CN113116881A - 一种用于治疗肿瘤的药物组合及其应用 - Google Patents
一种用于治疗肿瘤的药物组合及其应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一种用于治疗肿瘤的药物组合及其应用。
背景技术
恶性肿瘤的精准治疗是肿瘤药物发展的必然趋势,也是今后的发展方向。聚腺苷二磷酸核糖聚合酶(PARP)是近年体现肿瘤精准治疗理念的热点药物靶标,其抑制剂通过抑制DNA碱基切除修复(BER)通路关键酶PARP1/2,与DNA同源重组修复通路缺陷(HRD)包括BRCA1/2、PTEN、EWS-FLI等产生协同致死效应。由于HRD仅发生于肿瘤细胞,正常细胞的HR功能正常,因此PARP抑制剂对HR通路缺陷肿瘤具有高度选择性。2014年PARP抑制剂奥拉帕利(olaparib)同时在欧盟和美国被批准上市用于晚期卵巢癌的治疗,标志着PARP抑制剂作为抗肿瘤靶点和协同致死理论的可行性首次在临床确立。目前,全球范围共有4个PARP抑制剂上市,奥拉帕利在2018年进入了中国市场。而中国原创的PARP抑制剂目前无新药上市,少数几个PARP抑制剂处于临床起步阶段。
在专利WO2013117120中公开的盐酸美呋哌瑞(其结构式为),结构新颖,其母核2-芳基呋喃广泛存在于活性天然产物中,也是药物化学优势结构之一,成药前景好。该PARP抑制剂具有水溶性好(>35mg/ml,比奥拉帕尼高350倍以上)、合成工艺简洁、制剂简单稳定性好、药代性质优异、组织分布高、易透过血脑屏障等优势。这些特征为盐酸美呋哌瑞治疗多种恶性肿瘤提供了重要基础。
肿瘤免疫治疗是通过调动机体的免疫系统,增强抗肿瘤免疫力,从而抑制和杀伤肿瘤细胞。肿瘤免疫治疗是当前肿瘤治疗领域中最具前景的研究方向之一。PD-1(programmed death-1)是在凋亡的T细胞杂交瘤中得到的,由于其和细胞凋亡相关而被命名为程序性死亡PD-1受体,PD-1程序性死亡受体是一种重要的免疫抑制分子,为CD28超家族成员。PD-1主要在激活的T细胞和B细胞中表达,是激活型T细胞的一种表面受体,PD-1有两个配体,分别是PD-L1(B7-H1)和PD-L2(B7-DC)。机体内的肿瘤微环境会诱导浸润的T细胞高表达PD-1分子,肿瘤细胞会高表达PD-1的配体PD-L1和PD-L2,导致肿瘤微环境中PD-1通路持续激活,PD-L1与PD-1联接后,T细胞功能被抑制,不能向免疫系统发出攻击肿瘤的信号。PD-1抑制剂,包括PD-1抗体和PD-L1抗体,是一种肿瘤免疫治疗新药。不同于手术、放化疗和靶向药,PD-1抑制剂本身并不能直接杀伤癌细胞,而是通过激活病人自身的免疫系统来抗癌。
截止目前,已有5种PD-1/PD-L1抑制剂在美欧等几十个国家上市,包括2种PD-1抗体和3种PD-L1抗体,分别为Opdivo(Nivolumab)、Keytruda(Pembrolizumab)、Tecentriq(Atezolizumab)、Imfinzi(Durvalumab)、Bavencio(Avelumab),其中,Opdivo和Keytruda已经先后在中国国内上市。此外,4款来自国内药企的PD-1也已经上市,分别是君实的特瑞普利单抗(拓益),信达的信迪利单抗(达伯舒),恒瑞的卡瑞利珠单抗(艾瑞卡),以及百济神州的替雷利珠单抗(百泽安)。
在2017年举办的圣安东尼奥乳腺癌大会上,研究者公布了一个重磅的研究成果:MEDIOLAⅡ期试验是一个PD-L1抗体Imfinzi(Durvalumab)联合PARP抑制剂Olaparib(奥拉帕利,Lynparza),用于BRCA基因突变的、HER2扩增阴性的晚期乳腺癌患者的临床试验。数据显示,12周的疾病控制率为80%,28周的有效率为63%,28周的中位DoR为9.2个月,28周的中位PFS为8.2个月,28周的疾病控制率为50%。优于此前接受Olaparib单药治疗的患者,其有效率为59.9%、中位PFS为7.0个月。奥拉帕尼相关的最常见3级不良反应有,贫血(12%)和中性粒细胞减少(6%);durvalumab相关的最常见的3级不良反应是胰腺炎(6%)。
