CN116173220A - Ctla-4抑制剂和非类固醇抗炎药的抗癌联合治疗方法 - Google Patents
Ctla-4抑制剂和非类固醇抗炎药的抗癌联合治疗方法 Download PDFInfo
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Abstract
本发明提供了CTLA‑4抑制剂和非类固醇抗炎药的抗癌联合治疗方法，具体地，本发明提供了一种产品组合，包括：(i)第一药物组合物，所述第一药物组合物含有(a)第一活性成分，所述第一活性成分为CTLA‑4抑制剂，以及药学上可接受的载体；和(ii)第二药物组合物，所述第二药物组合物含有(b)第二活性成分，所述第二活性成分为非类固醇抗炎药，以及药学上可接受的载体；其中，所述的第一药物组合物和第二药物组合物为不同的药物组合物，或同一药物组合物。本发明的产品组合可协同治疗肿瘤。
Description
技术领域
本发明涉及生物医药领域，具体地，涉及CTLA-4抑制剂和非类固醇抗炎药的抗癌联合治疗方法。
背景技术
重组抗CTLA-4全人源单克隆抗体，其通过与T淋巴细胞膜上CTLA-4高亲和力的结合，阻断CTLA-4于B7-1/B7-2的结合，使B7-1/B7-2能与T细胞的共刺激分子信号分子CD28结合，增强和维持抗肿瘤淋巴细胞共刺激信号的激活状态，促进淋巴细胞的激活、增殖以及浸润肿瘤组织，最终杀伤肿瘤细胞。
目前免疫检查点抑制剂治疗虽然在多个癌种中取得了一定的突破，但是单药免疫治疗的疗效有待提高，CTLA4抑制剂联合PD1抑制剂的组合虽然显著提高了患者的缓解率及生存预后，但是联合用药的毒性也显著增加。目前临床上仍在寻找能辅助免疫治疗的药物，在进一步提高疗效的同时，不增加严重的不良反应。
以布洛芬、阿司匹林为代表的NSAIDs类药物，从机制上NSAIDs可以通过抑制环氧化酶(COX)通路进而减少前列腺素E2(PGE2)的产生，既往认为COX2通路与组织充血、水肿、外周神经疼痛有关。
本领域迫切需要探索与免疫治疗协同的更有效、更安全的联合用药组合。
发明内容
本发明的目的在于开发与免疫治疗协同的更有效、更安全的联合用药组合。本发明的目的在于提供一种治疗肿瘤的联合用药物，以提高抗CTLA-4抗体单独用药的治疗效果。
本发明第一方面提供了一种产品组合，包括：
(i)第一药物组合物，所述第一药物组合物含有(a)第一活性成分，所述第一活性成分为CTLA-4抑制剂，以及药学上可接受的载体；和
(ii)第二药物组合物，所述第二药物组合物含有(b)第二活性成分，所述第二活性成分为非类固醇抗炎药，以及药学上可接受的载体；
其中，所述的第一药物组合物和第二药物组合物为不同的药物组合物，或同一药物组合物。
在另一优选例中，所述抑制剂选自下组：抗体、小分子化合物、microRNA、siRNA、shRNA、或其组合。
在另一优选例中，所述抗体包括KD6001、伊匹木单抗(Ipilimumab)、曲美木单抗(Tremelimmab)、泽弗利单抗(Zalifrelimab)、Quavonlimab、REGN4659、YH001。
在另一优选例中，KD6001的抗体序列如PCT/CN2015/095072中所示。
在另一优选例中，所述非类固醇抗炎药为非甾体类抗炎药(NSAIDs)。
在另一优选例中，所述非类固醇抗炎药选自下组：水杨酸类药物、苯胺类药物、乙酸类药物、苯乙酸类药物、丙酸类药物、昔康类药物、昔布类药物、或其组合。
在另一优选例中，所述水杨酸类药物包括阿司匹林、贝诺酯。
在另一优选例中，所述苯胺类药物包括对乙酰氨基酚、尼美舒利。
