CN118557559A - 用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物 - Google Patents
用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物 Download PDFInfo
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Abstract
本申请涉及用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物。[问题]本发明的目的是提供用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物。[解决方案]提供了用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物,所述药物组合物包含5‑氨基乙酰丙酸(ALA)作为活性成分。
Description
本申请是申请日为2018年11月28日、申请号为“201880065357.4”、发明名称为“用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物”的中国专利申请的分案申请,原申请是国际申请PCT/JP2018/043704的中国国家阶段申请。
技术领域
本发明涉及5-氨基乙酰丙酸(下文中也简称为“ALA”)或其衍生物的新用途,具体地涉及5-氨基乙酰丙酸或其衍生物用于增强免疫检查点抑制剂之抗肿瘤作用的用途。
背景技术
人体中已出现的肿瘤在其扩散至其对人体具有有害作用的程度之前,由通常固有的免疫机制除去。对于该机制,已知以下现象。即,对癌细胞具有特异性的蛋白质(肿瘤抗原)与癌细胞中被称为I类MHC分子的蛋白质结合,并呈递在细胞表面上。当该I类MHC和肿瘤抗原与负责免疫的T细胞表面上的TCR(T细胞受体)蛋白结合时,T细胞将该细胞识别为癌细胞。识别癌细胞的T细胞启动增殖,并破坏呈递肿瘤抗原的癌细胞。
然而,已知当癌细胞与I类MHC一起表达被称为PD-L1的膜蛋白时,通过与在T细胞中表达的被称为PD-1的膜蛋白结合,上述T细胞的活化被抑制。由于已经获得了通常用于抑制过度免疫的免疫逃逸机制的这种癌细胞继续增殖,因此PD-L1与PD-1之间的结合抑制已经作为新的抗癌剂的靶标而备受瞩目(专利文献1)。注意,PD-L1也在“专职抗原呈递细胞”(例如专门向T细胞呈递抗原的树突状细胞)中表达。近年来,已经开发出抗PD-1抗体纳武单抗和派姆单抗并作为抗癌剂投入实际应用,并且还已经开发出抗PD-L1抗体阿替利珠单抗、度伐单抗、阿维单抗(BavencioTM)等并投入实际应用。
在另一个方面,在癌细胞(或专职抗原呈递细胞)向T细胞的抗原呈递中,抑制免疫反应的另一些机制(免疫检查点)也是已知的,其代表是抗原呈递侧上的B7家族分子和T细胞侧上的CTLA4的组合,并且已经开发了例如伊匹单抗和曲美木单抗的药物。另外,CD137L-CD137、MHC-LAG-3/KIR、CD48-CD244、GAL9-TIM3、HVEM-BTLA/CD160、CD40L-CD40、OX40L-OX40、GITRL-GITR等是已知的(在全部这些中,前者是抗原呈递侧的分子)(非专利文献1和2)。
最近,有报道称,抗PD-1抗体的抗肿瘤作用与T细胞中活性氧的产生相关,并且所述抗肿瘤作用由通过添加低浓度的活性氧产生剂的胞内信号转导和线粒体活化而增强。此外,同时报道了在模拟该胞内信号转导的药物中,也增强了抗PD-1抗体的抗肿瘤作用(非专利文献3)。
