CN113164778A - 抗ceacam6和tim3抗体的药物组合 - Google Patents
抗ceacam6和tim3抗体的药物组合 Download PDFInfo
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- CN113164778A CN113164778A CN201980078825.6A CN201980078825A CN113164778A CN 113164778 A CN113164778 A CN 113164778A CN 201980078825 A CN201980078825 A CN 201980078825A CN 113164778 A CN113164778 A CN 113164778A
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Abstract
本发明涉及至少两种组分(组分A和组分B)的组合,组分A为抗CEACAM6抗体TPP‑3310,组分B为抗TIM‑3抗体,优选考伯利单抗、MBG‑453、BMS‑986258、Sym‑023、LY‑3321367或INCAGN‑2390。
Description
本发明涉及至少两种组分(组分A和组分B)的组合,组分A为抗CEACAM6抗体TPP-3310,组分B为抗TIM-3抗体,优选考伯利单抗(cobolimab)、MBG-453、BMS-986258、Sym-023、LY-3321367或INCAGN-2390。
本发明的另一个方面涉及本文所述的这种组合在制备用于治疗或预防癌症的药物中的用途。
本发明的又一个方面涉及治疗或预防受试者癌症的方法,其包括向所述受试者给予治疗有效量的本文所述的组合。
此外,本发明涉及一种试剂盒,其包含以下组分的组合:
-组分A,为抗CEACAM6抗体TPP-3310;
-组分B,优选为考伯利单抗、MBG-453、BMS-986258、Sym-023、LY-3321367或INCAGN-2390,和任选地
-一种或多种药物制剂C;
其中任选地,所述组分A和B之一或两者均为同时、并行(concurrently)、分别(separately)或顺序给药的即用型(ready for use)药物制剂的形式。
组分A和B优选通过静脉途径给药。
在一些实施方案中,所述癌症为肺癌,特别是非小细胞肺癌(NSCLC)、胰腺癌、胃癌、结直肠癌、头颈癌、膀胱癌、胆管癌、乳腺癌、宫颈癌、食道癌。
背景技术
癌症是美国第二大最常见的死亡原因,每年导致450,000例死亡。尽管在确定癌症的一些可能的环境和遗传原因方面已取得实质性进展,但仍需要靶向癌症和相关疾病的其他治疗方式。特别地,需要用于治疗与生长/增殖失调有关的疾病的治疗方法。
癌症是对具有后天功能性能力(如增强的对细胞凋亡的生存力/抗性和无限的增殖潜力)的细胞进行选择过程后产生的复杂疾病。因此,优选开发用于癌症疗法的药物,以解决已建立的肿瘤的不同特征。
已经在许多肿瘤中描述了针对肿瘤相关抗原的T细胞应答,其通常引起肿瘤特异性记忆T细胞在淋巴器官或在血液中的积累。然而,T细胞对自体肿瘤细胞反应的能力通常较低。许多肿瘤具有阻断T细胞的效应子功能的能力,这导致了肿瘤免疫疗法的有限活性。对于多种癌症,T细胞针对肿瘤细胞的无应答性已被证明。
免疫系统依赖于多个检查点或“免疫制动子(immunological brake)”,以避免免疫系统在健康细胞上的过度活化。肿瘤细胞通常利用这些检查点来逃避免疫系统的检测。CTLA-4和PD-1是已作为癌症疗法的靶点进行研究的检查点。
检查点蛋白调节T细胞的活化或功能。许多检查点蛋白是已知的,例如CTLA-4及其配体CD80和CD86;以及PD-1及其配体PD-L1和PD-L2。所述新型检查点蛋白质为TIM-3、LAG-3等。这些蛋白质负责T细胞应答的共刺激性或抑制性相互作用。免疫检查点蛋白调节并维持自我耐受性以及生理免疫应答的持续时间和幅度。免疫检查点抑制剂包括抗体或衍生自抗体。目前,不同的免疫疗法正成为各种恶性疾病的有力治疗策略。
最近一个非常著名的癌症免疫疗法成功的实例涉及免疫检查点阻断疗法,所述疗法通过靶向免疫效应子T细胞或包括肿瘤细胞在内的抗原呈递细胞上的抑制性分子的单克隆抗体(mAb)。用共抑制剂干预已被证明会释放出强大的抗肿瘤T细胞应答(Pardoll:Theblockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer 12:(2012)252–264)。
CTLA-4已被证明在某些癌症中被异常上调并存在于T细胞的表面,从而抑制了对肿瘤细胞应答的T细胞活化。PD-1是另一个已在某些肿瘤中被发现上调的免疫检查点;它抑制T细胞功能,从而有助于肿瘤逃避免疫系统的能力。
用于免疫细胞活化的免疫检查点分子的抗体阻断是经过临床验证的方法。在2011年,CTLA-4阻断抗体伊匹单抗(Ipilimumab)已被FDA批准用于转移性黑色素瘤(Yervoy)的二线疗法。另一个实例为阻断PD-1/PD-L1轴,为此批准了或正在临床研发几种药物,并已经报道了在黑色素瘤、肺癌、RCC、膀胱癌等中引人瞩目的临床反应(Shen和Zhao:Efficacy ofPD-1and PD-L1 inhibitors and PD-L1 expression status in cancer:meta-analysis.BMJ2018;362:k3529)。
在2013年,据报道,抗CTLA4和抗PD1 mAb的组合治疗在晚期黑色素瘤患者的生存率提高和肿瘤消退中具有协同作用(Wolchok等人:Nivolumab plus ipilimumab inadvanced melanoma.N Engl J Med 369:(2013)122-133)。
抗TIM-3单克隆抗体处于II期和I期临床研发中(clinicaltrials.gov)。它们的临床相关性和潜力记载于例如Marin-Acevedo等人,“Next generation of immunecheckpoint therapy in cancer:new developments and challenges”,2018Journal ofHematology&Oncology 11:39和Buruguru等人,“Emerging targets in cancerimmunotherapy”,Seminars in Cancer Biology 52(2018):39-52中。
CEACAM6还有助于调节CD8+T细胞应答。在表达若干个CEACAM家族成员的多发性骨髓瘤中,用抗CEACAM6 mAb或siRNA沉默CEACAM6治疗,恢复了针对恶性浆细胞的T细胞反应性,从而表明CEACAM6在CD8+T细胞应答调节中的作用(Witzens-Harig等人,Blood 2013May30;121(22):4493-503)。WO 2016/150899 A2中公开了包括TPP-3310在内的用于癌症免疫疗法的非常有效的抗CECAM6抗体。
定义
除非另有定义,否则本文中使用的所有技术和科学术语具有本发明所属领域的普通技术人员通常所理解的含义。但是,以下参考文献可以为本发明所属领域的技术人员提供本发明中所使用的许多术语的一般定义,并且只要这些定义与本领域中通常理解的含义相一致,就可以参考和使用。所述参考文献包括但不限于,Singleton等人,Dictionary ofMicrobiology and Molecular Biology(第2版1994);The Cambridge Dictionary ofScience and Technology(Walker编辑,1988);Hale&Marham,The Harper CollinsDictionary of Biology(1991);和Lackie等人,The Dictionary of Cell&MolecularBiology(第3版1999);和Cellular and Molecular Immunology,Eds.Abbas,Lichtman andPober,第2版,W.B.Saunders Company。可以咨询本领域普通技术人员可获得的任何其他技术资源,其提供本文所用术语的具有本领域通常理解的含义的定义。为了本发明的目的,进一步定义以下术语。其他的术语在说明书的其他地方定义。如本文和所附权利要求书中所用,除非上下文另有明确规定,否则单数形式“一(a)”和“所述(the)”包括复数参考物。因此,例如,对“基因”的提及是对一个或多个基因的提及,并且包括本领域技术人员已知的其等同物,等等。
术语“多肽”和“蛋白质”在本文中可互换使用,是指氨基酸残基的聚合物。该术语适用于其中一个或多个氨基酸残基为相应的天然存在的氨基酸的人工化学模拟物的氨基酸聚合物,以及适用于天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。除非另有说明,否则特定的多肽序列还隐含地包括其保守修饰的变体。
在本文中,氨基酸可以用其众所周知的三个字母符号或IUPAC-IUB生化命名委员会推荐的单字母符号来指代。同样,核苷酸可以用其通常被接受的单字母编码来指代。
根据本发明,术语“抗体”应以其最宽泛的含义理解并包含免疫球蛋白分子,例如完整或修饰的单克隆抗体、多克隆抗体或多特异性抗体(例如双特异性抗体)。免疫球蛋白分子优选由通常通过二硫键相互连接的四条多肽链——两条重(H)链和两条轻(L)链——组成。每条重链由重链可变区(本文中缩写为VH)和重链恒定区组成。重链恒定区可包含例如三个结构域CH1、CH2和CH3。每条轻链由轻链可变区(本文中缩写为VL)和轻链恒定区组成。轻链恒定区由一个结构域(CL)组成。所述VH和VL区可进一步细分为高变区,称为互补决定区(CDR),其间散布着更为保守的区,称为骨架区(FR)。每个VH和VL通常由三个CDR和最高达四个FR组成,从氨基端至羧基端排列,例如按以下顺序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。
如本文中所用,术语“互补决定区”(CDR;例如CDR1、CDR2和CDR3)是指抗体可变结构域的氨基酸残基,其存在对于抗原结合是必需的。每个可变结构域通常具有三个CDR区,标识为CDR1、CDR2和CDR3。每个互补决定区可包含来自Kabat定义的“互补决定区”的氨基酸残基(例如关于轻链可变结构域中的残基24-34(L-CDR1)、50-56(L-CDR2)和89-97(L-CDR3)以及重链可变结构域中的残基31-35(H-CDR1)、50-65(H-CDR2)和95-102(H-CDR3);(Kabat等人,Sequences of Proteins of Immulological Interest,第5版,Public HealthService,National Institutes of Health,Bethesda,MD.(1991))和/或来自“高变环(hypervariable loop)”的那些残基(例如关于轻链可变结构域中的残基26-32(L-CDR1)、50-52(L-CDR2)和91-96(L-CDR3)以及重链可变结构域中的残基26-32(H-CDR1)、53-55(H-CDR2)和96-101(H-CDR3)(Chothia和Lesk;J Mol Biol 196:901-917(1987))。在一些情况下,互补决定区可包括来自根据Kabat定义的CDR区和高变环的氨基酸。
