CN110464845A - 一种用于乳腺癌免疫治疗的联合用药物组合及其应用 - Google Patents
一种用于乳腺癌免疫治疗的联合用药物组合及其应用 Download PDFInfo
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Abstract
本发明公开一种用于乳腺癌免疫治疗的联合用药物组合及其应用,包括有效量SR1664抑制剂和有效量的免疫检查点阻断抗体。本发明进一步提供了一种肿瘤免疫治疗联合用药方法。本发明发现SR1664可作用于CDK5介导的PPARγ磷酸化抑制肿瘤恶性进展,通过调控肿瘤微环境中肿瘤相关巨噬细胞表型及功能,提高T细胞浸润,进而逆转了免疫抑制性肿瘤微环境,SR1664与免疫检查点阻断抗体协同作用,进一步增强对于肿瘤的抑制。
Description
技术领域
本发明属于医药生物技术领域,具体为一种用于乳腺癌免疫治疗的联合用药物组合及其应用。
背景技术
乳腺癌已成为全球女性最为常见的恶性肿瘤之一,我国近年来乳癌发病率正以每年3%的速度递增,成为城市中死亡率增长最快的癌症,发病年龄也呈逐渐年轻化的趋势。由于其高度异质性,乳腺癌分为4种类型即:Luminal A(ER+/PR+Her2-)、Luminal B(ER+/PR+Her2+或ER+/PR+Ki67>14%)、Her2+(ER-PR-Her2+)、以及Basal-like型(Triple-negativebreast cancer,TNBC)(ER-PR-Her2-)。其中三阴型乳腺癌(triple-negative breastcancer,TNBC)是特指雌激素受体(ER)、孕激素受体(PR)及人表皮生长因子受体2(HER2)均阴性的乳腺癌患者,其恶性程度高、复发转移快、病死率高,占所有乳腺癌的15%~20%,并多发于年轻的女性。由于TNBC不表达激素受体,对内分泌治疗不反应,临床尚无可利用的分子靶向药物,改善患者预后差的现状,因此,探索一种新的有效的治疗策略迫在眉睫。
氧化物酶体增殖物激活受体(peroxisome proliferatoractivated receptors,PPARs)是一类由配体激活的核转录因子,属II型核激素受体超家族成员,包括PPARα、β/δ、γ3种受体亚型。PPARγ在多种肿瘤细胞中均有表达,经PPARγ的配体激活后,能抑制癌细胞的生长,如乳腺癌、胰腺癌、结肠癌、胃癌等。SR1664是PPARγ非激动抑制剂,可抑制Cdk5介导的PPARγ磷酸化,临床上SR1664已作为药物用于II型糖尿病的治疗。鉴于PPARγ磷酸化与多种肿瘤关系紧密,可拓展SR1664在肿瘤的免疫治疗中的应用。
不同于传统肿瘤治疗策略,免疫治疗靶向患者免疫系统,提高肿瘤细胞的免疫原性和对效应细胞杀伤的敏感性,激发和增强机体的抗肿瘤免疫应答,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。程序性死亡受体-1(programmed death-1,PD-1)表达与T细胞中,属于免疫球蛋白超家族I型跨膜糖蛋白。经FDA批准上市的两种靶向PD-1的阻断抗体(Pembrolizumab,Nivolumab)在黑色素瘤治疗中效果显著。然而,靶向PD-1免疫治疗策略在其他实体瘤,如乳腺癌、肝癌等中疗效有限,并且出现了不同程度的免疫治疗抵抗以及复发。如何提高免疫治疗疗效,成为当前免疫治疗研究热点之一。
发明内容
鉴于此,本发明提供一种可用于肿瘤免疫治疗的联合用药物组合及其应用。所述免疫治疗药物包括有效量的PPARγ磷酸化抑制剂和有效量的免疫检查点阻断抗体。
所述PPARγ磷酸化抑制剂是指对于PPARγ磷酸化具有抑制效果的化合物。
对于PPARγ磷酸化具有抑制效果包括但不限于:抑制PPARγ磷酸化,或者与PPARγ磷酸化调控相关其他信号通路相关分子的抑制剂。
所述的PPARγ磷酸化抑制剂可为siRNA、shRNA、抗体、小分子化合物、短肽。
本发明实施例列举的,所述PPARγ磷酸化抑制剂为SR1664。
所述免疫检查点阻断抗体可选抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体等之一或其组合。在本发明优选的实施例中,所述免疫检查点阻断抗体疗法药物为抗PD-1抗体。
所述联合治疗药物组合可以是以下形式中的任意一种:
1)将PPARγ磷酸化抑制剂和免疫检查点阻断抗体分别制成独立的制剂,制剂的剂型可相同或不同,给药途径可相同或不同。