本发明人已发现,ALA或其衍生物通过以下推定机制而对癌症治疗有效:在癌细胞或已经在细胞核中形成异常的几乎变成癌细胞的细胞的线粒体中增强血红素或细胞色素,改善线粒体的活性(例如电子传递链和TCA循环),而且当核中存在不能恢复的异常时唤起Bax和Bak系统以引起胱天蛋白酶IX型凋亡(专利文献2)。
在另一个方面,ALA与任意的柠檬酸亚铁钠(SFC)一起在体内变成血红素,并且该血红素由被称为血红素加氧酶1(HO-1)的酶降解而变成胆红素和一氧化碳(非专利文献4)。已知该胆红素和一氧化碳具有高抗氧化作用,并且可直接/间接消除活性氧类(ROS)(非专利文献5)。
此外,已知ALA与任意SFC一起具有抑制免疫的免疫耐受作用。认为该机制是在作为抗原呈递细胞的树突状细胞中,上述HO-1(或胆红素和一氧化碳)将树突状细胞改变(分化)为被称为致耐受性树突状细胞的细胞。已知致耐受性细胞高度地表达PD-L1,并对存在于T细胞上的抗原执行特异性免疫耐受(免疫抑制),并且实际上,在通过施用ALA和SFC被识别为树突状细胞的细胞中已经观察到PD-L1的mRNA的升高(非专利文献6)。
引文列表
[专利文献1]日本专利No.5885764
[专利文献2]日本专利No.5611548
[非专利文献1]Nat Rev Cancer.2012 Mar 22;12(4):252-64。
[非专利文献2]Ann Transl Med.2015 Oct;3(18):267。
[非专利文献3]Proc Natl Acad Sci USA.2017 Jan 31;114(5):E761-E770。[非专利文献4]Am J Physiol Renal Physiol.2013 Oct 15;305(8)F1149-57
[非专利文献5]Am J Physiol Cell Physiol.2015 Apr 15;308(8)C665-72。
[非专利文献6]J Heart Lung Transplant.2015 Feb;34(2):254-63。
发明内容
本发明要解决的问题
如上所述,已经产生了包含抗PD-1抗体或抗PD-L1抗体作为活性成分的癌症治疗剂,并且此外,这些癌症治疗剂与现有药物的组合治疗方法已引起关注。实际上,已经计划了模拟上述信号转导的药物(激活转录因子PPAR的降脂药物苯扎贝特)和抗PD-1抗体的组合的临床试验。即,需要寻找或产生与免疫检查点抑制剂(例如抗PD-1抗体或抗PD-L1抗体)具有高相关性并且可增强免疫检查点抑制剂之抗肿瘤作用的药物或药物组合物。
因此,本发明的目的是提供用于增强免疫检查点抑制剂(例如抗PD-1抗体或抗PD-L1抗体)之抗肿瘤作用的药物组合物。
解决问题的手段
作为为了解决上述问题而反复深入研究的结果,本发明人发现5-氨基乙酰丙酸(ALA)可显著增强免疫检查点抑制剂的抗肿瘤作用。如上所述,尽管ALA本身可用于癌症治疗,但是考虑到施用ALA所产生的由胆红素和一氧化碳(CO)的高抗氧化作用或ALA的免疫耐受作用,当在通过免疫检查抑制剂(例如抗PD-1抗体或抗PD-L1抗体)进行癌症治疗期间施用ALA时,认为由于ALA引起表达PD-L1的树突状细胞提高或T细胞中的活性氧被胆红素和CO去除而将抵消免疫检查点抑制剂的作用,并且因此该结果出乎意料。
即,本发明涵盖以下特征:
[1]用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物,其包含下式(I)所示化合物或者其盐或酯:
[化学式1]
R1-NHCH2COCH2CH2COOR2 (I)
(其中R1表示氢原子或酰基,并且R2表示氢原子、直链或支链烷基、环烷基、芳基或芳烷基)。
