CN114191557A - Cdk4/6抑制剂联合免疫治疗在制备抗癌药物中的用途 - Google Patents
Cdk4/6抑制剂联合免疫治疗在制备抗癌药物中的用途 Download PDFInfo
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- CN114191557A CN114191557A CN202010912875.4A CN202010912875A CN114191557A CN 114191557 A CN114191557 A CN 114191557A CN 202010912875 A CN202010912875 A CN 202010912875A CN 114191557 A CN114191557 A CN 114191557A
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Abstract
本发明涉及CDK4/6抑制剂联合免疫治疗在制备抗癌药物中的用途，属于生物医药技术领域，具体涉及吡罗西尼或其药用盐联合PD‑1或PD‑L1抑制剂在制备治疗癌症如肺癌、黑素瘤、脑癌、乳腺癌、肝癌、胶质母细胞瘤、胃癌、肠癌、胰腺癌、肾癌、前列腺癌、卵巢癌、子宫内膜癌、甲状腺癌、淋巴瘤的药物中的应用。本发明提供的联合治疗具有协同效应，明显提高移植瘤小鼠的存活率和中位生存期，在抑制肿瘤生长及转移中具有良好的临床应用前景。
Description
技术领域
本发明涉及医药领域，具体涉及一种CDK4/6抑制剂联合免疫治疗在制备抗癌药物中的用途。
背景技术
周期蛋白依赖性激酶4/6(cyclin-dependent kinase4/6,CDK4/6)是一类丝/苏氨酸激酶，与细胞周期素D(cyclin D)结合，调节细胞由G1期向S期转换。在很多肿瘤中，都存在“cyclinD–CDK4/6–INK4–Rb通路”异常。这条通路的改变，加速了G1期进程，使得肿瘤细胞增殖加快而获得生存优势。
CDK4/6抑制剂的作用机制主要包括：恢复正常细胞周期抑制肿瘤细胞失控增殖、触发抗肿瘤免疫、改变肿瘤微环境，除了经典的作用机制外，CDK4/6还以其他方式调节淋巴细胞，例如：NFAT(活化T细胞核因子)蛋白是一类对T细胞活化至关重要的转录因子，CDK4/6抑制剂通过磷酸化NFAT，从而刺激IL2分泌增多，增强T细胞活性，触发有效免疫应答，增强免疫检查点封锁疗法的效果，进而实现抗癌效果。然而，一些CDK4/6抑制剂通过磷酸化NFAT来增强T细胞活性并不呈现浓度正相关性，当浓度增大到一定程度，T细胞活性呈现下降趋势，难以实现有效的抗肿瘤效果。为了达到更好的抗肿瘤效果，减小抗癌药物对正常细胞的毒性等副作用，领域内亟需更有效的药物或者药物组合物或者药物联合用药，来实现更好的抗肿瘤效果。
发明内容
本发明提供一种CDK4/6抑制剂或其药学上可接受的盐联合施用PD-1或PD-L1抑制剂在制备抗癌药物中的用途。
本发明的优选技术方案中，所述CDK4/6抑制剂选自吡罗西尼、艾博西尼、瑞博西尼、帕博西尼、lerociclib的任一种或其组合。
本发明的优选技术方案中，所述药学上可接受的盐选自盐酸盐、氢溴酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、醋酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、富马酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐的任一种或其组合。
