CN110475567A - 抗癌组合疗法 - Google Patents
抗癌组合疗法 Download PDFInfo
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- CN110475567A CN110475567A CN201880022457.9A CN201880022457A CN110475567A CN 110475567 A CN110475567 A CN 110475567A CN 201880022457 A CN201880022457 A CN 201880022457A CN 110475567 A CN110475567 A CN 110475567A
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Abstract
本发明描述了抗癌疗法,其包括使用各自如本申请所述的SMAC模拟物与PD‑1拮抗剂的组合。
Description
凋亡蛋白抑制剂(IAP)的结构特征在于存在至少一个BIR(杆状病毒IAP重复)结构域并且由8个家族成员构成。其中,XIAP、ML-IAP、cIAP1和cIAP2是细胞死亡和存活的关键调节子并且是癌症治疗的有吸引力的靶标。SMAC/DIABLO蛋白是XIAP、cIAP1和cIAP2的内源性拮抗剂,过去十年中的锐意研究工作已导致几种小分子SMAC模拟物的设计和开发,所述小分子SMAC模拟物现在用于癌症治疗的临床试验。
除了它们作为细胞凋亡抑制剂的作用外,最近的研究结果表明,一些IAP的主要功能在于调节炎症和先天免疫信号传导途径。这一功能归因于它们在由促炎细胞因子如TNF和模式识别受体(PRR)如Toll样受体4(TLR4)以及核苷酸结合寡聚化结构域1(NOD1)和结构域2(NOD2)受体激活的信号级联放大中的E3泛素连接酶活性[1]。cIAP蛋白的泛素连接酶功能使它们能够调节各种信号传导途径,最显著地是规范和非规范的NF-κB信号传导途径[2]。SMAC模拟物似乎主要不是通过减轻半胱天冬酶的抑制作用起作用,而是通过诱导cIAP1的快速降解(通过激活自身泛素连接酶活性并且将蛋白质靶向蛋白酶体降解)起作用,其导致免疫信号传导改变并且使肿瘤细胞对通过来自免疫系统的外在死亡配体例如TNFα、TRAIL和FasL引起的细胞死亡敏感[3]。作为单一药剂,SMAC模拟物在约5-15%的肿瘤细胞系中诱导细胞死亡,因为这些细胞可以内源性地产生TNFα。然而,通过添加外源性TNFα或TRAIL,这种细胞毒性可以增加至约50%的癌细胞系[4,5]。
TNFα与其受体的结合触发cIAP经由TRAF2和TRADD募集至TNFR1并且诱导RIP1的多聚泛素化(polyubiquitination),最终导致规范的NF-κB传导途径的激活,其诱导与存活、增殖或炎症相关的基因表达。在缺乏cIAP的条件下,例如在存在SMAC模拟物下,RIP1不再泛素化并且形成称为ripoptosome的默认死亡复合物,并且在某些情况下(例如,缺失半胱天冬酶8)导致形成涉及RIP3的坏死体(necrosome)。TNFα处理后形成的这些IAP调节的死亡复合物可诱导半胱天冬酶8介导的凋亡或坏死性凋亡,半胱天冬酶8介导的坏死性凋亡是诱导免疫原性肿瘤细胞死亡(ICD)和抗肿瘤免疫的强有力机制[6,7]。
当向动物或人给药时,SMAC模拟物具有免疫调节功能并且介导全身细胞因子(例如IL-6、TNFα等)和趋化因子(例如MCP-1)的诱导[8]。
癌症免疫疗法是肿瘤学的一个分支,其中免疫系统用于治疗癌症,这与现有的直接切除或治疗肿瘤的常用治疗方法形成鲜明对比。该治疗概念基于识别T细胞表面上的许多蛋白质,所述蛋白质起到抑制这些细胞免疫功能的作用。这些蛋白质中可列出PD-1。
PD-1(程序性细胞死亡1)是T细胞上表达的细胞表面受体蛋白质。蛋白质作为“免疫检查点”抑制剂起作用,即蛋白质起到调节免疫系统中细胞活性从而调节和限制自身免疫疾病的作用。最近已经了解到,许多癌症可以通过修饰“免疫检查点”抑制剂来保护自身免受免疫系统的影响,从而避免检测。
PD-1具有两种配体PD-L1和PD-L2,它们与细胞表面受体相互作用。在结合时,PD-1诱导细胞内信号,其负调节T细胞应答。
如上所述,PD-1是T细胞活性的关键调节剂。最近,已经在一系列不同的癌症环境中显示出,拮抗性PD-1抗体分子纳武单抗和帕博利珠单抗可用于刺激免疫系统并且由此治疗癌症。
通过使用与其它化合物的组合疗法(特别是在肿瘤学方面)和/或改善剂量方案,可以改善治疗剂的疗效。即使已经提出组合几种治疗剂的概念,并且尽管正在研究各种组合疗法并且在临床试验中,仍然需要用于治疗癌症疾病例如实体瘤的新的和有效的治疗概念,其显示出优于标准疗法的优点,例如较好的治疗结果、有益的效果、优越的疗效和/或改善的耐受性,例如,减少组合治疗的副作用。具体地,对于患有癌症例如肺癌(例如NSCLC)、乳腺癌(例如TNBC)和多发性骨髓瘤(MM)的患者,需要另外的治疗选择。
因此,本发明的目的是提供组合治疗/组合治疗方法,其与现有技术中目前使用和/或已知的治疗/治疗方法相比,提供某些优点。这些优点可包括体内疗效(例如改善临床反应,延长反应,增加反应速率、反应持续时间、疾病稳定率、稳定的持续时间、疾病进展时间、无进展生存期(PFS)和/或总生存期(OS),后来出现抗药性等),安全且耐受良好地给药以及降低不良事件的发生频率和严重程度。
在这种情况下,本申请的发明人惊奇地发现,SMAC模拟物(也称为IAP抑制剂)与PD-1(程序性细胞死亡1)拮抗剂(即,本发明上下文中抗PD-1或抗PD-L1抗体)的组合使用,与单独使用SMAC模拟物或PD-1拮抗剂相比,具有改善临床结果的潜力。
因此,本发明涉及治疗和/或预防肿瘤或过度增殖性疾病、特别是癌症的方法,其包括组合给药各自如本申请所述的SMAC模拟物和PD-1拮抗剂,并且涉及其医学用途、使用、包含这种治疗剂的药物组合物或组合和试剂盒。
此外,本发明涉及抗癌疗法,其包括组合使用各自如本申请所述的SMAC模拟物和PD-1拮抗剂。
对于肿瘤性质疾病的治疗,已经提出大量的抗癌剂(包括靶特异性抗癌剂和非靶特异性抗癌剂),其可以作为单一疗法或涉及多于一种的药剂的组合疗法(例如,双重或三重组合治疗)和/或可以与放射疗法(例如放射治疗)、放射免疫疗法和/或手术组合。
本发明的目的是提供与本申请所述治疗剂的组合疗法,用于治疗或控制各种恶性肿瘤(例如,基于组合中涉及的活性成分的协同作用、互补作用、交互作用或改善作用)。
因此,在一个方面,本发明提供治疗和/或预防肿瘤或过度增生性疾病、特别是癌症的方法,其包括向有此需要的患者给药各自如本申请所述的治疗有效量的SMAC模拟物和治疗有效量的PD-1拮抗剂。
在另一个方面,治疗和/或预防方法进一步包括给药如本申请所述的治疗有效量的一种或多种其它治疗剂。
这种组合治疗可以作为物质的非固定(例如自由)组合或以固定组合(包括试剂盒)的形式给出。
在另一个方面,本发明提供各自如本申请所述的SMAC模拟物和PD-1拮抗剂的组合,其特别是用于治疗和/或预防如本申请所述的肿瘤或过度增生性疾病、特别是癌症的方法,所述方法包括向有此需要的患者给药治疗有效量的组合。
在另一个方面,组合进一步包括如本申请所述的一种或多种其它治疗剂。
在另一个方面,本发明涉及如本申请所述SMAC模拟物以用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法,所述方法包括向有此需要的患者给药如本申请所述SMAC模拟物与PD-1拮抗剂的组合。
在另一个方面,治疗和/或预防方法进一步包括组合给药如本申请所述的一种或多种其它治疗剂。
在另一个方面,本发明涉及如本申请所述PD-1拮抗剂以用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法,所述方法包括向有此需要的患者给药如本申请所述的PD-1拮抗剂与SMAC模拟物的组合。
在另一个方面,治疗和/或预防方法进一步包括组合给药如本申请所述的一种或多种其它治疗剂。
在另一个方面,本发明涉及试剂盒,所述试剂盒包含
·第一药物组合物或剂型,其包含如本申请所述的SMAC模拟物和任选的一种或多种药学上可接受的载体、赋形剂和/或媒介物,和
·第二药物组合物或剂型,其包含如本申请所述的PD-1拮抗剂和任选的一种或多种药学上可接受的载体、赋形剂和/或媒介物。
在另一个方面,试剂盒包含一种或多种其它药物组合物或剂型,其各自包含如本申请所述的一种其它治疗剂和任选的一种或多种药学上可接受的载体、赋形剂和/或媒介物。
在另一个方面,本发明涉及上述试剂盒,其进一步包含
·包装说明书,其包含用于同时、并行、顺序、连续、交替或分开用于治疗和/或预防有此需要的患者的如本申请所述肿瘤或过度增生性疾病、特别是癌症的印刷说明书。
在另一个方面,本发明涉及上述试剂盒以用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法。
在另一个方面,本发明涉及药物组合物,其包含
·如本申请所述的SMAC模拟物,
·如本申请所述的PD-1拮抗剂,和,
·任选地,一种或多种药学上可接受的载体、赋形剂和/或媒介物。
在另一个方面,药物组合物包含如本申请所述的一种或多种其它治疗剂。
在另一个方面,本发明涉及如本申请所述SMAC模拟物用于制备用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法的药物组合物中的用途,其中所述SMAC模拟物与如本申请所述的PD-1拮抗剂组合使用。
在SMAC模拟物的用途的另一个方面,SMAC模拟物待与如本申请所述的PD-1拮抗剂和如本申请所述的一种或多种其它治疗剂组合使用。
在另一个方面,本发明涉及如本申请所述PD-1拮抗剂用于制备用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法的药物组合物中的用途,其中所述PD-1拮抗剂与如本申请所述的SMAC模拟物组合使用。
在PD-1拮抗剂的用途的另一个方面,PD-1拮抗剂待与如本申请所述的SMAC模拟物和如本申请所述的一种或多种其它治疗剂组合使用。
在另一个方面,本发明涉及各自如本申请所述的SMAC模拟物和PD-1拮抗剂用于制备用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法的药物组合物中的用途。
在另一个方面,本发明涉及各自如本申请所述的SMAC模拟物、PD-1拮抗剂和一种或多种其它治疗剂用于制备用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法的药物组合物中的用途。
在另一个方面,本发明涉及各自如本申请所述的根据本发明的组合、药物组合物或试剂盒,其包含各自如本申请所述的SMAC模拟物和PD-1拮抗剂、由各自如本申请所述的SMAC模拟物和PD-1拮抗剂组成或基本上由各自如本申请所述的SMAC模拟物和PD-1拮抗剂组成,用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法。
附图说明
图1显示示例性SMAC模拟物BIA-1作为单一药剂和与RMP1-14组合的抗肿瘤活性,RMP1-14即源自Balb/c小鼠的乳腺癌细胞系EMT6的皮下同源小鼠模型中的PD-1的小鼠工具抗体。
图2显示示例性SMAC模拟物BIA-1和BIA-2作为单一药剂和与RMP1-14组合的抗肿瘤活性,RMP1-14即源自C3H小鼠的膀胱癌细胞系MBT-2的皮下同源小鼠模型中的PD-1的小鼠工具抗体。