[2]根据[1]的药物组合物,其中所述免疫检查点抑制剂是选自以下的至少一种:抗PD-1抗体、抗PD-L1抗体、抗CTLA4抗体、抗B7抗体、抗C27抗体、抗KIR抗体、IDO抑制剂、抗CD137抗体和抗TIM3抗体。
[3]根据[2]的药物组合物,其特征在于所述免疫检查点抑制剂是抗PD-L1抗体或抗PD-1抗体。
[4]根据[1]的药物组合物,其中所述免疫检查点抑制剂选自阿替利珠单抗(atezolizumab)、度伐单抗(durvalumab)、阿维单抗(avelumab)、纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、皮地利珠单抗(pidilizumab)、BMS-936559、伊匹单抗(ipilimumab)、曲美木单抗(tremelimumab)、恩必利珠单抗(enoblituzumab)、瓦利路单抗(varlilumab)、立鲁单抗(lirilumab)、艾卡哚司他(epacadostat)、乌托米单抗(utomilumab)、乌瑞鲁单抗(urelumab)和TSR-022。
[5]根据[1]至[4]中任一个的药物组合物,其特征在于其与免疫检查点抑制剂同时或在不同的时间施用。
[6]根据[1]至[6]中任一项所述的药物组合物,其特征在于:
R1选自氢原子、具有1至8个碳的烷酰基、以及具有7至14个碳的芳酰基,并且
R2选自氢原子、具有1至8个碳的直链或支链烷基、具有3至8个碳的环烷基、具有6至14个碳的芳基、以及具有7至15个碳的芳烷基。
[7]根据[1]至[7]中任一项所述的药物组合物,其中R1和R2是氢原子。
[8]根据[1]至[8]中任一项所述的药物组合物,其还包含一种或两种或更多种类型的含金属化合物。
[9]根据[8]的药物组合物,其中所述含金属化合物是包含铁、镁、锌、镍、钒、铜、铬、钼或钴的化合物。
[10]根据[9]的药物组合物,其中所述含金属化合物是包含铁、镁或锌的化合物。
[11]根据[10]的药物组合物,其中所述含金属化合物是包含铁的化合物。
[12]根据[11]的药物组合物,其中所述包含铁的化合物是柠檬酸亚铁钠。
[13]下式(I)所示化合物或者其盐或酯在生产用于增强免疫检查点抑制剂之抗肿瘤作用的药物中的用途:
[化学式2]
R1-NHCH2COCH2CH2COOR2 (I)
(其中R1表示氢原子或酰基,并且R2表示氢原子、直链或支链烷基、环烷基、芳基或芳烷基)。
[14]用于增强免疫检查点抑制剂之抗肿瘤作用的方法,其包括向施用了或正在施用免疫检查点抑制剂的对象施用下式(I)所示化合物或者其盐或酯:
[化学式3]
R1-NHCH2COCH2CH2COOR2 (I)
(其中R1表示氢原子或酰基,并且R2表示氢原子、直链或支链烷基、环烷基、芳基或芳烷基)。
注意,上述本发明的一个或更多个特征的任意组合的发明也涵盖在本发明的范围内。
发明的效果
根据本发明,提供了用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物。
附图说明
图1示出了实施例1的测试中每种测试剂的施用时间表。
图2示出了肿瘤接种之后的肿瘤体积的未治疗组、抗PD-L1抗体施用组、抗PD-L1抗体+ALA施用组和抗PD-L1抗体+ALA+SFC施用组之间的比较。*显示当两个群体的方差不相等时,通过t检验的p<0.05。
图3示出了实施例2的测试中每种测试剂的施用时间表。
图4示出了肿瘤接种之后的肿瘤体积的未治疗组、抗PD-L1抗体施用组和抗PD-L1抗体+ALA+SFC施用组之间的比较。
具体实施方式
现在将详细描述本发明。
本发明涉及用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物(下文中也被称为“本发明的药物组合物”)。
