CN107922504B - 抗HER2抗体-药物缀合物和Bcl-2抑制剂的组合疗法 - Google Patents
抗HER2抗体-药物缀合物和Bcl-2抑制剂的组合疗法 Download PDFInfo
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- CN107922504B CN107922504B CN201680040184.1A CN201680040184A CN107922504B CN 107922504 B CN107922504 B CN 107922504B CN 201680040184 A CN201680040184 A CN 201680040184A CN 107922504 B CN107922504 B CN 107922504B
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Abstract
本发明涉及一种涉及抗HER2抗体‑药物缀合物和选择性Bcl‑2抑制剂的组合疗法,其用于治疗罹患癌症(具体而言表达HER‑2的癌症)的患者。
Description
序列表
本申请含有以ASCII格式电子提交的序列表,并且通过引用将其全部内容并入本文。在2016年6月28日创建的所述ASCII副本被命名为GNE-0416-WO.txt,并且大小为6,298字节。
技术领域
背景技术
抗HER2抗体-药物缀合物
HER2(ErbB2)受体酪氨酸激酶是跨膜受体的表皮生长因子受体(EGFR)家族的成员。HER2的过度表达在约20%的人乳腺癌(以下称为HER2阳性乳腺癌)中观察到,并且涉及与这些肿瘤相关的侵袭性生长和不良临床结果(Slamon et al(1987)Science 235:177-182)。HER2蛋白过度表达可使用基于免疫组织化学的固定肿瘤块评估来确定(Press MF,etal(1993)Cancer Res 53:4960-70)。
曲妥珠单抗(CAS 180288-69-1,huMAb4D5-8,rhuMAb HER2,Genentech)是重组DNA衍生的IgG1κ单克隆抗体,其在基于细胞的测定中以高亲和力(Kd=5nM)选择性结合至HER2的细胞外结构域的鼠抗-HER2抗体(4D5)的人源化形式(US5677171;US 5821337;US 6054297;US 6165464;US 6339142;US 6407213;US 6639055;US6719971;US 6800738;US 7074404;Coussens et al(1985)Science 230:1132-9;Slamonet al(1989)Science 244:707-12;Slamon et al(2001)New Engl.J.Med.344:783-792)。曲妥珠单抗在体外测定和动物中均显示抑制过度表达HER2的人肿瘤细胞的增殖(Hudziaket al(1989)Mol Cell Biol 9:1165-72;Lewis et al(1993)Cancer ImmunolImmunother;37:255-63;Baselga et al(1998)Cancer Res.58:2825-2831)。曲妥珠单抗是抗体依赖性细胞毒性(ADCC)的介体(Lewis et al(1993)Cancer Immunol Immunother 37(4):255-263;Hotaling et al(1996)[abstract].Proc.Annual Meeting Am AssocCancer Res;37:471;Pegram MD,et al(1997)[abstract].Proc Am Assoc Cancer Res;38:602;Sliwkowski et al(1999)Seminars in Oncology 26(4),Suppl 12:60-70;YardenY.and Sliwkowski,M.(2001)Nature Reviews:Molecular Cell Biology,MacmillanMagazines,Ltd.,Vol.2:127-137)。
在1998年被批准用于治疗已经接受广泛现有抗癌疗法的过度表达HER2的转移性乳腺癌患者(Baselga et al,(1996)J.Clin.Oncol.14:737-744),并且已经用于超过30万名患者(Slamon DJ,et al.N Engl J Med 2001;344:783-92;Vogel CL,etal.J Clin Oncol 2002;20:719-26;Marty M,et al.J Clin Oncol 2005;23:4265-74;Romond EH,et al.T N Engl J Med 2005;353:1673-84;Piccart-Gebhart MJ,et al.NEngl J Med 2005;353:1659-72;Slamon D,et al.[abstract].乳腺癌Res Treat 2006,100(Suppl 1):52)。2006年,FDA批准(曲妥珠单抗,Genentech Inc.)作为含有多柔比星(doxorubicin)、环磷酰胺(cyclophosphamide)和紫杉醇(paclitaxel)的治疗方案的一部分,用于HER2阳性、***阳性乳腺癌患者的辅助治疗。
抗体靶向疗法的替代方法是利用抗体特异性递送细胞毒性药物至表达抗原的癌细胞。抗体-药物缀合物或ADC是已与高度有效的细胞毒性剂缀合的单克隆抗体。ADC代表了对***施用的抗肿瘤治疗剂赋予肿瘤选择性的新方法。利用肿瘤特异性和/或过度表达的表面抗原,ADC被设计为集中高度有效的细胞毒剂向肿瘤细胞的递送。这种方法的潜力是为这些药物创造一个更有利的治疗窗,而不是通过其作为游离药物施用来实现的。
美登木素生物碱类(Maytansinoids)是抗有丝***药物美登素的衍生物,以类似于长春花生物碱药物的方式与微管结合(Issell BF et al(1978)Cancer Treat.Rev.5:199-207;Cabanillas F et al.(1979)Cancer Treat Rep,63:507-9)。DM1是衍生自天然存在的酯安丝菌素P3的含硫醇的美登木素生物碱(Remillard S,Rebhun LI,Howie GA,etal.(1975)Science 189(4207):1002-1005.3;Cassady JM,Chan KK,Floss HG.(2004)ChemPharm Bull 52(1):1-26.4)。在约800名患者中已经研究了相关植物酯美登素作为化学治疗剂以2.0mg/m2的剂量每3周一次作为单一剂量或连续3天施用(Issell BF,Crooke ST.(1978)Maytansine.Cancer Treat Rev 5:199-207)。尽管具有临床前活性,但是临床中美登素的活性在可安全递送的剂量是适度的。剂量限制性毒性(DLT)是胃肠道毒性,包括恶心、呕吐和腹泻(通常随后是便秘)。这些毒性是剂量依赖性的,但不是时间表依赖性的。周围神经病变(主要是感觉)已有报道且在具有先前存在的神经病变的患者中最为明显。报道了肝转氨酶、碱性磷酸酶和总胆红素的亚临床短暂升高。包括虚弱、嗜睡、烦躁不安和失眠的构成性毒性是常见的。不太常见的毒性包括输注部位静脉炎和轻度骨髓抑制。由于治疗窗狭窄,在1980年代放弃了药物的进一步开发。
曲妥珠单抗-MCC-DM1(T-DM1,曲妥珠单抗美坦新偶联物,ado-曲妥珠单抗美坦新偶联物,),一种用于治疗HER2阳性乳腺癌的新颖抗体-药物缀合物(ADC),由经由MCC接头在赖氨酸侧链与曲妥珠单抗缀合的细胞毒剂DM1(含巯基的美登木素生物碱抗微管剂)组成,其中平均药物载量(药物/抗体比率)为3.5。在与肿瘤细胞上表达的HER2结合之后,T-DM1经历受体介导的内化,导致细胞内释放含DM1的细胞毒性分解代谢物,并随后导致细胞死亡。
在T-DM1(TDM3569g)的I期研究中,每3周(q3w)通过IV输注施用的T-DM1的最大耐受剂量(MTD)是3.6mg/kg。DLT(剂量限制毒性)由在4.8mg/kg治疗的患者中的短暂性血小板减少症组成。用3.6mg/kg q3w的治疗耐受良好并与显著的临床活性相关(Krop(2010)J.Clin.Oncol.28(16):2698-2704)。同样的研究也表明每周2.4mg/kg的给药也耐受良好并具有抗肿瘤活性(Beeram(2012)Cancer 118(23):5733-5740)。
II期研究(TDM4374g)表明,以3.6mg/kg q3w施用的T-DM1在具有HER2阳性转移性乳腺癌的严重预处理患者群体中具有单一药物抗肿瘤活性(Krop(2012)30(26):3234-3241)。III期研究(TDM4370g)表明,在先前用曲妥珠单抗和紫杉烷治疗的HER2阳性晚期乳腺癌患者中,与用拉帕替尼+卡培他滨的治疗相比,以3.6mg/kg q3w施用的T-DM1显著延长无进展生存期和总生存期,毒性较低(Verma(2012)New England Journal of Medicine367:1783-1791)。
Bcl-2抑制剂
Bcl-2家族蛋白调节由发育线索触发的程序性细胞死亡并响应于多重应激信号(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)。虽然Bcl-2本身以及携带有三个或四个保守的Bcl-2同源性(BH)区域的几个近亲(Bcl-xL,Bcl-W,Mcl-1and Al)促进细胞存活,但是由两种其他亚家族驱动凋亡。细胞死亡的初始信号由不同组的仅含BH3结构域蛋白(BH3-only protein)传递,包括Bad、Bid、Bim、Puma和Noxa,其通常只有小的BH3相互作用结构域(Huang and Strasser,Ce11 103(2000)839-842)。然而,含有BH1-BH3的多结构域蛋白质Bax或Bak是细胞死亡所必需的(Cheng,etal.,Molecular Cell 8(2001)705-711;Wei,M.C.,et al.,Science 292(2001)727-730;Zong,W.X.,et al.,Genes and Development 15 148(2001)1-1486)。当被活化时,它们可穿透线粒体的外膜并释放活化拆散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 and Development 15(2001)2922-2933;(Adams,2003supra);Green,D.R.,and Kroemer,G.,Science 305(2004)626-629)。
