CN116617401A - 使用pd-1轴结合拮抗剂和mek抑制剂治疗癌症的组合物 - Google Patents
使用pd-1轴结合拮抗剂和mek抑制剂治疗癌症的组合物 Download PDFInfo
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Abstract
本发明涉及使用PD‑1轴结合拮抗剂和MEK抑制剂治疗癌症的组合物。本发明描述了包含PD‑1轴结合拮抗剂和MEK抑制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
本申请是申请日为2015年07月15日、中国申请号为201580030345.4、发明名称为“使用PD-1轴结合拮抗剂和MEK抑制剂治疗癌症的组合物”的发明申请的分案申请。
对相关申请的交叉引用
本申请要求2014年7月15日提交的美国临时申请流水号62/024,988的优先权权益,其内容通过援引完整收入本文。
ASCII文本文件的序列表的提交
通过援引将ASCII文本文件上的下述提交的内容完整收入本文:计算机可读形式(CRF)的序列表(文件名:146392027540SeqList.txt,记录日期:2015年7月8日,大小:22KB)。
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,Science169:1042-1049(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二者。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 2009 114(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。此外,对PD-1信号传导与在肿瘤细胞中脱调节的其它信号传导途径(例如MAPK途径,“MEK”)的组合抑制可以进一步增强治疗功效。然而,最佳的治疗性处理会组合PD-1受体/配体相互作用的阻断与直接抑制肿瘤生长的药剂,任选地进一步包括单独的PD-1阻断没有提供的独特免疫增强特性。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。
在此通过援引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轴结合拮抗剂和MEK抑制剂,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。在一些实施方案中,所述方法进一步包括诊断所述个体为具有对B-raf拮抗剂有抗性的癌症,其中所述诊断发生在施用有效量的PD-1轴结合拮抗剂和MEK抑制剂之前。在一些实施方案中,所述方法进一步包括基于所述个体具有对B-raf拮抗剂有抗性的癌症或评估所述个体有风险发生对B-raf拮抗剂有抗性的癌症来选择个体进行治疗,其中所述选择发生在施用有效量的PD-1轴结合拮抗剂和MEK抑制剂之前。在一些实施方案中,所述个体先前未曾用B-raf拮抗剂治疗。在一些实施方案中,所述个体先前已经用B-raf拮抗剂治疗。
另一方面,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(a)诊断所述个体为具有对B-raf拮抗剂有抗性的癌症;并(b)对所述个体施用有效量的PD-1轴结合拮抗剂和MEK抑制剂,其中所述施用发生在诊断所述个体之后。在一些实施方案中,所述个体先前未曾用B-raf拮抗剂治疗。在一些实施方案中,所述个体先前已经用B-raf拮抗剂治疗。
另一方面,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(a)基于所述个体具有对B-raf拮抗剂有抗性的癌症或评估所述个体有风险发生对B-raf拮抗剂有抗性的癌症来选择个体进行治疗;并(b)对所述个体施用有效量的PD-1轴结合拮抗剂和MEK抑制剂,其中所述施用发生在选择所述个体之后。在一些实施方案中,所述个体先前未曾用B-raf拮抗剂治疗。在一些实施方案中,所述个体先前已经用B-raf拮抗剂治疗。
另一方面,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轴结合拮抗剂和MEK抑制剂,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
在一些实施方案中,所述个体中的所述癌症已经在完成基于B-raf拮抗剂的疗法方案之后1个月,6个月,1年,或5年内进展。在一些实施方案中,所述B-raf拮抗剂是小分子抑制剂,抗体,肽,肽模拟物,适体或多核苷酸。在一些实施方案中,所述B-raf拮抗剂是dabrafenib,vemurafenib,GSK 2118436,RAF265,XL281,ARQ736,BAY73-4506,sorafenib,PLX4720,PLX-3603,GSK2118436,GDC-0879,或N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺。在一些实施方案中,所述B-raf拮抗剂是B-rafV600的选择性B-raf拮抗剂。在一些实施方案中,所述B-raf V600的选择性B-raf拮抗剂是B-raf V600E的选择性拮抗剂。在一些实施方案中,所述B-raf V600的选择性B-raf拮抗剂是B-raf V600E,B-raf V600K,和/或V600D的选择性拮抗剂。在一些实施方案中,所述B-rafV600的选择性B-raf拮抗剂是B-raf V600R的选择性拮抗剂。
在一些实施方案中,所述癌症含有BRAF V600E突变,BRAF野生型,KRAS野生型,或活化性KRAS突变。在一些实施方案中,所述治疗导致停止所述治疗后所述个体中持续的应答。在一些实施方案中,所述个体具有结肠直肠癌,黑素瘤,肺癌,卵巢癌,乳腺癌,胰腺癌,血液学恶性(malignancy),膀胱癌,和/或肾细胞癌。在一些实施方案中,所述癌症是转移性的。
在一些实施方案中,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。在一些实施方案中,所述PD-1轴结合拮抗剂是PD-1结合拮抗剂。在一些实施方案中,所述PD-1结合拮抗剂抑制PD-1与其配体结合配偶的结合。在一些实施方案中,所述PD-1结合拮抗剂抑制PD-1与PD-L1,PD-1与PD-L2,或PD-1与PD-L1和PD-L2二者的结合。在一些实施方案中,所述PD-1结合拮抗剂是抗体。在一些实施方案中,所述PD-1结合拮抗剂是MDX-1106,Merck 3745,CT-011,MEDI-0680,PDR001,REGN2810,BGB-108,BGB-A317,或AMP-224。在一些实施方案中,所述PD-1结合拮抗剂是nivolumab,pembrolizumab,pidilizumab,MEDI-0680,PDR001,REGN2810,BGB-108,BGB-A317,或AMP-224。在一些实施方案中,所述PD-1轴结合拮抗剂是PD-L1结合拮抗剂。在一些实施方案中,所述PD-L1结合拮抗剂抑制PD-L1与PD-1,PD-L1与B7-1,或PD-L1与PD-1和B7-1二者的结合。在一些实施方案中,所述PD-L1结合拮抗剂是抗PD-L1抗体。在一些实施方案中,所述抗PD-L1抗体是单克隆抗体。在一些实施方案中,所述抗PD-L1抗体是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,所述抗PD-L1抗体是人源化抗体或人抗体。在一些实施方案中,所述PD-L1结合拮抗剂选自下组:YW243.55.S70,MPDL3280A,MEDI4736,MDX-1105,和MSB0010718C。在一些实施方案中,所述PD-L1结合拮抗剂选自下组:YW243.55.S70,atezolizumab,durvalumab,MDX-1105,和avelumab。在一些实施方案中,所述抗体包含重链和轻链,所述重链包含HVR-H1序列SEQ ID NO:15,HVR-H2序列SEQ IDNO:16,和HVR-H3序列SEQ ID NO:3;所述轻链包含HVR-L1序列SEQ ID NO:17,HVR-L2序列SEQ ID NO:18,和HVR-L3序列SEQ ID NO:19。在一些实施方案中,所述抗体包含重链可变区和轻链可变区,所述重链可变区包含氨基酸序列SEQ ID NO:24或28,所述轻链可变区包含氨基酸序列SEQ ID NO:21。在一些实施方案中,所述PD-1轴结合拮抗剂是PD-L2结合拮抗剂。在一些实施方案中,所述PD-L2结合拮抗剂是抗体。在一些实施方案中,所述PD-L2结合拮抗剂是免疫粘附素。在一些实施方案中,所述MEK抑制剂是竞争性MEK抑制剂。在一些实施方案中,所述MEK抑制剂针对活化性KRAS突变更有选择性。在一些实施方案中,所述MEK抑制剂是变构性MEK抑制剂。在一些实施方案中,所述MEK抑制剂针对活化性BRAF突变更有选择性。在一些实施方案中,所述MEK抑制剂是式(I),(II),(III),(IV),(V),(VI)或(VII)的化合物,或其药学可接受盐或溶剂合物。在一些实施方案中,所述MEK抑制剂选自下组:G02442104,G-38963,G02443714,G00039805和GDC-0973,或其药学可接受盐或溶剂合物。在一些实施方案中,所述MEK抑制剂是G02443714,G02442104或G00039805。
在一些实施方案中,连续施用所述MEK抑制剂。在一些实施方案中,间歇施用所述MEK抑制剂。在一些实施方案中,在所述PD-1轴结合拮抗剂前施用所述MEK抑制剂。在一些实施方案中,与所述PD-1轴结合拮抗剂同时施用所述MEK抑制剂。在一些实施方案中,在所述PD-1轴结合拮抗剂后施用所述MEK抑制剂。在一些实施方案中,静脉内,肌肉内,皮下,表面,口服,经皮,腹膜内,眶内,通过植入,通过吸入,鞘内,室内,或鼻内施用所述PD-1轴结合拮抗剂和/或所述MEK抑制剂。
另一方面,本文中提供试剂盒,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MEK抑制剂组合使用所述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,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。另一方面,本文中提供试剂盒,其包含PD-1轴结合拮抗剂和MEK抑制剂及包装插页,该包装插页包含关于使用所述PD-1轴结合拮抗剂和所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。另一方面,本文中提供试剂盒,其包含MEK抑制剂和包装插页,该包装插页包含关于与PD-1轴结合拮抗剂组合使用所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。另一方面,本文中提供试剂盒,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MEK抑制剂组合使用所述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,其中所述个体先前已经用B-raf拮抗剂治疗癌症。另一方面,本文中提供试剂盒,其包含PD-1轴结合拮抗剂和MEK抑制剂及包装插页,该包装插页包含关于使用所述PD-1轴结合拮抗剂和所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体先前已经用B-raf拮抗剂治疗癌症。另一方面,本文中提供试剂盒,其包含MEK抑制剂和包装插页,该包装插页包含关于与PD-1轴结合拮抗剂组合使用所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
在一些实施方案中,所述个体是人。
要理解,可以组合本文所述各个实施方案的一个,一些,或所有特性以形成本发明的其它实施方案。本发明的这些和其它方面对本领域技术人员会变得显而易见。通过下面的详述进一步描述本发明的这些和其它实施方案。
附图简述
图1显示用抗PDL1,MEK抑制剂,或二者治疗后的肿瘤再生长。该图显示用所示药剂处理期间随时间的百分比肿瘤体积变化。
图2显示对用Vemurafenib继以抗PDL1,MEK抑制剂,或二者处理的个体动物响应。每条棒描绘个体动物中自Vemurafenib转换至所示处理时肿瘤生长的百分比变化。
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,MolecularCloning:A Laboratory Manual 3d edition(2001)Cold Spring Harbor LaboratoryPress,Cold Spring Harbor,N.Y.;Current Protocols in Molecular Biology(F.M.Ausubel等编,(2003));丛刊Methods in Enzymology(Academic Press,Inc.):PCR2: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 inMolecular Biology,Humana Press;Cell Biology:A Laboratory Notebook(J.E.Cellis编,1998)Academic Press;Animal Cell Culture(R.I.Freshney)编,1987);Introductionto Cell 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);CurrentProtocols in Immunology(J.E.Coligan等编,1991);Short Protocols in MolecularBiology(Wiley和Sons,1999);Immunobiology(C.A.Janeway和P.Travers,1997);Antibodies(P.Finch,1997);Antibodies:A Practical Approach(D.Catty.编,IRLPress,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 Spring Harbor Laboratory Press,1999);The Antibodies(M.Zanetti和J.D.Capra编,Harwood Academic Publishers,1995);及Cancer:Principlesand Practice of Oncology(V.T.DeVita等编,J.B.Lippincott Company,1993)。
II.定义
术语“拮抗剂”以最广义使用,包括部分或完全阻断,抑制,或中和本文中所公开的天然多肽的生物学活性的任何分子。类似的,术语“激动剂”以最广义使用,包括模拟本文中所公开的天然多肽的生物学活性的任何分子。合适的激动剂或拮抗剂分子明确包括激动性或拮抗性抗体或抗体片段,天然多肽的片段或氨基酸序列变体,肽,反义寡核苷酸,有机小分子等。用于鉴定多肽的激动剂或拮抗剂的方法可包括使多肽接触候选激动剂或拮抗剂分子并测量通常与所述多肽有关的一种或多种生物学活性的可检测变化。
术语“适体”指能够结合靶分子(诸如多肽)的核酸分子。例如,本发明的适体能特异性结合B-raf多肽,或调控B-raf表达或活性的信号传导途径中的分子。适体的生成和治疗用途是本领域已完善建立的。参见例如美国专利No.5,475,096,及(Eyetech,New York)用于治疗年龄相关黄斑变性的治疗功效。
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(例如增殖,细胞因子生成,靶细胞杀伤))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细胞不太有功能障碍(例如增强对抗原识别的效应器应答),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Merck3745。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细胞不太有功能障碍(例如增强对抗原识别的效应器应答),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。在又一个具体的方面,抗PD-L1抗体是本文中描述的MPDL3280A(atezolizumab)。
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细胞不太有功能障碍(例如增强对抗原识别的效应器应答),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结合拮抗剂是免疫粘附素。
术语“功能障碍”在免疫功能障碍的背景中指降低的对抗原性刺激的免疫响应性的状态。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/或无反应性二者的共同要素。
如本文中使用的,术语“功能障碍”还包括对抗原识别的不感受或不响应,特别地,将抗原识别转化成下游T细胞效应器功能,诸如增殖,细胞因子生成(例如IL-2)和/或靶细胞杀伤的能力受损。
术语“无反应性”指源自经由T细胞受体投递的不完全或不充分信号(例如在缺乏ras活化的情况中胞内Ca+2增加)的对抗原刺激的无响应性状态。T细胞无反应性也可以在缺乏共刺激的情况中在用抗原刺激后发生,生成即使在共刺激的背景中对抗原的随后活化变得不感受的细胞。无响应性状态经常可以被白介素-2的存在超越。无反应性T细胞不经历克隆扩充和/或获得效应器功能。
术语“耗竭”指作为源自在许多慢性感染和癌症期间发生的持续TCR信号传导的T细胞功能障碍状态的T细胞耗竭。它与无反应性的区别在于它不经由不完全或缺乏的信号传导,而是由于持续信号传导而发生。它以较差的效应器功能,持续的抑制性受体表达和与功能性效应或记忆T细胞的转录状态不同的转录状态限定。耗竭阻止感染和肿瘤的最佳控制。耗竭可以源自外在负调节途径(例如免疫调节细胞因子)及细胞固有负调节(共刺激)途径(PD-1,B7-H3,B7-H4,等等)二者。