图3显示示例性SMAC模拟物BIA-1和BIA-2作为单一药剂和与RMP1-14组合的抗肿瘤活性,RMP1-14即C57BL/6J小鼠的Vk12598多发性骨髓瘤可移植模型中的PD-1的小鼠工具抗体。
图4显示示例性SMAC模拟物BIA-1在抗PD1 MK3465刺激抗原特异性T细胞应答上的增强活性。
SMAC模拟物
本发明意义上的SMAC模拟物及其所有实施方案是与IAP蛋白结合并且诱导它们降解的化合物。
优选地,本发明中的SMAC模拟物及其所有实施方案选自以下(A0):
·如WO 2013/127729中(一般地和/或具体地)公开的SMAC模拟物(即,化合物)或其药学上可接受的盐;
·如WO 2015/025018中(一般地和/或具体地)公开的SMAC模拟物(即,化合物)或其药学上可接受的盐;
·如WO 2015/025019中(一般地和/或具体地)公开的SMAC模拟物(即,化合物)或其药学上可接受的盐;
·如WO 2016/023858中(一般地和/或具体地)公开的SMAC模拟物(即,化合物)或其药学上可接受的盐;
·如WO 2008/0016893中(一般地和/或具体地)公开的SMAC模拟物(即,化合物)或其药学上可接受的盐;
·LCL161,即WO 2008/016893(第28/29页;[122])的实施例1中的化合物A或其药学上可接受的盐;
·称为Debio-1143的SMAC模拟物或其药学上可接受的盐;
·称为birinapant的SMAC模拟物或其药学上可接受的盐;
·称为ASTX-660的SMAC模拟物或其药学上可接受的盐;
·称为CUDC-427的SMAC模拟物或其药学上可接受的盐;
·表1中SMAC模拟物1至26的任一种或其药学上可接受的盐:
表1
表1中的实例化合物1至10公开于WO2013/127729中。表1中的实例化合物11至26公开于WO 2016/023858中。
如本申请所用的术语“SMAC模拟物”也包括以上列出的SMAC模拟物的互变异构体、药学上可接受的盐、水合物或溶剂合物形式(包括药学上可接受的盐的水合物或溶剂合物)。它也包括所有其固体(优选结晶形式)及其药学上可接受的盐、水合物和溶剂合物的所有结晶形式的SMAC模拟物(包括药学上可接受的盐的水合物和溶剂合物)。
以上列出的所有SMAC模拟物在本领域中都是已知的,具有各自的合成和性质。以上提到的所有专利申请的全部内容都通过引用并入。
在一个实施方案中,SMAC模拟物是LCL161或其药学上可接受的盐(A1)。
在另一个实施方案中,SMAC模拟物是表1中的化合物1或其药学上可接受的盐(A2)。
在另一个实施方案中,SMAC模拟物是表1中的化合物2或其药学上可接受的盐(A3)。
在另一个实施方案中,SMAC模拟物是表1中的化合物3或其药学上可接受的盐(A4)。
在另一个实施方案中,SMAC模拟物是表1中的化合物4或其药学上可接受的盐(A5)。
在另一个实施方案中,SMAC模拟物是表1中的化合物5或其药学上可接受的盐(A6)。
在另一个实施方案中,SMAC模拟物是表1中的化合物6或其药学上可接受的盐(A7)。
在另一个实施方案中,SMAC模拟物是表1中的化合物7或其药学上可接受的盐(A8)。
在另一个实施方案中,SMAC模拟物是表1中的化合物8或其药学上可接受的盐(A9)。
在另一个实施方案中,SMAC模拟物是表1中的化合物9或其药学上可接受的盐(A10)。
在另一个实施方案中,SMAC模拟物是表1中的化合物10或其药学上可接受的盐(A11)。
在另一个实施方案中,SMAC模拟物是表1中的化合物11或其药学上可接受的盐(A12)。
在另一个实施方案中,SMAC模拟物是表1中的化合物12或其药学上可接受的盐(A13)。
在另一个实施方案中,SMAC模拟物是表1中的化合物13或其药学上可接受的盐(A14)。
在另一个实施方案中,SMAC模拟物是表1中的化合物14或其药学上可接受的盐(A15)。
在另一个实施方案中,SMAC模拟物是表1中的化合物15或其药学上可接受的盐(A16)。
在另一个实施方案中,SMAC模拟物是表1中的化合物16或其药学上可接受的盐(A17)。
在另一个实施方案中,SMAC模拟物是表1中的化合物17或其药学上可接受的盐(A18)。
在另一个实施方案中,SMAC模拟物是表1中的化合物18或其药学上可接受的盐(A19)。
在另一个实施方案中,SMAC模拟物是表1中的化合物19或其药学上可接受的盐(A20)。
在另一个实施方案中,SMAC模拟物是表1中的化合物20或其药学上可接受的盐(A21)。
在另一个实施方案中,SMAC模拟物是表1中的化合物21或其药学上可接受的盐(A22)。
在另一个实施方案中,SMAC模拟物是表1中的化合物22或其药学上可接受的盐(A23)。
在另一个实施方案中,SMAC模拟物是表1中的化合物23或其药学上可接受的盐(A24)。
在另一个实施方案中,SMAC模拟物是表1中的化合物24或其药学上可接受的盐(A25)。
在另一个实施方案中,SMAC模拟物是表1中的化合物25或其药学上可接受的盐(A26)。
在另一个实施方案中,SMAC模拟物是表1中的化合物26或其药学上可接受的盐(A27)。
就SMAC模拟物的性质而言,所有实施方案(A1)至(A27)都是实施方案(A0)的优选实施方案。
为了用于治疗,SMAC模拟物包括在适于促进向动物或人给药的药物组合物中。用于给药本发明SMAC模拟物的典型药物组合物包括例如,片剂,胶囊,栓剂,溶液(例如注射用溶液(皮下注射(s.c.)、静脉注射(i.v.)、肌肉注射(i.m.)),和输注用溶液),酏剂,乳液,或可分散粉末。药物活性化合物的含量可以是整个组合物的0.1重量%至90重量%,优选40重量%至60重量%,例如其量足以达到所需的剂量范围。如果需要,可以一天内数次给予单一剂量以递送所需的总每日剂量。
典型的片剂可以例如通过将活性物质(任选地组合)与如下物质混合得到:已知的赋形剂,例如,惰性稀释剂如碳酸钙、磷酸钙、纤维素或乳糖,崩解剂如玉米淀粉或海藻酸或交联聚乙烯吡咯烷酮,粘合剂如淀粉或明胶,润滑剂如硬脂酸镁或滑石,和/或用于延迟释放的试剂如羧甲基纤维素、醋酸邻苯二甲酸纤维素或聚乙酸乙烯酯。片剂可以通过常规方法制备,例如通过直接压片或碾压制备。片剂也可包含几层。
包衣片剂可相应地通过将通常用于片剂包衣的物质对以类似于片剂制备的核心进行包衣从而制备,所述物质例如为可力酮(collidone)或虫胶、阿拉伯树胶、滑石、二氧化钛或糖。为了实现延迟释放或防止不相容性,核心也可以由许多层构成。类似地,片剂包衣可以由许多层构成以实现延迟释放,可能使用上述用于片剂的赋形剂。
含有活性物质的糖浆或酏剂可另外含有甜味剂,例如糖精、环己烷氨基磺酸盐、甘油或糖和风味增强剂,例如香料,如香草醛或橙提取物。它们也可含有悬浮助剂或增稠剂如羧甲基纤维素钠、润湿剂例如脂肪醇与环氧乙烷的缩合产物、或防腐剂如对羟基苯甲酸酯。
注射和输注溶液以常规方式制备,例如,添加等渗剂、防腐剂如对羟基苯甲酸酯、或稳定剂如乙二胺四乙酸的碱金属盐,任选使用乳化剂和/或分散剂,同时如果水用作稀释剂,则例如有机溶剂可任选地用作溶剂化剂或溶解助剂,并且转移到注射瓶或安瓿或输液瓶中。
含有活性物质的胶囊可以例如通过将活性物质与惰性载体如乳糖或山梨糖醇混合并且将它们包装到明胶胶囊中来制备。
典型的栓剂可以例如通过将活性物质与为此目的提供的载体混合制备,所述载体例如中性脂肪或聚乙二醇或其衍生物。
可以使用的赋形剂包括,例如,水、药学上可接受的有机溶剂如石蜡(例如石油馏分)、植物油(例如花生油或芝麻油)、单官能醇或多官能醇(例如乙醇或甘油)、载体例如天然矿物粉末(例如高岭土、粘土、滑石、白垩)、合成矿物粉末(例如高度分散的硅酸和硅酸盐),糖类(如蔗糖、乳糖和葡萄糖)、乳化剂(例如木质素、亚硫酸盐废液、甲基纤维素、淀粉和聚乙烯吡咯烷酮)和润滑剂(例如硬脂酸镁、滑石、硬脂酸和十二烷基硫酸钠)。
本发明的SMAC模拟物及其所有实施方案都通过常规方法给药,优选通过口服或肠胃外途径给药,最优选通过口服途径给药。对于口服给药,片剂除了上述载体外还可以含有添加剂如柠檬酸钠、碳酸钙和磷酸二钙(dicalcium phosphate),以及各种添加剂如淀粉(优选马铃薯淀粉)、明胶等。此外,可以同时使用润滑剂如硬脂酸镁、十二烷基硫酸钠和滑石用于压片过程。在含水悬浮液的情况下,除了上述赋形剂之外,活性物质可以与各种风味增强剂或着色剂组合。
对于肠胃外使用,可以使用活性物质与适宜液体载体的溶液。
对于LCL161,口服使用剂量和给药方案例如公开于WO 2016/054555第14页第一段和第126/127页中。
表1中SMAC模拟物的口服使用剂量为每天1mg至2000mg(例如每天100mg至1000mg;在更优选的实施方案中,每天200mg至400mg;最优选每天300mg)。给出的所有量都是指表1中SMAC模拟物的游离碱,并且如果使用药学上可接受的盐或其它固体形式,则可以按比例地提高。
优选地,SMAC模拟物每天给药一次(每天一次(q.d.))。
静脉内使用的给药量为每小时1mg至1000mg,优选每小时5mg至500mg。
然而,有时可能需要偏离指定的量,这取决于体重、给药途径、个体对药物的反应、其制剂的性质以及给药的时间或间隔。因此,在某些情况下,使用少于以上给出的最小剂量可能就足够,而在其它情况下,可能必须超过上限。当大量给药时,推荐将它们在一天中分成分散的许多较小剂量。
PD-1拮抗剂
本发明意义上的PD-1拮抗剂及其所有实施方案是抑制PD-1与其受体或配体相互作用的化合物,优选地,PD-1拮抗剂是PD-1的抑制剂或PD-L1的抑制剂,更优选抗PD-1抗体或抗PD-L1抗体,最优选人源化或全人抗PD-1抗体或人源化或全人抗PD-L1抗体。
术语“抗体”包括抗体、抗体片段、抗体样分子和与上述任一种的缀合物。抗体包括但不限于多克隆或单克隆、嵌合、人源化、人、单、双或多特异性抗体。术语“抗体”应包括完全免疫球蛋白(因为所述完全免疫球蛋白由淋巴细胞产生并且例如存在于血清中),由杂交瘤细胞系分泌的单克隆抗体,通过在宿主细胞中重组表达产生的多肽(其具有免疫球蛋白或单克隆抗体的结合特异性),通过进一步加工同时保持其结合特异性而从这些免疫球蛋白、单克隆抗体或多肽衍生的分子。特别地,术语“抗体”包括包含两条重链和两条轻链的完全免疫球蛋白。在另一个实施方案中,术语包括免疫球蛋白片段,如Fab片段。在另一个实施方案中,术语“抗体”包括具有一个或多个衍生自免疫球蛋白的可变结构域的多肽,如单链抗体(scFv)、单结构域抗体等。
PD-1拮抗剂在本领域中是众所周知的,例如由Li等人,Int.J.Mol.Sci.2016,17,1151综述(通过引用并入本申请)。可以根据本发明使用任何PD-1拮抗剂、特别是抗体,例如Li等人公开的那些以及下文公开的其它抗体。
最优选地,本发明中的PD-1拮抗剂及其所有实施方案都选自以下(B0):
·帕博利珠单抗(抗PD-1抗体);
·纳武单抗(抗PD-1抗体);
·pidilizumab(抗PD-1抗体);
·PDR-001(抗PD-1抗体);
·阿特珠单抗(抗PD-L1抗体);
·阿维鲁单抗(抗PD-L1抗体);
·德瓦鲁单抗(抗PD-L1抗体);
·WO 2015/112900中(一般地和/或具体地)公开的抗PD-1抗体:
ο如WO 2015/112900的表1中定义的抗体中的任一种(第171页)
ο如WO 2015/112900的表1中定义的人源化抗体中的任一种(第171页)
ο如WO 2015/112900的表1中定义的BAP049-hum01至BAP049-hum16中的任一种(第171页)
ο如WO 2015/112900的表1中定义的BAP049-Clone-A至BAP049-Clone-E中的任一种(第171页)
·WO 2016/061142中(一般地和/或具体地)公开的抗PD-L1抗体:
οWO 2016/061142的表1中定义的抗体中的任一种(第265页);
οWO 2016/061142的表1中定义的人源化抗体中的任一种(第265页);
οWO 2016/061142的表1中定义的BAP058-hum01至BAP058-hum17中的任一种(第265页)
οWO 2016/061142的表1中定义的BAP058-Clone-K至
BAP058-Clone-O中的任一种(第265页)
·如下文中公开的PD1-1、PD1-2、PD1-3、PD1-4和PD1-5(抗PD-1抗体)
公开于例如Hamid,O.等人,(2013)New England Journal of Medicine369(2):134-44的帕博利珠单抗(以前也称为lambrolizumab;商品名称Keytruda;也称为MK-3475)是与PD-1结合的人源化IgG4单克隆抗体;它含有在C228P的突变,其设计以防止Fc介导的细胞毒性。帕博利珠单抗例如公开于US 8,354,509和WO 2009/114335中。它被FDA批准用于治疗患有不可切除的或转移性黑素瘤的患者和患有转移性NSCLC的患者。
纳武单抗(CAS登记号:946414-94-4;BMS-936558或MDX1106b)是全人IgG4单克隆抗体,其可特异性阻断PD-1,缺乏可检测的抗体依赖性细胞毒性(ADCC)。纳武单抗例如公开于US 8,008,449和WO 2006/121168中。它已被FDA批准用于治疗患有不可切除的或转移性黑素瘤、转移性NSCLC和晚期肾细胞癌的患者。
pidilizumab(CT-011;Cure Tech)是与PD-1结合的人源化IgG1k单克隆抗体。pidilizumab例如公开于WO 2009/101611中。
PDR-001或PDR001是高亲和力、配体阻断的人源化抗PD-1IgG4抗体,其阻断PD-L1和PD-L2与PD-1的结合。PDR-001公开于WO 2015/112900和WO 2017/019896中。
抗体PD1-1至PD1-5是由表2中所示序列定义的抗体分子,其中HC表示(全长)重链,LC表示(全长)轻链:
表2
具体地,上文所述的抗PD-1抗体分子具有:
(PD1-1):包含SEQ ID NO:1的氨基酸序列的重链和包含SEQ ID NO:2的氨基酸序列的轻链;或
(PD1-2):包含SEQ ID NO:3的氨基酸序列的重链和包含SEQ ID NO:4的氨基酸序列的轻链;或
(PD1-3):包含SEQ ID NO:5的氨基酸序列的重链和包含SEQ ID NO:6的氨基酸序列的轻链;或
(PD1-4):包含SEQ ID NO:7的氨基酸序列的重链和包含SEQ ID NO:8的氨基酸序列的轻链;或
(PD1-5):包含SEQ ID NO:9的氨基酸序列的重链和包含SEQ ID NO:10的氨基酸序列的轻链。
阿特珠单抗(Tecentriq,也称为MPDL3280A)是靶向PD-L1的噬菌体衍生的人IgG1k单克隆抗体,并且描述于例如Deng等人,mAbs 2016;8:593-603中。它已被FDA批准用于治疗患有尿路上皮癌的患者。
阿维鲁单抗是全人抗PD-L1 IgG1单克隆抗体并且描述于例如Boyerinas等人,Cancer Immunol.Res.2015;3:1148-1157中。
德瓦鲁单抗(MEDI4736)是对PD-L1具有高度特异性的人IgG1k单克隆抗体并且描述于例如Stewart等人,Cancer Immunol.Res.2015;3:1052-1062或Ibrahim等人,Semin.Oncol.2015;42:474-483中。
由Li等人(同上)公开或在临床试验中已知的其它PD-1拮抗剂,例如AMP-224、MEDI0680(AMP-514)、REGN2810、BMS-936559、JS001-PD-1、SHR-1210、BMS-936559、TSR-042、JNJ-63723283、MEDI4736、MPDL3280A和MSB0010718C,可以用作上述拮抗剂的替代或补充。
如本申请所用的INN也意指包括具有与起始抗体相同或基本相同的氨基酸序列的所有生物类似物抗体,包括但不限于根据美国的42USC§262子部分(k)和其它司法管辖区的同等规定所授权的那些生物类似物抗体。
以上列出的所有PD-1拮抗剂在本领域中是已知的,具有它们各自的制造、治疗用途和性质。以上提到的所有专利申请的全部内容都通过引用并入。
在一个实施方案中,PD-1拮抗剂是帕博利珠单抗(B1)。
在另一个实施方案中,PD-1拮抗剂是纳武单抗(B2)。
在另一个实施方案中,PD-1拮抗剂是pidilizumab(B3)。
在另一个实施方案中,PD-1拮抗剂是阿特珠单抗(B4)。
在另一个实施方案中,PD-1拮抗剂是阿维鲁单抗(B5)。
在另一个实施方案中,PD-1拮抗剂是德瓦鲁单抗(B6)。
在另一个实施方案中,PD-1拮抗剂是PDR-001(B7)。
在另一个实施方案中,PD-1拮抗剂是如WO 2015/112900(第171页)的表1中定义的BAP049-Clone-B(B8)。
在另一个实施方案中,PD-1拮抗剂是如WO 2015/112900(第171页)的表1中定义的BAP049-Clone-E(B9)。
在另一个实施方案中,PD-1拮抗剂选自如WO 2016/061142(第265页)的表1中定义的BAP058-Clone-K至BAP058-Clone-O(B10)。
在另一个实施方案中,PD-1拮抗剂是PD1-1(B11)。
在另一个实施方案中,PD-1拮抗剂是PD1-2(B12)。
在另一个实施方案中,PD-1拮抗剂是PD1-3(B13)。
在另一个实施方案中,PD-1拮抗剂是PD1-4(B14)。
在另一个实施方案中,PD-1拮抗剂是PD1-5(B15)。
就PD-1拮抗剂的性质而言,所有实施方案(B1)至(B15)都是实施方案(B0)的优选实施方案。
为了用于治疗,相应的抗PD1和/或抗PD-L1抗体分子包含在适于促进向动物或人给药的药物组合物中。
对于药物用途,本发明的抗体分子可以配制成药物制剂,其包含(i)至少一种本发明的抗体和(ii)至少一种药学上可接受的载体、稀释剂、赋形剂、佐剂和/或(iii)任选的一种或多种其它药理学活性多肽和/或化合物。“药学上可接受的”是指相应的物质在给药至个体时不显示任何生物学上的或其它不良作用,并且不以有害的方式与所包含的药物组合物的任何其它组分(例如药学活性成分)相互作用。具体的实例可以得自标准手册,例如Remington's Pharmaceutical Sciences,18th Ed.,Mack Publishing Company,USA(1990)。例如,本发明的抗体可以以本身对于常规抗体和抗体片段及其它药学活性蛋白质已知的任何方式配制和给药。因此,根据一个其它实施方案,本发明涉及药物组合物或制剂,其含有至少一种本发明的抗体和至少一种药学上可接受的载体、稀释剂、赋形剂、佐剂和/或稳定剂以及任选的一种或多种其它药理活性物质。
用于肠胃外给药例如静脉内、肌肉内、皮下注射或静脉内输注的药物制剂可以是例如无菌溶液、悬浮液、分散液、乳液或粉末,其包含活性成分并且任选地在进一步溶解或稀释步骤后适于输注或注射。用于这种制剂的适宜载体或稀释剂例如包括但不限于无菌水和药学上可接受的含水缓冲液和溶液,例如生理磷酸盐缓冲盐水、林格氏溶液、右旋糖溶液和Hank溶液;水油(water oils);甘油;乙醇;二醇如丙二醇,以及矿物油、动物油,和植物油例如花生油、大豆油,及其适宜的混合物。
本发明抗体分子的溶液也可含有防腐剂以防止微生物的生长,如抗菌和抗真菌剂,例如对羟基苯甲酸盐、对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞、乙二胺四乙酸(碱金属盐)等。在许多情况下,优选包括等渗剂,例如糖、缓冲液或氯化钠。任选地,可以使用乳化剂和/或分散剂。例如,通过形成脂质体、在分散体的情况下保持所需的粒度或使用表面活性剂,可以保持适当的流动性。也可以加入其它延迟吸收的试剂,例如单硬脂酸铝和明胶。可以将溶液填充到注射小瓶、安瓿、输液瓶等中。
在所有情况下,最终剂型必须是无菌的流体并且在制造和储存条件下是稳定的。通过将所需量的活性化合物与适当的溶剂和以上列举的各种其它成分(如果需要)混合,然后过滤除菌,制备无菌的注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥技术,其产生活性成分粉末加上先前无菌过滤的溶液中存在的任何其它所需成分。
通常,水溶液或悬浮液是优选的。通常,适用于治疗性蛋白质例如本发明抗体的制剂是缓冲蛋白质溶液,例如包含适宜浓度(例如0.001mg/mL至400mg/mL、优选0.005mg/mL至200mg/mL、更优选0.01mg/mL至200mg/mL、更优选1.0-100mg/mL,例如1.0mg/mL(静脉注射(i.v.)给药)或100mg/mL(皮下注射(s.c.)给药))的蛋白质溶液和含水缓冲液,例如:
-磷酸盐缓冲盐水,pH 7.4,
-其它磷酸盐缓冲液,pH 6.2至8.2,
-醋酸盐缓冲液,pH 3.2至7.5,优选pH 4.8至5.5,
-组氨酸缓冲液,pH 5.5至7.0,
-琥珀酸盐缓冲液,pH 3.2至6.6,和
-柠檬酸盐缓冲液,pH 2.1至6.2,
并且任选地,盐(例如NaCl)和/或糖(例如蔗糖和海藻糖)和/或其它多元醇(例如甘露醇和甘油)用于提供溶液的等渗性。
优选的缓冲蛋白质溶液是包含溶解在25mM磷酸盐缓冲液(pH6.5)中、通过加入220mM海藻糖调节至等渗性的约0.05mg/mL的本发明抗体的溶液。此外,其它试剂如洗涤剂、例如0.02%的吐温20或吐温80可以包含在这种溶液中。用于皮下施用的制剂可包括显著较高浓度的本发明抗体,例如浓度高达100mg/mL或甚至高于100mg/mL。然而,本领域技术人员清楚,如上给出的成分和其量仅代表一种优选的选择。其替代和变化形式对于本领域技术人员而言很明显,或者可以从上述公开内容容易地构思出。
抗体可以1mg/kg至20mg/kg的剂量,通过一次或多次单独给药或连续输注、例如1小时内输注,给药至患者。典型的治疗方案通常包括每周一次至每三周一次来给药抗体。
在一个实施方案中,如WO 2015/112900(第171页)的表1中定义的BAP049-Clone-E根据WO 2017/019896(第336页最后一段)中公开的程序给予剂量和给药。
对于已经上市的PD-1拮抗剂的更详细描述及其用途,参考相应的产品特征概述(通过引用整体并入)。
组合疗法
在本发明中,应当理解,根据本发明使用的组合、组合物、试剂盒、方法、用途或化合物可预想活性成分或组分的同时、并行、顺序、连续、交替或分开给药。应当理解,SMAC模拟物和PD-1拮抗剂可以非独立地或独立地配制,例如SMAC模拟物和PD-1拮抗剂可以作为相同药物组合物/剂型的一部分给药,或优选以单独的药物组合物/剂型给药。
在本文中,本发明含义内的“组合”或“组合的”包括但不限于由多于一种活性成分的混合或组合得到的产品,包括固定和非固定(例如自由)组合(包括试剂盒)和用途,例如组分或成分的同时、并行、顺序、连续、交替或分开使用。术语“固定组合”是指活性成分以单一实体或剂量的形式同时给药至患者。术语“非固定组合”是指活性成分作为单独的实体同时地、并行地或顺序地而没有特定时间限制地给药至患者,其中这种给药在患者体内提供治疗有效水平的两种化合物。非固定组合也适用于鸡尾酒疗法,例如给药三种或更多种活性成分。