在另一优选例中，所述乙酸类药物包括吲哚美辛。
在另一优选例中，所述苯乙酸类药物包括双氯芬酸、舒林酸。
在另一优选例中，所述丙酸类药物包括布洛芬、萘普生、洛索洛芬。
在另一优选例中，所述昔康类药物包括吡罗昔康、美洛昔康。
在另一优选例中，所述昔布类药物包括塞来昔布、伐地昔布、罗非昔布、艾瑞昔布、依托考昔、尼美舒利、帕瑞昔布。
在另一优选例中，所述组分(i)与组分(ii)的重量比为1:2-500，较佳地，1:2-200，更佳地，1:2-100，更佳地，1:2-50，更佳地，1:2-10，更佳地，1：2-6。
在另一优选例中，所述产品组合中，所述CTLA-4抑制剂的含量为1％－99％，较佳地，1％－60％，更佳地，1％－30％。
在另一优选例中，所述产品组合中，所述非类固醇抗炎药的含量为1％－99％，较佳地，10％－90％，更佳地，50％－90％。
在另一优选例中，所述产品组合中，所述组分(i)和组分(ii)占所述产品组合总重的0.01-99.99wt％，较佳地0.1-90wt％，更佳地1-80wt％。
在另一优选例中，所述的药物组合物的剂型包括注射剂型、和口服剂型。
在另一优选例中，所述口服剂型包括片剂、胶囊剂、膜剂、和颗粒剂。
在另一优选例中，所述的药物组合物的剂型包括缓释型剂型、和非缓释型剂型。
本发明第二方面提供了一种组合物，所述组合物包括：
(i)CTLA-4抑制剂；
(ii)非类固醇抗炎药；和
(iii)药学上可接受的载体。
在另一优选例中，所述组合物中，所述组分(i)、组分(ii)占所述药盒总重的0.01-99.99wt％，较佳地0.1-90wt％，更佳地1-80wt％。
在另一优选例中，所述组合物还包括其他治疗肿瘤的药物。
在另一优选例中，所述肿瘤包括实体瘤。
在另一优选例中，所述肿瘤选自下组：结直肠癌、非小细胞肺癌、小细胞肺癌、头颈部鳞状细胞癌、肝癌、宫颈癌、B细胞淋巴瘤、多发性骨髓癌、非霍奇金淋巴瘤、黑色素瘤、卵巢癌、乳腺癌、前列腺癌、胸膜间皮瘤、肾癌、尿路上皮癌、鼻咽癌、子宫内膜癌、胶质瘤、胃癌、食管癌、食管-胃交界癌、甲状腺癌、胰腺癌、胆管癌、原发性脑癌、或其组合。
在另一优选例中，所述其他治疗肿瘤的药物选自下组：免疫检查点抑制剂药物、免疫激动剂、或其组合。
在另一优选例中，所述免疫检查点抑制剂药物包括PD-1,4-1BB，IDO(IDO2和TDO)，LAG-3，OX40，GITR，CD27，CD30，TIM-3，CD3，ICOS，CD73/CD39，CD2/SLAM家族，PD-L1，CD47，TIGIT，CD73，CD33，CEACAM1/5/6，STING，WNT/Beta catenin，B7-H3，VISITA。
在另一优选例中，所述免疫激动剂包括CD40，CSF1R，TLR家族及其受体IFN，IL因子及其受体如IL-2，IL-15，IL-21，GMCSF/GMCSFR，RIG-1，TNF家族，CD25，趋化因子CCR和CXC，NKG2D。
本发明第三方面提供了一种药盒，包括：
(a1)第一容器，以及位于所述第一容器中的CTLA-4抑制剂，或含有CTLA-4抑制剂的药物；
(b1)第二容器，以及位于所述第二容器中的非类固醇抗炎药，或含有非类固醇抗炎药的药物。
在另一优选例中，所述的第一容器和第二容器是相同或不同的容器。
在另一优选例中，所述的第一容器的药物是含CTLA-4抑制剂的单方制剂。
在另一优选例中，所述的第二容器的药物是含非类固醇抗炎药的单方制剂。
在另一优选例中，所述药物的剂型为口服剂型或注射剂型。
在另一优选例中，所述的试剂盒还含有说明书。