“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,病原体,或肿瘤清除)。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用抗PDL抗体和MEK抑制剂处理。
“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。
如本文中使用的,“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但不限于鳞状细胞癌,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,胃的癌或胃癌(包括胃肠癌),胰腺癌,成胶质细胞瘤,宫颈癌,卵巢癌,肝癌,膀胱癌,肝瘤,乳腺癌,结肠癌,结肠直肠癌,子宫内膜癌或子宫癌,唾液腺癌,肾癌或肾的癌,肝癌,前列腺癌,外阴癌,甲状腺癌,肝的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。癌症的例子可以包括任何上述类型癌症的原发性肿瘤或第二部位处自任何上述类型癌症衍生的转移性肿瘤。
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 TristramG.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 of Immunological 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:ALaboratory Manual,(Cold Spring Harbor Laboratory Press,2nd ed.1988);Hammerling等,in:Monoclonal Antibodies 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WO1998/24893;WO 1996/34096;WO 1996/33735;WO 1991/10741;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;和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 ofMonoclonal 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EP 404,097;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残基替换的人免疫球蛋白。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 and Hamilton,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,MonoclonalAntibodies and Cancer 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);Johnsonand Wu,于:Methods in Molecular Biology 248:1-25(Lo编,Human Press,Totowa,NJ,2003)。事实上,仅由重链组成的天然存在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,NatureStruct.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 of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD.(1991))。Chothia改为指结构环的位置(Chothia and Lesk J.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OxfordMolecular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 of Health,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:4),WVRQAPGKGLEWV(HC-FR2),(SEQ ID NO:5),RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(HC-FR3,SEQ ID NO:6),WGQGTLVTVSA(HC-FR4),(SEQ ID NO:7)。
“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:11),WYQQKPGKAPKLLIY(LC-FR2)(SEQ ID NO:12),GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(LC-FR3)(SEQ ID NO:13),FGQGTKVEIKR(LC-FR4)(SEQ ID NO:14)。
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-L1 ECD–Fc,PD-L2 ECD–Fc,和PD-1ECD-Fc。Ig Fc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 asAntigens,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“拮抗剂”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,阻断性抗体或拮抗剂抗体实质性或完全抑制抗原的生物学活性。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(例如增殖,细胞因子生成,靶细胞杀伤)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,或者混合了有和无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);de Haas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);及WO2004/92219(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。WO2004/42072(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,“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。
如本文中使用的,“降低或抑制癌症复发”意指降低或抑制肿瘤或癌症复发或肿瘤或癌症进展。如本文中使用的,癌症复发和/或癌症进展包括但不限于癌症转移。
“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,可以实现或者实现期望的结果,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。
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(meturedepa)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(trietylenephosphoramide),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(scopoletin)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(nitrogen mustards),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 oxide hydrochloride),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(ranimnustine);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(mycophenolicacid),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(folinic 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 Natural Products,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)。
化疗剂的别的例子包括作用为调节,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(goserelin acetate),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erlotinib或西妥昔单抗(cetuximab);抗VEGF抑制剂,诸如贝伐单抗(bevacizumab);arinotecan;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,术语“烷基”指1至12个碳原子的饱和线性或支链单价烃基。烷基基团的例子包括但不限于甲基(Me,-CH3),乙基(Et,-CH2CH3),1-丙基(n-Pr,n-丙基,-CH2CH2CH3),2-丙基(i-Pr,i-丙基,-CH(CH3)2),1-丁基(n-Bu,n-丁基,-CH2CH2CH2CH3),2-甲基-1-丙基(i-Bu,i-丁基,-CH2CH(CH3)2),2-丁基(s-Bu,s-丁基,-CH(CH3)CH2CH3),2-甲基-2-丙基(t-Bu,t-丁基,-C(CH3)3),1-戊基(n-戊基,-CH2CH2CH2CH2CH3),2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-CH(CH2CH3)2),2-甲基-2-丁基(-C(CH3)2CH2CH3),3-甲基-2-丁基(-CH(CH3)CH(CH3)2),3-甲基-1-丁基(-CH2CH2CH(CH3)2),2-甲基-1-丁基(-CH2CH(CH3)CH2CH3),1-己基(-CH2CH2CH2CH2CH2CH3),2-己基(-CH(CH3)CH2CH2CH2CH3),3-己基(-CH(CH2CH3)(CH2CH2CH3)),2-甲基-2-戊基(-C(CH3)2CH2CH2CH3),3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3),4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2),3-甲基-3-戊基(-C(CH3)(CH2CH3)2),2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2),2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2),3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3,1-庚基,1-辛基,等等。
术语“烯基”指2至12个碳原子的,有至少一个不饱和位点(即碳-碳,sp2双键)的,线性的或分支的单价烃基,其中烯基包括具有“顺式”和“反式”取向或者“E”和“Z”取向的根。实例包括但不限于乙烯基(-CH=CH2),丙烯基(-CH2CH=CH2),等等。
术语“炔基”指2至12个碳原子的,有至少一个不饱和位点(即碳-碳,sp三键)的,线性的或分支的单价烃基。例子包括但不限于乙炔基(-C≡CH),丙炔基或炔丙基(-CH2C≡CH),等等。
术语“碳环”,“碳环基”,“碳环环”和“环烃基”指作为单环环具有3至12个碳原子或作为双环环具有7-12个碳原子的,单价的,非芳香族的,饱和的或部分未饱和的环。具有7-12个原子的双环碳环可以排列成例如双环[4,5],[5,5],[5,6]或[6,6]体系,而具有9或10个环原子的双环碳环可以排列成双环[5,6]或[6,6]体系,或者桥连体系诸如双环[2.2.1]庚烷,双环[2.2.2]辛烷和双环[3.2.2]壬烷。单环碳环的实例包括但不限于环丙基,环丁基,环戊基,1-环戊-1-烯基,1-环戊-2-烯基,1-环戊-3-烯基,环己基,1-环己-1-烯基,1-环己-2-烯基,1-环己-3-烯基,环己二烯基,环庚基,环辛基,环壬基,环癸基,环十一烷基,环十二烷基,等等。
“芳基”指6至18个碳原子的,通过从亲本芳香族环体系的一个碳原子除去一个氢原子而衍生的,单价芳香族烃基。有些芳基在例示结构中以“Ar”来代表。芳基包括包含与饱和的,部分未饱和的环或芳香族碳环或杂环环融合的芳香环的双环基。典型的芳基包括但不限于自苯(苯基),取代的苯,萘,蒽,茚基,茚满基,1,2-二氢萘,1,2,3,4-四氢萘基,等等衍生的基。
术语“杂环”,“杂环基”和“杂环环”在本文中可互换使用,指3至18个环原子的(其中至少一个环原子是选自氮,氧和硫的杂原子,其余环原子是C),饱和的或部分未饱和的(即在环内具有一个或多个双键和/或三键)碳环基,其中一个或多个环原子是任选用下文所述一种或多种取代基独立取代的。杂环可以是具有3-7个环成员(2-6个碳原子和1-4个选自N,O,P和S的杂原子)的单环或具有7-10个环成员(4-9个碳原子和1-6个选自N,O,P和S的杂原子)的双环,例如双环[4,5],[5,5],[5,6]或[6,6]体系。杂环记载于Paquette,Leo A.;“Principles of Modern Heterocyclic Chemistry”(W.A.Benjamin,New York,1968),特别是第1,3,4,6,7,和9章;“The Chemistry of Heterocyclic Compounds,A series ofMonographs”(John Wiley&Sons,New York,1950至今),特别是第13,14,16,19,和28卷;及J.Am.Chem.Soc.(1960)82:5566。“杂环基”还包括杂环基与饱和的,部分未饱和的环或芳香族碳环或杂环环融合的根。杂环环的实例包括但不限于吡咯烷基(pyrrolidinyl),四氢呋喃基(tetrahydrofuranyl),二氢呋喃基(dihydrofuranyl),四氢噻吩基(tetrahydrothienyl),四氢吡喃基(tetrahydropyranyl),二氢吡喃基(dihydropyranyl),四氢硫代吡喃基(tetrahydrothiopyranyl),哌啶基(piperidinyl),吗啉基(morpholinyl),硫代吗啉基(thiomorpholinyl),噻口恶烷基(thioxanyl),哌嗪基(piperazinyl),高哌嗪基(homopiperazinyl),氮杂环丁烷基(azetidinyl),氧杂环丁烷基(oxetanyl),硫杂环丁烷基(thietanyl),高哌啶基(homopiperidinyl),氧杂环庚烷基(oxepanyl),硫杂环庚烷基(thiepanyl),氧氮杂基(oxazepinyl),二氮杂/>基(diazepinyl),硫杂/>基(thiazepinyl),2-吡咯啉基(2-pyrrolinyl),3-吡咯啉基(3-pyrrolinyl),二氢吲哚基(indolineyl),2H-吡喃基(2H-pyranyl),4H-吡喃基(4H-pyranyl),二口恶烷基(dioxanyl),1,3-二氧戊环基(1,3-dioxolanyl),吡唑啉基(pyrazolinyl),二噻烷基(dithianyl),二硫戊环基(dithiolanyl),二氢吡喃基(dihydropyranyl),二氢噻吩基(dihydrothienyl),二氢呋喃基(dihydrofuranyl),吡唑烷基(pyrazolidinyl)咪唑啉基(imidazolinyl),咪唑烷基(imidazolidinyl),3-氮双环[3.1.0]己烷基(3-azabicyco[3.1.0]hexanyl),3-氮双环[4.1.0]庚烷基(3-azabicyclo[4.1.0]heptanyl),和氮双环[2.2.2]己烷基(azabicyclo[2.2.2]hexanyl)。螺模块也包括在此定义的范围内。其中环原子被氧(=O)模块取代的杂环基的例子有嘧啶酮基(pyrimidinonyl)和1,1-二氧-硫代吗啉基(1,1-dioxo-thiomorpholinyl)。
术语“杂芳基”指5或6元环的单价芳香基,而且包括5-18个原子(含有一个或多个独立选自氮,氧和硫的杂原子)的稠环体系(其中至少一个是芳香族的)。杂芳基的实例有吡啶基(pyridinyl)(包括例如2-羟基吡啶基),咪唑基(imidazolyl),咪唑并吡啶基(imidazopyridinyl),嘧啶基(pyrimidinyl)(包括例如4-羟基嘧啶基),吡唑基(pyrazolyl),三唑基(triazolyl),吡嗪基(pyrazinyl),四唑基(tetrazolyl),呋喃基(furyl),噻吩基(thienyl),异口恶唑基(isoxazolyl),噻唑基(thiazolyl),口恶唑基(oxazolyl),异噻唑基(isothiazolyl),吡咯基(pyrrolyl),喹啉基(quinolinyl),异喹啉基(isoquinolinyl),吲哚基(indolyl),苯并咪唑基(benzimidazolyl),苯并呋喃基(benzofuranyl),噌啉基(cinnolinyl),吲唑基(indazolyl),吲嗪基(indolizinyl),酞嗪基(phthalazinyl),哒嗪基(pyridazinyl),三嗪基(triazinyl),异吲哚基(isoindolyl),喋啶基(pteridinyl),嘌呤基(purinyl),口恶二唑基(oxadiazolyl),三唑基(triazolyl),噻二唑基(thiadiazolyl),呋咱基(furazanyl),苯并呋咱基(benzofurazanyl),苯并噻吩基(benzothiophenyl),苯并噻唑基(benzothiazolyl),苯口恶基(benzoxazolyl),喹唑啉基(quinazolinyl),喹口恶啉基(quinoxalinyl),二氮杂萘基(naphthyridinyl)和呋喃并吡啶基(furopyridinyl)。