2018年美国妇科肿瘤学年会(SGO)上,TOPACIO研究(PARP抑制剂Niraparib联合PD-1抑制剂Keytruda)的结果被报道,显示对铂类耐药/难治性卵巢癌和三阴乳腺癌患者,PARP抑制剂联合PD-1抑制剂疗效持久。在铂类继发耐药或原发耐药的卵巢癌患者或三阴性乳腺癌患者中,总的ORR(包括CR和PR)为25%,DCR(CR+PR+SD)为68%;在铂类原发耐药的患者中,ORR为24%。患者的疗效与标志物的状态无关:在BRCA野生型的患者中,ORR为26%(9/34);在HRD-阴性的患者中,ORR为29%(7/24)。目前疗效持续时间的数据尚未成熟,60%(9/15)有响应的患者仍在接受治疗,超过一半取得疾病控制的患者已经接受了超过6个月的治疗。副作用方面,3级以上不良事件发生32例/共58例(55%),最常见的3级或以上不良反应是贫血(18%)、血小板减少(15%)和疲劳(4%)。主要的不良反应来自PARP抑制剂。此外,有15%(8名)患者有免疫相关的不良反应。
综上,PARP抑制剂联合PD-1抗体用于治疗癌症,在临床当中既有显著的治疗获益,同时仍存在较大的副作用风险,从现有临床的数据报道,副作用主要来源于PARP抑制剂。所以,PARP抑制剂联合PD-1抗体用于治疗癌症具有广阔的市场前景,而更好的临床效果和更低的副作用仍是临床开发的必然趋势。
发明内容
本发明提供了一种与现有技术不同的用于治疗肿瘤的药物组合及其应用。本发明的药物组合的各组分联合使用,能够显著性的提高各自单药对肿瘤生长的抑制率,且给药后的小鼠均没有出现急性的不良反应,显示这一联合疗法具有良好的安全性和有效性。
本发明提供了一种药物组合,其包括如式A所示的化合物或其药学上可接受的盐、和“PD-1抑制剂和/或PD-L1抑制剂”;
在某一实施方案中,所述的如式A所示的化合物药学上可接受的盐为美呋哌瑞盐酸盐。
在某一实施方案中,所述的PD-1抑制剂可以为PD-1抗体、PD-1多肽和PD-1小分子抑制剂中的一种或多种,进一步可以为特瑞普利单抗(拓益)、信迪利单抗(达伯舒)、卡瑞利珠单抗(艾瑞卡)、替雷利珠单抗(百泽安)、帕博利珠单抗(Pembrolizumab,可瑞达(Keytruda))和纳武利尤单抗(Nivolumab,欧狄沃(opdivo))中的一种或多种,进一步还可以为特瑞普利单抗。
在某一实施方案中,所述的PD-L1抑制剂可以为PD-L1抗体、PD-L1多肽和PD-L1小分子抑制剂中的一种或多种,进一步可以为阿替利株单抗(Atezolizumab,商品名为特善奇(Tecentriq))、度伐利尤单抗(Durvalumab,商品名为英飞凡(Imfinzi))和阿利库单抗(Avelumab,商品名为Bavencio)中的一种或多种。
在某一实施方案中,所述的“PD-1抑制剂和/或PD-L1抑制剂”和,所述的如式A所示的化合物或其药学上可接受的盐可以同时施用或分别施用,还可以分别施用。所述的分别施用还可以为依次施用。
所述的同时施用可以为,“所述的PD-1抑制剂和/或PD-L1抑制剂”和“所述的如式A所示的化合物或其药学上可接受的盐”包含在单独药物组合中同时施用;或者,包含“所述的PD-1抑制剂和/或PD-L1抑制剂”的单独药物组合物与包含“所述的如式A所示的化合物或其药学上可接受的盐”的单独药物组合物同时施用。
所述的分别施用可以为,包含“所述的PD-1抑制剂和/或PD-L1抑制剂”的单独药物组合物与包含“所述的如式A所示的化合物或其药学上可接受的盐”的单独药物组合物在不同时间分开施用。所述的分开施用可在时间上距离接近或时间上距离较远。
所述的依次施用可以为,包含“所述的PD-1抑制剂和/或PD-L1抑制剂”的单独药物组合物和包含所述的“如式A所示的化合物或其药学上可接受的盐”的单独药物组合物其中之一首先施用,另一个随后施用。所述的分开施用可在时间上距离接近或时间上距离较远。