2)将PPARγ磷酸化抑制剂和免疫检查点阻断抗体配置成复方制剂。在PPARγ磷酸化抑制剂和免疫检查点阻断抗体采用相同给药途径给药并同时施加时,可采用将两者配置成复方制剂的形式。
本发明第二方面提供了一种肿瘤免疫治疗联合用药治疗方法,为向对象联合施用有效量的PPARγ磷酸化抑制剂,以及有效量的免疫检查点阻断抗体。
所述的对象为哺乳动物或所述哺乳动物的T细胞、巨噬细胞、肿瘤细胞。所述哺乳动物优选为啮齿目动物、偶蹄目动物、奇蹄目动物、兔形目动物、灵长目动物等。所述灵长目动物优选为猴、猿或智人。
所述对象可以是罹患肿瘤的患者或期待提高抗肿瘤免疫力的个体,或者为罹患肿瘤的患者或期待提高抗肿瘤免疫力的个体的离体CTL细胞。
可以同步的或顺序地给予有效量的PPARγ磷酸化抑制剂和有效量的免疫检查点阻断抗体。
基于SR1664首次用于肿瘤免疫治疗,本发明经研究发现,在与免疫检查点阻断抗体联合用药中,两者可以起到协同效果,进一步增强对于肿瘤的抑制。
所述肿瘤免疫治疗针对的肿瘤包括乳腺癌各种亚型,包括但不局限于:Luminal A(ER+/PR+Her2-)、Luminal B(ER+/PR+Her2+或ER+/PR+Ki67>14%)、Her2+(ER-PR-Her2+)、以及三阴乳腺癌(Triple-negative breast cancer,TNBC)(ER-PR-Her2-)。
所述PPARγ磷酸化抑制剂及免疫检查点阻断抗体疗法药物可以在接受肿瘤免疫治疗前、中、后向对象施用。
本发明的优点在于:
(1)通过一系列体外实验,发现SR1664在调控肿瘤细胞干性转化过程中发挥至关重要的作用,通过抑制PPARγ磷酸化可以显著抑制肿瘤细胞干性转化,EMT,侵袭,转移等各个过程。
(2)在动物水平上,抑制PPARγ磷酸化显著改善肿瘤免疫微环境:一方面,显著增加肿瘤组织中T细胞浸润,这一过程可能同肿瘤相关巨噬细胞表型及功能转化相关(从免疫抑制的M2型巨噬细胞向促进抗肿瘤免疫的M1型巨噬细胞);另一方面,显著抑制肿瘤细胞恶性转化。在与抗PD-1抗体的联合治疗小鼠原位接种乳腺癌实验中,PPARγ磷酸化抑制剂SR1664可以与PD-1抗体协同促进免疫细胞(CD8T细胞、肿瘤相关巨噬细胞等)介导的抗肿瘤活性。
(3)本发明在肿瘤免疫治疗领域给SR1664提供了新的临床应用价值,不仅为其进一步的市场应用提供了广阔的前景,也为肿瘤患者提供了更加有效的治疗方案。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下将以本发明的较佳实施案例并配合附图进行详细说明。本发明的具体实施方式由以下实施例及其附图详细给出。
附图说明
此处所说明的附图用来提供对本发明的进一步理解,构成本发明的一部分,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定,在附图中:
图1.SR1664抑制肿瘤细胞增殖和侵袭。
a.运用Transwell小室侵袭实验,体外验证SR1664抑制剂对乳腺癌细胞侵袭能力的影响。
b.通过QPCR检测增殖相关基因(ANGPT1、CHRNB2、LEP等)在SR1664抑制剂作用下表达情况。
图2.PPARγ磷酸化抑制剂SR1664与PD-1阻断抗体联合处理抑制小鼠乳腺癌发展进程
a.Western Blot显示SR1664对PPARγ Ser273磷酸化有明显的抑制效果(见图2A)。
b.对4T1原位种植乳腺癌小鼠进行SR1664与PD-1阻断抗体联合治疗,检测肿瘤生长曲线和小鼠生存率,比较联合治疗与单一疗法效果的差异,给药20天后,处死小鼠分离肿瘤组织,称量肿瘤重量以及体重,比较联合治疗与单一疗法的效果差异。小鼠生存曲线用log-rank(Mantel-Cox)统计方法进行分析(n=10)(见图2B、C、D)。
d.通过流式分析各处理组小鼠肿瘤组织中浸润的CD8T细胞与Treg细胞浸润情况,并比较联合治疗与单一疗法对T细胞浸润程度的影响。同时分析CD8T细胞与Treg比例(见图2E)。
具体实施方式
本发明经研究发现,SR1664可以通过调控CDK5介导的PPARγ磷酸化,调节肿瘤免疫微环境。因此认为SR1664可用作肿瘤免疫治疗调节剂与其他肿瘤免疫治疗剂联合使用以提高肿瘤免疫治疗疗效。进一步的研究表明,在与抗PD-L1抗体联合用药中,两者可以起到协同效果,可以进一步增强对于肿瘤的抑制。