在另一优选例中，所述说明书记载了如下说明：
(a)将CTLA-4抑制剂和非类固醇抗炎药联用协同治疗肿瘤的方法。
本发明第四方面提供了一种组合的用途，所述组合包括CTLA-4抑制剂和非类固醇抗炎药，用于制备一药物组合物或药盒，所述药物组合物或药盒用于治疗肿瘤。
在另一优选例中，所述肿瘤选自下组：结直肠癌、非小细胞肺癌、小细胞肺癌、头颈部鳞状细胞癌、肝癌、宫颈癌、B细胞淋巴瘤、多发性骨髓癌、非霍奇金淋巴瘤、黑色素瘤、卵巢癌、乳腺癌、前列腺癌、胸膜间皮瘤、肾癌、尿路上皮癌、鼻咽癌、子宫内膜癌、胶质瘤、胃癌、食管癌、食管-胃交界癌、甲状腺癌、胰腺癌、胆管癌、原发性脑癌、或其组合。
在另一优选例中，所述CTLA-4抑制剂的作用浓度为0.1-30mg/kg，较佳地，0.2-20mg/kg，较佳地，0.3-10mg/kg。
在另一优选例中，所述非类固醇抗炎药的作用浓度为0.1-100mg/kg，较佳地，0.3-30mg/kg，较佳地，1-15mg/kg。
在另一优选例中，所述药物组合物或药盒包括(a)CTLA-4抑制剂和非类固醇抗炎药；和(b)药学上可接受的载体。
在另一优选例中，所述药物组合物或药盒中，所述CTLA-4抑制剂和非类固醇抗炎药占所述所述药物组合物或药盒总重的0.01-99.99wt％,较佳地0.1-90wt％，更佳地1-80wt％。
在另一优选例中，所述药物组合物或药盒还包括其他治疗肿瘤的药物。
在另一优选例中，所述其他治疗肿瘤的药物选自下组：免疫检查点抑制剂药物、免疫激动剂、或其组合。
本发明第五发明提供了一种治疗肿瘤的方法，包括：
给需要的对象施用CTLA-4抑制剂和非类固醇抗炎药，或本发明第一方面所述的产品组合或本发明第二方面所述的组合物或本发明第三方面所述的药盒。
在另一优选例中，所述对象包括患有肿瘤的人或非人哺乳动物。
在另一优选例中，所述非人哺乳动物包括啮齿动物和灵长目动物，优选小鼠、大鼠、兔、猴。
在另一优选例中，所述CTLA-4抑制剂的施用剂量为0.1-30mg/kg，较佳地，0.2-20mg/kg，更佳地，0.3-10mg/kg。
在另一优选例中，所述非类固醇抗炎药的施用剂量为0.1-100mg/kg，较佳地，0.3-30mg/kg，更佳地，1-15mg/kg。
在另一优选例中，所述CTLA-4抑制剂施用频率为每周1次或每两周1次或每三周一次或每6周一次或每12周一次或每24周一次，较佳的，每2-6周一次。
在另一优选例中，所述CTLA-4抑制剂的施用时间为1－4000天，较佳地为1－1000天，最佳地为1－365天。
在另一优选例中，所述非类固醇抗炎药的施用频率为每天1-6次，较佳地，每天2-4次。
在另一优选例中，所述非类固醇抗炎药的施用时间为1－4000天，较佳地为1－1000天，最佳地为1－365天。
在另一优选例中，所述CTLA-4抑制剂与非类固醇抗炎药同时或先后施用。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了KD6001与布洛芬联用对荷瘤MC38小鼠体重的影响。结肠癌细胞MC38在接入小鼠皮下后在D8、D11、D15、D19，共4次腹腔注射给予KD6001、或PBS，在D8至D17天每天两次灌胃给予布洛芬。每周称量小鼠体重2次。各组小鼠体重数值以“算术平均值±标准误差”形式呈现。对各时间点小鼠个体体重数据进行组间统计学差异分析，低中高剂量组分别与对照组经单因素方差分析，各剂量组P值均大于0.05。
