CN108601839A - 用于治疗癌症的Bcl-2抑制剂和MEK抑制剂组合产品 - Google Patents
用于治疗癌症的Bcl-2抑制剂和MEK抑制剂组合产品 Download PDFInfo
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Abstract
本发明涉及包括选择性Bcl‑2抑制剂和MEK抑制剂的组合疗法,其用于治疗需要所述疗法的患者。所述需要组合疗法的患者罹患癌症,诸如急性骨髓性白血病。
Description
相关申请的交叉引用
本申请要求于2015年11月3日提交的第62/250,231号美国临时专利申请的优先权,其内容在此引入作为参考,如同其全部内容一样。本申请要求于2015年12月4日提交的第62/263,082号美国临时专利申请的优先权,其内容在此引入作为参考,如同其全部内容一样。
技术领域
本发明涉及用于治疗需要这种治疗的患者的包括选择性Bcl-2抑制剂和MEK抑制剂的组合疗法,并且更具体地涉及维奈托克(venetoclax)(ABT-199/GDC-0199)和考比替尼(cobimetinib)(GDC-0973)。
背景技术
蛋白激酶是催化蛋白质磷酸化的酶,特别是催化蛋白质的酪氨酸、丝氨酸和苏氨酸残基上的羟基。这个看似简单的活动的后果是有重大意义的。细胞分化和增殖(即细胞生命的几乎所有方面,以单向或另一种方式)依赖于蛋白激酶活性。此外,异常蛋白激酶活性已经与许多疾病有关,从相对不危及生命的疾病(诸如牛皮癣)到极度致命的疾病(诸如胶质母细胞瘤(脑癌))。
蛋白激酶可分为受体型或非受体型。受体型酪氨酸激酶具有细胞外、跨膜和细胞内部分,而非受体型酪氨酸激酶完全是细胞内的。它们由大量具有不同生物活性的跨膜受体组成。事实上,已经鉴定出约20种不同的受体型酪氨酸激酶亚家族。一种称为HER亚家族的酪氨酸激酶亚家族由EGFR(HER1)、HER2、HER3和HER4组成。迄今为止鉴定的该亚家族受体的配体包括上皮生长因子、TGF-α、双调蛋白(amphiregulin)、HB-EGF、β-细胞素(betacellulin)和调节蛋白(heregulin)。这些受体型酪氨酸激酶的另一个亚家族是胰岛素亚家族,其包括INS-R、IGF-IR和IR-R。PDGF亚家族包括PDGF-α和β受体、CSFIR、c-kit和FLK-II。此外,存在FLK家族,其由激酶插入区受体(KDR)、胎儿肝脏激酶-1(FLK-1)、胎儿肝脏激酶-4(FLK-4)和fms样酪氨酸激酶-1(flt-1)组成。由于两组的相似性,通常将PDGF和FLK家族一起考虑。(关于受体型酪氨酸激酶的详细讨论,参见Plowman et al.,DN&P 7(6):334-339,1994,其在此引入作为参考)。
非受体型酪氨酸激酶也由许多亚家族组成,包括Src、Frk、Btk、Csk、Abl、Zap70、Fes/Fps、Fak、Jak、Ack和LIMK。这些亚家族中的每一个进一步细分为不同的受体。例如,Src亚家族是最大的一个,包括Src、Yes、Fyn、Lyn、Lck、Blk、Hck、Fgr和Yrk。酶的Src亚家族与肿瘤发生有关。(关于非受体型酪氨酸激酶的更详细的讨论,参见Bolen,Oncogene,8:2025-2031(1993),其在此引入作为参考)。
由于蛋白激酶及其配体在各种细胞活动中起关键作用,因此蛋白激酶酶活性的失调可导致细胞特性改变,诸如与癌症相关的不受控制的细胞生长。除了肿瘤学适应症之外,改变的激酶信号传导还涉及许多其他病理学疾病。这些包括但不限于:免疫性病症、心血管疾病、炎性疾病和退行性疾病。因此,受体和非受体蛋白激酶都是小分子药物发现的有吸引力的靶标。
治疗应用激酶调节的一个特别有吸引力的目标涉及肿瘤学适应症。例如,用FDA批准格列卫(由新泽西州东汉诺威的诺华制药公司生产的甲磺酸伊马替尼)治疗慢性骨髓性白血病(CML)和胃肠道间质癌已经成功地证明了用于治疗癌症的蛋白激酶活性的调节。格列卫是一种选择性Abl激酶抑制剂。
细胞增殖和血管生成的调节(特别是抑制)是肿瘤生长和存活所需的两个关键细胞过程(Matter A.Drug Disc Technol 2001 6,1005-1024),是对于小分子药物的开发具有吸引力的靶标。抗血管生成疗法代表用于治疗实体瘤和与血管生成失调相关的其他疾病(包括缺血性冠状动脉疾病、糖尿病性视网膜病、牛皮癣和类风湿性关节炎)的潜在重要方法。细胞抗增殖剂对减缓或阻止肿瘤生长是理想的。
关于抗血管生成和抗增殖活性的小分子调节的一个特别有吸引力的靶标是MEK。抑制MEK1(MAPK/ERK Kinase)(MAPK/ERK激酶)是控制依赖异常ERK/MAPK途径信号传导的肿瘤生长的有前途的策略(Solit et al.,2006;Wellbrock et al.,2004)。MEK-ERK信号转导级联是一条保守的途径,调节相应于生长因子、细胞因子和激素的细胞生长、增殖、分化和细胞凋亡。该途径在Ras下游起作用,其在人类肿瘤中经常上调或突变。已经证明MEK是Ras功能的关键效应物。在所有肿瘤的30%中ERK/MAPK途径上调,K-Ras和B-Raf中的致癌活化突变分别在所有癌症的22%和18%中被鉴定出(Allen等,2003;Bamford S,2004;Davies等,2002;Malumbres and Barbacid,2003)。据报道,大部分人类癌症,包括66%(B-Raf)的恶性黑素瘤、60%(K-Ras)和4%(B-Raf)的胰腺癌的、50%的结肠直肠癌(结肠癌,尤其是K-Ras:30%,B-Raf:15%)、20%(K-Ras)的肺癌、27%(B-Raf)的乳头状癌和甲状腺未分化癌,以及10-20%(B-Raf)的子宫内膜癌卵巢癌,具有激活的Ras和Raf突变。已经表明,ERK途径的抑制,特别是MEK激酶活性的抑制,导致抗转移和抗血管生成作用,这主要是由于细胞-细胞接触和运动性的降低以及血管内皮生长因子(VEGF)表达的下调。此外,显性负性MEK或ERK的表达降低了突变Ras的转化能力,如在细胞培养物和体内人肿瘤异种移植物的原发和转移性生长中所见。因此,MEK-ERK信号转导途径是目标在于治疗干预的适当途径。
Bcl-2蛋白家族调节由发育线索触发和响应于多重压力信号的程序性细胞死亡(Cory.S.,and Adams,J.M.,Nature Reviews Cancer 2(2002)647-656;Adams,Genes undDevelopment 17(2003)2481-2495;Danial,N.N.,and Korsmeyer,S.J.,Cell 116(2004)205-219)。鉴于Bcl-2本身以及带有三个或四个保守的Bcl-2同源性(BH)区的几个相关物(Bcl-xL、Bcl-W、Mcl-1和Al)促进细胞存活,而另外两个亚家族则驱动细胞凋亡。细胞死亡的初始信号由不同组的BH3-only蛋白传递,包括Bad、Bid、Bim、Puma和Noxa,其通常仅具有小的BH3相互作用结构域(Huang and Strasser,Cell 103(2000)839-842)。然而,Bax或Bak是含有BH1-BH3的多结构域蛋白,是对细胞死亡的承担所必需的(Cheng等,Molecular Cell8(2001)705-711;Wei,M.C.等,Science 292(2001)727-730;Zong,W.X.等,Genes andDevelopment 15 148(2001)1-1486)。当被激活时,它们可透化线粒体的外膜并释放激活拆解细胞的半胱天冬酶所需的促凋亡因子(例如细胞色素C)(Wang,K.,Genes andDevelopment 15(2001)2922-2933;(Adams,2003同上);Green,D.R.,and Kroemer,G.,Science 305(2004)626-629)。
Bcl-2家族的这三派成员之间的相互作用可决定细胞是否存活或死亡。当BH3-only蛋白被激活时,例如响应于DNA损伤,它们可经由其BH3结构域结合到其促活相对物上的沟(Sattler等,Science 275(1997)983-986)。然而,仅BH3-only和Bcl-2样蛋白如何控制Bax和Bak的活化仍然不甚了解(Adams,2003同上)。大多数关注都集中在Bax上。这种可溶性单体蛋白(Hsu,Y.T.等,Journal of Biological Chemistry 272(1997)13289-1 3834;Wolter,K.G.等,Journal of Cell Biology 139(1997)1281-92)通常具有插入其槽中的其膜定向结构域,可能是其胞质定位的原因(Nechushtan.A.等,EMBO Journal 18(1999)2330-2341;Suzuki等,Cell 103(2000)645-654;Schinzel,A.等,J Cell Biol 164(2004)1021-1032)。已经提出了几种不相关的肽/蛋白质调节Bax活性(参见例如Lucken-Ardjomande,S.,and Martinou,J.C.,J Cell Sci 118(2005)473-483),但是它们的生理相关性仍有待确定。或者,Bax可经由某些BH3-only蛋白的直接参与而被激活(Lucken-Ardjomande,S.,and Martinou,J.C,2005同上),最好记录为Bid的截短形式tBid(Wei,M.C.等,Genes und Development 14(2000)2060-2071;Kuwana,T.等,Cell 111(2002)331-342;Roucou,X.等,Biochemical Journal 368(2002)915-921;Catron,P.F.等,Mol Cell 16(2004)807-818)。如别处讨论的(Adams 2003同上),其中Bcl-2直接参与Bax(Oltvai,Z.N.等,Cell 74(1993)609-619)的最老模型已经成为潜在的问题,因为Bcl-2是膜结合的而Bax是胞质的,并且它们的相互作用似乎高度依赖于用于细胞裂解的清洁剂(Hsu,Y.T.,andYoule,1997同上)。尽管如此,已经确定Bax的BH3区域可介导与Bcl-2的结合(Zha,H.andReed,J.,Journal of Biological Chemistry 272(1997)31482-88;Wang,K.等,Molecularand Cellular Biology 18(1998)6083-6089),即使没有检测到异二聚体,Bcl-2也可阻止Bax的寡聚化(Mikhailov,V.等,Journal of Biological Chemistry 276(2001)18361-18374)。因此,促活蛋白是否直接或间接抑制Bax活化仍然不确定。
尽管在大多数情况下Bax和Bak看起来在功能上是等同的(Lindsten,T.等,Molecular Cell 6(2000)1389-1399;Wei,M.C.等,2001同上),但其调控的实质性差异是预计它们在健康细胞中的独特定位。与主要为胞质的Bax不同,Bak存在于线粒体外膜上和健康细胞内质网上的复合物中(Wei,M.C.等,2000同上;Zong,W.X.等,Journal of CellBiology 162(2003)59-69)。尽管如此,在接受细胞毒性信号时,Bax和Bak两者均改变构象,并且Bax易位至细胞器膜,其中Bax和Bak两者随后形成可结合的同源寡聚体,导致膜透化(Hsu.Y.T.等,PNAS 94(1997)3668-3672;Wolter,K.G.等,1997同上;Antonsson,B.等,Journal of Biological Chemistry 276(2001)11615-11623;Nechushtan,A.等,Journalof Cell Biology 153(2001)1265-1276:Wei,M.C.等,2001同上;Mikhailov,V.等,Journalof Biological Chemistry 278(2003)5367-5376)。
存在多种Bcl-2抑制剂,其都具有抑制Bcl-2家族蛋白的促活成员的相同特性,因此是治疗癌症的有希望的候选物。这样的Bcl-2抑制剂包括,例如:奥利默森(Oblimersen)、SPC-2996、RTA-402、棉酚、AT-101、甲磺酸奥巴克拉(Obatoclax mesylate)、A-371191、A-385358、A-438744、ABT-737、ABT-263、AT-101、BL-11、BL-193、GX-15-003、2-甲氧基抗霉素A3、HA-14-1。KF-67544、红棓酚(Purpurogallin)、TP-TW-37、YC-137和Z-24,并且描述于例如Zhai,D.等,Cell Death and Differentiation 13(2006)1419-1421中。
发明内容
本发明涉及治疗增殖性病症的方法,所述方法包括对有此需要的哺乳动物施用治疗有效量的MEK抑制剂和选择性Bcl-2抑制剂的组合。
本发明进一步涉及药物产品,其包含(i)第一组合物,所述第一组合物包含[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼)或其药学上可接受的盐,和(ii)第二组合物,所述第二组合物包含4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(ABT-199)或其药学上可接受的盐。
其他目的和特征将部分显而易见,并在下文中部分指出。
附图说明
图1A至1L是描绘考比替尼和维奈托克对AML细胞系的体外细胞毒性的图。(图1A)将AML细胞系用考比替尼或维奈托克以0.001、0.01、0.1和1.0μM处理72小时。基于与通过CellTiter-Glo测定确定的活细胞数量相关的发光强度,使用Calcusyn软件计算IC50值和组合指数(CI)。使用流式细胞术确定P-ERK,并使用p-ERK的MFI确定相对中值荧光强度(R-MFI)。显示响应模式1-5。(图1B至1L)来自每个响应模式的代表性细胞系的生长曲线。