可以通过共同给药活性组分或成分来进行SMAC模拟物和PD-1拮抗剂的给药,例如,通过以一个或两个单独的制剂或剂型同时地或并行地给药SMAC模拟物和PD-1拮抗剂。或者,可以例如在两种单独的制剂或剂型中通过顺序地或交替地给药活性组分或成分来进行SMAC模拟物和PD-1拮抗剂的给药。
例如,同时给药包括基本上同时给药。这种给药形式也可称为“伴随”给药。并行施用包括在相同的一般时间段内、例如在同一天但不一定在同一时间给药活性剂。交替给药包括在一段时间期间、例如在几天或一周的过程中给药一种药剂,然后在随后的一段时间期间、例如在几天或一周的过程中给药另一种药剂,然后重复该模式一个或多个循环。顺序给药或连续给药包括在第一时间段期间(例如在几天或一周的过程中)使用一种或多种剂量给药一种药剂,然后在第二时间段期间(例如几天或一周的过程中)使用一个或多个剂量给药另一种药剂。还可以采用重叠的时间表,其包括在治疗期间的不同日期、不一定按照规律顺序来给药活性剂。也可以采用这些一般准则的变化,例如根据使用的药剂和受试者的状况。
如果组合设置不是双重组合而是三重或更高的多重组合方法,则上述相应地适用。
本发明组合的要素可以通过本领域技术人员常用的方法给药(无论是非独立地还是独立地),例如,通过口服、肠溶、肠胃外(例如,肌肉内、腹膜内、静脉内、透皮或皮下注射或植入)、鼻、阴道、直肠或局部给药途径,可以含有适合于每种给药途径的常规无毒的药学上可接受的载体、赋形剂和/或媒介物的适当剂量单位制剂进行单独配制或一起配制。
因此,在本发明的一个方面,本发明提供治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法,其包括向有此需要的患者给药各自如本申请所述的治疗有效量的SMAC模拟物和治疗有效量的PD-1拮抗剂和任选的一种或多种其它治疗剂,其中所述SMAC模拟物与PD-1拮抗剂和任选的一种或多种其它治疗剂(如果存在)同时地、并行地、顺序地、连续地、交替地或分开地给药。
在另一个方面,本发明提供如本申请所述SMAC模拟物用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法,所述方法包括给药各自如本申请所述的SMAC模拟物与PD-1拮抗剂的组合和任选的一种或多种其它治疗剂,其中所述SMAC模拟物与PD-1拮抗剂和任选的一种或多种其它治疗剂(如果存在)同时地、并行地、顺序地、连续地、交替地或分开地给药。
在另一个方面,本发明提供如本申请所述PD-1拮抗剂用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法,所述方法包括给药各自如本申请所述的PD-1拮抗剂与SMAC模拟物和任选的一种或多种其它治疗剂的组合,其中将所述PD-1拮抗剂与SMAC模拟物和任选的一种或多种其它治疗剂(如果存在)同时地、并行地、顺序地、连续地、交替地或分开地给药。
在另一个方面,本发明提供如本申请所述的SMAC模拟物用于制备用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法的药物组合物中的用途,其中各自如本申请所述的SMAC模拟物与PD-1拮抗剂和任选的一种或多种其它治疗剂组合使用,和其中所述SMAC模拟物待与PD-1拮抗剂和任选的一种或多种其它治疗剂(如果存在)同时地、并行地、顺序地、连续地、交替地或分开地给药。
在另一个方面,本发明提供如本申请所述PD-1拮抗剂用于制备用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法的药物组合物中的用途,其中所述PD-1拮抗剂与各自如本申请所述的SMAC模拟物和任选的一种或多种其它治疗剂组合使用,和其中PD-1拮抗剂待与SMAC模拟物和任选的一种或多种其它治疗剂(如果存在)同时地、并行地、顺序地、连续地、交替地或分开地给药。
在另一个方面,本发明提供试剂盒,其包含
·第一药物组合物或剂型,其包含如本申请所述的SMAC模拟物和任选的一种或多种药学上可接受的载体、赋形剂和/或媒介物,
·第二药物组合物或剂型,其包含如本申请所述的PD-1拮抗剂和任选的一种或多种药学上可接受的载体、赋形剂和/或媒介物,和任选地
·一种或多种其它药物组合物或剂型,其各自包含如本申请所述的一种其它治疗剂和任选的一种或多种药学上可接受的载体、赋形剂和/或媒介物,
所述试剂盒用于治疗和/或预防如本申请所述肿瘤或过度增生性疾病、特别是癌症的方法,其中第一药物组合物待与第二药物组合物或剂型和任选的一种或多种其它药物组合物或剂型(如果存在)同时地、并行地、顺序地、连续地、交替地或分开地给药。
在本发明的一个进一步的实施方案中,将根据本发明使用的组合的组分(即组合伴用物)、试剂盒、用途、方法和化合物(包括所有实施方案)同时地给药。
在本发明的一个进一步的实施方案中,将根据本发明使用的组合的组分(即组合伴用物)、试剂盒、用途、方法和化合物(包括所有实施方案)并行地给药。
在本发明的一个进一步的实施方案中,将根据本发明使用的组合的组分(即组合伴用物)、试剂盒、用途、方法和化合物(包括所有实施方案)顺序地给药。
在本发明的一个进一步的实施方案中,将根据本发明使用的组合的组分(即组合伴用物)、试剂盒、用途、方法和化合物(包括所有实施方案)连续地给药。
在本发明的一个进一步的实施方案中,将根据本发明使用的组合的组分(即组合伴用物)、试剂盒、用途、方法和化合物(包括所有实施方案)交替地给药。
在本发明的一个进一步的实施方案中,将根据本发明使用的组合的组分(即组合伴用物)、试剂盒、用途、方法和化合物(包括所有实施方案)分开地给药。
在一个优选的实施方案中,如本申请所述SMAC模拟物待口服给药。
在另一个优选的实施方案中,如本申请所述PD-1拮抗剂待静脉注射给药。
待给药的活性化合物的“治疗有效量”是预防、改善或治疗疾病或病症所需的最小量。
本发明的组合可以以治疗有效的单次或分次每日剂量给药。组合的活性成分可以以单一疗法中治疗有效的剂量给药,或者以比单一疗法使用的剂量低的剂量给药,但是当组合时产生所需(联合)治疗有效量。
实施方案(A0)至(A27)(关于SMAC模拟物)与实施方案(B0)至(B15)(关于PD-1拮抗剂)的排列方式导致448特定的双重组合C0至C447(C0=A0B0、C1=A0B1、C2=A0B2、......等)都应视为具体地公开,并且其全部视为是本发明所具体公开或作为本发明实施方案的所有使用的组合、组合物、试剂盒、方法、用途和化合物。
其它治疗剂
根据本发明使用的包括如本申请所述SMAC模拟物和PD-1拮抗剂两者的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)可任选地包括一种或多种其它治疗剂。
这种/这些其它治疗剂可以(各自)选自以下(而不限于此):
·免疫治疗剂,例如以下检查点抑制剂的调节剂:TIM3、PD-L1、PD-L2、CTLA-4、VISTA、BTLA、TIGIT、CD160、LAIR1、2B4、CEACAM;
·癌症疫苗;
·DNA损伤剂;
·血管生成抑制剂;
·信号转导途径抑制剂;
·有丝分裂检查点抑制剂;和
激素、激素类似物及抗激素(例如,他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、氟维司群(fulvestrant)、乙酸甲地孕酮、氟他胺、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、胺麸精(aminoglutethimide)、乙酸环丙孕酮(cyproterone acetate)、非那雄胺(finasteride)、乙酸布舍瑞林(buserelinacetate)、氟氢可的松(fludrocortisone)、氟甲睾酮(fluoxymesterone)、甲羟孕酮(medroxyprogesterone)、奥曲肽(octreotide))、芳香酶抑制剂(例如,阿那曲唑(anastrozole)、来曲唑(letrozole)、利阿唑(liarozole)、伏氯唑(vorozole)、依西美坦(exemestane)、阿他美坦(atamestane))、LHRH激动剂及拮抗剂(例如,乙酸戈舍瑞林(goserelin acetate)、柳菩林(luprolide))、生长因子之抑制剂(生长因子,诸如(例如)“血小板衍生型生长因子(PDGF)”、“纤维母细胞生长因子(FGF)”、“血管内皮生长因子(VEGF)”、“表皮生长因子(EGF)”、“胰岛素样生长因子(IGF)”、“人类表皮生长因子(HER,例如HER2、HER3、HER4)”及“肝细胞生长因子(HGF)”),抑制剂为(例如)“生长因子”抗体、“生长因子受体”抗体及酪氨酸激酶抑制剂,诸如(例如)西妥昔单抗(cetuximab)、吉非替尼(gefitinib)、伊马替尼(imatinib)、拉帕替尼(lapatinib)、博舒替尼(bosutinib)及曲妥珠单抗(trastuzumab));抗代谢物(例如,抗叶酸药(诸如,甲胺喋呤、雷替曲塞(raltitrexed))、嘧啶类似物(诸如,5-氟尿嘧啶(5-FU)、卡培他滨(capecitabine)及吉西他滨(gemcitabine))、嘌呤及腺苷类似物(诸如巯基嘌呤、硫鸟嘌呤、克拉屈滨(cladribine)及喷托他丁(pentostatin))、阿糖胞苷(cytarabine)(ara C)、氟达拉滨(fludarabine));抗肿瘤抗生素(例如,蒽环霉素(诸如多柔比星(doxorubicin))、doxil(聚乙二醇化脂质体多柔比星盐酸盐、myocet(非聚乙二醇化脂质体多柔比星)、道诺霉素(daunorubicin)、表柔比星(epirubicin)及伊达比星(idarubicin)、丝裂霉素-C、博来霉素(bleomycin)、放线菌素(dactinomycin)、普卡霉素(plicamycin)、链脲霉素(streptozocin));铂衍生物(例如,顺铂、奥沙利铂(oxaliplatin)、卡铂);烷基化剂(例如,雌氮芥(estramustin)、氮芥(meclorethamine)、美法仑(melphalan)、氯芥苯丁酸(chlorambucil)、白消安(busulphan)、达卡巴嗪(dacarbazin)、环磷酰胺、异环磷酰胺(ifosfamide)、替莫唑胺(temozolomide)、亚硝基脲(诸如(例如)卡莫司汀(carmustin)及洛莫司汀(lomustin))、噻替哌(thiotepa));抗有丝分裂剂(例如,长春花(Vinca)生物碱,诸如(例如)长春花碱(vinblastine)、长春地辛(vindesin)、长春瑞滨(vinorelbin)及长春新碱(vincristine);及紫杉烷类,诸如太平洋紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel));血管生成抑制剂(例如他喹莫德(tasquinimod))、微管蛋白抑制剂;DNA合成抑制剂(例如沙帕他滨(sapacitabine))、PARP抑制剂、拓朴异构酶抑制剂(例如表鬼臼毒素(epipodophyllotoxins)(诸如(例如)依托泊苷(etoposide)及凡毕复(etopophos))、替尼泊苷(teniposide)、安吖啶(amsacrin)、拓朴替康(topotecan)、伊立替康(irinotecan)、米托蒽醌(mitoxantrone))、丝氨酸/苏氨酸激酶抑制剂(例如,PDK 1抑制剂、Raf抑制剂、A-Raf抑制剂、B-Raf抑制剂、C-Raf抑制剂、mTOR抑制剂、mTORC1/2抑制剂、PI3K抑制剂、PI3Kα抑制剂、双重mTOR/PI3K抑制剂、STK 33抑制剂、AKT抑制剂、PLK 