图2显示了KD6001与布洛芬联用对荷瘤MC38小鼠肿瘤体积的影响。结肠癌细胞MC38在接入小鼠皮下后在D8、D11、D15、D19，共4次腹腔注射给予KD6001、或PBS，在D8至D17天每天两次灌胃给予布洛芬。每周测量肿瘤体积2次。在D26结束实验。A：各组小鼠肿瘤平均体积变化曲线；B：实验结束时肿瘤体积和重量；C：实验结束后处死小鼠，剥离肿瘤拍照。对各实验结束时(D26)小鼠个体肿瘤体积数据进行组间统计学差异分析，各给药组分别与对照组经T-test分析，KD6001 50μg+布洛芬200μg组、KD6001 50μg+布洛芬60μg组小鼠肿瘤体积与对KD6001 50μg单药治疗组的相比具有统计学意义的显著差异。*p<0.05。
具体实施方式
本发明人通过广泛而深入的研究，首次意外发现，将本发明的CTLA-4抑制剂和非类固醇抗炎药联用，可有效治疗肿瘤，并具有协同作用，此外，还可以有效提高抗CTLA-4抗体单药的抗肿瘤效果。在此基础上，本发明人完成了本发明。
如本文所用，Quavonlimab由默沙东公司研发，序列信息由PCT公开文本WO2020185722披露。
如本文所用，REGN4659由再生元制药公司(Regeneron Pharmaceuticals)研发，序列信息由PCT公开文本WO2019023482披露。
如本文所用，YH001由祐和医药研发，序列信息由中国申请CN111406069披露。
CTLA-4抑制剂
CTLA-4是T淋巴细胞上的免疫检查点受体，通过和抗原提呈细胞上的B7-1(CD80)和B7-2(CD86)的结合，抑制T细胞的过度活化。CTLA-4抑制剂，比如CTLA-4抗体，能够特异性结合T淋巴细胞上的CTLA-4，阻断CTLA-4与B7分子结合，拮抗CTLA-4抑制T细胞的活化作用，从而使T淋巴细胞共刺激因子CD28和抗原提呈细胞上的B7分子结合，持续激活T淋巴细胞，从而发挥其抗肿瘤作用。
在本发明中，CTLA-4抑制剂选自下组：抗体、小分子化合物、microRNA、siRNA、shRNA、或其组合。
在有一些实施方式中，CTLA-4抑制剂为CTLA-4抗体，包括KD6001、伊匹木单抗(Ipilimumab)、曲美木单抗(Tremelimmab),泽弗利单抗(Zalifrelimab)、Quavonlimab、REGN4659、YH001，优选KD6001，其抗体序列如PCT/CN2015/095072中以及本发明的实施例的表1中所示。
非类固醇抗炎药
非类固醇抗炎药也称为非甾体类抗炎药(NSAIDs)，是一类具有解热、镇痛，多数还有抗炎、抗风湿作用的药物，对于一些风湿性疾病，如早期类风湿关节炎、老年性关节炎及早期强直性脊柱炎等是首选药物。研究表明，环氧合酶(COX)在肿瘤的发生、发展及预后等方面起着重要作用，非类固醇抗炎可以通过抑制COX的合成而促进癌细胞凋亡，抑制肿瘤血管生成等，因此它不仅可用于肿瘤的化学治疗，还很有可能用于临床治疗。
在一优选实施方式中，非类固醇抗炎选自下组：水杨酸类药物、苯胺类药物、乙酸类药物、苯乙酸类药物、丙酸类药物、昔康类药物、昔布类药物、或其组合。
其中，水杨酸类药物包括：阿司匹林、贝诺酯；苯胺类药物包括：对乙酰氨基酚、尼美舒利；乙酸类药物包括：吲哚美辛；苯乙酸类药物包括：双氯芬酸、舒林酸；
丙酸类药物包括：布洛芬、萘普生、洛索洛芬；昔康类药物包括：吡罗昔康、美洛昔康。
昔布类药物包括：塞来昔布、伐地昔布、罗非昔布、艾瑞昔布、依托考昔、尼美舒利、帕瑞昔布。