Bcl-2家族三个成员之间的相互作用决定一个细胞是存活还是死亡。当仅含BH3结构域蛋白被活化时,例如,对DNA损伤作出响应,它们可经其BH3结构域结合至其促活相关物上的沟(Sattler,et al.,Science 275(1997)983-986)。然而,仅含BH3结构域蛋白和Bcl-2样蛋白如何控制Bax和Bak的活化仍然不甚了解(Adams,2003supra)。大部分注意力集中在Bax上。这种可溶性单体蛋白质(Hsu,Y.T.,et al.,Journal of Biological Chemistry272(1997)13289-1 3834;Wolter,K.G.,et al.,Journal of Cell Biology 139(1997)1281-92)通常具有其***其沟中的膜靶向结构域,这可能是其胞质定位的原因(Nechushtan,A.,et al.,EMBO Journal 18(1999)2330-2341;Suzuki,et al.,Cell 103(2000)645-654;Schinzel,A.,et al.,J Cell Bio1 164(2004)1021-1032)。在Lucken-Ardjomande,S.,and Martinou,J.C.,J Cell Sci 118(2005)473-483中综述了已经提出几种不相关的肽/蛋白质调节Bax活性,但是它们的生理学相关性还有待确定。或者,Bax可经直接接合某些仅含BH3结构域蛋白而被活化(Lucken-Ardjomande,S.,and Martinou,J.C,2005supra),最好记录为Bid的截短形式tBid(Wei,M.C.,et al.,Genes und Development14(2000)2060-2071;Kuwana,T.,et al.,Cell 111(2002)331-342;Roucou,X.,et al.,Biochemical Journal 368(2002)915-921;Cartron,P.F.,et al.,Mol Cell 16(2004)807-818)。如别处讨论的(Adams 2003supra),其中Bcl-2直接参与Bax的最老的模型(Oltvai,Z.N.,et al.,Cell 74(1993)609-619)已经成为问题,因为Bcl-2是膜结合的而Bax是胞质的(cytosolic),并且它们的相互作用似乎高度依赖于用于细胞裂解的洗涤剂(Hsu,Y.T.,and Youle,1997supra)。尽管如此,公认的是,Bax的BH3区域可介导与Bcl-2的结合(Zha,H.,and Reed,J.,Journal of Biological Chemistry 272(1997)31482-88;Wang,K.,et al.,Molecular und Cellular Biology 18(1998)6083-6089),并且Bcl-2阻止Bax的寡聚化,即使不能检测到异二聚体(Mikhailov,V.,et al.,Journal ofBiological Chemistry 276(2001)18361-18374)。因此,促活蛋白是否直接或间接限制Bax活化仍然不确定。
尽管Bax和Bak在大多数情况下似乎在功能上是等同的(Lindsten,T.,et al.,Molecular Cell 6(2000)1389-1399;Wei,M.C.,et al.,2001supra),但是其调控中的实质差异从其在健康细胞中的独特定位可以预料到。不同于Bax(其主要为胞质的),Bak位于线粒体外膜上和健康细胞内质网上的复合物中(Wei,M.C.,et al.,2000supra;Zong,W.X.,etal.,Journal of Ce11Biology 162(2003)59-69)。尽管如此,在接受细胞毒素信号时,Bax和Bak两者都改变构象,并且Bax易位至细胞器膜,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.,et al.,PNAS 94(1997)3668-3672;Wolter,K.G.,et al.,1997supra;Antonsson,B.,et al.,Journal of Biological Chemistry 276(2001)11615-11623;Nechushtan,A.,et al.,Journal of Cell Biology 153(2001)1265-1276;Wei,M.C.,et al.,2001supra;Mikhailov,V.,et al.,Journal of Biological Chemistry 278(2003)5367-5376)。
存在多种Bcl-2抑制剂,它们都具有抑制Bcl-2家族蛋白的促活成员的相同性质,并且因此是治疗癌症的有希望的候选者。这样的Bcl-2抑制剂是例如奥利莫森(Oblimersen)、SPC-2996、RTA-402、棉酚(Gossypol)、AT-101、甲磺酸Obatoclax、A-371191、A-385358、A-438744、ABT-737、ABT-263(navitoclax)、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,并且例如描述于Zhai,D.,et al.,Cell Death and Differentiation 13(2006)1419-1421。
其它Bcl-2家族蛋白和癌症之间的联系也已经很好地建立并被充分证明(Strasser,A.2011EMBO J.30,3667-3683),并且其它Bcl家族成员的抑制剂也是已知的。Bcl-XL选择性抑制剂A-1155463和A-1331852描述于例如Leverson et al.,ScienceTranslational Medicine Vol 7,Issue 279 279ra40中。Bcl-XL的选择性苯并噻唑腙抑制剂公开于Sleebs et al.,J.Med.Chem.2013,56,5514-5540。对于其他Bcl-XL抑制剂的描述见例如Koehler et al.,ACS Med.Chem.Lett.2014,5,662-667;and Tao et al,ACSMed.Chem.Lett.2014,5,1088-10。MCI-1抑制剂及其作为癌症治疗剂的用途描述于例如Leverson et al.,Cell Death and Disease(2015)6,e1590;Bruncko et al.,J.Med.Chem.2015,58,2180-2194;Petros et al.,Bioorganic&Medicinal ChemistryLetters 24(2014)1484-1488;Abulwerdi et al.,Mol Cancer Ther 2014;13:565-5;Abulwerdi et al.,J.Med.Chem.2014,57,4111-4133;Burke et al.,J.Med.Chem.2015,58,3794-3805;Friberg et al.,J.Med.Chem.2013,56,15-30;and belmar et al.,Pharmacology&Therapeutics 145(2015)76-84.Mcl-1/Bcl-xL dual inhibitors aredisclosed by Tanaka et al.,J.Med.Chem.2013,56,9635-9645。
发明内容
在一个方面,本发明涉及在有此需要的人中治疗癌症的方法,包括向该人施用治疗量的抗HER2抗体-药物缀合物和Bcl家族蛋白的抑制剂。
在另一方面,本发明涉及在有此需要的人中治疗癌症的方法,包括向这样的人施用治疗量的抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂。
在一个实施方案中,所述癌症为HER2阳性癌症。
在另一个实施方案中,所述癌症为HER2阳性乳腺癌或胃癌。
在另一个实施方案中,所述HER2阳性乳腺癌或胃癌具有2+或3+的HER2免疫组织化学(IHC)评分和/或≥2.0的原位杂交(ISH)扩增率(her2:CEP17原位杂交(ISH)扩增率)。
在另一个实施方案中,所述HER2阳性癌症,诸如乳腺癌或胃癌,对使用作为单一药剂施用的抗HER2抗体-药物缀合物的治疗具有抗性。
在另一个实施方案中,所述HER2阳性癌症,诸如乳腺癌或胃癌,对使用作为单一药剂施用的抗HER2抗体-药物缀合物的治疗具有敏感性,并且可将抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂的组合施用至未耐受使用抗HER2抗体-药物缀合物的治疗的患者。
在不同的实施方案中,抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂显示协同活性,包括但不限于,在对使用作为单一药剂施用的抗HER2抗体-药物缀合物的治疗具有抗性的HER2阳性癌症(诸如乳腺癌或胃癌)中的协同活性。
在所有实施方案中,所述抗HER2抗体-药物缀合物可例如为曲妥珠单抗-MCC-DM1。
在所有实施方案中,所述选择性Bcl-2抑制剂可例如为2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐。
在另一方面,本发明涉及在有此需要的人中治疗HER阳性癌症的方法,包括向该人施用有效量的曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐。
在一个实施方案中,所述癌症为HER2阳性乳腺癌或胃癌。
在另一个实施方案中,所述HER2阳性乳腺癌或胃癌具有2+或3+的HER2免疫组织化学(IHC)评分和/或≥2.0的原位杂交(ISH)扩增率(her2:CEP17原位杂交(ISH)扩增率)。
在另一个实施方案中,所述HER2阳性癌症,诸如乳腺癌或胃癌,对使用作为单一药剂施用的曲妥珠单抗-MCC-DM1的治疗具有抗性。
在另一个实施方案中,所述HER2阳性癌症,诸如乳腺癌或胃癌,对使用作为单一药剂施用的曲妥珠单抗-MCC-DM1的治疗具有敏感性,并且可将曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐的组合施用至未耐受使用曲妥珠单抗-MCC-DM1的治疗的患者。
在另一个实施方案中,所述HER2阳性癌症,诸如乳腺癌或胃癌,对使用作为单一药剂施用的抗HER2抗体-药物缀合物的治疗具有敏感性,并且可将抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂的组合施用至未耐受使用抗HER2抗体-药物缀合物的治疗的患者。在另一个实施方案中,曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐显示协同活性,包括但不限于,HER2阳性癌症(诸如乳腺癌或胃癌)中的协同活性。
在另一个实施方案中,曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐共同施用。
在另一个实施方案中,曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐同时施用。
在另一个实施方案中,曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐连续施用。
在另一方面,本发明涉及抗HER2抗体-药物缀合物和Bcl家族蛋白的抑制剂的组合在制备用于治疗癌症的药物中的用途。
在一个实施方案中,所述Bcl家族蛋白为Bcl-2样蛋白,诸如Mcl-1、Bcl-xl、Bcl-w(BCL2L2)或Bcl-xs,优选Mcl-1或Bcl-xl。