PPARγ磷酸化抑制剂是指对于PPARγ磷酸化具有抑制效果的化合物。PPARγ磷酸化具有抑制效果包括但不限于:抑制PPARγ磷酸化,或者与PPARγ磷酸化调控相关其他信号通路相关分子的抑制剂。
所述的PPARγ磷酸化抑制剂包括但不限于为siRNA、shRNA、抗体、小分子化合物。
本领域技术人员可以使用常规方法对PPARγ磷酸化进行调节,如基因突变、RNA干扰等。
SR1664抑制PPARγ磷酸化可以通过Western Blot验证(图2A)。
联合治疗药物组合和施用方法
所述联合治疗药物组合可以使以下形式中的任意一种:
一)将PPARγ磷酸化抑制剂和免疫检测点阻断抗体分别制成独立的药物制剂,制剂的剂型可相同或不同,给药途径亦可相同或不同。使用时,可两种药同时使用,也可两种药先后使用。先后给药时应当在先用药物仍对机体有效的期间内向机体施加其他药物。
二)将PPARγ磷酸化抑制剂和免疫检测点阻断抗体配置成复方制剂。在将PPARγ磷酸化抑制剂和免疫检测点阻断抗体采用相同给药途径给药并同时施加时,可采用将两者配置成复方制剂的形式。
免疫检测点阻断抗体常用的用药方法为静脉注射、静脉滴注或动脉灌注。其用法用量可参考现有技术。
小分子化合物常用的用药方法可以使胃肠道给药或者是胃肠外给药。siRNA、shRNA、抗体则一般采用胃肠外给药。可以是局部给药亦可以为全身给药。
可以同步的或顺序地给予有效量的PPARγ磷酸化抑制剂和有效量的免疫检测点阻断抗体。在部分实施例中,PPARγ磷酸化抑制剂采用胃肠道给药剂型,免疫检测点阻断抗体采用胃肠外给药剂型。或者,PPARγ磷酸化抑制剂及免疫检测点阻断抗体均采用胃肠外给药剂型。使用时,可两种药同时使用,也可两种药先后使用。先后给药时,应当在先用药物仍对生物体有效的期间内向生物体施加其他药物。
在以PPARγ磷酸化抑制剂为主要活性成分或主要活性成分之一制备药物或药物组合时。通常,药物中除了有效成分外,根据不同剂型的需要,还会包括一种或多种药学上可接受的载体或辅料。
“药学上可接受的”是指当分子本体和组合物适当的给予动物或人时,它们不会产生不利的、过敏的或其它不良反应。
“药学上可接受的载体或辅料”应当与PPARγ磷酸化抑制剂相容,即能与其共混而不会在通常情况下大幅度降低药物组合物的效果。可作为药学上可接受的载体或辅料的一些物质的具体例子是糖类,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和土豆淀粉;纤维素及其衍生物,如甲基纤维素钠、乙基纤维素和甲基纤维素;明胶;滑石;固体润滑剂;多元醇;乳化剂;着色剂;调味剂;压片剂、稳定剂;抗氧化剂;防腐剂;无热原水;等渗盐溶液。这些物质根据需要用于帮助配方的稳定性或有助于提高活性或它的生物有效性或在口服情况下产生可接受的口感或气味。
本发明中,除非特别说明,药物剂型并无特别限定,可以被制成针剂、口服液、片剂、胶囊、滴丸、喷剂等剂型,可通过常规方法进行制备。药物剂型的选择应与给药方式相匹配。
在进一步描述本发明具体实施方式之前,应理解,本发明的保护范围不局限于下述特定的具体实施方案;还应当理解,本发明实施例中使用的术语是为了描述特定的具体实施方案,而不是为了限制本发明的保护范围。
除非另外定义,本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外,根据本技术领域的技术人员对现有技术的掌握及本发明的记载,还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。
除非另外说明,本发明中所公开的实验方法、检测方法、制备方法均采用本技术领域常规的分子生物学、生物化学、染色质结构和分析、分析化学、细胞培养、重组DNA技术以及相关领域的常规技术。这些技术在现有文献中也有完善说明,具体可参见Sambrook等MOLECULAR CLONING:A LABORATORY MANUAL,Second edition,Cold Spring HarborLaboratory Press,1989 andThird edition,2001;Ausubel等,CURRENT PROTOCOLS INMOLECULAR BIOLOGY,John Wiley&Sons,New York,1987 and periodic updates;theSeries METHODS IN ENZYMOLOGY,Academic Press,San Diego;Wolffe,CHROMATINSTRUCTURE AND FUNCTION,Third edition,Academic Press,San Diego,1998;METHODS INENZYMOLOGH,Vol.304,Chromation(P.M.Wassarman and A.P.Wolffe,eds.),AcademicPress,San Diego,1999;和METHODS IN MOLECULAR BIOLOGY,Vol.119,ChromatinProtocols(P.B.Becker,ed.)Humana Press,Totowa,1999等。