杂环或杂芳基可以是碳(碳连的)或氮(氮连的)附着的,在那里可能的情况中。举例而非限制,碳键合的杂环或杂芳基在吡啶的2,3,4,5或6位,哒嗪的3,4,5或6位,嘧啶的2,4,5或6位,吡嗪的2,3,5或6位,呋喃,四氢呋喃,硫代呋喃(thiofuran),噻吩,吡咯或四氢吡咯的2,3,4或5位,口恶唑,咪唑或噻唑的2,4或5位,异口恶唑,吡唑或异噻唑的3,4或5位,氮丙啶的2或3位,吖丁啶的2,3或4位,喹啉的2,3,4,5,6,7或8位,或异喹啉的1,3,4,5,6,7或8位处键合。
举例而非限制,氮键合的杂环或杂芳基在氮丙啶,吖丁啶,吡咯,吡咯烷,2-吡咯啉,3-吡咯啉,咪唑,咪唑烷,2-咪唑啉,3-咪唑啉,吡唑,吡唑啉,2-吡唑啉,3-吡唑啉,哌啶,哌嗪,吲哚,二氢吲哚,1H-吲唑的1位,异吲唑或异二氢吲哚的2位,吗啉的4位,和咔唑或β-咔啉的9位处键合。
杂芳基或杂环基中存在的杂原子包括氧化形式,诸如N+→O-,S(O)和S(O)2。
术语“卤素”指F,Cl,Br或I。
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。
“溶剂合物”指一种或多种溶剂分子和本发明的化合物的联合或复合物。形成溶剂合物的溶剂的例子包括但不限于水,异丙醇,乙醇,甲醇,DMSO,乙酸乙酯,乙酸,和乙醇胺。术语“水合物”指溶剂分子是水的复合物。
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
在一个方面,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,其包括对个体施用有效量的PD-1轴结合拮抗剂和MEK抑制剂。
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,所述癌症包括但不限于可以含有B-raf V600E突变的癌症,可以含有B-raf野生型的癌症,可以含有KRAS野生型的癌症,或可以含有活化性KRAS突变的癌症。
在一些实施方案中,所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。在一些实施方案中,所述个体先前已经用B-raf拮抗剂治疗癌症。在一些实施方案中,所述个体先前未曾用B-raf拮抗剂治疗。B-raf是一种已知在癌症(例如恶性黑素瘤,结肠直肠,卵巢,和甲状腺癌)中频繁突变的丝氨酸-苏氨酸激酶。典型地,在癌症中观察到的B-raf突变包括活化性突变,诸如V600E突变。不希望受理论束缚,认为B-raf中的活化性突变促进失调的MAPK/ERK信号传导,导致肿瘤细胞增殖和存活。
虽然已知B-raf拮抗剂(例如B-raf抑制剂)在患者存活和肿瘤消退中产生有效的短期升高,但是频繁观察到针对B-raf抑制的抗性(参见例如Tentori,L.,et al.TrendsPharmacol.Sci.34(12):656-66(2013))。针对B-raf抑制的抗性特征可在于众多现象。在一些实施方案中,针对B-raf抑制的抗性特征可在于MAPK途径再活化,PI3K活化,CRAF上调,NRAS突变,PDGFR过表达,COT1过表达,IGFR-1过表达,MEK1突变,HGF表达,PD-L1过表达,MEK2突变,MITF局灶性扩增,AKT突变(例如AKT1或AKT3),B-raf扩增,和RAF二聚体(例如CRAF/CRAF二聚体,CRAF/B-raf二聚体,和突变型二聚化B-raf诸如缺乏外显子4-8的B-raf变体)形成中的一项或多项。
在一些实施方案中,针对B-raf抑制的抗性可以指对B-raf抑制不应的癌细胞或肿瘤。针对B-raf抑制的抗性在本文中以最广义使用,而且可以包括先前是或可以预期经由任何特定机制或在任何特定剂量的本公开文本的B-raf拮抗剂对B-raf抑制敏感的任何癌细胞。针对B-raf抑制的抗性可以指在B-raf拮抗剂存在下的B-raf活性。针对B-raf抑制的抗性可以指在B-raf拮抗剂存在下生长而预期它在此类条件下不生长的细胞,不管可能存在的B-raf的酶活性。
在一些实施方案中,所述B-raf拮抗剂是小分子抑制剂,抗体,肽,肽模拟物,适体或多核苷酸。
在一些实施方案中,所述个体先前已经用B-raf拮抗剂治疗。在一些实施方案中,B-raf拮抗剂可包括vemurafenib(也称作),dabrafenib(也称作),LGX818,GSK 2118436,RAF265,XL281,ARQ736,BAY73-4506,sorafenib,PLX4720,PLX-3603,GSK2118436,GDC-0879,或N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺。在一些实施方案中,B-raf拮抗剂可包括MLN2480,LY3009120,MEK抑制剂诸如trametinib(也称作/>),或EGFR抑制剂诸如erlotinib(也称作/>)。B-raf抑制剂的别的描述可以见Zambon,A.etal.Bioorg.Med.Chem.Lett.22(2):789-92(2012);Tentori,L.,et al.TrendsPharmacol.Sci.34(12):656-66(2013);和Martin-Liberal,J.and Larkin,J.ExpertOpin.Pharmacother.15(9):1235-45(2014),WO2007/002325,WO2007/002433,WO2009111278,WO2009111279,WO2009111277,WO2009111280和美国专利No.7,491,829。
在一些实施方案中,所述B-raf拮抗剂是B-raf V600的选择性B-raf拮抗剂。在一些实施方案中,所述B-raf V600的选择性B-raf拮抗剂是B-raf V600E的选择性拮抗剂。在一些实施方案中,所述B-raf V600的选择性B-raf拮抗剂是B-raf V600E,B-raf V600K,和/或V600D的选择性拮抗剂。在一些实施方案中,所述B-raf V600的选择性B-raf拮抗剂是B-raf V600R的选择性拮抗剂。用于生成和测定对B-raf V600选择性的B-raf拮抗剂的技术在本领域中已有描述;参见例如Tsai,J,et al.,Proc.Natl.Acad.Sci.105(8):3041-6(2008)。
在一些实施方案中,所述癌症含有BRAF V600E突变,BRAF野生型,KRAS野生型,或活化性KRAS突变。用于检测此类突变的存在的方法可以包括但不限于PCR,Sanger测序,使用突变特异性抗体,等等。用于测定癌症是否表达B-raf V600的方法是本领域已知的,包括但不限于4800B-raf V600突变测试试剂盒(Roche)。
在一些实施方案中,所述患者的癌症已经显示表达B-raf生物标志物。在一些实施方案中,B-raf生物标志物是突变型B-raf。在一些实施方案中,突变型B-raf是B-raf V600。在一些实施方案中,B-raf V600是B-raf V600E。在一些实施方案中,突变型B-raf是组成性有活性的。
在一些实施方案中,癌症患者在接受B-raf拮抗剂疗法时已经进展(即,所述患者是“B-raf不应的”),或者患者已经在完成基于B-raf拮抗剂的疗法方案之后1个月,2个月,3个月,4个月,5个月,6个月,7个月,8个月,9个月,10个月,11个月,12个月,或更久内进展。
在一些实施方案中,vemurafenib抗性癌症表示癌症患者在接受基于vemurafenib的疗法时已经进展(即,所述患者是“vemurafenib不应的”)。在一些实施方案中,患者中的癌症已经在完成基于vemurafenib的疗法方案之后1个月,2个月,3个月,4个月,5个月,6个月,7个月,8个月,9个月,10个月,11个月,12个月,或更久内进展。在一些实施方案中,个体中的癌症已经在完成基于B-raf拮抗剂的疗法方案之后1个月,2个月,3个月,4个月,5个月,6个月,7个月,8个月,9个月,10个月,11个月,1年,2年,3年,4年,或5年内进展。
在一些实施方案中,所述治疗导致停止所述治疗后所述个体中持续的应答。
在一些实施方案中,在用B-raf拮抗剂治疗之后发生(获得)针对例如B-raf抑制剂的抗性。在其它实施方案中,患者(例如具有B-raf抗性癌症的患者)先前未曾用B-raf拮抗剂治疗。
在一些实施方案中,所述患者当前正在用B-raf拮抗剂,诸如B-raf抑制剂治疗。在一些实施方案中,所述患者先前用B-raf拮抗剂治疗过。在一些实施方案中,所述患者先前没有用B-raf拮抗剂治疗过。
在一些实施方案中,所述个体具有结肠直肠癌,黑素瘤,肺癌,卵巢癌,乳腺癌,胰腺癌,血液学恶性,膀胱癌,和/或肾细胞癌。在一些实施方案中,所述个体具有非小细胞肺癌。所述非小细胞肺癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有小细胞肺癌。所述小细胞肺癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有肾细胞癌。所述肾细胞癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有结肠直肠癌。所述结肠直肠癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有卵巢癌。所述卵巢癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有乳腺癌。所述乳腺癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有胰腺癌。所述胰腺癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有胃癌。所述胃癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有膀胱癌。所述膀胱癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有食道癌。所述食道癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有间皮瘤。所述间皮瘤可以处于早期或处于晚期。在一些实施方案中,所述个体具有黑素瘤。所述黑素瘤可以处于早期或处于晚期。在一些实施方案中,所述个体具有头和颈癌。所述头和颈癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有甲状腺癌。所述甲状腺癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有肉瘤。所述肉瘤可以处于早期或处于晚期。在一些实施方案中,所述个体具有前列腺癌。所述前列腺癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有成胶质细胞瘤。所述成胶质细胞瘤可以处于早期或处于晚期。在一些实施方案中,所述个体具有宫颈癌。所述宫颈癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有胸腺癌。所述胸腺癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有白血病。所述白血病可以处于早期或处于晚期。在一些实施方案中,所述个体具有淋巴瘤。所述淋巴瘤可以处于早期或处于晚期。在一些实施方案中,所述个体具有骨髓瘤。所述骨髓瘤可以处于早期或处于晚期。在一些实施方案中,所述个体具有蕈样肉芽肿病。所述蕈样肉芽肿病可以处于早期或处于晚期。在一些实施方案中,所述个体具有梅克尔细胞癌。所述梅克尔细胞癌可以处于早期或处于晚期。在一些实施方案中,所述个体具有血液学恶性。所述血液学恶性可以处于早期或处于晚期。在一些实施方案中,所述个体是人。在一些实施方案中,所述癌症是转移性的。
在一些实施方案中,个体是哺乳动物,诸如驯养动物(例如牛,绵羊,猫,犬,和马),灵长类(例如人和非人灵长类诸如猴),兔,和啮齿类(例如小鼠和大鼠)。在一些实施方案中,处理的个体是人。
在另一个方面,本文中提供了在具有癌症的个体中增强免疫功能的方法,其包括施用有效量的PD-1轴结合拮抗剂和MEK抑制剂。
在一些实施方案中,相对于施用PD-1途径拮抗剂和MEK抑制剂前,个体中的CD8 T细胞具有增强的引发,活化,增殖和/或细胞裂解活性。在一些实施方案中,CD8 T细胞引发以CD8 T细胞中升高的CD44表达和/或增强的细胞裂解活性为特征。在一些实施方案中,CD8T细胞活化以升高的γ-IFN+CD8T细胞频率为特征。在一些实施方案中,CD8 T细胞是抗原特异性T细胞。在一些实施方案中,抑制通过经由PD-L1表面表达的信号传导实现的免疫逃避。
在一些实施方案中,相对于施用PD-1途径拮抗剂和MEK抑制剂前,个体中的癌细胞具有MHC I类抗原表达的升高的表达。
在一些实施方案中,相对于施用PD-1途径拮抗剂和MEK抑制剂前,个体中的抗原呈递细胞具有增强的成熟和活化。在一些实施方案中,其中所述抗原呈递细胞是树突细胞。在一些实施方案中,抗原呈递细胞的成熟以升高的CD83+树突细胞频率为特征。在一些实施方案中,抗原呈递细胞的活化以树突细胞上升高的CD80和CD86表达为特征。
在一些实施方案中,相对于施用抗PD-L1抗体和MEK抑制剂前,个体中细胞因子IL-10和/或趋化因子IL-8(鼠KC的人同系物)的血清水平是降低的。
在一些实施方案中,癌症具有升高的T细胞浸润水平。
在一些实施方案中,本发明的联合疗法包括施用PD-1轴结合拮抗剂和MEK抑制剂。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MEK抑制剂。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MEK抑制剂。
在一些实施方案中,连续施用MEK抑制剂。在一些实施方案中,间歇施用MEK抑制剂。在一些实施方案中,在施用PD-1轴结合拮抗剂前施用MEK抑制剂。在一些实施方案中,与施用PD-1轴结合拮抗剂同时施用MEK抑制剂。在一些实施方案中,在施用PD-1轴结合拮抗剂后施用MEK抑制剂。
在一些实施方案中,提供了用于在个体中治疗癌症或延迟癌症进展的方法,其包括对个体施用有效量的PD-1轴结合拮抗剂和MEK抑制剂,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。在一些实施方案中,别的疗法是γ照射。在一些实施方案中,别的疗法是靶向PI3K/AKT/mTOR途径的疗法,HSP90抑制剂,微管蛋白抑制剂,凋亡抑制剂,和/或化学预防剂。别的疗法可以是上文描述的一种或多种化疗剂。
可以通过相同施用路径或者通过不同施用路径施用PD-1轴结合拮抗剂和MEK抑制剂。在一些实施方案中,静脉内,肌肉内,皮下,表面,口服,经皮,腹膜内,眶内,通过植入,通过吸入,鞘内,室内,或鼻内施用PD-1轴结合拮抗剂。在一些实施方案中,静脉内,肌肉内,皮下,表面,口服,经皮,腹膜内,眶内,通过植入,通过吸入,鞘内,室内,或鼻内施用MEK抑制剂。可以施用有效量的PD-1轴结合拮抗剂和MEK抑制剂以预防或治疗疾病。PD-1轴结合拮抗剂和/或MEK抑制剂的合适剂量可以基于要治疗的疾病的类型,PD-1轴结合拮抗剂和MEK抑制剂的类型,疾病的严重性和过程,个体的临床状况,个体的临床史和对治疗的响应,和主治内科医生的判断确定。
可以在方法中使用本领域中已知或下文描述的任何PD-1轴结合拮抗剂和MEK抑制剂。
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,其包括对个体施用有效量的PD-1轴结合拮抗剂和MEK抑制剂。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。“PD-1”的备选名称包括CD279和SLEB2。“PD-L1”的备选名称包括B7-H1,B7-4,CD274,和B7-H。“PD-L2”的备选名称包括B7-DC,Btdc,和CD273。在一些实施方案中,PD-1,PD-L1,和PD-L2是人PD-1,PD-L1和PD-L2。
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结合拮抗剂是抗PD-1抗体(例如人抗体,人源化抗体,或嵌合抗体)。在一些实施方案中,抗PD-1抗体选自下组:MDX-1106(nivolumab,),Merck 3745(MK-3475,pembrolizumab,/>),CT-011(pidilizumab),MEDI-0680(AMP-514),PDR001,REGN2810,BGB-108,和BGB-A317。在一些实施方案中,PD-1结合拮抗剂是免疫粘附素(例如包含与恒定区(例如免疫球蛋白序列的Fc区)融合的PD-L1或PD-L2的胞外或PD-1结合部分的免疫粘附素)。在一些实施方案中,PD-1结合拮抗剂是AMP-224。在一些实施方案中,PD-L1结合拮抗剂是抗PD-L1抗体。在一些实施方案中,抗PD-L1结合拮抗剂选自下组:YW243.55.S70,MPDL3280A(atezolizumab),MEDI4736(durvalumab),MDX-1105,和MSB0010718C(avelumab)。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和21中分别显示的重和轻链可变区序列)是一种在WO 2010/077634A1中描述的抗PD-L1。MEDI4736是一种在WO2011/066389和US2013/034559中描述的抗PD-L1抗体。MDX-1106,又称为nivolumab,MDX-1106-04,ONO-4538,BMS-936558,或/>是一种在WO2006/121168中描述的抗PD-1抗体。Merck3745,又称为MK-3475,pembrolizumab,lambrolizumab,/>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。
