CN104271601A - 使用pd-1轴结合拮抗剂和vegf拮抗剂治疗癌症的方法 - Google Patents
使用pd-1轴结合拮抗剂和vegf拮抗剂治疗癌症的方法 Download PDFInfo
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Abstract
本发明描述了包含PD-1轴结合拮抗剂、化疗和任选的VEGF拮抗剂的联合治疗及其使用方法,包括治疗期望增强的免疫原性的状况(诸如提高肿瘤免疫原性以治疗癌症)的方法。
Description
对相关申请的交叉引用
本申请要求2012年5月31日提交的美国临时申请号61/653,861的权益,通过提及将其完整收入本文。
序列表
本申请含有序列表,已经以ASCII格式经EFS-Web提交且通过述及完整收入本文。2013年5月28日创建的所述ASCII拷贝命名为P4926R1WO.txt,并且大小为14,285个字节。
发明背景
对T细胞提供两种截然不同的信号是一种关于抗原呈递细胞(APC)对静息T淋巴细胞的淋巴细胞活化的广泛公认的模型。Lafferty等,Aust.J.Exp.Biol.Med.ScL 53:27-42(1975)。此模型进一步提供了自身与非自身的辨别和免疫耐受性。Bretscher等,Science 169:1042-1049(1970);Bretscher,P.A.,P.N.A.S.USA 96:185-190(1999);Jenkins等,J.Exp.Med.165:302-319(1987)。在主要组织相容性复合体(MHC)的背景中呈递的外来抗原肽的识别后,第一信号,或抗原特异性信号经由T细胞受体(TCR)转导。第二或共刺激信号通过抗原呈递细胞(APC)上表达的共刺激分子投递至T细胞,并且诱导T细胞以促进克隆扩充,细胞因子分泌和效应器功能。Lenschow等,Ann.Rev.Immunol.14:233(1996)。在缺乏共刺激的情况中,T细胞能对抗原刺激变得不应,不发起有效的免疫应答,并且进一步可以导致对外来抗原的耐受性或耗竭。
在两信号模型中,T细胞接受正和负第二共刺激信号两者。此类正和负信号的调节对于在维持免疫耐受性和防止自身免疫的同时使宿主的保护性免疫应答最大化是至关重要的。负第二信号对于诱导T细胞耐受性似乎是必需的,而正信号促进T细胞活化。虽然简单的两信号模型仍然为未免疫淋巴细胞提供有效解释,但是宿主的免疫应答是一个动态过程,并且也可以对抗原暴露的T细胞提供共刺激信号。共刺激的机制是治疗学方面感兴趣的,因为已经显示了共刺激信号的操作提供增强或终止基于细胞的免疫应答的手段。最近,已经发现了T细胞功能障碍或无反应性与抑制性受体(编程性死亡1多肽(PD-1))的诱导且持续的表达并行发生。因此,PD-1和经由与PD-1的相互作用发信号的其它分子,诸如编程性死亡配体1(PD-Ll)和编程性死亡配体2(PD-L2)的治疗性靶向是强烈感兴趣的领域。
PD-L1在许多癌症中过表达,并且经常与不良预后关联(Okazaki T等,Intern.Immun.2007,19(7):813;Thompson RH等,Cancer Res 2006,66(7):3381)。令人感兴趣地,与正常组织中的T淋巴细胞和外周血T淋巴细胞形成对比,大多数肿瘤浸润性T淋巴细胞主要表达PD-1,这指示肿瘤反应性T细胞上PD-1的上调可以促成受损的抗肿瘤免疫应答(Blood 2009114(8):1537)。这可以是由于利用由与PD-1表达T细胞相互作用的PD-L1表达肿瘤细胞介导的PD-L1信号传导以导致T细胞活化的减弱及逃避免疫监视(Sharpe等,NatRev 2002)(Keir ME等,2008Annu.Rev.Immunol.26:677)。因此,对PD-L1/PD-1相互作用的抑制可以增强CD8+T细胞介导的肿瘤杀伤。
已经提出经由其直接配体(例如PD-Ll,PD-L2)抑制PD-1轴信号传导为增强T细胞免疫以治疗癌症(例如肿瘤免疫)的手段。此外,已经通过抑制PD-L1与结合配偶B7-1的结合观察到对T细胞免疫的类似增强。最佳的治疗性处理可组合PD-1受体/配体相互作用的阻断与其它抗癌剂。仍然需要用于治疗各种癌症,稳定化各种癌症,预防各种癌症,和/或延迟各种癌症形成的此类最佳疗法。
在此通过提及将本文中公开的所有参考文献,出版物,和专利申请完整收录。
发明概述
本发明描述了联合治疗,其在有或无VEGF拮抗剂的情况下包含奥沙利铂、亚叶酸和5-FU及PD-1轴结合拮抗剂。
本文中提供了在个体中治疗癌症或延迟癌症进展的方法,其包括对所述个体施用有效量的PD-1轴结合拮抗剂及奥沙利铂、亚叶酸和5-FU。在一些方面,所述方法进一步包括施用VEGF拮抗剂。
癌症可以是黑素瘤、结肠直肠癌、非小细胞肺癌、卵巢癌、乳腺癌、前列腺癌、胰腺癌、血液学恶性(malignancy)或肾细胞癌。癌症可以为早期阶段或晚期阶段。在一些实施方案中,治疗的受试者是人。
在一些实施方案中,治疗导致停止治疗后个体中持续的应答。在一些实施方案中,治疗在受试者中产生完全应答,部分应答,或稳定疾病。
在一些实施方案中,PD-1轴结合拮抗剂是PD-1结合拮抗剂,PD-L1结合拮抗剂或PD-L2结合拮抗剂。在一些实施方案中,PD-1结合拮抗剂抑制PD-1与PD-L1的结合和/或PD-1与PD-L2的结合。在一些实施方案中,PD-1结合拮抗剂是抗体(例如本文中描述的抗体MDX-1106,CT-011和Merck 3745),其抗原结合片段,免疫粘附素,融合蛋白,或寡肽。在一些实施方案中,PD-L1结合拮抗剂抑制PD-L1与PD-1的结合和/或PD-L1与B7-1的结合。在一些实施方案中,PD-L1结合拮抗剂是抗体(例如本文中描述的抗体YW243.55.S70和MDX-1105),其抗原结合片段,免疫粘附素,融合蛋白,或寡肽。在一些实施方案中,PD-L2结合拮抗剂抑制PD-L2与PD-1的结合。在一些实施方案中,PD-L2结合拮抗剂是抗体,其抗原结合片段,免疫粘附素(例外本文所述AMP-224),融合蛋白,或寡肽。
在一些实施方案中,VEGF拮抗剂是抗体,例如单克隆抗体。在一些实施方案中,抗VEGF抗体与由杂交瘤ATCC HB 10709生成的单克隆抗VEGF抗体A4.6.1结合相同表位。抗VEGF抗体可以是人源化抗体或人抗体。在一些实施方案中,抗VEGF抗体是贝伐单抗(bevacizumab)。在一些实施方案中,抗VEGF抗体具有包含下述氨基酸序列的重链可变区:
EVQLVESGGG LVQPGGSLRL SCAASGYTFT NYGMNWVRQA PGKGLEIVVGW
INTYTGEPTY AADFKRRFTF SLDTSKSTAY LQMNSLRAED TAVYYCAKYP
HYYGSSHWYF DVWGQGTLVT VSS(SEQ ID NO:22)
和包含下述氨基酸序列的轻链可变区:
DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP GKAPKVLIYF
TSSLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSTVPWTFGQ
GTKVEIKR(SEQ ID NO:23)。
在另一个方面,提供了在有或无VEGF拮抗剂的情况下包含PD-1轴结合拮抗剂、奥沙利铂、亚叶酸和5-FU的试剂盒,其用于在个体中治疗癌症或延迟癌症进展或者在具有癌症的个体中增强免疫功能。试剂盒可以包含PD-1轴结合拮抗剂和包装插页,该包装插页包含关于在有或无VEGF拮抗剂的情况下与奥沙利铂、亚叶酸和5-FU组合使用PD-1轴结合拮抗剂在个体中治疗癌症或延迟癌症进展或在具有癌症的个体中增强免疫功能的用法说明书。试剂盒可以包含VEGF拮抗剂和包装插页,该包装插页包含关于与PD-1轴结合拮抗剂及奥沙利铂、亚叶酸和5-FU组合使用VEGF拮抗剂在个体中治疗癌症或延迟癌症进展或在具有癌症的个体中增强免疫功能的用法说明书。试剂盒可以包含PD-1轴结合拮抗剂和VEGF拮抗剂,及包装插页,该包装插页包含关于使用PD-1轴结合拮抗剂和VEGF拮抗剂在个体中治疗癌症或延迟癌症进展或在具有癌症的个体中增强免疫功能的用法说明书。
附图简述
图1是描绘在抗PD-L1抗体和FOLFOX共处理的情况中肿瘤体积变化的图。数据表明与仅抗PD-L1抗体或FOLFOX处理相比显著的肿瘤生长降低和持续的抗肿瘤效果。
图2是显示图1所示处理组的体重变化的图。
图3是描绘在抗PD-L1抗体与FOLFOX组合的情况中与抗PD-L1抗体与FOLFOX和抗VEGF抗体组合相比肿瘤体积变化的图。数据表明与抗PD-L1抗体与FOLFOX组合处理相比额外施用抗VEGF抗体显著降低肿瘤生长且导致持久的抗肿瘤效应。
图4是显示图3所示处理组的体重变化的图。
发明详述
I.通用技术
本文中描述或提及的技术和规程是本领域技术人员一般充分了解且通常采用的,其使用常规方法,诸如例如广泛利用的方法进行,该方法记载于Sambrook等,Molecular Cloning:A Laboratory Manual 3d edition(2001)ColdSpring Harbor Laboratory Press,Cold Spring Harbor,N.Y.;Current Protocols inMolecular Biology(F.M.Ausubel等编,(2003));丛刊Methods in Enzymology(Academic Press,Inc.):PCR 2:A Practical Approach(M.J.MacPherson,B.D.Hames and G.R.Taylor编(1995)),Harlow和Lane编(1988)Antibodies,ALaboratory Manual,and Animal Cell Culture(R.I.Freshney编(1987));Oligonucleotide Synthesis(M.J.Gait编,1984);Methods in Molecular Biology,Humana Press;Cell Biology:A Laboratory Notebook(J.E.Cellis编,1998)Academic Press;Animal Cell Culture(R.I.Freshney)编,1987);Introduction toCell and Tissue Culture(J.P.Mather和P.E.Roberts,1998)Plenum Press;Cell andTissue Culture:Laboratory Procedures(A.Doyle,J.B.Griffiths,和D.G.Newell编,1993-8)J.Wiley and Sons;Handbook of Experimental Immunology(D.M.Weir和C.C.Blackwell编);Gene Transfer Vectors for Mammalian Cells(J.M.Miller和M.P.Calos编,1987);PCR:The Polymerase Chain Reaction,(Mullis等编,1994);Current Protocols in Immunology(J.E.Coligan等编,1991);ShortProtocols in Molecular Biology(Wiley和Sons,1999);Immunobiology(C.A.Janeway和P.Travers,1997);Antibodies(P.Finch,1997);Antibodies:A PracticalApproach(D.Catty.编,IRL Press,1988-1989);Monoclonal Antibodies:APractical Approach(P.Shepherd和C.Dean编,Oxford University Press,2000);Using Antibodies:A Laboratory Manual(E.Harlow和D.Lane(Cold SpringHarbor Laboratory Press,1999);The Antibodies(M.Zanetti和J.D.Capra编,Harwood Academic Publishers,1995);及Cancer:Principles and Practice ofOncology(V.T.DeVita等编,J.B.Lippincott Company,1993)。
II.定义
术语“PD-1轴结合拮抗剂”是一种抑制PD-1轴结合配偶与一种或多种其结合配偶的相互作用,使得消除源自PD-1信号传导轴上的信号传导的T细胞功能障碍(结果是恢复或增强T细胞功能)的分子。如本文中使用的,PD-1轴结合拮抗剂包括PD-1结合拮抗剂、PD-L1结合拮抗剂和PD-L2结合拮抗剂。
术语“PD-1结合拮抗剂”是一种降低、阻断、抑制、消除或干扰源自PD-1与一种或多种其结合配偶,诸如PD-L1,PD-L2的相互作用的信号转导的分子。在一些实施方案中,PD-1结合拮抗剂是一种抑制PD-1与其结合配偶结合的分子。在一个具体的方面,PD-1结合拮抗剂抑制PD-1与PD-L1和/或PD-L2的结合。例如,PD-1结合拮抗剂包括降低、阻断、抑制、消除或干扰源自PD-1与PD-L1和/或PD-L2相互作用的信号转导的抗PD-1抗体、其抗原结合片段、免疫粘附素、融合蛋白、寡肽和其它分子。在一个实施方案中,PD-1结合拮抗剂降低负共刺激信号,从而使功能障碍T细胞不太为非功能障碍的,所述负共刺激信号经由PD-1由或经由T淋巴细胞上表达的细胞表面蛋白质介导的信号传导介导。在一些实施方案中,PD-1结合拮抗剂是抗PD-1抗体。在一个具体的方面,PD-1结合拮抗剂是本文中描述的MDX-1106。在另一个具体的方面,PD-1结合拮抗剂是本文中描述的Merck 3745。在另一个具体的方面,PD-1结合拮抗剂是本文中描述的CT-011。
术语“PD-L1结合拮抗剂”是一种降低、阻断、抑制、消除或干扰源自PD-L1与一种或多种其结合配偶,诸如PD-1,B7-1的相互作用的信号转导的分子。在一些实施方案中,PD-L1结合拮抗剂是抑制PD-L1与其结合配偶结合的分子。在一个具体的方面,PD-L1结合拮抗剂抑制PD-L1与PD-1和/或B7-1的结合。在一些实施方案中,PD-L1结合拮抗剂包括降低、阻断、抑制、消除或干扰源自PD-L1与一种或多种其结合配偶,诸如PD-1,B7-1的相互作用的信号转导的抗PD-L1抗体,其抗原结合片段,免疫粘附素,融合蛋白,寡肽和其它分子。在一个实施方案中,PD-L1结合拮抗剂降低负共刺激信号,从而使功能障碍T细胞不太为非功能障碍的,所述负共刺激信号经由PD-L1由或经由T淋巴细胞上表达的细胞表面蛋白质介导的信号传导介导。在一些实施方案中,PD-L1结合拮抗剂是抗PD-L1抗体。在一个具体的方面,抗PD-L1抗体是本文中描述的YW243.55.S70。在另一个具体的方面,抗PD-L1抗体是本文中描述的MDX-1105。