根据其重链恒定结构域的氨基酸序列,可将完整抗体分成不同的“类别”。完整抗体有五种主要类别:IgA、IgD、IgE、IgG和IgM,并且其中几种可进一步分为“亚类”(同型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。用于本发明的一类优选的免疫球蛋白为IgG。
对应于不同类别的抗体的重链恒定结构域分别称为[α]、[δ]、[ε]、[γ]和[μ]。不同类别的免疫球蛋白的亚基结构和三维构型是众所周知的。如本文中所用,抗体为常规已知的抗体及其功能性片段。
“抗-抗原”抗体是指与抗原特异性结合的抗体。例如,抗PD-1抗体特异性结合PD-1,抗CECAM6抗体特异性结合CECAM6,以及抗TIM-3抗体特异性结合TIM-3。
术语“特异性结合(specific binding或bind specifically)”是指与预定的抗原/靶分子结合的抗体或结合剂(binder)。抗体或结合剂的特异性结合通常描述了亲和力为至少10-7M(以Kd值表示;即优选Kd值小于10-7M的那些)的抗体或结合剂,其中该抗体或结合剂对预定的抗原/靶分子的亲和力比对不是预定的抗原/靶分子或密切相关的抗原/靶分子的非特异性抗原/靶分子(例如牛血清白蛋白或酪蛋白)的亲和力高至少两倍。抗体或结合剂的特异性结合不排除抗体或结合剂与多种抗原/靶分子(例如不同物种的直系同源物)的结合。抗体优选具有的亲和力为至少10-7M(以Kd值表示;换言之,优选Kd值小于10-7M的那些),优选至少10-8M,更优选10-9M至10-11M。Kd值可例如通过表面等离子体共振光谱测定。
“功能性片段”、“抗原结合抗体片段”或“抗体片段”是指抗体的一个或多个片段,其保留与整个抗体所结合的抗原特异性结合的能力。本发明的“功能性片段”、“抗原结合抗体片段”或“抗体片段”包括但不限于Fab、Fab'、Fab'-SH、F(ab')2和Fv片段;双体;单结构域抗体(DAb)、线性抗体;单链抗体分子(scFv);以及由抗体片段形成的多特异性(例如双特异性和三特异性)抗体(C.A.K Borrebaeck,编辑(1995)Antibody Engineering(Breakthroughs in Molecular Biology),Oxford University Press;R.Kontermann&S.Duebel,编辑(2001)Antibody Engineering(Springer Laboratory Manual),SpringerVerlag)。
术语“免疫疗法”是指通过包括诱导、增强、抑制或以其他方式改变免疫应答的方法来治疗患有疾病,或有感染或患有疾病复发风险的受试者。
受试者的“治疗(treatment)或“疗法(therapy)”是指对受试者进行的任何类型的干预或过程,或向受试者给予活性剂,目的是逆转、缓解(alleviating)、改善、抑制、减缓或预防与疾病相关的症状、并发症或病况(condition)或生化标记的发作、进展、发展、严重程度或复发。
如本文中所用,“CEACAM6”指“癌胚抗原相关细胞粘附分子6”,也称为“CD66c”(分化簇66c)或非特异性交叉反应抗原或NCA或NCA-50/90。CEACAM6为糖基磷脂酰肌醇(GPI)连接的细胞表面蛋白,其参与细胞间粘附。如本文中所用,术语“CEACAM6”包括人CEACAM6(hCEACAM6),hCEACAM6的变体、同种型(isoform)和物种同系物,以及与hCEACAM6具有至少一个共同表位的类似物。人CEACAM6的参考序列可从UniProtKB/Swiss-Prot数据库获得,登录号为P40199.3。
“程序性死亡-1(PD-1)”是指属于CD28家族的免疫抑制受体。PD-1主要在体内先前活化的T细胞上表达,并与两个配体PD-L1和PD-L2结合。如本文中所用,术语“PD-1”包括人PD-1(hPD-1),hPD-1的变体、同种型和物种同系物,以及与hPD-1具有至少一个共同表位的类似物。完整的hPD-1序列可在GenBank登录号U64863下找到。
“程序性死亡配体-1(PD-L1)”是PD-1的两个细胞表面糖蛋白配体之一(另一个为PD-L2),其在与PD-1结合后下调T细胞活化和细胞因子分泌。如本文中所用,术语“PD-L1”包括人PD-L1(hPDL1),hPD-L1的变体、同种型和物种同系物,以及与hPD-L1具有至少一个共同表位的类似物。完整的hPD-L1序列可在GenBank登录号Q9NZQ7下找到。
如本文中所用,“TIM-3”指TIM家族的成员“T细胞免疫球蛋白结构域和粘蛋白结构域3”(也称为HAVCAR2)。TIM-3为细胞表面上的跨膜蛋白质。它被描述为一种与耐受性有关的活化诱导的抑制分子,并表明会诱导T细胞衰竭。如本文中所用,术语“TIM-3”包括人TIM-3(hTIM-3),hTIM-3的变体、同种型和物种同系物,以及与hTIM-3具有至少一个共同表位的类似物。人TIM-3的参考序列可由以下获得:UniProtKB/Swiss-Prot数据库,登录号为UniProtKB Q8TDQ0(HAVR2_HUMAN);和NCBI数据库,NCBI参考序列:NP_116171.3。
如本文中所用,术语“患者”或“受试者”可互换使用,并意指哺乳动物,包括但不限于人类或非人类哺乳动物,例如牛、马、犬、绵羊或猫。优选地,所述患者为人类。
发明内容
出人意料地观察到,在用于评估药物组合对肿瘤退缩的治疗潜力的体外试验中,TIM-3免疫检查点抑制剂和抗CECAM6抗体TPP-3310的组合的作用远大于加和作用。出人意料地,这种作用甚至比PD-1或PD-L1免疫检查点抑制剂与抗CEACAM6抗体TPP-3310的组合更强。
因此,本发明提供至少两种组分(组分A和组分B)的组合,组分A为抗CEACAM6抗体TPP-3310,组分B为抗TIM-3抗体,优选考伯利单抗、MBG-453、BMS-986258、Sym-023、LY-3321367或INCAGN-2390。
如本文中所述和所定义的,包含至少两种组分A和B的组合也称为“本发明的组合”。
此外,本发明涉及一种试剂盒,其包含:
以下组分的组合:
-组分A,为抗CEACAM6抗体TPP-3310;
-组分B,为抗TIM-3抗体,优选考伯利单抗、MBG-453、BMS-986258、Sym-023、LY-3321367或INCAGN-2390,和任选地
-一种或多种药物制剂C;
其中任选地,所述组分A和B之一或两者为同时、并行、分别或顺序给药的即用型药物制剂的形式。
本发明还提供一种抗CEACAM6抗体(组分A),其用于与抗TIM-3抗体(组分B)同时、分别或顺序结合治疗癌症,其中所述抗CEACAM6抗体包含抗体TPP-3310的H-CDR1、H-CDR2、H-CDR3、L-CDR1、L-CDR2和L-CDR3。
本发明还提供一种抗CEACAM6抗体(组分A),其用于与抗TIM-3抗体(组分B)同时、分别或顺序结合治疗癌症,其中所述抗CEACAM6抗体包含抗体TPP-3310的可变重链序列和可变轻链序列。
本发明还提供一种抗CEACAM6抗体(组分A),其用于与抗TIM-3抗体(组分B)同时、分别或顺序结合治疗癌症,其中所述抗CEACAM6抗体包含抗体TPP-3310的重链区和轻链区。
本发明还提供抗CEACAM6抗体TPP-3310(组分A),其用于与抗TIM-3抗体(组分B)同时、分别或顺序结合治疗癌症,其中所述抗TIM-3抗体为考伯利单抗、MBG-453、BMS-986258、Sym-023、LY-3321367或INCAGN-2390。
本发明还提供抗CEACAM6抗体TPP-3310(组分A),其用于与抗TIM-3抗体(组分B)同时、分别或顺序结合治疗癌症,其中所述癌症为肺癌,特别是非小细胞肺癌、卵巢癌、间皮瘤、胰腺癌、胃癌、结直肠癌、头颈癌、膀胱癌、胆管癌、乳腺癌、宫颈癌或食道癌。
本发明还提供抗CEACAM6抗体TPP-3310(组分A),其用于与抗TIM-3抗体(组分B)同时、分别或顺序结合治疗癌症,其中至少一种抗CEACAM6抗体或抗TIM-3抗体与一种或多种药物制剂(药剂C)同时、分别或顺序结合给药。
本发明还提供一种治疗癌症的方法,所述方法包括将有效量的抗CEACAM6抗体TPP-3310(组分A)与抗TIM-3抗体(组分B)同时、分别或顺序结合给予有需要的患者。
本发明还提供一种治疗癌症的方法,所述方法包括将有效量的抗CEACAM6抗体TPP-3310(组分A)与抗TIM-3抗体(组分B)同时、分别或顺序结合给予有需要的患者,其中所述抗TIM-3抗体为考伯利单抗、MBG-453、BMS-986258、Sym-023、LY-3321367或INCAGN-2390。
本发明还提供抗CEACAM6抗体TPP-3310(组分A)与抗TIM-3抗体(组分B)同时、分别或顺序结合在制备用于治疗癌症的药物中的用途。
本发明还提供抗CEACAM6抗体TPP-3310(组分A)与抗TIM-3抗体(组分B)同时、分别或顺序结合在制备用于治疗癌症的药物中的用途,其中所述抗TIM-3抗体为考伯利单抗、MBG-453、BMS-986258、Sym-023、LY-3321367或INCAGN-2390。
所述组分可以通过口服、静脉内、局部、局部装置、腹膜内或鼻腔途径彼此独立地给药。
根据另一个方面,本发明涵盖如上所述的用于治疗或预防癌症的组合。
根据另一个方面,本发明涵盖如上所述的这种组合在制备用于治疗或预防癌症的药物中的用途。
组合的组分A
组分A为WO 2016/150899 A2中公开的抗CEACAM6抗体TPP-3310。WO 2016150899A2中公开的其他抗CECAM6抗体为例如TPP-3714、TPP-3820、TPP-3821、TPP-3707和TPP-3705。这些抗体是与人CEACAM6以高亲和力结合的人抗体或人源化抗体,与猴CEACAM6交叉反应,不与任何旁系同源物(paralog)(特别是CEACAM1、CEACAM3和CEACAM5)结合,并且能够缓解CEACAM6介导的免疫抑制。
术语“抗CEACAM6抗体”涉及特异性结合癌症靶分子CEACAM6的抗体,优选具有足以用于诊断和/或治疗应用的亲和力的抗体。在某些实施方案中,抗CEACAM6抗体与在不同物种之间保守的表位结合。