在一些实施方案中,抗PD-1抗体是MDX-1106。“MDX-1106”的备选名称包括MDX-1106-04,ONO-4538,BMS-936558或nivolumab。在一些实施方案中,抗PD-1抗体是Nivolumab(CAS登录号:946414-94-4)。在又一个实施方案中,提供了分离的抗PD-1抗体,其包含重链可变区和/或轻链可变区,所述重链可变区包含来自SEQ ID NO:22的重链可变区氨基酸序列,所述轻链可变区包含来自SEQ ID NO:23的轻链可变区氨基酸序列。在又一个实施方案中,提供了分离的抗PD-1抗体,其包含重链和/或轻链序列,其中:
(a)重链序列与下述重链序列具有至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%或100%序列同一性:
QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWV
AVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCAT
NDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE
PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVD
HKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPE
VTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL
TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE
EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:22),或
(b)轻链序列与下述轻链序列具有至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%或100%序列同一性:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS
NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:23)。
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WO2010/077634 A1,其通过援引收入本文。
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WO2010/077634 A1的抗PD-L1抗体可以与MEK抑制剂组合使用以治疗癌症。在一些实施方案中,抗PD-L1抗体含有包含氨基酸序列SEQ ID NO:20的重链可变区和包含氨基酸序列SEQID NO:21的轻链可变区。
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,和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,和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 IDNO: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 ID NO: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,和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,和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:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVA WISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARR HWPGGFDYWGQGTLVTVSA(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:DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTK VEIKR(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,和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,和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,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:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVA WISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARR HWPGGFDYWGQGTLVTVSS(SEQ ID NO:24),或
(b)轻链序列与下述轻链序列具有至少85%序列同一性:DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTK VEIKR(SEQ ID NO:21)。
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:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVA WISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARR HWPGGFDYWGQGTLVTVSSASTK(SEQ ID NO:28),或
(b)轻链序列与下述轻链序列具有至少85%序列同一性:DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTK VEIKR(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 WGQGTLVTVSS(SEQ ID NO:25)。
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,和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,和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,抗PD-1抗体是MPDL3280A(atezolizumab)。在又一个实施方案中,提供了分离的抗PD-1抗体,其包含重链可变区和/或轻链可变区,所述重链可变区包含来自SEQ ID NO:24的重链可变区氨基酸序列,所述轻链可变区包含来自SEQ ID NO:25的轻链可变区氨基酸序列。在又一个实施方案中,提供了分离的抗PD-1抗体,其包含重链和/或轻链序列,其中:
(a)重链序列与下述重链序列具有至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%或100%序列同一性:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVA
WISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARR
HWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK
DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD
TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:26),或
(b)轻链序列与下述轻链序列具有至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%或100%序列同一性:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSA
SFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTK
VEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA
LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:27)。
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 IDNO: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 ID NO: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,本文中描述的抗体(诸如抗PD-1抗体,抗PD-L1抗体,或抗PD-L2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,和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,和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。在又一个方面,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,本文中提供了编码本文中描述的任何抗体的核酸。在一些实施方案中,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PD-1,或抗PD-L2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PD-1,或抗PD-L2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PD-1,或抗PD-L2抗体或其抗原结合片段和至少一种药学可接受载体。在一些实施方案中,对个体施用的抗PD-L1,抗PD-1,或抗PD-L2抗体或其抗原结合片段是包含一种或多种药学可接受载体的组合物。可以使用本文中描述的或本领域中已知的任何药学可接受载体。
MEK抑制剂
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,包括施用有效量的PD-1途径拮抗剂和MEK抑制剂。任何已知的MEK抑制剂是有意图的,诸如PCT专利申请WO 03/077914A1,WO 2005/121142 A1,WO 2007/044515A1,WO 2008/024725 A1和WO 2009/085983A1(通过援引将其内容收入本文)中描述的MEK抑制剂化合物。施用的MEK抑制剂可以在药物组合物或配制剂中。在一些实施方案中,药物组合物或配制剂包含本文中描述的一种或多种MEK抑制剂和药学可接受载体或赋形剂。
在一些实施方案中,MEK抑制剂是竞争性MEK抑制剂。在一些实施方案中,MEK抑制剂针对活化性KRAS突变更有选择性。在一些实施方案中,MEK抑制剂是变构性MEK抑制剂。在一些实施方案中,MEK抑制剂针对活化性Braf突变(例如Braf V600E突变)更有选择性。在一些实施方案中,MEK抑制剂结合MEK1和/或MEK2(诸如人MEK1和/或人MEK2)并抑制其活性。
在一些实施方案中,MEK抑制剂是选自下组的化合物:GDC-0973(又称为“Cobimetinib”或“XL518”),G-38963,G02443714(又称为“AS703206”),G02442104(又称为“GSK-1120212”),和G00039805(又称为“AZD-6244”),或其药学可接受盐或溶剂合物。
在一些实施方案中,MEK抑制剂是式(I)的化合物,
或其药学可接受盐或溶剂合物,其中A,X,R1,R2,R3,R4,R5,R6,和R7如组A,组B,组C,或组D中限定:
组A:
A是任选用1,2,3或4个选自R10,R12,R14,R16,和R19的基团取代的亚芳基,其中R10,R12,R14和R16独立是氢,烷基,烯基,炔基,卤素,卤代烷氧基,羟基,烷氧基,氨基,烷基氨基,二烷基氨基,卤代烷基,-NHS(O)2R8,-CN,-C(O)R8,-C(O)OR8,-C(O)NR8R8’和-NR8C(O)R8’且其中R19是氢,烷基,或烯基;
X是烷基,卤素,卤代烷基,或卤代烷氧基;
R1,R2,R3,R4,R5和R6独立是氢,卤素,硝基,-NR8R8’,-OR8,-NHS(O)2R8,-CN,-S(O)mR8,-S(O)2NR8R8’,-C(O)R8,-C(O)OR8,-C(O)NR8R8’,-NR8C(O)OR8’,-NR8C(O)NR8’R8”,-NR8C(O)OR8’,-NR8C(O)R8’,-CH2N(R25)(NR25aR25b),-CH2NR25C(=NH)(NR25aR25b),-CH2NR25C(=NH)(N(R25a)(NO2)),-CH2NR25C(=NH)(N(R25a)(CN)),-CH2NR25C(=NH)(R25),-CH2NR25C(NR25aR25b)=CH(NO2),烷基,烯基,炔基,环烷基,杂芳基,或杂环烷基;其中烷基,烯基,炔基,环烷基,杂芳基,和杂环烷基独立是任选用1,2,3,4,5,6或7个基团取代的,所述基团独立选自卤素,烷基,卤代烷基,硝基,任选取代的环烷基,任选取代的杂环烷基,任选取代的芳基,任选取代的芳基烷基,任选取代的杂芳基,-OR8,-NR8R8’,-NR8S(O)2R9,-CN,-S(O)mR9,-C(O)R8,-C(O)OR8,-C(O)NR8R8’,-NR8C(O)NR8’R8”,-NR8C(O)OR8’和-NR8C(O)R8’;或R1和R2与其附接的碳一起,R3和R4与其附接的碳一起,和R5和R6与其附接的碳一起之一形成C(O)或C(=NOH);
m是0,1,或2;
R7是氢,卤素或烷基;
R8,R8’和R8”各自独立选自氢,羟基,任选取代的烷氧基,烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基;其中烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基独立是用1,2,3,4或5个基团任选取代的,所述基团独立选自烷基,卤素,羟基,羟烷基,任选取代的烷氧基,烷氧基烷基,卤代烷基,羧基,烷氧基羰基,烯基氧羰基,任选取代的环烷基,任选取代的环烷基氧羰基,任选取代的芳基,任选取代的芳氧基,任选取代的芳氧基羰基,任选取代的芳基烷基,任选取代的芳基烷基氧基,任选取代的芳基烷基氧羰基,硝基,氰基,任选取代的杂环烷基,任选取代的杂芳基,-S(O)R31(其中n是0,1,或2且R31是任选取代的烷基,任选取代的芳基,任选取代的杂环烷基,或任选取代的杂芳基),-NR34SO2R34a(其中R34是氢或烷基且R34a是烷基,烯基,环烷基,芳基,杂芳基,或杂环烷基),-SO2NR35R35a(其中R35是氢或烷基且R35a是烷基,烯基,环烷基,芳基,杂芳基,或杂环烷基),-NR32C(O)R32a(其中R32是氢或烷基且R32a是烷基,烯基,烷氧基,或环烷基),-NR30R30’(其中R30和R30’独立是氢,烷基,或羟烷基),和-C(O)NR33R33a(其中R33是氢或烷基且R33a是烷基,烯基,炔基,或环烷基);且
每个R9独立选自烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基;其中烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基独立是用1,2,3,4,或5个基团任选取代的,所述基团选自卤素,羟基,烷基,卤代烷基,卤代烷氧基,氨基,烷基氨基,和二烷基氨基;
组B:
A是任选用1,2,3或4个选自R10,R12,R14,R16,和R19的基团取代的杂亚芳基,其中R10,R12,R14和R16独立是氢,烷基,烯基,炔基,卤素,卤代烷氧基,羟基,烷氧基,氰基,氨基,烷基氨基,二烷基氨基,卤代烷基,烷基磺酰基氨基,烷基羰基,烯基羰基,烷氧基羰基,烯基氧羰基,氨基羰基,烷基氨基羰基,二烷基氨基羰基,或烷基羰基氨基;其中R19是氢,烷基,或烯基;且其中单独或作为R10,R12,R14,R16,和R19内另一基团的一部分的烷基和烯基各自独立是任选用卤素,羟基,或烷氧基取代的;
X是烷基,卤素,卤代烷基,或卤代烷氧基;
R1,R2,R3,R4,R3和R6独立是氢,卤素,硝基,-NR8R8’,-OR8,-NHS(O)2R8,-CN,-S(O)mR8,-S(O)2NR8R8’,-C(O)R8,-C(O)OR8,-C(O)NR8R8’,-NR8C(O)OR8’,-NR8C(O)NR8’R8”,-NR8C(O)OR8’,-NR8C(O)R8’,-CH2N(R25)(NR25aR25b) , -CH2NR25C(=NH)(NR25aR25b) ,-CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(NH)(N(R25a)(CN)),-CH2NR25C(=NH)(R25),-CH2NR25C(NR25aR25b)=CH(NO2),烷基,烯基,炔基,环烷基,杂芳基,或杂环烷基,其中烷基,烯基,炔基,环烷基,杂芳基,和杂环烷基独立是任选用1,2,3,4,5,6,或7个基团取代的,所述基团独立选自卤素,烷基,卤代烷基,硝基,任选取代的环烷基,任选取代的杂环烷基,任选取代的芳基,任选取代的芳基烷基,任选取代的杂芳基,-OR8,-NR8R8’,-NR8S(O)2R9,-CN,-S(O)mR9,-C(O)R8,-C(O)OR8,-C(O)NR8R8’,-NR8C(O)NR8’R8”,-NR8C(O)OR8’和-NR8C(O)R8’;或R1和R2与其附接的碳一起,R3和R4与其附接的碳一起,和R5和R6与其附接的碳一起之一形成C(O)或C(=NOH);
m是1或2;
R7是氢,卤素或烷基;且