以下实施例将结合附图对本发明作进一步的说明。
实施例1:SR1664抑制肿瘤细胞增殖和侵袭。
本实施例目的是验证SR1664抑制剂在肿瘤细胞恶性转化中的作用。PPARγ磷酸化抑制剂SR1664已经作为临床药物用于II型糖尿病的治疗,但是其对肿瘤的治疗还在研究阶段。因此,选用SR1664验证其作为肿瘤免疫治疗靶点的可能性。体外实验表明,SR1664可以显著的抑制乳腺癌细胞侵袭能力(图1.A、B)。通过QPCR检测肿瘤细胞增殖相关基因ANGPT1、CHRNB2、LEP等表达情况,结果显示SR1664抑制剂可以显著抑制ANGPT1、CHRNB2、LEP等基因的表达,抑制肿瘤细胞的增殖。
实施例2:PPARγ磷酸化抑制剂SR1664与PD-1阻断抗体联合处理抑制小鼠乳腺癌发展进程。
目前肿瘤免疫治疗方法中,PD-1阻断抗体和CTLA-4阻断抗体在黑色素瘤以及非小细胞肺癌中取得了较好的治疗效果,但由于肿瘤微环境的复杂性以及高度免疫抑制性限制了肿瘤免疫治疗的效果。本实施例的目的是验证SR1664作为改善肿瘤细胞自身恶性程度,调节免疫微环境抑制性特点在联合免疫检查点阻断抗体在肿瘤免疫治疗过程中的增效作用。结果表明SR1664在与PD-1阻断抗体联合治疗中取得更好的疗效,小鼠肿瘤的生长显著减慢,同时小鼠的生存时间显著延长(图2.B,C,D)。通过对肿瘤浸润T细胞进行分析发现,SR1664治疗后,显著增加肿瘤组织中T细胞的浸润(图2.E),而T细胞浸润少是限制免疫治疗最重要的因素之一。综上所述,SR1664与PD-1阻断抗体的联合治疗具有协同效应,可以抑制肿瘤细胞恶性转化的同时影响肿瘤微环境免疫状态,联合PD-1阻断抗体进一步促进T细胞介导的抗肿瘤免疫,从而极大的延长荷瘤小鼠生存率。
以上所述仅为本发明的优选实例,并不限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化,凡在本发明的精神和原则之内所作的任何修改等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种用于治疗乳腺癌联合用药物组合,所述药物组合包括有效量的SR1664或其类似物作用于PPARγ磷酸化和有效量的免疫检查点阻断抗体。
2.如权利要求1所述的用于乳腺癌免疫治疗的联合用药物组合,其特征在于,所述SR1664抑制剂可以阻断CDK5介导的PPARγ磷酸化,包括PPARγ Ser273磷酸化。
3.如权利要求1所述乳腺癌免疫治疗联合用药治疗方法,其特征在于,同步的或顺序地给予有效量的PPARγ磷酸化抑制剂和有效量的免疫检查点阻断抗体。
4.如权利要求3所述乳腺癌免疫治疗联合用药治疗方法,其特征在于,所述免疫治疗针对的乳腺癌各个亚型:Luminal A(ER+/PR+Her2-)、Luminal B(ER+/PR+Her2+或ER+/PR+Ki67>14%)、Her2+(ER-PR-Her2+)、以及三阴乳腺癌(Triple-negative breast cancer,TNBC)(ER-PR-Her2-)。
5.如权利要求3所述乳腺癌免疫治疗联合用药治疗方法,其特征在于,所述的PPARγ磷酸化抑制剂选自siRNA、shRNA、抗体、小分子化合物、肽段,优选SR1664。
6.如权利要求3所述乳腺癌免疫治疗联合用药治疗方法,其特征在于,所述免疫检查点阻断抗体选自抗PD-1抗体、抗PD-L1抗体或抗CTLA-4抗体。
7.如权利要求3所述乳腺癌免疫治疗联合用药治疗方法,其特征在于,所述的对象为哺乳动物或所述哺乳动物的免疫细胞,优选CD8T细胞,巨噬细胞。
8.如权利要求3所述乳腺癌免疫治疗联合用药治疗方法,其特征在于,所述的哺乳动物为人。
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