图2A、2B和2C。考比替尼/维奈托克抗原代AML原始细胞的抗白血病活性。(图2A)将原代AML外周血单核细胞在补充有BIT 9500血清替代物和细胞因子(包括干细胞因子(100ng/ml)、Flt3配体(50ng/ml)、IL-3(20ng/ml)和G-CSF(20ng/ml)以及SR1(1μM))的无血清扩增培养基(SFEM)中培养。培养5天后,细胞用CD45-PE、膜联蛋白-V-APC和DAPI-染色。通过流式细胞术确定凋亡白血病原始细胞(CD45dimAnnexin-V+)。结果表示为通过下式计算的特异性细胞凋亡的百分比:100×(%经处理的细胞的凋亡-%对照细胞的凋亡)/(100-%对照细胞的凋亡),或使用由膜联蛋白-/DAPI确定的活细胞计数的对照的%生长抑制。(图2B)显示来自3个AML样品的代表性数据,用于显示协同作用的那些。将从具有AML(100,000)或健康供体(50,000)患者分离的MNC以每个条件一式三份接种于甲基纤维素培养基(1mL/孔;目录号04435;STEMCELL Technologies Inc.,Vancouver,BC,Canada)中。培养2周后对集落进行评分。(图2C)。基于活细胞计数的临床数据和组合指数值。**p<0.01,***p<0.001。
图3A、3B、3C、3D和3E展示了考比替尼/维奈托克组合的基础机制的药效学研究。(图3A、3B、3C和3D)RPPA数据表明在用0.5×、1×和2×IC50值的考比替尼或/和维奈托克处理24小时的敏感性或抗性AML细胞系(对于单一药物或组合)中差异表达的蛋白质。显示在组合敏感性和组合耐药性细胞之间差异表达的代表性蛋白质。(图3E)Bcl-2:BIM复合物通过MSD ELISA测定在AML细胞系(未经处理、仅用维奈托克处理、仅用考比替尼处理、或用考比替尼/维奈托克以1×IC50值4小时)中测量。
图4A、4B和4C表明细胞亚群中细胞内蛋白的质谱流式细胞术分析。用1.0μM的考比替尼处理来自原代AML的单核细胞2小时,随后用G-CSF(100ng/ml)加或减10分钟刺激。SPADE树使用包括CD7、CD117、CD123、CD64、CD34、CD26、CD45、TIM3、CD33、CD19、CD56、CD2、CD15、CD41、CD38、CD166、CD3、CD90、CD11b、CD135和HLA-DR的标志物产生。图4A描绘了来自这些测试标志物的代表性标志物。灰度色代表每种指示蛋白质的表达水平。(图4A)在门控干/祖AML细胞群(AML4295468:CD34+CD38+CD123+CD33+;AML 4366894:CD34+CD38-CD123+CD33+)中基线的Bcl-2家族成员。(图4B)上述门控细胞群中每种蛋白质的中值强度。(图4C)上述门控群体中的细胞内信号传导蛋白激活。
图5A、5B、5C、5D和5E表明考比替尼和维奈托克在OCI-AML3和MOLM13 AML模型中的体内抗白血病功效。将OCI-AML3/Luc/GFP细胞(1×106个/小鼠)静脉内注射到NSG小鼠中。(图5A)荧光素酶强度通过在注射后第5周从来自4个组的8只代表性小鼠进行系列生物发光成像来量化。(图5B)通过Kaplan-Meier法估计各组的总生存率。将1×106个MOLM13-luci-GFP细胞注射到NSGS小鼠中。在第3天使用生物发光成像(BLI)确认白血病植入。小鼠每天口服给药考比替尼(10mg/kg)或维奈托克(100mg/kg)或组合,持续14天。在第17天显示荧光素酶强度(图5C)。BM和脾中的人CD45植入通过CyTOF确定。(图5D)。使用Vi-Cell测量活细胞计数。(图5E)。**P:0.01;***P:0.001。
具体实施方式
本发明涉及用于治疗需要这种治疗的哺乳动物例如人类患者的涉及选择性Bcl-2抑制剂和MEK抑制剂的组合疗法。包括Bcl-2的促活分子在白血病转化和化疗耐药中发挥关键作用。ABT-199(也称为并且在本文中任选称为GDC-0199或维奈托克)是口服可用的BH3-模拟物,其以高亲和力与Bcl-2结合,但对Bcl-XL和Mcl-1缺乏亲和性。最近证明了维奈托克在急性骨髓性白血病(AML)模型中的抗白血病效力(参见例如Pan et al.,CancerDiscovery 2014)。然而,维奈托克很少抑制Mcl-1,导致依赖Mcl-1存活的白血病细胞产生耐药性。RAF/MEK/ERK(MAPK)级联是AML中的主要效应器途径,其由上游突变蛋白诸如FLT3、KIT和RAS激活。另外,MAPK途径通过稳定抗凋亡Mcl-1和灭活促凋亡BIM来调节Bcl-2家族蛋白。在一些实施方案中,本发明涉及组合疗法,其组合维奈托克与MEK1/2抑制剂考比替尼组合的伴随Bcl-2和MAPK阻断的抗肿瘤作用。
在一些实施方案中,需要组合疗法的哺乳动物,例如人类患者患有癌症,诸如急性骨髓性白血病。在一些实施方案中,组合疗法包括施用治疗有效量的选择性Bcl-2抑制剂和治疗有效量的MEK抑制剂,用于治疗需要这种疗法的哺乳动物例如人类患者。
在一些实施方案中,需要组合疗法的哺乳动物例如人类患者患有癌症,诸如多发性骨髓瘤。在一些实施方案中,组合疗法包括施用治疗有效量的选择性Bcl-2抑制剂和治疗有效量的MEK抑制剂,用于治疗需要这种疗法的哺乳动物例如人类患者。
在一些实施方案中,所述选择性Bcl-2抑制剂包括4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(也称为并且在本文中任选称为维奈托克或ABT-199或GDC-0199)或其药学上可接受的盐。在一些实施方案中,本发明的组合疗法涉及向有此需要的哺乳动物例如人类患者施用治疗有效量的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(维奈托克或ABT-199/GDC-0199)或其药学上可接受的盐。维奈托克具有以下结构:
在一些实施方案中,所述MEK抑制剂包括[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(也称为并且在本文中任选称为考比替尼或GDC-0973)或其药学上可接受的盐。在一些实施方案中,本发明的组合疗法涉及向有此需要的哺乳动物例如人类患者施用治疗有效量的[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢
-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺环丁烷-1-基}甲酮(考比替尼或GDC-0973)或其药学上可接受的盐。考比替尼具有以下结构:
[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮
如使用ACD/Labs命名软件8.00发布,产品版本8.08所生成,该化合物的名称为1-({3,4-二氟-2-[(2-氟-4-碘苯基)氨基]苯基}羰基)-3-[(2S)-哌啶-2-基]氮杂环丁烷-3-醇。
在一些实施方案中,所述组合物疗法包括向需要这种疗法的哺乳动物例如人类患者施用治疗有效量的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(ABT-199)或其药学上可接受的盐和治疗有效量的[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼)或其药学上可接受的盐。需要本发明组合疗法的患者可患有癌症。在一些实施方案中,所述癌症为急性骨髓性白血病。在一些实施方案中,所述癌症为多发性骨髓瘤。
I.定义
术语“哺乳动物”包括但不限于人、小鼠、大鼠、豚鼠、猴、犬、猫、马、牛、猪、绵羊和家禽。术语患者是指哺乳动物,并且在一个实施方案中,患者为男人或女人。
在本文中,“患者”(可互换地称为“个体”)是人类患者。患者可为“癌症患者”,即患有或有患上一种或多种癌症症状的风险的人。用于治疗目的的“受试者”或“个体”是指被归类为哺乳动物的任何动物,包括人、家养动物和农场动物,以及动物园、运动或宠物动物,诸如犬、马、猫、牛等。优选地,哺乳动物为人类。
患者的“群体”是指一组具有癌症的患者,诸如在临床试验中,或者如肿瘤学家在FDA批准用于特定适应症(诸如不可切除或转移性黑素瘤癌症疗法)后所看到的。
“病症”是将从治疗中受益的任何病症,包括但不限于,慢性和急性病症或疾病,包括使哺乳动物易患所述病症的那些病理状况。
术语“细胞增殖性病症”和“增殖性病症”是指与一定程度的异常细胞增殖相关的病症。在一个实施方案中,细胞增殖性病症为癌症。在一个实施方案中,细胞增殖性病症为肿瘤。
本文使用的“肿瘤”是指所有肿瘤细胞生长和增殖,无论是恶性的还是良性的,以及所有的癌前和癌细胞和组织。本文提及的术语“癌症”、“癌性”、“细胞增殖性病症”、“增殖性病症”和“肿瘤”并不互斥。
术语“癌症”和“癌性”是指或描述哺乳动物的生理状况,其典型特征在于不受调节的细胞生长。癌症的实例包括但不限于,癌、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴恶性肿瘤。此类癌症的更具体实例包括但不限于,鳞状细胞癌(例如上皮鳞状细胞癌);肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞癌)、腹膜癌、肝细胞癌、胃癌或胃部癌(包括胃肠道癌和胃肠道间质癌)、胰腺癌、胶质母细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、泌尿道癌、肝癌、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌或肾部癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌、黑素瘤、浅表扩散性黑素瘤、恶性雀斑样痣黑色素瘤、肢端雀斑样痣性黑素瘤、结节性黑素瘤、多发性骨髓瘤和B细胞淋巴瘤(包括低级/滤泡性非霍奇金淋巴瘤(NHL);小淋巴细胞性(SL)NHL;中级/滤泡性NHL;中级弥漫性NHL;高级免疫母细胞性NHL;高级淋巴母细胞性NHL;高级小型非裂解细胞NHL;肿瘤体积较大的NHL(bulky disease NHL);套细胞淋巴瘤;AIDS相关性淋巴瘤;以及瓦尔登斯特伦巨球蛋白血症);慢性淋巴细胞白血病(CLL);急性淋巴细胞白血病(ALL);毛细胞白血病;慢性骨髓性白血病;和移植后淋巴增殖性疾病(PTLD)、以及与瘢痣病相关的异常血管增殖、水肿(诸如与脑肿瘤相关的水肿)、Meigs综合征、脑以及头颈部癌,及相关的转移。在某些实施方案中,适合用本发明抗体治疗的癌症包括乳腺癌、结肠直肠癌、直肠癌、非小细胞肺癌、胶质母细胞瘤、非霍奇金淋巴瘤(NHL)、肾细胞癌、前列腺癌、肝癌、胰腺癌、软组织肉瘤、卡波西肉瘤、类癌瘤、头颈癌、卵巢癌、间皮瘤和多发性骨髓瘤。在一些实施方案中,癌症选自:小细胞肺癌、胶质母细胞瘤、神经母细胞瘤、黑素瘤、乳腺癌、胃癌、结肠直肠癌(CRC)和肝细胞癌。
除非另有说明,否则本文使用的术语“治疗”意指在患者中部分或完全逆转、减轻、抑制肿瘤、肿瘤转移或其他致癌或肿瘤细胞的生长的进展,或预防肿瘤、肿瘤转移或其他致癌或肿瘤细胞的生长。目的是预防或减缓(减少)不期望的生理变化或障碍,诸如癌症的生长、发展或传播。为了本发明的目的,有益的或期望的临床结果包括但不限于,症状的缓解、疾病程度的减少、疾病状态的稳定(即不恶化)、疾病进展的延迟或减缓、改善或缓和的疾病状态、和缓解(无论是部分还是全部),无论是可检测的还是不可检测的。
本文使用的术语“治疗”是指设计用于改变在临床病理学过程中被治疗的个体或细胞的自然进程的临床干预。治疗的理想效果包括降低疾病进展速度、改善或减轻疾病状态、缓解或改善预后。例如,如果一种或多种与癌症相关的症状得到缓解或消除,则个体被成功“治疗”,包括但不限于减少癌细胞增殖(或破坏),减少由所述疾病引起的症状,提高患有所述疾病的人的生活质量,减少治疗所述疾病所需的其他药物的剂量,和/或延长个体的存活。“治疗”既指治疗性治疗,也指预防或防止性措施。如果不接受治疗,则“治疗”也意味着与预期生存期相比延长生存期。需要治疗的那些人包括那些已经具有病状或病症的人,例如具有癌症的患者。
当应用于例如癌症时,术语“治疗方法”或其等价物指被设计用于减少或消除患者中癌细胞数量或减轻患者症状的程序或作用过程。“治疗癌症或另一种增殖性病症的方法”并不一定意味着实际上将消除癌细胞或其他病症,实际上可减少细胞或病症的数量,或实际上癌症或其他病症的症状将得到缓解。通常,治疗癌症的方法即使成功的可能性较低也将进行,但考虑到患者的病史和估计的生存期望,其仍然被视为诱导整体有益的行动过程。术语“共同施用”或“共同给药”是指将所述MEK抑制剂和所述选择性Bcl-2抑制剂作为两种单独的制剂或在一种单一制剂内施用。共同施用可同时或按照任意顺序依序进行。在另一个实施方案中,存在两个(或全部)活性剂同时发挥其生物活性的时间段。所述MEK抑制剂和所述选择性Bcl-2抑制剂通过连续输注(一种用于MEK抑制剂,最后一种用于Bcl-2抑制剂;或Bcl-2抑制剂口服施用)同时或顺序共同施用(例如经由静脉内(i.v.))。当两种治疗剂依序共同施用时,所述药剂以两次分开施用的方式施用,其以“特定的时间段”分开。术语特定的时间段意指1小时至15天。例如,可在约施用其他试剂15、14、13、12、11、10、9、8、7、6、5、4、3、2或1天或24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2或1小时内施用一种药剂,并且在一个实施方案中,特定的时间段是10、9、8、7、6、5、4、3、2或1天或24、23、22、21、20、19、18、17、16,15、14、13、12、11、10、9、8、7、6、5、4、3、2或1小时。
与参照相比,“抑制”是降低或减少活性、功能和/或量。
为了本文的目的,“先前治疗过的”癌症患者已经接受过先前的癌症治疗。“先前治疗的”不可切除的或转移性黑素瘤患者已经接受了对不可切除或转移性黑素瘤的先前治疗。
“癌症药物”是有效治疗癌症的药物。
为了本文的目的,“先前治疗过的”癌症患者已经接受过先前的癌症疗法。“先前治疗国的”不可切除的或转移性黑素瘤患者已经接受过对不可切除或转移性黑素瘤的先前疗法。
“癌症药物”是有效治疗癌症的药物。
本文中的术语“口服可递送的”、“口服施用”和“口服施用的”是指口服施用至受试者(p.o.),即其中立即吞服组合物的施用,例如借助于合适体积的水或其他可饮用液体。本文中“口服施用”不同于口内施用,例如舌下或口腔施用或局部施用至口腔内组织诸如牙周组织,其不涉及立即吞咽组合物。
术语“同时”意指同时或在短时间内,通常少于1小时。