R8,R8’和R8”各自独立选自氢,羟基,任选取代的烷氧基,烷基,卤代烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基,其中烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基独立是任选用1,2,3,4,或5个基团取代的,所述基团独立选自烷基,卤素,羟基,羟烷基,任选取代的烷氧基,烷氧基烷基,卤代烷基,羧基,羧基酯,硝基,氰基,-S(O)nR31(其中n是0,1,或2且R31是任选取代的烷基,任选取代的芳基,任选取代的环烷基,任选取代的杂环烷基,或任选取代的杂芳基),-NR36S(O)2R36a(其中R36是氢,烷基,或烯基且R36a是烷基,烯基,任选取代的芳基,任选取代的环烷基,任选取代的杂环烷基,或任选取代的杂芳基),-S(O)2NR37R37a(其中R37是氢,烷基,或烯基且R37a是烷基,烯基,任选取代的芳基,任选取代的环烷基,任选取代的杂环烷基,或任选取代的杂芳基),任选取代的环烷基,任选取代的杂环烷基,任选取代的芳基,任选取代的芳基烷基,任选取代的芳氧基,任选取代的芳基烷基氧基,任选取代的杂芳基,-NHC(O)R32(其中R32是烷基,烯基,烷氧基,或环烷基)和-NR30R30’(其中R30和R30’独立是氢,烷基,或羟烷基),和-C(O)NHR33(其中R33是烷基,烯基,炔基,或环烷基);
组C:
A是
其中R10是氢,烷基,烯基,炔基,卤素,卤代烷氧基,羟基,烷氧基,氨基,烷基氨基,二烷基氨基,卤代烷基,-NHS(O)2R8,-CN,-C(O)R8,-C(O)OR8,-C(O)NR8R8’和-NR8C(O)R8’;
R10a是氢,烷基,或烯基;
Y1是=CH-或=N-;
X是烷基,卤素,卤代烷基,或卤代烷氧基;
R1,R2,R3,R4,R5和R6独立是氢,卤素,硝基,-NR8R8’,-OR8,-NHS(O)2R8,-CN,-S(O)mR8,-S(O)2NR8R8’,-C(O)R8,-C(O)OR8,-C(O)NR8R8’,-NR8C(O)OR8’,-NR8C(O)NR8’R8”,-NR8C(O)OR8’,-NR8C(O)R8’,-CH2N(R25)NR25aR25b),-CH2NR25C(=NH)(NR25aR25b),-CH2NR25C(=NH)(N(R25a)(NO2)),-CH2NR25C(=NH)(N(R25a)(CN)),-CH2NR25C(=NH)(R25),-CH2NR25C(NR25aR25b)=CH(NO2),烷基,烯基,炔基,环烷基,杂芳基,或杂环烷基,其中烷基,烯基,炔基,环烷基,杂芳基,和杂环烷基独立是任选用1,2,3,4,5,6或7个基团取代的,所述基团独立选自卤素,烷基,卤代烷基,硝基,任选取代的环烷基,任选取代的杂环烷基,任选取代的芳基,任选取代的芳基烷基,任选取代的杂芳基,-OR8,-NR8R8’,-NR8S(O)2R9,-CN,-S(O)mR9,-C(O)R8,-C(O)OR8,-C(O)NR8R8’,-NR8C(O)NR8’R8”,-NR8C(O)OR8’和-NR8C(O)R8’;或R1和R2与其附接的碳一起,R3和R4与其附接的碳一起,和R5和R6与其附接的碳一起之一形成C(O)或C(NOH);
m是1或2;
R7是氢,卤素或烷基;且
R8,R8’和R8”各自独立选自氢,羟基,任选取代的烷氧基,烷基,卤代烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基,其中烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基独立是任选用1,2,3,4,或5个基团取代的,所述基团独立选自烷基,卤素,羟基,羟烷基,任选取代的烷氧基,烷氧基烷基,卤代烷基,羧基,羧基酯,硝基,氰基,-S(O)nR31(其中n是0,1,或2且R31是任选取代的烷基,任选取代的芳基,任选取代的环烷基,任选取代的杂环烷基,或任选取代的杂芳基),-NR36S(O)2R36a(其中R36是氢,烷基,或烯基且R36a是烷基,烯基,任选取代的芳基,任选取代的环烷基,任选取代的杂环烷基,或任选取代的杂芳基),-S(O)2NR37R37a(其中R37是氢,烷基,或烯基且R37a是烷基,烯基,任选取代的芳基,任选取代的环烷基,任选取代的杂环烷基,或任选取代的杂芳基),任选取代的环烷基,任选取代的杂环烷基,任选取代的芳基,任选取代的芳基烷基,任选取代的芳氧基,任选取代的芳基烷基氧基,任选取代的杂芳基,-NHC(O)R32(其中R32是烷基,烯基,烷氧基,或环烷基)和-NR30R30’(其中R30和R30’独立是氢,烷基,或羟烷基),和-C(O)NHR33(其中R33是烷基,烯基,炔基,或环烷基);或
组D:
A是
R40和R40a独立是氢或烷基;
X是烷基,卤素,卤代烷基,或卤代烷氧基;
R1,R2,R3,R4,R5和R6独立是氢,卤素,硝基,-NR8R8’,-OR8,-NHS(O)2R8,-CN,-S(O)mR8,-S(O)2NR8R8’,-C(O)R8,-C(O)OR8,-C(O)NR8R8’,-NR8C(O)OR8’,-NR8C(O)NR8’R8”,-NR8C(O)OR8’,-NR8C(O)R8’,-CH2N(R25)(NR25aR25b),-CH2NR25C(=NH)(NR25aR25b),-CH2NR25C(=NH)(N(R25a)(NO2)),-CH2NR25C(=NH)(N(R25a)(CN)),-CH2NR25C(=NH)(R25),-CH2NR25C(NR25aR25b)=CH(NO2),烷基,烯基,炔基,环烷基,杂芳基,或杂环烷基,其中烷基,烯基,炔基,环烷基,杂芳基,和杂环烷基独立是任选用1,2,3,4,5,6或7个基团取代的,所述基团独立选自卤素,烷基,卤代烷基,硝基,任选取代的环烷基,任选取代的杂环烷基,任选取代的芳基,任选取代的芳基烷基,任选取代的杂芳基,-OR8,-NR8R8’,-NR8S(O)2R9,-CN,-S(O)mR9,-C(O)R8,-C(O)OR8,-C(O)NR8R8’,-NR8C(O)NR8’R8”,-NR8C(O)OR8’和-NR8C(O)R8’;或R1和R2与其附接的碳一起,R3和R4与其附接的碳一起,和R5和R6与其附接的碳一起之一形成C(O)或C(NOH);
m是1或2;
R7是氢,卤素或烷基;且
R8,R8’和R8”独立选自氢,羟基,任选取代的烷氧基,烷基,卤代烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基,其中烷基,烯基,炔基,芳基,环烷基,杂芳基,和杂环烷基独立是任选用1,2,3,4,或5个基团取代的,所述基团独立选自烷基,卤素,羟基,羟烷基,任选取代的烷氧基,烷氧基烷基,卤代烷基,羧基,羧基酯,硝基,氰基,-S(O)nR31(其中n是0,1,或2且R31是任选取代的烷基,任选取代的芳基,任选取代的环烷基,任选取代的杂环烷基,或任选取代的杂芳基),-NR36S(O)2R36a(其中R36是氢,烷基,或烯基且R36a是烷基,烯基,任选取代的芳基,任选取代的环烷基,任选取代的杂环烷基,或任选取代的杂芳基),-S(O)2NR37R37a(其中R37是氢,烷基,或烯基且R37a是烷基,烯基,任选取代的芳基,任选取代的环烷基,任选取代的杂环烷基,或任选取代的杂芳基),任选取代的环烷基,任选取代的杂环烷基,任选取代的芳基,任选取代的芳基烷基,任选取代的芳氧基,任选取代的芳基烷基氧基,任选取代的杂芳基,-NHC(O)R32(其中R32是烷基,烯基,烷氧基,或环烷基)和-NR30R30’(其中R30和R30’独立是氢,烷基,或羟烷基),和-C(O)NHR33(其中R33是烷基,烯基,炔基,或环烷基)。
在一些变型中,式(I)的MEK抑制剂化合物是具有式I(a)或I(b)的组A化合物:
或其药学可接受盐或溶剂合物,其中变量如对式(I),组A限定的,或者如在WO2007/044515A1(通过援引将其收入本文)中限定的。
在一些变型中,式(I)的MEK抑制剂化合物是组B的化合物,其具有式I(c),I(d),I(e),I(f),I(g),I(h),I(i),I(j),I(k),I(m),I(n),I(o),I(p),I(q),I(r),I(s),I(u),I(v),I(w),I(x),I(cc)或I(dd):
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或其药学可接受盐或溶剂合物,其中变量如对式(I),组B限定的,或者如WO 2007/044515A1(通过援引将其收入本文)中限定的。
在一些变型中,式(I)的MEK抑制剂化合物是组C的化合物,具有式I(y)或I(z):
或其药学可接受盐或溶剂合物,其中变量如对式(I),组C限定的,或者如WO 2007/044515A1(通过援引将其收入本文)中限定的。
在一些变型中,式(I)的MEK抑制剂化合物是组D的化合物,具有式I(aa)或I(bb):
或其药学可接受盐或溶剂合物,其中变量如对式(I),组D限定的,或者如WO 2007/044515A1(通过援引将其收入本文)中限定的。
在一些实施方案中,式(I)的MEK抑制剂化合物是选自如WO 2007/044515A1,第71-144页上表1中列出的化合物No.1-362的化合物(本文中统称为式I种类)或其药学可接受盐或溶剂合物。
还涵盖如WO 2007/044515 A1(通过援引将其收入本文)中描述的式(I)的任何变型。可以使用本领域中已知的方法,例如WO 2007/044515 A1(通过援引将其收入本文)中描述的合成方法合成式(I)的化合物或其任何变型。
除非本文中另有定义,用于描述式(I)的化合物的术语应当理解为与WO 2007/044515A1中的定义具有相同的含义。
在一些实施方案中,MEK抑制剂是式(II)的化合物:
或其药学可接受盐或溶剂合物,其中:
Z1是CR1或N;
Z2是CR2或N;
Z3是CR3或N;
Z4是CR4或N;
其中Z1,Z2,Z3,和Z4中一项或两项是N;
R1,R2,R3和R4独立选自H,卤素,CN,CF3,-OCF3,-NO2,-(CR14R15)nC(=Y)R11,-(CR14R15)nC(=Y)OR11,-(CR14R15)nC(=Y)NR11R12,-(CR14R15)nNR11R12, -(CR14R15)nOR11, -(CR14R15)nSR11,-(CR14R15)nNR12C(=Y)R11 , -(CR14R15)nNR12C(=Y)OR11 ,-(CR14R15)nNR13C(=Y)NR11R12 , -(CR14R15)nNR12SO2R11 ,-(CR14R15)nOC(=Y)R11,-(CR14R15)nOC(=Y)OR11,-(CR14R15)nOC(=Y)NR11R12,-(CR14R15)nOS(O)2(OR11),-(CR14R15)nOP(=Y)(OR11)(OR12),-(CR14R15)nOP(OR11)(OR12),-(CR14R15)nS(O)R11,-(CR14R15)nS(O)2R11,-(CR14R15)n S(O)2NR11R12,-(CR14R15)nS(O)(OR11),-(CR14R15)nS(O)2(OR11),-(CR14R15)n SC(=Y)R11,-(CR14R15)nSC(=Y)OR11,-(CR14R15)nSC(=Y)NR11R12,C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,和杂芳基;
W是或/>
R5和R6独立选自H或C1-C12烷基;
X1选自R11,-OR11,-NR11R12,-S(O)R11,和-S(O)2R11;在X1是R11或-OR11时,任选地,X1的R11或-OR11和-R5与它们附接的氮原子一起采用,形成4-7元饱和或不饱和的环,该环具有0-2个额外的选自O,S和N的杂原子,其中所述环是任选用一个或多个基团取代的,所述基团选自卤素,CN,CF3,-OCF3,-NO2,氧基,-Si(C1-C6烷基),-(CR19R20)nC(=Y’)R16,-(CR19R20)nC(=Y’)OR16,-(CR19R20)nC(=Y’)NR16R17,-(CR19R20)nNR16R17,-(CR19R20)nOR16,-(CR19R20)n-SR16,-(CR19R20)nNR16C(=Y’)R17,-(CR19R20)nNR16C(=Y’)OR17,-(CR19R20)n NR18C(=Y’)NR16R17,-(CR19R20)nNR17SO2R16,-(CR19R20)nOC(=Y’)R16,-(CR19R20)nOC(=Y’)OR16,-(CR19R20)nOC(=Y’)NR16R17 , -(CR19R20)nOS(O)2(OR16) ,-(CR19R20)nOP(=Y’)(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),-(CR19R20)nS(O)R16,-(CR19R20)nS(O)2R16,-(CR19R20)nS(O)2NR16R17,-(CR19R20)nS(O)(OR16),-(CR19R20)nS(O)2(OR16),-(CR19R20)nSC(=Y’)R16,-(CR19R20)nSC(=Y’)OR16,-(CR19R20)nSC(=Y’)NR16R17,和R21;
X2选自碳环基,杂环基,芳基,和杂芳基;
R11,R12和R13独立是H,C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,或杂芳基,
或者R11和R12与其附接的氮一起形成3-8元饱和的,不饱和的或芳香族的环,该环具有0-2个选自O,S和N的杂原子,其中所述环是任选用一个或多个基团取代的,所述基团选自卤素,CN,CF3,-OCF3,-NO2,C1-C6烷基,-OH,-SH,-O(C1-C6烷基),-S(C1-C6烷基),-NH2,-NH(C1-C6烷基),-N(C1-C6烷基)2,-SO2(C1-C6烷基),-CO2H,-CO2(C1-C6烷基),-C(O)NH2,-C(O)NH(C1-C6烷基),-C(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)(C1-C6烷基),-NHC(O)(C1-C6烷基),-NHSO2(C1-C6烷基),-N(C1-C6烷基)SO2(C1-C6烷基),-SO2NH2,-SO2NH(C1-C6烷基),-SO2N(C1-C6烷基)2,-OC(O)NH2,-OC(O)NH(C1-C6烷基),-OC(O)N(C1-C6烷基)2,-OC(O)O(C1-C6烷基),-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)NH(C1-C6烷基),-N(C1-C6烷基)C(O)N(C1-C6烷基)2,-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-NHC(O)O(C1-C6烷基),和-N(C1-C6烷基)C(O)O(C1-C6烷基);
R14和R15独立选自H,C1-C12烷基,芳基,碳环基,杂环基,和杂芳基;
m和n独立选自0,1,2,3,4,5,或6;
Y独立是O,NR11,或S;
其中R1,R2,R3,R4,R5,R6,X1,X2,R11,R12,R13,R14,和R15的所述烷基,烯基,炔基,碳环基,杂环基,芳基和杂芳基各自独立是任选用一个或多个基团取代的,所述基团独立选自卤素,CN,CF3,-OCF3,-NO2,氧基,-Si(C1-C6烷基),-(CR19R20)nC(=Y’)R16,-(CR19R20)n C(=Y’)OR16,-(CR19R20)nC(=Y’)NR16R17,-(CR19R20)nNR16R17,-(CR19R20)nOR16,-(CR19R20)n-SR16,-(CR19R20)n NR16C(=Y’)R17,-(CR19R20)n NR16C(=Y’)OR17,-(CR19R20)nNR18C(=Y’)NR16R17 , -(CR19R20)nNR17SO2R16 ,-(CR19R20)nOC(=Y’)R16 , -(CR19R20)nOC(=Y’)OR16 ,-(CR19R20)nOC(=Y’)NR16R17 , -(CR19R20)nOS(O)2(OR16) ,-(CR19R20)nOP(=Y’)(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),-(CR19R20)nS(O)R16,-(CR19R20)nS(O)2R16,-(CR19R20)nS(O)2NR16R17,-(CR19R20)nS(O)(OR16),-(CR19R20)nS(O)2(OR16),-(CR19R20)nSC(=Y’)R16,-(CR19R20)nSC(=Y’)OR16,-(CR19R20)nSC(=Y’)NR16R17,和R21;
R16,R17和R18各自独立是H,C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,或杂芳基,其中所述烷基,烯基,炔基,碳环基,杂环基,芳基,或杂芳基是任选用一个或多个基团取代的,所述基团选自卤素,氧基,CN,-OCF3,CF3,-NO2,C1-C6烷基,-OH,-SH,-O(C1-C6烷基),-S(C1-C6烷基),-NH2,-NH(C1-C6烷基),-N(C1-C6烷基)2,-SO2(C1-C6烷基),-CO2H,-CO2(C1-C6烷基),-C(O)NH2,-C(O)NH(C1-C6烷基),-C(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)(C1-C6烷基),-NHC(O)(C1-C6烷基),-NHSO2(C1-C6烷基),-N(C1-C6烷基)SO2(C1-C6烷基),-SO2NH2,-SO2NH(C1-C6烷基),-SO2N(C1-C6烷基)2,-OC(O)NH2,-OC(O)NH(C1-C6烷基),-OC(O)N(C1-C6烷基)2,-OC(O)O(C1-C6烷基),-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)NH(C1-C6烷基),-N(C1-C6烷基)C(O)N(C1-C6烷基)2,-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-NHC(O)O(C1-C6烷基),和-N(C1-C6烷基)C(O)O(C1-C6烷基);