TPP-3310为一种抗体,其包含含有SEQ ID NO:2的氨基酸序列的H-CDR1、含有SEQID NO:3的氨基酸序列的H-CDR2、含有SEQ ID NO:4的氨基酸序列的H-CDR3、含有SEQ IDNO:6的氨基酸序列的L-CDR1、含有SEQ ID NO:7的氨基酸序列的L-CDR2和含有SEQ ID NO:8的氨基酸序列的L-CDR3。
优选地,TPP-3310为包含SEQ ID NO:1的可变重链序列(VH)和SEQ ID NO:5的可变轻链序列(VL)的抗体。
高度优选地,TPP-3310为包含SEQ ID NO:9的重链区(HC)和SEQ ID NO:10的轻链区(LC)的抗体。
组合的组分B
组分B为特异性结合TIM-3受体并抑制TIM-3活性的抗体或其抗原结合部分(“抗TIM-3抗体”)。
抗TIM-3抗体
在某些实施方案中,抗TIM-3抗体或其抗原结合部分为考伯利单抗(TSR-022,Tesaro)或具有与考伯利单抗相同的CDR区。考伯利单抗为一种TIM-3免疫检查点抑制剂抗体,其选择性地阻止与一些已知的TIM-3配体(HMGB1、半乳凝素-9、磷脂酰丝氨酸(PS))相互作用,从而阻断抗肿瘤T细胞功能的下调。考伯利单抗记载于例如WO2016161270A1和WO2018129553 A1中。考伯利单抗目前正在临床试验中;ClinicalTrials.gov标识符:NCT02817633和NCT03680508。
在其他实施方案中,抗TIM-3抗体或其抗原结合部分为MBG-453(Novartis)或具有与MBG-453相同的CDR区。MBG-453为一种TIM-3免疫检查点抑制剂抗体,其选择性地阻止与一些已知的TIM-3配体(HMGB1、半乳凝素-9、磷脂酰丝氨酸(PS))相互作用,从而阻断抗肿瘤T细胞功能的下调。MBG-453记载于例如WO 2015117002 A1中。MBG-453以CAS号:2128742-61-8注册。MBG-453目前正在临床试验中;ClinicalTrials.gov标识符:NCT02608268和NCT03066648。
在其他实施方案中,抗TIM-3抗体或其抗原结合部分为BMS-986258(Bristol-Myers Squibb,Five Prime)或具有与BMS-986258相同的CDR区。BMS-986258为一种TIM-3免疫检查点抑制剂抗体,其选择性地阻止与一些已知的TIM-3配体(HMGB1、半乳凝素-9、磷脂酰丝氨酸(PS))相互作用,从而阻断抗肿瘤T细胞功能的下调。BMS-986258目前正在临床试验中;ClinicalTrials.gov标识符:NCT03446040。BMS-986258记载于例如WO 2018013818A2中。
在其他实施方案中,抗TIM-3抗体或其抗原结合部分为Sym-023(Symphogen)或具有与Sym-023相同的CDR区。Sym-023为一种TIM-3免疫检查点抑制剂抗体,其选择性地阻止与一些已知的TIM-3配体(HMGB1、半乳凝素-9、磷脂酰丝氨酸(PS))相互作用,从而阻断抗肿瘤T细胞功能的下调。Sym-023目前正在临床试验中;ClinicalTrials.gov标识符:NCT03489343。Sym-023记载于例如WO 2017178493 A1中。
在其他实施方案中,抗TIM-3抗体或其抗原结合部分为LY-3321367(Eli Lilly)或具有与LY-3321367相同的CDR区。LY-3321367为一种TIM-3免疫检查点抑制剂抗体,其选择性地阻止与一些已知的TIM-3配体(HMGB1、半乳凝素-9、磷脂酰丝氨酸(PS))相互作用,从而阻断抗肿瘤T细胞功能的下调。LY-3321367目前正在临床试验中;ClinicalTrials.gov标识符:NCT03099109。LY-3321367记载于例如WO2018039020A1中。
在其他实施方案中,抗TIM-3抗体或其抗原结合部分为INCAGN-2390(Agenus)或具有与INCAGN-2390相同的CDR区。INCAGN-2390为一种TIM-3免疫检查点抑制剂抗体,其选择性地阻止与一些已知的TIM-3配体(HMGB1、半乳凝素-9、磷脂酰丝氨酸(PS))相互作用,从而阻断抗肿瘤T细胞功能的下调。INCAGN-2390目前正在临床试验中;ClinicalTrials.gov标识符:NCT03652077。INCAGN-2390记载于例如WO 2017205721 A1中。
在其他实施方案中,抗TIM-3抗体或其抗原结合部分为来自R&D JacksonImmunoresearch的MAB2365或具有与MAB2365相同的CDR区。MAB2365为rIgG2抗体。
在某些实施方案中,所述抗TIM-3抗体包含:
(i)含有SEQ ID NO:12的氨基酸序列的H-CDR1、含有SEQ ID NO:13的氨基酸序列的H-CDR2、含有SEQ ID NO:14的氨基酸序列的H-CDR3、含有SEQ ID NO:16的氨基酸序列的L-CDR1、含有SEQ ID NO:17的氨基酸序列的L-CDR2和含有SEQ ID NO:18的氨基酸序列的L-CDR3。
在某些实施方案中,所述抗TIM-3抗体包含:
(i)SEQ ID NO:11的可变重链序列(VH)和SEQ ID NO:15的可变轻链序列(VL)。
在某些实施方案中,所述抗TIM-3抗体包含:
(i)SEQ ID NO:19的重链区(HC)和SEQ ID NO:20的轻链区(LC)。
抗体的产生
结合靶分子的抗体或抗原结合抗体片段可由本领域普通技术人员使用已知方法(例如化学合成或重组表达)来制备。用于癌症靶分子的结合剂可商购获得,或者可由本领域普通技术人员使用已知方法(例如化学合成或重组表达)来制备。用于制备抗体或抗原结合抗体片段的其他方法记载于WO 2007/070538(参见第22页“抗体”)中。本领域技术人员知晓如何编译例如噬菌体展示库(例如Morphosys HuCAL Gold),并用于发现抗体或抗原结合抗体片段的过程(参见WO 2007/070538,第24页及后页,以及第70页的AK实施例1、第72页的AK实施例2)。使用来自B细胞的DNA库制备抗体的其他方法记载于例如第26页(WO 2007/070538)。人源化抗体的方法记载于WO2007070538的第30-32页,并详细记载于Queen等人,Pros.Natl.Acad.Sci.USA 8610029-10033,1989或WO 90/0786中。此外,本领域技术人员通常已知重组表达蛋白质的方法,且特别已知重组表达抗体的方法(参见,例如Berger和Kimmel(Guide to Molecular Cloning Techniques,Methods in Enzymology,第152卷,Academic Press,Inc.);Sambrook等人,(Molecular Cloning A Laboratory Manual,(第二版,Cold Spring Harbor Laboratory Press;Cold Spring Harbor,N.Y.;1989)第1-3卷);Current Protocols in Molecular Biology,(F.M.Ausabel等人[编辑],CurrentProtocols,Green Publishing Associates,Inc./John Wiley&Sons,Inc.);Harlow等人,(Monoclonal Antibodies A Laboratory Manual,Cold Spring Harbor LaboratoryPress(19881,Paul[编辑]);Fundamental Immunology,(Lippincott Williams&Wilkins(1998));和Harlow等人,(Using Antibodies A Laboratory Manual,Cold Spring HarborLaboratory Press(1998)))。本领域技术人员知晓表达蛋白质/抗体所必需的相应的载体、启动子和信号肽。常见的方法还记载于WO 2007/070538的第41-45页中。制备IgG1抗体的方法记载于例如WO 2007/070538的第74页及后页的实施例6中。能够测定抗体在与其抗原结合后的内化的方法是本领域技术人员已知的,并记载于例如WO 2007/070538的第80页中。本领域技术人员能够使用WO 2007/070538中所记载的方法,所述方法已用于制备碳酸酐酶IX(Mn)抗体,类似于制备具有不同靶分子特异性的抗体。
细菌表达
本领域技术人员知晓借助细菌表达可以产生抗体、其抗原结合片段或其变体的方式。
通过插入DNA序列以及合适的翻译起始和翻译终止信号以及功能性启动子构建用于所需蛋白质的细菌表达的合适的表达载体,所述DNA序列编码功能性阅读框内的所需蛋白质。所述载体包含一个或多个表型可选择标记和复制起点,以便能够保留载体,并且如果需要,使其在宿主内扩增。用于转化的合适的原核宿主包括但不限于大肠杆菌(E.coli)、枯草芽孢杆菌(Bacillus subtilis)、鼠伤寒沙门氏菌(Salmonella typhimurium)和来自假单胞菌属(Pseudomonas)、链霉菌属(Streptomyces)和葡萄球菌属(Staphylococcus)的各种物种。细菌载体可以基于例如噬菌体、质粒或噬菌粒。这些载体可包含可选择标记和细菌复制起点,其来源于可商购获得的质粒。许多可商购获得的质粒通常包含众所周知的克隆载体pBR322(ATCC 37017)的元件。在细菌系统中,可以根据待表达蛋白质的预期用途选择许多有利的表达载体。
在转化合适的宿主菌株并将宿主菌株生长至适当的细胞密度后,所选择的启动子通过合适的方法(例如温度变化或化学诱导)进行去启动(de-reprimed)/诱导,并将细胞培养额外一段时间。细胞通常通过离心而收集,并且如果需要,以物理方式或通过化学方法消化,并保留所得的原始提取物用于进一步纯化。
哺乳动物细胞表达
本领域技术人员知晓借助哺乳动物细胞表达可以产生抗体、其抗原结合片段或其变体的方式。
优选的哺乳动物细胞宿主中表达的调控序列包括导致哺乳动物细胞中高表达的病毒元件,例如来源于以下病毒的启动子和/或表达扩增子:巨细胞病毒(CMV)(例如CMV启动子/增强子)、猿猴病毒40(SV40)(例如SV40启动子/增强子)、腺病毒(例如腺病毒主要晚期启动子(AdMLP))和多瘤病毒。抗体的表达可以是组成型或调节型(例如通过添加或去除与Tet系统结合的小分子诱导剂如四环素而诱导)。
为了进一步说明病毒调控元件及其序列,参考例如Stinski的美国5,168,062、Bell等人的美国4,510,245和Schaffner等人的美国4,968,615。重组表达载体可同样包括复制起点和可选择标记(参见例如美国4,399,216、4,634,665和美国5,179,017)。当载体已被引入到细胞中时,合适的可选择标记包括赋予对物质的抗性的基因,所述物质为例如G418、嘌呤霉素(puromycin)、潮霉素(hygromycin)、杀稻瘟菌素(blasticidin)、博莱霉素(zeocin/bleomycin)或甲氨蝶呤(methotrexate);或导致宿主细胞营养缺陷型的可选择标记,例如谷氨酰胺合成酶(Bebbington等人,Biotechnology(N Y).1992Feb;10(2):169-75)。