“免疫检查点抑制剂”是通过与抑制由于抗原的呈递引起的T细胞活性的免疫检查点分子结合并抑制其信号转导而抑制癌症扩散的抗癌剂。免疫检查点分子可包含作为免疫检查点发挥作用的受体和配体二者。
在本发明的一个实施方案中,“免疫检查点抑制剂”包括但不限于例如可抑制PD-1L与PD-1之间的结合或相互作用、CD80/CD86与CTLA4之间的结合或相互作用、CD137L与CD137之间的结合或相互作用、MHC与LAG-3/KIR之间的结合或相互作用、CD48与CD244之间的结合或相互作用、GAL9与TIM3之间的结合或相互作用、HVEM与BTLA/CD160之间的结合或相互作用、CD40L与CD40之间的结合或相互作用、OX40L与OX40之间的结合或相互作用、以及GITRL与GITR之间的结合或相互作用的任何抗体或化合物。
在本发明的另一个实施方案中,“免疫检查点抑制剂”选自但不限于:抗PD-1抗体、抗PD-L1抗体、抗CTLA4抗体、抗B7抗体、抗C27抗体、抗KIR抗体、IDO抑制剂、抗CD137抗体和抗TIM3抗体。
在本发明的另一个实施方案中,“免疫检查点抑制剂”选自但不限于:阿替利珠单抗、度伐单抗、阿维单抗、纳武单抗、派姆单抗、皮地利珠单抗、BMS-936559、伊匹单抗、曲美木单抗、恩必利珠单抗、瓦利路单抗、立鲁单抗、艾卡哚司他、乌托米单抗、乌瑞鲁单抗和TSR-022。
在本发明的另一个实施方案中,“免疫检查点抑制剂”是抗PD-L1抗体或抗PD-1抗体。
本发明的药物组合物的特征在于其具有ALA或其衍生物、盐或酯(下文中也简称为“ALA”)作为活性成分。
本文中所用的ALA意指5-氨基乙酰丙酸。ALA也被称为δ-氨基乙酰丙酸,并且其是一种类型的氨基酸。
下式(I)所示化合物可示例为ALA衍生物。在式(I)中,R1表示氢原子或酰基,并且R2表示氢原子、直链或支链烷基、环烷基、芳基或芳烷基。注意,在式(I)中,ALA对应于R1和R2为氢原子的情况。
[化学式4]
R1-NHCH2COCH2CH2COOR2 (I)
ALA可以以式(I)的ALA或其衍生物的形式在体内充当活性成分,并且还可作为经体内酶降解的前药(前体)施用。
式(I)的R1中的酰基可包含具有1至8个碳的直链或支链烷酰基,例如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基、辛酰基和苄基羰基;或具有7至14个碳的芳酰基,例如苯甲酰基、1-萘甲酰基、2-萘甲酰基。
式(I)的R2中的烷基可包含具有1至8个碳的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基和辛基。
式(I)的R2中的环烷基可包含具有3至8个碳的可以是饱和或具有部分不饱和键的环烷基,例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环十二烷基和1-环己烯基。
式(I)的R2中的芳基可包含具有6至14个碳的芳基,例如苯基、萘基、蒽基和菲基。
式(I)的R2中的芳烷基可示例为与上述芳基部分相同的芳基和与上述烷基部分相同的烷基,并且可具体包含具有7至15个碳的芳烷基,例如苄基、苯乙基、苯丙基、苯丁基、二苯甲基、三苯甲基、萘甲基和萘乙基。
优选的ALA衍生物包含其中R1为甲酰基、乙酰基、丙酰基、丁酰基等的化合物。此外,优选的ALA衍生物还包含其中上述R2为甲基、乙基、丙基、丁基、戊基等的化合物。此外,优选的ALA衍生物还包含其中上述R1和R2的组合为(甲酰基与甲基)、(乙酰基与甲基)、(丙酰基与甲基)、(丁酰基与甲基)、(甲酰基与乙基)、(乙酰基与乙基)、(丙酰基与乙基)和(丁酰基和乙基)的每种组合的化合物。