或者R16和R17与其附接的氮一起形成3-8元饱和的,不饱和的或芳香族的环,该环具有0-2个选自O,S和N的杂原子,其中所述环是任选用一个或多个基团取代的,所述基团选自卤素,CN,-OCF3,CF3,-NO2,C1-C6烷基,-OH,-SH,-O(C1-C6烷基),-S(C1-C6烷基),-NH2,-NH(C1-C6烷基),-N(C1-C6烷基)2,-SO2(C1-C6烷基),-CO2H,-CO2(C1-C6烷基),-C(O)NH2,-C(O)NH(C1-C6烷基),-C(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)(C1-C6烷基),-NHC(O)(C1-C6烷基),-NHSO2(C1-C6烷基),-N(C1-C6烷基)SO2(C1-C6烷基),-SO2NH2,-SO2NH(C1-C6烷基),-SO2N(C1-C6烷基)2,-OC(O)NH2,-OC(O)NH(C1-C6烷基),-OC(O)N(C1-C6烷基)2,-OC(O)O(C1-C6烷基),-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)NH(C1-C6烷基),-N(C1-C6烷基)C(O)N(C1-C6烷基)2,-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-NHC(O)O(C1-C6烷基),和-N(C1-C6烷基)C(O)O(C1-C6烷基);
R19和R20独立选自H,C1-C12烷基,-(CH2)n-芳基,-(CH2)n-碳环基,-(CH2)n-杂环基,和-(CH2)n-杂芳基;
R21是C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,或杂芳基,其中R21的每个成员是任选用一个或多个基团取代的,所述基团选自卤素,CN,-OCF3,CF3,-NO2,C1-C6烷基,-OH,-SH,-O(C1-C6烷基),-S(C1-C6烷基),-NH2,-NH(C1-C6烷基),-N(C1-C6烷基)2,-SO2(C1-C6烷基),-CO2H,-CO2(C1-C6烷基),-C(O)NH2,-C(O)NH(C1-C6烷基),-C(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)(C1-C6烷基),-NHC(O)(C1-C6烷基),-NHSO2(C1-C6烷基),-N(C1-C6烷基)SO2(C1-C6烷基),-SO2NH2,-SO2NH(C1-C6烷基),-SO2N(C1-C6烷基)2,-OC(O)NH2,-OC(O)NH(C1-C6烷基),-OC(O)N(C1-C6烷基)2,-OC(O)O(C1-C6烷基),-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)NH(C1-C6烷基),-N(C1-C6烷基)C(O)N(C1-C6烷基)2,-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-NHC(O)O(C1-C6烷基),和-N(C1-C6烷基)C(O)O(C1-C6烷基);
每个Y’独立是O,NR22,或S;且
R22是H或C1-C12烷基。
在一些变型中,式(II)的MEK抑制剂化合物是式(II-1-a),(II-1-b),(II-1-c),(II-1-d),(II-1-e),(II-1-f),(II-1-g),(II-1-h),(II-1-i),(II-2-a),(II-2-b),(II-2-c),(II-2-d),(II-2-e),(II-2-f),(II-2-g),(II-2-h),(II-2-i),(II-3-a),(II-3-b),(II-3-c),
/>
或其药学可接受盐或溶剂合物,其中变量如对式(II)限定的,或者如在WO 2008/024725A1(通过援引将其收入本文)中限定的。
在一些实施方案中,式(II)的MEK抑制剂化合物是选自WO 2008/024725 A1中的例子5-18,20-102,105-109,111-118,120-133,136-149和151-160的化合物的化合物(在本文中统称为式II种类),或其药学可接受盐或溶剂合物。这些化合物在实施例8a或8b中描述的测定法(MEK活性测定法)中展现出小于10μM的IC50。大多数这些化合物展现出小于5μM的IC50。见WO 2008/024725A1中的第62页。
还涵盖的是WO 2008/024725 A1(通过援引将其收入本文)中描述的MEK抑制剂化合物(和/或其溶剂合物和盐),例如式(II)(在WO 2008/024725A1中,例如第3页上称为式I)的氮杂-苯并呋喃化合物及其变型,如WO 2008/024725 A1中描述的。可以使用本领域中已知的方法,例如WO 2008/024725 A1(通过援引将其收入本文)中描述的合成方法合成式(II)的化合物。
在一些实施方案中,MEK抑制剂是式(III)的化合物:
或其药学可接受盐或溶剂合物,其中:
Z1是CR1或N;
R1是H,C1-C3烷基,卤素,CF3,CHF2,CN,ORA或NRARA;
R1’是H,C1-C3烷基,卤素,CF3,CHF2,CN,ORA,或NRARA;
其中每个RA独立是H或C1-C3烷基;
Z2是CR2或N;
Z3是CR3或N;前提是仅Z1,Z2和Z3之一可以同时是N;
R2和R3独立选自H,卤素,CN,CF3,-OCF3,-NO2,-(CR14R15)nC(=Y’)R11,-(CR14R15)nC(=Y’)OR11,-(CR14R15)nC(=Y’)NR11R12,-(CR14R15)nNR11R12,-(CR14R15)nOR11,-(CR14R15)nSR11,-(CR14R15)nNR12C(=Y’)R11,-(CR14R15)nNR12C(=Y’)OR11,-(CR14R15)nNR13C(=Y’)NR11R12,-(CR14R15)nNR12SO2R11,-(CR14R15)nOC(=Y’)R11,-(CR14R15)nOC(=Y’)OR11,-(CR14R15)nOC(=Y’)NR11R12 , -(CR14R15)nOS(O)2(OR11) ,-(CR14R15)nOP(=Y’)(OR11)(OR12), -(CR14R15)nOP(OR11)(OR12),-(CR14R15)nS(O)R11,-(CR14R15)nS(O)2R11,-(CR14R15)nS(O)2NR11R12,-(CR14R15)nS(O)(OR11),-(CR14R15)nS(O)2(OR11),-(CR14R15)nSC(=Y’)R11,-(CR14R15)nSC(=Y’)OR11,-(CR14R15)nSC(=Y’)NR11R12,C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,和杂芳基;
R4是H,C1-C6烷基或C3-C4碳环基;
Y是W-C(O)-或W’;
W是或/>
R5是H或C1-C12烷基;
X1选自R11’和-OR11’;在X1是R11’时,任选地,X1与R5和与它们结合的氮原子一起采用,形成4-7元饱和或不饱和的环,该环具有0-2个额外的选自O,S和N的杂原子,其中所述环是任选用一个或多个基团取代的,所述基团选自卤素,CN,CF3,-OCF3,-NO2,氧基,-(CR19R20)nC(=Y’)R16,-(CR19R20)nC(=Y’)OR16,-(CR19R20)nC(=Y’)NR16R17,-(CR19R20)nNR16R17,-(CR19R20)nOR16,-(CR19R20)n-SR16,-(CR19R20)n NR16C(=Y’)R17,-(CR19R20)nNR16C(=Y’)OR17,-(CR19R20)n NR18C(=Y’)NR16R17,-(CR19R20)nNR17SO2R16,-(CR19R20)nOC(=Y’)R16 , -(CR19R20)nOC(=Y’)OR16 ,-(CR19R20)nOC(=Y’)NR16R17 , -(CR19R20)nOS(O)2(OR16) ,-(CR19R20)nOP(=Y’)(OR16)(OR17), -(CR19R20)nOP(OR16)(OR17),-(CR19R20)nS(O)R16,-(CR19R20)nS(O)2R16,-(CR19R20)nS(O)2NR16R17,-(CR19R20)nS(O)(OR16),-(CR19R20)nS(O)2(OR16),-(CR19R20)nSC(=Y’)R16,-(CR19R20)nSC(=Y’)OR16,-(CR19R20)nSC(=Y’)NR16R17,和R21;
每个R11’独立是H,C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,或杂芳基;
R11,R12和R13独立是H,C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,或杂芳基,
或R11和R12与其附接的氮一起形成3-8元饱和的,不饱和的或芳香族的环,该环具有0-2个选自O,S和N的杂原子,其中所述环是任选用一个或多个基团取代的,所述基团选自卤素,CN,CF3,-OCF3,-NO2,C1-C6烷基,-OH,-SH,-O(C1-C6烷基),-S(C1-C6烷基),-NH2,-NH(C1-C6烷基),-N(C1-C6烷基)2,-SO2(C1-C6烷基),-CO2H,-CO2(C1-C6烷基),-C(O)NH2,-C(O)NH(C1-C6烷基),-C(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)(C1-C6烷基),-NHC(O)(C1-C6烷基),-NHSO2(C1-C6烷基),-N(C1-C6烷基)SO2(C1-C6烷基),-SO2NH2,-SO2NH(C1-C6烷基),-SO2N(C1-C6烷基)2,-OC(O)NH2,-OC(O)NH(C1-C6烷基),-OC(O)N(C1-C6烷基)2,-OC(O)O(C1-C6烷基),-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)NH(C1-C6烷基),-N(C1-C6烷基)C(O)N(C1-C6烷基)2,-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-NHC(O)O(C1-C6烷基),和-N(C1-C6烷基)C(O)O(C1-C6烷基);
R14和R15独立选自H,C1-C12烷基,芳基,碳环基,杂环基,和杂芳基;
W’是
其中是
每个X2独立是O,S,或NR9;
每个R7独立选自H,卤素,CN,CF3,-OCF3,-NO2,-(CR14R15)nC(=Y’)R11,-(CR14R15)nC(=Y’)OR11,-(CR14R15)nC(=Y’)NR11R12,-(CR14R15)nNR11R12,-(CR14R15)nOR11,-(CR14R15)nSR11,-(CR14R15)nNR12C(=Y’)R11,-(CR14R15)nNR12C(=Y’)OR11,-(CR14R15)nNR13C(=Y’)NR11R12,-(CR14R15)nNR12SO2R11,-(CR14R15)nOC(=Y’)R11,-(CR14R15)nOC(=Y’)OR11,-(CR14R15)nOC(=Y’)NR11R12 , -(CR14R15)nOS(O)2(OR11) ,-(CR14R15)nOP(=Y’)(OR11)(OR12), -(CR14R15)nOP(OR11)(OR12),-(CR14R15)nS(O)R11,-(CR14R15)nS(O)2R11,-(CR14R15)nS(O)2NR11R12,-(CR14R15)nS(O)(OR11),-(CR14R15)nS(O)2(OR11),-(CR14R15)nSC(=Y’)R11,-(CR14R15)nSC(=Y’)OR11,-(CR14R15)nSC(=Y’)NR11R12,C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,和杂芳基;
每个R8独立选自C1-C12烷基,芳基,碳环基,杂环基,和杂芳基;
R9选自H,-(CR14R15)nC(=Y’)R11,-(CR14R15)nC(=Y’)OR11,
-(CR14R15)nC(=Y’)NR11R12,-(CR14R15)qNR11R12,-(CR14R15)qOR11,-(CR14R15)qSR11,-(CR14R15)qNR12C(=Y’)R11,-(CR14R15)qNR12C(=Y’)OR11,-(CR14R15)qNR13C(=Y’)NR11R12 , -(CR14R15)qNR12SO2R11 ,-(CR14R15)qOC(=Y’)R11 , -(CR14R15)qOC(=Y’)OR11 ,-(CR14R15)qOC(=Y’)NR11R12 , -(CR14R15)qOS(O)2(OR11) ,-(CR14R15)qOP(=Y’)(OR11)(OR12), -(CR14R15)qOP(OR11)(OR12),-(CR14R15)nS(O)R11,-(CR14R15)nS(O)2R11,-(CR14R15)n S(O)2NR11R12,C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,和杂芳基;
R10是H,C1-C6烷基或C3-C4碳环基;
X4是
R6是H,卤素,C1-C6烷基,C2-C8烯基,C2-C8炔基,碳环基,杂芳基,杂环基,-OCF3,-NO2,-Si(C1-C6烷基),-(CR19R20)nNR16R17,-(CR19R20)nOR16,或-(CR19R20)n-SR16;
R6’是H,卤素,C1-C6烷基,碳环基,CF3,-OCF3,-NO2,-Si(C1-C6烷基),-(CR19R20)nNR16R17,-(CR19R20)nOR16,-(CR19R20)n-SR16,C2-C8烯基,C2-C8炔基,杂环基,芳基,或杂芳基;
p是0,1,2或3;
n是0,1,2或3;
q是2或3;
其中R1,R2,R3,R4,R5,R6,R6’,R7,R8,R9,R10,R11,R11’,R12,R13,R14,R15和RA的所述烷基,烯基,炔基,碳环基,杂环基,芳基和杂芳基各自独立是任选用一个或多个基团取代的,所述基团独立选自卤素,CN,CF3,-OCF3,-NO2,氧基,-Si(C1-C6烷基),-(CR19R20)nC(=Y’)R16,-(CR19R20)nC(=Y’)OR16,-(CR19R20)nC(=Y’)NR16R17,-(CR19R20)nNR16R17,-(CR19R20)nOR16,-(CR19R20)nSR16,-(CR19R20)nNR16C(=Y’)R17,-(CR19R20)nNR16C(=Y’)OR17,-(CR19R20)nNR18C(=Y’)NR16R17,-(CR19R20)nNR17SO2R16,-(CR19R20)nOC(=Y’)R16,-(CR19R20)nOC(=Y’)OR16,-(CR19R20)nOC(=Y’)NR16R17 , -(CR19R20)nOS(O)2(OR16) ,-(CR19R20)nOP(=Y’)(OR16)(OR17),-(CR19R20)nOP(OR16)(OR17),-(CR19R20)nS(O)R16,-(CR19R20)nS(O)2R16,-(CR19R20)nS(O)2NR16R17,-(CR19R20)nS(O)(OR16),-(CR19R20)n S(O)2(OR16),-(CR19R20)nSC(=Y’)R16,-(CR19R20)nSC(=Y’)OR16,-(CR19R20)n SC(=Y’)NR16R17,和R21;
R16,R17和R18各自独立是H,C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,或杂芳基,其中所述烷基,烯基,炔基,碳环基,杂环基,芳基,或杂芳基是任选用一个或多个基团取代的,所述基团选自卤素,CN,-OCF3,CF3,-NO2,C1-C6烷基,-OH,-SH,-O(C1-C6烷基),-S(C1-C6烷基),-NH2,-NH(C1-C6烷基),-N(C1-C6烷基)2,-SO2(C1-C6烷基),-CO2H,-CO2(C1-C6烷基),-C(O)NH2,-C(O)NH(C1-C6烷基),-C(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)(C1-C6烷基),-NHC(O)(C1-C6烷基),-NHSO2(C1-C6烷基),-N(C1-C6烷基)SO2(C1-C6烷基),-SO2NH2,-SO2NH(C1-C6烷基),-SO2N(C1-C6烷基)2,-OC(O)NH2,-OC(O)NH(C1-C6烷基),-OC(O)N(C1-C6烷基)2,-OC(O)O(C1-C6烷基),-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)NH(C1-C6烷基),-N(C1-C6烷基)C(O)N(C1-C6烷基)2,-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-NHC(O)O(C1-C6烷基),和-N(C1-C6烷基)C(O)O(C1-C6烷基);
或R16和R17与其附接的氮一起形成3-8元饱和的,不饱和的或芳香族的环,该环具有0-2个选自O,S和N的杂原子,其中所述环是任选用一个或多个基团取代的,所述基团选自卤素,CN,-OCF3,CF3,-NO2,C1-C6烷基,-OH,-SH,-O(C1-C6烷基),-S(C1-C6烷基),-NH2,-NH(C1-C6烷基),-N(C1-C6烷基)2,-SO2(C1-C6烷基),-CO2H,-CO2(C1-C6烷基),-C(O)NH2,-C(O)NH(C1-C6烷基),-C(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)(C1-C6烷基),-NHC(O)(C1-C6烷基),-NHSO2(C1-C6烷基),-N(C1-C6烷基)SO2(C1-C6烷基),-SO2NH2,-SO2NH(C1-C6烷基),-SO2N(C1-C6烷基)2,-OC(O)NH2,-OC(O)NH(C1-C6烷基),-OC(O)N(C1-C6烷基)2,-OC(O)O(C1-C6烷基),-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)NH(C1-C6烷基),-N(C1-C6烷基)C(O)N(C1-C6烷基)2,-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-NHC(O)O(C1-C6烷基),和-N(C1-C6烷基)C(O)O(C1-C6烷基);