无论同时施用还是分别施用,所述的“PD-1抑制剂和/或PD-L1抑制剂”和所述的“如式A所示的化合物或其药学上可接受的盐”的施用方案(包括施用途径、施用剂量、施用间隔等)可以相同或不同,其可以由本领域技术人员根据需要进行调整,以提供最优的治疗效果。
在某一实施方案中,所述的药物组合为美呋哌瑞盐酸盐和特瑞普利单抗。
本发明还提供了一种药物组合物X,其包括:
所述的如式A所示的化合物或其药学上可接受的盐;
所述的“PD-1抑制剂和/或PD-L1抑制剂”;
和,药用辅料。
所述的药物组合物,根据给药方式不同可制成各种合适的剂型,包括经胃肠道给药剂型(例如口服剂型(片剂、丸剂、胶囊剂、粉剂、颗粒剂)、气态剂型(吸入剂))和非经胃肠道给药剂型(例如注射剂型、膏剂、乳剂)。
在某一实施方案中,所述药物组合物X以注射剂型形式或口服剂型形式呈现。所述的口服剂型可以片剂型。
本发明还提供了一种药物组合物Y,其包括第I药物组合物和第II药物组合物;
所述的第I药物组合物,其包括上述的如式A所示的化合物或其药学上可接受的盐,和药用辅料;
所述的第II药物组合物,其包括上述的“PD-1抑制剂和/或PD-L1抑制剂”,和药用辅料。
在某一实施方案中,所述的第I药物组合物以口服剂型形式呈现,进一步为片剂型形式呈现。
在某一实施方案中,所述的第II药物组合物以注射剂型形式呈现。
在某一实施方案中,所述的第I药物组合物以片剂型形式呈现,所述的第II药物组合物以注射剂型形式呈现。
本发明提供还提供了一种药盒,其包含:
第一容器,其包含如上所述的第I药物组合物;和,
第二容器,其包含如上所述的第II药物组合物。
本发明还提供了一种物质M在制备用于预防和/或治疗肿瘤的药物中的应用;其中,所述的物质M为上述的药物组合、上述的药物组合物X或上述的药物组合物Y。
所述的肿瘤可以为实体肿瘤和/或血液肿瘤。所述的实体肿瘤可以为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
所述的应用中,所述的如式A所示的化合物或其药学上可接受的盐、和、“PD-1抑制剂和/或PD-L1抑制剂”的施用方案(包括施用途径、施用剂量、施用间隔等)可以相同或不同,其可以由本领域技术人员根据需要进行调整,以提供最优的治疗效果。
所述的如式A所示的化合物或其药学上可接受的盐、和、所述的“PD-1抑制剂和/或PD-L1抑制剂”的剂量均可以根据受试者的体重来施用。
在某一实施方案中,所述的如式A所示的化合物或其药学上可接受的盐、和、“PD-1抑制剂和/或PD-L1抑制剂”为同时施用或分别施用。
在某一实施方案中,所述的如式A所示的化合物或其药学上可接受的盐的施用剂量为100-1000mg/次。
在某一实施方案中,所述的如式A所示的化合物施用频率为0.5-2次/天。
在某一实施方案中,所述的如式A所示的化合物或其药学上可接受的盐经口服施用。
在某一实施方案中,所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用剂量为50-500mg/次。
在某一实施方案中,所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用频率为每7-31天施用一次。
在某一实施方案中,所述的“PD-1抑制剂和/或PD-L1抑制剂”经口服施用或者注射施用。
在某一实施方案中,所述的如式A所示的化合物的经口服施用,施用剂量为100-1000mg/kg,施用频率为0.5-2次/天;
和,所述的“PD-1抑制剂和/或PD-L1抑制剂”的经注射施用,施用剂量为50-500mg/kg,施用频率为每7-31天施用一次。
本发明还提供了一种上述的如式A所示的化合物或其药学上可接受的盐在制备用于治疗肿瘤的药物中的应用,其中,所述的如式A所示的化合物或其药学上可接受的盐与所述的“PD-1抑制剂和/或PD-L1抑制剂”联用;
其中,所述的“如式A所示的化合物或其药学上可接受的盐”和所述的“PD-1抑制剂和/或PD-L1抑制剂”可以同时施用或分别施用,还可以分别施用。所述的分别施用还可以为依次施用。
其中,所述的如式A所示的化合物或其药学上可接受的盐可经口服施用。