1抑制剂、CDK之抑制剂、Aurora激酶抑制剂)、酪氨酸激酶抑制剂(例如PTK2/FAK抑制剂)、蛋白质蛋白质相互作用抑制剂(例如IAP活化剂、Mcl-1、MDM2/MDMX)、MEK抑制剂(例如匹马色替(pimasertib))、ERK抑制剂、FLT3抑制剂(例如奎扎替尼(quizartinib))、BRD4抑制剂、IGF-1R抑制剂、TRAILR2激动剂、Bcl-xL抑制剂、Bcl-2抑制剂(例如凡尼托可拉斯(venetoclax))、Bcl-2/Bcl-xL抑制剂、ErbB受体抑制剂、BCR-ABL抑制剂、ABL抑制剂、Src抑制剂、雷帕霉素(rapamycin)类似物(例如依维莫司(everolimus)、替西罗莫司(temsirolimus)、利达慕斯(ridaforolimus)、西罗莫司(sirolimus))、雄激素合成抑制剂(例如阿比特龙(abiraterone)、TAK-700)、雄激素受体抑制剂(例如恩杂鲁胺(enzalutamide)、ARN-509)、免疫治疗剂(例如西普鲁塞-T(sipuleucel-T))、DNMT抑制剂(例如SGI 110、替莫唑胺(temozolomide)、沃扎若辛(vosaroxin))、HDAC抑制剂(例如伏立诺他(vorinostat)、恩替司他(entinostat)、普辛司他(pracinostat)、帕比司他(panobinostat))、ANG1/2抑制剂(例如曲班那尼(trebananib))、CYP17抑制剂(例如加勒特龙(galeterone))、放射性药物(例如镭-223、氯化镭-223(alpharadin))、免疫治疗剂(例如基于痘病毒之疫苗、易普利单抗(ipilimumab)、免疫检核点抑制剂)及各种化疗剂(诸如阿米福汀(amifostin)、anagrelid、氯膦酸盐(clodronat)、非格司亭(filgrastin)、干扰素、干扰素α、左旋亚叶酸钙(leucovorin)、利妥昔单抗(rituximab)、丙卡巴肼(procarbazine)、左美索(levamisole)、美司那(mesna)、米托坦(mitotane)、帕米膦酸盐(pamidronate)及卟吩姆(porfimer));
2-氯脱氧腺苷、2-氟脱氧胞苷、2-甲氧基雌二醇、2C4、3-丙胺酰基-半胱胺-二硫化物(3-alethine)、131-I-TM-601、3CPA、7--乙基-10-羟基喜树碱、16-氮杂埃坡霉素B、ABT-199、ABT-263/那托克斯(navitoclax)、ABT-737、A105972、A 204197、阿地白介素(aldesleukin)、阿立塞替(alisertib)/MLN8237、阿曲诺英(alitretinoin)、allovectin-7、六甲蜜胺(altretamine)、阿瓦西地(alvocidib)、氨萘非特(amonafide)、蒽吡唑(anthrapyrazole)、AG-2037、AP-5280、阿普净醌(apaziquone)、阿坡胺(apomine)、阿拉糖(aranose)、阿格拉宾(arglabin)、阿佐昔芬(arzoxifene)、阿他美坦(atamestane)、阿曲生坦(atrasentan)、奥瑞司他汀PE(auristatin PE)、AVLB、AZ10992、ABX-EGF、AMG-479(戈尼土单抗(ganitumab))、AMG-232、AMG-511、AMG 2520765、AMG 2112819、ARRY 162、ARRY438162、ARRY-300、ARRY-142886/AZD-6244(司美替尼(selumetinib))、ARRY-704/AZD-8330、ATSP-7041、AR-12、AR-42、AS-703988、AXL-1717、AZD-1480、AZD-4547、AZD-8055、AZD-5363、AZD-6244、AZD-7762、ARQ-736、ARQ 680、AS-703026(普利色替(primasertib))、阿伐司汀(avastin)、AZD-2014、阿札胞苷(azacitidine)(5-aza)、氮杂埃坡霉素B(azaepothilone B)、偶氮萘非特(azonafide)、巴拉色替(barasertib)/AZD1152、BAY-43-9006、BAY 80-6946、BBR-3464、BBR-3576、贝伐单抗(bevacizumab)、BEZ-235/达托利斯(dactolisib)、比立考达二柠檬酸盐(biricodar dicitrate)、比立那班(birinapant)、BCX-1777、BKM-120/5-(2,6-二吗啉并嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺(buparlisib)、博来霉素(bleocin)、BLP-25、BMS-184476、BMS-247550、BMS-188797、BMS-275291、BMS-663513、BMS-754807、BNP-1350、BNP-7787、BIBW 2992/阿法替尼(afatinib)、BIBF 1120/尼达尼布(nintedanib)、BI 836845、BI 2536、BI 6727/沃拉赛蒂(volasertib)、BI 836845、BI 847325、BI 853520、BIIB-022、博来霉素酸(bleomycinic acid)、博来霉素A、博来霉素B、布瑞法尼(brivanib)、苔藓虫素-1(bryostatin-1)、波替单抗(bortezomib)、伯斯他素(brostallicin)、白消安、BYL-719/阿培利斯(alpelisib)、CA-4前药、CA-4、卡巴他赛(cabazitaxel)、卡博替尼(cabozantinib)、CapCell、骨化三醇(calcitriol)、卡纳替尼(canertinib)、坎磷酰胺(canfosfamide)、卡培他滨(capecitabine)、羧基酞铂、CCI-779、CC-115、CC-223、CEP-701、CEP-751、CBT-1头孢克肟(CBT-1cefixime)、西福拉特宁(ceflatonin)、头孢曲松(ceftriaxone)、塞来考昔(celecoxib)、西莫白介素(celmoleukin)、西马多丁(cemadotin)、CGM-097、CH4987655/RO-4987655、氯烯雌醚(chlorotrianisene)、西仑吉肽(cilengitide)、环孢素(ciclosporin)、CD20抗体、CDA-II、CDC-394、CKD-602、CKI-27、克罗拉滨(clofarabine)、秋水仙碱(colchicin)、考布他汀A4(combretastatin A4)、COT抑制剂、CHS-828、CH-5132799、CLL-Thera、CMT-3克利特非辛52(CMT-3cryptophycin 52)、CPI-613、CTP-37、CTLA-4单株抗体(例如易普利单抗(ipilimumab))、CP-461、克唑替尼(crizotinib)、CV-247、氰基吗啉并多柔比星、阿糖胞苷(cytarabine)、D 24851、达沙替尼(dasatinib)、地西他滨(decitabine)、多柔比星(deoxorubicin)、去氧比星(deoxyrubicin)、去氧助间霉素(deoxycoformycin)、缩肽(depsipeptide)、去氧埃坡霉素B(desoxyepothilone B)、地塞米松(dexamethasone)、得拉唑沙(dexrazoxanet)、二乙基乙烯雌酚(diethylstilbestrol)、二氟莫替康(diflomotecan)、二氧杂环己烷(didox)、DMDC、海兔毒素(dolastatin 10)、多拉达唑(doranidazole)、DS-7423、DS-3032、E7010、E-6201、依达曲沙(edatrexat)、依度曲肽(edotreotide)、乙丙昔罗(efaproxiral)、依氟鸟氨酸(eflornithine)、EGFR抑制剂、EKB-569、EKB-509、因扎斯道宁(enzastaurin)、伊利司莫(elesclomol)、依沙芦星(elsamitrucin)、埃坡霉素B、依帕珠单抗(epratuzumab)、EPZ-004777、ER-86526、厄洛替尼(erlotinib)、ET-18-OCH3、乙炔基胞苷(ethynylcytidine)、乙炔基雌二醇、依克沙替康(exatecan)、甲磺酸依克沙替康(exatecan mesylate)、依西美坦(exemestane)、依昔舒林(exisulind)、芬维A胺(fenretinide)、氟吉妥单抗(figitumumab)、氟尿苷、叶酸、FOLFOX、FOLFOX4、FOLFIRI、福美斯坦(formestane)、福他替尼(fostamatinib)、福莫司汀(fotemustine)、加兰柔比星(galarubicin)、麦芽酚镓(gallium maltolate)、更特匹(ganetespib)、吉非替尼(gefinitib)、吉妥珠单抗(gemtuzumab)、吉妥珠单抗奥唑米星(gemtuzumab ozogamicin)、吉马替康(gimatecan)、葡磷酰胺(glufosfamide)、GCS-IOO、GDC-0623、GDC-0941(2-(1H-吲唑-4-基)-6-[[4-(甲基磺酰基)-1-哌嗪基]甲基]-4-(4-吗啉基)噻吩并[3,2-d]嘧啶(pictrelisib))、GDC-0980、GDC-0032、GDC-0068、GDC-0349、GDC-0879、G17DT抗原体、GMK、GMX-1778、GPX-100、gp100-肽疫苗、GSK-5126766、GSK-690693、GSK-1120212(曲美替尼(trametinib))、GSK-1995010、GSK-2118436(达拉菲尼(dabrafenib))、GSK-2126458、GSK-2132231A、GSK-2334470、GSK-2110183、GSK-2141795、GSK-2636771、GSK-525762A/I-BET-762、GW2016、格拉司琼(granisetron)、赫赛汀(herceptine)、六甲蜜胺、组织胺、高三尖杉酯碱(homoharringtonine)、玻尿酸(hyaluronic acid)、羟基脲、己酸羟孕酮、HDM-201、伊班膦酸盐(ibandronate)、替伊莫单抗(ibritumomab)、依布鲁替尼(ibrutinib)/PCI-32765、伊达沙诺林(idasanutlin)、伊达曲沙(idatrexate)、艾代拉里斯(idelalisib)/CAL-101、双烯雌酚(idenestrol)、IDN-5109、IGF-1R抑制剂、IMC-1C11、IMC-A12(西妥木单抗(cixutumumab))、免疫(immunol)、N-(3-氯-1H-吲哚-7-基)-1,4-苯二磺酰胺(indisulam)、干扰素α-2a、干扰素α-2b、聚乙二醇化干扰素α-2b、介白素--2、INK--1117、INK-128、INSM-18、洛那法尼(ionafarnib)、异丙铂(iproplatin)、伊罗夫文(irofulven)、异同型软海绵素-B(isohomohalichondrin-B)、异黄酮(isoflavone)、异维甲酸(isotretinoin)、伊沙匹隆(ixabepilone)、JRX-2、JSF-154、JQ-1、J-107088、偶联雌激素、哈利德-F(kahalid