在另一方面,本发明涉及抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂的组合在制备用于治疗癌症的药物中的用途。
在一个实施方案中,本发明涉及曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐的组合在制备用于治疗癌症的药物中的用途。
在所有实施方案中,所述癌症可为HER2阳性癌症。
在所有实施方案中,所述癌症可为例如乳腺癌或胃癌。
在所有实施方案中,所述HER2阳性癌症,诸如乳腺癌或胃癌,可对使用作为单一药剂施用的曲妥珠单抗-MCC-DM1的治疗具有抗性。
在所有实施方案中,所述HER2阳性癌症,诸如乳腺癌或胃癌,可对使用作为单一药剂施用的曲妥珠单抗-MCC-DM1的治疗具有敏感性,并且曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐的组合可用于治疗未耐受使用曲妥珠单抗-MCC-DM1的治疗的患者。
在另一方面,本发明涉及抗HER2抗体-药物缀合物和Bcl家族蛋白的抑制剂的组合在制备用于治疗癌症的药物中的用途。
在一个实施方案中,所述Bcl家族蛋白为Bcl-2样蛋白,诸如Mcl-1、Bcl-xl、Bcl-w(BCL2L2)或Bcl-xs,优选Mcl-1或Bcl-xl。
在另一方面,本发明涉及抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂的组合,其用于治疗癌症。
在一个实施方案中,曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐的组合用于治疗癌症。
在所有组合中,所述癌症可为例如HER2阳性癌症,诸如HER2阳性乳腺癌或胃癌。
在一个具体实施方案中,当作为单一药剂施用时,所述癌症,诸如乳腺癌或胃癌,可对使用抗HER2抗体-药物缀合物或曲妥珠单抗-MCC-DM1的治疗具有耐受性。
在另一个实施方案中,当作为单一药剂施用时,所述HER2阳性癌症,诸如乳腺癌或胃癌,可对使用抗HER2抗体-药物缀合物例如曲妥珠单抗-MCC-DM1的治疗具有敏感性,并且所述组合可用于治疗未耐受使用抗HER2抗体-药物缀合物例如曲妥珠单抗-MCC-DM1的治疗的患者。
在另一方面,本发明涉及诊断HER2阳性肿瘤对使用HER2抗体-药物缀合物的治疗具有抗性的方法,包括确定获自具有HER2阳性癌症的患者的肿瘤样品中相对于对照样品中表达水平的Bcl-2基因或其产物的表达水平,以及当所述肿瘤样品中的表达水平比所述对照样品中的表达水平高至少2倍或至少3倍或至少4倍或至少5倍时,诊断为所述癌症对使用所述抗HER2抗体-药物缀合物的治疗具有抗性。
在另一方面,本发明涉及诊断HER2阳性肿瘤对使用HER2抗体-药物缀合物的治疗易感的方法,包括确定获自具有HER2阳性癌症的患者的肿瘤样品中相对于对照样品中表达水平的Bcl-2基因或其产物的表达水平,以及当所述肿瘤样品中的表达水平比所述对照样品中的表达水平高至少2倍或至少3倍或至少4倍或至少5倍时,诊断为所述癌症对使用所述抗HER2抗体-药物缀合物的治疗易感。
在另一方面,本发明涉及诊断具有HER2阳性肿瘤的受试者对使用抗HER2抗体-药物缀合物的治疗具有抗性或易感的方法,包括(i)自所述受试者获得肿瘤样品,(ii)测量所述肿瘤样品中相对于对照样品表达水平的Bcl-2基因或其产物的表达水平,和(iii)当所述肿瘤样品中所测量的Bcl-2表达水平比所述对照样品中的表达水平高至少2倍,或至少3倍,或至少4倍,或至少5倍时,诊断为所述肿瘤对使用抗HER2抗体-药物缀合物的治疗具有抗性,或当在所述肿瘤样品中测量的Bcl-2表达水平比所述对照样品中的表达水平高不到2倍,或不到3倍,或不到4倍,或不到5倍时,诊断为所述对使用抗HER2抗体-药物缀合物的治疗易感。
在一个实施方案中,所述受试者为人患者。
在另一个实施方案中,所述对照样品为对使用所述抗HER2抗体-药物缀合物的治疗不具有抗性的具有相同细胞类型的肿瘤样品。
在另一个实施方案中,所述肿瘤为乳腺癌或胃癌。
在另一个实施方案中,所述肿瘤样品是***固定的、石蜡包埋的肿瘤样品。
在所有实施方案中,所述诊断方法可还包括测量肿瘤样品中HER2基因或其产物的表达水平的步骤。
在所有实施方案中,所述诊断方法可还包括当所测量的肿瘤样品中Bcl-2的表达水平比所述对照样品中的表达水平高至少2倍,或至少3倍,或至少4倍,或至少5倍时,使用抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂治疗受试者的步骤。
在所有实施方案中,所述诊断方法还可包括当肿瘤样品中测量的Bcl-2的表达水平比所述对照中的表达水平低不到2倍时,使用抗HER2抗体-药物缀合物治疗所述患者的步骤。
在一个实施方案中,所述抗HER2抗体-药物缀合物为曲妥珠单抗-MCC-DM1。
在另一个实施方案中,所述选择性Bcl-2抑制剂为2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐。
在另一方面,本发明涉及用于在获自患者的生物样品中对使用抗HER2抗体-药物缀合物的治疗具有抗性的HER2阳性肿瘤的体外诊断或预后的试剂盒,其包含Bcl-2基因或其表达产物的特异性结合配偶体。
在一个实施方案中,所述结合配偶体为抗Bcl-2抗体
在另一个实施方案中,所述结合配偶体为与Bcl-2基因杂交的核酸。
在另一方面,本发明涉及包含抗HER2抗体药物缀合物和选择性Bcl-2抑制剂的试剂盒,其用于组合治疗具有表达HER2的癌症的患者。
在本发明的一个实施方案中,所述试剂盒还包含药学上可接受的载体。所述试剂盒还可包含无菌稀释剂,其优选储存在单独的另外容器中。所述试剂盒还可包括包装说明书,其包括印刷的说明,指导使用组合治疗作为表达HER2的癌症诸如表达HER2的乳腺癌或胃癌的方法。
正如在其他方面一样,表达HER2的癌症可为例如乳腺癌或胃癌,并且在各种实施方案中,所述抗HER2抗体药物缀合可为曲妥珠单抗-MCC-DM1和/或所述选择性Bcl-2抑制剂可为2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐。
在一个具体实施方案中,所述待治疗的表达HER2的癌症,诸如乳腺癌或胃癌,当作为单一药剂施用时,对使用抗HER2抗体-药物缀合物或曲妥珠单抗-MCC-DM1的治疗具有抗性。
在另一个实施方案中,所述的表达HER2的癌症,诸如乳腺癌或胃癌,当作为单一药剂施用时,可对抗HER2抗体-药物缀合物(例如曲妥珠单抗-MCC-DM1)的治疗具有敏感性,并且该组合可用于治疗为耐受使用抗HER2抗体-药物缀合物(例如曲妥珠单抗-MCC-DM1)的治疗的患者。
附图说明
图1A和1B示出相对于亲代细胞,在T-DM1抗性KPL-4和BT-474M1人乳腺癌细胞(HER2阳性)中Bcl-2家族促活分子的表达。图1A示出通过TaqMan qRT-PCR分析评估的mRNA表达;图1B示出通过Western印迹分析的蛋白表达。
图2示出细胞活力测定的结果,显示T-DM1+GDC-0199组合在KPL-4T-DM1抗性人乳腺癌细胞中具有协同作用,而在KPL-4亲代细胞中未观察到协同作用。
图3示出测定半胱天冬酶3和7活化的半胱天冬酶活化测定的结果。结果显示,在药物处理24小时,在GDC-0199存在下,T-DM1抗性KPL-4人乳腺癌细胞再次对T-DM1敏感,而在24小时时,在KPL-4亲代细胞中没有T-DM1+/-GDC-0199的作用。
图4A和4B示出半胱天冬酶活化测定的结果,其在药物治疗48小时后测量T-DM1抗性KPL-4人乳腺癌细胞中相对于亲代细胞的半胱天冬酶3和7的活化。结果显示,随着添加GDC-0199至T-DM1中,半胱天冬酶3和7活化呈剂量依赖性增加,其中单独T-DM1的作用最小。在KPL-4亲代细胞中,T-DM1诱导半胱天冬酶3和7的强烈活化,其中在添加GDC-0199时具有最小的增加。
图5A示出半胱天冬酶活化测定的结果,测量在用1ug/mL T-DM1单独或与指定剂量的GDC-0199组合处理48小时的克隆#17T-DM1抗性KPL-4人乳腺癌细胞系中半胱天冬酶3和7的活化。结果显示,随着添加GDC-0199至T-DM1中,半胱天冬酶3和7活化呈剂量依赖性增加,其中单独T-DM1的作用最小。
图5B示出T-DM1(5mg/kg每天一次施用)、GDC-0199(100mg/kg qd x21)或其组合对SCID米色小鼠中克隆#17T-DM1抗性KPL-4人乳腺癌异种移植物的肿瘤生长(通过肿瘤体积测量)的作用。组合药物治疗导致肿瘤停滞,其中单一药剂治疗无活性。
图6A和6B示出半胱天冬酶活化测定的结果,分别在0.1μg/mL和1μg/mL T-DM1浓度,在克隆#8T-DM1抗性KPL-4人乳腺细胞系中,单独或与指定浓度的GDC-0199组合,测量半胱天冬酶3和7的活化。
图6C示出T-DM1(5mg/kg q3w x 2)、GDC-0199(100mg/kg qd x 21)或组合对SCID米色小鼠中克隆#8T-DM1抗性KPL-4人乳腺癌异种移植物的肿瘤生长(通过肿瘤体积测量)的作用。
图7A示出使用DAB检测方法通过免疫组织化学(IHC)确定的***固定的石蜡包埋的T-DM1抗性KPL-4异种移植肿瘤样品(克隆#8和#17)中Bcl-2的表达。
图7B示出使用DAB检测方法通过免疫组织化学(IHC)确定的***固定的石蜡包埋的T-DM1抗性KPL-4异种移植肿瘤样品(克隆#8和#17)中HER2(ErbB2)的表达。
图8示出在用GDC-0199、T-DM1或T-DM-1+GDC-0199处理的克隆#17KPL-4T-DM1抗性异种移植物肿瘤中通过Bcl-2和HER2的Western印迹分析测量的蛋白表达。
图9A示出半胱天冬酶3/7活化发光体外凋亡测定的结果,在HER2+MDA-MB-361乳腺癌细胞(T-DM1未耐受细胞)中处理24小时后测试5种不同浓度的GDC-0199(μM)与9种不同浓度的T-DM1的作用。结果表明,使用所有测试的组合,增强的凋亡比单独的T-DM1更大。
图9B示出动力学半胱天冬酶3/7活化荧光体外细胞凋亡测定的结果,在HER2+MDA-MB-361乳腺癌细胞中,单独或与T-DM1(0.1μg/mL)组合测试3种不同浓度的GDC-0199(0.63μM、1.25μM、2.5μM)的作用。结果表明,使用所有测试的组合,增强的半胱天冬酶活化比单独的T-DM1更大。
图10A示出半胱天冬酶3/7活化发光体外凋亡测定的结果,测试5种不同浓度的GDC-0199(μM)与9种不同浓度在HER2+HCC1569乳腺癌细胞(T-DM1未耐受细胞)中处理24小时的效果。结果表明,单独的T-DM1未诱导凋亡,但是使用所有测试的组合都增强了凋亡。
图10B示出动力学半胱天冬酶3/7荧光体外细胞凋亡测定的结果,单独测试3种不同浓度的GDC-0199(0.63μM、1.25μM、2.5μM)单独及与T-DM1(0.1μg/mL)组合在HER2+HCC1569乳腺癌细胞中的效果。结果表明,组合治疗剂量依赖性增强半胱天冬酶活化。
图11示出T-DM1(1mg/kg、3mg/kg、7mg/kg,iv q3wx1)和GDC-0199(100mg/kg,po,qdx 21)单独或组合使用对HER2+MDA-MB-361乳腺癌异种移植物模型中肿瘤生长的影响。使用与7mg/kg T-DM1组合的GDC-0199观察到显著的肿瘤生长延迟。