其中,所述的如式A所示的化合物的施用剂量可为100-1000mg/kg。
其中,所述的如式A所示的化合物施用频率可为0.5-2次/天。
其中,所述的“PD-1抑制剂和/或PD-L1抑制剂”可经口服施用或者注射施用。
其中,所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用剂量可为50-500mg/次。
其中,所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用频率可为每7-31天施用一次。
其中,所述的肿瘤可以为实体肿瘤和/或血液肿瘤。所述的实体肿瘤可以为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
在某一实施方案中,所述的如式A所示的化合物的经口服施用,施用剂量为100-1000mg/次,施用频率为0.5-2次/天;
和,所述的“PD-1抑制剂和/或PD-L1抑制剂”的经注射施用,施用剂量为50-500mg/次,施用频率为每7-31天施用一次。
本发明还提供了一种上述的“PD-1抑制剂和/或PD-L1抑制剂”在制备用于治疗肿瘤的药物中的应用,其中,所述的“PD-1抑制剂和/或PD-L1抑制剂”与“如式A所示的化合物或其药学上可接受的盐”联用;
其中,所述的“如式A所示的化合物或其药学上可接受的盐”和所述的“PD-1抑制剂和/或PD-L1抑制剂”可以同时施用或分别施用,还可以分别施用。所述的分别施用还可以为依次施用。
其中,所述的“PD-1抑制剂和/或PD-L1抑制剂”可经口服施用或者注射施用。
其中,所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用剂量可为50-500mg/次。
其中,所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用频率可为每7-31天施用一次。
其中,所述的如式A所示的化合物或其药学上可接受的盐可经口服施用。
其中,所述的如式A所示的化合物的施用剂量可为100-1000mg/次。
其中,所述的如式A所示的化合物施用频率可为0.5-2次/天。
其中,所述的肿瘤可以为实体肿瘤和/或血液肿瘤。所述的实体肿瘤可以为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
在某一实施方案中,所述的如式A所示的化合物的经口服施用,施用剂量为100-1000mg/次,施用频率为0.5-2次/天;
和,所述的“PD-1抑制剂和/或PD-L1抑制剂”的经注射施用,施用剂量为50-500mg/次,施用频率为每7-31天施用一次。
术语“PD-1抗体”是指能与T细胞表面的PD-1相结合,阻断PD-1与其配体结合的抗体。PD-1的全称为程序性细胞死亡蛋白1(programmed cell death protein 1),是一种重要的免疫抑制分子。
术语“PD-1多肽”是指能与T细胞表面的PD-1相结合,阻断PD-1与其配体结合的多肽。。
术语“PD-1小分子抑制剂”是指能与T细胞表面的PD-1相结合,阻断PD-1与其配体结合的化学小分子。
术语“PD-L1抗体”是指能与肿瘤细胞表面的PD-L1相结合,阻断PD-L1与T细胞表面PD-1结合的抗体。PD-L1的全称为程序性细胞死亡蛋白1配体1(programmed cell deathprotein 1ligand 1)。
术语“PD-L1多肽”是指能与肿瘤细胞表面的PD-L1相结合,阻断PD-L1与T细胞表面PD-1结合的多肽。
术语“PD-L1小分子抑制剂”是指能与肿瘤细胞表面的PD-L1相结合,阻断PD-L1与T细胞表面PD-1结合的小分子化合物。“小分子化合物”是指分子量小于1000的化合物。