本发明的研究表明，本发明的非类固醇抗炎药与CTLA-4抑制剂，比如CTLA-4抗体的联合使用治疗肿瘤可以发挥协同增效的作用，有效提高抗CTLA-4抗体单药的抗肿瘤效果，将非类固醇抗炎药与CTLA-4抑制剂，比如CTLA-4抗体制成联合用药物的治疗肿瘤的疗效优良，临床应用前景良好。
组合物和施用方法
如本文所用，术语“组合物”包括(a1)第一活性成分，所述第一活性成分为CTLA-4抑制剂；和(a2)第二活性成分，所述第二活性成分为非类固醇抗炎药；和(b)药学上可接受的载体。此外，所述的组合物包括药物组合物。
通常，可将本发明的活性成分配制于无毒的、惰性的和药学上可接受的载体介质。配制好的药物组合物可以通过常规途径进行给药，其中包括(但并不限于)：口服、肌内、腹膜内、静脉内、皮下、皮内、或局部给药。
本发明还提供了一种药物组合物，它含有安全有效量的本发明的活性成分以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于)：盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。药物制剂应与给药方式相匹配。本发明的药物组合物可以被制成针剂形式，例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。诸如片剂和胶囊之类的药物组合物，可通过常规方法进行制备。药物组合物如针剂、溶液、片剂和胶囊宜在无菌条件下制造。活性成分的给药量是治疗有效量，例如每天约1微克-10毫克/千克体重，优选地，EP4受体拮抗剂的用量可以为：成年人每日0.1～2000mg，优选1～300mg/天。PD-1抑制剂的用量可以为：成年人每两周0.1～2000mg，优选1～300mg/两周。作为肿瘤协同治疗的药物，可以制成口服和非口服制剂。口服给药可制成片剂、散剂、颗粒剂、胶囊剂等常用剂型，所用的赋型剂可以为淀粉、乳糖、蔗糖、甘露糖、羟甲基纤维素等中的一种或几种。崩解剂可以为马铃薯淀粉、羟甲基纤维素等中的一种或几种。粘合剂可以为阿拉伯胶、玉米淀粉、明胶、糊精等中的一种或几种。口服制剂除上述剂型外，还可以制成乳剂、糖浆剂等。
非口服制剂可以制成注射剂，可以与注射用水、生理盐水、葡萄糖水制成注射剂，也可以在其中加入一定比例的乙醇、丙醇、乙二醇等。此外也可制成滴鼻剂、喷雾剂、直肠栓剂、直肠保留灌肠液等常用剂型。
此外，本发明的活性成分还特别适合与其他治疗肿瘤的药物(如免疫检查点抑制剂药物、免疫激动剂)联合使用，从而更有效的抑制肿瘤。
药盒
本发明还提供了一种药盒，所述的药盒含有：
(a1)第一容器，以及位于所述第一容器中的CTLA-4抑制剂，或含有CTLA-4抑制剂的药物；
(b1)第二容器，以及位于所述第二容器中的非类固醇抗炎药，或含有非类固醇抗炎药的药物。
在一优选实施方式中，所述的第一容器和第二容器是相同或不同的容器。
所述含有CTLA-4抑制剂的制剂可以是含有CTLA-4抑制剂的单元剂型，所述含有非类固醇抗炎药的制剂可以是含有非类固醇抗炎药的单元剂型。
如本文所用，术语“单元剂型”是指为了服用方便，将组合物制备成单次服用所需的剂型，包括但不限于各种固体剂(如片剂)、液体剂、胶囊剂、缓释剂。
在另一优选例中，所述说明书记载了如下使用方法：
(I)给需要的对象同时施用含有CTLA-4抑制剂的制剂和含有非类固醇抗炎药的制剂；和任选的(II)重复步骤(I)-(II)。
本发明制剂可以每一天服用三次到每二十天服用一次，或者以缓释方式每十天服用一次。优选的方式是每天服用一次，因为这样便于病人坚持，从而显著提高病人服药的顺应性。
服用时，极大多数病例一般每天应用的总剂量应低于(或少数病例等于或略大于)各个单药的每天常用剂量，当然，所用的活性成分的有效剂量可随给药的模式和待治疗的疾病的严重程度等而有所变化。