在ALA中,ALA或其衍生物的盐可包含可药用酸加成盐、金属盐、铵盐、有机胺加成盐等。酸加成盐可示例为例如,各种无机酸盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、磷酸盐、硝酸盐和硫酸盐,以及各种有机酸加成盐,例如甲酸盐、乙酸盐、丙酸盐、甲苯磺酸盐、琥珀酸盐、草酸盐、乳酸盐、酒石酸盐、乙醇酸盐、甲磺酸盐、丁酸盐、戊酸盐、柠檬酸盐、富马酸盐、马来酸盐和苹果酸盐。金属盐可示例为各种碱金属盐,例如锂盐、钠盐和钾盐;各种碱土金属盐,例如镁盐和钙盐;以及各种金属盐,例如铝和锌。铵盐可示例为例如铵盐和烷基铵盐(例如四甲基铵盐)。有机胺盐可示例为例如以下的各种盐:三乙胺盐、哌啶盐、吗啉盐和甲苯胺盐。注意,这些盐也可在使用时作为溶液使用。
ALA酯可包括但不限于甲酯、乙酯、丙酯、丁酯、戊酯等。
在上述ALA中,最优选的是ALA和多种酯,例如ALA甲酯、ALA乙酯、ALA丙酯、ALA丁酯和ALA戊酯,及其盐酸盐、磷酸盐和硫酸盐。特别地,ALA盐酸盐和ALA磷酸盐可例示为特别有利的。
上述ALA可通过例如公知的方法(例如化学合成、通过微生物生产和通过酶生产)来制造。此外,上述ALA还可形成水合物或溶剂合物,并且可将ALA单独使用或以两种或更多种的适当组合使用。
当将上述ALA准备成水溶液时,必须注意不要使水溶液变成碱性,以防止ALA的降解。在其变成碱性的情况下,可通过除去氧来防止降解。
在一个实施方案中,在本发明的药物组合物中,组合使用一种或更多种类型的含金属化合物。因此,本发明的药物组合物可以还包含一种或更多种类型的含金属化合物。这样的含金属化合物的金属部分可包含铁、镁、锌、镍、钒、钴、铜、铬和钼。在一个优选的实施方案中,含金属化合物的金属部分优选为铁、镁或锌,特别是铁。
在本发明中,铁化合物可以是有机盐或无机盐。无机盐可包含氯化铁、三氧化二铁、硫酸铁和焦磷酸亚铁。有机盐可包含羧酸盐,例如羟基羧酸盐;柠檬酸盐,例如柠檬酸亚铁、柠檬酸铁钠、柠檬酸亚铁钠(SFC)和柠檬酸铁铵;有机酸盐,例如焦磷酸铁、血红素铁、右旋糖酐铁、乳酸铁、葡萄糖酸亚铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺五乙酸铁铵、二羧甲基谷氨酸铁钠、二羧甲基谷氨酸铁铵、富马酸亚铁、乙酸铁、草酸铁、琥珀酸亚铁和柠檬酸琥珀酸铁钠;以及三亚乙基四胺铁、乳铁蛋白铁、转铁蛋白铁、叶绿素铁钠、铁蛋白铁、糖化铁氧化物和硫酸甘氨酸亚铁。
在本发明中,镁化合物可包含柠檬酸镁、苯甲酸镁、乙酸镁、氧化镁、氯化镁、氢氧化镁、碳酸镁、硫酸镁、硅酸镁、硝酸镁、二亚乙基三胺五乙酸二铵镁、乙二胺四乙酸二钠镁和原卟啉镁。
在本发明中,锌化合物可包含氯化锌、氧化锌、硝酸锌、碳酸锌、硫酸锌、二亚乙基三胺五乙酸二铵锌、乙二胺四乙酸二钠锌、原卟啉锌和含锌酵母。
向对象的含金属化合物的剂量相对于向对象的ALA的剂量摩尔比可以是0至100倍,期望地为0.01至10倍,并且更期望地为0.1至8倍。
本发明的药物组合物中包含的ALA和含金属化合物可以作为包含ALA和含金属化合物的组合物施用,或者可各自单独施用,尽管即使在各自单独施用时,也优选将其同时施用。此处,同时不仅意指同时施用,而且即使不是同时施用,也意指彼此之间没有显著间隔的施用,使得ALA和含金属化合物的施用可发挥相加作用,优选协同作用。
本发明中ALA和含金属化合物的施用途径不受限制,并且可以是全身施用药或局部施用。施用途径可包含例如经口施用,包含舌下施用,或肠胃外施用,例如吸入施用、静脉内施用(包含输注)、透皮施用(例如通过贴剂)、栓剂,或通过使用鼻胃管、鼻肠管、胃造口管或肠造口管的强制肠内营养进行施用。而且,如上所述,ALA和含金属化合物可从不同的途径施用。