本文使用的剂量给药期意指一段时间,在此期间每种治疗剂已被施用至少一次。剂量给药期通常为约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天,并且在一个实施方案中为6、7、8、9、10、11、12、13或14天,例如7或14天。
在某些实施方案中,剂量给药期是剂量给药周期。
不言而喻,以“治疗有效量”(或简称“有效量”)将药物活性剂施用于患者,所述“治疗有效量”(或简称“有效量”)是研究人员、兽医、医生或其他临床医师正在寻找的将引起组织、系统、动物或人类的生物学或医学应答的相应化合物或组合的量。施用有效量的药物活性剂可以是单次施用或分次剂量施用。“分次剂量施用”意指将有效量分成多个剂量,优选2个,并且在1或2天内施用。例如,如果100mg的选择性Bcl-2抑制剂被认为是有效的,则其可以一次100mg施用或两次50mg施用进行施用。有时在施用期开始时需要分次剂量施用,以减少副作用。当以分次剂量施用有效量时,仍被认为是有效量的一次施用。例如,当100mg是选择性Bcl-2抑制剂的有效量并且该量在一段时间内以两个50mg剂量施用时,例如,2天内,在此期间只施用一次有效量。
术语“药物制剂”是指无菌制剂,其形式使得药物的生物学活性有效,并且不含对受试者(对其施用制剂)具有不可接受的毒性的额外组分。
本文使用的“药学上可接受的载体”旨在包括与药物施用相容的任何和所有材料,包括溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂以及与药物施用相容的其他材料和化合物。示例性药学上可接受的载体的非限制性列表为缓冲剂、赋形剂、稳定剂或防腐剂。除了任何常规介质或试剂与活性化合物不相容之外,还考虑将其用于本发明的组合物中。补充活性化合物也可掺入组合物中。
本文使用的短语“药学上可接受的盐”是指化合物的药学上可接受的有机或无机盐。示例性盐包括但不限于,双甲磺酸盐、硫酸盐、柠檬酸盐、乙酸盐、草酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐“甲磺酸盐”、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1'-亚甲基-双-(2-羟基-3-萘甲酸)盐)。药学上可接受的盐可涉及另一种分子,诸如乙酸根离子、琥珀酸根离子或其他抗衡离子的内含物(inclusion)。抗衡离子可为使母体化合物上的电荷稳定的任何有机或无机部分。此外,药学上可接受的盐在其结构中可具有多于一个带电荷的原子。其中多个带电原子是药学上可接受的盐的一部分的实例可具有多个抗衡离子。因此,药学上可接受的盐可具有一个或多个带电荷的原子和/或一个或多个抗衡离子。
期望的药学上可接受的盐可通过本领域可用的任何合适的方法来制备。例如,用无机酸诸如盐酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等,或用有机酸诸如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷酸诸如葡糖醛酸或半乳糖醛酸、α-羟基酸诸如柠檬酸或酒石酸、氨基酸诸如天冬氨酸或谷氨酸、芳香酸诸如苯甲酸或肉桂酸、磺酸诸如对甲苯磺酸或乙磺酸等处理游离碱。通常认为适合由碱性药物化合物形成药学上有用或可接受的盐的酸例如由P.Stahl et al,Camille G.(eds.)Handbookof Pharmaceutical Salts.Properties,Selection and Use.(2002)Zurich:Wiley-VCH;S.Berge et al,Journal of Pharmaceutical Sciences(1977)66(1)1 19;P.Gould,International J.of Pharmaceutics(1986)33 201 217;Anderson et al,The Practiceof Medicinal Chemistry(1996),Academic Press,New York;Remington'sPharmaceutical Sciences,18.sup.th ed.,(1995)Mack Publishing Co.,Easton Pa.;和橙皮书(The Orange Book)(Food&Drug Administration,Washington,D.C.在其网站上)讨论。这些公开内容通过引用并入本文。
II.选择性Bcl-2抑制剂
本发明的组合疗法涉及施用选择性Bcl-2抑制剂。第2012/0129853号美国公开中公开了使用选择性Bcl-2抑制剂的治疗方法,其公开内容通过引用整体并入本文。在这方面,选择性Bcl-2抑制剂是选择性结合Bcl-2家族内特定蛋白质的抑制剂。在一些实施方案中,本发明的组合疗法涉及施用选择性抑制Bcl-2蛋白的选择性Bcl-2抑制剂。例如,4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(也称为并且任选称为维奈托克或ABT-199/GDC-0199)是一种口服可用、有效且高度选择性的Bcl-2抑制剂,Bcl-2是调节细胞凋亡的调节蛋白Bcl-2家族的成员。ABT-199选择性与Bcl-2蛋白结合并引发对Bcl-2蛋白的响应,其浓度远低于与Bcl-xL结合并引发Bcl-xL响应所需的浓度。因此,当向患者施用ABT-199时,抑制剂更倾向于抑制Bcl-2,而不是Bcl-xL。相比于对Bcl-xL的结合亲和力,ABT-199倾向于对Bcl-2具有小至少约500倍、至少约1000倍、至少约2000倍、至少约2500倍、至少约3000倍、至少约3500倍和至少约4000倍的竞争性结合亲和力(Ki)。因此,即使在低浓度(即皮摩尔浓度),ABT-199也会与Bcl-2蛋白结合并抑制Bcl-2蛋白。
在一些实施方案中,所述选择性Bcl-2抑制剂包括4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(维奈托克或ABT-199/GDC-0199)或其药学上可接受的盐。在一些实施方案中,本发明的组合疗法涉及向有此需要的哺乳动物例如人类患者施用治疗有效量的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(维奈托克或ABT-199/GDC-0199)或其药学上可接受的盐。维奈托克具有以下结构:
4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺
维奈托克(或ABT-199/GDC-0199)可以其母体化合物形式(即作为游离碱),以所述化合物的药学上可接受的盐形式,或者所述母体化合物形式和所述药学上可接受的盐形式的组合配制。其他合适的形式包括ABT-199的水合物或溶剂化形式。在一些实施方案中,ABT-199可为适合掺入药物组合物中的结晶多晶型物,所述药物组合物还包含药学上可接受的赋形剂。第2012/0157470号美国公开中公开了ABT-199的盐和结晶形式,其公开内容通过引用整体并入本文。本文使用的短语“药学上可接受的盐”意指ABT-199的那些盐,其对于施用于患者是安全和有效的,并且不会不利地影响化合物的治疗质量。药学上可接受的盐包括存在于本发明化合物中的酸性或碱性基团的盐。ABT-199的盐可在分离期间或化合物纯化后制备。
酸加成盐是由维奈托克(或ABT-199/GDC-0199)与酸反应得到的那些盐。例如,ABT-199化合物的盐,包括乙酸盐、酸式磷酸盐、己二酸盐、海藻酸盐、抗坏血酸盐、碳酸氢盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯基磺酸盐(苯磺酸盐)、硫酸氢盐、酒石酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、乙磺酸盐、乙二磺酸盐、甲酸盐、富马酸盐、龙胆酸盐、甘油磷酸盐、葡糖酸盐、葡糖醛酸盐、谷氨酸盐、半硫酸盐、庚酸盐、己酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、异烟酸盐、1-羟基-2-萘甲酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、均三甲苯磺酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、硝酸盐、草酸盐、对甲苯磺酸盐、双羟萘酸盐(即,1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐)、泛酸盐、果胶酸盐、过硫酸盐、磷酸盐、苦味酸盐、丙酸盐、糖酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、三氯乙酸盐、三氟乙酸盐、对甲苯磺酸盐和十一酸盐可用于本发明的组合物中。碱加成盐,包括由ABT-199与阳离子诸如铝、锂、钠、钾、钙、锌和镁的碳酸氢盐、碳酸盐、氢氧化物或磷酸盐反应衍生的盐同样可使用。(关于药学上可接受的盐的综述参见例如Berge et al.,66J.Pharm.Sci.,1-19(1977),其全文以引用的方式整体并入本文)。
维奈托克(或ABT-199/GDC-0199)或其药学上可接受的盐可以一定量的剂型呈现,当根据适当的方案向有此需要的受试者施用组合物时,所述量可以是治疗有效的量。除非上下文另有要求,否则剂量在本文中表示为母体化合物当量。通常,取决于所讨论的化合物,可以适当频率(例如每日两次至每周一次)施用的单位剂量(单次施用的量)为约10mg至约1,000mg。在每日给药频率(q.d.)的情况下,单位剂量和每日剂量是相同的。说明性地,单位剂量通常为约25mg至约1,000mg,更通常约50mg至约500mg,例如约50mg,约100mg,约150mg,约200mg,约250mg,约300mg,约350mg,约400mg,约450mg或约500mg。在剂型包含包封剂型例如固体分散体的胶囊壳或其中剂型(例如固体分散体)与其他成分一起配制的片剂时,单位剂量可以以单一剂型或多种剂型,最通常为1至约10种剂型递送。
维奈托克(或ABT-199/GDC-0199)或其药学上可接受的盐的“治疗有效量”是指所施用的足以防止一定程度上发展或减轻所治疗的病症或障碍的一种或多种症状的化合物的量。ABT-199的治疗有效量取决于治疗的接受者、所治疗的病症及其严重程度、含有化合物的组合物、施用时间、施用途径、治疗持续时间、化合物效力、清除率和是否共同施用另一种药物。通常,本发明的方法涉及施用约0.001mg/kg至约1000mg/kg范围的选择性Bcl-2抑制剂的剂量。在一个实施方案中,所述方法涉及施用约0.01mg/kg至约500mg/kg范围的选择性Bcl-2抑制剂的剂量。在另一个实施方案中,所述方法涉及施用约0.1mg/kg至约300mg/kg范围的ABT-199的剂量。
由于事实上ABT-199可选择性地抑制Bcl-2蛋白,因此本发明的方法与本领域当前已知的方法相比可说明治疗疾病状态的改善的功效。Bcl-2家族蛋白是一组对多种发育和稳态功能(诸如细胞凋亡(程序性细胞死亡))具有调节作用的蛋白质。Bcl-2家族包括其他蛋白质,包括Bcl-xL和Bcl-w。然而,Bcl-xL蛋白的抑制已显示对血小板计数具有不利影响,在某些情况下导致血小板减少症。与其他Bcl-2家族蛋白(诸如Bcl-xL和Bcl-w)相比,选择性Bcl-2抑制剂化合物对Bcl-2显示出更高的结合亲和力(如通过较低的Ki值所证明的)。因此,本发明的方法提供了抑制Bcl-2蛋白的优点,同时降低了与Bcl-xL和Bcl-w抑制相关的不利作用(诸如血小板减少症)的风险。这可能允许与其他药物诸如考比替尼更可耐受的组合。此外,ABT-199是比本领域已知的一些Bcl-2抑制剂更有效的Bcl-2抑制剂。最后,已经观察到急性骨髓性白血病细胞比Bcl-xL更依赖于Bcl-2存活,这是该领域意外发现的。与考比替尼组合的基本原理是治疗Bcl-2和Mcl-1共表达的肿瘤。
将各种蛋白质的结合亲和力测量为Ki值,其表示抑制生理学过程或化合物(诸如蛋白质)50%所需的化合物的量。参见第2012/0129853号美国公开,其公开内容通过引用整体并入本文。本发明方法中使用的选择性Bcl-2化合物对Bcl-2通常具有以下结合亲和力(Ki):小于约1微摩尔浓度、小于约500纳摩尔浓度、小于约400纳摩尔浓度、小于约300纳摩尔浓度、小于约200纳摩尔浓度、小于约100纳摩尔浓度、小于约50纳摩尔浓度、小于约25纳摩尔浓度、小于约10纳摩尔浓度、小于约5纳摩尔浓度、小于约1纳摩尔浓度、小于约900皮摩尔浓度、小于约800皮摩尔浓度、小于约700皮摩尔浓度、小于约600皮摩尔浓度、小于约500皮摩尔浓度、小于约400皮摩尔浓度、小于约300皮摩尔浓度、小于约200皮摩尔浓度和小于约100皮摩尔浓度。
III.考比替尼
考比替尼(也称为并且在本文中任选称为GDC-0973)是一种口服有效的、高度选择性的MEK1和MEK2抑制剂。MEK1和MEK2是RAS/RAF途径的中心组成部分。包括考比替尼在内的选择性MEK抑制剂公开于第7,803,839号美国专利,其公开内容通过引用并入本文,如同其全部内容一样。
在一些实施方案中,所述MEK抑制剂包括[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼或GDC-0973)或其药学上可接受的盐。在一些实施方案中,本发明的组合疗法涉及向有此需要的哺乳动物例如人类患者施用治疗有效量的[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼或GDC-0973)或其药学上可接受的盐。考比替尼具有以下结构:
[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮
考比替尼可以其母体化合物形式(即,作为游离碱),以所述化合物的药学上可接受的盐形式或者母体化合物形式和药学上可接受的盐形式的组合配制。其他合适的形式包括考比替尼的水合物或溶剂化形式。在一些实施方案中,考比替尼可为适合掺入药物组合物中的结晶多晶型物,所述药物组合物还包含药学上可接受的赋形剂。考比替尼的盐和结晶形式公开地7,803,839号美国专利和第PCT/EP2013/067050号国际申请(公开号为WO2014/027056),其公开内容通过引用整体并入本文,如同其全部内容一样。本文使用的短语“药学上可接受的盐”是指那些对于施用于患者是安全和有效的并且不会不利地影响该化合物的治疗品质的考比替尼的盐。药学上可接受的盐包括存在于本发明化合物中的酸性或碱性基团的盐。考比替尼盐可以在分离化合物期间或纯化化合物后制备。