例如,二氢叶酸还原酶(DHFR)基因赋予对甲氨蝶呤的抗性,neo基因赋予对G418的抗性,来自土曲霉(Aspergillus terreus)的bsd基因赋予对杀稻瘟菌素的抗性,嘌呤霉素N-乙酰基转移酶赋予对嘌呤霉素的抗性,Sh ble基因产物赋予对博莱霉素的抗性,以及大肠杆菌潮霉素抗性基因(hyg或hph)赋予对潮霉素的抗性。可选择标记例如DHFR或谷氨酰胺合成酶还有助于与MTX和MSX结合使用的扩增技术。
表达载体转染到宿主细胞中可以借助标准技术而实现,包括通过电穿孔、核转染、磷酸钙沉淀、脂质转染、基于聚阳离子的转染(例如基于聚亚乙基亚胺(PEI)的转染和DEAE-葡聚糖转染)而实现。
用于表达抗体、其抗原结合片段或其变体的合适的哺乳动物宿主细胞包括中国仓鼠卵巢(CHO)细胞,例如CHO-K1、CHO-S、CHO-K1SV[包括DHFR-CHO细胞,记载于Urlaub和Chasin,(1980)Proc.Natl.Acad.Sci.USA 77:4216-4220以及Urlaub等人,Cell.1983Jun;33(2):405-12中,与DHFR可选择标记一起使用,如R.J.Kaufman和P.A.Sharp(1982)Mol.Biol.159:601-621中所记载,以及其他敲除(knockout)细胞,如详述于Fan等人,Biotechnol Bioeng.2012Apr;109(4):1007-15中)、NS0骨髓瘤细胞、COS细胞、HEK293细胞、HKB11细胞、BHK21细胞、CAP细胞、EB66细胞和SP2细胞。
抗体、其抗原结合片段或其变体的表达还可以在表达系统中以瞬态或半稳定方式被影响,所述表达系统为例如HEK293、HEK293T、HEK293-EBNA、HEK293E、HEK293-6E、HEK293Freestyle、HKB11、Expi293F、293EBNALT75、CHO Freestyle、CHO-S、CHO-K1、CHO-K1SV、CHOEBNALT85、CHOS-XE、CHO-3E7或CAP-T细胞(例如如Durocher等人,Nucleic AcidsRes.2002Jan 15;30(2):E9)。
在一些实施方案中,表达载体以这样的方式构建,使得待表达蛋白质被分泌到宿主细胞正在其中生长的细胞培养基中。抗体、其抗原结合片段或其变体可借助本领域技术人员已知的蛋白质纯化方法从细胞培养基中获得。
纯化
抗体、其抗原结合片段或其变体可借助众所周知的方法从重组细胞培养物中获得并纯化,其实例包括硫酸铵或乙醇沉淀、酸萃取、蛋白A色谱法、蛋白G色谱法、阴离子或阳离子交换色谱法、磷酸纤维素色谱法、疏水作用色谱法(HIC)、亲和色谱法、羟磷灰石色谱法和凝集素色谱法。高效液相色谱法(“HPLC”)同样可用于纯化。参见,例如Colligan,CurrentProtocols in Immunology,或Current Protocols in Protein Science,John Wiley&Sons,NY,N.Y.,(1997-2001),例如第1、4、6、8、9、10章。
本发明的抗体或其抗原结合片段或其变体包括天然纯化的产物、来自化学合成方法的产物以及借助于重组技术在原核或真核宿主细胞中产生的产物。真核宿主包括例如酵母细胞、高等植物细胞、昆虫细胞和哺乳动物细胞。取决于为重组表达所选择的宿主细胞,表达的蛋白质可为糖基化或非糖基化形式。
在一个优选的实施方案中,将抗体纯化(1)至大于95重量%的程度,例如通过Lowry方法、通过UV可见光谱法或通过SDS毛细管凝胶电泳(例如用Caliper LabChip GXII,GX 90或Biorad Bioanalyzer仪器)测量,并且在更优选的实施方案中大于99重量%,(2)至适合于测定N端或内部氨基酸序列的至少15个残基的程度,或(3)至均质性,所述均质借助于考马斯蓝(Coomassie blue)或优选银染色,在还原或非还原条件下通过SDS-PAGE测定。
通常,借助于至少一个蛋白质纯化步骤获得分离的抗体。
表1:优选抗体的蛋白质序列
表2:优选抗体的序列
治疗癌症的方法
在本发明的上下文中,术语“癌症”包括但不限于乳腺癌、肺癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、肝癌、眼癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌及其远处转移。那些疾病还包括多发性骨髓瘤、淋巴瘤、肉瘤和白血病。
乳腺癌的实例包括但不限于浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌。
呼吸道癌症的实例包括但不限于肺癌,特别是小细胞和非小细胞肺癌,以及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的实例包括但不限于脑干和垂体胶质瘤(hypophtalmic glioma)、小脑和脑星形细胞瘤、成神经管细胞瘤、室管膜瘤以及神经外胚层和松果体瘤。
男性生殖器官肿瘤包括但不限于前列腺癌和睾丸癌。女性生殖器官肿瘤包括但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌和外阴癌以及子宫肉瘤。
消化道肿瘤包括但不限于肛门癌、结肠癌、结直肠癌、食道癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
泌尿道肿瘤包括但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌、尿道癌和人乳头状肾癌。
眼癌包括但不限于眼内黑色素瘤和视网膜母细胞瘤。
肝癌的实例包括但不限于肝细胞癌(具有或不具有纤维板层(fibrolamellar)变体的肝细胞癌)、胆管癌(肝内胆管癌)和混合肝细胞胆管癌。
皮肤癌包括但不限于鳞状细胞癌、卡波西肉瘤、黑色素瘤(特别是恶性黑色素瘤)、默克尔细胞皮肤癌和非黑色素瘤皮肤癌。
头颈癌包括但不限于喉癌、下咽癌、鼻咽癌、口咽癌、唇癌和口腔癌以及鳞状细胞癌。
淋巴瘤包括但不限于AIDS相关的淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、伯基特氏淋巴瘤、霍奇金病和中枢神经系统淋巴瘤。
肉瘤包括但不限于软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
白血病包括但不限于急性骨髓性白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病和毛细胞白血病。
本发明涉及一种使用本发明的组合来治疗或预防癌症的方法,所述癌症特别是(但不限于)结直肠癌、肺癌、胰腺癌、乳腺癌、前列腺癌、膀胱癌、胃癌、头颈癌、肝癌、脑癌、黑色素瘤、子宫内膜癌、淋巴瘤、白血病等。组合可用于在治疗或预防癌症中抑制、阻断、减少、降低(等等)细胞增殖和/或细胞分裂,和/或产生细胞凋亡,所述癌症特别是(但不限于)结直肠癌、肺癌、乳腺癌、前列腺癌、膀胱癌、胃癌、头颈癌、肝癌、脑癌、黑色素瘤、子宫内膜癌、淋巴瘤、白血病等。该方法包括向有需要的哺乳动物(包括人)给予对治疗或预防癌症有效的量的本发明的组合或其药学上可接受的盐、异构体、多晶型物、代谢物、水合物、溶剂化物或酯等,所述癌症特别是(但不限于)结直肠癌、肺癌、胰腺癌、乳腺癌、前列腺癌、膀胱癌、胃癌、头颈癌、肝癌、脑癌、黑色素瘤、子宫内膜癌、淋巴瘤、白血病等。
贯穿本文所述的术语“治疗(treating或treatment)”通常用于例如管理或护理受试者,以用于对抗、缓解、减少、减轻、改善疾病或病症例如癌的病况等的目的。
在优选的实施方案中,所述癌症为肺癌,特别是非小细胞肺癌(NSCLC)、卵巢癌、间皮瘤、胰腺癌或胃癌、结直肠癌、头颈癌、膀胱癌、胆管癌、乳腺癌、宫颈癌、食道癌。
剂量和给药
基于已知的评估可用于治疗或预防癌症的化合物的标准实验室技术,所述癌症特别是(但不限于)结直肠癌、肺癌、胰腺癌、乳腺癌、前列腺癌、膀胱癌、胃癌、头颈癌、肝癌、脑癌、黑色素瘤、子宫内膜癌、淋巴瘤、白血病等,通过标准毒性测试和标准药理学试验以确定对哺乳动物中上述鉴定的病况的治疗,并通过将这些结果与用于治疗这些病况的已知药物的结果进行比较,可容易地确定用于适应症(indication)治疗的本发明的组合的有效剂量。根据这样的考虑如特定组合和所用剂量单位,给药方式,治疗时间,被治疗患者的年龄、体重和性别以及所治疗病况的性质和程度,在治疗该病况中给予的活性成分的量可在很大范围内变化。
待给予的活性成分的总量通常为每日约0.001mg/kg体重至约200mg/kg体重,且优选每日约0.01mg/kg体重至约30mg/kg体重。临床上有用的给药时间表从每日一至三次给药到每四周一次给药。此外,在某一段时间内不给患者服用药物的“药物假期”可有益于药理作用和耐受性之间的总体平衡。单位剂量可包含约0.5mg至约2,500mg的活性成分,并且可以每日一次或多次给药或每日少于一次给药。注射(包括静脉内、肌肉、皮下和肠胃外注射)给药的平均剂量和使用输注技术给药的平均剂量优选为0.01至200mg/kg总体重。
当然,针对每个患者的具体初始和连续给药方案将根据以下因素不同:主治诊断医师所确定的病况的性质和严重程度,所用特定组合的活性,患者的年龄、体重和一般情况,给药时间,给药途径,药物排泄速率,药物组合等。本发明的组合或其药学上可接受的盐或酯或组合物的期望的治疗方式和剂量数可由本领域技术人员使用常规的治疗测试来确定。
使用如上所述的组分A、如上所述的组分B和组分C:一种或多种其他药物制剂的组合的疗法。
本发明的组分A和组分B的组合可作为唯一的药物制剂给药或与一种或多种其他药物制剂结合给药,其中所得的组分A、B和C的组合不会引起不可接受的副作用。例如,本发明的组分A和B的组合可与组分C,即一种或多种其他药物制剂结合,所述其他药物制剂为例如已知的抗血管生成剂、抗增生过多剂、抗炎剂、镇痛剂、免疫调节剂、利尿剂、抗心律失常(anti-arrhytmic)剂、抗高胆固醇血症(anti-hypercholsterolemia)剂、抗血脂异常剂、抗糖尿病剂或抗病毒剂等,以及其混合物和组合。