本发明的优选技术方案中，所述PD-1抑制剂选自替雷利珠、尼伏单抗(nivolumab)、帕博利珠单抗(MK-3475)、纳武利尤单抗、Cemiplimab、卡瑞利珠单抗(SHR1210)、信迪利单抗(IBI308)、特瑞普利单抗(JS 001)、Spartalizumab(PDR001)、替雷利珠单抗(BGB-A317)、纳武单抗(nivolumab)、AMP-224、AMP-514、Pidilizumab、Genolimzumab、Camrelizumab、GLS-010、REGN-2810、PF-06801591、TSR-042、LZM-009、AK-103、Geptanolimab、曲妥珠单抗、贝伐单抗(Bevacizumab)、西妥昔单抗(Cetuximab)的任一种或其组合。
本发明的优选技术方案中，所述PD-L1抑制剂选自阿维鲁单抗(avelumab)、度伐单抗(durvalumab)、阿替珠单抗(Atezolizumab)、KN035、CK-301、AUNP12、CA-170的任一种或其组合。
本发明的优选技术方案中，所述CDK4/6抑制剂与PD-1或PD-L1抑制剂同时或分开给药。
本发明的优选技术方案中，所述CDK4/6抑制剂的剂量为0.1～10.0mg/kg，优选为0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg的任一种或其组合。
本发明的优选技术方案中，所述CDK4/6抑制剂的用量为1～1000mg，优选为5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、125mg、150mg、175mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg的任一种或其组合。
本发明的优选技术方案中，所述PD-1抑制剂或PD-L1抑制剂的剂量为0.1～10.0mg/kg，优选为0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg的任一种或其组合。
本发明的优选技术方案中，所述PD-1抑制剂或PD-L1抑制剂的用量为1～600mg，优选为1.0mg、1.2mg、1.4mg、1.6mg、1.8mg、2.0mg、2.2mg、2.4mg、2.6mg、2.8mg、3.0mg、3.2mg、3.4mg、3.6mg、3.8mg、4.0mg、4.2mg、4.4mg、4.6mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg的任一种或其组合。
本发明的优选技术方案中，所述CDK4/6抑制剂的用量为20～500mg，所述PD-1抑制剂或PD-L1抑制剂的用量为1～600mg。
本发明的优选技术方案中，所述CDK4/6抑制剂的给药频次为一日一次、一日二次、一日三次、一周两次、一周一次、二周一次、三周一次、四周一次或一月一次；所述PD-1抑制剂或PD-L1抑制剂的给药频次为两天一次、四天一次、一周一次、二周一次、三周一次、四周一次或一月一次。
本发明的优选技术方案中，所述CDK4/6抑制剂的用量为20～500mg，每日给药；所述PD-1抑制剂或PD-L1抑制剂的用量为1～600mg，两日一次～每4周一次。
本发明的优选技术方案中，所述CDK4/6抑制剂的用量为20～500mg；所述PD-1抑制剂或PD-L1抑制剂的用量为100～300mg。
本发明的优选技术方案中，给药途径选自经口给药、胃肠外给药、经皮给药的任一种。
本发明的优选技术方案中，所述胃肠外给药选自静脉注射、皮下注射、肌肉注射、透皮给药、皮下给药、粘膜给药的任一种。
本发明的优选技术方案中，PD-1抑制剂或PD-L1抑制剂以注射方式给药。
本发明的优选技术方案中，PD-1抑制剂或PD-L1抑制剂以注射液或冻干粉针制剂形式存在。
本发明的优选技术方案中，癌症患者曾接受过肿瘤治疗，其中，所述肿瘤治疗选自化疗、免疫治疗、外科手术、放射治疗、疫苗中的任一种或其组合。
本发明的优选技术方案中，所述癌症患者的靶病灶直径相对减少了至少30％。
本发明的优选技术方案中，所述癌症患者的靶病灶直径相对增加了至少20％或出现一个或多个新病灶。
本发明的优选技术方案中，所述癌症患者的靶病灶直径相对增加了至多20％或靶向病灶直径相对减少了至多30％。