图12示出在HER2+乳腺癌细胞系BT-474、EFM192A、KPL-4、HCC1569、HCC1954、MDA-361、UACC-812、ZR-75-30中,T-DM1(有或没有GDC-0199)对Bcl-2家族成员(全部和磷酸-Bcl-2和-Bcl-xL、总Mcl-1和Bim)的Western印迹分析。
图13示出曲妥珠单抗轻链(SEQ ID NO:1)的氨基酸序列。
图14示出曲妥珠单抗重链(SEQ ID NO:2)的氨基酸序列。
具体实施方式
现将详细描述本发明某些实施方案,其实施例在所附结构和式中说明。当结合所列实施方案来描述本发明时,应理解的是,所述实施方案不是意在将本发明限于这些实施方案。相反地,本发明意在包括可包括在如权利要求书所定义的本发明范围内的所有可选形式、修改形式和等价形式。本领域技术人员将认识到与本申请描述的方法和物质类似或等价的可用于实施本发明的那些方法和物质。本发明绝不限于所描述的方法和物质。
通过引用的方式将本申请引用的所有参考文献全部引入到本申请中。若一篇或多篇所引入的文献、专利和类似材料与本申请不同或矛盾(包括但不限于所定义的术语、术语用法、所描述的技术等),则以本申请为准。
定义
本申请的术语“抗体”以最广泛的意义使用,并且包括各种抗体结构,包括但不限于单克隆抗体、多克隆抗体、多特异性抗体(例如双特异性抗体)和抗体片段,只要它们展现出所需的抗原结合活性。
本申请使用的术语“单克隆抗体”是指从基本上同质的抗体群体获得的抗体,即包含该群体的单个抗体是相同的和/或结合相同的表位,除了可能的变体抗体,例如含有天然存在的突变或单克隆抗体制备物的生产期间发生突变,这种变体通常以少量存在。与通常包含针对不同决定簇(表位)的不同抗体的多克隆抗体制备物相比,单克隆抗体制备物的每种单克隆抗体针对抗原上的单一决定簇。因此,修饰语“单克隆”表示从基本上同质的抗体群体获得的抗体的特性,并且不被解释为需要通过任何特定方法产生抗体。例如,根据本发明使用的单克隆抗体可通过多种技术来制备,所述技术包括但不限于杂交瘤方法、重组DNA方法、噬菌体展示方法和利用转基因动物的方法,所述转基因动物包含全部或部分人免疫球蛋白基因座,诸如本申请描述的用于制备单克隆抗体的此类方法和其他示例性方法。
本申请抗体-药物缀合物中使用的抗HER2抗体为单克隆抗体。
术语“嵌合抗体”是指包含来自一种来源或物种的可变区(即结合区)和衍生自不同来源或物种的恒定区的至少一部分的单克隆抗体,通常通过重组DNA技术来制备。包含鼠可变区和人恒定区的嵌合抗体是特别优选的。这种鼠/人嵌合抗体是包含编码鼠免疫球蛋白可变区的DNA区段和编码人免疫球蛋白恒定区的DNA区段的表达免疫球蛋白基因的产物。本发明所涵盖的其他形式的“嵌合抗体”是其中类别或亚类已经原始抗体的类别或亚类被修饰或改变的那些。这种“嵌合”抗体也被称为“类别转换抗体”。生产嵌合抗体的方法涉及现有技术中公知的常规重组DNA和基因转染技术。参见例如Morrison,S.L.,et al.,Proc.Natl.Acad Sci.USA 81(1984)6851-6855;US 5,202,238and US 5,204,244。
术语“人源化抗体”是指框架或“互补决定区”(CDR)已被修饰以包含与亲代免疫球蛋白相比具有不同特异性的免疫球蛋白的CDR的抗体。在一个优选的实施方案中,将鼠CDR移植入人抗体的框架区以制备“人源化抗体”。参见例如Riechmann,L.,et al.,Nature 332(1988)323-327;和Neuberger,M.S.,et al.,Nature 314(1985)268-270。特别优选的CDR对应于那些代表识别上文针对嵌合抗体和双功能抗体所述的抗原的序列的CDR。
本申请使用术语“人抗体”意在包括具有源自人种系免疫球蛋白序列的可变区和恒定区的抗体。人抗体是现有技术中公知的(van Dijk,M.A.,and van de Winkel,J.G.,Curr.Opin.Pharmacol.5(2001)368-374),并且可通过多种技术产生,包括噬菌体展示。基于这种技术,可产生针对多种靶标的人抗体。人抗体的实例例如描述于Kellermann,S.A.,et al.,Curr Opin Biotechnol.13(2002)593-597。对于使用噬菌体展示技术来产生和选择人抗体,参见例如Winter et al.,Ann Review Immunol,1994,12:433-455;对于用于从转基因小鼠和噬菌体展示平台产生完全人抗体的方法,参见例如Lonberg,CurrentOpinion Immunol,2008,20(4):450-459。
本申请使用的术语“重组人抗体”意在包括通过重组手段制备、表达、产生或分离的所有人抗体,诸如例如从宿主细胞诸如NS0或CHO细胞或从转基因人免疫球蛋白基因的动物(例如小鼠)分离的抗体或使用转染入宿主细胞的重组表达载体表达的抗体。这种重组人抗体具有以重排形式来源于人种系免疫球蛋白序列的可变区和恒定区。
本申请使用“特异性结合”或“特异性结合至”是指对靶标足够选择性以将其与不需要的或非特异性靶标的结合区分开的结合。在一个实施方案中,与靶标特异性结合的抗体对靶标的结合亲和力(Kd)≤1μM、≤100nM、≤10nM、≤1nM、≤0.1nM、≤0.01nM或≤0.001nM(例如10-8M或更低,例如10-8M至10-13M,例如10-9M至10-13M)。在另一个实施方案中,KD为10-10mol/l或更低(例如10-12mol/l)。用标准结合测定法,诸如对表达靶抗原的细胞进行Scatchard图分析,确定结合亲和力。
本申请使用的术语“核酸分子”意在包括DNA分子和RNA分子。核酸分子可为单链或双链的。在一个实施方案中,其为双链DNA。
“恒定结构域”不直接参与抗体与抗原的结合,但参与效应物功能(ADCC、补体结合和CDC)。
术语“可变区”或“可变结构域”是指涉及抗体与抗原结合的抗体重链或轻链的结构域。天然抗体的重链和轻链(分别为VH和VL)的可变结构域通常具有相似的结构,每个结构域包含四个保守框架区(FR)和三个高变区(HVR)。(参见例如Kindt et al.KubyImmunology,6th ed.,W.H.Freeman and Co.,page 91(2007).)。
本申请使用的术语“高变区”或“HVR”是指序列高度可变的抗体可变结构域的每个区域(“互补决定区”或“CDR”)和/或形成结构限定的环(“高变环”)和/或含有抗原接触残基(“抗原接触”)。通常,抗体包含六个HVR:VH中的三个(H1、H2、H3)和VL中的三个(L1、L2、L3)。本申请的示例性HVR包括:
(a)存在于氨基酸残基26-32(L1)、50-52(L2)、91-96(L3)、26-32(H1)、53-55(H2)和96-101(H3)的高变环(Chothia and Lesk,J.Mol.Biol.196:901-917(1987));
(b)存在于氨基酸残基24-34(L1)、50-56(L2)、89-97(L3)、31-35b(H1)、50-65(H2)和95-102(H3)的CDR(Kabat et al.,Sequences of Proteins of ImmunologicalInterest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD(1991));
(c)存在于氨基酸残基27c-36(L1)、46-55(L2)、89-96(L3)、30-35b(H1)、47-58(H2)和93-101(H3)的抗原接触(MacCallum et al.J.Mol.Biol.262:732-745(1996));和
(d)(a)、(b),和/或(c)的组合,包括HVR氨基酸残基46-56(L2)、47-56(L2)、48-56(L2)、49-56(L2)、26-35(H1)、26-35b(H1)、49-65(H2)、93-102(H3)和94-102(H3)。
本发明的术语“抗HER2抗体”为特异性结合HER2抗原的抗体。
“表位4D5”或“4D5表位”或“4D5”是抗体4D5(ATCC CRL 10463)和曲妥珠单抗结合的HER2的胞外结构域中的区域。该表位接近HER2的跨膜结构域,并在HER2的结构域IV内。为了筛选与4D5表位结合的抗体,可进行例如Antibodies,A Laboratory Manual,ColdSpring Harbor Laboratory,Ed Harlow and David Lane(1988)中所述的常规交叉阻断测定。或者,可进行表位作图以评估抗体是否结合HER2的4D5表位(例如HER2的大约残基529至大约残基625(含)的区域中的任何一个或多个残基)。
“表位2C4”或“2C4表位”是抗体2C4结合的HER2胞外结构域中的区域,为了筛选与2C4表位结合的抗体,进行常规交叉阻断测定,可进行Antibodies,A Laboratory Manual,Cold Spring Harbor Laboratory,Ed Harlow and David Lane(1988)中所述的常规交叉阻断测定。或者,可进行表位作图以评估抗体是否与HER2的2C4表位结合。表位2C4包含来自HER2的胞外结构域中结构域II的残基。2C4抗体和帕妥珠单抗在结构域I、II和III的连接处结合HER2的细胞外结构域(Franklin et al.Cancer Cell 5:317-328(2004))。
本申请定义的术语“T-DM1”、“曲妥珠单抗-MCC-DM1”、“ado-曲妥珠单抗美坦新偶联物”、“曲妥珠单抗美坦新偶联物”和可互换使用,并且是指通过接头部分MCC连接至美登木素生物碱药物部分DM1的曲妥珠单抗,包括各种负载和连接的抗体-药物缀合物的所有混合物,其中1、2、3、4、5、6、7和8个药物部分共价连接至抗体曲妥珠单抗(US 7097840;US 2005/0276812;US 2005/0166993)。
本申请使用的术语“Bcl-2”是指Bcl-2家族蛋白的成员Bcl-2蛋白(Swiss Prot IDNo.P10415)(Cory,S.,and Adams,J.M.,Nature Reviews Cancer 2(2002)647-656;Adams,Genes und Development 17(2003)2481-2495;Danial,N.N.,and Korsmeyer,S.J.,Cell116(2004)205-219;Petros,A.M.,Biochim Biophys Acta 1644(2004)83-94)。
本申请使用的术语“选择性Bcl-2抑制剂”是指抑制Bcl-2家族蛋白的促活成员的多肽和小分子。优选地,所述选择性Bcl-2抑制剂为2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺(又称为ABT-199或GDC-0199)或其药学上可接受的盐,其为式I的Bcl-2抑制剂,述于国际公开No.WO2010/0138588和美国公开No.US2010/0305122,通过引用将其并入本申请。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺
式I.