本发明的主要优点包括：
(1)本发明首次发现，将本发明的CTLA-4抑制剂和非类固醇抗炎药联用，可有效治疗肿瘤，并具有协同作用，此外，还可以有效提高抗CTLA-4抗体单药的抗肿瘤效果。
(2)本发明首次发现，本发明的非类固醇抗炎药(如布洛芬)与CTLA-4抑制剂(比如抗CTLA-4单克隆抗体)的联合使用治疗肿瘤可以发挥协同增效的作用，有效提高抗CTLA-4抗体单药的抗肿瘤效果，将非类固醇抗炎药(如布洛芬)与CTLA-4抑制剂(比如抗CTLA-4单克隆抗体)制成联合用药物的疗效优良，临床应用前景良好。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
如无特别说明，则本发明说明书中的材料和试剂均为市售产品。
实施例1联合疗法(抗CTLA-4抗体和非类固醇抗炎药布洛芬)对小鼠实体癌(以结肠癌细胞MC38为例)的体内药效学研究
1.材料：
药品：抗CTLA-4抗体：KD6001注射液，上海赛金生物医药有限公司，批号20180201；其序列如PCT/CN2015/095072中所示。序列的具体信息如表1所示。
表1 KD6001的序列信息
布洛芬混悬液：上海强生制药有限公司，规格100ml:2g/瓶 批号 190121046
细胞株：结肠癌细胞MC38，上海南方模式生物科技股份有限公司
动物：人CTLA-4基因敲入(knock in)小鼠
2.实验方法
2.1给药制剂配制：
用无菌PBS配制0.25mg/ml的CTLA-4抗体(KD6001)注射液
用无菌注射用水配制0.1mg/ml、0.3mg/ml和1mg/ml的布洛芬混悬液
2.2MC38细胞培养：
小鼠结肠癌细胞MC38培养在含10％FBS的DMEM培养基或含10％FBS的DMEM/F12培养基中，每周传代2次。在给小鼠接种当天，用胰酶处理细胞，收集在50ml离心管里，离心沉淀细胞，弃上清，用PBS洗细胞2次，最后悬浮细胞在PBS里，细胞密度为5×106cells/ml。
2.3小鼠皮下移植鼠结肠癌细胞MC38：
把收集到的细胞置于冰上，带到小鼠饲养场所，每只小鼠背部皮下注射0.1ml细胞悬液，含5×105个细胞。
2.4小鼠给药
小鼠给药方式为腹腔注射，每只小鼠给药容积为0.2ml。在D8、D12、D15、D19共给药4次。D8-D19布洛芬以灌胃方式给药，给药体积为0.2ml，每天两次。每周测量小鼠体重2次和肿瘤体积2次(给药期间在给药前测量体重及肿瘤体积)，(肿瘤体积V(mm3)＝1/2×肿瘤长径a(mm)×肿瘤短径b2(mm))。具体的实验分组如表2所示。
表2给药剂量分组表
2.5统计分析
实验组与对照组的小鼠体重数据、肿瘤体积、肿瘤重量数据采用(算术平均值±标准误差)的形式表示。对组间数据进行T-test分析，判断组间数据是否具有显著差异。
3.实验结果
3.1小鼠体重监测结果
各组小鼠平均体重变化见图1。对各时间点小鼠个体体重数据进行组间统计学差异分析，各组分别与对照组经单因素方差分析，各剂量组P值均大于0.05。在本实验条件下，药物联用高中低剂量组小鼠分别给予KD6001 2.5mg/kg+布洛芬10mg/kg、KD6001 2.5mg/kg+布洛芬3mg/kg、KD6001 2.5mg/kg+布洛芬1mg/kg对荷瘤MC38小鼠的体重没有影响。实验结果表明，在本实验条件下，KD6001和布洛芬联用对小鼠没有明显的毒性。
3.2小鼠肿瘤体积监测结果