本文描述了药学上可接受的盐并且是本领域已知的。示例性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖二酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐“甲磺酸盐”、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1'-亚甲基-双-(2-羟基-3-萘甲酸)盐)。药学上可接受的盐可涉及包含另一种分子,诸如乙酸根离子、琥珀酸根离子或其他抗衡离子。抗衡离子可以是使母体化合物上的电荷稳定的任何有机或无机部分。此外,药学上可接受的盐在其结构中可具有多于一个带电荷的原子。其中多个带电原子是药学上可接受的盐的一部分的实例可具有多个抗衡离子。因此,药学上可接受的盐可具有一个或多个带电荷的原子和/或一个或多个抗衡离子。如果化合物为碱,则所需的药学上可接受的盐可通过本领域可用的任何合适的方法制备,例如用无机酸诸如盐酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等,或用有机酸诸如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷基酸诸如葡糖醛酸或半乳糖醛酸、α-羟基酸诸如柠檬酸或酒石酸、氨基酸诸如天冬氨酸或谷氨酸、芳香酸诸如苯甲酸或肉桂酸、磺酸诸如对甲苯磺酸或乙磺酸等处理游离碱。通常认为适合由碱性药物化合物形成药学上有用或可接受的盐的酸例如由P.Stahl et al,CamilleG.(eds.)Handbook of Pharmaceutical Salts.Properties,Selection and Use.(2002)Zurich:Wiley-VCH;S.Berge et al,Journal of Pharmaceutical Sciences(1977)66(1)119;P.Gould,International J.of Pharmaceutics(1986)33 201 217;Anderson et al,The Practice of Medicinal Chemistry(1996),Academic Press,New York;Remington'sPharmaceutical Sciences,18.sup.th ed.,(1995)Mack Publishing Co.,Easton Pa.;和橙皮书(The Orange Book)(Food&Drug Administration,Washington,D.C.在其网站上)讨论。如果化合物为酸,则可通过任何合适的方法制备期望的药学上可接受的盐,例如用无机或有机碱诸如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等处理游离酸。合适的盐的说明性实例包括但不限于由氨基酸诸如甘氨酸和精氨酸、氨、伯胺、仲胺和叔胺以及环胺诸如哌啶、吗啉和哌嗪衍生的有机盐,和由钠、钙、钾、镁、锰、铁、铜、锌、铝和锂衍生的无机盐。
考比替尼或其药学上可接受的盐可以这样的剂量存在,当该组合物根据适当的方案施用于有需要的受试者时所述量可在治疗上有效。除非上下文另有要求,否则剂量在本文中表示为母体化合物当量。通常,取决于所讨论的化合物,可以适当频率(例如每日两次至每周一次)施用的单位剂量(单次施用的量)为约10mg至约1,000mg。在每日一次施用频率(q.d.)的情况下,单位剂量和每日剂量是相同的。说明性地,单位剂量通常为约25mg至约1,000mg,更通常约50至约500mg,例如约50mg、约100mg、约150mg、约200mg、约250mg、约300mg、约350mg、约400mg、约450mg或约500mg。在剂型包含包封剂型(例如固体分散体)的胶囊壳或其中剂型(例如固体分散体)与其它成分一起配制的片剂的情况下,单位剂量可以单一剂型或多种剂型递送,最通常为1至约10种剂型。
考比替尼或其药学上可接受的盐的“治疗有效量”是指所施用的足以防止一定程度上发展或缓解所治疗的病症或障碍的一种或多种症状的化合物的量。考比替尼的治疗有效量取决于治疗的接受者、所治疗的病症及其严重程度、含有化合物的组合物、施用时间、施用途径、治疗持续时间、化合物效力、清除率和是否共同施用另一种药物。通常,本发明的方法涉及施用约0.001mg/kg至约1000mg/kg范围的考比替尼的剂量。在一个实施方案中,所述方法涉及施用约0.01mg/kg至约500mg/kg范围的考比替尼的剂量。在另一个实施方案中,所述方法涉及施用约0.1mg/kg至约300mg/kg范围的考比替尼的剂量。
IV.药物制剂
通常,药物制剂中药物或药物组合的浓度为母体化合物当量重量的至少约1%,例如约1%至约50%,但在具体案例中更低和更高的浓度可以是可接受的或可达到的。说明性地,各种实施方案中的药物浓度为母体化合物当量重量的至少约2%,例如约2%至约50%,或至少约5%,例如约5%至约40%,例如约5%、约10%、约15%、约20%、约25%、约30%、约35%或约40%。在一些实施方案中,药物浓度可为约5%至约15%,诸如约5%至约12%,诸如约5%、约6%、约7%、约8%、约9%、约10%、约11%或约12%。
本发明的口服可递送固体剂型包括但不限于胶囊、糖锭、颗粒剂、丸剂、粉剂和片剂。常用于配制这种剂型的赋形剂包括囊化材料或制剂添加剂,诸如吸收促进剂、抗氧化剂、粘合剂、缓冲剂、包衣剂、着色剂、稀释剂、崩解剂、乳化剂、增量剂、填充剂、调味剂、湿润剂、润滑剂、防腐剂、推进剂、释放剂、灭菌剂、甜味剂、增溶剂及其混合物。许多赋形剂在药物组合物中具有两种或更多种功能。特定赋形剂在本文中具有某种功能的表征,例如稀释剂、崩解剂、粘合剂等,不应被理解为限制该功能。关于赋形剂的进一步信息可在标准参考著作诸如Handbook of Pharmaceutical Excipients,3rd ed.(Kibbe,ed.(2000),Washington:American Pharmaceutical Association)中找到。
在一些实施方案中,可将合适的制剂制备成固体分散体,例如通过熔融-挤出法或通过溶剂蒸发法。可将固体分散体施用于有此需要的患者,或者固体分散体可与其他药学上可接受的赋形剂压片。
熔融-挤出法(Meltrex)公开于第2012/0108590号美国公开,其公开内容通过引用整体并入本文,如同其全部内容一样。所述Meltrex法包括:(a)使(i)活性药物成分(API)或其药学上可接受的盐、(ii)药学上可接受的水溶性聚合物载体和(iii)药学上可接受的表面活性剂经受升高的温度,得到可挤出的半固体混合物;(b)例如通过冲头挤出半固体混合物;和(c)冷却所得挤出物,得到包含聚合物载体和表面活性剂并且具有其中以基本上非结晶形式分散的化合物或其盐的固体基质。本文中的“熔体”是由升高的温度引起的液体或半固体(例如橡胶)状态,其中第一组分可以均匀分布在包含第二组分的基质中。通常,将第二(基质)组分(例如聚合物载体处于这种状态)和其他组分(例如包括式I的化合物或其盐)溶于熔体中,从而形成溶液。本文中“升高的温度”是指聚合物载体的软化点以上的温度,受其它组分(如果存在的话)诸如增塑剂或表面活性剂的影响。
溶剂蒸发法公开于第2012/0277210号美国公开,其公开内容通过引用整体并入本文,如同其全部内容一样。溶剂蒸发法包括:(a)将(i)活性药物成分(API)或其药学上可接受的盐、(ii)药学上可接受的水溶性聚合物载体和(iii)药学上可接受的表面活性剂溶于合适的溶剂;和(b)除去溶剂,得到包含聚合物载体和表面活性剂并且在其中以基本上非结晶形式分散的化合物或其盐的固体基质。
说明性地,合适的稀释剂单独或组合地包括:乳糖,包括无水乳糖和乳糖一水合物;乳糖醇;麦芽糖醇;甘露糖醇;山梨糖醇;木糖醇;右旋糖和右旋糖一水合物;果糖;蔗糖和基于蔗糖的稀释剂,诸如可压缩糖、糖果糖和糖球;麦芽糖;肌醇;水解的谷物固体;淀粉(例如玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、木薯淀粉等)、淀粉组分诸如直链淀粉和葡萄糖结合剂(dextrate),以及改性或加工淀粉诸如预胶化淀粉;糊精;纤维素,包括粉状纤维素、微晶纤维素、硅化微晶纤维素、食品级来源的α-和无定形纤维素和粉末状纤维素以及乙酸纤维素;钙盐,包括碳酸钙、磷酸三钙、磷酸二钙(例如磷酸氢钙二水合物)、硫酸钙一水合物(monobasic calcium sulfate monohydrate)、硫酸钙和颗粒乳酸钙三水合物;碳酸镁;氧化镁;膨润土;高岭土;氯化钠;等等。如果存在,这些稀释剂通常占组合物重量的约1%至约95%,例如约5%至约50%,或约10%至约30%。所选择的一种或多种稀释剂优选表现出合适的流动性能,并且在需要片剂的情况下,具有可压缩性。
微晶纤维素和硅化微晶纤维素是特别有用的稀释剂,并且任选与水溶性稀释剂诸如甘露糖醇组合使用。说明性地,微晶纤维素或硅化微晶纤维素与甘露糖醇的合适重量比为约10:1至约1:1,但在此范围之外的比率可用于特定情况。
合适的崩解剂包括单独或组合的聚合物材料,诸如淀粉,包括预胶化淀粉和淀粉羟乙酸钠;粘土;硅酸镁铝;基于纤维素的崩解剂,诸如粉状纤维素、微晶纤维素、甲基纤维素、低取代羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠和交联羧甲基纤维素钠;海藻酸盐;聚维酮;交聚维酮;波拉克林钾;树胶,诸如琼脂、瓜尔胶、刺槐豆胶、刺梧桐树胶、果胶和黄蓍胶;胶态二氧化硅;等等。一种或多种崩解剂(如果存在)通常占组合物重量的约0.2%至约30%,例如约0.5%至约20%或约1%至约10%。
羟乙酸淀粉钠是特别有用的崩解剂,并且通常占组合物重量的约1%至约20%,例如约2%至约15%,或约5%至约10%。
粘合剂或粘着剂是有用的赋形剂,特别是当组合物呈片剂形式时。这种粘合剂和粘着剂应该对所制片的共混物赋予足够的内聚力,以允许进行正常的加工操作,诸如分选、润滑、压缩和包装,但仍然摄入后允许片剂崩解及组合物吸收。合适的粘合剂和粘着剂包括单独或组合的阿拉伯胶;黄蓍胶;葡萄糖;聚葡萄糖;淀粉,包括预胶化淀粉;明胶;改性纤维素,包括甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素(HPMC)、羟丙基纤维素、羟乙基纤维素和乙基纤维素;糊精,包括麦芽糖糊精;玉米醇溶蛋白(zein);海藻酸和海藻酸的盐,例如海藻酸钠;硅酸镁铝;膨润土;聚乙二醇(PEG);聚氧化乙烯;瓜尔胶;多糖酸;聚乙烯吡咯烷酮(聚维酮或PVP),例如聚维酮K-15、K-30和K-29/32;聚丙烯酸(卡波姆);聚甲基丙烯酸酯;等等。一种或多种粘合剂和/或粘着剂(如果存在)通常占组合物重量的约0.5%至约25%,例如约1%至约15%或约1.5%至约10%。
聚维酮和羟丙基纤维素单独或组合是对于片剂制剂特别有用的粘合剂,并且(如果存在)通常占组合物重量的约0.5%至约15%,例如约1%至约10%,或约2%至约8%。
除了固体分散体的表面活性剂组分之外,如果需要,润湿剂例如增溶剂可添加至制剂中。可用作润湿剂的表面活性剂的非限制性实例包括单独或组合的季铵化合物,例如苯扎氯铵、苄索氯铵和氯化十六烷基吡啶鎓;二辛基磺基琥珀酸钠;聚氧乙烯烷基苯基醚,例如壬苯醇醚9,壬苯醇醚10和辛苯醇醚9;泊洛沙姆(聚氧乙烯和聚氧丙烯嵌段共聚物);聚氧乙烯脂肪酸甘油酯和油,例如聚氧乙烯(8)辛酸/癸酸甘油单酯和甘油二酯、聚氧乙烯(35)蓖麻油和聚氧乙烯(40)氢化蓖麻油;聚氧乙烯烷基醚,例如鲸蜡醇聚醚-10、月桂醇聚醚-4、月桂醇聚醚-23、油醇聚醚-2、油醇聚醚-10、油醇聚醚-20、硬脂醇聚醚-2、硬脂醇聚醚-10、硬脂醇聚醚-20、硬脂醇聚醚-100和聚氧乙烯(20)鲸蜡硬脂基醚;聚氧乙烯脂肪酸酯,例如聚氧乙烯(20)硬脂酸酯,聚氧乙烯(40)硬脂酸酯和聚氧乙烯(100)硬脂酸酯;山梨聚糖酯,例如山梨聚糖单月桂酸酯、山梨聚糖单油酸酯,山梨聚糖单棕榈酸酯和山梨聚糖单硬脂酸酯;聚氧乙烯山梨聚糖酯,例如聚山梨酯20和聚山梨酯80;丙二醇脂肪酸酯,例如丙二醇月桂酸酯;月桂基硫酸钠;脂肪酸及其盐,例如油酸、油酸钠和三乙醇胺油酸酯;甘油基脂肪酸酯,例如单油酸甘油酯、单硬脂酸甘油酯和棕榈酸硬脂酸甘油酯;α-生育酚聚乙二醇(1000)琥珀酸酯(TPGS);泰洛沙泊;等等。一种或多种润湿剂(如果存在)通常占组合物重量的约0.1%至约15%,例如约0.2%至约10%,或约0.5%至约7%,不包括存在于固体分散体中的表面活性剂。
非离子表面活性剂,更特别是泊洛沙姆,是可用于本文的润湿剂的实例。说明性地,泊洛沙姆诸如PluronicTMF127(如果存在)可占组合物重量的约0.1%至约10%,例如约0.2%至约7%,或约0.5%至约5%,不包括存在于固体分散体中的表面活性剂。
润滑剂减少片剂制剂压缩期间制片混合物和制片设备之间的摩擦。合适的润滑剂包括单独或组合的山嵛酸甘油酯;硬脂酸及其盐,包括硬脂酸镁、硬脂酸钙和硬脂酸钠;氢化植物油;棕榈酸硬脂酸甘油酯;滑石;蜡;苯甲酸钠;乙酸钠;富马酸钠;硬脂酰富马酸钠;PEG(例如PEG 4000和PEG 6000);泊洛沙姆;聚乙烯醇;油酸钠;月桂基硫酸钠;月桂基硫酸镁;等等。一种或多种润滑剂(如果存在)通常占组合物重量的约0.05%至约10%,例如约0.1%至约5%,或约0.2%至约2%。硬脂酰富马酸钠是特别有用的润滑剂。
抗粘剂减少片剂制剂对设备表面的粘附。合适的抗粘剂单独或组合包括滑石粉、胶体二氧化硅、淀粉、DL-亮氨酸、月桂基硫酸钠和硬脂酸金属盐。一种或多种抗粘剂(如果存在)通常占组合物重量的约0.05%至约10%,例如约0.1%至约7%,或约0.2%至约5%。胶体二氧化硅是特别有用的抗粘剂。
助流剂改善流动性并减少制片混合物中的静电。合适的助流剂包括单独或组合的胶体二氧化硅、淀粉、粉状纤维素、月桂基硫酸钠、三硅酸镁和硬脂酸金属盐。一种或多种助流剂(如果存在)通常占组合物重量的约0.05%至约10%,例如约0.1%至约7%,或约0.2%至约5%,不包括存在于固体分散体中的助流剂。胶体二氧化硅是特别有用的助流剂。