组分C可为一种或多种药物制剂,例如131I-chTNT、阿巴瑞克(abarelix)、阿比特龙(abiraterone)、阿柔比星(aclarubicin)、阿达木单抗(adalimumab)、曲妥珠单抗-美坦新偶联物(ado-trastuzumab emtansine)、阿法替尼(afatinib)、阿柏西普(aflibercept)、阿地白介素(aldesleukin)、阿来替尼(alectinib)、阿仑单抗(alemtuzumab)、阿仑膦酸(alendronic acid)、阿利维A酸(alitretinoin)、六甲蜜胺(altretamine)、氨磷汀(amifostine)、氨鲁米特(aminoglutethimide)、氨基乙酰丙酸己酯(hexylaminolevulinate)、氨柔比星(amrubicin)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、安塞司亭(ancestim)、anethole dithiolethione、anetumab ravtansine、血管紧张素II(angiotensin II)、抗凝血酶III(antithrombin III)、阿瑞匹坦(aprepitant)、阿西莫单抗(arcitumomab)、阿格拉宾(arglabin)、三氧化二砷(arsenic trioxide)、天冬酰胺酶(asparaginase)、阿特珠单抗(atezolizumab)、阿西替尼(axitinib)、阿扎胞苷(azacitidine)、巴利昔单抗(basiliximab)、贝洛替康(belotecan)、苯达莫司汀(bendamustine)、贝索单抗(besilesomab)、贝利司他(belinostat)、贝伐单抗(bevacizumab)、贝沙罗汀(bexarotene)、比卡鲁胺(bicalutamide)、比生群(bisantrene)、博莱霉素、博纳吐单抗(blinatumomab)、硼替佐米(bortezomib)、布舍瑞林(buserelin)、博舒替尼(bosutinib)、本妥昔单抗(brentuximab vedotin)、白消安(busulfan)、卡巴他赛(cabazitaxel)、卡博替尼(cabozantinib)、降钙素(calcitonine)、亚叶酸钙(calciumfolinate)、左亚叶酸钙(calcium levofolinate)、卡培他滨(capecitabine)、卡罗单抗(capromab)、卡马西平(carbamazepine)、卡铂(carboplatin)、卡波醌(carboquone)、卡非佐米(carfilzomib)、卡莫氟(carmofur)、卡莫司汀(carmustine)、卡妥索单抗(catumaxomab)、塞来昔布(celecoxib)、西莫白介素(celmoleukin)、色瑞替尼(ceritinib)、西妥昔单抗(cetuximab)、苯丁酸氮芥(chlorambucil)、氯地孕酮(chlormadinone)、氮芥(chlormethine)、西多福韦(cidofovir)、西那卡塞(cinacalcet)、顺铂(cisplatin)、克拉屈滨(cladribine)、氯膦酸(clodronic acid)、氯法拉滨(clofarabine)、考比替尼(cobimetinib)、库潘尼西(copanlisib)、克立他酶(crisantaspase)、克唑替尼(crizotinib)、环磷酰胺(cyclophosphamide)、环丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、放线菌素D(dactinomycin)、达雷木单抗(daratumumab)、阿法达贝泊汀(darbepoetin alfa)、达拉非尼(dabrafenib)、达沙替尼(dasatinib)、柔红霉素(daunorubicin)、地西他滨(decitabine)、地加瑞克(degarelix)、地尼白介素(denileukin diftitox)、地诺单抗(denosumab)、地普奥肽(depreotide)、地洛瑞林(deslorelin)、二去水卫矛醇(dianhydrogalactitol)、右雷佐生(dexrazoxane)、二溴螺氯铵(dibrospidiumchloride)、卫康醇(dianhydrogalactitol)、双氯芬酸(diclofenac)、地努妥昔单抗(dinutuximab)、多西他赛(docetaxel)、多拉司琼(dolasetron)、去氧氟尿苷(doxifluridine)、阿霉素(doxorubicin)、阿霉素+雌酮(doxorubicin+estrone)、屈大麻酚(dronabinol)、依库丽单抗(eculizumab)、依决洛单抗(edrecolomab)、依利醋铵(elliptinium acetate)、埃罗妥珠单抗(elotuzumab)、艾曲波帕(eltrombopag)、内皮抑素(endostatin)、依诺他滨(enocitabine)、恩杂鲁胺(enzalutamide)、表柔比星(epirubicin)、环硫雄醇(epitiostanol)、依伯汀α(epoetin alfa)、依泊汀β(epoetinbeta)、依伯汀ζ(epoetin zeta)、依铂(eptaplatin)、艾日布林(eribulin)、厄洛替尼(erlotinib)、埃索美拉唑(esomeprazole)、雌二醇(estradiol)、雌莫司汀(estramustine)、乙炔雌二醇(ethinylestradiol)、依托泊苷(etoposide)、依维莫司(everolimus)、依西美坦(exemestane)、法倔唑(fadrozole)、芬太尼(fentanyl)、非格司亭(filgrastim)、氟羟甲睾酮(fluoxymesterone)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、氟尿嘧啶(fluorouracil)、氟他胺(flutamide)、亚叶酸(folinic acid)、福美斯坦(formestane)、福沙吡坦(fosaprepitant)、福莫司汀(fotemustine)、氟维司群(fulvestrant)、钆布醇(gadobutrol)、钆特醇(gadoteridol)、钆特酸葡胺(gadotericacid meglumine)、钆弗塞胺(gadoversetamide)、钆塞酸(gadoxetic acid)、硝酸镓(gallium nitrate)、加尼瑞克(ganirelix)、吉非替尼(gefitinib)、吉西他滨(gemcitabine)、吉妥珠单抗(gemtuzumab)、谷卡匹酶(Glucarpidase)、氧化型谷胱甘肽(glutoxim)、GM-CSF、戈舍瑞林(goserelin)、格拉司琼(granisetron)、粒细胞集落刺激因子(granulocyte colony stimulating factor)、组胺二盐酸盐(histaminedihydrochloride)、组氨瑞林(histrelin)、羟基脲(hydroxycarbamide)、I-125粒子(I-125seed)、兰索拉唑(lansoprazole)、伊班膦酸(ibandronic acid)、替伊莫单抗(ibritumomab tiuxetan)、依鲁替尼(ibrutinib)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、伊马替尼(imatinib)、咪喹莫特(imiquimod)、英丙舒凡(improsulfan)、吲地司琼(indisetron)、英卡膦酸(incadronic acid)、巨大戟醇甲基丁烯酸酯(ingenolmebutate)、干扰素α(interferon alfa)、干扰素β(interferon beta)、干扰素γ(interferon gamma)、碘比醇(iobitridol)、碘苄胍(iobenguane)(123I)、碘美普尔(iomeprol)、伊匹单抗、伊立替康(irinotecan)、伊曲康唑(Itraconazole)、伊沙匹隆(ixabepilone)、伊沙佐米(ixazomib)、兰瑞肽(lanreotide)、兰索拉唑(lansoprazole)、拉帕替尼(lapatinib)、Iasocholine、来那度胺(lenalidomide)、乐伐替尼(lenvatinib)、来格司亭(lenograstim)、香菇多糖(lentinan)、来曲唑(letrozole)、亮丙瑞林(leuprorelin)、左旋咪唑(levamisole)、左炔诺孕酮(levonorgestrel)、左旋甲状腺素钠(levothyroxine sodium)、麦角乙脲(lisuride)、洛铂(lobaplatin)、洛莫司汀(lomustine)、氯尼达明(lonidamine)、马索罗酚(masoprocol)、甲羟孕酮(medroxyprogesterone)、甲地孕酮(megestrol)、美拉胂醇(melarsoprol)、美法仑(melphalan)、美雄烷(mepitiostane)、巯基嘌呤(mercaptopurine)、美司钠(mesna)、美沙酮(methadone)、甲氨蝶呤、甲氧沙林(methoxsalen)、氨基乙酰丙酸甲酯(methylaminolevulinate)、甲基强的松龙(methylprednisolone)、甲基睾酮(methyltestosterone)、甲酪氨酸(metirosine)、米伐木肽(mifamurtide)、米替福新(miltefosine)、米铂(miriplatin)、二溴甘露醇(mitobronitol)、米托胍腙(mitoguazone)、二溴卫矛醇(mitolactol)、丝裂霉素(mitomycin)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、莫加珠单抗(mogamulizumab)、莫拉司亭(molgramostim)、莫哌达醇(mopidamol)、盐酸吗啡(morphine hydrochloride)、硫酸吗啡(morphine sulfate)、大麻隆(nabilone)、nabiximols、那法瑞林(nafarelin)、纳洛酮+喷他佐辛(naloxone+pentazocine)、纳曲酮(naltrexone)、那托司亭(nartograstim)、耐昔妥珠单抗(necitumumab)、奈达铂(nedaplatin)、奈拉滨(nelarabine)、奈立膦酸(neridronicacid)、奈妥吡坦/帕洛诺司琼(netupitant/palonosetron)、纳武单抗(nivolumab)、喷曲肽(pentetreotide)、尼罗替尼(nilotinib)、尼鲁米特(nilutamide)、尼莫拉唑(nimorazole)、尼妥珠单抗(nimotuzumab)、尼莫司汀(nimustine)、尼达尼布(nintedanib)、硝氨丙吖啶(nitracrine)、纳武单抗、阿托珠单抗(obinutuzumab)、奥曲肽(octreotide)、奥法木单抗(ofatumumab)、奥拉帕尼(olaparib)、奥拉木单抗(olaratumab)、高三尖杉酯碱(omacetaxine