图2A显示了各组小鼠肿瘤平均体积在实验过程中的变化。从D15(第3次给药前)开始，3个联合给药组的小鼠肿瘤平均体积开始表现出明显小于其它组的小鼠肿瘤平均体积，尤其是显著小于对照组。D26(实验结束)，对照组小鼠的肿瘤平均体积约为1908.6mm3，单药治疗的KD6001 2.5mg/kg组、布洛芬10mg/kg、布洛芬3mg/kg、布洛芬1mg/kg组小鼠的肿瘤平均体积分别为1763.3mm3、1189.6mm3、1975.8mm3、1344.2mm3；联合给药治疗的KD60012.5mg/kg+布洛芬10mg/kg、KD6001 2.5mg/kg+布洛芬3mg/kg、KD6001 2.5mg/kg+布洛芬1mg/kg组小鼠的肿瘤平均体积分别为419.6mm3、704.2mm3、872.8mm3(图2B左)。在实验结束时(D26)各组小鼠肿瘤的重量显示在图2B(右)。与单药KD6001的肿瘤抑制效果相比，KD6001联合10mg/kg和联合3mg/kg布洛芬的肿瘤抑制效果具有显著的差异(p值分别小于0.01和0.05)(图2B)。图2C显示了各组小鼠剥离下来的肿瘤照片。
不同剂量的布洛芬与固定剂量的KD6001(KD6001 2.5mg/kg)联用均显示出抗肿瘤作用的叠加效应，并且叠加效应随布洛芬联用剂量的增加而增加，布洛芬高中低剂量与KD6001联用组的肿瘤平均体积显著小于KD6001单药治疗组。
对剂量组与对照组之间肿瘤体积大小进行的统计学差异分析，各剂量组分别与对照组进行小鼠个体肿瘤体积数据进行T-test分析，结果显示联合用药组小鼠肿瘤体积与PBS组相比，具有统计学意义的显著差异(p<0.05)。联合给药组与KD6001单药治疗组进行小鼠个体肿瘤体积数据进行T-test分析，结果显示联合给药组与单药治疗组相比，同样具有统计学意义的显著差异(p<0.05)。
表3为本实验剂量组的相对肿瘤体积(RTV)和相对肿瘤增殖率(T/C％)结果。从相对肿瘤体积(RTV)和相对肿瘤增殖率(T/C％)来看，试验结束时(D26)单药治疗的KD60012.5mg/kg组、布洛芬10mg/kg组小鼠的肿瘤相对抑制率(T/C)分别为112.3％、68.1％；联合给药治疗的KD6001 2.5mg/kg+布洛芬10mg/kg、KD6001 2.5mg/kg+布洛芬3mg/kg、KD60012.5mg/kg+布洛芬1mg/kg组小鼠的T/C在D26时，分别为31.7％、43.0％、54.6％。三个不同剂量的联合给药治疗的抗肿瘤效果均优于单药治疗组，显示出KD6001与布洛芬联合用药具有协同效应，最佳效果为KD6001 2.5mg/kg+布洛芬10mg/kg，KD6001和布洛芬的重量比为1：4。
表3相对肿瘤体积(RTV)和相对肿瘤增殖率(T/C)
V8代表MC38细胞接种到小鼠后第8天时(D8，第1次给药前)的肿瘤平均体积，Vt表示所示时间的肿瘤平均体积。Ibuprofen：布洛芬；RTV：相对肿瘤体积；T/C：相对于PBS组的肿瘤增殖率
4.实验结论
本实验通过腹腔注射KD6001和灌胃给予布洛芬的联合给药的方式，给予荷结肠癌MC38小鼠KD6001每周2次，共给药4次；布洛芬每天给药2次，共给药12天，同时设置KD6001、布洛芬单药给药组和PBS阴性对照组，考察KD6001、布洛芬联合用药在小鼠结肠癌MC38模型体内抗肿瘤效果的药物联用是否具有协同效应。