本发明的优选技术方案中，所述肿瘤患者为治疗失败。
本发明的优选技术方案中，所述化疗是指施用用于治疗癌症的化合物治疗，所述治疗癌症的化合物选自但不限于烷化剂，如噻替派、环磷酰胺、异环磷酰胺；烷基磺酸盐类，如白消安、英丙舒凡及哌泊舒凡；氮丙啶类，如苯唑多巴、卡巴醌、meturedopa及uredopa；甲基密胺类，包括altretamine、triethylenemelamine、trietylenephosphoramide、三伸乙基硫代磷酰胺(triethiylenethiophosphoramide)及三甲密胺(trimethylolomelamine)；β-拉帕酮(beta-lapachone)；拓扑异构酶抑制剂类；诸如，喜树碱(camptothecin)(包括合成类似物拓朴替康(topotecan)、CPT-11(伊诺替康(irinotecan)、乙酰基喜树碱(acetylcamptothecin)、斯考普莱叮(scopolectin)及9-胺基喜树碱)、依托泊苷；苔藓虫素(bryostatin)；卡利斯塔叮(callystatin)；CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)；氮芥类，如苯丁酸氮芥、萘氮芥(chlomaphazine)、雌氮芥(estramustine)；抗癌代谢物，诸如甲胺蝶呤及5-氟尿嘧啶(5-fluorouracil)(5-FU)；叶酸类似物，诸如傣诺特呤(denopterin)、甲胺蝶呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate)；雄性激素，诸如二甲睾酮(calusterone)、环硫雄醇(epitiostanol)、睾内酯(testolactone)；抗肾上腺剂，诸如胺基苯乙哌啶酮(aminoglutethimide)；二氟甲基鸟胺酸(difluoromethylornithine)(DMFO)；类视色素类，诸如视黄酸(retinoic acid)；卡培他滨(capecitabine)；PARP抑制剂，诸如奥拉帕利、氟唑帕利、尼拉帕利；Raf抑制剂，诸如索拉非尼；mTOR抑制剂,诸如依维莫司；微管抑制剂，诸如艾日布林、长春新碱；酪氨酸激酶抑制剂，诸如来那替尼、伊马替尼、吉非替尼、厄洛替尼、舒尼替尼、仑伐替尼、达克替尼、Foretinib、他菲替尼、伊布替尼、阿卡替尼、Velexbru(Tirabrutinib)、泽布替尼、卡博替尼；BCL-2(B细胞淋巴瘤-2)抑制剂,诸如维奈托克；蛋白酶体抑制剂，诸如硼替佐米；血管内皮生长因子受体抑制剂，诸如范得他尼、西地尼布、瓦他拉尼、阿西替尼；免疫调节剂，诸如沙利度胺、来那度胺、泊马度胺中的至少一种或其组合或其可药用盐或衍生物。
本发明的优选技术方案中，所述的联合任选的还包含其他组分，所述其他组分包括但不限于其他抗癌药等。
本发明的优选技术方案中，所述其他抗癌药选自但不限于烷化剂，如噻替派、环磷酰胺、异环磷酰胺；烷基磺酸盐类，如白消安、英丙舒凡及哌泊舒凡；氮丙啶类，如苯唑多巴、卡巴醌、meturedopa及uredopa；甲基密胺类，包括altretamine、triethylenemelamine、trietylenephosphoramide、三伸乙基硫代磷酰胺(triethiylenethiophosphoramide)及三甲密胺(trimethylolomelamine)；β-拉帕酮(beta-lapachone)；拓扑异构酶抑制剂类；诸如，喜树碱(camptothecin)(包括合成类似物拓朴替康(topotecan)、CPT-11(伊诺替康(irinotecan)、乙酰基喜树碱(acetylcamptothecin)、斯考普莱叮(scopolectin)及9-胺基喜树碱)、依托泊苷；苔藓虫素(bryostatin)；卡利斯塔叮(callystatin)；CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