mepesuccinate)、奥美拉唑(omeprazole)、昂丹司琼(ondansetron)、奥普瑞白介素(oprelvekin)、奥古蛋白(orgotein)、orilotimod、奥希替尼(osimertinib)、奥沙利铂(oxaliplatin)、羟考酮(oxycodone)、羟甲烯龙(oxymetholone)、奥佐米星(ozogamicine)、p53基因疗法、紫杉醇(paclitaxel)、帕博西尼(palbociclib)、帕利夫明(palifermin)、钯-103粒子(palladium-103seed)、帕洛诺司琼、帕米膦酸(pamidronic acid)、帕尼单抗(panitumumab)、帕比司他(panobinostat)、泮托拉唑(pantoprazole)、帕唑帕尼(pazopanib)、培门冬酶(pegaspargase)、PEG-依泊汀β(PEG-epoetin beta)(甲氧基PEG-依泊汀β)、派姆单抗(pembrolizumab)、培非格司亭(pegfilgrastim)、聚乙二醇干扰素α-2b(peginterferon alfa-2b)、派姆单抗、培美曲塞(pemetrexed)、喷他佐辛、喷司他丁(pentostatin)、培洛霉素(peplomycin)、全氟丁烷(Perflubutane)、培磷酰胺(perfosfamide)、帕妥珠单抗(Pertuzumab)、溶链菌(picibanil)、匹鲁卡品(pilocarpine)、吡柔比星(pirarubicin)、匹杉琼(pixantrone)、普乐沙福(plerixafor)、普卡霉素(plicamycin)、聚氨葡糖(poliglusam)、聚磷酸雌二醇(polyestradiol phosphate)、聚乙烯吡咯烷酮+透明质酸钠、多糖K、泊马度胺(pomalidomide)、帕纳替尼(ponatinib)、卟吩姆钠(porfimer sodium)、普拉曲沙(pralatrexate)、泼尼莫司汀(prednimustine)、强的松(prednisone)、甲基苄肼(procarbazine)、丙考达唑(procodazole)、普萘洛尔(propranolol)、喹高利特(quinagolide)、雷贝拉唑(rabeprazole)、雷妥莫单抗(racotumomab)、镭-223氯化物、雷多替尼(radotinib)、雷洛昔芬(raloxifene)、雷替曲塞(raltitrexed)、雷莫司琼(ramosetron)、雷莫芦单抗(ramucirumab)、雷莫司汀(ranimustine)、拉布立酶(rasburicase)、丙亚胺(razoxane)、瑞法替尼(refametinib)、瑞格非尼(regorafenib)、利塞膦酸(risedronic acid)、铼-186依替膦酸钠(rhenium-186etidronate)、利妥昔单抗(rituximab)、罗拉吡坦(rolapitant)、罗米地辛(romidepsin)、罗米司亭(romiplostim)、罗莫肽(romurtide)、roniciclib、芦卡帕尼(rucaparib)、钐(153Sm)来昔决南(samarium(153Sm)lexidronam)、沙格司亭(sargramostim)、沙妥莫单抗(satumomab)、促胰液素(secretin)、司妥昔单抗(siltuximab)、西普鲁塞-T(sipuleucel-T)、西佐喃(sizofiran)、索布佐生(sobuzoxane)、甘氨双唑钠(sodium glycididazole)、索尼德吉(sonidegib)、索拉非尼(sorafenib)、司坦唑醇(stanozolol)、链脲霉素(streptozocin)、舒尼替尼(sunitinib)、他拉泊芬(talaporfin)、溶瘤病毒(talimogene laherparepvec)、他米巴罗汀(tamibarotene)、他莫昔芬(tamoxifen)、他喷他多(tapentadol)、他索纳明(tasonermin)、替西白介素(teceleukin)、锝(99mTc)巯诺莫单抗(technetium(99mTc)nofetumomab merpentan)、99mTc-HYNIC-[Tyr3]-奥曲肽(99mTc-HYNIC-[Tyr3]-octreotide)、替加氟(tegafur)、替加氟+吉莫斯特(gimeracil)+奥替拉西(oteracil)、替莫泊芬(temoporfin)、替莫唑胺(temozolomide)、替西罗莫司(temsirolimus)、替尼泊苷(teniposide)、睾酮(testosterone)、替曲膦(tetrofosmin)、沙利度胺(thalidomide)、塞替派(thiotepa)、胸腺法新(thymalfasin)、促甲状腺激素α(thyrotropin alfa)、硫鸟嘌呤(tioguanine)、托珠单抗(tocilizumab)、拓扑替康(topotecan)、托瑞米芬(toremifene)、托西莫单抗(tositumomab)、曲贝替定(trabectedin)、曲美替尼(trametinib)、曲马多(tramadol)、曲妥珠单抗(trastuzumab)、曲妥珠单抗-美坦新(trastuzumab emtansine)、曲奥舒凡(treosulfan)、维甲酸(tretinoin)、曲氟尿苷+替吡嘧啶(trifluridine+tipiracil)、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、曲美替尼、曲洛磷胺(trofosfamide)、促血小板生成素(thrombopoietin)、色氨酸(tryptophan)、乌苯美司(ubenimex)、瓦他拉尼(valatinib)、戊柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽(vapreotide)、维罗非尼(vemurafenib)、长春花碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)、长春氟宁(vinflunine)、长春瑞滨(vinorelbine)、维莫德吉(vismodegib)、伏立诺他(vorinostat)、伏氯唑(vorozole)、钇-90玻璃微球(yttrium-90glass microspheres)、净司他丁(zinostatin)、净司他丁苯马聚合物(zinostatin stimalamer)、唑来膦酸(zoledronic acid)、佐柔比星(zorubicin)。
通常,将组分C与本发明的组分A和B的组合结合使用将有助于:
(1)与单独给予任一种药剂相比,在减少肿瘤生长甚至消除肿瘤方面产生更好的功效,
(2)提供更少量的被给予的化疗剂的给药,
(3)提供一种在患者中具有良好耐受性的化疗治疗,其中有害的药理学并发症比用单一药剂化疗和某些其他联合疗法所观察到的更少,
(4)提供对哺乳动物特别是人的更广谱的不同癌症类型的治疗,
(5)在接受治疗的患者中提供更高的反应率,
(6)与标准化疗治疗相比,在接受治疗的患者中提供更长的生存时间,
(7)为肿瘤进展提供更长的时间,和/或
(8)与其他癌症药剂组合产生拮抗作用的已知情况相比,产生至少与单独使用的药剂的结果一样好的功效和耐受性结果。
实施例
下列实施例描述了本发明的可行性,但本发明并不仅限于这些实施例。
实施例1:针对人CEACAM6的抗体TPP-3310与针对PD-L1或PD-1的抗体的联合治疗对PD-1阳性病毒肽特异性T细胞的活化的作用
由于CEACAM6不在啮齿动物(不在啮齿动物直系同源物)中表达,因此不可能进行体内功效研究,并且不能进行临床前体内组合研究来评估药物组合的治疗潜力。
或者,建立体外细胞试验系统以测试针对CEACAM6和PD-1或PD-L1的抗体的组合的体外功效和治疗潜力。
在该细胞试验系统中,PD-1阳性FluM1病毒肽特异性T细胞用作效应子T细胞。在针对CEACAM6、PD-1或PD-L1的检查点抑制性抗体以单一制剂或其组合的形式存在下,将它们与PD-L1和CEACAM6阳性以及负载有FLuM1肽的癌细胞HCC2935共培养24小时至48小时。测量促炎细胞因子(IFNg)的诱导作为功效的读数。
抗体
所使用的抗体为TPP-3310(抗CEACAM6),其为针对在癌细胞和骨髓细胞上过表达的免疫检查点分子CEACAM6的huIgG2抗体;TPP-3615,其为抗PD-L1 huIgG2抗体,并使用阿特珠单抗的可变结构域克隆;和TPP-2596,其为抗PD-1HuIgG4 Pro抗体,使用纳武单抗的可变结构域克隆。TPP-1238(huIgG2)和TPP1240(huIgG4)已用作同型对照抗体。
细胞系和培养
在RPMI-1640、10%FCS、5%CO2中培养HCC2935癌细胞(ATCC-CRL-2869,肺腺癌)。通过FACS分析确认了CEACAM6和PD-L1表达。对于与病毒肽特异性T细胞的共培养试验,用0.2μg/ml或按指示的病毒FluM1肽脉冲癌细胞。
FluM1病毒肽特异性T细胞的产生和细胞培养
PD-1表达的病毒(流感)肽特异性T细胞由HLA-A*0201+健康供体的初始PBMC产生,所述供体通过血沉棕黄层(buffy coat)的Ficoll密度离心而获得(Deutsches RotesKreuz,Mannheim)。根据制造商的协议,用MACS阴性选择试剂盒(Miltenyi,130-096-495)富集CD8+T细胞。将CD8阴性细胞辐照(35Gy),并在X-Vivo-20培养基(化学定义,无血清造血细胞培养基,Lonza,#BE04-448Q)中用1μg/ml的流感HLA-A*0201表位GILGFVFTL(ProImmune)在37℃下脉冲1.5小时,然后洗涤。用经辐照的T2细胞再次刺激细胞,并在第7天用1μg/ml的其相关GILGFVFTL肽脉冲细胞。在第14天,将等分试样冷冻。将样品解冻并立即洗涤,然后将其用于功能性试验。在第14天的共培养实验之前,通过四聚体(F391-4A-E,ProImmune)染色和FACS分析确认了病毒肽特异性T细胞的适用性。
体外试验:结合抗体在T细胞和癌细胞的共培养中的功效分析
对于共培养,将癌细胞用PBS-EDTA非酶促地分离5至15分钟,以1400rpm离心5分钟,洗涤并计数。将癌细胞在X-Vivo-20(Lonza,#BE04-448Q)中稀释为1x105个细胞/ml,在冰上用TPP-3310、aPD-L1和/或同型对照抗体预处理10分钟。孵育后,将10,000个靶癌细胞一式三份接种到96孔ELISA U板中。