本申请的“抗肿瘤剂”是指用于治疗癌症的药物。本申请的抗肿瘤剂的非限制性实例包括化学治疗剂、HER二聚化抑制剂、HER抗体、针对肿瘤相关抗原的抗体、抗激素化合物、细胞因子、EGFR靶向药物、抗血管生成剂、酪氨酸激酶抑制剂、生长抑制剂和抗体、细胞毒性剂、诱导凋亡的抗体、COX抑制剂、法尼基转移酶抑制剂、结合癌胚蛋白CA 125的抗体、HER2疫苗、Raf或ras抑制剂,脂质体多柔比星、托泊替康(topotecan)、紫杉烷、双重酪氨酸激酶抑制剂、TLK286、EMD-7200、帕妥珠单抗(pertuzumab)、曲妥珠单抗、厄洛替尼(erlotinib)和贝伐珠单抗(bevacizumab)。
“化学疗法”是使用可用于治疗癌症的化学治疗剂。
“化学治疗剂”是可用于治疗癌症的化合物,而与其作用机理无关。化学治疗剂包括,但是不限于:烷化剂、抗代谢药、纺丝体毒植物生物碱(spindle poison plantalkaloids)、细胞毒性/抗肿瘤抗生素(cytotoxic/antitumor antibiotics)、拓扑异构酶(topoisomerase)抑制剂、抗体、光敏性药物和激酶抑制剂。化学治疗剂的实例包括:厄洛替尼(erlotinib)(Genentech/OSI Pharm.)、多西他赛(docetaxel)(Sanofi-Aventis)、5-FU(氟尿嘧啶,5-氟尿嘧啶,CAS No.51-21-8)、吉西他滨(gemcitabine)(Lilly)、PD-0325901(CAS No.391210-10-9,Pfizer)、顺铂(cisplatin)(顺-二胺,二氯化铂(II),CAS No.15663-27-1)、卡铂(carboplatin)(CASNo.41575-94-4)、紫杉醇(paclitaxel)(Bristol-Myers Squibb Oncology,Princeton,N.J.)、替莫唑胺(temozolomide)(4-甲基-5-氧代-2,3,4,6,8-五氮杂二环[4.3.0]壬-2,7,9-三烯-9-甲酰胺、CAS No.85622-93-1,Schering Plough)、他莫昔芬(tamoxifen)((Z)-2-[4-(1,2-二苯基丁-1-烯基)苯氧基]-N,N-二甲基-乙基胺,)、多柔比星(doxorubicin)Akti-1/2、HPPD和雷帕霉素(rapamycin)。
化学治疗剂的其它实例包括:奥沙利铂(oxaliplatin)(Sanofi)、硼替佐米(bortezomib)(Millennium Pharm.)、舒尼替尼(sutent)(SU11248,Pfizer)、来曲唑(letrozole)(Novartis)、甲磺酸伊马替尼(imatinib mesylate)(Novartis)、XL-518(Mek抑制剂,Exelixis,WO 2007/044515)、ARRY-886(MEK抑制剂,AZD6244,Array BioPharma,Astra Zeneca)、SF-1126(PI3K抑制剂,Semafore Pharmaceuticals)、BEZ-235(PI3K抑制剂,Novartis)、XL-147(PI3K抑制剂,Exelixis)、PTK787/ZK 222584(Novartis)、氟维司群(fulvestrant)(AstraZeneca)、甲酰四氢叶酸(leucovorin)(亚叶酸)、雷帕霉素(西罗莫司,Wyeth)、拉帕替尼(lapatinib)(GSK572016,GlaxoSmith Kline)、lonafarnib(SARASARTM,SCH 66336,Schering Plough)、索拉非尼(sorafenib)(BAY43-9006、Bayer Labs)、吉非替尼(gefitinib)(AstraZeneca)、伊立替康(irinotecan)(CPT-11,Pfizer)、替吡法尼(tipifarnib)(ZARNESTRATM,Johnson&Johnson)、ABRAXANETM(不含克列莫佛(Cremophor-free))、紫杉醇的白蛋白工程化纳米微粒制剂(American PharmaceuticalPartners,Schaumberg,Il)、凡德他尼(vandetanib)(rINN,ZD6474,AstraZeneca)、苯丁酸氮芥(chloranmbucil)、AG1478、AG1571(SU 5271;Sugen)、替西罗莫司(temsirolimus)(Wyeth)、帕唑帕尼(pazopanib)(GlaxoSmithKline)、坎磷酰胺(canfosfamide)(Telik)、塞替派(thiotepa)和环磷酰胺(cyclosphosphamide)磺酸烷基酯类(alkylsulfonate),诸如白消安、英丙舒凡和哌泊舒凡(piposulfan);氮丙啶类(aziridine),诸如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺(ethylenimine)和甲基氨基吖啶(methylamelamine),包括六甲蜜胺、三亚胺嗪(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫化磷酰胺(triethylenethiophosphoramide)和trimethylomelamine;番荔枝内酯(acetogenin)(尤其是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));喜树碱(包括合成性类似物托泊替康(topotecan));苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成性类似物);cryptophycins(特别是cryptophycin 1和cryptophycin 8);多拉司他汀(dolastatin);duocarmycin(包括合成性类似物KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;spongistatin;氮芥类,诸如苯丁酸氮芥、萘氮芥、氯磷酰胺(chlorophosphamide)、雌莫司汀、异环磷酰胺、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);硝基脲类,诸如卡莫司汀、氯脲菌素(chlorozotocin)、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素类,诸如烯二炔(enediyne)抗生素(例如刺孢霉素(calicheamicin),刺孢霉素γ1I、刺孢霉素ωI1(AngewChem.Intl.Ed.Engl.(1994)33:183-186);蒽环类抗生素(dynemicin),dynemicin A;二膦酸盐类(bisphosphonate),诸如氯膦酸盐(clodronate);埃斯培拉霉素(esperamicin);以及新抑癌蛋白生色团(neocarzinostatin chromophore)和相关色蛋白烯二炔抗生素生色团(enediyne antibiotic chromophore)、aclacinomysin、放线菌素(actinomycin)、authramycin、偶氮丝氨酸(azaserine)、博来霉素、放线菌素C(cactinomycin)、carabicin、去甲柔红霉素(carminomycin)、嗜癌素(carzinophilin)、色霉素(chromomycin)、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine)、吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉子基-多柔比星和去氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类,诸如丝裂霉素C、麦考酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(porfiromycin)、嘌罗霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星;抗代谢物,诸如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、甲氨喋呤(methotrexate)、喋罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷(azacytidine)、6-氮鸟苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、伊诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素类,诸如卡普睾酮(calusterone)、丙酸甲雄烷酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺素类(anti-adrenal),诸如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂(folicacid replenisher),诸如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);伊达曲杀(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptinium acetate);埃坡霉素(epothilone);依托格鲁(etoglucid);硝酸镓(gallium nitrate);羟基脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登素类化合物(maytansinoid),诸如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);mopidanmol;根瘤菌剂(nitraerine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基肼;丙卡巴肼(procarbazine);多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2"-三氯三乙胺;单端孢菌毒素(trichothecene)(T-2毒素、verracurin A、杆孢菌素A和anguidine);乌拉坦;长春地辛;达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(Ara-C);环磷酰胺;塞替派;6-硫代鸟嘌呤;巯嘌呤;甲氨喋呤;铂类似物,诸如顺铂和卡铂;长春碱;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨诺消灵(novantrone);替尼泊苷(teniposide);伊达曲杀(edatrexate);柔红霉素;氨基喋呤(aminopterin);卡培他滨(capecitabine)(Roche);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(二氟甲基ornithine、DMFO);类视黄醇(retinoid),诸如视黄酸(retinoic acid);以及上述任何物质的药学上可接受的盐、酸和衍生物。
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控的细胞生长。“肿瘤”包含一个或多个癌细胞。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。这种癌症的更具体的实例包括乳腺癌、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("NSCLC")、肺腺癌和肺鳞癌)、胃部癌或胃癌(包括胃肠道癌)、胰腺癌、成胶质细胞瘤、***、卵巢癌、肝癌、膀胱癌、肝细胞瘤、结肠癌、直肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾部癌或肾癌、***癌、外阴癌、甲状腺癌、肝癌、***癌、***癌以及头颈癌。在一个优选的实施方案中,所述癌症为乳腺癌。在另一个优选实施方案中,所述癌症为胃癌。