术语“药学上可接受的盐”是指化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸,所述无机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硝酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、亚磷酸、硫酸、硫酸氢根等。所述的药学上可接受的酸包括有机酸,所述有机酸包括但不限于:乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当化合物中含有相对酸性和相对碱性的官能团时,可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.HeinrichStahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明的药物组合物对肿瘤生长抑制率可达60%,且试验阶段,受试体无急性的不良反应。
附图说明
图1为治疗开始后的实验动物体重变化百分比。
图2为治疗开始后的实验动物肿瘤生长曲线。
图3为给药后(PG-D24)的实验动物个体肿瘤体积,其中“-”表示中位数。
图4为PBMC接种3周后实验动物外周血的hCD45 FACS检测,其中“-”表示中位数。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
1、供试药物
供试药物1:拓益(特瑞普利单抗)注射液。
供试药物2:盐酸美呋哌瑞。
2、供试品配制
2.1、溶媒选择:拓益PD-1单抗注射液:PBS;美呋哌瑞盐酸盐:生理盐水。
2.2、配制方法:
表1.受试物的配制及储存
3、实验材料和仪器设备
表2.实验所用试剂
名称 | 规格 | 生产厂家 |
胎牛血清(FBS) | 500ml/瓶 | Gibco |
Leibovitz's L-15培养基 | 500ml/瓶 | Gibco |
青链霉素混合液 | 100ml/瓶 | Solarbio |
胰蛋白酶-EDTA消化液(0.25%) | 100ml/瓶 | Solarbio |
Matrigel | 10ml/瓶 | Corning |
PBS(磷酸盐缓冲液) | 500ml/瓶 | Gibco |
生理盐水(0.9%氯化钠注射液) | 500ml/瓶 | 石家庄四药有限公司 |
PE-Cy7 anti-Hu CD45 | 100Tests | Invitrogen |
PE-Cy7 mouse IgG1κIso Control | 20Tests | Invitrogen |
表3.实验所用仪器设备
4、实验动物和饲养管理
4.1、实验动物
种属品系:Mus Musculus,NCG(NOD-Prkdcem26Cd52Il2rgem26Cd22/Nju);性别:雌性;体重:18-22g;数量:55只;实验动物提供商:江苏集萃药康生物科技有限公司。
4.2、饲养管理
饲养管理:实验动物饲养在SPF级恒温恒湿的层流清洁房间内,使用独立通风笼具IVC,每5只鼠一笼。
温度/湿度:控制在(23±3)℃/40-70%范围。
笼具:由聚碳酸酯制成。体积为370mm×155mm×135mm。软制玉米芯高压消毒清洁垫料,每周更换两次。每只笼具具有笼具标签,标明动物数量、性别、品系、接收时间、组别以及实验开始时间。
饲料和饮水:SPF级鼠料,钴60照射消毒。饮用水为超滤净化水,并经过高压灭菌处理。动物可以自由摄取无菌食物和饮水。
动物编号:耳朵打孔。
5、实验方法
5.1、细胞培养
MDA-MB-436肿瘤细胞(YK-CL-075)购自ATCC。用含有灭活的10%胎牛血清,100U/ml青霉素和100μg/ml链霉素的Leibovitz's L-15培养基在37℃、5%CO2的培养箱中培养肿瘤细胞,每隔3至4天待细胞长满后分瓶传代,将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
PBMC(人外周血单个核细胞):来源于ALLCELLS(Donor#:A0075)。
5.2、肿瘤细胞接种与分组