术语“PD-L2结合拮抗剂”是一种降低、阻断、抑制、消除或干扰源自PD-L2与一种或多种其结合配偶,诸如PD-1的相互作用的信号转导的分子。在一些实施方案中,PD-L2结合拮抗剂是抑制PD-L2与其结合配偶结合的分子。在一个具体的方面,PD-L2结合拮抗剂抑制PD-L2与PD-1的结合。在一些实施方案中,PD-L2拮抗剂包括降低、阻断、抑制、消除或干扰源自PD-L2与一种或多种其结合配偶,诸如PD-1的相互作用的信号转导的抗PD-L2抗体,其抗原结合片段,免疫粘附素,融合蛋白,寡肽和其它分子。在一个实施方案中,PD-L2结合拮抗剂降低负共刺激信号,从而使功能障碍T细胞不太为非功能障碍的,所述负共刺激信号经由PD-L2由或经由T淋巴细胞上表达的细胞表面蛋白质介导的信号传导介导。在一些实施方案中,PD-L2结合拮抗剂是PD-L2免疫粘附素。在一个具体的方面,PD-L2免疫粘附素是本文中描述的AMP-224。
“VEGF拮抗剂”指能够中和、阻断、抑制、消除、降低或干扰VEGF活性(包括其与一种或多种VEGF受体的结合)的分子。VEGF拮抗剂包括抗VEGF抗体及其抗原结合片段、特异性结合VEGF由此使其隔绝与一种或多种受体结合的受体分子及衍生物、抗VEGF受体抗体和VEGF受体拮抗剂诸如VEGFR酪氨酸激酶的小分子抑制剂。
术语“VEGF”或“VEGF-A”用于指165个氨基酸的人血管内皮细胞生长因子及相关的121个、145个、189个和206个氨基酸的人血管内皮细胞生长因子,如例如Leung et al.Science,246:1306(1989);及Houck et al.Mol.Endocrin.,5:1806(1991)所述,及其天然存在的等位基因形式和加工形式。VEGF-A是包括VEGF-B、VEGF-C、VEGF-D、VEGF-E、VEGF-F和PlGF在内的基因家族的一部分。VEGF-A主要结合两种高亲和力受体酪氨酸激酶,即VEGFR-1(Flt-1)和VEGFR-2(Flk-1/KDR),后者是VEGF-A血管内皮细胞有丝分裂信号的主要递质。另外,神经毡蛋白-1已经被鉴定为肝素结合VEGF-A同种型(isoform)的受体,而且可在血管发育中发挥作用。术语“VEGF”或“VEGF-A”还指来自非人物种诸如小鼠、大鼠或灵长类动物的VEGF。有时,来自特定物种的VEGF表示如下,hVEGF表示人VEGF,mVEGF表示鼠VEGF。术语“VEGF”还用于指包含165个氨基酸的人血管内皮细胞生长因子的氨基酸第8-109位或第1-109位的截短形式多肽。本申请中可能通过例如“VEGF(8-109)”、“VEGF(1-109)”或“VEGF165”来鉴别任何此类形式VEGF。“截短的”天然VEGF的氨基酸位置如天然VEGF序列中所示编号。例如,截短的天然VEGF中的第17位氨基酸(甲硫氨酸)也是天然VEGF中的第17位(甲硫氨酸)。截短的天然VEGF具有与天然VEGF相当的对KDR和Flt-1受体的结合亲和力。
“抗VEGF抗体”指以足够亲和力和特异性结合VEGF的抗体。所选择的抗体通常会具有对VEGF的结合亲和力,例如,该抗体可以以介于100nM-1pM之间的Kd值结合hVEGF。抗体亲和力可通过例如基于表面等离振子共振的测定法(诸如PCT申请公开文本No.WO2005/012359中所记载的BIAcore测定法);酶联免疫吸附测定法(ELISA);和竞争测定法(例如RIA)来测定。在某些实施方案中,本发明的抗VEGF抗体可用作治疗剂,用于靶向和干扰其中涉及VEGF活性的疾病或疾患。还有,可对该抗体进行其它生物学活性测定法,例如为了评估其作为治疗剂的效力所进行的生物学活性测定法。此类测定法是本领域已知的,而且取决于抗体的靶抗原和预定用途。例子包括HUVEC抑制测定法;肿瘤细胞生长抑制测定法(如例如WO 89/06692中所记载的);抗体依赖性细胞的细胞毒性(ADCC)和补体介导的细胞毒性(CDC)测定法(美国专利5,500,362);及激动活性或造血测定法(参见WO 95/27062)。抗VEGF抗体通常不会结合其它VEGF同系物,诸如VEGF-B或VEGF-C,也不会结合其它生长因子,诸如PlGF、PDGF或bFGF。
“嵌合VEGF受体蛋白”指具有衍生自至少两种不同蛋白质(其中至少一种是VEGF受体蛋白)的氨基酸序列的VEGF受体分子。在某些实施方案中,嵌合VEGF受体蛋白能够结合VEGF并抑制VEGF的生物学活性。
“抗血管发生剂”或“血管发生抑制剂”指或直接或间接抑制血管发生(angiogenesis)、血管生成(vasculogenesis)、或不想要的血管通透性的小分子量物质、多核苷酸、多肽、分离的蛋白质、重组蛋白、抗体、或其偶联物或融合蛋白。应当理解,抗血管发生剂包括那些结合并阻断血管发生因子或其受体的血管发生活性的药剂。例如,抗血管发生剂是上文定义的血管发生剂的抗体或其它拮抗剂,例如VEGF-A的抗体、VEGF-A受体(例如KDR受体或Flt-1受体)的抗体、抗PDGFR抑制剂诸如GleevecTM(Imatinib Mesylate)。抗血管发生剂还包括天然血管发生抑制剂,例如血管他丁(angiostatin)、内皮他丁(endostatin)等。参见例如Klagsbrun and D’Amore,Annu.Rev.Physiol.53:217-39(1991);Streit and Detmar,Oncogene 22:3172-3179(2003)(例如列举恶性黑素瘤中抗血管发生疗法的表3);Ferrara&Alitalo,Nature Medicine5:1359-1364(1999);Tonini等,Oncogene 22:6549-6556(2003)(例如列举已知抗血管发生因子的表2);Sato,Int.J.Clin.Oncol.8:200-206(2003)(例如列举临床试验中所使用的抗血管发生剂的表1)。
术语“功能障碍”在免疫功能障碍的背景中指对抗原性刺激的响应性降低的免疫状态。该术语包括可以发生抗原识别,但是随后的免疫应答对于控制感染或肿瘤生长无效的耗竭和/或无反应性两者的共同要素。
“增强T细胞功能”意指诱导,引起或刺激T细胞具有持续或放大的生物学功能,或者恢复或再活化耗竭的或无活性的T细胞。增强T细胞功能的例子包括:相对于干预前的此类水平,升高的来自CD8+T细胞的γ-干扰素分泌,升高的增殖,升高的抗原响应性(例如病毒或病原体清除)。在一个实施方案中,增强的水平是至少50%,或者60%,70%,80%,90%,100%,120%,150%,200%。测量此增强的方式是本领域普通技术人员已知的。
“T细胞功能障碍性病症”是以降低的对抗原性刺激的响应性为特征的T细胞病症或状况。在一个具体的实施方案中,T细胞功能障碍性病症是明确与经由PD-1的不适当升高的信号传导有关的病症。在另一个实施方案中,T细胞功能障碍性病症是如下的病症,其中T细胞是无反应性的或者具有降低的分泌细胞因子,增殖,或者执行细胞裂解活性的能力。在一个具体的方面,降低的响应性导致对表达免疫原的病原体或肿瘤的无效控制。以T细胞功能障碍为特征的T细胞功能障碍性病症的例子包括未分辨的急性感染,慢性感染和肿瘤免疫。
“肿瘤免疫”指肿瘤逃避免疫识别和清除的过程。如此,作为治疗概念,肿瘤免疫在此类逃避减弱时得到“治疗”,并且肿瘤被免疫系统识别并攻击。肿瘤识别的例子包括肿瘤结合,肿瘤收缩和肿瘤清除。
“免疫原性”指特定物质引发免疫应答的能力。肿瘤是免疫原性的,并且增强肿瘤免疫原性有助于通过免疫应答清除肿瘤细胞。增强肿瘤免疫原性的例子包括在有或无VEGF拮抗剂的情况下用抗PDL抗体、奥沙利铂、亚叶酸和5-FU处理。
“持续应答”指在停止处理后对降低肿瘤生长的持续影响。例如,与施用阶段开始时的大小相比,肿瘤大小可以保持为相同或更小。在一些实施方案中,持续应答具有与处理持续时间至少相同的持续时间,处理持续时间的至少1.5倍,2.0倍,2.5倍,或3.0倍长度。
术语“抗体”包括单克隆抗体(包括具有免疫球蛋白Fc区的全长抗体),具有多表位特异性的抗体组合物,多特异性抗体(例如双特异性抗体),双抗体,和单链分子,及抗体片段(例如Fab,F(ab’)2,和Fv)。术语“免疫球蛋白”(Ig)在本文中与“抗体”可互换使用。
基本的4链抗体单元是由两条相同的轻链(L)和两条相同的重链(H)构成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元及称作J链的另外多肽组成,而且包含10个抗原结合位点,而IgA抗体包含与J链组合的2-5个能聚合而形成多价装配物的基本4链单元。在IgG的情况中,4链单元通常是约150,000道尔顿。每条轻链通过一个共价二硫键与重链相连,而两条重链通过一个或多个二硫键彼此相连,二硫键的数目取决于重链的同种型。每条重链和轻链还具有间隔规律的链内二硫桥。每条重链在N-末端具有一个可变域(VH),接着是三个(对于α和γ链)或四个(对于μ和ε同种型)恒定域(CH)。每条轻链在N-末端具有一个可变域(VL),接着是其另一端的一个恒定域(CL)。VL与VH排列在一起,而CL与重链第一恒定域(CH1)排列在一起。认为特定的氨基酸残基在轻链和重链可变域之间形成界面。一个VH和一个VL一起配对而形成一个抗原结合位点。关于不同类别抗体的结构和性质,参见例如Basicand Clinical Immunology,第8版,Daniel P.Sties,Abba I.Terr and Tristram G.Parsolw(编),Appleton&Lange,Norwalk,CT,1994,第71页和第6章。根据其恒定域氨基酸序列,来自任何脊椎动物物种的L链可归入两种截然不同类型中的一种,称作卡帕(κ)和拉姆达(λ)。根据其重链恒定域(CH)氨基酸序列,免疫球蛋白可归入不同的类别或同种型。有五类免疫球蛋白:IgA、IgD、IgE、IgG和IgM,分别具有称作α、δ、ε、γ和μ的重链。根据CH序列和功能的较小差异,γ和α类可进一步分为亚类,例如人类表达下列亚类:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgA2。
抗体的“可变区”或“可变域”指抗体重链或轻链的氨基末端结构域。重链可变域和轻链可变域分别可以称为“VH”和“VL”。这些结构域一般是抗体的最易变部分(相对于同一类的其它抗体而言)且包含抗原结合位点。
术语“可变的”指可变域中的某些区段在抗体间序列差异广泛的实情。V结构域介导抗原结合且限定特定抗体对其特定抗原的特异性。然而,变异性并非均匀分布于可变域的整个跨度。而是,它集中于轻链和重链可变域二者中称作高变区(HVR)的三个区段。可变域中更加高度保守的部分称作框架区(FR)。天然重链和轻链的可变域各自包含四个FR区,它们大多采取β-折叠片构象,通过形成环状连接且在有些情况中形成β-折叠片结构一部分的三个HVR连接。每条链中的HVR通过FR区非常接近的保持在一起,并与另一条链的HVR一起促成抗体的抗原结合位点的形成(参见Kabat等,Sequences ofImmunological Interest,第5版,National Institute of Health,Bethesda,MD.(1991))。恒定域不直接参与抗体与抗原的结合,但展现出多种效应器功能,诸如抗体在抗体依赖性细胞的细胞毒性中的参与。
术语“单克隆抗体”在用于本文时指从一群基本上同质的抗体获得的抗体,即构成群体的各个抗体相同,除了可能以极小量存在的可能的天然存在突变和/或翻译后修饰(例如异构化、酰胺化)外。单克隆抗体是高度特异性的,针对单一抗原性位点。与典型的包含针对不同决定簇(表位)的不同抗体的多克隆抗体制备物不同,每种单克隆抗体针对抗原上的单一决定簇。在它们的特异性以外,单克隆抗体的优势在于它们是由杂交瘤培养物合成的,未受到其它免疫球蛋白的污染。修饰语“单克隆”指示抗体从基本上同质的抗体群获得的特征,不应解释为要求通过任何特定方法来生成抗体。例如,有待依照本发明使用的单克隆抗体可通过多种技术来生成,包括例如杂交瘤法(例如Kohler and Milstein.,Nature,256:495-97(1975);Hongo等,Hybridoma,14(3):253-260(1995),Harlow等,Antibodies:A Laboratory Manual,(Cold SpringHarbor Laboratory Press,2nd ed.1988);Hammerling等,in:MonoclonalAntibodies and T-Cell Hybridomas 563-681(Elsevier,N.Y.,1981))、重组DNA法(参见例如美国专利No.4,816,567)、噬菌体展示技术(参见例如Clackson等,Nature 352:624-628(1991);Marks等,J.Mol.Biol.222:581-597(1992);Sidhu等,J.Mol.Biol.338(2):299-310(2004);Lee等,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Nat.Acad.Sci.USA 101(34):12467-12472(2004);Lee等,J.Immunol.Methods 284(1-2):119-132(2004))、及用于在具有部分或整个人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物中生成人或人样抗体的技术(参见例如WO 1998/24893;WO 1996/34096;WO 1996/33735;WO1991/10741;Jakobovits等,Proc.Natl.Acad.Sci.USA 90:2551(1993);Jakobovits等,Nature 362:255-258(1993);Bruggemann等,Year in Immunol.7:33(1993);美国专利No.5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;5,661,016;Marks等,Bio/Technology 10:779-783(1992);Lonberg等,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild等,Nature Biotechnol.14:845-851(1996);Neuberger,Nature Biotechnol.14:826(1996);Lonberg and Huszar,Intern.Rev.Immunol.13:65-93(1995))。
术语“裸抗体(裸露的抗体)”指未缀合细胞毒性模块或放射性标记物的抗体。
术语“全长抗体”、“完整抗体”和“全抗体”可互换使用,指基本上完整形式的抗体,与抗体片段不同。具体而言,完整抗体包括那些具有重链和轻链(包括Fc区)的。恒定域可以是天然序列恒定域(例如人天然序列恒定域)或其氨基酸序列变体。在有些情况中,完整抗体可具有一项或多项效应器功能。
“抗体片段”包含完整抗体的一部分,优选完整抗体的抗原结合和/或可变区。抗体片段的例子包括Fab、Fab’、F(ab’)2和Fv片段;双抗体;线性抗体(参见美国专利5,641,870,实施例2;Zapata等,Protein Eng.8(10):1057-1062(1995));单链抗体分子;及由抗体片段形成的多特异性抗体。用木瓜蛋白酶消化抗体产生两个相同的抗原结合片段,称作“Fab”片段,和一个残余“Fc”片段,其名称反映了它易于结晶的能力。Fab片段由完整L链及H链可变区域(VH)和重链第一恒定域(CH1)组成。每个Fab片段对于抗原结合是单价的,即它具有一个抗原结合位点。胃蛋白酶处理抗体产生一个较大F(ab’)2片段,它大体相当于两个通过二硫键相连的Fab片段,具有不同抗原结合活性且仍能够交联抗原。Fab’片段因在CH1结构域的羧基末端增加了少数残基而与Fab片段有所不同,包括来自抗体铰链区的一个或多个半胱氨酸。Fab’-SH是本文中对其中恒定域半胱氨酸残基携带游离硫醇基的Fab’的称谓。F(ab’)2抗体片段最初是作为成对Fab’片段生成的,在Fab’片段之间具有铰链半胱氨酸。还知道抗体片段的其它化学偶联。