)；氮芥类，如苯丁酸氮芥、萘氮芥(chlomaphazine)、雌氮芥(estramustine)；抗癌代谢物，诸如甲胺蝶呤及5-氟尿嘧啶(5-fluorouracil)(5-FU)；叶酸类似物，诸如傣诺特呤(denopterin)、甲胺蝶呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate)；雄性激素，诸如二甲睾酮(calusterone)、环硫雄醇(epitiostanol)、睾内酯(testolactone)；抗肾上腺剂，诸如胺基苯乙哌啶酮(aminoglutethimide)；二氟甲基鸟胺酸(difluoromethylornithine)(DMFO)；类视色素类，诸如视黄酸(retinoic acid)；卡培他滨(capecitabine)；PARP抑制剂，诸如奥拉帕利、氟唑帕利、尼拉帕利；Raf抑制剂，诸如索拉非尼；mTOR抑制剂,诸如依维莫司；微管抑制剂，诸如艾日布林、长春新碱；酪氨酸激酶抑制剂，诸如来那替尼、伊马替尼、吉非替尼、厄洛替尼、舒尼替尼、仑伐替尼、达克替尼、Foretinib、他菲替尼、伊布替尼、阿卡替尼、Velexbru(Tirabrutinib)、泽布替尼、卡博替尼；BCL-2(B细胞淋巴瘤-2)抑制剂,诸如维奈托克；蛋白酶体抑制剂，诸如硼替佐米；血管内皮生长因子受体抑制剂，诸如范得他尼、西地尼布、瓦他拉尼、阿西替尼；免疫调节剂，诸如沙利度胺、来那度胺、泊马度胺中的至少一种或其组合或其可药用盐或衍生物。
本发明的优选技术方案中，所述癌症选自肺癌、黑素瘤、脑癌、头颈癌、乳腺癌、肝癌、胶质母细胞瘤、鼻咽癌、胃癌、结直肠癌、胰腺癌、肾癌、膀胱癌、前列腺癌、卵巢癌、子宫内膜癌、宫颈癌、甲状腺癌、淋巴瘤、黑色素瘤、血癌、多发性骨髓瘤、脂肪肉瘤的任一种或其并发症。
本发明的另一目的还提供了一种降低PD-1抑制剂或PD-L1抑制剂、吡罗西尼或其药学上可接受的盐所导致的不良反应的方法，包括同步向肿瘤患者施用有效剂量的PD-1抑制剂或PD-L1抑制剂和吡罗西尼或其药学上可接受的盐。
本发明的优选技术方案中，所述药学上可接受的盐选自盐酸盐、氢溴酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、醋酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、富马酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐的任一种或其组合。
本发明的另一目的还提供了一种减少PD-1抑制剂或PD-L1抑制剂、吡罗西尼或其药学上可接受的盐单独施用剂量的方法，包括同步向肿瘤患者施用有效剂量的PD-1抑制剂或PD-L1抑制剂和吡罗西尼或其药学上可接受的盐。
本发明的优选技术方案中，所述药学上可接受的盐选自盐酸盐、氢溴酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、醋酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、富马酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐的任一种或其组合。
除非另有说明，本发明涉及液体与液体之间的百分比时，所述的百分比为体积/体积百分比；本发明涉及液体与固体之间的百分比时，所述百分比为体积/重量百分比；本发明涉及固体与液体之间的百分比时，所述百分比为重量/体积百分比；其余为重量/重量百分比。
与现有技术相比，本发明具有下述有益技术效果：
(1)通过联合用药，改善了CDK4/6抑制剂浓度增大到一定程度后T细胞活性下降的趋势，以实现有效的抗肿瘤治疗。
(2)通过联合用药，肿瘤生长明显得到抑制，存活率明显提高，中位生存期明显延长。
本发明术语具有如下含义：