其他赋形剂诸如缓冲剂、稳定剂、抗氧化剂、抗微生物剂、着色剂,调味剂和甜味剂在制药领域中是已知的并且可用于本发明的组合物中。片剂可为未包衣的或者可包含例如用无功能膜或释放改性或肠溶衣包衣的芯。胶囊可具有硬壳或软壳,其包含例如明胶(呈硬明胶胶囊或软弹性明胶胶囊形式)、淀粉、角叉菜胶和/或HPMC,任选与一种或多种增塑剂一起。
根据本发明的一些实施方案,提供了药物产品,所述药物产品包含(i)第一组合物,其包含[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼)或其药学上可接受的盐,和(ii)第二组合物,其包含4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(ABT-199)或其药学上可接受的盐。如上所述,在一些实施方案中,第一组合物还包含药学上可接受的赋形剂。在一些实施方案中,第二组合物还包含药学上可接受的赋形剂。在一些实施方案中,第一组合物和第二组合物是相同的。在一些实施方案中,第一组合物和第二组合物是不同的。
V.适应症
在一些实施方案中,本发明的方法涉及向需要此种疗法的哺乳动物例如人类患者施用治疗有效量的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(维奈托克或ABT-199/GDC-0199)或其药学上可接受的盐和治疗有效量的[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼或GDC-0973)或其药学上可接受的盐,以治疗其中过度表达一种或多种抗凋亡Bcl-2蛋白、抗凋亡Bcl-XL蛋白和抗凋亡Bcl-w蛋白的疾病。
在另一个实施方案中,向有需要的受试者施用治疗有效量的本发明组合物以治疗异常的细胞生长和/或调节异常的细胞凋亡。
所述疾病的实例包括但不限于癌症、间皮瘤、膀胱癌、胰腺癌、皮肤癌、头或颈部癌、皮肤或眼内黑素瘤、卵巢癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、骨癌、结肠癌、直肠癌、肛门区癌、胃癌、胃肠道癌(胃癌、结肠直肠癌和/或十二指肠癌)、慢性淋巴细胞性白血病、急性淋巴细胞性白血病、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、睾丸癌、肝细胞癌(肝癌和/或胆管癌)、原发性或继发性中枢神经系统肿瘤、原发性或继发性脑肿瘤、霍奇金病、慢性或急性白血病、慢性骨髓性白血病、淋巴细胞性淋巴瘤、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源性淋巴恶性肿瘤、黑素瘤、多发性骨髓瘤、口腔癌、非小细胞肺癌、前列腺癌、小细胞肺癌、肾和/或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤、原发性中枢神经系统淋巴瘤、非霍奇金淋巴瘤、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、肾上腺皮质癌、胆囊癌、脾癌、胆管癌、纤维肉瘤、成神经细胞瘤、成视网膜细胞瘤或其组合。
在一个更具体的实施方案中,本发明的方法涉及向需要此种疗法的哺乳动物例如人类患者施用治疗有效量的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(维奈托克或ABT-199/GDC-0199)或其药学上可接受的盐和治疗有效量的[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼或GDC-0973)或其药学上可接受的盐,以治疗膀胱癌、脑癌、乳腺癌、骨髓癌、宫颈癌、慢性淋巴细胞性白血病、急性淋巴细胞白血病、结肠直肠癌、食管癌、肝细胞癌、成淋巴细胞性白血病、滤泡淋巴瘤、T细胞或B细胞源性淋巴恶性肿瘤、黑素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌或脾癌。
在一个更具体的实施方案中,本发明的方法涉及向需要此种疗法的哺乳动物例如人类患者施用治疗有效量的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(维奈托克或ABT-199/GDC-0199)或其药学上可接受的盐和治疗有效量的[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼或GDC-0973)或其药学上可接受的盐,以治疗急性骨髓性白血病。
在一个更具体的实施方案中,本发明的方法涉及向需要此种疗法的哺乳动物例如人类患者施用治疗有效量的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)(维奈托克或ABT-199/GDC-0199)或其药学上可接受的盐和治疗有效量的[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼或GDC-0973)或其药学上可接受的盐,以治疗多发性骨髓瘤。
举例而言,一种在受试者中治疗间皮瘤、膀胱癌、胰腺癌、皮肤癌、头或颈部癌、皮肤或眼内黑素瘤、卵巢癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、骨癌、结肠癌、直肠癌、肛门区癌、胃癌、胃肠道癌(胃癌、结肠直肠癌和/或十二指肠癌)、慢性淋巴细胞性白血病、急性淋巴细胞性白血病、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、睾丸癌、肝细胞癌(肝癌和/或胆管癌)、原发性或继发性中枢神经系统肿瘤、原发性或继发性脑肿瘤、霍奇金病、慢性或急性白血病、慢性骨髓性白血病、淋巴细胞性淋巴瘤、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源性淋巴恶性肿瘤、黑素瘤、多发性骨髓瘤、口腔癌、非小细胞肺癌、前列腺癌、小细胞肺癌、肾和/或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤、原发性中枢神经系统淋巴瘤、非霍奇金淋巴瘤、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、肾上腺皮质癌、胆囊癌、脾癌、胆管癌、纤维肉瘤、成神经细胞瘤、成视网膜细胞瘤或其组合的方法,包括向所述受试者使用治疗有效量的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(维奈托克或ABT-199/GDC-0199)或其药学上可接受的盐和治疗有效量的[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼或GDC-0973)或其药学上可接受的盐。
在另一个实施方案中,本发明的方法涉及向需要此种疗法的哺乳动物例如人类患者施用治疗有效量的4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(维奈托克或ABT-199/GDC-0199)或其药学上可接受的盐和治疗有效量的[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼或GDC-0973)或其药学上可接受的盐,以治疗免疫疾病或自身免疫疾病。所述疾病包括获得性免疫缺陷综合征(AIDS)、自身免疫淋巴增殖综合征、溶血性贫血、炎性疾病、血小板减少症、与器官移植相关的急性和慢性免疫疾病、艾迪生病、过敏性疾病、脱发、斑秃、动脉粥样硬化病/动脉硬化、动脉粥样硬化、关节炎(包括骨关节炎、青少年慢性关节炎、脓毒性关节炎、莱姆关节炎、银屑病关节炎和反应性关节炎)、自身免疫性大疱性疾病、胎儿性别异常、获得性免疫缺陷相关疾病、与器官移植相关的急性免疫疾病、获得性手足发绀症、急性和慢性寄生或感染过程、急性胰腺炎、急性肾衰竭、急性风湿热、急性横贯性脊髓炎、腺癌、房性异位搏动(aerial ectopic beat)、成人(急性)呼吸窘迫综合征、AIDS痴呆综合征、酒精性肝硬化、酒精性肝损伤、酒精性肝炎、过敏性结膜炎、变应性接触性皮炎、变应性鼻炎、变态反应和哮喘、同种异体移植排斥、α-1-抗胰蛋白酶缺乏症、阿尔茨海默病、肌萎缩性侧索硬化、贫血、心绞痛、强直性脊柱炎相关性肺病、前角细胞变性、抗体介导的细胞毒性、抗磷脂综合征、抗受体超敏反应、主动脉和外周动脉瘤、主动脉夹层、动脉高血压、动脉硬化、动静脉瘘、关节病、虚弱、哮喘、共济失调、特应性变态反应、心房颤动(持续性或阵发性)、心房扑动、房室传导阻滞、萎缩性自身免疫性甲状腺功能减退症、自身免疫性溶血性贫血、自身免疫性肝炎、1型自身免疫性肝炎(典型的自身免疫性或类肝炎)、自身免疫介导的低血糖症、自身免疫性中性粒细胞减少症、自身免疫性血小板减少症、自身免疫性甲状腺疾病、B-细胞淋巴瘤、骨移植排斥、骨髓移植(BMT)排斥、闭塞性细支气管炎、束支阻滞、烧伤、恶病质、心律不齐、心脏骤停综合征、心脏肿瘤、心肌病、心肺旁路炎症反应、软骨移植排斥、小脑皮质退化、小脑障碍、混沌或多焦房性心动过速、化疗相关病症、衣原体(chlamydia)、胆汁阻滞(choleosatatis)、慢性酒精中毒、慢性活动性肝炎、慢性疲劳综合征、与器官移植相关的慢性免疫疾病、慢性嗜酸性粒细胞性肺炎、慢性炎症病理学、慢性皮肤粘膜念珠菌病、慢性阻塞性肺病(COPD)、慢性水杨酸盐中毒、结直肠常见变异性免疫缺陷(常见变量低丙种球蛋白血症)、结膜炎、结缔组织病相关性间质性肺病、接触性皮炎、Coombs阳性溶血性贫血、肺心病、Creutzfeldt-Jakob病、隐源性自身免疫性肝炎、隐源性纤维化肺泡炎、培养阴性败血症、囊性纤维化、细胞因子疗法相关病症、克罗恩病、拳击员痴呆、脱髓鞘疾病、登革出血热、皮炎、皮炎硬皮病、皮肤病、皮肌炎/多肌炎相关肺病、糖尿病、糖尿病动脉硬化性疾病、糖尿病、弥漫性路易体病、扩张型心肌病、扩张型充血性心肌病、盘状红斑狼疮、基底节病症、弥漫性血管内凝血、中年唐氏综合征、药物诱导的间质性肺病、药物诱导的肝炎、阻断CNS多巴胺受体的药物诱导的运动障碍、药物敏感性、湿疹、脑脊髓炎、心内膜炎、内分泌病、肠病性滑膜炎、会厌炎、EB病毒感染、红斑性肢痛、锥体束外和小脑障碍、家族性嗜血细胞性淋巴组织细胞增多症、胎儿胸腺植入物排斥、Friedreich共济失调、功能性外周动脉疾病、女性不育症、纤维化、纤维化肺病、真菌性败血症、气性坏疽、胃溃疡、巨细胞动脉炎、肾小球肾炎(glomerular nephritis)、肾小球性肾炎(glomerulonephritides)、Goodpasture综合征、甲状腺自身免疫性甲状腺功能减退症(桥本病)、痛风性关节炎、任何器官或组织的移植排斥、移植物抗宿主病、革兰氏阴性败血症、革兰氏阳性败血症、细胞内生物体引起的肉芽肿、B族链球菌(GBS)感染、格雷夫斯病、血铁质沉着症相关性肺病、毛细胞白血病、Hallerrorden-Spatz病、桥本甲状腺炎、花粉热、心脏移植排斥、血色素沉着症、造血系统恶性肿瘤(白血病和淋巴瘤)、溶血性贫血、溶血性尿毒症综合征/溶栓血小板减少性紫癜、出血、Henoch-Schoenlein紫癜、甲型肝炎、乙型肝炎、丙型肝炎、HIV感染/HIV神经病、霍奇金病、甲状旁腺功能减退症、亨廷顿舞蹈病、过动力运动障碍、超敏反应、超敏反应性肺炎、甲亢、低动力运动障碍、下丘脑-垂体-肾上腺轴评估、特发性艾迪生病、特发性白细胞减少症、特发性肺纤维化、特发性血小板减少症、特异性肝病、婴儿型脊髓性肌萎缩症、感染性疾病、主动脉炎症、炎性肠病、胰岛素依赖性糖尿病、间质性肺炎、虹膜睫状体炎/葡萄膜炎/视神经炎、局部缺血-再灌注损伤、缺血性中风、青少年恶性贫血、青少年类风湿性关节炎、青少年脊髓性肌萎缩症、卡波西肉瘤、川崎病、肾移植排斥、军团菌(legionella)、利什曼病、麻风病、皮质脊髓系统病变、线性IgA疾病、脂质瘤、肝移植排斥、莱姆病、lymphederma、淋巴细胞浸润性肺病、疟疾、男性不育(特发性或NOS)、恶性组织细胞增多症、恶性黑色素瘤、脑膜炎、脑膜炎球菌血症、肾小管血管炎、偏头痛、线粒体多系统病症、混合性结缔组织病、混合性结缔组织病相关性肺病、单克隆丙种球蛋白病、多发性骨髓瘤、多系统变性(Mencel、Dejerine Shy-Drager和Machado-Joseph)、肌炎性脑炎/慢性疲劳综合症(Royal Free Disease)、重症肌无力、肾的显微血管炎、胞内鸟分枝杆菌(mycobacterium avium intracellulare)、结核分枝杆菌(mycobacteriumtuberculosis)、骨髓增生异常综合征、心肌梗塞、心肌缺血性疾病、鼻咽癌、新生儿慢性肺病、肾炎、肾病、肾病综合征、神经变性疾病、神经源性I型肌肉萎缩、中性粒细胞减少症发热、非酒精性脂肪性肝炎、腹主动脉及其分支闭塞、闭塞性动脉疾病、器官移植排斥、睾丸炎/附睾炎、睾丸炎/输精管结扎逆转手术、器官肿大、骨关节病、骨质疏松症、卵巢衰竭、胰腺移植排斥、寄生虫病、甲状旁腺移植排斥、帕金森病、盆腔炎、寻常性天疱疮、小叶性天疱疮、类天疱疮、多年生鼻炎、心包疾病、外周动脉粥样硬化性疾病、外周血管疾病、腹膜炎、恶性贫血、致蓝细胞性葡萄膜炎、卡氏肺囊虫肺炎、肺炎、POEMS综合征(多发性神经病、器官肿大、内分泌病、单克隆丙种球蛋白病和皮肤变化综合征)、灌注后综合征、泵后综合征、心肌梗塞(MI)后心脏病综合征、感染后间质性肺病、卵巢早衰、原发性胆汁性肝硬化、原发性硬化性肝炎、原发性粘液性水肿、原发性肺动脉高压、原发性硬化性胆管炎、原发性血管炎、进行性核上性麻痹、银屑病、1型银屑病、2型银屑病、银屑病性关节病、继发于结缔组织病的肺高血压、结节性多动脉炎的肺部表现、炎症后间质性肺病、放射性纤维化、放射疗法、Raynaud现象和疾病、Raynoud病、Refsum病、常规窄QRS心动过速、Reiter病、肾病NOS、肾血管性高血压、再灌注损伤、限制性心肌病、类风湿性关节炎相关性间质性肺病、类风湿性脊椎炎、结节病、Schmidt综合征、硬皮病、老年舞蹈病、路易体型老年性痴呆、败血症综合征、感染性休克、血清阴性关节病、休克、镰状细胞性贫血、舍格伦病相关性肺病、舍格伦综合征、皮肤同种移植排斥反应、皮肤变化综合征、小肠移植排斥反应、精子自体免疫、多发性硬化症(所有亚型)、脊髓共济失调、脊髓小脑变性、脊柱关节病、I型散发性多腺体缺陷、II型散发性多腺体缺陷、斯蒂尔病、链球菌性肌炎、中风、小脑结构性病变、亚急性硬化性全脑炎、交感性眼炎、晕厥、心血管系统梅毒、全身性过敏症、全身性炎症反应综合征、全身性发作的幼年类风湿性关节炎、系统性红斑狼疮、系统性红斑狼疮相关性肺病、狼疮肾炎、系统性硬化症、系统性硬化相关性间质性肺病、T细胞或FAB ALL、高安病/动脉炎、毛细血管扩张症、Th2型和Th1型介导的疾病、血栓闭塞性脉管炎、血小板减少症、甲状腺炎、毒性、中毒性休克综合征、移植物、创伤/出血、2型自身免疫性肝炎(抗LKM抗体肝炎)、B型胰岛素抵抗伴随黑棘皮病、III型超敏反应、IV型超敏反应、溃疡性结肠炎性关节病、溃疡性结肠炎、不稳定型心绞痛、尿毒症、尿路感染、荨麻疹、葡萄膜炎、瓣膜性心脏病、静脉曲张、脉管炎、脉管炎弥漫性肺病、静脉疾病、静脉血栓形成、心室颤动、白癜风急性肝病、病毒和真菌感染、致命性脑炎/无菌性脑膜炎、生命相关性血细胞减少症综合征、韦格纳肉芽肿病、Wernicke-Korsakoff综合征、Wilson病、任何器官或组织的异种移植排斥、耶尔森氏菌和沙门氏菌相关性关节病等。