Fc片段包含通过二硫键保持在一起的两条H链的羧基末端部分。抗体的效应器功能由Fc区中的序列来决定,该区域也受到在某些类型的细胞上找到的Fc受体(FcR)识别。
“Fv”是包含完整抗原识别和结合位点的最小抗体片段。此片段由紧密、非共价结合的一个重链可变区和一个轻链可变区的二聚体组成。从这两个结构域的折叠中生发出六个高变环(重链和轻链各3个环),贡献出抗原结合的氨基酸残基并赋予抗体以抗原结合特异性。然而,即使是单个可变域(或只包含对抗原特异的三个HVR的半个Fv)也具有识别和结合抗原的能力,尽管亲和力低于完整结合位点。
“单链Fv”,也缩写成“sFv”或“scFv”,是包含连接成一条多肽链的VH和VL抗体结构域的抗体片段。优选的是,sFv多肽在VH与VL结构域之间进一步包含多肽接头,其使得sFv能够形成结合抗原的期望结构。关于sFv的综述参见Pluckthun,于《The Pharmacology of Monoclonal Antibodies》,第113卷,Rosenburg和Moore编,Springer-Verlag,New York,第269-315页,1994。
本发明抗体的“功能性片段”包含完整抗体的一部分,一般包括完整抗体的抗原结合或可变区或抗体的保留或具有改良FcR结合能力的Fc区。抗体片段的例子包括线性抗体、单链抗体分子和自抗体片段形成的多特异性抗体。
术语“双抗体”指通过在VH和VL结构域之间使用短接头(约5-10个残基)构建sFv片段(见上一段)而制备的小型抗体片段,由于接头短,使得V结构域实行链间而非链内配对,由此导致二价片段,即具有两个抗原结合位点的片段。双特异性双抗体是两个“交叉”sFv片段的异二聚体,其中两种抗体的VH和VL结构域存在于不同多肽链上。双抗体更详细的描述于例如EP404,097;WO 93/11161;Hollinger等,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993)。
单克隆抗体在本文中明确包括“嵌合”抗体(免疫球蛋白),其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而链的剩余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,以及此类抗体的片段,只要它们展现出期望的生物学活性(美国专利No.4,816,567;Morrison等,Proc.Natl.Acad.Sci.USA 81:6851-6855(1984))。本文中感兴趣的嵌合抗体包括“灵长类化”抗体,其中抗体的抗原结合区衍生自通过用例如感兴趣抗原免疫短尾猴(macaque monkey)而生成的抗体。如本文中所使用的,“人源化抗体”是“嵌合抗体”的一个子集。
非人(例如鼠)抗体的“人源化”形式指最低限度包含衍生自非人免疫球蛋白的序列的嵌合抗体。在一个实施方案中,人源化抗体指人免疫球蛋白(受体抗体)中的HVR残基(下文限定)用具有期望特异性、亲和力和/或能力的非人物种(供体抗体)(诸如小鼠、大鼠、家兔或非人灵长类动物)的HVR残基替换的免疫球蛋白。在有些情况中,将人免疫球蛋白的框架(“FR”)残基用相应的非人残基替换。此外,人源化抗体可包含在受体抗体中或在供体抗体中没有找到的残基。进行这些修饰可以是为了进一步改进抗体的性能,诸如结合亲和力。一般而言,人源化抗体将包含至少一个、通常两个基本上整个如下的可变域,其中所有或基本上所有高变环对应于非人免疫球蛋白序列的高变环,且所有或基本上所有FR区是人免疫球蛋白序列的FR区,尽管FR区可包含一处或多处改进抗体性能(诸如结合亲和力、异构化、免疫原性等)的个别FR残基替代。FR中这些氨基酸替代的数目,H链中通常不超过6处,L链中通常不超过3处。人源化抗体任选还将包含至少部分免疫球蛋白恒定区(Fc),通常是人免疫球蛋白的恒定区。更多细节参见例如Jones等,Nature 321:522-525(1986);Riechmann等,Nature 332:323-329(1988);及Presta,Curr.Op.Struct.Biol.2:593-596(1992)。还可参见例如Vaswani andHamilton,Ann.Allergy,Asthma&Immunol.1:105-115(1998);Harris,Biochem.Soc.Transactions 23:1035-1038(1995);Hurle and Gross,Curr.Op.Biotech.5:428-433(1994);及美国专利No.6,982,321和7,087,409。
“人抗体”指拥有与由人生成的抗体的氨基酸序列对应的氨基酸序列和/或使用本文所公开的用于生成人抗体的任何技术生成的抗体。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。人抗体可使用本领域已知的多种技术来生成,包括噬菌体展示文库(Hoogenboom and Winter,J.Mol.Biol.227:381(1991);Marks等,J.Mol.Biol.222:581(1991))。还可用于制备人单克隆抗体的是以下文献中记载的方法:Cole等,Monoclonal Antibodies andCancer Therapy,Alan R.Liss,p.77(1985);Boerner等,J.Immunol.147(1):86-95(1991)。还可参见van Dijk and van de Winkel,Curr.Opin.Pharmacol.,5:368-74(2001)。可通过给已经修饰以应答抗原性刺激而生成人抗体但其内源基因座已经失去能力的转基因动物例如经过免疫的异种小鼠(xenomice)施用抗原来制备人抗体(参见例如美国专利No.6,075,181和6,150,584,关于XENOMOUSETM技术)。还可参见例如Li等,Proc.Natl.Ascad.Sci.USA,103:3557-3562(2006),关于经人B-细胞杂交瘤技术生成的人抗体。
术语“高变区”、“HVR”或“HV”在用于本文时指抗体可变域中序列上高度可变和/或形成结构上定义的环的区域。通常,抗体包含六个HVR:三个在VH中(H1、H2、H3),三个在VL中(L1、L2、L3)。在天然抗体中,H3和L3展示这六个HVR的最大多样性,而且认为特别是H3在赋予抗体以精密特异性中发挥独特作用。参见例如Xu等,Immunity 13:37-45(2000);Johnson and Wu,于:Methods in Molecular Biology 248:1-25(Lo编,HumanPress,Totowa,NJ,2003)。事实上,仅由重链组成的天然存在骆驼(camelid)抗体在缺乏轻链时是有功能的且稳定的。参见例如Hamers-Casterman等,Nature363:446-448(1993);Sheriff等,Nature Struct.Biol.3:733-736(1996)。
本文中使用且涵盖许多HVR的叙述。Kabat互补决定区(CDR)是以序列变异性为基础的,而且是最常用的(Kabat等,Sequences of Proteins ofImmunological Interest,5th Ed.Public Health Service,National Institutes ofHealth,Bethesda,MD.(1991))。Chothia改为指结构环的位置(Chothia and LeskJ.Mol.Biol.196:901-917(1987))。AbM HVR代表Kabat HVR与Chothia结构环之间的折衷,而且得到Oxford Molecular的AbM抗体建模软件的使用。“接触”HVR是以对可获得的复合物晶体结构的分析为基础的。下文记录了这些HVR中每一个的残基。
HVR可包括如下“延伸的HVR”:VL中的24-36或24-34(L1)、46-56或50-56(L2)和89-97或89-96(L3)及VH中的26-35(H1)、50-65或49-65(H2)和93-102、94-102、或95-102(H3)。对于这些定义中的每一个,可变域残基是依照Kabat等,见上文编号的。
表述“依照Kabat的可变域残基编号方式”或“依照Kabat的氨基酸位置编号方式”及其变体指Kabat等,见上文中用于抗体重链可变域或轻链可变域编辑的编号系统。使用此编号系统,实际的线性氨基酸序列可包含较少或另外的氨基酸,对应于可变域FR或HVR的缩短或插入。例如,重链可变域可包含H2残基52后的单一氨基酸插入(依照Kabat为残基52a)及重链FR残基82后的插入残基(例如依照Kabat为残基82a、82b和82c等)。给定抗体的Kabat残基编号方式可通过将抗体序列与“标准”Kabat编号序列对比同源区来确定。
“框架”或“FR”残基指可变域中除本文中所定义的HVR残基外的那些残基。
“人共有框架”或“受体人框架”指代表人免疫球蛋白VL或VH框架序列选集中最常见的氨基酸残基的框架。通常,人免疫球蛋白VL或VH序列选集来自可变域序列亚组。通常,序列亚组是如Kabat等,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes ofHealth,Bethesda,MD(1991)中的亚组。例子包括对于VL,亚组可以是亚组κI、κII、κIII或κIV,如在Kabat等,见上文中的。另外,对于VH,亚组可以是亚组I、亚组II、或亚组III,如在Kabat等,见上文中的。或者,人共有框架可以自上述框架衍生,其中特定残基,诸如人框架残基通过比对供体框架序列与各种人框架序列的集合基于其与供体框架的同源性选择。自人免疫球蛋白框架“衍生”的受体人框架或人共有框架可以包含其相同的氨基酸序列,或者它可以含有先前存在的氨基酸序列变化。在一些实施方案中,先前存在的氨基酸变化的数目是10或更少,9或更少,8或更少,7或更少,6或更少,5或更少,4或更少,3或更少,或2或更少。
“VH亚组III共有框架”包含从Kabat等,见上文的可变重链亚型III中的氨基酸序列获得的共有序列。在一个实施方案中,VH亚型III共有框架氨基酸序列包含下列各序列中每一项的至少一部分或整个全部:
EVQLVESGGGLVQPGGSLRLSCAAS(HC-FR1)(SEQ ID NO:30)、
WVRQAPGKGLEWV(HC-FR2)(SEQ ID NO:31)、
RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(HC-FR3)(SEQ ID NO:32)、
WGQGTLVTVSA(HC-FR4)(SEQ ID NO:33)。
“VLκI共有框架”包含从Kabat等,见上文的可变轻链κ亚型I中的氨基酸序列获得的共有序列。在一个实施方案中,VL亚型I共有框架氨基酸序列包含下列各序列中每一项的至少一部分或整个:
DIQMTQSPSSLSASVGDRVTITC(LC-FR1)(SEQ ID NO:34)、
WYQQKPGKAPKLLIY(LC-FR2)(SEQ ID NO:35)、
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(LC-FR3)(SEQ ID NO:36)、
FGQGTKVEIKR(LC-FR4)(SEQ ID NO:37)。
指定位置(例如Fc区的)处的“氨基酸修饰”指指定残基的替代或删除,或指定残基附近至少一个氨基酸残基的插入。指定残基“附近”的插入意味着其一个至两个残基内的插入。插入可以在指定残基的N端或C端。本文中优选的氨基酸修饰是替代。
“亲和力成熟的”抗体指在抗体的一个或多个HVR中具有一处或多处改变、导致该抗体对抗原的亲和力与没有这些改变的亲本抗体相比有所改进的抗体。在一个实施方案,亲和力成熟的抗体具有纳摩尔或甚至皮摩尔量级的对靶抗原的亲和力。亲和力成熟的抗体可通过本领域已知规程来生成。例如,Marks等,Bio/Technology 10:779-783(1992)记载了通过VH和VL结构域改组进行的亲和力成熟。以下文献记载了HVR和/或框架残基的随机诱变:例如,Barbas等,Proc.Nat.Acad.Sci.USA 91:3809-3813(1994);Schier等,Gene169:147-155(1995);Yelton等,J.Immunol.155:1994-2004(1995);Jackson等,J.Immunol.154(7):3310-9(1995);Hawkins等,J.Mol.Biol.226:889-896(1992)。
如本文中使用的,术语“特异性结合”或“对…特异性的”指可测量且可再现的相互作用,诸如靶物和抗体之间的结合,其确定在存在分子(包括生物学分子)的异质群体的情况中靶物的存在。例如,特异性结合靶物(其可以是表位)的抗体是以比其结合其它靶物更大的亲和力,亲合力,更容易,和/或以更大的持续时间结合此靶物的抗体。在一个实施方案中,抗体结合无关靶物的程度小于抗体结合此靶物的约10%,如例如通过放射性免疫测定法(RIA)测量的。在某些实施方案中,特异性结合靶物的抗体具有≤1μM,≤100nM,≤10nM,≤1nM,或≤0.1nM的解离常数(Kd)。在某些实施方案中,抗体特异性结合蛋白质上在来自不同物种的蛋白质间保守的表位。在另一个实施方案中,特异性结合可以包括但不需要排他结合。
如本文中使用的,术语“免疫粘附素”指组合异源蛋白质(“粘附素”)的结合特异性与免疫球蛋白恒定域的效应器功能的抗体样分子。在结构上,免疫粘附素包含具有与抗体的抗原识别和结合位点不同的期望结合特异性的氨基酸序列(即,是“异源的”)和免疫球蛋白恒定域序列的融合物。免疫粘附素分子的粘附素部分通常是至少包含受体或配体的结合位点的连续氨基酸序列。免疫粘附素中的免疫球蛋白恒定域序列可以获自任何免疫球蛋白,诸如IgG-1,IgG-2(包括IgG2A和IgG2B),IgG-3,或IgG-4亚型,IgA(包括IgA-1和IgA-2),IgE,IgD或IgM。优选地,Ig融合物包含用本文中描述的多肽或抗体的域替换Ig分子内的至少一个可变区的取代。在一个特别优选的实施方案中,免疫球蛋白融合物包括IgG1分子的铰链,CH2和CH3,或铰链,CH1,CH2和CH3区。为了生成免疫球蛋白融合物,还可见1995年6月27日公告的美国专利No.5,428,130。例如,作为可用于本文中的联合疗法的第二药物的有用的免疫粘附素包括包含与免疫球蛋白质序列的恒定域融合的PD-L1或PD-L2的胞外或PD-1结合部分或PD-1的胞外或PD-L1或PD-L2结合部分的多肽,诸如分别为PD-L1ECD–Fc,PD-L2ECD–Fc,和PD-1ECD-Fc。IgFc和细胞表面受体ECD的免疫粘附素组合有时称作可溶性受体。