F)、酮康唑(ketoconazole)、KW-2170、KW-2450、KU-55933、LCL-161、乐铂(lobaplatin)、来氟米特(leflunomide)、来那度胺(lenalidomide)、雷诺格拉斯蒂姆(lenograstim)、亮丙瑞林(leuprolide)、亮丙瑞林(leuporelin)、来昔决南钐(lexidronam)、LGD-1550、利奈唑胺(linezolid)、洛伐他汀(lovastatin)、得克萨菲啉镥(lutetium texaphyrin)、洛美曲索(lometrexol)、氯尼达明(lonidamine)、洛索蒽醌(losoxantrone)、LU 223651、乐宾可啶(lurbinectedin)、勒托替康(lurtotecan)、LY-S6AKT1、LY-2780301、LY-2109761/加鲁什替(galunisertib)、马磷酰胺(mafosfamide)、马立马司他(marimastat)、马索罗酚(masoprocol)、氮芥(mechloroethamine)、MEK抑制剂、MEK-162、甲基睾酮(methyltestosteron)、甲泼尼龙(methylprednisolone)、MEDI-573、MEN-10755、MDX-H210、MDX-447、MDX-1379、MGV、米哚妥林(midostaurin)、米诺膦酸(minodronic acid)、丝裂霉素(mitomycin)、米伐布林(mivobulin)、MK-2206、MK-0646(达洛珠单抗(dalotuzumab))、MLN518、MLN-0128、MLN-2480、莫特沙芬钆(motexafin gadolinium)、MS-209、MS-275、MX6、奈力膦酸(neridronate)、来那替尼(neratinib)、蕾莎瓦(Nexavar)、尼华司他(neovastat)、尼勒替尼(nilotinib)、尼美舒利(nimesulide)、硝基甘油、诺拉曲塞(nolatrexed)、诺瑞林(norelin)、N--乙酰基半胱氨酸、NU-7441 06-苄基鸟嘌呤、奥利默森(oblimersen)、奥美拉唑(omeprazole)、奥拉帕利(olaparib)、奥克噬菌体(oncophage)、oncoVEXGM-CSF、奥密铂(ormiplatin)、欧塔他赛(ortataxel)、OX44抗体、OSI-027、OSI-906(林西替尼(linsitinib))、4-1BB抗体、奥杉三唑(oxantrazole)、雌激素、奥那司酮(onapristone)、帕布昔利布(palbociclib)/PD-0332991、盘尼图单抗(panitumumab)、帕比司他(panobinostat)、帕土匹龙(patupilone)、帕唑帕尼(pazopanib)、乙二醇化非格司亭(pegfilgrastim)、PCK-3145、乙二醇化非格司亭、PBI-1402、PBI-05204、PD0325901、PD-1及PD-L1抗体(例如帕姆单抗(pembrolizumab)、纳武单抗(nivolumab)、彼地利株单抗(pidilizumab)、MEDI-4736/度法鲁单抗(durvalumab)、RG-7446/阿特珠单抗(atezolizumab))、PD-616、PEG-太平洋紫杉醇(PEG-paclitaxel)、经白蛋白稳定之太平洋紫杉醇、PEP-005、PF-05197281、PF-05212384、PF-04691502、PF-3758309、PHA-665752、PHT-427、P-04、PKC412、P54、PI-88、培利替尼(pelitinib)、培美曲塞(pemetrexed)、皮特里斯(pentrix)、哌立福新(perifosine)、紫苏醇(perillylalcohol)、皮妥珠单抗(pertuzumab)、皮伐那地他(pevonedistat)、PI3K抑制剂、PI3K/mTOR抑制剂、PG-TXL、PG2、PLX-4032/RO-5185426(维罗非尼(vemurafenib))、PLX-3603/RO-5212054、PT-100、PWT-33597、PX-866、吡铂(picoplatin)、丁酸特戊酰氧基甲酯、匹杉琼(pixantrone)、苯氧二醇O(phenoxodiol O)、PKI166、普来曲塞(plevitrexed)、普卡霉素(plicamycin)、聚烯瑞尼酸(polyprenic acid)、帕纳替尼(ponatinib)、泊非霉素(porfiromycin)、泊沙康唑(posaconazole)、强的松(prednisone)、脱氢皮质醇(prednisolone)、PRT-062607、喹那麦得(quinamed)、喹奴普丁(quinupristin)、奎扎替尼(quizartinib)/AC220、R115777、RAF-265、雷莫司琼(ramosetron)、豹蛙酶(ranpirnase)、RDEA-119/BAY 869766、RDEA-436、雷贝卡霉素(rebeccamycin)类似物、受体酪氨酸激酶(RTK)抑制剂、雷维米德(revimid)、RG-7167、RG-7112、RG-7304、RG-7421、RG-7321、RG-7356、RG 7440、RG-7775、根霉素(rhizoxin)、rhu-MAb、利格色替林菲培(rigosertib rinfabate)、利塞磷酸盐(risedronate)、利妥昔单抗(rituximab)、罗巴木单抗(robatumumab)、罗福克西(rofecoxib)、罗咪酯肽(romidepsin)、RO-4929097、RO-31-7453、RO-5126766、RO-5068760、RPR 109881A、红比腙(rubidazone)、鲁比替康(rubitecan)、R-氟比洛芬(R-flurbiprofen)、RX-0201、鲁索替尼(ruxolitinib)、S-9788、萨巴比星(sabarubicin)、SAHA、沙帕他滨(sapacitabine)、SAR-405838、沙格司亭(sargramostim)、赛特铂(satraplatin)、SB-408075、SB-431542、Se-015/Ve-015、SU5416、SU6668、SDX-101、利尼克扎(selinexor)、司莫司汀(semustin)、西奥骨化醇(seocalcitol)、SM-11355、SN-38、SN-4071、SR-27897、SR-31747、SR-13668、SRL-172、索拉非尼(sorafenib)、螺铂(spiroplatin)、角鲨胺(squalamine)、STF-31、辛二酰苯胺羟肟酸、索坦(sutent)、T900607、T 138067、TAE-684、TAK-733、TAS-103、泰克地那林(tacedinaline)、他拉泊芬(talaporfin)、坦螺旋霉素(tanespimycin)、得舒缓(Tarceva)、塔喹达(tariquitar)、他斯索兰(tasisulam)、多西紫杉醇(taxotere)、泰索普星(taxoprexin)、他佐罗汀(tazarotene)、替加氟(tegafur)、替莫唑胺(temozolamide)、替米利芬(tesmilifene)、睾固酮(testosterone)、丙酸睾固酮(testosterone propionate)、替米利芬、四铂、河豚毒素(tetrodotoxin)、替扎他滨(tezacitabine)、撒利多胺(thalidomide)、沙拉卢克(theralux)、四氢吡喃阿霉素(therarubicin)、胸腺法新(thymalfasin)、赛麦他新(thymectacin)、噻唑呋林(tiazofurin)、替吡法尼(tipifarnib)、替拉扎明(tirapazamine)、托拉地新(tocladesine)、托穆戴克斯(tomudex)、托瑞米芬(toremofin)、托舍多特(tosedostat)、曲贝替定(trabectedin)、TransMID-107、反式视黄酸(transretinic acid)、曲珠土单抗(traszutumab)、曲美目单抗(tremelimumab)、维甲酸(tretinoin)、三乙酰尿苷、非洛地平(triapine)、曲西立滨(triciribine)、曲美沙特(trimetrexate)、TLK-286TXD 258、泰嘉锭(tykerb)/拉帕替尼(tyverb)、优若西啶(urocidin)、丙戊酸、伐芦比星(valrubicin)、凡德他尼(vandetanib)、瓦他拉尼(vatalanib)、长春新碱、长春氟宁(vinflunine)、维如利金(virulizin)、维莫德吉(vismodegib)、沃扎若辛(vosaroxin)、WX-UK1、WX-554、维克替比(vectibix)、XAV-939、希罗达(xeloda)、XELOX、XL-147、XL-228、XL-281、XL-518/R-7420/GDC-0973、XL-765、YM-511、YM-598、ZD-4190、ZD-6474、ZD-4054、ZD-0473、ZD-6126、ZD-9331、ZDI839、ZSTK-474、唑来磷酸(zoledronat)及唑喹达(zosuquidar)。
肿瘤或过度增生性疾病/癌症
根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)可用于治疗和/或预防肿瘤和过度增殖性疾病。
在某些实施方案中,根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)可用于治疗肿瘤和过度增殖性疾病。
在某些实施方案中,过度增殖性疾病是癌症。
癌症有两种分类方式:依癌症起源的组织类型(组织学类型)和依原发部位(或癌症首次发展的身体部位)。癌症发展的最常见部位包括皮肤、肺、乳腺、前列腺、结肠和直肠、子宫颈和子宫以及血液学区室。
根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)可用于治疗各种肿瘤和过度增殖性疾病、特别是癌症,包括例如但不限于以下癌症:
·脑相关癌症,如成人脑肿瘤、儿童脑干胶质瘤、儿童小脑星形细胞瘤、儿童脑星形细胞瘤/恶性胶质瘤、儿童室管膜瘤、儿童成神经管细胞瘤、儿童幕上原始神经外胚层肿瘤、儿童视觉通路和下丘脑神经胶质瘤及其他儿童脑肿瘤;
·乳腺癌;
·消化/胃肠相关癌症,如肛门癌、肝外胆管癌、胃肠道类癌、胆管癌、结肠癌、食道癌、胆囊癌、成人原发性肝癌(肝细胞癌、肝母细胞瘤)、儿童肝癌、胰腺癌、直肠癌、小肠癌和胃癌(stomach cancer)(胃癌(gastric cancer));
·内分泌相关癌症,如肾上腺皮质癌、胃肠道类癌、胰岛细胞癌(内分泌胰腺)、甲状旁腺癌、嗜铬细胞瘤、垂体瘤和甲状腺癌;
·眼睛相关癌症,如眼内黑色素瘤和视网膜母细胞瘤;
·泌尿生殖系统相关癌症,如膀胱癌、肾(肾细胞)癌、阴茎癌、前列腺癌、移行细胞肾盂和输尿管癌、睾丸癌、尿道癌、肾母细胞瘤和其他儿童肾脏肿瘤;
·生殖细胞相关癌症,如儿童颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、卵巢生殖细胞肿瘤和睾丸癌;
·妇科癌症,如宫颈癌、子宫内膜癌、妊娠滋养细胞肿瘤、卵巢上皮癌、卵巢生殖细胞肿瘤、卵巢低恶性潜能肿瘤、子宫肉瘤、阴道癌和外阴癌;
·头颈癌相关癌症,如下咽癌、喉癌、唇癌和口腔癌、转移性鳞状细胞颈癌伴隐匿原发灶(metastatic squamous neck cancer with occult primary)、鼻咽癌、口咽癌、鼻窦和鼻腔癌(如鼻窦鳞状细胞癌)、甲状旁腺癌和唾液腺癌;