VI.组合给药方案
本文中的术语“口服可递送”,“口服施用”和“口服给药”是指经口施用至受试者(p.o.),即其中立即吞咽组合物的施用,例如借助于合适体积的水或其他饮用液体。本文中“口服施用”不同于口腔内施用,例如舌下或口腔施用或局部施用至口腔内组织诸如牙周组织,其不涉及立即吞咽组合物。
应选择活性成分形式(例如母体化合物或盐)、聚合物载体、表面活性剂和其它任选成分,并且应使用这些组分的相对量,以提供当口服施用时具有可接受的生物吸收的固体分散体或剂型。这种生物吸收可例如通过在特定剂量或在一定范围的剂量内固体分散体或剂型的药代动力学(PK)曲线,更具体地通过Cmax或AUC,例如AUC0–24或AUC0–∞来证明。说明性地,生物利用度可表示为百分比,例如使用参数F,其计算用于口服递送测试组合物的AUC作为在合适溶剂中静脉内(iv)递送药物的AUC的百分比,考虑到口服与静脉内剂量的区别。
生物利用度可通过人体或任何合适模型物种的PK研究来确定。为了当前目的,犬模型通常是合适的。在各种示例性实施方案中,本发明组合物在犬模型中表现出的口服生物利用度为至少约15%,至少约20%,至少约25%或至少约30%,直至或超过约50%,当以约2.5至约10mg/kg的单剂量施用至禁食或非禁食动物时。
本文包含的组合物可用于将药物或其药学上可接受的盐口服递送至受试者。因此,用于将这种药物递送至受试者的本发明的方法包括口服施用如上所述的组合物。
受试者可为人类或非人类(例如,农场、动物园、工作或伴侣动物,或用作模型的实验动物),但在重要的实施方案中,所述受试者为需要该药物的人类患者,例如以治疗特征在于凋亡功能障碍和/或抗凋亡Bcl-2家族蛋白的过度表达的疾病。人类受试者可为男性或女性并且可为任何年龄。患者通常是成年人,但本发明的方法可用于在儿科患者中治疗儿童癌症,诸如白血病,例如急性淋巴细胞性白血病。
通常以提供治疗有效日剂量的药物的量施用组合物。本文中的术语“日剂量”意指每天施用的药物量,而与施用频率无关。例如,如果受试者每天两次接受150mg的单位剂量,则日剂量为300mg。术语“日剂量”的使用将被理解为不意味着指定的剂量必须每天一次施用。然而,在具体的实施方式中,给药频率是每天一次(q.d.),并且日剂量和单位剂量在该实施方式中是相同的。
构成治疗有效剂量的因素取决于特定化合物,受试者(包括受试者的物种和体重),待治疗的疾病(例如特定类型的癌症),疾病的阶段和/或严重程度,个体受试者对化合物的耐受性,化合物是以单一疗法施用还是与一种或多种其他药物(例如用于治疗癌症的其他化学治疗剂)组合施用,以及其他因素。因此,日剂量可在很宽的范围内变化,例如从约10至约1,000mg。在特定情况下,更大或更小的日剂量可能是适当的。应该理解,本文中对“治疗有效的”剂量的叙述并不一定要求如果仅给予单一这样的剂量该药物是治疗有效的;通常治疗功效依赖于根据涉及适当频率和施用持续时间的方案重复施用的组合物。强烈优选的是,尽管所选择的日剂量足以在治疗癌症方面提供益处,但不应该足以引起对不可接受或不可耐受的程度的不利副作用。考虑到诸如上述那些因素,基于本文中公开的内容和本文引用的技术,无需过多实验即可由普通技术人员选择合适的治疗有效剂量。例如,医师在治疗过程中可用相对较低的日剂量启动癌症患者,并且在几天或几周的时间内向上滴定剂量以降低不良副作用的风险。
说明性地,合适的剂量通常为约25至约1,000mg/天,更通常约50至约500mg/天或约200至约400mg/天,例如约50、约100、约150、约200、约250、约300、约350、约400、约450或约500mg/天,以约3小时至约7天,例如约8小时至约3天,或约12小时至约2天的平均剂量间隔施用。在大多数情况下,每日一次(q.d.)施用方案是合适的。
本文中的“平均剂量间隔”被定义为一段时间(例如一天或一周)除以在该段时间内施用的单位剂量的数量。例如,在上午八点左右、中午左右和下午六点左右一天三次施用的情况下,平均剂量间隔为8小时(24小时时间除以3)。如果药物被配制成离散剂型诸如片剂或胶囊,为了确定平均剂量间隔的目的,一次施用多个(例如2-约10个)剂型被认为是单位剂量。
在组合物呈胶囊形式的情况下,可整体吞服一个至多个胶囊,通常借助于水或其他可吸收液体来帮助吞咽过程。合适的胶囊壳材料包括但不限于明胶(以硬明胶胶囊或软弹性明胶胶囊的形式)、淀粉,角叉菜胶和HPMC。
施用可给予或不给予食物,即处于非禁食或禁食状态。通常优选将本发明组合物施用至非禁食患者。
VII.其他组合
本发明的组合疗法可适用于其他化学治疗剂或电离辐射。组合疗法说明性地包括施用本发明的组合疗法,伴随有一种或多种以下药物:硼替佐米、卡铂、顺铂、环磷酰胺、达卡巴嗪、地塞米松、多西他赛、多柔比星、依托泊苷、氟达拉滨、伊立替康、紫杉醇、雷帕霉素、利妥昔单抗、长春新碱等,例如伴随多药疗法诸如CHOP(环磷酰胺+多柔比星+长春新碱+泼尼松)、RCVP(利妥昔单抗+环磷酰胺+长春新碱+泼尼松)、R-CHOP(利妥昔单抗+CHOP)或DA-EPOCH-R(剂量调整的依托泊苷、泼尼松、长春新碱、环磷酰胺、多柔比星和利妥昔单抗)。
一种或多种治疗剂的其他实例包括但不限于烷化剂,血管生成抑制剂,抗体,抗代谢物,抗有丝分裂剂,抗增殖剂,抗病毒剂,极光激酶抑制剂,其他细胞凋亡诱导剂(例如Bcl-xL,Bcl-W和Bfl-1抑制剂),死亡受体途径的激活剂,Bcr-Abl激酶抑制剂,BiTE(双特异性T细胞衔接物)抗体,抗体-药物缀合物,生物反应调节剂,细胞周期蛋白依赖性激酶(CDK)抑制剂、细胞周期抑制剂,环氧合酶-2(COX-2)抑制剂,双可变结构域结合蛋白(DVD),人表皮生长因子受体2(ErbB2或HER/2neu)受体抑制剂,生长因子抑制剂,热休克蛋白(HSP)-90抑制剂,组蛋白脱乙酰酶(HDAC)抑制剂,激素疗法,免疫药物,凋亡蛋白抑制剂(IAP),插入抗生素,激酶抑制剂,驱动蛋白抑制剂,JAK2抑制剂,哺乳动物靶向的雷帕霉素(mTOR)抑制剂,微小RNA,促分裂原活化的细胞外信号调节激酶(MEK)抑制剂,多价结合蛋白,非甾体抗炎药(NSAID),聚-ADP(腺苷二磷酸)-核糖聚合酶(PARP)抑制剂、铂化疗药、Polo样激酶(PIK)抑制剂,磷酸肌醇-3激酶(PI3K)抑制剂,蛋白酶体抑制剂,嘌呤类似物,嘧啶类似物,受体酪氨酸激酶抑制剂,类视黄醇,deltoid,植物生物碱,小抑制性核糖核酸(siRNA),拓扑异构酶抑制剂,泛素连接酶抑制剂等。
BiTE抗体是双特异性抗体,其通过同时结合两种细胞来指导T细胞攻击癌细胞。T细胞然后攻击目标癌细胞。BiTE抗体的实例包括但不限于阿德木单抗(adecatumumab)(Micromet MT201),博纳吐单抗(blinatumomab)(Micromet MT103)等。不受理论的限制,T细胞诱导靶癌细胞凋亡的机制之一是通过细胞溶解颗粒组分的胞吐作用,其中包括穿孔素和粒酶B。在这方面,已显示Bcl-2减弱穿孔素和粒酶B两者诱导细胞凋亡。这些数据表明,当靶向癌细胞时,Bcl-2的抑制可增强T细胞引发的细胞毒效应(Sutton et al.(1997)J.Immunol.158:5783–5790)。
siRNA是具有内源性RNA碱基或化学修饰的核苷酸的分子。这些修饰不会消除细胞活性,而是会赋予稳定性增加和/或细胞效力提高。化学修饰的实例包括硫代磷酸酯基,2'-脱氧核苷酸,含2'-OCH3的核糖核苷酸,2'-F-核糖核苷酸,2'-甲氧基乙基核糖核苷酸及其组合等。siRNA可具有不同的长度(例如10-200碱基对)和结构(例如发夹、单/双链、突起、缺口/空隙、错配),并在细胞中加工以提供活性基因沉默。双链siRNA(dsRNA)可以在每条链(平端)或不对称端(悬突)上具有相同数量的核苷酸。1-2个核苷酸的悬突可存在于有义链和/或反义链上,以及存在于给定链的5'-和/或3'-端。例如,已经显示靶向Mcl-1的siRNA在各种肿瘤细胞系中增强ABT-263或ABT-737的活性(Tse et al.(2008)Cancer Res.68:3421–3428及其中引用的文献)。
多价结合蛋白是包含两个或更多个抗原结合位点的结合蛋白。多价结合蛋白被工程化以具有三个或更多个抗原结合位点并且通常不是天然存在的抗体。术语“多特异性结合蛋白”意指能够结合两个或更多个相关或不相关靶标的结合蛋白。双重可变结构域(DVD)结合蛋白是包含两个或更多个抗原结合位点的四价或多价结合蛋白结合蛋白。这种DVD可为单特异性的(即能够结合一种抗原)或多特异性的(即能够结合两种或更多种抗原)。包含两条重链DVD多肽和两条轻链DVD多肽的DVD结合蛋白被称为DVD Ig。DVD Ig的每一半都包含重链DVD多肽、轻链DVD多肽和两个抗原结合位点。每个结合位点包含重链可变结构域和轻链可变结构域,其中每个抗原结合位点总共有6个CDR参与抗原结合。
烷基化剂包括六甲蜜胺、AMD-473、AP-5280、apaziquone、苯达莫司汀、brostallicin、白消安、卡波醌、卡莫司汀(BCNU),苯丁酸氮芥、CloretazineTM(laromustine,VNP 40101M)、环磷酰胺、达卡巴嗪、雌莫司汀、福莫司汀、葡磷酰胺、异环磷酰胺、KW-2170,洛莫司汀(CCNU),马磷酰胺、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、氮芥N-氧化物、雷莫司汀、替莫唑胺、噻替派、曲奥舒凡、曲磷胺等。
血管生成抑制剂包括表皮生长因子受体(EGFR)抑制剂、内皮特异性受体酪氨酸激酶(Tie-2)抑制剂、胰岛素生长因子-2受体(IGFR-2)抑制剂、基质金属蛋白酶-2(MMP-2)抑制剂、基质金属蛋白酶-9(MMP-9)抑制剂、血小板源性生长因子受体(PDGFR)抑制剂、血小板反应蛋白类似物、血管内皮生长因子受体酪氨酸激酶(VEGFR)抑制剂等。
抗代谢物包括AlimtaTM(培美曲塞二钠,LY231514,MTA)、5-阿扎胞苷、XelodaTM(卡培他滨)、卡莫氟、LeustatTM(克拉屈滨)、氯法拉滨、阿糖胞苷(cytarabine)、十八烷基磷酸阿糖胞苷(cytarabine ocfosfate)、阿糖胞苷(cytosine arabinoside)、地西他滨,去铁胺,去氧氟尿苷,依氟鸟氨酸,EICAR(5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺)、依诺他宾、乙烯基胞苷(ethenylcytidine)、氟达拉滨、5-氟尿嘧啶(5-FU)(单独或与亚叶酸组合)、GemzarTM(吉西他滨)、羟基脲、AlkeranTM(美法仑)、巯嘌呤、6-巯基嘌呤核苷、甲氨蝶呤、麦考酚酸、奈拉滨、诺拉曲塞、ocfosfate、培利曲索、喷司他丁、雷替曲塞、利巴韦林、S-1、triapine、三甲曲沙、TS-1、噻唑呋林、替加氟、阿糖腺苷、UFT等。
抗病毒药物包括利托那韦、羟氯喹等。
极光激酶抑制剂包括ABT-348、AZD-1152、MLN-8054、VX-680、极光A-特异性激酶抑制剂、极光B-特异性激酶抑制剂、泛极光激酶抑制剂等。
除了式I化合物以外的Bcl-2家族蛋白抑制剂包括AT-101((–)棉酚)、GenasenseTMBcl-2靶向反义寡核苷酸(G3139或奥利默森)、IPI-194、IPI-565、ABT-737、ABT-263、GX-070(obatoclax)等。
Bcr-Abl激酶抑制剂包括达沙替尼(BMS-354825),GleevecTM(伊马替尼)等。
CDK抑制剂包括AZD-5438、BMI-1040、BMS-387032、CVT-2584、夫拉平度、GPC-286199、MCS-5A、PD0332991、PHA-690509、seliciclib(CYC-202或R-roscovitine)、ZK-304709等。
COX-2抑制剂包括ABT-963、ArcoxiaTM(依托考昔)、BextraTM(伐地考昔)、BMS-347070、CelebrexTM(塞来昔布)、COX-189(鲁米考昔)、CT-3、DeramaxxTM(地拉考昔)、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰基苯基)-1H-吡咯、MK-663(艾托考昔)、NS-398、帕瑞考昔、RS-57067、SC-58125、SD-8381、SVT-2016、S-2474、T-614、VioxxTM(罗非考昔)等。
EGFR抑制剂包括ABX-EGF、抗EGFR免疫脂质体、EGF-疫苗、EMD-7200、ErbituxTM(西妥昔单抗)、HR3、IgA抗体、IressaTM(吉非替尼)、TarcevaTM(厄洛替尼或OSI-774)、TP-38、EGFR融合蛋白、TykerbTM(拉帕替尼)等。
ErbB2受体抑制剂包括CP-724714、CI-1033(卡奈替尼)、HerceptinTM(曲妥珠单抗)、TykerbTM(拉帕替尼)、OmnitargTM(2C4,帕妥珠单抗)、TAK-165、GW-572016(洛那法尼)、GW-282974、EKB-569、PI-166、dHER2(HER2疫苗)、APC-8024(HER2疫苗)、抗HER/2neu双特异性抗体、B7.her2IgG3、AS HER2三功能双特异性抗体、mAB AR-209、mAB 2B-1等。