R19和R20独立选自H,C1-C12烷基,-(CH2)n-芳基,-(CH2)n-碳环基,-(CH2)n-杂环基,和-(CH2)n-杂芳基;
R21是C1-C12烷基,C2-C8烯基,C2-C8炔基,碳环基,杂环基,芳基,或杂芳基,其中R21的每个成员是任选用一个或多个基团取代的,所述基团选自卤素,氧基,CN,-OCF3,CF3,-NO2,C1-C6烷基,-OH,-SH,-O(C1-C6烷基),-S(C1-C6烷基),-NH2,-NH(C1-C6烷基),-N(C1-C6烷基)2,-SO2(C1-C6烷基),-CO2H,-CO2(C1-C6烷基),-C(O)NH2,-C(O)NH(C1-C6烷基),-C(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)(C1-C6烷基),-NHC(O)(C1-C6烷基),-NHSO2(C1-C6烷基),-N(C1-C6烷基)SO2(C1-C6烷基),-SO2NH2,-SO2NH(C1-C6烷基),-SO2N(C1-C6烷基)2,-OC(O)NH2,-OC(O)NH(C1-C6烷基),-OC(O)N(C1-C6烷基)2,-OC(O)O(C1-C6烷基),-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-N(C1-C6烷基)C(O)NH(C1-C6烷基),-N(C1-C6烷基)C(O)N(C1-C6烷基)2,-NHC(O)NH(C1-C6烷基),-NHC(O)N(C1-C6烷基)2,-NHC(O)O(C1-C6烷基),和-N(C1-C6烷基)C(O)O(C1-C6烷基);
每个Y’独立是O,NR22,或S;且
R22是H或C1-C12烷基。
在一些变型中,式(III)的MEK抑制剂化合物具有式(III-a)或(III-b):
或其药学可接受盐或溶剂合物,其中变量如对式(III)限定的,或者如在WO 2009/085983A1(通过援引将其收入本文)中限定的。
在一些实施方案中,式(III)的MEK抑制剂化合物是选自表1中所列的化合物的化合物,或其药学可接受盐或溶剂合物。
表1
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表1中的化合物对应于WO 2009/085983 A1中的例子5-25。化合物(III)-5–(III)-20和(III)-22–(III)-24在实施例8b中描述的测定法(MEK活性测定法)中展现出小于0.5μM的IC50。这些化合物中的一些展现出小于0.1μM的IC50。化合物(III)-21和(III)-25展现出小于10μM的IC50。见WO 2009/085983 A1中的第49页。
还涵盖的是WO 2009/085983 A1(通过援引将其收入本文)中描述的MEK抑制剂化合物(和/或其溶剂合物和盐),例如式(III)的咪唑并吡啶化合物(在WO 2009/085983 A1中,例如在第3页上称为式I)及其变型,如WO 2009/085983A1中描述的。可以使用本领域中已知的方法,例如WO 2009/085983A1(通过援引将其收入本文)中描述的合成方法合成式(III)的化合物。
在一些实施方案中,MEK抑制剂是式(IV)的化合物,
或其药学可接受盐或溶剂合物,其中变量如WO 03/077914A1中对第4-9页上的式I或WO 03/077914A1(通过援引将其收入本文)中描述的任何可适用变型限定的。
在一些变型中,式(IV)的MEK抑制剂化合物是式(IV-a),(IV-b),(IV-c),或(IV-d)的化合物:
或其药学可接受盐或溶剂合物,其中变量如WO 03/077914A1中对分别在第10-13页上的式II,III,IIIa和IIIb或WO 03/077914A1(通过援引将其收入本文)中描述的任何可适用变型限定的。
在一些实施方案中,式(IV)的MEK抑制剂化合物是选自下组的化合物:7-氟-6-(4-溴-2-甲基-苯基氨基)-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺;6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸环丙基甲氧基-酰胺;6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺;
6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2,3-二羟基-丙氧基)-酰胺;
6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢-吡喃-2-基甲基)-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺;
[6-(5-氨基-[1,3,4]口恶二唑-2-基)-4-氟-lH-苯并咪唑-5-基]-(4-溴-2-甲基-苯基)-胺;
1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-基]-2-羟基-乙酮;1-[6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-基]-2-甲氧基乙酮;
6-(4-溴-2-氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-1,1-二甲基-乙氧基)-酰胺;
6-(4-溴-2-氯-苯基氨基)-7-氟-3-(四氢-呋喃-2-基甲基)-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺;
6-(4-溴-2-氯-苯基氨基)-7-氟-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺;6-(-溴-2-氟-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺;和
6-(2,4-二氯-苯基氨基)-7-氟-3-甲基-3H-苯并咪唑-5-羧酸(2-羟基-乙氧基)-酰胺;
或其药学可接受盐或溶剂合物。
还涵盖的是如WO 03/077914A1(通过援引将其收入本文)中描述的式(IV)的任何变型。可以使用本领域中已知的方法,例如WO 03/077914A1(通过援引将其收入本文)中描述的合成方法合成式(IV)的化合物或其任何变型。
在一些实施方案中,MEK抑制剂是式(V)的化合物,
或其药学可接受盐或溶剂合物,其中变量如WO 2005/121142 A1中对第6-10页上的式[I]或WO 2005/121142 A1(通过援引将其收入本文)中描述的任何可适用变型限定的。
还涵盖的是如WO 2005/121142 A1中描述的式(V)的任何变型,诸如WO 2005/121142A1中描述的个别MEK抑制剂化合物,例如表1中的例子1-1至1-343,表2中的例子2-1和2-2,表3中的例子3-1至3-9,表4中的例子4-1至4-148。可以使用本领域中已知的方法,例如WO 2005/121142 A1(通过援引将其收入本文)中描述的合成方法合成式(V)的化合物或其任何变型。
在一些实施方案中,MEK抑制剂是式(VI)的化合物,
或其药学可接受盐或酯,其中:
R1选自下组:溴,碘,乙炔基,环烷基,烷氧基,氮杂丁基(azetidinyl),乙酰基,杂环基,氰基,直链烷基和支链烷基;
R2选自下组:氢,氯,氟,和烷基;
R3选自下组:氢,氯,和氟;
R4选自下组:氢,任选取代的芳基,烷基,和环烷基;
R5选自下组:氢和
其中R6选自下组:羟基,烷氧基,环烷基,任选取代的烷基,任选取代的芳基,和任选取代的杂芳基;
R7和R8独立选自下组:氢和任选取代的烷基;
或R6和R7可以一起形成环烷基基团且R8是氢。
在一些变型中,MEK抑制剂化合物是式(VI)的化合物,或其药学可接受盐或酯,其中变量如WO 2007/096259 A1中对式I或WO 2007/096259 A1(通过援引将其收入本文)中第4-10页上描述的任何可适用变型限定的。进一步涵盖的MEK抑制剂是WO 2007/096259 A1(通过援引将其收入本文)中的例子1-182中描述的化合物。
在一些实施方案中,式(VI)的MEK抑制剂化合物是选自下组的化合物:(2S,3S)-N-(4-溴-苯基)-2-[(R)-4-(4-甲氧基-苯基)-2,5-二氧基-咪唑啉-1-基]-3-苯基-丁酰胺;
(2S,3S)-N-(4-碘-苯基)-2-[(R)-4-(4-甲氧基-苯基)-2,5-二氧基-咪唑啉-1-基]-3-苯基-丁酰胺;
(2S,3S)-N-(2-氟-4-碘-苯基)-2-{(R)-4-[4-(2-羟基-乙氧基)-苯基]-2,5-二氧基-咪唑啉-1-基}-3-苯基-丁酰胺;
(2S,3S)-N-(4-乙炔基-2-氟-苯基)-2-{(R)-4-[4-(2-羟基-乙氧基)-苯基]-2,5-二氧基-咪唑啉-1-基}-3-苯基-丁酰胺;
(2R,3S)-N-(4-乙炔基-2-氟-苯基)-2-{(R)-4-[4-(2-羟基-乙氧基)-苯基]-2,5-二氧基-咪唑啉-1-基}-3-苯基-丁酰胺;
(2S,3S)-N-(2-氯-4-碘-苯基)-2-{(R)-4-[4-(2-羟基-乙氧基)-苯基]-2,5-二氧基-咪唑啉-1-基}-3-苯基-丁酰胺;
(2S,3S)-2-{(R)-4-[4-(2-羟基-乙氧基)-苯基]-2,5-二氧基-咪唑啉-1-基}-N-(4-碘-2-甲基-苯基)-3-苯基-丁酰胺;
(2S,3S)-N-(2-氯-4-碘-苯基)-2-{(R)-4-[4-((R)-2,3-二羟基-丙氧基)-苯基]-2,5-二氧基-咪唑啉-1-基}-3-苯基-丁酰胺;
(2S,3S)-N-(2-氯-4-碘-苯基)-2-{(R)-4-[4-((S)-2,3-二羟基-丙氧基)-苯基]-2,5-二氧基-咪唑啉-1-基}-3-苯基-丁酰胺;
(2S,3S)-2-{(R)-2,5-二氧基-4-[4-(2-氧基-2-吡咯烷-1-基-乙氧基)-苯基]-咪唑啉-1-基}-N-(2-氟-4-碘-苯基)-3-苯基-丁酰胺;
(2S,3S)-2-((R)-2,5-二氧基-4-噻吩-3-基-咪唑啉-1-基)-N-(4-碘-苯基)-3-苯基-丁酰胺;
(S)-2-[(R)-4-(2,3-二氢-苯并[1,4]二口恶英-6-基)-2,5-二氧基-咪唑啉-1-基]-N-(2-氟-4-碘-苯基)-3-苯基-丙酰胺;
(S)-2-[(R)-4-(4-乙酰基氨基-苯基)-2,5-二氧基-咪唑啉-1-基]-N-(2-氟-4-碘-苯基)-3-苯基-丙酰胺;
(4-{(R)-1-[(1S,2S)-1-(2-氟-4-碘-苯基氨基甲酰基)-2-苯基-丙基]-2,5-二氧基-咪唑啉-4-基}-苯氧基甲基)-膦酸二甲酯;
(2S,3S)-N-(2-氟-4-碘-苯基)-2-((R)-4-异丙基-2,5-二氧基-咪唑啉-1-基)-3-苯基-丁酰胺;
(S)-N-(2-氟-4-碘-苯基)-2-{(R)-4-[4-(2-羟基-乙氧基)-苯基]-2,5-二氧基-咪唑啉-1-基}-3-甲基-丁酰胺;
(S)-N-(2-氟-4-碘-苯基)-2-[(R)-4-(4-甲氧基-苯基)-2,5-二氧基-咪唑啉-1-基]-3-邻-甲苯基-丙酰胺;
(S)-N-(2-氟-4-碘-苯基)-2-[(R)-4-(4-甲氧基-苯基)-2,5-二氧基-咪唑啉-1-基]-3-间-甲苯基-丙酰胺;
(S)-N-(2-氟-4-碘-苯基)-2-[(R)-4-(4-甲氧基-苯基)-2,5-二氧基-咪唑啉-1-基]-3-对-甲苯基-丙酰胺;和
(S)-N-(4-环丙基-2-氟-苯基)-3-(4-氟-苯基)-2-{(R)-4-[4-(2-羟基-1-羟基甲基-乙氧基)-苯基]-2,5-二氧基-咪唑啉-1-基}-丙酰胺;
或其药学可接受盐或酯。
在一些实施方案中,MEK抑制剂是式(VII)的化合物,
或其药学可接受盐或酯,其中:
R1选自下组:卤素,乙炔基,和环烷基;
R2选自下组:氢和CH(R3)(R4);
R3选自下组:低级烷基,低级烷氧基,任选取代的芳基,和任选取代的杂芳基;
R4选自下组:氢和低级烷基;
R5是氢或者与R2及R2和R5附接的碳一起采用,形成低级环烷基;且
R6选自下组:氢,低级烷基,低级环烷基,任选取代的芳基,和任选取代的杂芳基。
在一些变型中,MEK抑制剂化合物是式(VI)的化合物,或其药学可接受盐或酯,其中变量如WO 2009/021887 A1中对式I或WO 2009/021887 A1(通过援引将其收入本文)中第4-5页上描述的任何可适用变型限定的。进一步涵盖的MEK抑制剂是2009/021887A1(通过援引将其收入本文)中的例子1-21中描述的化合物。
在一些实施方案中,式(VI)的MEK抑制剂化合物是选自下组的化合物:(R)-5-[4-(2-羟基-乙氧基)-苯基]-3-[(S)-1-(6-碘-1H-苯并咪唑-2-基)-2-苯基-乙基]-咪唑啉-2,4-二酮;
(R)-5-[4-(2-羟基-乙氧基)-苯基]-3-(5-碘-1H-苯并咪唑-2-基甲基)-咪唑啉-2,4-二酮;
(R)-5-[4-(2-羟基-乙氧基)-苯基]-3-[(S)-1-(5-碘-1H-苯并咪唑-2-基)-2-甲基-丙基]-咪唑啉-2,4-二酮;
(R)-5-[4-(2-羟基-乙氧基)-苯基]-3-[(1R,2R)-1-(5-碘-1H-苯并咪唑-2-基)-2-甲氧基-丙基]-咪唑啉-2,4-二酮;
3-[(S)-1-(5-碘-1H-苯并咪唑-2-基)-2-苯基-乙基]-咪唑啉-2,4-二酮;与三氟乙酸复合;
(R)-3-[(S)-2-(4-氟-苯基)-1-(5-碘-1H-苯并咪唑-2-基)-乙基]-5-[4-(2-羟基-乙氧基)-苯基]-咪唑啉-2,4-二酮;
(R)-5-[4-(2-羟基-乙氧基)-苯基]-3-[(S)-1-(5-碘-1H-苯并咪唑-2-基)-2-(4-甲氧基-苯基)-乙基]-咪唑啉-2,4-二酮;
(R)-5-[4-(2-羟基-乙氧基)-苯基]-3-[(S)-1-(5-碘-1H-苯并咪唑-2-基)-2-噻吩-2-基-乙基]-咪唑啉-2,4-二酮;
(R)-3-[(1S,2S)-1-(6-碘-1H-苯并咪唑-2-基)-2-苯基-丙基]-5-苯基-咪唑啉-2,4-二酮;
(R)-3-[(1S,2S)-1-(6-碘-1H-苯并咪唑-2-基)-2-苯基-丙基]-5-(4-甲氧基-苯基)-咪唑啉-2,4-二酮;
(R)-5-[4-(2-羟基-乙氧基)-苯基]-3-[(1S,2S)-1-(6-碘-1H-苯并咪唑-2-基)-2-苯基-丙基]-咪唑啉-2,4-二酮;
(R)-3-[(1S,2S)-1-(6-碘-1H-苯并咪唑-2-基)-2-苯基-丙基]-5-[4-(2-甲氧基-乙氧基)-苯基]-咪唑啉-2,4-二酮;
2-(4-{(R)-1-[(1S,2S)-1-(6-碘-1H-苯并咪唑-2-基)-2-苯基-丙基]-2,5-二氧基-咪唑啉-4-基}-苯氧基)-N,N-二甲基-乙酰胺;
N,N-二-(2-羟基-乙基)-2-(4-{(R)-1-[(1S,2S)-1-(6-碘-1H-苯并咪唑-2-基)-2-苯基-丙基]-2,5-二氧基-咪唑啉-4-基}-苯氧基)-乙酰胺;
(R)-3-[(1S,2S)-1-(5-碘-1H-苯并咪唑-2-基)-2-苯基-丙基]-5-异丙基-咪唑啉-2,4-二酮;
(R)-5-环己基-3-[(1S,2S)-1-(5-碘-1H-苯并咪唑-2-基)-2-苯基-丙基]-咪唑啉-2,4-二酮;
(R)-5-[4-(2-羟基-乙氧基)-苯基]-3-[1-(5-碘-1H-苯并咪唑-2-基)-环丙基]-咪唑啉-2,4-二酮;
(R)-3-[(1S,2S)-1-(6-溴-1H-苯并咪唑-2-基)-2-苯基-丙基]-5-[4-(2-羟基-乙氧基)-苯基]-咪唑啉-2,4-二酮;
(R)-3-[(S)-1-(5-环丙基-1H-苯并咪唑-2-基)-2-苯基-乙基]-5-[4-(2-羟基-乙氧基)-苯基]-咪唑啉-2,4-二酮;
(R)-3-[(S)-1-(5-乙炔基-1H-苯并咪唑-2-基)-2-苯基-乙基]-5-[4-(2-羟基-乙氧基)-苯基]-咪唑啉-2,4-二酮;和
(R)-3-[(1S,2S)-1-(5-乙炔基-1H-苯并咪唑-2-基)-2-苯基-丙基]-5-[4-(2-羟基-乙氧基)-苯基]-咪唑啉-2,4-二酮;
或其药学可接受盐或溶剂合物。
在一些实施方案中,MEK抑制剂是选自下组的化合物:GDC-0973(甲酮,[3,4-二氟-2-[(2-氟-4-碘苯基)氨基]苯基][3-羟基-3-(2S)-2-哌啶基-1-氮杂丁基]-),G-38963,G02443714,G02442104,和G00039805,或其药学可接受盐或溶剂合物。
IV.试剂盒
在另一个方面,本文中提供了包含PD-L1轴结合拮抗剂和/或MEK抑制剂的试剂盒,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与MEK抑制剂组合使用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,该试剂盒包含MEK抑制剂和包装插页,该包装插页包含关于与PD-1轴结合拮抗剂组合使用MEK抑制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,该试剂盒包含PD-1轴结合拮抗剂和MEK抑制剂及包装插页,该包装插页包含关于使用PD-1轴结合拮抗剂和MEK抑制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。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MEK抑制剂。