本发明中所述“免疫疗法”是利用免疫系统来治疗疾病，主要通过提高肿瘤细胞的免疫原性和对效应细胞杀伤的敏感性，激发和增强机体抗肿瘤免疫应答，并应用免疫细胞和效应分子输注宿主体内，协同机体免疫系统杀伤肿瘤、抑制肿瘤生长。
本发明中的“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的CDK4/6抑制剂或其药学上可接受的盐和至少一种剂量的PD-1抑制剂或PD-L1抑制剂，两种物质都显示药理学作用。所述的时间期限可以是一个给药周期内，包括4周内，3周内，2周内，1周内、24小时以内、12小时以内的任一种。可以同时或依次给予CDK4/6抑制剂或其可药用盐和PD-1抑制剂或PD-L1抑制剂。这种期限包括这样的治疗，通过相同给药途径或不同给药途径给予CDK4/6抑制剂或其可药用盐和PD-1抑制剂或PD-L1抑制剂。本发明中所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药或序贯给药。
本发明中所述“治疗失败”是指受试者在基线时伴有可测量的肿瘤病灶，根据RECIST 1.1疗效评定标准为疾病进展(PD)或不能耐受的。
本发明中所述“不能耐受的”是指因药物引起的不良反应不能继续接受治疗。
附图说明
图1a：CDK4/6抑制剂NFAT活性变化；
图1b：CDK4/6抑制剂NFAT活性变化；
图1c：吡罗西尼+Geptanolimab组NFAT活性变化；
图1d：吡罗西尼+Geptanolimab组NFAT活性变化；
图2a：吡罗西尼组小鼠肿瘤体积变化；
图2b：Geptanolimab组小鼠肿瘤体积变化；
图2c：吡罗西尼+Geptanolimab组小鼠肿瘤体积变化；
图3：小鼠给药后各组治疗效果。
具体实施方式
下面列举一部分具体实施例对本发明进行说明，有必要在此指出的是以下具体实施例只用于对本发明作进一步说明，不代表对本发明保护范围的限制。其他人根据本发明做出的一些非本质的修改和调整仍属于本发明的保护范围。
实施例1 NFAT活性测试
1、吡罗西尼组
Jurkat/PD1细胞悬液加入白色不透细胞培养板，依次加入XZP-3287稀释液(10μM起始浓度，3倍稀释)。将加样的细胞培养板置于37℃、5％CO2培养箱孵育6h后，室温放置10min。每孔加入80μL的Bio-GloTM底物液，室温孵育5min。用多功能酶标仪读取每孔的全波长化学发光值(Luminescence)。结果见图1a、1b。
2、Geptanolimab(GB226)组、吡罗西尼+Geptanolimab组
CHO/PD-L1细胞接种于白色不透细胞培养板过夜培养，将GB226稀释液(10μg起始浓度，2.5倍稀释)，单独用药或与固定浓度XZP-3287(40nM、100nM、400nM、1000nM)联合用药，Jurkat/PD1细胞悬液加入白色不透细胞培养板，将加样的细胞培养板置于37℃、5％CO2培养箱孵育6h后，室温放置10min每孔加入80μL的Bio-GloTM底物液，室温孵育5min。用多功能酶标仪读取每孔的全波长化学发光值(Luminescence)。结果见图1c、1d。
结果表明，Jurkat T细胞吡罗西尼给药后，在一定范围内，NFAT活性呈现浓度依赖，但到达一定程度后，呈下降趋势。但吡罗西尼和Geptanolimab的联合用药，明显改善该现象，且可显著增强效应T细胞的活性。
实施例2吡罗西尼联合Geptanolimab在EMT-6小鼠移植瘤模型体内药效学实验
40只移植瘤EMT-6小鼠分为4组，饲养7天后，分别给与阴性对照(口服给药)、吡罗西尼50mg/kg(口服给药)、Geptanolimab10mg/kg(腹腔注射)、吡罗西尼50mg/kg+Geptanolimab 10mg/kg(同上)；从第7天起，每4天测量肿瘤直径，计算肿瘤体积。
结果表明，与吡罗西尼组、吡罗西尼组相比，吡罗西尼+Geptanolimab联合给药组肿瘤体积明显下降，其差异具有统计学意义。
实施例3吡罗西尼联合Geptanolimab在CT26小鼠移植瘤模型体内药效学实验