本发明药物组合物的剂型可根据所述施用途径适当确定,并且可包括但不限于注射剂、输注剂、片剂、胶囊剂、细颗粒剂、散剂、液体剂、溶解于糖浆等中的溶液剂、贴剂、栓剂等。
可根据需要向根据本发明的药物组合物添加其他任选的成分,例如其他药用成分、营养物和载体。例如,作为任选的成分,用于制备药物的多种调和成分,例如可药用普通载体(例如结晶纤维素、明胶、乳糖、淀粉、硬脂酸镁、滑石、植物和动物脂肪、油、树胶和聚亚烷基二醇)、黏合剂、稳定剂、溶剂、分散介质、增量剂、赋形剂、稀释剂、pH缓冲剂、崩解剂、增溶剂、助溶剂和等张剂。
本发明的药物组合物的施用对象是施用了或正在施用免疫检查点抑制剂的对象,通常是患有癌症的对象。根据所使用的免疫检查点抑制剂,将成为治疗对象的癌症类型可发生变化。
由本发明的药物组合物施用的ALA的剂量可根据对象的身高、体重、年龄和症状,当转换成ALA时(即转换成当式(I)中R1和R2为氢原子时的质量时)以按对象体重计每kg为1mg至1,000mg、优选5mg至100mg、更优选10mg至30mg、进一步优选15mg至25mg施用。
对于本发明的药物组合物,适当的施用次数和施用频率可由本领域技术人员考虑组合使用的免疫检查点抑制剂的施用条件(施用间隔、施用数目以及施用持续时间)而合适地确定。在本发明的一个实施方案中,本发明的药物组合物从免疫检查点抑制剂的施用之前、施用时或施用之后每天施用。
在本发明中,可向对象同时或在不同时间、连续或间隔地施用有效量的每种本发明的药物组合物和免疫检查点抑制剂。本发明的药物组合物和免疫检查点抑制剂可以以相同的施用周期向肿瘤患者施用,或者可各自以不同的施用周期施用。在本发明的一个实施方案中,每种本发明的药物组合物和免疫检查点抑制剂以不同的施用周期施用。
在本发明的一个实施方案中,在开始施用免疫检查点抑制剂之前开始向对象施用本发明的药物组合物。例如,本发明的药物组合物可从开始施用免疫检查点抑制剂之前一周每天施用。
在本发明的另一个实施方案中,在与施用免疫检查点抑制剂的同一天开始向对象施用本发明的药物组合物。例如,本发明的药物组合物可从开始施用免疫检查点抑制剂的当天每天施用。当同时施用本发明的药物组合物和免疫检查点抑制剂时,可将其作为单一制剂来制备和施用,或者可以以分开的施用途径同时施用。
在本发明的另一个实施方案中,在施用免疫检查点抑制剂之后开始向对象施用本发明的药物组合物。例如,本发明的药物组合物可在施用免疫检查点抑制剂之后每天施用。只要可增强免疫检查点抑制剂的抗肿瘤作用,则对本发明的药物组合物的开始时间点没有特别限制,并且优选从免疫检查点抑制剂的开始时间点起尚未经过很长时间,例如一个月或更长时间,优选三个星期或更长时间,更优选两个星期或更长时间,并且更优选十天或更长时间。
除了特别定义的那些之外,本文中使用的术语用于描述一些特定的实施方案,并不旨在限制本发明。
此外,除非内容清楚地指出另外的理解,否则本文中使用的术语“包含/包括”旨在存在所述项目(例如组件、步骤、要素和数字),并且不排除存在其他项目(例如组件、步骤、要素和数字)。
除非另外限定,否则本文中使用的所有术语(包括技术和科学术语)具有与本发明所属技术领域的技术人员广泛认可的含义相同的含义。除非另外明确限定,否则本文中使用的术语应被解释为具有与本文中和相关技术领域的含义一致的含义,并且不应被解释为具有理想化或过度正式的含义。
现在将参照实施例更详细地描述本发明。然而,本发明可通过多种方面实现,且不应被解释为限于本文中描述的实施例。
实施例
<实施例1>通过组合使用ALA和PD-L1抗体而增强抗肿瘤作用