“融合蛋白”和“融合多肽”指具有两个共价连接在一起的部分的多肽,其中每个部分是具有不同特性的多肽。特性可以是生物学特性,诸如体外或体内活性。特性也可以是简单的化学或物理特性,诸如对靶分子的结合,反应的催化,等等。两个部分可以通过单一肽键直接连接,或者经由肽接头连接,但是为彼此以符合读码框的方式。
“PD-1寡肽”、“PD-L1寡肽”、或“PD-L2寡肽”是分别结合(优选特异性结合)PD-1、PD-L1或PD-L2负共刺激多肽的寡肽,分别包括受体、配体或信号传导组分,如本文中描述的。此类寡肽可以使用已知的寡肽合成技术化学合成或者可以使用重组技术制备并纯化。此类寡肽的长度通常是至少约5个氨基酸,或者长度为至少约6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,或100个氨基酸或更多。可以使用公知的技术鉴定此类寡肽。在这点上,注意到用于对寡肽文库筛选能够特异性结合多肽靶物的寡肽的技术是本领域中公知的(见例如美国专利No.5,556,762,5,750,373,4,708,871,4,833,092,5,223,409,5,403,484,5,571,689,5,663,143;PCT公开文本No.WO 84/03506和WO84/03564;Geysen等,Proc.Natl.Acad.Sci.U.S.A.,81:3998-4002(1984);Geysen等,Proc.Natl.Acad.Sci.U.S.A.,82:178-182(1985);Geysen等,于Synthetic Peptides as Antigens,130-149(1986);Geysen等,J.Immunol.Meth.,102:259-274(1987);Schoofs等,J.Immunol.,140:611-616(1988),Cwirla,S.E.等,Proc.Natl.Acad.Sci.USA,87:6378(1990);Lowman,H.B.等,Biochemistry,30:10832(1991);Clackson,T.等,Nature,352:624(1991);Marks,J.D.等,J.Mol.Biol.,222:581(1991);Kang,A.S.等,Proc.Natl.Acad.Sci.USA,88:8363(1991),及Smith,G.P.,Current Opin.Biotechnol.,2:668(1991)。
“阻断性”抗体或“拮抗性”抗体是抑制或降低其结合的抗原的生物学活性的抗体。在一些实施方案中,阻断性抗体或拮抗性抗体实质性或完全抑制抗原的生物学活性。例如,VEGF特异性拮抗性抗体结合VEGF并抑制VEGF诱导血管内皮细胞增殖或诱导血管通透性的能力。本发明的抗PD-L1抗体阻断经由PD-1的信号传导,使得将T细胞的功能性应答从功能障碍状态恢复至抗原刺激。
“激动剂”或活化性抗体是通过与其结合的抗原增强或启动信号传导的抗体。在一些实施方案中,激动剂抗体在不存在天然配体的情况中引起或激活信号传导。
术语“Fc区”在本文中用于定义免疫球蛋白重链的C端区,包括天然序列Fc区和变异Fc区。虽然免疫球蛋白重链Fc区的边界可以变化,但是人IgG重链Fc区通常定义为自其Cys226或Pro230位置的氨基酸残基至羧基末端的区段。Fc区的C-末端赖氨酸(残基447,依照EU编号系统)可以消除,例如在生产或纯化抗体的过程中,或者通过对编码抗体重链的核酸进行重组工程改造。因而,完整抗体的组合物可包括所有K447残基都被消除的抗体群、无一K447残基被消除的抗体群、以及混合了有和无K447残基的抗体的抗体群。对于在本发明的抗体中使用而言合适的天然序列Fc区包括人IgG1、IgG2(IgG2A,IgG2B)、IgG3和IgG4。
“Fc受体”或“FcR”描述结合抗体Fc区的受体。优选的FcR是天然序列人FcR。此外,优选的FcR是结合IgG抗体的FcR(γ受体),包括FcγRI、FcγRII和FcγRIII亚类的受体,包括这些受体的等位变体和可变剪接形式。FcγRII受体包括FcγRIIA(“活化受体”)和FcγRIIB(“抑制受体”),它们具有相似的氨基酸序列,区别主要在其胞质结构域中。活化受体FcγRIIA在其胞质结构域中包含免疫受体基于酪氨酸的活化基序(ITAM)。抑制受体FcγRIIB在其胞质结构域中包含免疫受体基于酪氨酸的抑制基序(ITIM)(参见M.Annu.Rev.Immunol.15:203-234(1997))。FcR的综述参见Ravetch and Kinet,Annu.Rev.Immunol.9:457-492(1991);Capel等,Immunomethods 4:25-34(1994);deHaas等,J.Lab.Clin.Med.126:330-41(1995)。术语“FcR”在本文中涵盖其它FcR,包括那些未来将会鉴定的。
术语“Fc受体”或“FcR”还包括新生儿受体,FcRn,它负责将母体IgG转移给胎儿(Guyer等,J.Immunol.117:587(1976)和Kim等,J.Immunol.24:249(1994))。测量对FcRn的结合的方法是已知的(参见例如Ghetie and Ward,Immunol Today 18(12):592-8(1997);Ghetie等,Nature Biotechnology,15(7):637-40(1997);Hinton等,J.Biol.Chem 279(8):6213-6(2004);andWO2004/92219(Hinton等))。可测定人FcRn高亲和力结合多肽与FcRn的体内结合和血清半衰期,例如在表达人FcRn的转基因小鼠或经转染的人细胞系中,或者在施用了具有变异Fc区的多肽的灵长类动物中。WO2000/42072(Presta)记载了对FcR的结合得到改良或消除的抗体变体。还可参见例如Shields等,J.Biol.Chem.9(2):6591-6604(2001)。
短语“实质性降低”或“实质性不同”在用于本文时表示两个数值(通常一个与某分子有关而另一个与参照/比较分子有关)之间足够高的差异程度,以致本领域技术人员将认为在用所述数值(例如Kd值)所测量的生物学特性背景内两个数值之间的差异具有统计学显著性。作为参照/比较分子该数值的函数,所述两个数值之间的差异例如大于约10%,大于约20%,大于约30%,大于约40%,和/或大于约50%。
短语“基本上相似”或“基本上相同”在用于本文时表示两个数值(例如,一个涉及本发明的抗体而另一个涉及参照/比较抗体)之间足够高的相似程度,以致本领域技术人员将认为在用所述数值(例如Kd值)所测量的生物学特性背景内两个数值之间的差异具有很小的或没有生物学和/或统计学显著性。作为参照/比较值的函数,所述两个数值之间的差异例如小于约50%,小于约40%,小于约30%,小于约20%,和/或小于约10%。
“载体”在用于本文时包括药剂学可接受的载体、赋形剂或稳定剂,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。通常,生理学可接受的载体是pH缓冲水溶液。生理学可接受载体的例子包括缓冲剂,诸如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸;低分子量(少于约10个残基)多肽;蛋白质,诸如血清清蛋白、明胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖醇,诸如甘露醇或山梨醇;成盐反荷离子,诸如钠;和/或非离子表面活性剂,诸如TWEENTM、聚乙二醇(PEG)和PLURONICSTM。
“包装插页”指通常包括在药物的商业包装中的说明书,它们包含有关涉及此类药物应用的适应征、用法、剂量、施用、禁忌症、与该包装产品联合的其它药物和/或警告等的信息。
如本文中使用的,术语“治疗/处理”指设计用于改变临床病理学过程期间所治疗个体或细胞的自然进程的临床干预。治疗的期望效果包括降低疾病进展速率,改善或减轻疾病状态,和消退或改善的预后。例如,若一种或多种与癌症有关的症状是减轻或消除的,包括但不限于对癌性细胞的降低增殖(或破坏),减少源自疾病的症状,提高那些患有疾病的个体的生命质量,降低治疗疾病需要的其它药物的剂量,延迟疾病的进展,和/或延长个体存活,则个体得到成功“治疗”。
如本文中使用的,“延迟疾病的进展”意指推迟、阻碍、减缓、延迟、稳定、和/或延缓疾病(诸如癌症)的形成。根据疾病史和/或治疗的个体,此延迟可以是不同时间长度的。如对于本领域技术人员明显的是,充分或显著的延迟实质上可以涵盖预防,因为个体不形成疾病。例如,可以延迟晚期阶段癌症,诸如转移的形成。
“有效量”至少是实现特定病症的可测量改善或预防需要的最小浓度。本文中的有效量可以随诸如患者的疾病状态、年龄、性别、和重量,和抗体引发个体中期望的应答的能力等因素而变化。有效量也是治疗有益效果超过治疗的任何毒性或不利效果的量。为了预防性使用,有益或期望的结果包括如下的结果,诸如消除或降低风险,减轻严重性,或者延迟疾病的发作,包括疾病的生物化学,组织学和/或行为症状,其并发症和疾病形成期间呈现的中间病理学表型。为了治疗性使用,有益或期望的结果包括临床结果,诸如减少源自疾病的一种或多种症状,提高那些患有疾病的对象的生命质量,降低治疗疾病需要的其它药物的剂量,增强另一种药物的效果(诸如经由靶向),延迟疾病的进展,和/或延长存活。在癌症或肿瘤的情况中,药物的有效量在减少癌细胞的数目;降低肿瘤大小;抑制(即在一定程度上减缓或者期望地停止)癌细胞浸润入外周器官中;抑制(即在一定程度上减缓且期望地停止)肿瘤转移;在一定程度上抑制肿瘤生长;和/或在一定程度上减轻一种或多种与病症有关的症状中可以具有效果。可以在一次或多次施用中施用有效量。出于本发明的目的,药物、化合物、或药物组合物的有效量是足以直接或间接实现预防或治疗性处理的量。如在临床背景中理解的,药物、化合物、或药物组合物的有效量可以与或不与另一种药物、化合物、或药物组合物一起实现。如此,可以在施用一种或多种治疗剂的背景中考虑“有效量”,并且若与一种或多种其它药剂一起,可以实现期望的结果或者实现了期望的结果,则可以认为单一药剂以有效量给予。
如本文中使用的,“与......联合/组合/一起”指在一种治疗形态外施用另一种治疗形态。因而,“与......联合/组合/一起”指在对个体施用一种治疗形态之前,期间,或者之后施用另一种治疗形态。
术语“癌症”和“癌性”指或描述哺乳动物中特征通常为细胞生长不受调控的生理疾患。此定义中包括良性和恶性癌症以及休眠肿瘤或微转移。癌症的例子包括但不限于癌、淋巴瘤、母细胞瘤、肉瘤、和白血病。此类癌症的更具体例子包括鳞状细胞癌、肺癌(包括小细胞肺癌、非小细胞肺癌、肺的腺癌、和肺的鳞癌)、腹膜癌、肝细胞癌、胃癌(gastric or stomach cancer)(包括胃肠癌)、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌(liver cancer,hepaticcarcinoma)、膀胱癌、肝瘤(hepatoma)、乳腺癌、结肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌(kidney or renal cancer)、前列腺癌、外阴癌、甲状腺癌、及各种类型的头和颈癌,以及B细胞淋巴瘤(包括低级/滤泡性非何杰金氏淋巴瘤(NHL)、小淋巴细胞性(SL)NHL、中级/滤泡性NHL、中级弥漫性NHL、高级成免疫细胞性NHL、高级成淋巴细胞性NHL、高级小无核裂细胞性NHL、贮积病(bulky disease)NHL、套细胞淋巴瘤、AIDS相关淋巴瘤、和瓦尔登斯特伦氏(Waldenstrom)巨球蛋白血症)、慢性淋巴细胞性白血病(CLL)、急性成淋巴细胞性白血病(ALL)、毛细胞性白血病、慢性成髓细胞性白血病、和移植后淋巴增殖性病症(PTLD)、以及与瘢痣病(phakomatoses)、水肿(诸如与脑瘤有关的)和梅格斯氏(Meigs)综合征有关的异常血管增殖。
“转移”指癌自其原发部位传播至身体中的其它位置。癌细胞能脱离原发性肿瘤,渗透入淋巴和血管,经由血流而循环,和在身体中其它地方的正常组织中的远端病灶(转移)中生长。转移可以是当地的或远端的。转移是一个连续过程,视肿瘤细胞自原发性肿瘤脱落、经由血流而传播、并在远端部位停止而定。在新的部位,该细胞建立血供且能生长至形成危及生命的团块。肿瘤细胞内的刺激性和抑制性分子途径调节这种行为,而且肿瘤细胞与远端部位中的宿主细胞之间的相互作用也是重要的。
“受试者”指哺乳动物,包括但不限于人或非人哺乳动物,诸如牛、马、犬、绵羊、或猫。优选地,受试者指人。在本文中,患者也是受试者。
如本文中使用的,“完全响应”或“CR”指所有靶损伤的消失;“部分响应”或“PR”指将基线SLD视为参照,靶损伤的最长直径和(SLD)的至少30%降低;且“稳定疾病”或“SD”指将治疗开始起的最小SLD视为参照,既没有足够的靶损伤收缩以符合PR,也没有足够的增加以符合PD。
如本文中使用的,“进行性疾病”或“PD”指将从治疗开始起记录的最小SLD视为参照,靶损伤的SLD的至少20%增加或一种或多种新损伤的存在。
如本文中使用的,“无进展存活”(PFS)指治疗期间和治疗后,所治疗疾病(例如癌症)不变坏的时间长度。无进展存活可以包括患者已经经历完全响应或部分响应的时间量,及患者已经经历稳定疾病的时间量。
如本文中使用的,“总体响应率”(ORR)指完全响应(CR)率和部分响应(PR)率的总和。
如本文中使用的,“总体存活”指组中在特定持续时间后有可能存活的个体的百分比。