40只移植瘤CT26小鼠分为4组，饲养7天后，分别给与阴性对照(口服给药)、吡罗西尼50mg/kg(口服给药)、Geptanolimab 50mg/kg(腹腔注射)、吡罗西尼50mg/kg+Geptanolimab 10mg/kg(同上)。
统计小鼠存活只数，计算存活率，并得出中位生存期，通过Wilcoxon Test统计学分析。结果见表1、图3。
表1
结果分析：1)各组与对照组间均存在显著差异；2)与吡罗西尼单药组、Geptanolimab单药组相比，吡罗西尼Geptanolimab联合给药组存活率明显增加，中位生存期显著延长，具有显著性差异。
以上所述仅是本发明的实施方式的举例，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。
Claims (10)
1.一种CDK4/6抑制剂或其药学上可接受的盐联合施用PD-1或PD-L1抑制剂在制备抗癌药物中的用途。
2.根据权利要求1所述的用途，其特征在于，所述CDK4/6抑制剂选自吡罗西尼、艾博西尼、瑞博西尼、帕博西尼、lerociclib的任一种或其组合。
3.根据权利要求1-2任一项所述的用途，其特征在于，所述PD-1抑制剂选自替雷利珠、尼伏单抗(nivolumab)、帕博利珠单抗(MK-3475)、纳武利尤单抗、Cemiplimab、卡瑞利珠单抗(SHR1210)、信迪利单抗(IBI308)、特瑞普利单抗(JS 001)、Spartalizumab(PDR001)、替雷利珠单抗(BGB-A317)、纳武单抗(nivolumab)、AMP-224、AMP-514、Pidilizumab、Genolimzumab、Camrelizumab、GLS-010、REGN-2810、PF-06801591、TSR-042、LZM-009、AK-103、Geptanolimab、曲妥珠单抗、贝伐单抗(Bevacizumab)、西妥昔单抗(Cetuximab)的任一种或其组合。
4.根据权利要求1-2任一项所述的用途，其特征在于，所述PD-L1抑制剂选自阿维鲁单抗(avelumab)、度伐单抗(durvalumab)、阿替珠单抗(Atezolizumab)、KN035、CK-301、AUNP12、CA-170的任一种或其组合。
5.根据权利要求1-4任一项所述的用途，其特征在于，所述CDK4/6抑制剂与PD-1或PD-L1抑制剂同时或分开给药。
6.根据权利要求1-5任一项所述的用途，其特征在于，所述的联合任选的还包含其他组分，所述其他组分包括但不限于其他抗癌药。
7.根据权利要求1-6任一项所述的用途，其特征在于，所述癌症选自肺癌、黑素瘤、脑癌、头颈癌、乳腺癌、肝癌、胶质母细胞瘤、鼻咽癌、胃癌、结直肠癌、胰腺癌、肾癌、膀胱癌、前列腺癌、卵巢癌、子宫内膜癌、宫颈癌、甲状腺癌、淋巴瘤、黑色素瘤、血癌、多发性骨髓瘤、脂肪肉瘤的任一种或其并发症。
8.一种降低PD-1抑制剂或PD-L1抑制剂、吡罗西尼或其药学上可接受的盐所导致的不良反应的方法，包括同步向肿瘤患者施用有效剂量的PD-1抑制剂或PD-L1抑制剂和吡罗西尼或其药学上可接受的盐。
9.一种减少PD-1抑制剂或PD-L1抑制剂、吡罗西尼或其药学上可接受的盐单独施用剂量的方法，包括同步向肿瘤患者施用有效剂量的PD-1抑制剂或PD-L1抑制剂和吡罗西尼或其药学上可接受的盐。
10.根据权利要求9所述的用途，其特征在于，所述药学上可接受的盐选自盐酸盐、氢溴酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、醋酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、富马酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐的任一种或其组合。
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