将肿瘤或癌症称作“0期”、“I期”、“II期”、“III期”或“IV期”及该分类中的各个亚阶段指示使用本领域已知的整体阶段分组(Overall Stage Grouping)或罗马数字分期(Roman Numeral Staging)方法对肿瘤或癌症的分类。虽然实际的癌症阶段取决于癌症的类型,一般而言,0期癌症为原位病灶,I期癌症为小的局限性肿瘤,II期和III期癌症是局部晚期肿瘤,其展现出涉及局部***,而IV期癌症代表转移性癌症。每类肿瘤的具体阶段是熟练临床医生已知的。
术语“转移性乳腺癌”是指乳腺癌的状态,其中癌细胞通过血管或***从原始位点传递到身体其他地方的一个或多个位点,以在***以外的一个或多个器官形成一个或多个继发性肿瘤。
“晚期”癌症是通过局部侵袭或转移扩散到原始位点或器官的外部。因此,术语“晚期”癌症包括局部晚期和转移性疾病。
“难治性”癌症是即使对癌症患者施用抗肿瘤剂(诸如化学疗法)仍会进展的癌症。难治性癌症的一个实例是铂难治性癌症。
“复发性”癌症是在对初始治疗(诸如手术)响应之后,在初始位点或在远处位点再生长的癌症。
“局部复发性”癌症是在与先前治疗的癌症相同的部位治疗后回转的癌症。
“可操作的”或“可切除的”癌症是限于原发性器官并适合于手术(切除)的癌症。
“不能切除的”或“不可切除的”的癌症不能通过手术去除(切除)。
术语“HER2阳性”和“表达HER2”在本申请中可互换使用。“HER2阳性”癌症包含具有高于正常水平的HER2的癌细胞。HER2阳性癌症的实例包括HER2阳性乳腺癌和HER2阳性胃癌。任选地,HER2阳性是过度表达HER2的癌症,并且在某些实施方案中,HER-2阳性癌症具有2+或3+的免疫组织化学(IHC)评分和/或原位杂交(ISH)扩增率≥2.0。
原位杂交(ISH)使用偶联至荧光、发色或银检测***(即FISH、CISH或SISH)或CISH和SISH***组合(明视野双ISH(BDISH)或双重半抗原、双色ISH(DDISH))的DNA探针确定her2拷贝的数量。ISH可使用单个探针仅对每个核计数her2拷贝,或者作为双重探针技术进行,其中染色体17着丝粒探针(染色体计数探针17,CEP17)的杂交允许确定her2:CEP17比率。双探针方法可作为双色技术进行,在相同的载玻片上共同杂交两个探针,或者作为单色测定,其中每个探针在连续的载玻片上使用。her2:CEP17比率有时被认为是her2扩增状态比平均her2拷贝数的更好反映,因为后者也依赖于其他参数,诸如肿瘤的有丝***指数、切片厚度、核截短效应和异常染色体拷贝数(异倍体)。短语“原位杂交(ISH)扩增率≥2.0”是指her2:CEP17比率≥2.0。有关详情,请参阅Sauter G,et al.Guidelines for humanepidermal growth factor receptor 2testing:biologic and methodologicconsiderations.J Clin Oncol 2009;27:1323–1333,and the review article by Hannaet al.Modern Pathology(2014)27,4–18。
本申请的“患者”或“受试者”是人患者。患者可为“癌症患者”,即罹患或处于罹患一种或多种癌症症状风险,特别是胃癌或乳腺癌的人。
“患者群体”是指一组癌症患者。这样的群体可用于证明药物诸如帕妥珠单抗具有统计学上显著的功效和/或安全性。
“复发”患者是缓解后具有癌症指征或症状的患者。任选地,患者在辅助或新辅助疗法后复发。
“展现HER表达、扩增或活化”的癌症或生物样品是在诊断测试中表达(包括过度表达)HER受体、具有扩增的HER基因和/或以其他方式证明HER受体的活化或磷酸化的癌症或生物样品。
本申请使用的术语“协同(性)”是指比两种或更多种单一药剂的累加效应更有效的治疗组合。抗Her2抗体-药物缀合物诸如曲妥珠单抗-MCC-DM1和选择性Bcl-2抑制剂之间的协同相互作用的确定可基于从本申请所述测定获得的结果,或在本领域已知的其它测定***中,使用用于量化抗癌剂之间的协同作用、累加作用和拮抗作用的标准程序。优选使用的程序是由Chou和Talalay在"New Avenues in Developmental Cancer Chemotherapy,"Academic Press,1987,Chapter 2描述的程序。小于0.8的组合指数(CI)值指示协同作用,大于1.2的值指示拮抗作用且0.8至1.2的值指示累加效应。组合疗法可提供“协同作用”并且证明是“协同的”,即当一起使用的活性成分时所达到的效果大于单独使用化合物产生的效果的总和。当活性成分:(1)在组合的单位剂量制剂中共同配制和同时施用或递送;(2)作为单独的制剂交替或平行递送;或(3)通过其他方案时,可获得协同效应。当以交替疗法递送时,当化合物依次施用或递送时,例如通过在单独的注射器中不同的注射,可获得协同效应。通常,在交替疗法期间,每种活性成分的有效剂量依次施用,即在时间上连续施用,而在组合疗法中,两种或更多种活性成分的有效剂量一起施用。
本申请的“新辅助疗法”或“术前疗法”是指在手术之前给予的疗法。新辅助疗法的目标是提供即时的全身性治疗,可能根除微转移,否则如果遵循手术随后进行全身性治疗的标准顺序,则微转移将会增殖。新辅助疗法还可有助于减小肿瘤大小,从而允许完全切除最初不能切除的肿瘤或保留部分器官及其功能。此外,新辅助疗法允许体内评估药物功效,其可指导后续治疗的选择。
本申请的“辅助疗法”是指在确定性手术后给予的疗法,其中不能检测到残留疾病的证据,从而降低疾病复发的风险。辅助疗法的目标是防止癌症复发,并因此减少癌症相关性死亡的机会。本申请的辅助疗法明确排除新辅助疗法。
“确定性手术(Definitive surgery)”作为医学界中使用的术语使用。确定性手术包括,例如导致肿瘤去除或切除的操作、手术或其他,包括那些导致所有明显可见肿瘤的去除或切除的操作、手术或其他。确定性手术包括,例如,肿瘤的完全或根治性切除或总的完全切除。确定性手术包括在一个或多个阶段发生的操作,并且包括例如其中在切除肿瘤之前进行一个或多个手术或其他操作的多阶段手术操作。确定性手术包括去除或切除肿瘤的操作,所述肿瘤包括所涉及的器官、器官的部分和组织以及周围器官,诸如***,器官的部分或组织。去除可能是不完全的,使得即使未被检测到,肿瘤细胞也可能保留。
“生存”是指患者仍然存活,并且包括无病生存期(DFS)、无进展生存期(PFS)和总生存期(OS)。生存期可通过Kaplan-Meier方法估计,并且生存期的任何差异使用分层对数秩检验(stratified log-rank test)计算。
“无进展生存期”(PFS)是从治疗的第一天到记录的疾病进展(包括单独的中枢神经***进展)或研究中任何病因导致的死亡(以先发生者为准)的时间。
“无病生存期(DFS)”是指患者仍然存活,没有癌症的回转,从初始治疗或从初始诊断开始持续一段确定的时间,诸如约1年、约2年、约3年、约4年,约5年、约10年等。在本发明的一个方面,根据意向治疗原则分析DFS,即根据其指定的疗法对患者进行评价。DFS的分析中使用的事件可包括局部、区域和远处的癌症复发,继发性癌症的发生,以及没有先前事件的患者中任何原因的死亡(例如乳腺癌复发或第二原发性癌症)。
“总体生存期”是指患者仍然存活,从初始治疗或从初始诊断开始持续一段确定的时间,诸如约1年、约2年、约3年、约4年,约5年、约10年等。在本发明的研究中,用于生存分析的事件是任何原因造成的死亡。
“延长存活”是指相对于未治疗的患者,或相对于对照治疗方案,在经治疗的患者中增加DFS和/或OS。在初始治疗之后或在初始诊断后,监测生存期至少约六个月,或至少约1年,或至少约2年,或至少约3年,或至少约4年,或至少约5年,或至少约10年等。
生存分析中的“风险比(Hazard ratio)”是两条生存曲线之间的差异的总结,表示在一段时间的随访期间,与对照相比,治疗的死亡风险降低。风险比是事件发生率的统计定义。为了本发明的目的,风险比定义为表示在任何特定时间点实验组中事件的概率除以对照组中事件的概率。
“单一疗法”是指在治疗过程期间,仅包括用于治疗癌症或肿瘤的单一治疗剂的治疗方案。
术语“治疗”和“处置”是指治疗性处置和预防性或防治性措施,其中目的是预防或减缓(减少)不期望的生理变化或障碍,诸如过度增殖性疾病诸如癌症的生长、发展或扩散。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、疾病的稳定化(即不恶化)状态、疾病进展的延迟或减缓、疾病状态的改善或减轻,和缓解(不论是部分还是全部),无论是可检测的还是不可检测的。如果未接受治疗,“治疗”还意味着与预期的生存期相比延长生存期。需要治疗的患者包括那些已经具有疾病或病症的人,以及那些易于具有疾病或病症的人,或那些其中疾病或病症待预防的人。
当应用于例如癌症时,术语“治疗方法”或其等价物是指被设计为减少或消除患者中癌细胞数量或减轻癌症症状的操作或作用过程。癌症或另一种增殖性疾病的“治疗方法”并不一定意味着实际上会消除癌细胞或其他病症,实际上会减少细胞的数量或减轻病症,或者实际上会缓解癌症或其他病症的症状。通常,治疗癌症的方法即使成功的可能性很小仍然会实施,但鉴于患者的病史和估计的预期生存期,其仍然被认为会引起整体有益的作用过程。
术语“共同施用”或“共同给药”是指将抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂作为两种单独的制剂施用。共同施用可同时进行,也可以按任意顺序依次进行。在另一个实施方案中,存在两个(或所有)活性剂同时发挥其生物活性的时间段。抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂可同时或依次共同给药(例如经静脉内(i.v.)通过连续输注(一个用于抗体-药物缀合物,最后一个用于Bcl-2抑制剂;或口服施用Bcl-2抑制剂)。当两种治疗剂依次共同施用时,药剂以两次分开“特定时间段”的分开施用方式施用。术语特定时间段是指1小时至15天的任何时间。例如,一种药剂可在施用另一种药剂的约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小时内进行施用,并且在一个实施方案中,特定时间段为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。
术语“同时”是指在同一时间或在短时间内,通常少于1小时。
与同一种或多种其他药物“同时”施用的药物在同一治疗周期期间,在与一种或多种其他药物治疗的同一天以及任选地在与一种或多种其他药物的同一时间施用。例如,对于每3周给予一次癌症疗法,同时施用的药物各自在3周周期的第1天施用。
本申请使用的给药期是指一段时间,在此期间每种治疗剂已被施用至少一次。给药周期通常为约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。
在某些实施方案中,给药周期为21天。
在本申请提供的治疗患者癌症的方法的某些实施方案中,所述方法包括向患者施用抗HER2抗体-药物缀合物和选择性Bcl-2抑制剂,持续一个或多个给药周期。在一个实施方案中,一个或多个给药周期各自持续至少一周。在另一个实施方案中,一个或多个给药周期各自持续至少两周、三周、四周、五周、六周、七周、八周、九周或超过九周。在一个实施方案中,每个给药周期为三周。
在一个优选的实施方案中,抗体-药物缀合物作为静脉内(i.v.)输液每三周(21天周期)施用一次。
在本申请提供的治疗方法的一些实施方案中,所述选择性Bcl-2抑制剂为2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺(GDC-0199)。在某些实施方案中,在第一个给药周期期间,每剂向患者施用的GDC-0199的量从10mg至80mg的初始量增加至190mg至400mg的最终量。在某些实施方案中,向患者施用的每剂GDC-0199的量以50mg或100mg开始,并增加至每剂300mg。在一些实施方案中,向患者施用的初始剂量中的GDC-0199的量可为例如20mg至60mg(例如20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg或60mg剂量),接着剂量为100mg、200mg、300mg或更多的GDC-0199。