收集病毒肽特异性T细胞,用X-Vivo-20洗涤,在X-Vivo-20中稀释为2x105个细胞/ml,并在冰上用抗PD-1或同型对照抗体预处理10分钟。所有抗体均以30μg/ml的最终浓度施用。对于联合治疗,TPP-3310大约以其半最大有效浓度(EC50)1μg/ml施用,以确保其他抗体对T细胞活化的作用。将经预处理的T细胞以20,000个细胞/孔接种到靶癌细胞上。
将癌细胞和效应子T细胞与抗体的共培养物在37℃、5%CO2下孵育约20小时。
然后收集上清液,并将共培养板以1400rpm离心3分钟。根据制造商的说明,通过ELISA(人IFN-γ-ELISA装置,BD,#555142)测量上清液中的IFN-γ水平。ELISA板的光密度使用Tecan Infinite M200酶标仪测量。
使用Microsoft Excel 2010和GraphPad Prism 6,通过配对或不配对的双尾学生t检验(Student’s t-test)对数据进行统计分析。p<0.05的结果被认为是显著的。通过标准曲线计算细胞因子浓度。通过将TPP-3310或给定组合的值除以各自的同型对照的值来计算因子或比率。
结果
在实验前,将负载有FLuM1肽的HCC2935癌细胞与FluM1病毒肽特异性T细胞共孵育。仅在同源病毒肽的存在下,T细胞的IFN-γ分泌增加。这种增加呈剂量依赖性。在抗CEACAM6抗体TPP-3310、抗PD-L1抗体TPP-3615的存在下或在抗PD-1抗体TPP-2596的存在下,共培养物中的IFN-γ分泌(p<0.05至0.0001)进一步增强。全部以单一药剂给药。这些数据证实,新建立的由PD-1阳性FluM1病毒肽特异性T细胞和负载有肽的HCC2935癌细胞组成的细胞试验系统适用于在基准点(benchmarking)和组合实验中测试抗CEACAM6、抗PD-1和抗PD-L1抗体的功效。
表3:在具有或不具有针对CEACAM6、PD-1或PD-L1的免疫检查点阻断抗体的负载有病毒肽的HCC2935癌细胞的共培养实验中,通过IFNg分泌测量的病毒肽特异性T细胞活化的肽特异性。
说明表:用经连续稀释的病毒肽脉冲的HCC2935肺癌细胞(HCC)刺激病毒肽特异性T细胞(TC)。抗体以30μg/ml添加。通过ELISA测定分泌的IFN-γ的浓度。数据是以pg/ml计的IFN-γ的绝对量。TPP-3310,aCEACAM6;TPP-3615,aPD-L1;TPP-2596,aPD1;TPP-1238,TPP-3310和TPP3615、aPD-1的同型对照;TPP-1240,TPP-2596的同型对照。
在7个独立的共培养实验(n=7)中,总体上确定了抗CEACAM6抗体TPP-3310与针对PD-L1的抗体的组合的作用。在抗体的存在下,当以单一药剂或组合给药时,我们始终观察到IFNg分泌(绝对平均值)的增加。在PD-L1抗体的存在下,总IFNg增加了39.6pg/ml,在抗CEACAM6抗体TPP-3310的存在下增加了196.6pg/ml,并且以组合给药时增加了279.9pg/ml。该结果表明,当PD-L1抗体与CEACAM6抗体组合时,IFNg分泌进一步增强,并且对IFNg分泌的作用大于加和作用。
表4:在抗CEACAM6和抗PD-L1抗体以单一药剂或组合形式存在下,FluM1病毒肽特异性T细胞和负载有FluM1肽的HCC2935细胞的共培养实验(n=7)中的总IFNg分泌
说明表:用0.2μg/ml的FluM1肽脉冲HCC2935肺癌细胞(HCC)以刺激共培养物中的病毒肽特异性T细胞(TC)。抗体以30μg/ml施用。对于联合治疗(n=7),TPP-3310以1μg/ml添加。通过ELISA测定分泌的IFN-γ的浓度,并且数据为同型校正值,并以pg/ml给出。TPP-3310,aCEACAM6;TPP-3615,aPD-L1;平均值的T检验,p值(<0.05):aPD-L1对CEACAM6,p=0.0439;aPD-L1对组合,p=0.001;aCEACAM6对组合,p=0.16
在另一项研究中,我们在总共7个独立的共培养实验(n=7)中确定了抗CEACAM6抗体TPP-3310与针对PD-1的抗体的组合的作用。在抗体的存在下,当以单一药剂或组合给药时,我们始终观察到IFNg分泌(绝对平均值)的增加。
在PD-1抗体的存在下,平均总IFNg增加了76.1pg/ml,在抗CEACAM6抗体TPP-3310的存在下增加了166.8pg/ml,并且以组合给药时增加了317.9pg/ml。该结果表明,当PD-1抗体与CEACMA6抗体组合时,IFNg分泌进一步增强,并且对IFNg分泌的作用大于加和作用。
表5:在抗CEACAM6和抗PD-1抗体以单一药剂或组合形式存在下,FluM1病毒肽特异性T细胞和负载有FluM1肽的HCC2935细胞的共培养实验(n=7)中的总IFNg分泌
说明表:用0.2μg/ml的FluM1肽脉冲HCC2935肺癌细胞(HCC)以刺激共培养物中的病毒肽特异性T细胞(TC)。抗体以30μg/ml施用。对于联合治疗(n=7),TPP-3310以1μg/ml添加。通过ELISA测定分泌的IFN-γ的浓度,并且数据为同型校正值,并以pg/ml给出。TPP-3310,aCEACAM6;TPP-2596,aPD-1。
平均值的T检验,p值(<0.05):aPD-1对CEACAM6,p=0.13;aPD-L1对组合,p=0.0034;aCEACAM6对组合,p=0.0011
实施例2:针对人CEACAM6的抗体TPP-3310与针对TIM-3的抗体的联合治疗对TIM-3和PD-1阳性病毒肽特异性T细胞的活化的作用
抗CEACAM6抗体TPP-3310与抗TIM3抗体的组合也在具有病毒肽特异性T细胞和负载有肽的癌细胞的体外共培养试验系统中进行了测试。
在该细胞试验系统中,PD1和TIM3阳性FluM1病毒抗原特异性T细胞用作效应子T细胞。在针对CEACAM6和TIM3的检查点抑制性抗体以单一药剂或其组合的形式存在下,将它们与PD-L1和CEACAM6阳性以及负载有FLuM1肽的癌细胞HCC2935共培养24小时至48小时。测量促炎细胞因子(IFNg)的诱导作为功效的读数。
抗体
所使用的抗体为TPP-3310(抗CEACAM6),其为针对在癌细胞和骨髓细胞上过表达的免疫检查点分子CEACAM6的huIgG2抗体;和MAB2365(rIgG2,R&D Jacksonimmunoresearch),其为抗TIM3抗体。TPP-1238(huIgG2)和MAB006(rIgG2;R&D)已用作同型对照抗体。
细胞系和培养
在RPMI-1640、10%FCS、5%CO2中培养HCC2935癌细胞(ATCC-CRL-2869,肺腺癌)。通过FACS分析确认了CEACAM6和PD-L1以及TIM-3表达。对于与病毒肽特异性T细胞的共培养试验,用0.2μg/ml或按指示的病毒FluM1肽脉冲癌细胞。
FluM1病毒肽特异性T细胞的产生和细胞培养
PD-1表达的病毒(流感)肽特异性T细胞由HLA-A*0201+健康供体的初始PBMC产生,所述供体通过血沉棕黄层的Ficoll密度离心而获得(Deutsches Rotes Kreuz,Mannheim)。根据制造商的协议,用MACS阴性选择试剂盒(Miltenyi,130-096-495)富集CD8+T细胞。将CD8阴性细胞辐照(35Gy),并在X-Vivo-20培养基(化学定义,无血清造血细胞培养基,Lonza,#BE04-448Q)中用1μg/ml的流感HLA-A*0201表位GILGFVFTL(ProImmune)在37℃下脉冲1.5小时,然后洗涤。用经辐照的T2细胞再次刺激细胞,并在第7天用1μg/ml的其相关GILGFVFTL肽脉冲细胞。在第14天,将等分试样冷冻。将样品解冻并立即洗涤,然后将其用于功能性试验。在第14天的共培养实验之前,通过四聚体(F391-4A-E,ProImmune)染色和FACS分析确认了病毒肽特异性T细胞的适用性。
体外试验:结合抗体在T细胞和癌细胞的共培养中的功效分析
对于共培养,将癌细胞用PBS-EDTA非酶促地分离5至15分钟,以1400rpm离心5分钟,洗涤并计数。将癌细胞在X-Vivo-20(Lonza,#BE04-448Q)中稀释为1x105个细胞/ml,在冰上用TPP-3310和/或同型对照抗体预处理10分钟。孵育后,将10,000个靶癌细胞一式三份接种到96孔ELISA U板中。
收集病毒肽特异性T细胞,用X-Vivo-20洗涤,在X-Vivo-20中稀释为2x105个细胞/ml,并在冰上用抗TIM3或同型对照抗体预处理10分钟。除抗TIM3抗体以50μg/ml使用以外,所有抗体均以30μg/ml的最终浓度施用。对于联合治疗,TPP-3310大约以其半最大有效浓度(EC50)1μg/ml施用,以确保其他抗体对T细胞活化的作用。将经预处理的T细胞以20,000个细胞/孔接种到靶癌细胞上。
将癌细胞和效应子T细胞与抗体的共培养物在37℃、5%CO2下孵育约20小时。
然后通过将共培养板以1400rpm离心3分钟来收集上清液。根据制造商的说明,通过ELISA(人IFN-γ-ELISA装置,BD,#555142)测量上清液中的IFN-γ水平。ELISA板的光密度使用Tecan Infinite M200酶标仪测量。
使用Microsoft Excel 2010和GraphPad Prism 6,通过配对或不配对的双尾学生t检验对数据进行统计分析。p<0.05的结果被认为是显著的。通过标准曲线计算细胞因子浓度。通过将TPP-3310或给定组合的值除以各自的同型对照的值来计算因子或比率。
结果
在实验前,将负载有FLuM1肽的HCC2935癌细胞与FluM1病毒肽特异性T细胞共孵育。仅在同源病毒肽的存在下,T细胞的IFN-γ分泌增加。这种增加呈剂量依赖性。在抗CEACAM6抗体TPP-3310的存在下或在抗TIM3抗体MAB2365的存在下,共培养物中的IFN-γ分泌(p<0.05至0.0001)进一步增强。全部以单一药剂给药。这些数据证实,新建立的由TIM-3和PD-1阳性FluM1病毒特异性T细胞和负载有肽的HCC2935细胞组成的细胞试验系统适用于在基准点和组合实验中测试抗CEACAM6和抗TIM3 mAbs的功效。
表6:在具有或不具有针对CEACAM6和TIM3的免疫检查点阻断抗体的负载有病毒肽的HCC2935的共培养实验中,通过IFNg分泌测量的病毒特异性T细胞活化的肽特异性。
说明表:用经连续稀释的病毒肽脉冲的HCC2935肺癌细胞(HCC)刺激病毒特异性T细胞(TC)。除抗TIM3 mAb以50μg/ml使用以外,抗体均以30μg/ml添加。通过ELISA测定分泌的IFN-γ的浓度。数据是以pg/ml计的IFN-γ的绝对量。TPP-3310,aCEACAM6;MAB2365,aTIM3;TPP-1238,huIgG2同型对照;MAB006,rIgG2同型对照。