·血液学/血液相关癌症,如白血病,如成人急性淋巴细胞白血病、儿童急性淋巴细胞白血病、成人急性髓性白血病、儿童急性髓性白血病、慢性淋巴细胞白血病、慢性粒细胞白血病和毛细胞白血病;和淋巴瘤,如艾滋病相关淋巴瘤、皮肤T细胞淋巴瘤、成人霍奇金淋巴瘤、儿童霍奇金淋巴瘤、妊娠期霍奇金淋巴瘤、蕈样真菌病、成人非霍奇金淋巴瘤、儿童非霍奇金淋巴瘤、妊娠期非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤、Sezary综合征、皮肤T细胞淋巴瘤和华氏巨球蛋白血症,和其它血液学/血液相关癌症,如慢性骨髓增生性疾病、多发性骨髓瘤/浆细胞肿瘤、骨髓增生异常综合征和骨髓增生异常/骨髓增生性疾病;
·肌肉骨骼相关癌症,如尤因氏肿瘤家族、骨肉瘤、骨恶性纤维组织细胞瘤、儿童横纹肌肉瘤、成人软组织肉瘤、儿童软组织肉瘤和子宫肉瘤;血管肉瘤(hemangiosarcomas)和血管肉瘤(angiosarcoma);
·神经系统相关癌症,如成人脑肿瘤、儿童脑肿瘤、脑干胶质瘤、小脑星形细胞瘤、脑星形细胞瘤/恶性胶质瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层肿瘤、视觉通路和下丘脑神经胶质瘤,以及其它脑肿瘤如神经母细胞瘤、垂体瘤肿瘤和原发性中枢神经系统淋巴瘤;
·呼吸/胸腔相关癌症,如非小细胞肺癌(NSCLC)、小细胞肺癌(SCLC)、肺鳞状细胞癌(SCC)、恶性间皮瘤、胸腺瘤(thymoma)和胸腺癌(thymic carcinoma);
·皮肤相关癌症,如皮肤T细胞淋巴瘤、卡波西肉瘤、黑色素瘤、Merkel细胞癌和皮肤癌;
·小蓝色圆形细胞肿瘤。
在一个进一步的实施方案中,用于本发明的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)有益于治疗:造血系统的癌症,包括白血病、淋巴瘤和骨髓瘤;胃肠道癌症,包括食道癌、胃癌、结肠直肠癌、胰腺癌、肝癌和胆囊癌以及胆管癌;肾、前列腺和膀胱癌;妇科癌症,包括乳腺癌、卵巢癌、子宫颈癌和子宫内膜癌;皮肤和头颈癌,包括恶性黑色素瘤;儿童癌症,如肾母细胞瘤、神经母细胞瘤和尤因氏肉瘤;脑癌,如胶质母细胞瘤;肉瘤,如骨肉瘤、软组织肉瘤、横纹肌肉瘤、血管肉瘤;肺癌,包括非小细胞肺癌,间皮瘤和甲状腺癌。
在本发明的一个进一步的实施方案中,根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)用于治疗非小细胞肺癌(NSCLC)(包括例如局部晚期或转移性NSCLC(IIIB/IV期)、NSCLC腺癌、具有鳞状组织学的NSCLC、具有非鳞状组织学的NSCLC)。
在本发明的一个进一步的实施方案中,根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)用于治疗非小细胞肺癌(NSCLC)、特别是NSCLC腺癌。
在本发明的一个进一步的实施方案中,根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)用于治疗多发性骨髓瘤(MM)。
在本发明的一个进一步的实施方案中,根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)用于治疗乳腺癌、特别是三阴性乳腺癌(TNBC)。
在本发明的一个进一步的实施方案中,根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)用于治疗尚未经过检查点抑制剂或免疫调节剂治疗的癌症患者,即,例如尚未经过PD-1拮抗剂治疗的患者。
在本发明的一个进一步的实施方案中,根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)用于治疗在用检查点抑制剂或免疫调节剂治疗期间复发的癌症患者,即,例如在用PD-1拮抗剂治疗期间复发的患者。
根据本发明的组合疗法的治疗适用性可包括患者的第一线治疗、第二线治疗、第三线治疗或其它线治疗。癌症可以对一种或多种抗癌治疗具有转移性、复发性、再发性、抗药性或难治性。因此,患者可以是尚未经过治疗的,或者可以已经接受过一种或多种先前抗癌疗法,所述一种或多种先前抗癌疗法尚未完全治愈疾病。
对一种或多种抗癌剂(例如组合的单一组分或标准化学治疗剂)具有复发性和/或抗药性的患者也适合于根据本发明的组合治疗,例如,适合于第二线或第三线治疗周期(任选地与一种或多种其它抗癌剂进一步组合),例如,作为附加组合或替代治疗。
因此,本发明的一些公开的组合疗法可有效治疗受试者,所述受试者所患的癌症已复发或其癌症已变得抗药性或多重抗药性或其癌症经一线、二线或更多线的单一疗法或与一种或多种抗癌剂(例如组合的单一组分或标准化学治疗剂)的组合疗法而失败。
最初对抗癌药物起反应的癌症可以复发,并且当抗癌药物不再有效治疗患有癌症的受试者时,尽管给药增加剂量的抗癌药物,但癌症变得对抗癌药物具有抗药性。据说对两种或多种抗癌药物产生抗药性的癌症具有多重抗药性。
因此,在本发明的一些组合治疗方法中,如果患者最初或之前给药时对一种或多种药剂具有抗药性或发展为抗药性,则开始第二次或第三次施用根据本发明的组合治疗。患者可以仅接受各药剂的单一疗程或一种、两种或更多种药剂的多个疗程。
在某些情况下,根据本发明的组合疗法因此可以包括初始或附加组合、替代或维持治疗。
在本发明的一个进一步的实施方案中,根据本发明使用的组合、组合物、试剂盒、用途、方法和化合物(包括所有实施方案)用于治疗一种癌症/多种癌症患者(患有如本申请所述的癌症、特别是患有如本申请所述的NSCLC),这些患者尚未经过治疗,即他们的癌症疾病先前尚未得到治疗。在进一步的实施方案中,一种癌症/多种癌症患者(患有如本申请所述的癌症、特别是患有如本申请所述的NSCLC)先前已经用一种或多种免疫检查点抑制剂和/或免疫调节剂例如一种或多种PD-1拮抗剂进行治疗。
本发明不限于本申请所述的具体实施方案的范围。除了本申请描述的那些实施方案之外,对于本领域技术人员而言,本发明的各种修改可以根据本申请的公开内容变得明显。这些修改意在落入所附权利要求的范围内。
本文引用的所有专利申请的全部内容在此都通过引用并入。
参考文献
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方法
实施例1
示例性SMAC模拟物BIA-1与RMP1-14(针对PD-1的小鼠工具抗体)的组合在源自Balb/c小鼠的乳腺癌细胞系EMT6的皮下同源小鼠模型中的抗肿瘤活性
在s.c.细胞系衍生的小鼠乳腺癌(EMT6)同源模型中测试了示例性SMAC模拟物BIA-1作为单一药剂和与RMP1-14(PD-1的小鼠抗体)(BioXCell#BE0146)组合的疗效。
该研究中使用BALB/cJBomTac小鼠。每只小鼠注射1×106个EMT6乳腺癌细胞以建立肿瘤。每周使用卡尺测量肿瘤体积至少三次。当肿瘤达到71-231mm3的中值肿瘤体积时开始治疗并且在33天后终止。
10只荷瘤动物每天用示例性SMAC模拟物BIA-1口服(p.o.)治疗,并且每周使用RMP1-14或两种化合物的组合腹腔注射两次。在媒介物/同种型对照治疗组中使用10只动物。在研究结束时,出于伦理原因基于肿瘤质量(肿瘤≥1.5cm3),对动物实施安乐死。
细胞
EMT6细胞得自ATCC(登记号CRL2755TM)。建立主细胞库(MCB)和工作细胞库(WCB)。将细胞在T175组织培养瓶中于37℃和5%CO2下培养。使用的培养基是Waymouth的MB 752/1,其补充有15%胎牛血清(胎牛血清的特征;Cat No SH30071.03;由Thermo Scientific提供),和2mM L-谷氨酰胺(L-谷氨酰胺200mM(100x);Ref 25030-024;由Life Technologies旗下的Gibco提供)。每两到三天将培养物按比例1:10/1:15分开。
小鼠
小鼠是7-8周龄BALB/cJBomTac,购自Taconic,Denmark。到达动物设施后,允许小鼠在用于实验之前调整至环境条件至少5天。将它们在标准条件下在21.5±1.5℃和55±10%湿度下以10只一组的方式饲养在III型笼盒中。随机提供标准化的辐照饮食(PROVIMI KLIBA)和高压灭菌的自来水。在异氟烷麻醉下皮下植入的微芯片用于识别每只小鼠。笼盒卡显示研究编号、动物编号、化合物和剂量水平、给药途径以及在整个研究期间动物保持的时间表。
给药测试化合物
将BIA-1悬浮于0.5%Natrosol中,并且使用管饲针以每只小鼠10mL/kg的施用体积胃内给药,每天一次。
将PD-1抗体在PBS中稀释并且以每只小鼠10mL/kg的体积腹膜内注射,每周两次。
监测肿瘤生长和疾病进展
用卡尺每周测量肿瘤直径三次(周一、周三和周五)。根据公式“肿瘤体积=长度*直径2*π/6”计算每个肿瘤的体积[以mm3计]。为了监测治疗的副作用,每天检查小鼠的异常情况并且每天测量体重。在研究结束时处死动物。出于伦理原因,在研究期间早期处死具有坏死性肿瘤或肿瘤大小超过1500mm3的动物。
结果
用SMAC模拟物BIA-1作为单一药剂治疗ETM6肿瘤显示出抗肿瘤疗效并且耐受性良好。用针对PD-1的小鼠工具抗体(RMP1-14)治疗导致中度肿瘤生长抑制。与单一药剂施用相比,SMAC模拟物与PD-1拮抗剂的组合导致疗效增加,在所有小鼠中诱导肿瘤消退。结果示于图1中。
实施例2
示例性SMAC模拟物BIA-1和BIA-2作为单一药剂和与RMP1-14(PD-1的小鼠工具抗体)的组合在源自C3H小鼠的膀胱癌细胞系MBT-2的皮下同源小鼠模型中的抗肿瘤活性。
在s.c.细胞系衍生的小鼠膀胱癌(MBT-2)同源模型中测试了示例性SMAC模拟物的BIA-1和BIA-2作为单一药物和与RMP1-14(PD-1的小鼠抗体)(BioXCell#BE0146)的组合的疗效。
该研究中使用C3H小鼠。每只小鼠在右侧腹部皮下接种MBT-2肿瘤细胞(4×105),所述MBT-2肿瘤细胞在与基质胶(1:1)混合的0.1mL PBS中用于肿瘤发展。在接种后第7天,平均肿瘤大小达到83mm3时开始治疗。
每组8只荷瘤小鼠每天用SMAC模拟物口服治疗,每周两次腹膜内注射有RMP1-14或两种化合物的组合。在媒介物/同种型对照治疗组中使用8只动物。对肿瘤大小超过1500mm3的动物实施安乐死,然后死亡。对于基于肿瘤大小(>1500mm3)杀死的动物,肿瘤体积的最后值继续进行检测直至研究结束或直至小于70%的小鼠仍然存活。
细胞
将MBT-2细胞系在补充有10%胎牛血清(FBS)的RPMI-1640中在37℃在5%CO2的气氛中维持为单层培养物。肿瘤细胞每周常规继代培养2次。收获处于指数生长期的细胞并且计数用于肿瘤接种。
小鼠
小鼠是7-8周龄C3H,购自Vital River Laboratory Animal Technology Co.(VR,Beijing,China)。
将小鼠在恒定温度和湿度下保持在独立通气笼盒(IVC)系统中,每个笼盒中有四只动物(-温度:21~25℃,-湿度:59~70%)。笼盒由聚碳酸酯制成。每个笼盒的大小是325mm×210mm×180mm。垫料是玉米芯(AWR Laboratory Animal Product Co.,Ltd)。小鼠饮食为Co60辐射的灭菌干燥颗粒食品(啮齿动物生长和繁殖饮食,Jiangsu ProvinceSynergistic Biological Engineering Co.,LTD)。在整个研究期间,动物可以自由进入。水为反渗透(RO)水,使用前进行高压灭菌。动物可以自由饮用无菌饮用水。每个笼盒的识别标签包含以下信息:动物数量、性别、菌株、接收日期、治疗、研究编号、组编号和治疗的开始日期。动物识别通过耳朵编码(切迹)完成。