“不良事件”是与使用研究性(医药)产品或其他方案强制干预相关的任何不利和不期望的指征、症状或疾病,不论其归因如何;并且包括:在方案指定的AE报告期间出现的患者中先前未观察到的不良事件(AE),包括在AE报告期之前不存在的与乳腺癌相关的指征或症状;由于方案授权的干预而发生的并发症(例如,侵入性操作诸如活组织检查);如果适用,在分配与药物洗脱(washout)相关的研究治疗、没有治疗导入(run-in)或其他方案授权的干预之前发生的AE;在方案指定的AE报告期间研究者判定预先存在的病情(研究条件除外)的严重程度或频率恶化或性质改变。
不言而喻,抗体-药物缀合物以“治疗有效量”(或简称为“有效量”)施用于患者,其是研究人员、兽医、医生或其他临床医师正在找寻的引起组织、***、动物或人的生物学或医学响应的相应化合物或组合的量。有效量的治疗剂的施用可以是单次施用或分次剂量施用。“分次剂量施用”是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,则它可以一次100mg施用或两次50mg施用的方式施用。有时在给药期开始时需要分次剂量施用,以减少副作用。当在分次给药中施用有效量时,其仍被认为是一次施用有效量。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(例如2天)内以两个50mg剂量施用时,在此期间只施用一个有效量。
本申请治疗剂的“固定(fixed)”或“固定(flat)”剂量是指不考虑患者的体重(WT)或体表面积(BSA)而施用于人患者的剂量。因此,固定剂量不以mg/kg剂量或mg/m2剂量提供,而是以治疗剂的绝对量提供。
本申请的“负载”剂量通常包含施用于患者的治疗剂的初始剂量,并且随后是一个或多个其维持剂量。通常,施用单一负载剂量,但是本申请涵盖多个负载剂量。通常,施用的负载剂量的量超过施用的维持剂量的量和/或负载剂量比维持剂量更频繁地施用,以比维持剂量可达到的治疗剂的所需稳态浓度更早地达到治疗剂的所需稳态浓度。
本申请的“维持”剂量是指在治疗期内向患者施用的一个或多个剂量的治疗剂。通常,维持剂量以间隔的治疗间隔施用,诸如大约每周、大约每2周、大约每3周,或大约每4周,优选每3周。
“输注”或“输液”是指为了治疗目的通过静脉将含药溶液引入体内。通常,这是经静脉(IV)袋实现的。
“静脉袋”或“IV袋”是可容纳可经患者的静脉施用的溶液的袋。在一个实施方案中,溶液是盐水溶液(例如约0.9%或约0.45%NaCl)。任选地,IV袋由聚烯烃或聚氯乙烯形成。
在本发明的上下文中,可在表达HER2的癌症的抗HER2抗体-药物缀合物和Bcl-2抑制剂组合治疗中使用另外的其他细胞毒性剂、化学治疗剂或抗癌剂或增强这些药剂(例如细胞因子)作用的化合物。这种分子适合以对于预期目的有效的量以组合形式存在。优选地,使用抗HER2抗体-药物缀合物和Bcl-2抑制剂组合治疗,而没有这种另外的细胞毒性剂、化学治疗剂或抗癌剂,或增强这些药剂作用的化合物。
这种药剂包括例如:烷化剂或具有烷化作用的药剂,诸如环磷酰胺(CTX;例如)、苯丁酸氮芥(chlorambucil)(CHL;例如)、顺铂(CisP;例如)、白消安(例如)、美法仑,卡莫司汀(BCNU)、链脲佐菌素(streptozotocin)、三亚胺嗪(TEM)、丝裂霉素C等;抗代谢物,诸如甲氨蝶呤(MTX)、依托泊苷(VP16;例如)、6-巯基嘌呤(6MP)、6-硫代鸟嘌呤(6TG)、阿糖胞苷(Ara-C)、5-氟尿嘧啶(5-FU)、卡培他滨(例如)、达卡巴嗪(DTIC)等;抗生素,诸如如放线菌素D、多柔比星(DXR;例如)、柔红霉素(道诺霉素)、博来霉素、光辉霉素等;生物碱,诸如长春花生物碱,诸如长春新碱(VCR)、长春碱等;和其它抗肿瘤剂,诸如紫杉醇(例如)和紫杉醇衍生物,细胞生长抑制剂,糖皮质激素诸如***(DEX;例如)和皮质类固醇诸如***,核苷酶抑制剂诸如羟基脲,氨基酸消耗酶诸如天冬酰胺酶,亚叶酸和其它叶酸衍生物,以及类似的多种抗肿瘤剂。还可使用以下药剂作为另外的药剂:阿尼夫定(arnifostine)(例如)、更生霉素、双氯乙基甲胺(氮芥)、链佐星、环磷酰胺、洛莫司汀(CCNU)、多柔比星脂质体(例如)、吉西他滨(例如)、柔红霉素脂质体(例如)、丙卡巴肼、丝裂霉素、多西他赛(例如)、阿地白介素、卡铂、奥沙利铂、克拉屈滨、喜树碱、CPT11(伊立替康)、10-羟基7-乙基喜树碱(SN38)、氟尿苷、氟达拉滨、异环磷酰胺、伊达比星、美司钠、干扰素β、干扰素α、米托蒽醌、托泊替康、亮丙瑞林、甲地孕酮、美法仑、巯嘌呤、普卡霉素、米托坦、培门冬酶、喷司他丁、哌泊溴烷、普卡霉素、他莫昔芬、替尼泊苷、睾内酯、硫鸟嘌呤、噻替派、尿嘧啶氮芥、长春瑞滨、苯丁酸氮芥。优选地,使用II型抗CD20抗体和Bcl-2抑制剂组合治疗而不使用上述另外的药剂。
在化学治疗方案中使用上述细胞毒性剂和抗癌剂以及抗增殖性靶特异性抗癌药诸如蛋白激酶抑制剂通常在癌症治疗领域中被良好表征,并且它们在本申请中的使用属于监测耐受性和有效性及控制施用途径和剂量的相同考量,并进行一些调整。例如,细胞毒性剂的实际剂量可取决于通过使用组织培养方法确定的患者的培养细胞响应而变化。通常,与不存在另外其他药剂的情况下使用的量相比,剂量会降低。
有效的细胞毒性剂的典型剂量可在制造商推荐的范围内,并且在通过体外响应或动物模型中的响应所指示的情况下,可降低高达约一个数量级的浓度或量。因此,实际剂量将取决于医生的判断、患者的状况和治疗方法的有效性,所述方法基于原代培养的恶性细胞或组织培养的组织样品的体外响应性或在适当的动物模型中观察到的响应。
在本发明的上下文中,除抗HER2抗体-药物缀合物和Bcl-2抑制剂组合治疗之外,还可进行有效量的电离辐射和/或可使用放射性药物。放射源可在待治疗的患者的外部或内部。当来源在患者外部时,该疗法被称为外部束放射疗法(EBRT)。当放射源位于患者内部时,该治疗称为近距离放射疗法(BT)。本发明上下文中使用的放射性原子可选自但不限于镭、铯-137、铱-192、镅-241、金-198、钴-57、铜-67、锝-99、碘-123、碘-131和铟-111。也可用这种放射性同位素标记抗体。优选使用II型抗CD20抗体和Bcl-2抑制剂组合治疗而不使用这种电离辐射。
放射疗法是控制不能切除或不能手术的肿瘤和/或肿瘤转移的标准治疗。当放射疗法与化学疗法组合时,已经看到结果改善。放射疗法基于这样的原理,即递送至目标区域的高剂量辐射会导致肿瘤和正常组织中生殖细胞的死亡。放射剂量方案通常根据放射吸收剂量(Gy)、时间和分级来限定,并且必须由肿瘤学家仔细限定。患者接受的放射量取决于各种考虑因素,但最重要的两个是肿瘤相对于身体的其他关键结构或器官的位置和肿瘤已经扩散的程度。经受放射疗法的患者的典型疗程将是1至6周的治疗时间表,总剂量为10至80Gy,以约1.8至2.0Gy的单一每日部分施用于患者,每周5天。在本发明的优选实施方案中,当用本发明的组合治疗和放射治疗人患者的肿瘤时具有协同作用。换言之,当与放射组合时,借助于包含本发明的组合的药剂抑制肿瘤生长,任选地与另外的化学治疗剂或抗癌剂组合。辅助放射疗法的参数例如包含在WO 99/60023中。
抗HER2抗体-药物缀合物根据已知方法,通过作为推注的静脉内施用或通过连续输注一段时间,通过肌内、腹膜内、脑脊髓内、皮下、关节内、滑膜内或鞘内途径施用。优选静脉内或皮下施用抗体。
Bcl-2抑制剂根据已知方法,通过作为推注的静脉内施用或通过连续输注一段时间,通过肌内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、鞘内或经口途径施用。优选静脉内、皮下或口服施用Bcl-2抑制剂。
本申请使用的“药学上可接受的载体”意在包括与药物施用相容的任何和全部材料,包括溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂以及与药物施用相容的其它材料和化合物。除任何常规介质或试剂与活性化合物不相容的情况之外,还包括其在本发明组合物中的用途。补充活性化合物也可掺入组合物中。
“小瓶”是适于盛装液体或冻干制剂的容器。在一个实施方案中,小瓶是一次性使用的小瓶,例如带有塞子的20-cc一次性小瓶。
术语“包装说明书”用于指通常包含在治疗产品的商业包装中的说明,其含有关于涉及使用此类治疗产品的适应症、用法、剂量、施用、禁忌症和/或警告的信息。
本发明包括治疗性组合产品,其包含具有以下结构的曲妥珠单抗-MCC-DM1:
其中Tr是曲妥珠单抗,p是1至8的整数。在曲妥珠单抗-MCC-DM1的上述结构中,药物与抗体的比率或药物载量由p表示。曲妥珠单抗-MCC-DM1包括各种负载和连接的抗体-药物缀合物的所有混合物,其中1、2、3、4、5、6、7和8个药物部分共价连接至抗体曲妥珠单抗。
曲妥珠单抗是由哺乳动物细胞(中华仓鼠卵巢,CHO)悬浮培养产生的。HER2(或c-erbB2)原癌基因编码185kDa的跨膜受体蛋白,其与表皮生长因子受体在结构上相关。在25%-30%的原发性乳腺癌中观察到HER2蛋白过度表达,并且可使用基于免疫组织化学的固定肿瘤块评估来确定(Press MF,et al(1993)Cancer Res 53:4960-70)。曲妥珠单抗是具有鼠源4D5抗体的抗原结合残基或自其衍生的抗体(ATCC CRL 10463,于1990年5月24日根据布达佩斯条约保藏于美国典型培养物保藏中心,12301Parklawn Drive,Rockville,Md.20852)。示例性的人源化4D5抗体包括如US 5821337中的huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8
抗体-药物缀合物曲妥珠单抗-MCC-DM1包含美登木素生物碱药物部分DM1(US5208020;US 6441163)并且可由安丝菌素发酵产物制备(US 6790954;US 2005/0170475)。
选择性Bcl-2抑制剂
在优选的实施方案中,本发明的选择性Bcl-2抑制剂为2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺(又称为ABT-199或GDC-0199),其为式I的Bcl-2抑制剂,述于国际公开No.WO2010/0138588和美国公开No.US2010/0305122,通过引用将其并入本申请。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺
式I
其它选择性Bcl-2抑制剂包括例如奥利莫森、SPC-2996、RTA-402、棉酚、AT-101、甲磺酸Obatoclax、A-371191、A-385358、A-438744、ABT-737、ABT-263(navitoclax)、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、TP-TW-37、YC-137和Z-24,述于例如Zhai,D.,et al.,Cell Death and Differentiation 13(2006)1419-1421。
药物组合物
本发明的药物组合物或制剂包含曲妥珠单抗-MCC-DM1、选择性Bcl-2抑制剂和一种或多种药学上可接受的载体、助流剂、稀释剂或赋形剂的组合。
本发明的曲妥珠单抗-MCC-DM1和选择性Bcl-2抑制剂可以非溶剂化形式以及与药学上可接受的溶剂诸如水、乙醇等的溶剂化形式存在,并且本发明意图包括溶剂化和非溶剂化形式两者。
本发明的曲妥珠单抗-MCC-DM1和选择性Bcl-2抑制剂还可以不同的互变异构形式存在,并且所有这些形式都包含在本发明的范围内。术语“互变异构体”或“互变异构形式”是指具有不同能量的结构异构体,其可通过低能垒互相转化。例如,质子互变异构体(也称为质子移变异构体)包括经质子迁移的相互转化,诸如酮-烯醇和亚胺-烯胺异构化。价键互变异构体包括通过重组一些成键电子而相互转化。