在7个独立的共培养实验(n=7)中总体上确定了抗CEACAM6抗体TPP-3310与抗TIM3 Mab 2365的组合的作用。在抗体的存在下,当以单一药剂或组合给药时,我们始终观察到IFNg分泌(绝对平均值)的增加。在TIM-3抗体的存在下,总IFNg增加了181.5pg/ml,在抗CEACAM6抗体TPP-3310的存在下增加了228.0pg/ml,并且以组合给药时增加了562.6pg/ml。该结果表明,当TIM-3抗体与CEACAM6抗体组合时,IFNg分泌进一步强烈增强,并且对IFNg分泌的作用大于加和作用。它还显示出在活性PD-L1/PD-1轴的存在下的活性,并且与之前的实施例相比,效果更强。
表7:在抗CEACAM6 TPP-3310和抗TIM-3抗体MAB2365以单一药剂或组合形式存在下,FluM1病毒肽特异性T细胞和负载有FluM1肽的HCC2935细胞的共培养实验(n=7)中的总IFNg分泌。
说明表:用0.2μg/ml的FluM1肽脉冲HCC2935肺癌细胞(HCC)以刺激共培养物中的病毒肽特异性T细胞(TC)。TIM3抗体以50μg/ml施用。对于联合治疗(n=7),TPP-3310以1μg/ml添加。通过ELISA测定分泌的IFN-γ的浓度。数据为同型校正值,并以pg/ml给出。TPP-3310,aCEACAM6;MAB2365,aTIM3
平均值的T检验,p值(<0.05):a-TIM3对CEACAM6,p=0.24;a-TIM3对组合,p=0.01;aCEACAM6对组合,p=0.016
实施例3:针对人CEACAM6的抗体TPP-3310与针对TIM-3的抗体的联合治疗对存活蛋白(Survivin)肽特异性T细胞的活化的作用
以前发现TPP-3310在与乳腺癌、结直肠癌和肺癌细胞的共培养物中通过存活蛋白肽特异性T细胞增加IFN-γ分泌。在另一个实施例中,将抗CEACAM6抗体TPP-3310与抗TIM3抗体MAB2365(R&D Jackson Immunoresearch)的组合在作为替代的T细胞来源的存活蛋白肽特异性T细胞与HCC2935肺癌或KS乳腺癌细胞的共培养物中进行了测试。
抗体
所使用的抗体为TPP-3310(抗CEACAM6),其为针对在癌细胞和骨髓细胞上过表达的免疫检查点分子CEACAM6的huIgG2抗体。MAB2365(rIgG2,R&D Jackson immunoresearch)为一种抗TIM3抗体。TPP-1238(huIgG2)和MAB006(rIgG2;R&D Jackson Immunoresearch)已用作同型对照抗体。
细胞系和培养
在RPMI-1640、10%FCS、5%CO2中培养HCC2935癌细胞(ATCC-CRL-2869,肺腺癌)。在DMEM、10%FCS中培养KS乳腺癌细胞。通过FACS分析确认了CEACAM6和PD-L1表达。
存活蛋白特异性T细胞的产生和细胞培养:
肿瘤抗原特异性(即存活蛋白肽特异性)T细胞由健康供体的外周血单核细胞(PBMC)产生,如文献中所记载(Moosmann A.Gezielte Reaktivierung spezifischerzytotoxischer T-Zellen mit Epstein-Barr-Virus-Vektoren.Dissertation,Ludwig-Maximilians-University Munich,Germany.2002;Brackertz B,Conrad H,Daniel J,KastB,H,Busch DH等人,FLT3-regulated antigens as targets for leukemia-reactive cytotoxic T lymphocytes.Blood Cancer Journal.2011;1(3):e11.)。
体外试验:结合抗体在T细胞和癌细胞的共培养中的功效分析
对于共培养,将癌细胞用PBS-EDTA非酶促地分离5至15分钟,以1400rpm离心5分钟,洗涤并计数。将癌细胞在X-Vivo-20(Lonza,#BE04-448Q)中稀释为1x105个细胞/ml,在冰上用TPP-3310和/或同型对照抗体预处理10分钟。孵育后,将10,000个靶癌细胞一式三份接种到96孔ELISA U板中。
收集存活蛋白肽特异性T细胞,用X-Vivo-20洗涤,在X-Vivo-20中稀释为2x105个细胞/ml,并在冰上用抗TIM-3MAB2365或同型对照抗体预处理10分钟。抗TIM-3抗体以50μg/ml的最终浓度施用。对于联合治疗,TPP-3310大约以其半最大有效浓度(EC50)1μg/ml施用,以确保其他抗体对T细胞活化的作用。将经预处理的T细胞以20,000个细胞/孔接种到靶癌细胞上。将癌细胞和效应子T细胞与抗体的共培养物在37℃、5%CO2下孵育约20小时。然后通过将共培养板以1400rpm离心3分钟来收集上清液。根据制造商的说明,通过ELISA(人IFN-γ-ELISA装置,BD,#555142)测量上清液中的IFN-γ水平。ELISA板的光密度使用TecanInfinite M200酶标仪测量。
使用Microsoft Excel 2010和GraphPad Prism 6,通过配对或不配对的双尾学生t检验对数据进行统计分析。p<0.05的结果被认为是显著的。通过标准曲线计算细胞因子浓度。通过将TPP-3310或给定组合的值除以各自的同型对照的值来计算因子或比率。
表8:在以单一药剂或组合形式给药的抗CEACAM6 TPP-3310和抗TIM-3MAB2365抗体的存在下,存活蛋白肽特异性T细胞和HCC2935肺细胞(HCC)的共培养实验(n=1)中的总IFNg分泌。
说明表:抗TIM-3抗体MAB2365以50μg/ml施用。对于联合治疗(n=1),TPP-3310以1μg/ml添加。通过ELISA测定分泌的IFN-γ的浓度。数据为同型校正值,并以pg/ml给出。TPP-3310,aCEACAM6,MAB2365,aTIM3
*一式三份的平均值,同型校正
**使用Excel软件从一式三份值计算得出的标准偏差
表9:在以单一药剂或组合形式给药的抗CEACAM6抗体TPP-3310和抗TIM-3抗体MAB2365的存在下,存活蛋白肽特异性T细胞和KS乳腺癌细胞的共培养实验(n=1)中的总IFNg分泌。
说明表:TIM3抗体MAB2365以50μg/ml施用。对于联合治疗(n=1),TPP-3310以1μg/ml添加。通过ELISA测定分泌的IFN-γ的浓度。数据为同型校正值,并以pg/ml给出。TPP-3310,aCEACAM6;MAB2365,aTIM3
*一式三份的平均值,同型校正
**使用Excel软件从一式三份值计算得出的标准偏差
作为单一药剂,TPP-3310和抗TIM-3MAB2365抗体在与HCC2935细胞系的共培养物中分别使存活蛋白肽特异性T细胞的IFN-γ分泌增加了343.1pg/ml和63.6pg/ml,以及在与KS细胞系的共培养物中分别使存活蛋白肽特异性T细胞的IFN-γ分泌增加了38.4pg/ml和18.3pg/ml。
当组合时,TPP-3310和抗TIM3抗体MAB2365在HCC2935细胞上使IFN-γ分泌增加了722.7pg/ml,以及在KS细胞上使IFN-γ分泌增加了77.5pg/ml。该结果表明,当TIM-3抗体与CEACAM6抗体组合时,IFNg分泌进一步增强,并且对IFNg分泌的作用明显大于加和作用。
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Claims (11)
1.抗CEACAM6抗体,其用于与抗TIM-3抗体同时、分别或顺序结合治疗癌症,其中所述抗CEACAM6抗体包含含有SEQ ID NO:2的氨基酸序列的H-CDR1、含有SEQ ID NO:3的氨基酸序列的H-CDR2、含有SEQ ID NO:4的氨基酸序列的H-CDR3、含有SEQ ID NO:6的氨基酸序列的L-CDR1、含有SEQ ID NO:7的氨基酸序列的L-CDR2和含有SEQ ID NO:8的氨基酸序列的L-CDR3。
2.根据权利要求1所述的具有所述用途的抗CEACAM6抗体,其中所述抗CEACAM6抗体包含SEQ ID NO:1的可变重链序列和SEQ ID NO:5的可变轻链序列。
3.根据权利要求1所述的具有所述用途的抗CEACAM6抗体,其中所述抗CEACAM6抗体包含SEQ ID NO:9的重链区和SEQ ID NO:10的轻链区。
4.根据权利要求1至3中任一项所述的具有所述用途的抗CEACAM6抗体,其中所述抗TIM-3抗体为考伯利单抗、MBG-453、BMS-986258、Sym-023、LY-3321367或INCAGN-2390。
5.根据权利要求1至3中任一项所述的具有所述用途的抗CEACAM6抗体,其中所述抗TIM-3抗体包含含有SEQ ID NO:12的氨基酸序列的H-CDR1、含有SEQ ID NO:13的氨基酸序列的H-CDR2、含有SEQ ID NO:14的氨基酸序列的H-CDR3、含有SEQ ID NO:16的氨基酸序列的L-CDR1、含有SEQ ID NO:17的氨基酸序列的L-CDR2和含有SEQ ID NO:18的氨基酸序列的L-CDR3。
6.根据权利要求1至3中任一项所述的具有所述用途的抗CEACAM6抗体,其中所述抗TIM-3抗体包含SEQ ID NO:11的可变重链序列(VH)和SEQ ID NO:15的可变轻链序列(VL)。
7.根据权利要求1至3中任一项所述的具有所述用途的抗CEACAM6抗体,其中所述抗TIM-3抗体包含SEQ ID NO:19的重链区(HC)和SEQ ID NO:20的轻链区(LC)。
8.根据权利要求1至7中任一项所述的具有所述用途的抗CEACAM6抗体,其中所述癌症为肺癌,特别是非小细胞肺癌、卵巢癌、间皮瘤、胰腺癌、胃癌、结直肠癌、头颈癌、膀胱癌、胆管癌、乳腺癌、宫颈癌或食道癌。
9.根据权利要求1至8中任一项所述的具有所述用途的抗CEACAM6抗体,其中所述抗CEACAM6抗体或抗TIM-3抗体中的至少一种与一种或多种药物制剂同时、分别或顺序结合给药。
10.治疗癌症的方法,所述方法包括向有需要的患者给予有效量的权利要求1至9中任一项所述的抗CEACAM6抗体。
11.权利要求1至9中任一项所述的抗CEACAM6抗体在制备用于治疗癌症的药物中的用途。
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PCT/EP2019/084849 WO2020126808A1 (en) | 2018-12-19 | 2019-12-12 | Pharmaceutical combination of anti ceacam6 and tim3 antibodies |
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SG11202104518WA (en) | 2021-05-28 |
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