给药测试化合物
将SMAC模拟物悬浮于0.5%Natrosol中,并且使用管饲针以每只小鼠10mL/kg的施用体积胃内给药,每天一次。
将PD-1抗体在PBS中稀释并且以每只小鼠10mL/kg的体积腹膜内注射,每周两次。
监测肿瘤生长和疾病进展
在肿瘤细胞接种后,每天检查动物的发病率和死亡率。在常规监测时,检查动物的肿瘤生长和治疗对正常行为例如活动性、食物和水消耗的视觉估计、体重增加/减少(每周测量体重三次)、眼睛/毛发消光的作用和任何其它异常作用。根据每个亚组内的动物数量记录死亡和观察到的临床症状。
使用卡尺每周在两个维度上测量肿瘤体积两次,并且使用以下公式以mm3表示体积:V=0.5a×b2,其中a和b分别是肿瘤的长径和短径。在研究终止时测量肿瘤重量。剂量给药以及肿瘤和体重测量的整个程序在层流柜中进行。
结果
用BIA-1或BIA-2单一疗法治疗MBT-2肿瘤导致肿瘤生长抑制。与单独的单一疗法相比,BIA-1和BIA-2与PD-1拮抗剂RMP1-14的组合产生较大的肿瘤生长抑制。结果示于图2中。
实施例3
示例性SMAC模拟物BIA-1和BIA-2作为单一药剂和与RMP1-14(PD-1的小鼠工具抗体)的组合在C57BL/6J小鼠的Vk12598多发性骨髓瘤可移植模型中的抗肿瘤活性。
在小鼠多发性骨髓瘤(Vk12598)的可移植模型中测试了示例性SMAC模拟物BIA-1和BIA-2作为单一药物和与RMP1-14(PD-1的小鼠抗体)(BioXCell#BE0146)的组合的疗效。
C57BL/6J野生型小鼠通过静脉内注射移入有来自Vk*MYC衍生的Vk12598肿瘤细胞的一百万个脾细胞。在移植后四周开始,每周通过尾部擦伤对受体小鼠进行放血,并且进行血清蛋白电泳(SPEP)和光密度分析以测量M-峰值水平和γ/白蛋白比率,作为肿瘤负荷的量度。
将M-峰值>7g/L的小鼠随机分入媒介物组或治疗组,每个治疗组7只小鼠。每天测量体重。每周进行SPEP,从第0天开始进行测量M-峰值水平,并且在第7天和第14天进行测量M-峰值水平作为第0天水平的分数。
给药测试化合物
将SMAC模拟物悬浮于0.5%Natrosol中,并且使用管饲针以每只小鼠10mL/kg的施用体积胃内给药,每天一次。
将PD-1抗体在PBS中稀释并且以每只小鼠10mL/kg的体积腹膜内注射,每周两次。
结果
通过比较治疗后第14天的M-峰值水平与第0天的M-峰值水平,评价单独的BIA-1和BIA-2以及BIA-1和BIA-2与PD-1拮抗剂的组合的抗肿瘤应答。在2只BIA-1治疗的小鼠(共7只)和7只BIA-2治疗的小鼠(共7只)中观察到应答(>50%的M-峰值降低)。BIA-1和BIA-2的组合分别有7只产生应答(分别共7只)。在媒介物组或抗PD-1治疗组中未观察到应答。结果示于图3中。
实施例4
示例性SMAC模拟物BIA-1对于抗PD1 MK3465刺激抗原特异性T细胞应答的增强活性
测试示例性SMAC模拟物BIA-1和SMAC模拟物LCL 161加强由抗PD1抗体MK3465(帕博利珠单抗)诱导的破伤风特异性CD4记忆T细胞的INFγ产生的刺激的能力。
来自健康供体PBMC(n=4)的T细胞在破伤风类毒素存在下扩增,并且与携带破伤风类毒素的自体成熟树突细胞(DC)共培养3天。在MK3465、BIA-1(500nM)、LCL 161(500nM)或BIA-1(50nM和500nM)+MK3465的组合或LCL 161(50nM、500nM)+MK3465的组合的存在下,第二次重复共培养步骤持续五天。在第二次共培养步骤结束时,通过ELISA分析上清液的INFγ分泌。500nM的BIA-1增强了MK3465刺激破伤风毒素特异性CD4记忆T细胞的INFγ产生的能力,结果示于图4中。
用于这些实验的示例性SMAC模拟物BIA-1是表1中公开的化合物之一。
Claims (18)
1.SMAC模拟物,其用于治疗和/或预防肿瘤或过度增生性疾病、特别是癌症的方法,所述方法包括向有此需要的患者给药所述SMAC模拟物与PD-1拮抗剂的组合,
其中所述SMAC模拟物选自化合物1至26中的任一种
或这些化合物之一的药学上可接受的盐;和
其中所述PD-1拮抗剂选自帕博利珠单抗、纳武单抗、pidilizumab、阿特珠单抗、阿维鲁单抗、德瓦鲁单抗、PDR-001、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
2.根据权利要求1所用的SMAC模拟物,其中将所述SMAC模拟物与所述PD-1拮抗剂同时地、并行地、顺序地、连续地、交替地或分开地给药。
3.治疗和/或预防肿瘤或过度增生性疾病、特别是癌症的方法,其包括向有此需要的患者给药治疗有效量的SMAC模拟物和治疗有效量的PD-1拮抗剂,
其中所述SMAC模拟物选自根据权利要求1所述的化合物1至26中的任一种或这些化合物之一的药学上可接受的盐;和
其中所述PD-1拮抗剂选自帕博利珠单抗、纳武单抗、pidilizumab、阿特珠单抗、阿维鲁单抗、德瓦鲁单抗、PDR-001、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
4.根据权利要求3的方法,其中所述SMAC模拟物与所述PD-1拮抗剂同时地、并行地、顺序地、连续地、交替地或分开地给药。
5.PD-1拮抗剂,其用于治疗和/或预防肿瘤或过度增生性疾病、特别是癌症的方法,所述方法包括向有此需要的患者给药所述PD-1拮抗剂与SMAC模拟物的组合,
其中所述SMAC模拟物选自根据权利要求1所述的化合物1至26中的任一种或这些化合物之一的药学上可接受的盐;和
其中所述PD-1拮抗剂选自帕博利珠单抗、纳武单抗、pidilizumab、阿特珠单抗、阿维鲁单抗、德瓦鲁单抗、PDR-001、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
6.根据权利要求5所用的PD-1拮抗剂,其中将所述PD-1拮抗剂与所述SMAC模拟物同时地、并行地、顺序地、连续地、交替地或分开地给药。
7.SMAC模拟物用于制备用于治疗和/或预防肿瘤或过度增生性疾病、特别是癌症的方法的药物组合物中的用途,
其中所述SMAC模拟物待与PD-1拮抗剂组合使用;
其中所述SMAC模拟物选自根据权利要求1所述的化合物1至26中的任一种或这些化合物之一的药学上可接受的盐;和
其中所述PD-1拮抗剂选自帕博利珠单抗、纳武单抗、pidilizumab、阿特珠单抗、阿维鲁单抗、德瓦鲁单抗、PDR-001、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
8.根据权利要求7所述的用途,其中所述SMAC模拟物待与所述PD-1拮抗剂同时地、并行地、顺序地、连续地、交替地或分开地给药。
9.PD-1拮抗剂用于制备用于治疗和/或预防肿瘤或过度增生性疾病、特别是癌症的方法的药物组合物中的用途,
其中所述PD-1拮抗剂待与SMAC模拟物组合使用;
其中所述SMAC模拟物选自根据权利要求1所述的化合物1至26中的任一种或这些化合物之一的药学上可接受的盐;和
其中所述PD-1拮抗剂选自帕博利珠单抗、纳武单抗、pidilizumab、阿特珠单抗、阿维鲁单抗、德瓦鲁单抗、PDR-001、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
10.根据权利要求9所述的用途,其中所述PD-1拮抗剂待与所述SMAC模拟物同时地、并行地、顺序地、连续地、交替地或分开地给药。
11.药物组合物,其包含:
·SMAC模拟物;
·PD-1拮抗剂;和
·任选地,一种或多种药学上可接受的载体、赋形剂和/或媒介物;
其中所述SMAC模拟物选自根据权利要求1所述的化合物1至26中的任一种或这些化合物之一的药学上可接受的盐;和
其中所述PD-1拮抗剂选自帕博利珠单抗、纳武单抗、pidilizumab、阿特珠单抗、阿维鲁单抗、德瓦鲁单抗、PDR-001、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
12.根据权利要求11所述的药物组合物,其用于治疗和/或预防肿瘤或过度增生性疾病、特别是癌症的方法。
13.试剂盒,所述试剂盒包含:
·第一药物组合物或剂型,所述第一药物组合物或剂型包含SMAC模拟物和任选的一种或多种药学上可接受的载体、赋形剂和/或媒介物;
·第二药物组合物或剂型,所述第二药物组合物或剂型包含PD-1拮抗剂和任选的一种或多种药学上可接受的载体、赋形剂和/或媒介物;
其中所述SMAC模拟物选自根据权利要求1所述的化合物1至26中的任一种或这些化合物之一的药学上可接受的盐;和
其中所述PD-1拮抗剂选自帕博利珠单抗、纳武单抗、pidilizumab、阿特珠单抗、阿维鲁单抗、德瓦鲁单抗、PDR-001、PD1-1、PD1-2、PD1-3、PD1-4和PD1-5。
14.根据权利要求13所述的试剂盒,其用于治疗和/或预防肿瘤或过度增生性疾病、特别是癌症的方法。
15.根据权利要求14所述的试剂盒,其中所述第一药物组合物或剂型待与所述第二药物组合物或剂型同时地、并行地、顺序地、连续地、交替地或分开地给药。
16.根据权利要求13至15中任一项所述的试剂盒,所述试剂盒进一步包含
·包装说明书,所述包装说明书包含用于同时、并行、顺序、连续、交替或分开用于治疗和/或预防有此需要的患者的肿瘤或过度增生性疾病、特别是癌症的印刷说明书。
17.根据权利要求1和2中任一项所用的SMAC模拟物,根据权利要求3和4中任一项所述的方法,根据权利要求5和6中任一项所用的PD-1拮抗剂,根据权利要求7和8中任一项所述的SMAC模拟物的用途,根据权利要求9和10中任一项所述的PD-1拮抗剂的用途,根据权利要求11和12中任一项所述的药物组合物,或根据权利要求13至16中任一项所述的试剂盒,其中待治疗的肿瘤疾病是选自如下的癌症:肺癌、特别是非小细胞肺癌(NSCLC),多发性骨髓瘤(MM),和乳腺癌、特别是三阴性乳腺癌(TNBC)。
18.根据权利要求1和2中任一项所用的SMAC模拟物,根据权利要求3和4中任一项所述的方法,根据权利要求5和6中任一项所用的PD-1拮抗剂,根据权利要求7和8中任一项所述的SMAC模拟物的用途,根据权利要求9和10中任一项所述的PD-1拮抗剂的用途,根据权利要求11和12中任一项所述的药物组合物,或根据权利要求13至16中任一项所述的试剂盒,其中所述癌症是非小细胞肺癌(NSCLC)、优选非小细胞肺癌腺癌。
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CN112266936A (zh) * | 2020-10-16 | 2021-01-26 | 中山大学 | Chaf1a作为hiv-1潜伏感染激活靶点的应用 |
CN114533879A (zh) * | 2020-11-19 | 2022-05-27 | 广州顺健生物医药科技有限公司 | 治疗癌症的联合疗法 |
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MX2019011572A (es) | 2019-11-18 |
CA3053226A1 (en) | 2018-10-04 |
US20200046684A1 (en) | 2020-02-13 |
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