“化疗剂”指可用于治疗癌症的化学化合物。化疗剂的实例包括烷化剂类(alkylating agents),诸如塞替派(thiotepa)和环磷酰胺(cyclophosphamide)磺酸烷基酯类(alkyl sulfonates),诸如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridines),诸如苯佐替派(benzodopa)、卡波醌(carboquone)、美妥替派(meturedopa)和乌瑞替派(uredopa);乙撑亚胺类(ethylenimines)和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(triethylenephosphoramide)、三乙撑硫代磷酰胺(triethiylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));δ-9-四氢大麻酚(tetrahydrocannabinol)(屈大麻酚(dronabinol),);β-拉帕醌(lapachone);拉帕醇(lapachol);秋水仙素类(colchicines);白桦脂酸(betulinic acid);喜树碱(camptothecin)(包括合成类似物托泊替康(topotecan)CPT-11(伊立替康(irinotecan),)、乙酰喜树碱、东莨菪亭(scopolectin)和9-氨基喜树碱);苔藓抑素(bryostatin);培美曲塞(pemetrexed);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素(podophyllotoxin);鬼臼酸(podophyllinic acid);替尼泊苷(teniposide);隐藻素类(cryptophycins)(特别是隐藻素1和隐藻素8);多拉司他汀(dolastatin);duocarmycin(包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;TLK-286;CDP323,一种口服α-4整联蛋白抑制剂;sarcodictyin;海绵抑素(spongistatin);氮芥类(nitrogenmustards),诸如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxidehydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝脲类(nitrosoureas),诸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimustine);抗生素类,诸如烯二炔类抗生素(enediyne)(如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1(参见例如Nicolaou等,Angew,Chem.Intl.Ed.Engl.33:183-186(1994));蒽环类抗生素(dynemicin),包括dynemicin A;埃斯波霉素(esperamicin);以及新制癌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、氨茴霉素(authramycin)、偶氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycinis)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-二氮-5-氧-L-正亮氨酸、多柔比星(doxorubicin)(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯代多柔比星、多柔比星盐酸脂质体注射液(和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类(mitomycins)诸如丝裂霉素C、霉酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物类,诸如甲氨蝶呤、吉西他滨(gemcitabine)替加氟(tegafur)卡培他滨(capecitabine)埃坡霉素(epothilone);和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、甲氨蝶呤、蝶酰三谷氨酸(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤(mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine)、和imatinib(一种2-苯基氨基嘧啶衍生物),以及其它c-Kit抑制剂;抗肾上腺类,诸如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptinium acetate);依托格鲁(etoglucid);硝酸镓;羟脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱类(maytansinoids),诸如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基酰肼(ethylhydrazide);丙卡巴肼(procarbazine);多糖复合物(JHS NaturalProducts,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西索菲兰(sizofiran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2″-三氯三乙胺;单端孢菌素类(trichothecenes)(尤其是T-2毒素、疣孢菌素(verracurin)A、杆孢菌素(roridin)A和蛇行菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine) 达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);塞替派(thiotepa);类紫杉醇(taxoids),例如帕利他塞(paclitaxel)清蛋白改造的纳米颗粒剂型帕利他塞(ABRAXANETM)、和多西他塞(doxetaxel)苯丁酸氮芥(chloranbucil);6-硫鸟嘌呤(thioguanine);巯基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂类似物,诸如顺铂(cisplatin)和卡铂(carboplatin);长春碱(vinblastine)铂;依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine)奥沙利铂(oxaliplatin);亚叶酸(leucovovin);长春瑞滨(vinorelbine)能灭瘤(novantrone);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);伊本膦酸盐(ibandronate);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类维A酸(retinoids),诸如维A酸(retinoic acid);任何上述物质的药学可接受盐、酸或衍生物;以及两种或更多种上述物质的组合,诸如CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松龙联合疗法的缩写)和FOLFOX(奥沙利铂(ELOXATINTM)联合5-FU和亚叶酸的治疗方案的缩写)。
此定义还包括作用为调节、降低、阻断、或抑制可促进癌生长的激素效果的抗激素剂,且常常是系统或全身治疗的形式。它们自身可以是激素。实例包括抗雌激素类和选择性雌激素受体调节剂类(SERM),包括例如他莫昔芬(tamoxifen)(包括他莫昔芬)、雷洛昔芬(raloxifene)屈洛昔芬(droloxifene)、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、那洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和托瑞米芬(toremifene)抗孕酮类;雌激素受体下调剂类(ERD);雌激素受体拮抗剂,诸如氟维司群(fulvestrant)功能为抑制或关闭卵巢的药剂,例如促黄体生成激素释放激素(LHRH)激动剂,诸如醋酸亮丙瑞林(leuprolide acetate)(和)、醋酸戈舍瑞林(goserelinacetate)、醋酸布舍瑞林(buserelin acetate)和曲普瑞林(tripterelin);抗雄激素类,诸如氟他米特(flutamide)、尼鲁米特(nilutamide)和比卡米特(bicalutamide);及抑制在肾上腺中调节雌激素生成的芳香酶的芳香酶抑制剂,诸如例如4(5)-咪唑、氨鲁米特(aminoglutethimide)、醋酸甲地孕酮(megestrol acetate)依西美坦(exemestane)福美坦(formestanie)、法倔唑(fadrozole)、伏罗唑(vorozole)来曲唑(letrozole)和阿那曲唑(anastrozole)另外,化疗剂的这种定义包括二膦酸盐类(bisphosphonates),诸如氯膦酸盐(clodronate)(例如或)、依替膦酸钠(etidronate)NE-58095、唑来膦酸/唑来膦酸盐(zoledronicacid/zoledronate)阿伦膦酸盐(alendronate)帕米膦酸盐(pamidronate)替鲁膦酸盐(tiludronate)或利塞膦酸盐(risedronate)以及曲沙他滨(troxacitabine)(1,3-二氧戊环核苷胞嘧啶类似物);反义寡核苷酸,特别是抑制涉及异常(abherant)细胞增殖的信号途经中的基因表达的反义寡核苷酸,诸如例如PKC-α、Raf、H-Ras和表皮生长因子受体(EGF-R);疫苗,诸如疫苗和基因疗法疫苗,例如疫苗、疫苗和疫苗;拓扑异构酶1抑制剂(例如);抗雌激素,诸如氟维司群(fulvestrant);Kit抑制剂,诸如伊马替尼(imatinib)或EXEL-0862(一种酪氨酸激酶抑制剂);EGFR抑制剂,诸如厄洛替尼(erlotinib)或西妥昔单抗(cetuximab);抗VEGF抑制剂,诸如贝伐单抗(bevacizumab);伊立替康(irinotecan);rmRH(例如);拉帕替尼(lapatinib)和二甲苯磺酸拉帕替尼(lapatinib ditosylate)(一种ErbB-2和EGFR双重酪氨酸激酶小分子抑制剂,也称作GW572016);17AAG(格尔德霉素(geldanamycin)衍生物,其是热休克蛋白(Hsp)90毒物);及任何上述物质的药学可接受盐、酸或衍生物。
如本文中使用的,术语“细胞因子”一般指由一种细胞群体释放的,作为细胞间介质对另一细胞起作用或者对生成该蛋白质的细胞具有自分泌影响的蛋白质。此类细胞因子的例子包括淋巴因子、单核因子;白介素(“IL”),诸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL10、IL-11、IL-12、IL-13、IL-15、IL-17A-F、IL-18至IL-29(诸如IL-23)、IL-31,包括rIL-2;肿瘤坏死因子,诸如TNF-α或TNF-β、TGF-β1-3;和其它多肽因子,包括白血病抑制因子(“LIF”)、睫状节神经细胞营养因子(“CNTF”)、CNTF样细胞因子(“CLC”)、心肌营养蛋白(“CT”),和kit配体(“KL”)。
如本文中使用的,术语“趋化因子”指具有选择性诱导白细胞的趋化性和活化的能力的可溶性因子(例如细胞因子)。它们还触发血管发生、炎症、伤口愈合、和肿瘤发生的过程。趋化因子例子包括IL-8,即鼠角质形成细胞化学引诱物(KC)的人同系物。
如本文及所附权利要求书中使用的,单数形式“一个”、“一种”、和“该/所述”包括复数提及物,除非上下文明确另有规定。
本文中提及“约”某个数值或参数包括(并描述)涉及所述数值或参数本身的变化。例如,提及“约X”的描述包括“X”的描述。
如本文中使用的,短语“药学可接受盐”指本发明化合物的药学可接受的有机或无机盐。例示性的盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲基磺酸盐(甲磺酸盐)、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和扑酸盐(即1,1’-亚甲基-双(2-羟基-3-萘甲酸))盐,碱金属(例如钠和钾)盐,碱土金属(例如镁)盐,和铵盐。药学可接受盐可能牵涉包含另一种分子,诸如乙酸盐离子、琥珀酸盐离子或其它抗衡离子。抗衡离子可以是稳定母体化合物电荷的任何有机或无机模块。另外,药学可接受盐可以在其结构中具有超过一种带电荷原子。在多种带电荷原子作为药学可接受盐的组成部分的情况中可以具有多种抗衡离子。因此,药学可接受盐可具有一种或多种带电荷原子和/或一种或多种抗衡离子。
如果本发明的化合物是碱,那么期望的药学可接受的盐可以通过本领域可得的任何合适方法来制备,例如用无机酸(诸如氢氯酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等等)或用有机酸(诸如乙酸、马来酸、琥珀酸、扁桃酸、富马酸/延胡索酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷酸(pyranosidyl acid)(诸如葡萄糖醛酸或半乳糖醛酸)、α羟酸(诸如柠檬酸或酒石酸)、氨基酸(诸如天冬氨酸或谷氨酸)、芳香酸(诸如苯甲酸或肉桂酸)、磺酸(诸如对甲苯磺酸或乙磺酸)、等等)处理游离碱。
如果本发明的化合物是酸,那么期望的药学可接受的盐可以通过任何合适方法来制备,例如用无机或有机碱(诸如胺(伯、仲或叔))、碱金属氢氧化物或碱土金属氢氧化物、等等处理游离酸。合适的盐的例示性例子包括但不限于自氨基酸(诸如甘氨酸和精氨酸)、铵、伯/仲/叔胺、和环胺(诸如哌啶、吗啉和哌嗪)衍生的有机盐,和自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂衍生的无机盐。
短语“药学可接受的”指明该物质或组合物必须是在化学和/或毒理学方面与构成配制剂的其它成分和/或用它治疗的哺乳动物相容的。
应当理解,本文中描述的本发明的方面和变型包括由和/或基本上由方面和变型“组成”。
III.方法
本发明的方法可以在治疗期望增强的免疫原性(诸如提高肿瘤免疫原性以治疗癌症)的状况中得到应用。可以治疗多种癌症,或者可以延迟其进展。
在一些实施方案中,个体具有黑素瘤。黑素瘤可以为早期阶段或晚期阶段。在一些实施方案中,个体具有结肠直肠癌。结肠直肠癌可以为早期阶段或晚期阶段。在一些实施方案中,个体具有非小细胞肺癌。非小细胞肺癌可以为早期阶段或晚期阶段。在一些实施方案中,个体具有胰腺癌。胰腺癌可以为早期阶段或晚期阶段。在一些实施方案中,个体具有血液学恶性。血液学恶性可以为早期阶段或晚期阶段。在一些实施方案中,个体具有卵巢癌。卵巢癌可以为早期阶段或晚期阶段。在一些实施方案中,个体具有乳腺癌。乳腺癌可以为早期阶段或晚期阶段。在一些实施方案中,个体具有肾细胞癌。肾细胞癌可以为早期阶段或晚期阶段。
在一些实施方案中,处理的受试者是人。
本发明的联合疗法包括施用PD-1轴结合拮抗剂和奥沙利铂、亚叶酸和5-FU。在另一个方面,本发明提供联合疗法,其包括施用PD-1轴结合拮抗剂、VEGF拮抗剂和奥沙利铂、亚叶酸和5-FU。可以以本领域中已知的任何合适的方式施用PD-1轴结合拮抗剂和VEGF拮抗剂。例如,可以序贯(在不同时间)或同时(在相同时间)施用PD-1轴结合拮抗剂和VEGF拮抗剂。
在一些实施方案中,本发明的方法可进一步包括施用别的疗法。别的疗法可以是放射疗法,手术(例如乳房肿瘤切除术和乳房切除术),化学疗法,基因疗法,DNA疗法,病毒疗法,RNA疗法,免疫疗法,骨髓移植,纳米疗法(nanotherapy),单克隆抗体疗法,或前述疗法的组合。别的疗法可以为辅助或新辅助疗法形式。在一些实施方案中,别的疗法是施用小分子酶促抑制剂或抗转移剂。在一些实施方案中,别的疗法是施用副作用限制剂(例如意图减轻治疗副作用的发生和/或严重性的药剂,诸如抗恶心剂等)。在一些实施方案中,别的疗法是放射疗法。在一些实施方案中,别的疗法是手术。在一些实施方案中,别的疗法是放射疗法和手术的组合。别的疗法可以是上文描述的一种或多种化疗剂。
可以在本发明的方法中使用下文描述的任何PD-1轴结合拮抗剂和VEGF拮抗剂。
PD-1轴结合拮抗剂
本文中提供了用于在个体中治疗癌症或延迟癌症进展的方法,其包括在有或无施用VEGF拮抗剂的情况下与奥沙利铂、亚叶酸和5-FU组合对个体施用有效量的PD-1轴结合拮抗剂。例如,PD-1轴结合拮抗剂包括PD-1结合拮抗剂,PD-L1结合拮抗剂和PD-L2结合拮抗剂。