单药KD6001在2.5mg/kg剂量下(腹腔注射)对肿瘤生长没有影响(RTV为112.3％)，抑制效果为0。单独应用布洛芬在剂量10mg/kg时的RTV为68.1％，对肿瘤的生长有部分抑制效果(约30％的抑制效果)，而KD6001(剂量为2.5mg/kg)和10mg/kg布洛芬联用时，其RTV为31.7％，抑制效果达到约70％，显示出KD6001与布洛芬在抑制肿瘤生长方面具有协同效果。KD6001(剂量为2.5mg/kg)在联合中低剂量(比如，剂量为1mg/kg或3mg/kg)布洛芬时，抑制肿瘤生长效果也都由于布洛芬单独应用或KD6001单独应用，也都显示了KD6001与布洛芬在抑制肿瘤生长方面的协同作用。
综上所示，在本实验条件下布洛芬同KD6001联用抗肿瘤作用具有协同效应。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
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<110> 上海赛金生物医药有限公司
<120> CTLA-4抑制剂和非类固醇抗炎药的抗癌联合治疗方法
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Claims (10)
1.一种产品组合，其特征在于，包括：
(i)第一药物组合物，所述第一药物组合物含有(a)第一活性成分，所述第一活性成分为CTLA-4抑制剂，以及药学上可接受的载体；和
(ii)第二药物组合物，所述第二药物组合物含有(b)第二活性成分，所述第二活性成分为非类固醇抗炎药，以及药学上可接受的载体；
其中，所述的第一药物组合物和第二药物组合物为不同的药物组合物，或同一药物组合物。
2.如权利要求1所述的产品组合，其特征在于，所述抑制剂选自下组：抗体、小分子化合物、microRNA、siRNA、shRNA、或其组合。
3.如权利要求2所述的产品组合，其特征在于，所述抗体包括KD6001、伊匹木单抗(Ipilimumab)、曲美木单抗(Tremelimmab)、泽弗利单抗(Zalifrelimab)、Quavonlimab、REGN4659、YH001。
4.如权利要求1所述的产品组合，其特征在于，所述非类固醇抗炎药为非甾体类抗炎药(NSAIDs)。
5.如权利要求1所述的产品组合，其特征在于，所述组分(i)与组分(ii)的重量比为1:2-500，较佳地，1:2-200，更佳地，1:2-100，更佳地，1:2-50，更佳地，1:2-10，更佳地，1：2-6。
6.一种组合物，其特征在于，所述组合物包括：
(i)CTLA-4抑制剂；
(ii)非类固醇抗炎药；和
(iii)药学上可接受的载体。
7.如权利要求6所述的组合物，其特征在于，所述组合物还包括其他治疗肿瘤的药物。
8.一种药盒，其特征在于，包括：
(a1)第一容器，以及位于所述第一容器中的CTLA-4抑制剂，或含有CTLA-4抑制剂的药物；
(b1)第二容器，以及位于所述第二容器中的非类固醇抗炎药，或含有非类固醇抗炎药的药物。
9.一种组合的用途，其特征在于，所述组合包括CTLA-4抑制剂和非类固醇抗炎药，用于制备一药物组合物或药盒，所述药物组合物或药盒用于治疗肿瘤。
10.如权利要求9所述的用途，其特征在于，所述肿瘤选自下组：结直肠癌、非小细胞肺癌、小细胞肺癌、头颈部鳞状细胞癌、肝癌、宫颈癌、B细胞淋巴瘤、多发性骨髓癌、非霍奇金淋巴瘤、黑色素瘤、卵巢癌、乳腺癌、前列腺癌、胸膜间皮瘤、肾癌、尿路上皮癌、鼻咽癌、子宫内膜癌、胶质瘤、胃癌、食管癌、食管-胃交界癌、甲状腺癌、胰腺癌、胆管癌、原发性脑癌、或其组合。
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