PBS与Matrigel按体积比1:1重悬的MDA-MB-436肿瘤细胞,浓度为1×108/ml,接种于小鼠的右侧胁肋部皮下,100μl/只,并在肿瘤体积生长至约1000mm3左右时,在无菌条件下取瘤,切成小块,每块大小约2mm×2mm×2mm,接种于实验动物的右侧胁肋部皮下,2周后将PBMC细胞用PBS重悬后,接种于小鼠体内,细胞接种量为2×106/鼠。在实验动物的肿瘤生长至93mm3左右时分组给药(当天记为PG-D0),共4组,每组10只,具体给药方案见表4。
5.3、小鼠体重的测量及实验指标
每周使用游标卡尺对肿瘤体积进行2次测量,测量肿瘤的长径和短径,其体积计算公式为:体积=0.5×长径×短径2。
根据肿瘤体积计算T/C值,其中T为各受试物处理组相对肿瘤体积(RTV)的平均值,C为对照组相对肿瘤体积(RTV)的平均值。RTV为给药后与给药前的肿瘤体积比值。肿瘤生长抑制率(TGI,%)=(1-T/C)×100%。
在PBMC接种3周后,采集小鼠外周血,通过流式细胞术(FACS)检测其中人源CD45+细胞(hCD45细胞)比例。
实验结束时,剥离肿瘤称重、摆放整齐拍照。
6、给药方案
表4.给药方案表
注:“*”给药容积依动物体重按10μl/g,如果出现体重下降15-20%时可停药至体重恢复至正常水平;
i.p.:腹腔注射;p.o.:口服;
qod×13:每隔一天给药一次,共给药13次;q4d×7:每四天给药一次,共给药7次。
7、统计学分析
应用IBM SPSS Statistics 22.0统计学软件,应用混合线性模型分析对肿瘤体积进行组间统计学分析,应用One-Way ANOVA分析对肿瘤重量进行组间统计学分析,p<0.05认为有显著性差异。
实施例1试验结果
1、实验动物给药后反应及体重变化
实验期间,各组小鼠在给药后未见明显的急性不良反应。在实验中后期,各组小鼠体重均出现下降,具体地见图1。上述实验证实美呋哌瑞盐酸盐+拓益PD-1单抗注射液联合使用的安全性良好。
2、肿瘤生长抑制结果
治疗后的实验动物肿瘤体积变化见表5、图2和图3。
表5.受试物对MDA-MB-436模型的抑瘤作用(肿瘤体积)
结论:在分组后24天(PG-D24),美呋哌瑞盐酸盐组、拓益PD-1单抗注射液组、美呋哌瑞盐酸盐+拓益PD-1单抗注射液组的肿瘤生长抑制率分别为54%、29%、60%,各治疗组的肿瘤体积均显著小于对照组(p<0.05);美呋哌瑞盐酸盐+拓益PD-1单抗注射液组的肿瘤体积显著小于拓益PD-1单抗注射液组(p<0.05)。表明联合用药产生了显著优于PD-1单药的疗效和优于美呋哌瑞盐酸盐的治疗趋势。
3、外周血FACS检测
PBMC接种3周后,小鼠外周血hCD45的FACS检测见图4。
由图4可知,小鼠外周血中hCD45细胞FACS检测结果阳性,表明人源化免疫重建模型建模成功,并且hCD45细胞百分比中位数在美呋哌瑞盐酸盐组、拓益PD-1单抗注射液组、美呋哌瑞盐酸盐+拓益PD-1单抗注射液组均高于对照组,其中美呋哌瑞盐酸盐+拓益PD-1单抗注射液组中位数高于美呋哌瑞盐酸盐组和拓益PD-1单抗注射液组。
综上所述,在PBMC人源化的MDA-MB-436皮下移植瘤模型中,拓益PD-1单抗注射液联合美呋哌瑞盐酸盐给药产生有统计学意义的抗肿瘤作用,能够有效地抑制肿瘤生长,其肿瘤抑制率显著高于拓益PD-1单抗注射液、小鼠外周血中hCD45细胞比例也相应增高。
Claims (13)
2.如权利要求1所述的药物组合,其特征在于,所述的如式A所示的化合物药学上可接受的盐为美呋哌瑞盐酸盐;
和/或,所述的PD-1抑制剂为PD-1抗体、PD-1多肽和PD-1小分子抑制剂中的一种或多种,进一步可以为特瑞普利单抗、信迪利单抗、卡瑞利珠单抗、替雷利珠单抗、帕博利珠单抗和纳武利尤单抗中的一种或多种,进一步还可以为特瑞普利单抗(拓益);
和/或,所述的PD-L1抑制剂为PD-L1抗体、PD-L1多肽和PD-L1小分子抑制剂中的一种或多种,进一步可以为阿替利株单抗、度伐利尤单抗和阿利库单抗中的一种或多种;
和/或,所述的“PD-1抑制剂和/或PD-L1抑制剂”和所述的“如式A所示的化合物或其药学上可接受的盐”同时施用或分别施用,进一步为依次施用;
和/或,所述的“PD-1抑制剂和/或PD-L1抑制剂”经口服施用或者注射施用;