在一些实施方案中,PD-1结合拮抗剂是抑制PD-1与其配体结合配偶结合的分子。在一个具体的方面,PD-1配体结合配偶是PD-L1和/或PD-L2。在另一个实施方案中,PD-L1结合拮抗剂是抑制PD-L1与其结合配偶结合的分子。在一个具体的方面,PD-L1结合配偶是PD-1和/或B7-1。在另一个实施方案中,PD-L2结合拮抗剂是抑制PD-L2与其结合配偶结合的分子。在一个具体的方面,PD-L2结合配偶是PD-1。拮抗剂可以是抗体,其抗原结合片段,免疫粘附素,融合蛋白,或寡肽。
在一些实施方案中,PD-1结合拮抗剂选自下组:MDX-1106,Merck 3475和CT-011。在一些实施方案中,PD-1结合拮抗剂选自下组:YW243.55.S70和MDX-1105。在一些实施方案中,PD-L2结合拮抗剂是AMP-224。MDX-1105,又称为BMS-936559,是一种在WO2007/005874中描述的抗PD-L1抗体。抗体YW243.55.S70(SEQ ID No.20)是一种在WO 2010/077634A1中描述的抗PD-L1。MDX-1106,又称为MDX-1106-04,ONO-4538或BMS-936558,是一种在WO2006/121168中描述的抗PD-1抗体。Merck 3745,又称为MK-3475或SCH-900475,是一种在WO2009/114335中描述的抗PD-1抗体。CT-011,又称为hBAT或hBAT-1,是一种在WO2009/101611中描述的抗PD-1抗体。AMP-224,又称为B7-DCIg,是一种在WO2010/027827和WO2011/066342中描述的PD-L2-Fc融合可溶性受体。
可用于本发明方法的抗PD-L1抗体及其生成方法的例子记载于PCT专利申请WO 2010/077634A1,其通过提及收入本文。
在一些实施方案中,PD-1轴结合拮抗剂是抗PD-L1抗体。在一些实施方案中,抗PD-L1抗体能够抑制PD-L1和PD-1之间和/或PD-L1和B7-1之间的结合。在一些实施方案中,抗PD-L1抗体是单克隆抗体。在一些实施方案中,抗PD-L1抗体是选自下组的抗体片段:Fab,Fab’-SH,Fv,scFv,和(Fab’)2片段。在一些实施方案中,抗PD-L1抗体是人源化抗体。在一些实施方案中,抗PD-L1抗体是人抗体。
可用于本发明的抗PD-L1抗体(包括含有此类抗体的组合物),诸如那些记载于WO 2010/077634A1的抗PD-L1抗体可以在有或无VEGF拮抗剂的情况下与奥沙利铂、亚叶酸、5-FU组合使用以治疗癌症。
在一个实施方案中,抗PD-L1抗体含有重链可变区多肽,其包含HVR-H1,HVR-H2和HVR-H3序列,其中:
(a)HVR-H1序列是GFTFSX1SWIH(SEQ ID NO:1);
(b)HVR-H2序列是AWIX2PYGGSX3YYADSVKG(SEQ ID NO:2);
(c)HVR-H3序列是RHWPGGFDY(SEQ ID NO:3);
进一步其中:X1是D或G;X2是S或L;X3是T或S。
在一个具体的方面,X1是D;X2是S且X3是T。在另一个方面,多肽进一步包含依照下式的HVR间并置的可变区重链框架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4)。在又一个方面,框架序列自人共有框架序列衍生。在别的方面,框架序列是VH亚组III共有框架。在又一个方面,至少一个框架序列如下:
HC-FR1是EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4)
HC-FR2是WVRQAPGKGLEWV(SEQ ID NO:5)
HC-FR3是RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6)
HC-FR4是WGQGTLVTVSA(SEQ ID NO:7)。
在又一个方面,重链多肽与可变区轻链进一步组合,所述可变区轻链包含HVR-L1,HVR-L2和HVR-L3,其中:
(a)HVR-L1序列是RASQX4X5X6TX7X8A(SEQ ID NO:8);
(b)HVR-L2序列是SASX9LX10S(SEQ ID NO:9);
(c)HVR-L3序列是QQX11X12X13X14PX15T(SEQ ID NO:10);
进一步其中:X4是D或V;X5是V或I;X6是S或N;X7是A或F;X8是V或L;X9是F或T;X10是Y或A;X11是Y,G,F,或S;X12是L,Y,F或W;X13是Y,N,A,T,G,F或I;X14是H,V,P,T或I;X15是A,W,R,P或T。
在又一个方面,X4是D;X5是V;X6是S;X7是A;X8是V;X9是F;X10是Y;X11是Y;X12是L;X13是Y;X14是H;X15是A。在又一个方面,轻链进一步包含依照下式的HVR间并置的可变区轻链框架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在又一个方面,框架序列自人共有框架序列衍生。在又一个方面,框架序列是VLκI共有框架。在又一个方面,至少一个框架序列如下:
LC-FR1是DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11)
LC-FR2是WYQQKPGKAPKLLIY(SEQ ID NO:12)
LC-FR3是GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13)
LC-FR4是FGQGTKVEIKR(SEQ ID NO:14)。
在另一个实施方案中,提供了分离的抗PD-L1抗体或抗原结合片段,其包含重链和轻链可变区序列,其中:
(a)重链包含HVR-H1,HVR-H2和HVR-H3,其中进一步:
(i)HVR-H1序列是GFTFSX1SWIH(SEQ ID NO:1),
(ii)HVR-H2序列是AWIX2PYGGSX3YYADSVKG(SEQ ID NO:2)
(iii)HVR-H3序列是RHWPGGFDY(SEQ ID NO:3),且
(b)轻链包含HVR-L1,HVR-L2和HVR-L3,其中进一步:
(i)HVR-L1序列是RASQX4X5X6TX7X8A(SEQ ID NO:8),
(ii)HVR-L2序列是SASX9LX10S(SEQ ID NO:9),和
(iii)HVR-L3序列是QQX11X12X13X14PX15T(SEQ ID NO:10)
进一步其中:X1是D或G;X2是S或L;X3是T或S;X4是D或V;X5是V或I;X6是S或N;X7是A或F;X8是V或L;X9是F或T;X10是Y或A;X11是Y,G,F,或S;X12是L,Y,F或W;X13是Y,N,A,T,G,F或I;X14是H,V,P,T或I;X15是A,W,R,P或T。
在一个具体的方面,X1是D;X2是S且X3是T。在另一个方面,X4是D;X5是V;X6是S;X7是A;X8是V;X9是F;X10是Y;X11是Y;X12是L;X13是Y;X14是H;X15是A。在又一个方面,X1是D;X2是S且X3是T,X4是D;X5是V;X6是S;X7是A;X8是V;X9是F;X10是Y;X11是Y;X12是L;X13是Y;X14是H且X15是A。
在别的方面,重链可变区包含如下的HVR间并置的一个或多个框架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),并且轻链可变区包含如下的HVR间并置的一个或多个框架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在又一个方面,框架序列自人共有框架序列衍生。在又一个方面,重链框架序列自Kabat亚组I、II、或III序列衍生。在又一个方面,重链框架序列是VH亚组III共有框架。在又一个方面,一个或多个重链框架序列如下:
HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4)
HC-FR2 WVRQAPGKGLEWV(SEQ ID NO:5)
HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6)
HC-FR4 WGQGTLVTVSA(SEQ ID NO:7)。
在又一个方面,轻链框架序列自KabatκI、II、II或IV亚组序列衍生。在又一个方面,轻链框架序列是VLκI共有框架。在又一个方面,一个或多个轻链框架序列如下:
LC-FR1 DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11)
LC-FR2 WYQQKPGKAPKLLIY(SEQ ID NO:12)
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13)
LC-FR4 FGQGTKVEIKR(SEQ ID NO:14)。
在又一个具体的方面,抗体进一步包含人或鼠恒定区。在又一个方面,人恒定区选自下组:IgG1,IgG2,IgG2,IgG3,IgG4。在又一个具体的方面,人恒定区是IgG1。在又一个方面,鼠恒定区选自下组:IgG1,IgG2A,IgG2B,IgG3。在又一个方面,鼠恒定区是IgG2A。在又一个具体的方面,抗体具有降低的或最小的效应器功能。在又一个具体的方面,最小效应器功能源自“效应器较小(effector-less)的Fc突变”或无糖基化(aglycosylation)。在又一个实施方案中,效应器较小的Fc突变是恒定区中的N297A或D265A/N297A替代。
在又一个实施方案中,提供了抗PD-L1抗体,其包含重链和轻链可变区序列,其中:
(a)重链进一步包含与GFTFSDSWIH(SEQ ID NO:15),AWISPYGGSTYYADSVKG(SEQ ID NO:16)和RHWPGGFDY(SEQ ID NO:3)分别具有至少85%序列同一性的HVR-H1,HVR-H2和HVR-H3序列,或
(b)轻链进一步包含与RASQDVSTAVA(SEQ ID NO:17),SASFLYS(SEQ IDNO:18)和QQYLYHPAT(SEQ ID NO:19)分别具有至少85%序列同一性的HVR-L1,HVR-L2和HVR-L3序列。
在一个具体的方面,序列同一性是86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%。在另一个方面,重链可变区包含如下的HVR间并置的一个或多个框架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且轻链可变区包含如下的HVR间并置的一个或多个框架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在又一个方面,框架序列自人共有框架序列衍生。在又一个方面,重链框架序列自Kabat亚组I,II,或III序列衍生。在又一个方面,重链框架序列是VH亚组III共有框架。在又一个方面,一个或多个重链框架序列如下:
HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4)
HC-FR2 WVRQAPGKGLEWV(SEQ ID NO:5)
HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6)
HC-FR4 WGQGTLVTVSA(SEQ ID NO:7)。
在又一个方面,轻链框架序列自KabatκI、II、II或IV亚组序列衍生。在又一个方面,轻链框架序列是VLκI共有框架。在又一个方面,一个或多个轻链框架序列如下:
LC-FR1 DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11)
LC-FR2 WYQQKPGKAPKLLIY(SEQ ID NO:12)
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13)
LC-FR4 FGQGTKVEIKR (SEQ ID NO:14)。
在又一个具体的方面,抗体进一步包含人或鼠恒定区。在又一个方面,人恒定区选自下组:IgG1,IgG2,IgG2,IgG3,IgG4。在又一个具体的方面,人恒定区是IgG1。在又一个方面,鼠恒定区选自下组:IgG1,IgG2A,IgG2B,IgG3。在又一个方面,鼠恒定区是IgG2A。在又一个具体的方面,抗体具有降低的或最小的效应器功能。在又一个具体的方面,最小效应器功能源自“效应器较小的Fc突变”或无糖基化。在又一个实施方案中,效应器较小的Fc突变是恒定区中的N297A或D265A/N297A替代。
在又一个实施方案中,提供了分离的抗PD-L1抗体,其包含重链和轻链可变区序列,其中:
(a)重链序列与下述重链序列具有至少85%序列同一性:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWIS
PYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFD
YWGQGTLVTVSA(SEQ ID NO:20),
或
(b)轻链序列与下述轻链序列具有至少85%序列同一性:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASF
LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR
(SEQ ID NO:21)。
在一个具体的方面,序列同一性是86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%。在另一个方面,重链可变区包含如下的HVR间并置的一个或多个框架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且轻链可变区包含如下的HVR间并置的一个或多个框架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在又一个方面,框架序列自人共有框架序列衍生。在又一个方面,重链框架序列自Kabat亚组I,II,或III序列衍生。在又一个方面,重链框架序列是VH亚组III共有框架。在又一个方面,一个或多个重链框架序列如下:
HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4)
HC-FR2 WVRQAPGKGLEWV(SEQ ID NO:5)
HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6)
HC-FR4 WGQGTLVTVSA(SEQ ID NO:7)。
在又一个方面,轻链框架序列自KabatκI,II,II或IV亚组序列衍生。在又一个方面,轻链框架序列是VLκI共有框架。在又一个方面,一个或多个轻链框架序列如下:
LC-FR1 DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11)
LC-FR2 WYQQKPGKAPKLLIY(SEQ ID NO:12)