组蛋白脱乙酰酶抑制剂包括缩酚酸肽、LAQ-824、MS-275、trapoxin,辛二酰苯胺异羟肟酸(SAHA)、TSA、丙戊酸等。
HSP-90抑制剂包括17AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格尔德霉素、IPI-504、KOS-953、MycograbTM(针对HSP-90的人重组抗体)、nab-17AAG、NCS-683664、PU24FCl、PU-3、根赤壳菌素、SNX-2112、STA-9090、VER-49009等。
凋亡蛋白抑制剂包括HGS-1029、GDC-0145、GDC-0152、LCL-161、LBW-242等。
抗体-药物缀合物包括抗-CD22-MC-MMAF、抗-CD22-MC-MMAE、抗-CD22-MCC-DM1、CR-011-vcMMAE、PSMA-ADC、MEDI-547、SGN-19A、SGN-35、SGN-75等。
死亡受体途径的激活剂包括TRAIL和靶向TRAIL或死亡受体(例如DR4和DR5)的抗体或其他药剂,诸如apomab、可那木单抗(conatumumab)、ETR2-ST01、GDC0145(来沙木单抗(lexatumumab))、HGS-1029、LBY-135、PRO-1762、曲妥珠单抗等。
驱动蛋白抑制剂包括Eg5抑制剂诸如AZD-4877和ARRY-520,CENPE抑制剂诸如GSK-923295A等。
JAK2抑制剂包括CEP-701(lesaurtinib)、XL019、INCB-018424等。
MEK抑制剂包括ARRY-142886、ARRY-438162、PD-325901、PD-98059等。
mTOR抑制剂包括AP-23573、CCI-779、依维莫司、RAD-001、雷帕霉素、替西罗莫司、ATP-竞争性TORC1/TORC2抑制剂,包括PI-103、PP242、PP30和Torin1等。
非甾体抗炎药包括AmigesicTM(双水杨酯)、DolobidTM(二氟尼柳)、MotrinTM(布洛芬)、OrudisTM(酮洛芬)、RelafenTM(萘丁美酮)、FeldeneTM(吡罗昔康)、布洛芬乳膏、AleveTM和NaprosynTM(萘普生)、VoltarenTM(双氯芬酸)、IndocinTM(吲哚美辛)、ClinorilTM(舒林酸)、TolectinTM(托美丁)、LodineTM(依托度酸)、ToradolTM(酮咯酸)、DayproTM(奥沙普秦)等。
PDGFR抑制剂包括CP-673451、CP-868596等。
铂化学治疗剂包括顺铂、EloxatinTM(奥沙利铂)、依他铂、洛铂、奈达铂、ParaplatinTM(卡铂)、吡铂、沙铂等。
Polo-样激酶抑制剂包括BI-2536等。
磷酸肌醇-3激酶抑制剂包括渥曼青霉素、LY-294002、XL-147、CAL-120、ONC-21、AEZS-127、ETP-45658、PX-866、GDC-0941、BGT226、BEZ235、XL765等。
血小板反应蛋白类似物包括ABT-510、ABT-567、ABT-898、TSP-1等。
VEGFR抑制剂包括AvastinTM(贝伐珠单抗)、ABT-869、AEE-788、AngiozymeTM(抑制血管生成的核酶(Ribozyme Pharmaceuticals(Boulder,CO)和Chiron(Emeryville,CA))、阿西替尼(AG-13736)、AZD-2171、CP-547632、IM-862、MacugenTM(pegaptanib)、NexavarTM(索拉非尼,BAY43-9006)、帕唑帕尼(GW-786034)、瓦他拉尼(PTK-787或ZK-222584)、SutentTM(舒尼替尼或SU-11248)、VEGF捕获剂、ZactimaTM(凡德他尼或ZD-6474)等。
抗生素包括嵌入抗生素,诸如阿柔比星、放线菌素D、氨柔比星、蒽环霉素(annamycin)、AdriamycinTM(阿霉素)、BlenoxaneTM(博来霉素),道诺霉素、CaelyxTM和MyocetTM(脂质体多柔比星)、依沙芦星,表柔比星,格拉替霉素(glarubicin)、伊达比星,丝裂霉素C、萘莫柔比星、新制癌菌素、培洛霉素、吡柔比星、蝴蝶霉素、stimalamer、链佐星、ValstarTM(戊柔比星)、净司他丁等。
拓扑异构酶抑制剂包括阿柔比星、9-氨基喜树碱、氨萘非特、安吖啶、becatecarin、贝洛替康、BN-80915、CamptosarTM(盐酸依立替康)、喜树碱、CardioxaneTM(右雷佐生)、二氟替康、edotecarin、EllenceTM和PharmorubicinTM(表柔比星)、依托泊苷、依沙替康、10-羟基喜树碱、吉马替康、鲁托替康、米托蒽醌、Orathecin、pirarbucin、匹杉琼、鲁比替康、索布佐生、SN-38、tafluposide、拓扑替康等。
抗体包括AvastinTM(贝伐珠单抗)、CD40-特异性抗体、chTNT-1/B、地诺单抗、ErbituxTM(西妥昔单抗)、Humax-CD4TM(扎木单抗)、IGF1R-特异性抗体、林妥珠单抗、PanorexTM(依决洛单抗)、RencarexTM(WX G250)、RituxanTM(利妥昔单抗)、替西木单抗、曲妥珠单抗、CD20抗体I型和II型等。
激素疗法包括ArimidexTM(阿那曲唑)、AromasinTM(依西美坦)、阿佐昔芬、CasodexTM(比鲁卡安)、CetrotideTM(西曲瑞克)、地加瑞克、地洛瑞林、DesopanTM(曲洛司坦)、地塞米松、DrogenilTM(氟他胺)、EvistaTM(雷洛昔芬)、AfemaTM(法倔唑)、FarestonTM(托瑞米芬)、FaslodexTM(氟维司群)、FemaraTM(来曲唑)、福美司坦、糖皮质激素、HectorolTM(度骨化醇)、RenagelTM(碳酸司维拉姆)、拉索昔芬、乙酸亮丙瑞林、MegaceTM(甲地孕酮)、MifeprexTM(米非司酮)、NilandronTM(尼鲁米特)、他莫昔芬包括NolvadexTM(枸橼酸他莫昔芬)、PlenaxisTM(阿巴瑞克)、强的松、PropeciaTM(非那雄胺)、rilostane、SuprefactTM(布舍瑞林)、促黄体激素释放激素(LHRH)包括TrelstarTM(曲普瑞林)、组胺瑞林包括VantasTM(组胺瑞林植入物)、ModrastaneTM(曲洛司坦)、ZoladexTM(戈舍瑞林)等。
Deltoids和类视黄醇包括西奥骨化醇(EB1089或CB1093)、来沙骨化醇(KH1060)、酚维A胺、PanretinTM(阿利维A胺)、维甲酸包括AtragenTM(脂质体维甲酸)、TargretinTM(贝沙罗汀),LGD-1550等。
PARP抑制剂包括ABT-888、奥拉帕尼、KU-59436、AZD-2281、AG-014699、BSI-201、BGP-15、INO-1001、ONO-2231等。
植物生物碱包括长春新碱、长春碱、长春地辛、长春瑞滨等。
蛋白酶体抑制剂包括VelcadeTM(硼替佐米)、MG132、NPI-0052、PR-171等。
免疫学药物的实例包括干扰素和其他免疫增强剂。干扰素包括干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a、ActimmuneTM(干扰素γ-1b)、干扰素γ-n1、其组合等。其他药剂包括Alfaferone(IFN-α)、BAM-002(氧化型谷胱甘肽)、BeromunTM(他索纳明)、BexxarTM(托西莫单抗)、CampathTM(阿伦单抗)、CTLA4(细胞毒性淋巴细胞抗原4)、达卡巴嗪、地尼白介素、依帕珠单抗、GranocyteTM(来格司亭)、香菇多糖、白细胞α干扰素、咪喹莫特、MDX-010(抗-CTLA-4)、黑素瘤疫苗、米妥莫单抗、莫拉司亭、MylotargTM(吉妥珠单抗奥佐米星)、NeupogenTM(非格司亭)、OncoVAC-CL、OvarexTM(奥戈伏单抗)、pemtumomab(Y-muHMFG1)、ProvengeTM(sipuleucel-T)、沙格司亭、西佐喃、替西白介素、TheracysTM(BCG或卡介苗)、乌苯美司、VirulizinTM(immunotherapeutic,Lorus Pharmaceuticals)、Z-100(Maruyama的特异性物质或SSM)、WF-10(tetrachlorodecaoxide或TCDO)、ProleukinTM(阿地白介素)、ZadaxinTM(胸腺法新)、ZenapaxTM(达克珠单抗)、ZevalinTM(90Y-替伊莫单抗)等。
生物响应调节剂是修饰活生物体的防御机制或生物响应诸如组织细胞的存活、生长或分化以指导它们具有抗肿瘤活性的药剂,并且包括云芝多糖、香菇多糖、西佐喃、picibanil、PF-3512676(CpG-8954)、乌苯美司等。
嘧啶类似物包括阿糖胞苷(胞嘧啶阿拉伯糖苷、ara C或阿拉伯糖苷C)、去氧氟尿苷、FludaraTM(氟达拉滨)、5-FU(5-氟尿嘧啶)、氟尿苷、GemzarTM(吉西他滨)、TomudexTM(雷替曲塞)、三乙酰基尿苷、TroxatylTM(曲沙他滨)等。
嘌呤类似物包括LanvisTM(硫鸟嘌呤)、PurinetholTM(巯嘌呤)等。
抗有丝分裂剂包括巴他布林、埃博霉素D(KOS-862)、N-(2-((4-羟基-苯基)氨基)吡啶-3-基)-4-甲氧基苯磺酰胺、伊沙匹隆(BMS-247550)、紫杉醇、TaxotereTM(多西他赛)、larotaxel(PNU-100940、RPR-109881或XRP-9881)、帕土匹龙、长春氟宁、ZK-EPO(合成性埃博霉素)等。
泛素连接酶抑制剂包括MDM2抑制剂诸如nutlins、NEDD8抑制剂诸如MLN4924等。
本发明的组合疗法也可用作增强放射治疗的疗效的放射增敏剂。放射治疗的实例包括但不限于:外束放射治疗(XBRT)、远距放射治疗、近距放射治疗、密封源放射治疗、非密封放射治疗等。
另外或可选地,本发明的组合疗法可与一种或多种选自以下的抗肿瘤或化学治疗剂组合治疗施用:AbraxaneTM(ABI-007)、ABT-100(法尼基转移酶抑制剂)、AdvexinTM(Ad5CMV-p53疫苗或contusugene ladenovec)、AltocorTM或MevacorTM(洛伐他汀)、AmpligenTM(聚(I)-聚(C12U),一种合成性RNA)、AptosynTM(依昔舒林)、ArediaTM(帕米膦酸)、arglabin、L-天冬酰胺酶、阿他美坦(1-甲基-3,17-二酮-雄甾-1,4-二烯)、AvageTM(他扎罗汀)、AVE-8062(考布他汀衍生物)、BEC2(米妥莫单抗)、恶病质素(cachectin或cachexin)(肿瘤坏死因子)、CanvaxinTM(黑素瘤疫苗)、CeaVacTM(癌症疫苗)、CeleukTM(西莫白介素)、组胺包括CepleneTM(组胺二盐酸盐)、CervarixTM(AS04佐剂吸附的人乳头瘤病(HPV)疫苗)、CHOP(CytoxanTM(环磷酰胺)+AdriamycinTM(多柔比星)+OncovinTM(长春新碱)+强的松)、考布他汀A4P、CypatTM(环丙孕酮)、DAB(389)EGF(通过His-Ala接头与人表皮生长因子融合的白喉毒素的催化和易位结构域)、达卡巴嗪、更生霉素、DimericineTM(T4N5脂质体乳液)、5,6-二甲基呫吨酮-4-乙酸(DMXAA)、圆皮海绵内酯、DX-8951f(甲磺酸伊沙替康)、恩尿嘧啶(乙炔基尿嘧啶)、角鲨胺包括EvizonTM(乳酸角鲨胺)、enzastaurin、EPO-906(埃博霉素B)、GardasilTM(四价人乳头瘤病毒(6、11、16、18型)重组疫苗)、GastrimmuneTM、GenasenseTM(奥利默森)、GMK(神经节苷脂缀合物疫苗)、GVAXTM(前列腺癌疫苗)、常山酮、组胺瑞林、羟基脲、伊班膦酸、IGN-101、IL-13-PE38、IL-13-PE38QQR(cintredekinbesudotox)、IL-13-假单胞菌外毒素、干扰素-α、干扰素-γ、JunovanTM和MepactTM(米伐木肽)、洛那法尼、5,10-亚甲基四氢叶酸、米替福新(十六烷基磷酸胆碱)、NeovastatTM(AE-941)、NeutrexinTM(葡糖醛酸三甲曲沙)、NipentTM(喷司他丁)、OnconaseTM(豹蛙酶,一种核糖核酸酶)、OncophageTM(vitespen,黑素瘤疫苗治疗)、OncoVAXTM(IL-2疫苗)、OrathecinTM(鲁比替康)、OsidemTM(基于抗体的细胞药物)、OvarexTMMAb(鼠源单克隆抗体)、紫杉醇白蛋白稳定化的纳米粒、紫杉醇、PandimexTM(来自人参的苷元皂苷,包括20(S)-原人参二醇(aPPD)和20(S)-原人参三醇(aPPT))、帕尼单抗、PanvacTM-VF(研究性癌症疫苗)、培门冬酶、peg干扰素α(PEG干扰素A)、脱氢雌马酚、丙卡巴肼、rebimastat、RemovabTM(卡妥索单抗)、RevlimidTM(来那度胺)、RSR13(乙丙昔罗)、SomatulineTMLA(兰瑞肽)、SoriataneTM(阿曲汀)、星孢菌素(星形孢链霉菌(Streptomyces staurospores))、talabostat(PT100)、TargretinTM(贝沙罗汀)、TaxoprexinTM(二十二碳六烯酸(DHA)+紫杉醇)、TelcytaTM(canfosfamide,TLK-286)、TemodarTM(替莫唑胺)、替米利芬、汉防己碱、沙利度胺、TheratopeTM(STn-KLH疫苗)、ThymitaqTM(盐酸诺拉曲塞)、TNFeradeTM(腺载体:DNA载体(含有针对肿瘤坏死因子-α的基因))、TracleerTM或ZavescaTM(波生坦)、TransMID-107RTM(KSB-311、白喉毒素)、维甲酸(视色素-A)、TrisenoxTM(三氧化二砷)、UkrainTM(来自白屈菜植物的生物碱的衍生物)、VirulizinTM、VitaxinTM(抗-αvβ3抗体)、XcytrinTM(莫特沙芬钆)、XinlayTM(阿曲生坦)、XyotaxTM(聚谷氨酸紫杉醇)、YondelisTM(曲贝替定)、ZD-6126(N-乙酰基秋水仙醇-O-磷酸)、ZinecardTM(右雷佐生)、唑来膦酸、佐柔比星等。