在一些实施方案中,试剂盒包含含有本文中描述的一种或多种PD-1轴结合拮抗剂和MEK抑制剂的容器。合适的容器包括例如瓶,管形瓶(例如双室管形瓶),注射器(诸如单或双室注射器)和试管。容器可以由多种材料诸如玻璃或塑料形成。在一些实施方案中,试剂盒可以包含标签(例如在容器上或与容器联合)或包装插页。标签或包装插页可以指示其中含有的化合物可用于或意图用于在个体中治疗癌症或延迟癌症的进展或者在具有癌症的个体中增强免疫功能。试剂盒可以进一步包含从商业和用户观点看期望的其它材料,包括其它缓冲剂,稀释剂,滤器,针,和注射器。
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:抗PDL1抗体和MEK抑制剂的组合处理在Vemurafenib进展性肿瘤中引起持续的肿瘤消退
虽然B-raf抑制(诸如通过用Vemurafenib处理)有效引发短期肿瘤消退,但是频繁观察到抗性。此实施例描述用PD-1轴结合拮抗剂和MEK抑制剂的组合处理在具有Vemurafenib进展性肿瘤的动物中诱导持续的肿瘤消退和升高的无进展存活的发现。此外,用PD-1轴结合拮抗剂和MEK抑制剂的组合处理令人惊讶地优于单独用任一药剂处理。
材料和方法
小鼠模型
使用黑素瘤GEM模型B-rafV600E;PTENfl/fl;TyCreER。B-rafV600E和TyCreER等位基因记载于Dankort,D.,et al.Nat.Genet.41(5):544-52(2009)。PTEN条件性等位基因记载于Lesche,R.et al.genesis 32:148-9(2002)。
肿瘤起始
如Dankort,D.,et al.Nat.Genet.41(5):544-52(2009)中记载的那样,通过应用他莫昔芬来起始肿瘤。一旦动物的肿瘤达到大于或等于400mm3的尺寸就将它们登记入研究。
处理
在开始处理之前,每只小鼠接受黑素瘤肿瘤的活检。在活检之后,容许小鼠在接受处理之前恢复多至一周。将小鼠指派入初始处理组(n=20),并在第0天开始处理。
对于Vemurafenib处理,给予小鼠MCT,200μL,PO,qd或PLX-4032(Vemurafenib),50mg/kg PO,BID(体积不超过300μL)任一。当任何组中的动物达到~2000mm3时,第二次对肿瘤进行活检。在活检规程之后,小鼠在接受进一步的治疗性处理之前恢复多至一周。然后将动物再指派至下述处理组:GDC-0973(Cobimetinib),7.5mg/kg PO,qd(体积不超过300μL)+豚草对照(IgG2a),10mg/kg IP,一周三次;GDC-0973,7.5mg/kg PO,qd(体积不超过300μL)+抗PDL1(IgG1-WT),10mg/kg IP,一周三次;或MCT,200uL,PO,qd+抗PDL1(IgG1-WT),10mg/kg IP,一周三次。IP给药体积不超过300μL。
至少一周一次对小鼠称重并测量肿瘤直至研究终止。小鼠每天接受处理直至达到均值肿瘤体积2500mm3。然后对小鼠处以安乐死,并收集黑素瘤肿瘤进行组织学和评估评估分子变化。在安乐死时在麻醉下对小鼠进行灌注。
贯穿研究,至少一周两次对小鼠监测临床表现(身体条件,皮毛外观,姿态,呼吸吃力,等),根据观察到的不利临床体征的严重性,提高频率,直至每天。对垂死的动物处以安乐死。对身体条件得分<2的小鼠处以安乐死。
结果
肿瘤诱导后,黑素瘤GEM模型B-rafV600E;PTENfl/fl;TyCreER引起肿瘤,该肿瘤在用B-raf抑制剂Vemurafenib处理后显示初始尺寸消退。在这种初始消退之后,肿瘤展示稳定的再生长,由此模拟Vemurafenib进展性肿瘤中针对B-raf抑制的抗性。
使用这种模型来测试PD-1轴结合拮抗剂和MEK抑制剂作为Vemurafenib进展性肿瘤的二线疗法的功效。如图1中所示,用Vemurafenib一线处理后,用针对PD-L1的抗体,MEK抑制剂(Cobimetinib),或二者处理动物。单独用抗PD-L1处理显示对肿瘤生长没有影响。用Cobimetinib处理引起初始肿瘤消退,但是这种响应不持久且观察到肿瘤再生长。然而,用抗PD-L1和Cobimetinib组合处理在每一个肿瘤中引起消退,而且这种消退是持久的。另外,肿瘤内GR1水平显著降低,而且观察到T细胞活化的标志(例如升高的CD8,PRF1,和MHC I)。重要的是,用抗PD-L1和Cobimetinib处理导致升高的无进展存活(PFS)。
图2显示自Vemurafenib转换至抗PD-L1,Cobimetinib,或组合处理后的个体动物响应。
这些结果证明与单独用每一种药剂处理相比,PD-1轴结合拮抗剂和MEK抑制剂的组合处理在Vemurafenib进展性肿瘤中导致显著的,持久的肿瘤消退。而且,这些结果证明组合PD-1轴/MEK抑制作为对B-raf抑制有抗性的肿瘤的二线治疗的卓越功效。
通过援引将本文中引用的所有专利,专利申请,文件,和文章完整收入本文。
本公开涉及下述实施方案。
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轴结合拮抗剂和MEK抑制剂,其中所述个体具有对B-raf
拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。
2.实施方案1的方法,其进一步包括诊断所述个体为具有对B-raf拮抗剂有抗性的癌症,其中所述诊断发生在施用有效量的PD-1轴结合拮抗剂和MEK抑制剂之前。
3.实施方案1或实施方案2的方法,其中所述个体先前未曾用B-raf拮抗剂治疗。
4.实施方案1或实施方案2的方法,其中所述个体先前已经用B-raf拮抗剂治疗。
5.一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轴结合拮抗剂和MEK抑制剂,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
6.实施方案4或5的方法,其中所述个体中的所述癌症已经在完成基于B-raf拮抗剂的疗法方案之后1个月,6个月,1年,或5年内进展。
7.实施方案1-6中任一项的方法,其中所述B-raf拮抗剂是小分子抑制剂,抗体,肽,肽模拟物,适体或多核苷酸。
8.实施方案7的方法,其中所述B-raf拮抗剂是dabrafenib,vemurafenib,GSK
2118436,RAF265,XL281,ARQ736,BAY73-4506,sorafenib,PLX4720,PLX-3603,GSK2118436,GDC-0879,或N-(3-(5-(4-氯苯基)-1H-吡咯并
[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺。
9.实施方案7的方法,其中所述B-raf拮抗剂是B-raf V600的选择性B-raf拮抗剂。
10.实施方案7的方法,其中所述B-raf V600的选择性B-raf拮抗剂是B-rafV600E的选择性拮抗剂。
11.实施方案7的方法,其中所述B-raf V600的选择性B-raf拮抗剂是B-rafV600E,B-raf V600K,和/或V600D的选择性拮抗剂。
12.实施方案7的方法,其中所述B-raf V600的选择性B-raf拮抗剂是B-rafV600R的选择性拮抗剂。
13.实施方案1-12中任一项的方法,其中所述癌症含有BRAF V600E突变,
BRAF野生型,KRAS野生型,或活化性KRAS突变。
14.实施方案1-13中任一项的方法,其中所述治疗导致停止所述治疗后所述个体中持续的应答。
15.实施方案1-14中任一项的方法,其中所述个体具有结肠直肠癌,黑素瘤,肺癌,卵巢癌,乳腺癌,胰腺癌,血液学恶性(malignancy),膀胱癌,和/或肾细胞癌。
16.实施方案15的方法,其中所述癌症是转移性的。
17.前述实施方案任一项的方法,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。
18.实施方案17的方法,其中所述PD-1轴结合拮抗剂是PD-1结合拮抗剂。
19.实施方案18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。
20.实施方案19的方法,其中所述PD-1结合拮抗剂抑制PD-1与PD-L1,PD-1与PD-L2,或PD-1与PD-L1和PD-L2二者的结合。
21.实施方案18-20任一项的方法,其中所述PD-1结合拮抗剂是抗体。
22.实施方案18-20任一项的方法,其中所述PD-1结合拮抗剂是nivolumab,pembrolizumab,pidilizumab,MEDI-0680,PDR001,REGN2810,
BGB-108,BGB-A317,或AMP-224。
23.实施方案17的方法,其中所述PD-1轴结合拮抗剂是PD-L1结合拮抗剂。
24.实施方案23的方法,其中所述PD-L1结合拮抗剂抑制PD-L1与PD-1,
PD-L1与B7-1,或PD-L1与PD-1和B7-1二者的结合。
25.实施方案23或实施方案24的方法,其中所述PD-L1结合拮抗剂是抗
PD-L1抗体。
26.实施方案25的方法,其中所述抗PD-L1抗体是单克隆抗体。
27.实施方案25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。
28.实施方案25-27中任一项的方法,其中所述抗PD-L1抗体是人源化抗体或人抗体。
29.实施方案25任一项的方法,其中所述PD-L1结合拮抗剂选自下组:
YW243.55.S70,atezolizumab,durvalumab,MDX-1105,和avelumab。
30.实施方案25-28任一项的方法,其中所述抗体包含重链和轻链,所述重链包含HVR-H1序列SEQ ID NO:15,HVR-H2序列SEQ ID NO:16,和
HVR-H3序列SEQ ID NO:3,所述轻链包含HVR-L1序列SEQ ID NO:17,
HVR-L2序列SEQ ID NO:18,和HVR-L3序列SEQ ID NO:19。
31.实施方案25-28任一项的方法,其中所述抗体包含重链可变区和轻链可变区,所述重链可变区包含氨基酸序列SEQ ID NO:24或SEQ ID NO:28,所述轻链可变区包含氨基酸序列SEQ ID NO:21。
32.实施方案17的方法,其中所述PD-1轴结合拮抗剂是PD-L2结合拮抗剂。
33.实施方案32的方法,其中所述PD-L2结合拮抗剂是抗体。
34.实施方案32的方法,其中所述PD-L2结合拮抗剂是免疫粘附素。
35.实施方案1-34中任一项的方法,其中所述MEK抑制剂是竞争性MEK抑制剂。
36.实施方案1-34中任一项的方法,其中所述MEK抑制剂针对活化性KRAS突变更有选择性。
37.实施方案1-34中任一项的方法,其中所述MEK抑制剂是变构性MEK抑制剂。
38.实施方案1-34中任一项的方法,其中所述MEK抑制剂针对活化性BRAF突变更有选择性。
39.实施方案1-34中任一项的方法,其中所述MEK抑制剂是式(I),(II),(III),
(IV),(V),(VI)或(VII)的化合物,或其药学可接受盐或溶剂合物。
40.实施方案1-34中任一项的方法,其中所述MEK抑制剂选自下组:
G02442104,G-38963,G02443714,G00039805和GDC-0973,或其药学可接受盐或溶剂合物。
41.实施方案40的方法,其中所述MEK抑制剂是G02443714,G02442104或G00039805。
42.实施方案1-41中任一项的方法,其中连续施用所述MEK抑制剂。
43.实施方案1-41中任一项的方法,其中间歇施用所述MEK抑制剂。
44.实施方案1-41中任一项的方法,其中在所述PD-1轴结合拮抗剂前施用所述MEK抑制剂。
45.实施方案1-41中任一项的方法,其中与所述PD-1轴结合拮抗剂同时施用所述MEK抑制剂。
46.实施方案1-41中任一项的方法,其中在所述PD-1轴结合拮抗剂后施用所述MEK抑制剂。
47.实施方案1-46中任一项的方法,其中静脉内,肌肉内,皮下,表面,口服,经皮,腹膜内,眶内,通过植入,通过吸入,鞘内,室内,或鼻内施用所述PD-1轴结合拮抗剂和/或所述MEK抑制剂。
48.一种试剂盒,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MEK抑制剂组合使用所述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,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。
49.一种试剂盒,其包含PD-1轴结合拮抗剂和MEK抑制剂及包装插页,该包装插页包含关于使用所述PD-1轴结合拮抗剂和所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。
50.一种试剂盒,其包含MEK抑制剂和包装插页,该包装插页包含关于与PD-1轴结合拮抗剂组合使用所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。
51.一种试剂盒,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MEK抑制剂组合使用所述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,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
52.一种试剂盒,其包含PD-1轴结合拮抗剂和MEK抑制剂及包装插页,该包装插页包含关于使用所述PD-1轴结合拮抗剂和所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
53.一种试剂盒,其包含MEK抑制剂和包装插页,该包装插页包含关于与PD-1轴结合拮抗剂组合使用所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
Claims (8)
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轴结合拮抗剂和MEK抑制剂,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。
2.一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轴结合拮抗剂和MEK抑制剂,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
3.一种试剂盒,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MEK抑制剂组合使用所述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,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。
4.一种试剂盒,其包含PD-1轴结合拮抗剂和MEK抑制剂及包装插页,该包装插页包含关于使用所述PD-1轴结合拮抗剂和所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。
5.一种试剂盒,其包含MEK抑制剂和包装插页,该包装插页包含关于与PD-1轴结合拮抗剂组合使用所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体具有对B-raf拮抗剂有抗性的癌症或有风险发生对B-raf拮抗剂有抗性的癌症。
6.一种试剂盒,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MEK抑制剂组合使用所述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,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
7.一种试剂盒,其包含PD-1轴结合拮抗剂和MEK抑制剂及包装插页,该包装插页包含关于使用所述PD-1轴结合拮抗剂和所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
8.一种试剂盒,其包含MEK抑制剂和包装插页,该包装插页包含关于与PD-1轴结合拮抗剂组合使用所述MEK抑制剂以在个体中治疗癌症或延迟癌症进展的用法说明书,其中所述个体先前已经用B-raf拮抗剂治疗癌症。
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KR20170026630A (ko) | 2017-03-08 |
PL3169361T3 (pl) | 2019-11-29 |
ES2742500T8 (es) | 2020-02-27 |
US20170112925A1 (en) | 2017-04-27 |
BR112017000672A2 (pt) | 2017-11-14 |
IL250021A0 (en) | 2017-03-30 |
AU2015289672A1 (en) | 2017-03-02 |
RU2733735C2 (ru) | 2020-10-06 |
RU2017102926A3 (zh) | 2018-12-21 |
WO2016011160A1 (en) | 2016-01-21 |
ES2742500T3 (es) | 2020-02-14 |
RU2017102926A (ru) | 2018-08-15 |
JP6673896B2 (ja) | 2020-03-25 |
EP3169361B1 (en) | 2019-06-19 |
CA2954508A1 (en) | 2016-01-21 |
ZA201701109B (en) | 2021-07-28 |
EP3563870A1 (en) | 2019-11-06 |
JP2017522307A (ja) | 2017-08-10 |
US10946093B2 (en) | 2021-03-16 |
EP3169361A1 (en) | 2017-05-24 |
IL276314A (en) | 2020-09-30 |
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