35位氨基酸残基的序列限定;
-14A5.2 mab的H-CDR2由SEQ ID NO:1中第50位氨基酸残基至第66位氨基酸残基的序列限定;
-14A5.2 mab的H-CDR3由SEQ ID NO:1中第99位氨基酸残基至第104位氨基酸残基的序列限定;
-14A5.2 mab的L-CDR1由SEQ ID NO:2中第24位氨基酸残基至第38位氨基酸残基的序列限定;
-14A5.2 mab的L-CDR2由SEQ ID NO:2中第54位氨基酸残基至第60位氨基酸残基的序列限定;和
-14A5.2 mab的L-CDR3由SEQ ID NO:2中第93位氨基酸残基至第101位氨基酸残基的序列限定。
2.根据权利要求1所述的抗体,具有与SEQ ID NO:1具有至少70%同一性的重链和与SEQ ID NO:2具有至少70%同一性的轻链。
3.根据权利要求2所述的抗体,具有与SEQ ID NO:1相同的重链和与SEQ ID NO:2相同的轻链。
4.根据权利要求1所述的抗体,其是嵌合抗体。
5.根据权利要求1所述的抗体,其是包含14A5.2 mab抗体的CDR的人源化抗体。
6.编码根据权利要求1所述的抗体的核酸分子。
7.根据权利要求1所述的抗体,其与细胞毒性部分偶联。
8.根据权利要求7所述的抗体,其与选自以下细胞毒性部分偶联:紫杉醇;细胞松弛素B;短杆菌肽D;溴化乙锭;吐根碱;丝裂霉素;依托泊苷;替尼泊苷;长春新碱;长春碱;秋水仙碱;多柔比星;柔红霉素;二羟基蒽二酮;微管蛋白抑制剂如美登素或其类似物或衍生物;抗有丝分裂剂如单甲基奥瑞他汀E或F或其类似物或衍生物;海兔毒素10或15或其类似物;伊立替康或其类似物;米托蒽醌;光辉霉素;放线菌素D;1-脱氢睾酮;糖皮质激素;普鲁卡因;丁卡因;利多卡因;普萘洛尔;嘌呤霉素;卡奇霉素或其类似物或衍生物;抗代谢物,如甲氨喋呤、6巯基嘌呤、6硫鸟嘌呤、阿糖胞苷、氟达拉滨、5氟尿嘧啶、氨烯咪胺、羟基脲、天冬酰胺酶、吉西他滨或克拉屈滨;烷化剂,如二氯甲基二乙胺、硫代嘌呤、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲佐菌素、达卡巴嗪(DTIC)、丙卡巴嗪、丝裂霉素C;铂类衍生物,如顺铂或卡铂;多卡霉素A、多卡霉素SA、雷切霉素(CC-1065)或其类似物或衍生物;抗生素,如放线菌素、博来霉素、柔红霉素、多柔比星、伊达比星、光霉素、丝裂霉素、米托蒽醌、普力霉素、安定霉素(AMC);吡咯并[2,1-c][1,4]-苯并二氮杂卓(PDB);白喉毒素及相关分子如白喉A链及其活性片段和杂合分子、蓖麻毒素如蓖麻毒素A或去糖基化蓖麻毒素A链毒素、霍乱毒素、志贺样毒素如SLT I、SLT II、SLT IIV、LT毒素、C3毒素、志贺毒素、百日咳毒素、破伤风毒素、大豆Bowman-Birk蛋白酶抑制剂、假单胞菌外毒素、阿罗林、皂草素、蒴莲根毒素、胶凝蛋白、相思豆毒素A链、蒴莲根毒素A链、α-八叠球菌素(alpha-sarcin)、油桐(Aleurites fordii)蛋白、石竹素蛋白、美洲商陆蛋白如PAPI、PAPII和PAP-S、苦瓜(momordica charantia)抑制剂、泻果素、巴豆毒素、肥阜草(sapaonaria officinalis)抑制剂、白树毒素、米托菌素、局限曲菌素、酚霉素和依诺霉素毒素;核糖核酸酶(RNase);DNase I、葡萄球菌内毒素A;商陆抗病毒蛋白;白喉毒素和假单胞菌内毒素。
9.根据权利要求1所述的抗体用作药物的用途。
10.一种治疗有需要的受试者的癌症的方法,包括向所述受试者施用治疗有效量的根据权利要求1所述的抗体。
11.根据权利要求11所述的方法,其中所述癌症是乳腺癌、卵巢癌或肺癌。
12.根据权利要求11所述的方法,其中所述癌症是转移性癌症。
13.包含根据权利要求1所述的抗体的药物组合物。
14.一种嵌合抗原受体,其包含至少一个权利要求1所述的抗体的VH和/或VL序列。
15.与权利要求1所述的抗体竞争结合Nectin-4的抗体。
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CN113527486A (zh) * | 2020-04-21 | 2021-10-22 | 迈威(上海)生物科技股份有限公司 | 一种抗Nectin-4的抗体及其应用 |
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WO2022228406A1 (zh) * | 2021-04-26 | 2022-11-03 | 江苏恒瑞医药股份有限公司 | 抗Nectin-4抗体和抗Nectin-4抗体-药物偶联物及其医药用途 |
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CN114702588B (zh) * | 2022-04-27 | 2022-11-22 | 博际生物医药科技(杭州)有限公司 | 抗Nectin-4抗体和双特异性抗体 |
CN114702588A (zh) * | 2022-04-27 | 2022-07-05 | 博际生物医药科技(杭州)有限公司 | 抗Nectin-4抗体和双特异性抗体 |
WO2023221971A1 (zh) * | 2022-05-16 | 2023-11-23 | 江苏恒瑞医药股份有限公司 | 一种含抗Nectin-4抗体药物偶联物的药物组合物及其用途 |
CN117986367A (zh) * | 2024-04-02 | 2024-05-07 | 上海美迪西生物医药股份有限公司 | 靶点为Nectin-4的抗体及其应用 |
CN117986367B (zh) * | 2024-04-02 | 2024-07-16 | 上海美迪西生物医药股份有限公司 | 靶点为Nectin-4的抗体及其应用 |
Also Published As
Publication number | Publication date |
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WO2018158398A1 (en) | 2018-09-07 |
JP2020510432A (ja) | 2020-04-09 |
EP3589654A1 (en) | 2020-01-08 |
US11274160B2 (en) | 2022-03-15 |
US20210324104A1 (en) | 2021-10-21 |
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