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13)
LC-FR4 FGQGTKVEIKR(SEQ ID NO:14)。
在又一个具体的方面,抗体进一步包含人或鼠恒定区。在又一个方面,人恒定区选自下组:IgG1,IgG2,IgG2,IgG3,IgG4。在又一个具体的方面,人恒定区是IgG1。在又一个方面,鼠恒定区选自下组:IgG1,IgG2A,IgG2B,IgG3。在又一个方面,鼠恒定区是IgG2A。在又一个具体的方面,抗体具有降低的或最小的效应器功能。在又一个具体的方面,最小的效应器功能源自原核细胞中的生成。在又一个具体的方面,最小的效应器功能源自“效应器较小的Fc突变”或无糖基化。在又一个实施方案中,效应器较小的Fc突变是恒定区中的N297A或D265A/N297A替代。
在又一个实施方案中,本发明提供了组合物,其包含与至少一种药学可接受载体组合的任一种上文描述的抗PD-L1抗体。
在又一个实施方案中,提供了分离的核酸,其编码抗PD-L1抗体的轻链或重链可变区序列,其中:
(a)重链进一步包含与GFTFSDSWIH(SEQ ID NO:15),AWISPYGGSTYYADSVKG(SEQ ID NO:16)和RHWPGGFDY(SEQ ID NO:3)分别具有至少85%序列同一性的HVR-H1、HVR-H2和HVR-H3序列,和
(b)轻链进一步包含与RASQDVSTAVA(SEQ ID NO:17)、SASFLYS(SEQ IDNO:18)和QQYLYHPAT(SEQ ID NO:19)分别具有至少85%序列同一性的HVR-L1、HVR-L2和HVR-L3序列。
在一个具体的方面,序列同一性是86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%。在各方面,重链可变区包含如下的HVR间并置的一个或多个框架序列:(HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4),且轻链可变区包含如下的HVR间并置的一个或多个框架序列:(LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4)。在又一个方面,框架序列自人共有框架序列衍生。在别的方面,重链框架序列自Kabat亚组I,II,或III序列衍生。在又一个方面,重链框架序列是VH亚组III共有框架。在又一个方面,一个或多个重链框架序列如下:
HC-FR1 EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4)
HC-FR2 WVRQAPGKGLEWV(SEQ ID NO:5)
HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6)
HC-FR4 WGQGTLVTVSA(SEQ ID NO:7)。
在又一个方面,轻链框架序列自KabatκI、II、II或IV亚组序列衍生。在又一个方面,轻链框架序列是VLκI共有框架。在又一个方面,一个或多个轻链框架序列如下:
LC-FR1 DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11)
LC-FR2 WYQQKPGKAPKLLIY(SEQ ID NO:12)
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13)
LC-FR4 FGQGTKVEIKR(SEQ ID NO:14)。
在又一个具体的方面,抗体进一步包含人或鼠恒定区。在又一个方面,人恒定区选自下组:IgG1,IgG2,IgG2,IgG3,IgG4。在又一个具体的方面,人恒定区是IgG1。在又一个方面,鼠恒定区选自下组:IgG1,IgG2A,IgG2B,IgG3。在又一个方面,鼠恒定区是IgG2A。在又一个具体的方面,抗体具有降低的或最小的效应器功能。在又一个具体的方面,最小的效应器功能源自原核细胞中的生成。在又一个具体的方面,最小的效应器功能源自“效应器较小的Fc突变”或无糖基化。在又一个实施方案中,效应器较小的Fc突变是恒定区中的N297A或D265A/N297A替代。
在又一个方面,核酸进一步包含适合于表达核酸的载体,所述核酸编码先前描述的抗PD-L1抗体之任一种。在又一个具体的方面,载体进一步包含适合于表达核酸的宿主细胞。在又一个具体的方面,宿主细胞是真核细胞或原核细胞。在又一个具体的方面,真核细胞是哺乳动物细胞,诸如中国仓鼠卵巢(CHO)。
可以使用本领域中已知的方法,例如通过如下的方法生成抗PD-L1抗体或其抗原结合片段,所述方法包括在适合于生成此类抗体或片段的条件下培养含有核酸的宿主细胞,并回收抗体或片段,所述核酸编码适合于表达的形式的先前描述的抗PD-L1抗体或抗原结合片段之任一种。
在又一个实施方案中,本发明提供了组合物,其包含如本文中提供的抗PD-L1抗体或其抗原结合片段和至少一种药学可接受载体。
VEGF拮抗剂
本发明提供了用于在个体中治疗癌症或减缓癌症进展的方法,包括与奥沙利铂、亚叶酸和5-FU组合施用有效量的PD-1途径拮抗剂和VEGF拮抗剂。任何已知的VEGF拮抗剂是有意图的。
(i)VEGF抗原
要用于生成抗体的VEGF抗原可以是例如VEGF165分子以及VEGF的其它同等型或其含有期望表位的片段。可用于生成本发明的抗VEGF抗体的其它形式的VEGF对于本领域技术人员会是显而易见的。
人VEGF首先是使用牛VEGF cDNA作为杂交探针筛选自人细胞制备的cDNA文库而获得的。Leung等(1989)Science,246:1306。一种由此鉴定出的cDNA编码一种165个氨基酸的蛋白质,其与牛VEGF具有超过95%的同源性;此165个氨基酸的蛋白质通常称作人VEGF(hVEGF)或VEGF165。人VEGF的促有丝分裂活性通过在哺乳动物宿主细胞中表达人VEGF cDNA得到了验证。由经人VEGF cDNA转染的细胞条件化的培养基促进毛细血管内皮细胞增殖,而对照细胞不然。Leung等(1989)Science,见上文。
虽然可以自天然来源分离和纯化血管内皮细胞生长因子,随后用于治疗用途,但是该蛋白质在滤泡细胞中相对低的浓度和回收VEGF所需要的努力和费用两个方面的高成本证明在商业上是无益的。因而,进行进一步努力来经重组DNA技术克隆和表达VEGF。(参见例如Ferrara,LaboratoryInvestigation 72:615-618(1995)及其中引用的参考文献)。
源自可变RNA剪接,VEGF在多种组织中作为多种同二聚体形式(每个单体121、145、165、189、和206个氨基酸)表达。VEGF121是一种可溶性丝裂原,不结合肝素;更长形式的VEGF以越来越高的亲和力结合肝素。肝素结合形式的VEGF可以在羧基末端被纤溶酶切割以释放可扩散形式的VEGF。纤溶酶切割后鉴定出的羧基末端肽的氨基酸测序是Arg110-Ala111。作为同二聚体分离到的氨基末端“核心”蛋白,VEGF(1-110)以与完整VEGF165同二聚体相比相似的亲和力结合中和性单克隆抗体(诸如称作4.6.1和3.2E3.1.1的抗体)和可溶性形式的VEGF受体。
还鉴定出数种在结构上与VEGF有关的分子,包括胎盘生长因子(PIGF)、VEGF-B、VEGF-C、VEGF-D和VEGF-E。Ferrara和Davis-Smyth(1987)Endocr.Rev.,见上文;Ogawa等J.Biological Chem.273:31273-31281(1998);Meyer等EMBO J.,18:363-374(1999)。受体酪氨酸激酶Flt-4(VEGFR-3)鉴定为VEGF-C和VEGF-D的受体。Joukov等EMBO.J.15:1751(1996);Lee等Proc.Natl.Acad.Sci.USA 93:1988-1992(1996);Achen等(1998)Proc.Natl.Acad.Sci.USA 95:548-553。VEGF-C显示出涉及对淋巴管发生的调节。Jeltsch等Science 276:1423-1425(1997)。
已经鉴定出两种VEGF受体,即Flt-1(也称作VEGFR-1)和KDR(也称作VEGFR-2)。Shibuya等(1990)Oncogene 8:519-527;de Vries等(1992)Science 255:989-991;Terman等(1992)Biochem.Biophys.Res.Commun.187:1579-1586。神经毡蛋白-1显示为选择性VEGF受体,能够结合肝素结合性VEGF同等型(Soker等(1998)Cell 92:735-45)。Flt-1和KDR都属于受体酪氨酸激酶(RTK)家族。RTK包含具有多样生物学活性的跨膜受体的大家族。目前,鉴定出至少十九(19)个独特RTK亚家族。受体酪氨酸激酶(RTK)家族包括对于多种细胞类型的生长和分化至关重要的受体(Yarden和Ullrich(1988)Ann.Rev.Biochem.57:433-478;Ullrich和Schlessinger(1990)Cell61:243-254)。RTK的内在功能在配体结合后被活化,导致受体和多种细胞底物磷酸化,随后导致多种细胞应答(Ullrich和Schlessinger(1990)Cell 61:203-212)。如此,受体酪氨酸激酶介导的信号转导通过与特定生长因子(配体)的细胞外相互作用而启动,通常接着是受体二聚化、刺激内在蛋白质酪氨酸激酶活性和受体转磷酸。由此为细胞内信号转导分子创建结合位点,并导致与一系列细胞质信号传导分子的复合物形成,推动适宜细胞应答。(例如细胞分裂、分化、代谢影响、细胞外微环境的变化)参见Schlessinger和Ullrich(1992)Neuron 9:1-20。在结构上,Flt-1和KDR都具有胞外域中的七个免疫球蛋白样结构域、单个跨膜区、和被激酶插入域中断的共有酪氨酸激酶序列。Matthews等(1991)Proc.Natl.Acad.Sci.USA 88:9026-9030;Terman等(1991)Oncogene 6:1677-1683。
(ii)抗VEGF抗体
在本发明的方法中有用的抗VEGF抗体包括任何抗体或其抗原结合片段,它们以足够亲和力和特异性结合VEGF且能降低或抑制VEGF的生物学活性。抗VEGF抗体通常不会结合其它VEGF同源物,诸如VEGF-B或VEGF-C,也不会结合其它生长因子,诸如PlGF、PDGF、或bFGF。
在本发明的某些实施方案中,抗VEGF抗体包括但不限于与由杂交瘤ATCC HB 10709生成的单克隆抗VEGF抗体A4.6.1;依照Presta等(1997)Cancer Res.57:4593-4599生成的重组人源化抗VEGF单克隆抗体结合相同表位的单克隆抗体。在一个实施方案中,抗VEGF抗体是“贝伐单抗(BV)”,也称作“rhuMAb VEGF”或“”。它包含经过突变的人IgG1框架区和来自小鼠抗hVEGF单克隆抗体A.4.6.1的抗原结合互补决定区,阻断人VEGF结合其受体。贝伐单抗大约93%的氨基酸序列(包括大部分框架区)是自人IgG1衍生,而且约7%的序列是自小鼠抗体A4.6.1衍生的。
贝伐单抗和其它人源化抗VEGF抗体进一步记载于2005年2月26日公告的美国专利No.6,884,879。别的抗体包括G6或B20系列抗体(例如G6-31、B20-4.1),如记载于PCT公开号WO2005/012359、PCT公开号WO2005/044853、和美国专利申请60/991,302,通过述及明确将这些专利申请的内容收入本文。对于别的抗体,参见美国专利No.7,060,269,6,582,959,6,703,020;6,054,297;WO98/45332;WO 96/30046;WO94/10202;EP0666868B1;美国专利申请公开文本No.2006009360,20050186208,20030206899,20030190317,20030203409,和20050112126;和Popkov等,Journal of Immunological Methods 288:149-164(2004)。其它抗体包括那些结合人VEGF上包含残基F17、M18、D19、Y21、Y25、Q89、I91、K101、E103、和C104或者包含残基F17、Y21、Q22、Y25、D63、I83和Q89的功能性表位的。
在本发明的一个实施方案中,抗VEGF抗体包含重链可变区,其包含下述氨基酸序列:
EVQLVESGGG LVQPGGSLRL SCAASGYTFT NYGMNWVRQA PGKGLEWVGW
INTYTGEPTY AADFKRRFTF SLDTSKSTAY LQMNSLRAED TAVYYCAKYP
HYYGSSHWYF DVWGQGTLVT VSS(SEQ ID NO:22)
和轻链可变区,其包含下述氨基酸序列:
DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP GKAPKVLIYF
TSSLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSTVPWTFGQ
GTKVEIKR(SEQ ID NO:23)。
在一些实施方案中,抗VEGF抗体包含:CDRH1,其包含下述氨基酸序列,GYTFTNYGMN(SEQ ID NO:24);CDRH2,其包含下述氨基酸序列,WINTYTGEPTYAADFKR(SEQ ID NO:25);CDRH3,其包含下述氨基酸序列,YPHYYGSSHWYFDV(SEQ ID NO:26);CDRL1,其包含下述氨基酸序列,SASQDISNYLN(SEQ ID NO:27);CDRL2,其包含下述氨基酸序列,FTSSLHS(SEQ ID NO:28);和CDRL3,其包含下述氨基酸序列,QQYSTVPWT(SEQ ID NO:29)。
依照本发明的“G6系列抗体”指自G6抗体的序列衍生的抗VEGF抗体或依照PCT公开文本No.WO2005/012359的图7、24-26、和34-35之任一的G6衍生抗体,通过述及将其整个公开内容收入本文。还可参见PCT公开文本No.WO2005/044853,通过述及将这些专利申请的内容明确收入本文。在一个实施方案中,G6系列抗体结合人VEGF上的功能性表位,其包含残基F17、Y21、Q22、Y25、D63、I83和Q89。
依照本发明的“B20系列抗体”指自B20抗体的序列衍生的抗VEGF抗体或依照PCT公开文本No.WO2005/012359的图27-29之任一的B20衍生抗体,通过述及将其整个公开内容收入本文。还可参见PCT公开文本No.WO2005/044853和美国专利申请60/991,302,通过述及将这些专利申请的内容明确收入本文。在一个实施方案中,B20系列抗体结合人VEGF上的功能性表位,其包含残基F17、M18、D19、Y21、Y25、Q89、I91、K101、E103、和C104。