实验方法
对于C57BL/6小鼠,将3×105个小鼠黑素瘤细胞株B16F10接种在胁部,并使肿瘤生长28天。在接种的第10天和第15天,向仅PD-L1抗体施用组、抗PD-L1抗体+ALA施用组、以及抗PD-L1抗体+ALA+SFC施用组腹膜内施用200μg/头的抗小鼠PD-L1抗体(克隆:MIH5)(图1)。对于抗PD-L1抗体+ALA+SFC施用组,从接种的第10天至第16天,每天一次经口施用100mg/kg的ALA盐酸盐(来自neo ALA CO.,LTD.)和157mg/kg的柠檬酸亚铁钠(SFC;来自KOMATSUYACORPORATION)。此外,对于抗PD-L1抗体+ALA施用组,从接种的第10天至第16天每天一次经口施用100mg/kg的ALA盐酸盐(来自neo ALA CO.,LTD.)。接种之后不进行处理的组作为对照组。
每两天测量肿瘤直径,并将v(其中v=(短径,mm)2×(长径,mm)/2)记录为肿瘤体积(mm3)。N值为对照组为13只小鼠(第16天有8只小鼠存活)、仅抗PD-L1抗体组为10只小鼠(第16天有9只小鼠存活)、抗PD-L1抗体+ALA施用组为4只小鼠(第16天所有小鼠均存活),并且抗PD-L1抗体+ALA+SFC施用组为9只小鼠(第16天所有小鼠均存活)。
结果
在接种的第16天,与仅抗PD-L1抗体组相比,抗PD-L1抗体+ALA施用组的肿瘤体积明显更小(图2)。此外,当添加ALA并进一步施用SFC时,抗PD-L1抗体的作用更为显著(抗PD-L1抗体+ALA+SFC施用组)。该结果表明,通过组合使用ALA+SFC增强了抗PD-L1抗体的抗肿瘤作用,并且预期有助于进一步延长小鼠存活率。
<实施例2>通过组合使用ALA和PD-1抗体而增强抗肿瘤作用
实验方法
对于C57BL/6小鼠,将3×105个小鼠黑素瘤细胞株B16F10接种在胁部,并使肿瘤生长16天。在接种的第8天和第12天,向仅PD-1抗体施用组、抗PD-1抗体+ALA施用组、以及抗PD-1抗体+ALA+SFC施用组腹膜内施用200μg/小鼠的抗小鼠PD-1抗体(克隆:RMP1-14)(图3)。对于抗PD-1抗体+ALA+SFC施用组,从接种的第8天至第16天,每天一次经口施用100mg/kg的ALA盐酸盐(来自neo ALA CO.,LTD.)和157mg/kg的柠檬酸亚铁钠(SFC;来自KOMATSUYACORPORATION)。接种之后不进行处理的组作为对照组。
每两天测量肿瘤直径,并将v(其中v=(短径,mm)2×(长径,mm)/2)记录为肿瘤体积(mm3)。N值为对照组为18只小鼠(第16天有10只小鼠存活)、仅抗PD-1抗体组为10只小鼠(第16天所有小鼠均存活),并且抗PD-1抗体+ALA +SFC施用组为10只小鼠(第16天有9只小鼠存活)。
结果
接种的第16天,与仅抗PD-1抗体组相比,抗PD-1抗体+ALA+SFC施用组的肿瘤体积明显更小(图4)。该结果表明,通过组合使用ALA+SFC增强了抗PD-1抗体的抗肿瘤作用,并且预期有助于进一步延长小鼠存活率。
工业适用性
根据本发明,提供了用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物。因此,通过组合使用免疫检查点抑制剂和根据本发明的药物组合物,预期导致癌症患者的寿命延长并提高缓解率。
另外,由于作为根据本发明的药物组合物的活性成分的ALA是在动物、植物、真菌等中广泛存在的体内含有的天然氨基酸的一种类型,因此其具有能够在体内安全使用的优点。
本申请还涉及以下实施方案:
1.用于增强免疫检查点抑制剂之抗肿瘤作用的药物组合物,其包含下式(I)所示化合物或者其盐或酯:
[化学式1]
R1-NHCH2COCH2OH2COOR2 (I)
(其中R1表示氢原子或酰基,并且R2表示氢原子、直链或支链烷基、环烷基、芳基或芳烷基)。
2.根据实施方案1所述的药物组合物,其中所述免疫检查点抑制剂是选自以下的至少一种:抗PD-1抗体、抗PD-L1抗体、抗CTLA4抗体、抗B7抗体、抗C27抗体、抗KIR抗体、IDO抑制剂、抗CD137抗体和抗TIM3抗体。
3.根据实施方案2所述的药物组合物,其特征在于所述免疫检查点抑制剂是抗PD-L1抗体或抗PD-1抗体。
4.根据实施方案1所述的药物组合物,其中所述免疫检查点抑制剂选自:阿替利珠单抗、度伐单抗、阿维单抗、纳武单抗、派姆单抗、皮地利珠单抗、BMS-936559、伊匹单抗、曲美木单抗、恩必利珠单抗、瓦利路单抗、立鲁单抗、艾卡哚司他、乌托米单抗、乌瑞鲁单抗和TSR-022。
5.根据实施方案1至4中任一项所述的药物组合物,其特征在于其与所述免疫检查点抑制剂同时或在不同的时间施用。
6.根据实施方案1至5中任一项所述的药物组合物,其特征在于:
R1选自氢原子、具有1至8个碳的烷酰基、以及具有7至14个碳的芳酰基,并且
R2选自氢原子、具有1至8个碳的直链或支链烷基、具有3至8个碳的环烷基、具有6至14个碳的芳基、以及具有7至15个碳的芳烷基。
7.根据实施方案1至6中任一项所述的药物组合物,其中R1和R2是氢原子。
8.根据实施方案1至7中任一项所述的药物组合物,其还包含一种或两种或更多种类型的含金属化合物。
9.根据实施方案8所述的药物组合物,其中所述含金属化合物是包含铁、镁、锌、镍、钒、铜、铬、钼或钴的化合物。
10.根据实施方案9所述的药物组合物,其中所述含金属化合物是包含铁、镁或锌的化合物。
11.根据实施方案10所述的药物组合物,其中所述含金属化合物是包含铁的化合物。
12.根据实施方案11所述的药物组合物,其中所述包含铁的化合物是柠檬酸亚铁钠。
13.下式(I)所示化合物或者其盐或酯在生产用于增强免疫检查点抑制剂之抗肿瘤作用的药物中的用途:
[化学式2]
R1-NHCH2COCH2CH2COOR2 (I)
(其中R1表示氢原子或酰基,并且R2表示氢原子、直链或支链烷基、环烷基、芳基或芳烷基)。
14.用于增强免疫检查点抑制剂之抗肿瘤作用的方法,其包括向施用了或正在施用免疫检查点抑制剂的对象施用下式(I)所示化合物或者其盐或酯:
[化学式3]
R1-NHCH2COCH2CH2COOR2 (I)
(其中R1表示氢原子或酰基,并且R2表示氢原子、直链或支链烷基、环烷基、芳基或芳烷基)。
Claims (5)
1.下式(I)所示化合物或者其盐或酯在制备用于增强免疫检查点抑制剂对癌症之抗肿瘤作用的药物中的用途:
[化学式1]
R1-NHCH2COCH2CH2COOR2 (I)
其中R1表示氢原子或酰基,并且R2表示氢原子、直链或支链烷基、环烷基、芳基或芳烷基,
其中所述药物还包含柠檬酸亚铁钠,并且
其中所述免疫检查点抑制剂是抗PD-L1抗体或抗PD-1抗体。
2.根据权利要求1所述的用途,其特征在于所述药物与所述免疫检查点抑制剂同时或在不同的时间施用。
3.根据权利要求1或2所述的用途,其特征在于:
R1选自氢原子、具有1至8个碳的烷酰基、以及具有7至14个碳的芳酰基,并且
R2选自氢原子、具有1至8个碳的直链或支链烷基、具有3至8个碳的环烷基、具有6至14个碳的芳基、以及具有7至15个碳的芳烷基。
4.根据权利要求1或2所述的用途,其中R1和R2是氢原子。
5.根据权利要求1或2所述的用途,其中所述癌症是黑素瘤。
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