和/或,所述的如式A所示的化合物或其药学上可接受的盐经口服施用。
3.如权利要求1所述的药物组合,其特征在于,所述的药物组合为美呋哌瑞盐酸盐和特瑞普利单抗。
4.一种药物组合物X,其特征在于,所述的药物组合物X包括:
如权利要求1~3任一项所述的如式A所示的化合物或其药学上可接受的盐;
如权利要求1~3任一项所述的“PD-1抑制剂和/或PD-L1抑制剂”;
和,药用辅料。
5.如权利要求4所述的药物组合物X,其特征在于,所述的药物组合物X以注射剂型形式或口服剂型形式呈现。
6.一种药物组合物Y,其特征在于,所述的药物组合物Y包括第I药物组合物和第II药物组合物;
所述的第I药物组合物,其包括如权利要求1~3任一项所述的如式A所示的化合物或其药学上可接受的盐,和药用辅料;
所述的第II药物组合物,其包括如权利要求1~3任一项所述的“PD-1抑制剂和/或PD-L1抑制剂”,和药用辅料。
7.如权利要求6所述的药物组合物Y,其特征在于,所述的第I药物组合物以口服剂型形式呈现,进一步为片剂型形式呈现;
和/或,所述的第II药物组合物以注射剂型形式呈现。
8.一种药盒,其包含:
第一容器,其包含如权利要求6或7所述的第I药物组合物;和,
第二容器,其包含如权利要求6或7所述的第II药物组合物。
9.一种物质M在制备用于预防和/或治疗肿瘤的药物中的应用,其中,所述的物质M为如权利要求1~3任一项所述的药物组合、如权利要求4或5所述的药物组合物X、或、如权利要求6或7所述的药物组合物Y。
10.如权利要求9所述的应用,其特征在于,所述的肿瘤为实体肿瘤和/或血液肿瘤,具体的为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种;和/或,所述的“如式A所示的化合物或其药学上可接受的盐”和所述的“PD-1抑制剂和/或PD-L1抑制剂”为同时施用或分别施用,进一步为依次施用;
和/或,所述的如式A所示的化合物的施用剂量为100-1000mg/次;
和/或,所述的如式A所示的化合物施用频率为0.5-2次/天;
和/或,所述的如式A所示的化合物或其药学上可接受的盐经口服施用;
和/或,所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用剂量为50-500mg/次;
和/或,所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用频率为每7-31天施用一次;
和/或,所述的“PD-1抑制剂和/或PD-L1抑制剂”经口服施用或者注射施用。
11.如权利要求10所述的应用,其特征在于,所述的如式A所示的化合物或其药学上可接受的盐经口服施用,施用剂量为100-1000mg/次,施用频率为0.5-2次/天;
和,所述的“PD-1抑制剂和/或PD-L1抑制剂”的经注射施用,施用剂量为50-500mg/次,施用频率为每7-31天施用一次。
12.一种如权利要求1~3任一项所述的“如式A所示的化合物或其药学上可接受的盐”在制备用于治疗肿瘤的药物中的应用,其特征在于,所述的“如式A所示的化合物或其药学上可接受的盐”与如权利要求1~3任一项所述的“PD-1抑制剂和/或PD-L1抑制剂”联用;
优选,所述的肿瘤为实体肿瘤和/或血液肿瘤,具体为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
13.一种如权利要求1~3任一项所述的“PD-1抑制剂和/或PD-L1抑制剂”在制备用于治疗肿瘤的药物中的应用,其特征在于,所述的“PD-1抑制剂和/或PD-L1抑制剂”与如权利要求1~3任一项所述的“如式A所示的化合物或其药学上可接受的盐”联用;
优选,所述的肿瘤为实体肿瘤和/或血液肿瘤,所述的实体肿瘤为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
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