其他目标和特征将部分显而易见并且部分在下文中指出。
实施例
提供以下非限制性实例以进一步说明本发明。
在一组具有不同遗传改变的骨髓性白血病细胞系中进行检查4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(ABT-199或维奈托克)和[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼)的活性。药物处理72小时后考比替尼的IC50值<0.01μM至>1μM,但与p-ERK1/2的基础水平不相关(图1A)。在11种细胞系中的7种中,所述药剂的组合引起协同性生长抑制。值得注意的是,在维奈托克耐药细胞系(MOLM14、OCI-AML3、NB4和THP1)中观察到维奈托克和考比替尼的协同作用(图1B至1L)。在原代AML原始细胞的长期培养中,维奈托克和考比替尼的组合主要抑制一部分AML样品中的细胞增殖并诱导明显的凋亡细胞死亡。骨髓祖细胞的克隆形成潜力被该组合显著抑制,而正常的祖细胞功能受到最小程度的影响(图2A、2B和2C)。
药物动力学标志物的持续分析包括通过RNA测序的转录组评估,通过反相蛋白阵列(RPPA)的功能蛋白质组学和使用电化学发光ELISA测定法(Meso Scale Discovery,MSD-ELISA)定量Bcl-2:BIM和MCL-1:BIM复合物。RPPA是一种同时对数千个样品进行蛋白质测定的高通量技术。该蛋白质阵列平台测量蛋白质表达以及蛋白质修饰诸如磷酸化的水平。RPPA数据表明在考比替尼或维奈托克作为单一药剂或组合的敏感和耐药细胞系中差异表达的蛋白质。参见下表1、2和3。
表1.考比替尼:敏感性V.耐药性
表2.维奈托克:敏感性V.耐药性
蛋白质 | P值 | 平均值耐药性 | 平均值敏感性 |
bRaf(T401) | 5.44E-10 | 1.263 | 0.927 |
Bax | 1.48E-15 | 0.958 | 1.227 |
Bcl-2 | 1.28E-19 | 0.817 | 1.081 |
Bim | 3.41E-20 | 1.143 | 0.811 |
p16INK4a | 3.09E-06 | 1.989 | 1.593 |
PTEN | 2.39E-20 | 0.704 | 1.495 |
PTEN(S380) | 1.88E-09 | 0.839 | 1.369 |
S6(S240/244) | 8.51E-05 | 1.918 | 1.571 |
表3.组合:敏感性V.耐药性
在敏感性和耐药性细胞系中差异表达的代表性蛋白质组合。(图3A、3B、3C和3D)。初步的MSD数据揭示,Bcl-2:BIM复合物在大多数细胞系中被维奈托克破坏,而在OCI-AML3细胞中在考比替尼处理后累积,这可能是由于通过抑制MEK破坏MCL-1:BIM复合物,释放BIM与Bcl-2结合(图3E)。
我们接下来使用34-抗体板(panel)和飞行时间质谱流式细胞术(CyTOF)研究AML干/祖细胞中的信号传导模式和Bcl-2家族蛋白表达。CyTOF是流式细胞术的一种变体,其中抗体用重金属离子标签而不是荧光染料标记。读数是通过飞行时间质谱法。这允许在单个样品中组合更多的抗体特异性,而没有显著的通道间溢出。在AML 4295468中,Bcl-2在白血病原始细胞中表达,在表型上定义为CD45dimCD34+CD38+CD123+CD33+的祖细胞AML群体中富集(图4A)。在AML 4295468中,Bcl-2的高表达水平及MCL-1和BCL-XL的低表达可解释对维奈托克的敏感性。维奈托克耐药性AML(4366894)显示,Bcl-2在CD45dimCD34+CD38-CD123+CD33+群体中低表达(图4B)。在AML 4295468中,考比替尼有效下调基础和G-CSF或SCF刺激的p-ERK;然而,G-CSF诱发的p-STAT3/5和SCF诱导的p-AKT仅稍微降低(图4C)。值得注意的是,我们观察到用考比替尼处理后STAT5途径的磷酸化增加,表明活性MAPK信号抑制JAK-STAT途径的磷酸化,如先前所报道(Krasilnikov et al.Oncogene,2003and Lee atal.Cancer Cell,2014)。在AML 4366894中,p-ERK也降低,然而,G-CSF诱导的p-STAT3/5没有显著改变。为了测试两种化合物在体内的功效,我们给NSG小鼠注射基因工程化的OCI-AML3/Luc/GFP细胞。与对照相比,生物发光成像(BLI)显示治疗组中的白血病负荷显著减少,在考比替尼单剂和维奈托克加考比替尼共同治疗的小鼠中更显著(图5A和5B)。为了进一步探索这两种化合物的抗白血病功效,我们给NSGS小鼠注射基因工程化的MOLM3/Luc/GFP细胞。与对照组相比,生物发光成像显示治疗组中的白血病负荷显著降低,在维奈托克组和维奈托克加考比替尼共同治疗的小鼠中更显著(图5C)。当维奈托克与考比替尼组合使用时,骨髓和脾脏两者中人CD45植入和细胞计数均表现出趋于减少肿瘤负荷的趋势(图5D和5E)。
总之,数据表明,在大多数测试的AML细胞系中MAPK和Bcl-2途径的组合阻断是协同性的,并且可克服对维奈托克的固有耐药性。此外,考比替尼/维奈托克组合抑制原代AML样本亚群中的增殖,诱导细胞凋亡和减少克隆形成,但在正常造血前体细胞中并非如此。另外,在对单一药物或对考比替尼/维奈托克组合敏感或耐受的细胞系中鉴定差异过表达的蛋白质。MSD测定显示维奈托克而非考比替尼破坏了Bcl-2:BIM复合物。CyTOF质谱流式细胞术能够测量抗原定义的AML干/祖细胞群中的细胞内信号传导途径和Bcl-2家族成员。最后,维奈托克和考比替尼的组合降低AML肿瘤负荷并延长体内OCI-AML3 AML模型和MOLM13 AML模型的存活。
当介绍本发明的要素或其优选实施方案时,冠词“一”、“一个”、“该”和“所述”旨在表示存在一个或多个要素。术语“包括”、“包含”和“具有”旨在是包含性的并且意指除了列出的要素之外还可有其他要素。
鉴于以上所述,可以看到,实现了本发明的几个目的并且获得了其他有利的结果。
由于可在不脱离本发明的范围的情况下对上述组合物和方法进行各种改变,所以包含在上述说明书中和附图中示出的所有内容应该被解释为说明性的而不是限制性的。
Claims (20)
1.一种治疗增殖性病症的方法,所述方法包括向有此需要的哺乳动物施用治疗有效量的MEK抑制剂和选择性Bcl-2抑制剂的组合。
2.权利要求1的方法,其中所述增殖性病症选自肿瘤性疾病、免疫性疾病或自身免疫性疾病。
3.权利要求1或2的方法,其中所述增殖性病症是癌症。
4.权利要求1至3中任一项的方法,其中所述增殖性病症选自癌症、间皮瘤、膀胱癌、胰腺癌、皮肤癌、头或颈部癌、皮肤或眼内黑素瘤、卵巢癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、骨癌、结肠癌、直肠癌、肛门区癌、胃癌、胃肠道癌(胃癌、结肠直肠癌和/或十二指肠癌)、慢性淋巴细胞性白血病、急性淋巴细胞性白血病、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、睾丸癌、肝细胞癌(肝癌和/或胆管癌)、原发性或继发性中枢神经系统肿瘤、原发性或继发性脑肿瘤、霍奇金病、慢性或急性白血病、急性骨髓性白血病、慢性骨髓性白血病、淋巴细胞性淋巴瘤、成淋巴细胞性白血病、滤泡性淋巴瘤、T细胞或B细胞源性淋巴恶性肿瘤、黑素瘤、多发性骨髓瘤、口腔癌、非小细胞肺癌、前列腺癌、小细胞肺癌、肾和/或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤、原发性中枢神经系统淋巴瘤、非霍奇金淋巴瘤、脊柱轴肿瘤、脑干胶质瘤、垂体腺瘤、肾上腺皮质癌、胆囊癌、脾癌、胆管癌、纤维肉瘤、成神经细胞瘤、成视网膜细胞瘤及其组合。
5.权利要求1至3中任一项的方法,其中所述增殖性病症是急性骨髓性白血病。
6.权利要求1至3中任一项的方法,其中所述增殖性病症是多发性骨髓瘤。
7.权利要求1至6中任一项的方法,其中所述哺乳动物是人。
8.权利要求1至7中任一项的方法,其中所述MEK抑制剂和所述选择性Bcl-2抑制剂同时施用。
9.权利要求1至8中任一项的方法,其中所述MEK抑制剂和所述选择性Bcl-2抑制剂共同配制。
10.权利要求10的方法,其中所述MEK抑制剂和所述选择性Bcl-2抑制剂共同配制在药物组合物中,所述药物组合物还包含药学上可接受的赋形剂。
11.权利要求1至7中任一项的方法,其中所述MEK抑制剂与所述选择性Bcl-2抑制剂依序施用。
12.权利要求11的方法,其中所述MEK抑制剂和所述选择性Bcl-2抑制剂被配制成单独的口服可用剂型。
13.权利要求1至12中任一项的方法,其中所述MEK抑制剂抑制MEK1、MEK2或MEK1和MEK2两者。
14.权利要求1至13中任一项的方法,其中所述MEK抑制剂是[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼)或其药学上可接受的盐。
15.权利要求1至14中任一项的方法,其中所述选择性Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(ABT-199)或其药学上可接受的盐。
16.权利要求1至15中任一项的方法,其中所述MEK抑制剂是考比替尼或其药学上可接受的盐并且所述选择性Bcl-2抑制剂是4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺或其药学上可接受的盐。
17.一种药物产品,其包含(i)第一组合物,所述第一组合物包含[3,4-二氟-2-(2-氟-4-碘苯胺基)苯基]{3-羟基-3-[(2S)-哌啶-2-基]氮杂环丁烷-1-基}甲酮(考比替尼)或其药学上可接受的盐,和(ii)第二组合物,所述第二组合物包含4-(4-{[2-(4-氯苯基)-4,4-二甲基环己-1-烯-1-基]甲基}哌嗪-1-基)-N-({3-硝基-4-[(四氢-2H-吡喃-4-基甲基)氨基]苯基}磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲酰胺(ABT-199)或其药学上可接受的盐。
18.权利要求17的药物产品,其中所述第一组合物还包含药学上可接受的赋形剂。
19.权利要求17或18的药物产品,其中所述第二组合物还包含药学上可接受的赋形剂。
20.权利要求17至19中任一项的药物产品,其中所述第一组合物和所述第二组合物是相同的。
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PCT/US2016/060271 WO2017079399A1 (en) | 2015-11-03 | 2016-11-03 | Combination of bcl-2 inhibitor and mek inhibitor for the treatment of cancer |
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CN113853217A (zh) * | 2019-04-29 | 2021-12-28 | 伊缪诺金公司 | 包含抗cd123免疫缀合物的治疗组合 |
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TW202023568A (zh) * | 2018-07-30 | 2020-07-01 | 瑞典商阿斯特捷利康公司 | 用於治療癌症之組合療法 |
KR20210094532A (ko) | 2018-10-16 | 2021-07-29 | 더 존스 홉킨스 유니버시티 | 혈관형 엘러스 단로스 증후군 및 연관 장애를 치료하기 위한 조성물 및 방법 |
WO2020181219A1 (en) * | 2019-03-06 | 2020-09-10 | The Regents Of The University Of Colorado, A Body Corporate | Methods of detecting and treating venetoclax-resistant acute myeloid leukemia |
EP3976200A4 (en) * | 2019-06-03 | 2023-07-05 | Sanford Burnham Prebys Medical Discovery Institute | USE OF SYNTHETIC LETHAL PARTNERS TO TREAT CANCER |
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US20210169865A1 (en) | 2021-06-10 |
MA43170A (fr) | 2018-09-12 |
IL258741A (en) | 2018-06-28 |
BR112018008882A8 (pt) | 2019-02-26 |
CA3001880C (en) | 2021-08-17 |
AU2016349279A1 (en) | 2018-05-10 |
HK1259545A1 (zh) | 2019-11-29 |
BR112018008882A2 (pt) | 2018-11-06 |
EP3370775B1 (en) | 2023-04-19 |
US20180303815A1 (en) | 2018-10-25 |
KR20180054852A (ko) | 2018-05-24 |
US10959993B2 (en) | 2021-03-30 |
CN108601839B (zh) | 2021-10-26 |
KR102124715B1 (ko) | 2020-06-18 |
JP2018534298A (ja) | 2018-11-22 |
MX2018005233A (es) | 2019-04-29 |
JP6724136B2 (ja) | 2020-07-15 |
WO2017079399A1 (en) | 2017-05-11 |
EP3370775A1 (en) | 2018-09-12 |
IL258741B (en) | 2021-08-31 |
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