依照本发明的“功能性表位”指抗原中有力地促进抗体结合的氨基酸残基。抗原中贡献巨大的残基中任一个的突变(例如,丙氨酸或同系物突变对野生型VEGF的突变)会破坏抗体的结合,使得抗体的相对亲和力比(IC50突变型VEGF/IC50野生型VEGF)会大于5(参见WO2005/012359的实施例2)。在一个实施方案中,相对亲和力比是通过溶液结合噬菌体展示ELISA测定的。简言之,将96孔Maxisorp免疫板(NUNC)用Fab形式的待测试抗体以PBS中2ug/ml的浓度于4℃包被过夜,并用PBS、0.5%BSA、和0.05%Tween20(PBT)于室温封闭2小时。首先将展示hVEGF丙氨酸点突变体(残基8-109形式)或野生型hVEGF(8-109)的噬菌体在PBT中的连续稀释液在Fab包被的板上于室温温育15分钟,并用PBS、0.05%Tween20(PBST)清洗板。用在PBT中1:5000稀释的抗M13单克隆抗体辣根过氧化物酶(Amersham Pharmacia)偶联物检测所结合的噬菌体,用3,3’,5,5’-四甲基联苯胺(TMB,Kirkegaard&Perry Labs,Gaithersburg,MD)底物显色大约5分钟,用1.0M H3PO4淬灭,并以分光光度法于450nm读数。IC50值的比(IC50,ala/IC50,wt)代表了结合亲和力的降低倍数(相对结合亲和力)。
(iii)VEGF受体分子
两种表征最全面的VEGF受体是VEGFR1(也称作Flt-1)和VEGFR2(鼠同系物也称作KDR和FLK-1)。每一种受体对每一种VEGF家族成员的特异性有所不同,但是VEGF-A结合Flt-1和KDR二者。全长Flt-1受体包括具有七个Ig结构域的胞外结构域、跨膜结构域、和具有酪氨酸激酶活性的胞内结构域。胞外结构域涉及VEGF结合,而胞内结构域涉及信号转导。
特异性结合VEGF的VEGF受体分子或其片段可以在本发明的方法中用于结合和隔绝VEGF蛋白,由此阻止它发信号。在某些实施方案中,VEGF受体分子或其VEGF结合片段是可溶性形式,诸如sFlt-1。受体的可溶性形式发挥对VEGF蛋白生物学活性的抑制效应,其通过结合VEGF,由此阻止它结合其在靶细胞表面上存在的天然受体来实现。还包括VEGF受体融合蛋白,下文描述了它们的例子。
嵌合VEGF受体蛋白指具有自至少两种不同蛋白质(其中至少一种是VEGF受体蛋白,例如flt-1或KDR受体)衍生的氨基酸序列且能够结合并抑制VEGF生物学活性的受体分子。在某些实施方案中,本发明的嵌合VEGF受体蛋白由自只有两种不同VEGF受体分子衍生的氨基酸序列组成;然而,可以将包含一个、两个、三个、四个、五个、六个、或所有七个来自flt-1和/或KDR受体胞外配体结合区的Ig样结构域的氨基酸序列连接至来自其它无关蛋白质的氨基酸序列,例如免疫球蛋白序列。与Ig样结构域组合的其它氨基酸序列对于本领域普通技术人员会是显而易见的。嵌合VEGF受体蛋白的例子包括例如可溶性Flt-1/Fc、KDR/Fc、或FLt 1/KDR/Fc(也称作VEGF Trap)(参见例如PCT申请公开文本No.WO97/44453)。
本发明的可溶性VEGF受体蛋白或嵌合VEGF受体蛋白包括没有经跨膜结构域而固定至细胞表面的VEGF受体蛋白。因此,VEGF受体(包括嵌合受体蛋白)的可溶性形式,虽然能够结合并灭活VEGF,但是不包含跨膜结构域,并如此一般不会变成与该分子在其中表达的细胞的细胞膜相结合。
IV.试剂盒
在另一个方面,提供了包含PD-L1轴结合拮抗剂和/或VEGF拮抗剂的试剂盒,用于在个体中治疗癌症或延迟癌症的进展或者用于在具有癌症的个体中增强免疫功能。在一些实施方案中,该试剂盒包含PD-1轴结合拮抗剂和包装插页,该包装插页包含关于在有或无VEGF拮抗剂的情况下与奥沙利铂、亚叶酸、5-FU组合使用PD-1轴结合拮抗剂以在个体中治疗癌症或延迟癌症进展或者在具有癌症的个体中增强免疫功能的用法说明书。在一些实施方案中,该试剂盒在有或无VEGF拮抗剂的情况下包含奥沙利铂、亚叶酸、5-FU和包装插页,该包装插页包含关于在有或无VEGF拮抗剂的情况下与PD-1轴结合拮抗剂组合使用奥沙利铂、亚叶酸、5-FU以在个体中治疗癌症或延迟癌症进展或者在具有癌症的个体中增强免疫功能的用法说明书。在一些实施方案中,该试剂盒在有或无VEGF拮抗剂的情况下包含PD-1轴结合拮抗剂和奥沙利铂、亚叶酸、5-FU及包装插页,该包装插页包含关于在有或无VEGF拮抗剂的情况下使用PD-1轴结合拮抗剂和奥沙利铂、亚叶酸、5-FU以在个体中治疗癌症或延迟癌症进展或者在具有癌症的个体中增强免疫功能的用法说明书。试剂盒中可以包含本文中描述的任何PD-1轴结合拮抗剂和/或VEGF拮抗剂。
实施例
本发明可以通过参考以下实施例进一步理解,所述实施例作为例示提供而并不意图为限制性的。
实施例1:在有或无抗VEGF抗体的情况下FOLFOX增强抗PD-L1的抗肿瘤活性
为了测定在有或无抗VEGF抗体的情况下FOLFOX(奥沙利铂、亚叶酸和5-FU)是否增强抗PD-L1的抗肿瘤活性,用联合治疗处理结直肠癌的小鼠模型。简言之,对雌性C57BL/6小鼠在单侧胸部区中皮下接种100μL HBSS:基质胶中100,000个MC38鼠结直肠细胞。在小鼠达到220mm3的均值肿瘤体积时,将它们在实验日0随机归入下文概述的处理组之一。在实验日1启动处理。每周2至3次对小鼠称重和测量肿瘤,持续整个研究。
实验组:
1)对照(同种型对照抗体(抗gp120抗体)),10mg/kg ip,100μL,一周施用三次,持续三周,n=10
2)抗PD-L1抗体,10mg/kg ip,100μL,一周施用三次,持续三周,n=10
3)FOLFOX(见下文),一周施用一次,持续两周,n=10
4)FOLFOX(见下文),一周施用一次,持续两周+抗PD-L1抗体,10mg/kgip,100μL,一周施用三次,持续三周,n=10
5)FOLFOX(见下文),一周施用一次,持续两周+抗VEGF抗体,5mg/kgip,100μL,一周施用两次,持续三周,n=10
6)FOLFOX(见下文),一周施用一次,持续两周+抗VEGF抗体,5mg/kgip,100μL,一周施用两次,持续三周+抗PD-L1抗体,10mg/kg ip,100μL,一周施用三次,持续三周,n=10
ip=腹膜内
sc=皮下
对于这些研究,如下进行FOLFOX剂量给药:在实验日1和实验日8,给小鼠施用奥沙利铂(5mg/kg,ip,50μL水中),紧接着是亚叶酸(100mg/kg,ip,250μL水中)(施用时间=0小时)和5-FU(25mg/kg,ip),紧接着是5-FU(25mg/kg,sc)(施用时间=2小时)。抗PD-L1抗体和抗gp120抗体在实验日1、3、5、8、10、12、15、17、和19(施用时间=4小时)给药。抗VEGF抗体在实验日1、4、8、11、15、18(施用时间=6小时)给药。
对小鼠监测肿瘤生长和体重变化。使用UltraCal-IV测径器(54-10-111型;Fred V.Fowler Company;Newton,MA)测量肿瘤体积。使用下面的等式计算肿瘤体积:
肿瘤体积(mm3)=(长度x宽度2)x 0.5。
彼此垂直测量长度和宽度。使用Adventura Pro AV812天平(OhausCorporation;Pine Brook,NJ)测量动物体重。使用下面的等式计算百分比体重变化:
体重变化(%)=[(重量日新–重量日0)/重量日0]x 100。
使用R,第2.9.2版(R Development Core Team 2008;R Foundation forStatistical Computing;Vienna,Austria)分析数据,并且使用nlme包,版本3.1-96(Pinheiro等,2009)在R内拟合混合模型。在Prism,第5.0b版(用于Mac)(GraphPad Software,Inc.;La Jolla,CA)中实施绘图。
使用混合建模方法分析随时间来自同一动物的肿瘤体积的重复测量(Pinheiro和Bates 2010)。此办法解决重复测量和研究结束前的适度退出(对于统计学上可分类为随机缺失(MAR)的原因)两者。将按时间和剂量的以log2(体积)计的固定效应变化以时间的天然立方回归样条基与剂量的自动确定天然样条基的相互作用和主要效应的总和建模。假设截距和生长率(斜率)随动物而随机变化。作为对照处理组百分比的肿瘤生长抑制(%TGI)使用下面的等式在对照处理小鼠仍在研究的情况中相对于对照每天相应处理组的拟合曲线下面积(AUC)的百分比计算:
%TGI=100x(1–AUC剂量/AUC媒介物)。
对于这些研究,完全响应(CR)定义为肿瘤体积在研究期间的任何时间时降到低于检测限(LOD)的个体动物。部分响应(PR)定义为肿瘤体积在研究期间的任何时间时降低50%其初始肿瘤体积的个体动物。总体响应率(ORR)定义为完全和部分响应的总和。
进展前时间5X(TTP5X)定义为组的拟合肿瘤体积(基于上文描述的混合建模分析)超出起始体积的5倍的以天数计的时间,其舍入至最近的半天,并且以所述组的TTP5X报告。还采用线性混合效应分析分析随时间来自同一动物的体重变化的重复测量。
使用抗PD-L1抗体阻断PD-l轴在预防肿瘤生长方面作为单一药剂疗法是有效的。抗PD-L1抗体与奥沙利铂、亚叶酸和5-FU(FOLFOX)的联合治疗显著抑制肿瘤生长,指示这种化疗组合增强抗PD-L1抗体的抗肿瘤活性(图1)。将抗VEGF添加至这种联合治疗进一步增强这种抗肿瘤活性以及抗肿瘤响应的持久性,甚至在治疗停止之后(图4)。
实施例2:在有或无改良FOLFOX-6的情况下MPDL3280A与贝伐单抗的1b期研究
研究的主要目的是评估与贝伐单抗一起(分支A)及与贝伐单抗加FOLFOX(具体是改良FOLFOX-6或mFOLFOX-6)一起(分支B)施用MPDL3280A在具有实体瘤(包括转移性结直肠癌(mCRC))的患者中的安全性、药理学和初步功效。分支A以每3周(q3w)的日程表评估10mg/kg(或不超过单药MTD或MAD的选定剂量水平)的MPDL3280A与贝伐单抗(15mg/kg),长至一年。未因转移性疾病而接受奥沙利铂的患者注册分支B,以每2周(q2w)的日程表接受MPDL3280A与贝伐单抗和FOLFOX。mFOLFOX-6方案组成如下:约120分钟里并行的静脉内(IV)施用的奥沙利铂(85mg/m2)和IV施用的亚叶酸(400mg/m2),接着是作为IV推注施用的5-FU(400mg/m2),接着是约46小时里通过连续IV输注施用的2400mg/m2。奥沙利铂施用多至8个周期。治疗持续长至1年。
Claims (40)
1.一种在个体中治疗癌症或延迟癌症进展的方法,其包括对所述个体施用有效量的PD-1轴结合拮抗剂、奥沙利铂、亚叶酸和5-FU。
2.权利要求1的方法,其中所述PD-1轴结合拮抗剂选自下组:PD-1结合拮抗剂、PD-L1结合拮抗剂和PD-L2结合拮抗剂。
3.权利要求2的方法,其中所述PD-1轴结合拮抗剂是PD-1结合拮抗剂。
4.权利要求3的方法,其中所述PD-1结合拮抗剂抑制PD-1与其配体结合配偶的结合。
5.权利要求4的方法,其中所述PD-1结合拮抗剂抑制PD-1与PD-L1的结合。
6.权利要求4的方法,其中所述PD-1结合拮抗剂抑制PD-1与PD-L2的结合。
7.权利要求4的方法,其中所述PD-1结合拮抗剂抑制PD-1与PD-L1和PD-L2两者的结合。
8.权利要求4的方法,其中所述PD-1结合拮抗剂是抗体。
9.权利要求8的方法,其中所述PD-1结合拮抗剂是MDX-1106。
10.权利要求8的方法,其中所述PD-1结合拮抗剂是Merck 3745。
11.权利要求8的方法,其中所述PD-1结合拮抗剂是CT-011。
12.权利要求2的方法,其中所述PD-1轴结合拮抗剂是PD-L1结合拮抗剂。
13.权利要求12的方法,其中所述PD-L1结合拮抗剂抑制PD-L1与PD-1的结合。
14.权利要求12的方法,其中所述PD-L1结合拮抗剂抑制PD-L1与B7-1的结合。
15.权利要求12的方法,其中所述PD-L1结合拮抗剂抑制PD-L1与PD-1和B7-1两者的结合。
16.权利要求12的方法,其中所述PD-L1结合拮抗剂是抗PD-L1抗体。
17.权利要求16的方法,其中所述抗PD-L1抗体是单克隆抗体。
18.权利要求16的方法,其中所述抗PD-L1抗体是选自下组的抗体片段:Fab,Fab’-SH,Fv,scFv,和(Fab’)2片段。
19.权利要求16的方法,其中所述抗PD-L1抗体是人源化抗体。
20.权利要求16的方法,其中所述抗PD-L1抗体是人抗体。
21.权利要求16的方法,其中所述PD-L1结合拮抗剂选自下组:YW243.55.S70和MDX-1105。
22.权利要求21的方法,其中所述PD-L1结合拮抗剂是YW243.55.S70。
23.权利要求21的方法,其中所述PD-L1结合拮抗剂是MDX-1105。
24.权利要求2的方法,其中所述PD-1轴结合拮抗剂是PD-L2结合拮抗剂。
25.权利要求24的方法,其中所述PD-L2结合拮抗剂是抗体。
26.权利要求24的方法,其中所述PD-L2结合拮抗剂是免疫粘附素。
27.权利要求24的方法,其中所述PD-L2结合拮抗剂是AMP-224。
28.权利要求1的方法,其中该方法进一步包括施用VEGF拮抗剂。
29.权利要求28的方法,其中所述VEGF拮抗剂是抗VEGF抗体。
30.权利要求29的方法,其中所述抗VEGF抗体与由杂交瘤ATCC HB 10709生成的单克隆抗VEGF抗体A4.6.1结合相同表位。
31.权利要求29的方法,其中所述抗VEGF抗体是人源化抗体。
32.权利要求29的方法,其中所述抗VEGF抗体是贝伐单抗(bevacizumab)。
33.权利要求29的方法,其中所述抗VEGF抗体具有包含下述氨基酸序列的重链可变区:
EVQLVESGGG LVQPGGSLRL SCAASGYTFT NYGMNWVRQA PGKGLEWVGWINTYTGEPTY AADFKRRFTF SLDTSKSTAY LQMNSLRAED TAVYYCAKYPHYYGSSHWYF DVWGQGTLVT VSS(SEQ ID NO:22)
和包含下述氨基酸序列的轻链可变区:
DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP GKAPKVLIYFTSSLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSTVPWTFGQGTKVEIKR(SEQ ID NO:23)。
34.权利要求1-33中任一项的方法,其中所述治疗导致所述个体中所述治疗停止后持久的响应。
35.权利要求1-33中任一项的方法,其中所述受试者具有结直肠癌。
36.一种试剂盒,其包含PD-1轴结合拮抗剂和包装插页,该包装插页包含关于与奥沙利铂、亚叶酸和5-FU组合使用所述PD-1轴结合拮抗剂以在个体中治疗癌症或延迟癌症进展的用法说明书。
37.一种试剂盒,其包含PD-1轴结合拮抗剂、奥沙利铂、亚叶酸和5-FU及包装插页,该包装插页包含关于使用所述PD-1轴结合拮抗剂和所述奥沙利铂、亚叶酸和5-FU以在个体中治疗癌症或延迟癌症进展的用法说明书。
38.权利要求36或37的试剂盒,其中所述PD-1轴结合拮抗剂是抗PD-L1抗体。
39.权利要求36或37的试剂盒,其中所述PD-1轴结合拮抗剂是抗PD-1抗体。
40.权利要求36或37的试剂盒,其中所述PD-1轴结合拮抗剂是PD-L2免疫粘附素。
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