药物组合物包括散装组合物和包含一种以上(例如两种)药学活性剂(包括曲妥珠单抗-MCC-DM1和选自本申请所述另外药剂的选择性Bcl-2抑制剂)的单个剂量单位,以及任何药学上无活性赋形剂、稀释剂、载体或助流剂。散装组合物和每个单个剂量单位可含有固定量的上述药物活性剂。散装组合物是尚未形成单个剂量单位的物质。说明性剂量单位是口服剂量单位,诸如片剂、丸剂、胶囊剂等。类似地,本申请所述的通过施用本发明的药物组合物治疗患者的方法也意在涵盖施用散装组合物和单个剂量单位。
药物组合物也包括同位素标记的本发明化合物,其与本申请所述的那些化合物相同,只是一个或多个原子被原子质量或质量数不同于通常在自然中发现的原子质量或质量数的原子替换。所指定的任何特定原子或元素的所有同位素均涵盖在本发明化合物及其用途的范围内。可掺入本发明化合物的示例性同位素包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,诸如2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I和125I。某些同位素标记的本发明化合物(例如用3H和14C标记的那些)可用于化合物和/或底物组织分布测定。氚化(3H)和碳-14(14C)同位素因其易于制备和可检测而是有用的。此外,用更重的同位素诸如氘(2H)取代可提供由更高代谢稳定性(例如增加的体内半衰期或降低的剂量需求)导致的某些治疗优势,并且因此在某些情况下可能是优选的。正电子发射同位素诸如15O、13N、11C和18F可用于正电子发射断层摄影术(PET)研究以检查底物受体占有率。同位素标记的本发明化合物通常可通过按照与在下文的方案和/或实施例中公开的操作类似的操作,通过用同位素标记的试剂取代非同位素标记的试剂来制备。
曲妥珠单抗-MCC-DM1和选择性Bcl-2抑制剂可根据标准药物实践配制,用于治疗性治疗(包括预防性治疗)哺乳动物(包括人)的过度增殖性病症的治疗组合。本发明提供了包含曲妥珠单抗-MCC-DM1与一种或多种药学上可接受的载体、助流剂、稀释剂或赋形剂的药物组合物。
合适的载体、稀释剂和赋形剂是本领域技术人员公知的,并且包括诸如碳水化合物、蜡、水溶性和/或水可溶胀性聚合物、亲水或疏水材料、明胶、油、溶剂、水等材料。所用的具体载体、稀释剂或赋形剂将取决于本发明化合物应用的手段和目的。溶剂通常基于本领域技术人员公认对哺乳动物施用是安全的(GRAS)溶剂选择。通常,安全溶剂是无毒的含水溶剂,诸如水和其它可溶于水或可混溶于水的无毒溶剂。合适的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG 400、PEG 300)等及其混合物。制剂还可包含一种或多种缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂和提供药物(即本发明的化合物或其药物组合物)的优雅呈现或有助于制造药品(即药物)的其他已知添加剂。
该制剂可使用常规的溶解和混合操作来制备。例如,在一种或多种上述赋形剂存在下,将散装药物物质(即本发明化合物或化合物的稳定化形式(例如与环糊精衍生物或其它已知络合剂的络合物))溶于合适的溶剂。通常将本发明化合物配制成药物剂型以提供易于控制剂量的药物并使患者能够顺应所开具的治疗方案。
取决于用于施用药物的方法,用于施用的药物组合物(或制剂)可以多种方式包装。通常,用于分配的物品包括其中已经以适当形式沉积药物制剂的容器。合适的容器是本领域技术人员公知的,并且包括诸如瓶(塑料瓶和玻璃瓶)、小袋、安瓿、塑料袋、金属圆筒等材料。该容器还可包括防干扰装置以防止对包装内容物的不谨慎存取。此外,容器上已经存放了描述容器内容物的标签。标签还可包含适当的警告。
本发明化合物的药物制剂可与药学上可接受的稀释剂、载体、赋形剂或稳定剂制备用于各种途径和类型的施用(Remington's Pharmaceutical Sciences(1995)18thedition,Mack Publ.Co.,Easton,PA),呈冻干制剂、研磨粉末或水溶液的形式。制剂可通过在环境温度在合适的pH并以所需的纯度,与生理上可接受的载体(即在所用剂量和浓度对接受者无毒的载体)混合来进行。制剂的pH主要取决于具体的用途和化合物的浓度,但可在约3至约8的范围内。
药物制剂优选是无菌的。具体地,用于体内施用的制剂必须是无菌的。通过无菌滤膜过滤可容易地完成这种灭菌。
药物制剂通常可作为固体组合物、冻干制剂或作为水溶液储存。
本发明的药物制剂将以一定的方式(即量、浓度、时间表、疗程、媒介物和施用途径)给药和施用,与良好的医疗实践一致。在这种情况下考虑的因素包括被治疗的具体病症、被治疗的具体哺乳动物、个体患者的临床状况、病症的原因、药剂的递送部位、施用方法、施用时间表和医师已知的其他因素。待施用的化合物的“治疗有效量”将受这些考虑因素支配,并且是预防、改善或治疗凝血因子介导的病症所需的最小量。该量优选低于对宿主有毒或使宿主显著更易于出血的量。
可接受的稀释剂、载体、赋形剂和稳定剂在所用剂量和浓度对接受者是无毒的,并且包括缓冲剂,诸如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(诸如十八烷基二甲基苄基氯化铵;六甲氯铵;苯扎氯铵、苄索氯铵;苯酚、丁醇、乙醇或苯甲醇;对羟基苯甲酸烷基酯诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(少于约10个残基)多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水聚合物诸如聚乙烯吡咯烷酮;氨基酸诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂诸如EDTA;糖诸如蔗糖、甘露糖醇、海藻糖或山梨糖醇;成盐抗衡离子诸如钠;金属络合物(例如Zn-蛋白质络合物);和/或非离子表面活性剂,诸如TWEENTM,包括吐温80、PLURONICSTM或聚乙二醇(PEG),包括PEG400。活性药物成分也可包封在例如通过凝聚技术或通过界面聚合制备的微胶囊中,例如,羟甲基纤维素或明胶微胶囊和聚-(甲基丙烯酸甲酯)微胶囊,分别在胶体药物递送***(例如,脂质体、白蛋白微球、微乳剂、纳米颗粒和纳米胶囊)中或在粗乳剂中。这些技术公开于Remington's Pharmaceutical Sciences 18thedition,(1995)Mack Publ.Co.,Easton,PA。
药物制剂包括适用于本文详述的施用途径的那些。制剂可方便地以单位剂量形式存在并且可通过药学领域中公知的任何方法制备。技术和制剂通常见于Remington'sPharmaceutical Sciences 18th Ed.(1995)Mack Publishing Co.,Easton,PA。这些方法包括使活性成分与构成一种或多种辅助成分的载体结合的步骤。通常,制剂通过如下制备:将活性成分与液体载体或细碎的固体载体或两者均匀且紧密地结合,然后如果需要,使产物成形。
作为一般建议,每剂量施用的曲妥珠单抗-MCC-DM1的初始药学有效量将在约0.01-100mg/kg,即约0.1-20mg/kg患者体重/天的范围内,所用化合物的典型起始范围是0.3-15mg/kg/天。
在一个优选的实施方案中,将曲妥珠单抗-MCC-DM1在含有100mg/小瓶或160mg/小瓶的一次性小瓶中配制成冻干粉剂,并以3.6mg/kg的剂量作为静脉内每3周输注一次。
单独使用抗Bcl-2活性剂(例如Bcl-2抑制剂)的药物组合物,取决于其药物性质;例如对于小化合物诸如ABT-737、ABT-199或ABT-263,一种制剂可以是例如以下:
a)片剂制剂(湿法制粒):
制备操作:
1.将项1、2、3和4混合并用纯水制粒。
2.在50℃干燥颗粒。
3.使颗粒通过合适的研磨设备。
4.添加项5并混合三分钟;在合适的压片机上压缩。
b)胶囊制剂:
制备操作:
1.项1、2和3在合适的混合器中混合30分钟。
2.添加项4和5并混合3分钟。
3.填充至合适的胶囊中。
活性成分还可包埋在例如通过凝聚技术或通过界面聚合制备的微胶囊中,例如,羟甲基纤维素或明胶微胶囊和聚-(甲基丙烯酸甲酯)微胶囊,分别在胶体药物递送***(例如,脂质体、白蛋白微球、微乳剂、纳米颗粒和纳米胶囊)中或在粗乳剂中。这些技术公开于Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980)。
可制备持续释放制剂。持续释放制剂的合适实例包括含有抗体的固体疏水性聚合物的半透性基质,所述基质呈成型制品的形式,例如,薄膜或微胶囊。缓释基质的实例包括聚酯、水凝胶(例如聚(2-羟基乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚交酯(US 3,773,919)、L-谷氨酸和γ-乙基-L-谷氨酸的共聚物、不可降解的乙烯-乙酸乙烯酯、可降解的乳酸-乙醇酸共聚物诸如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和乙酸亮丙瑞林组成的可注射微球)和聚-D-(-)-3-羟基丁酸。
要用于体内施用的制剂必须是无菌的。这很容易通过无菌滤膜过滤完成。
提供以下实施例、序列表和附图以帮助理解本发明,本发明的真实范围在所附权利要求书中阐述。应当理解的是,在不背离本发明的精神的情况下,可对所述操作进行修改。
实施例
实施例1
在T-DM1抗性乳腺癌细胞中Bcl-2家族促活分子的表达
制备T-DM1抗性细胞系
最初,通过在T-DM1存在下连续培养使KPL-4和BT-474M1细胞对T-DM1具有抗性,从10ng/mL的极低浓度开始,逐渐增加至2μg/mL。衍生的细胞是在2μg/mL T-DM1中保持在培养物的“抗性库”。为了得到稳定的抗性克隆,将每个库(KPL-4和BT-474M1)进行单细胞分选和克隆。保持克隆不含T-DM1,从而可鉴定在不存在T-DM1的情况下具有稳定抗性的克隆。
TaqMan分析
使用Qiagen RNeasy Mini试剂盒制备总RNA。基因组DNA通过DNA酶I去除。使用实时定量PCR(qPCR or TaqMan)定量基因表达。TaqMan One-Step Universal Master Mix(Applied Biosystems)用于所有反应。在标准96孔板格式中以ABI 7500实时定量PCR***进行反应。在每个反应中使用100ng总RNA作为模板。对于数据分析,将原始Ct归一化为管家基因HP1BP3。
TaqMan分析结果示于图1A。该图显示,相对于亲代、非抗性KPL-4和BT-474M1细胞,T-DM1抗性KPL-4和T-DM1抗性BT-474M1细胞系(归一化至管家基因HP1BP3)中Bcl-2mRNA表达增加。
如下进行Western印迹分析(blot analysis):将细胞在校正的FLAG洗脱缓冲液(CFEB)(19.17mM Tris(pH 7.5)、916.7μM MgCl2、92.5mM NaCl和0.1%Triton X-100)中用蛋白酶和磷酸酶抑制剂(Roche)裂解;在一些情况下添加6M尿素。定量清除的裂解物并按照标准操作将等量的蛋白质还原、烷基化、通过SDS-PAGE分离并转移到PVDF膜(Invitrogen)上。按照各抗体制造商的推荐进行Western印迹分析。图1B所示的Western印迹分析证实Bcl-2在T-DM1抗性KPL-4和BT-474细胞系中过度表达。
实施例2
细胞增殖测定-亲代和T-DM1抗性KPL-4乳腺癌细胞系
细胞增殖测定使用Cell-Titer Glo试剂进行3天。用T-DM1、GDC-0199或T-DM1和GDC-0199的组合在固定比率处理如实施例1中所述制备的KPL-4亲代乳腺癌细胞和KPL-4T-DM1抗性乳腺癌细胞。为了获得组合指数"CI"(Chou and Talalay(1984)Adv.EnzymeRegul.22:27-55),使用Chou和Talalay药物组合剂量效应分析以CalcuSyn软件分析协同作用。小于1的CI值表示协同作用,而CI=1表示加和性。
测定条件:将细胞维持在补充有10%热灭活的胎牛血清和2mM L-谷氨酰胺的Ham's F-12:高葡萄糖DMEM(1:1)中。将细胞铺板于96孔板(对于KPL-4亲代细胞为每孔4000个细胞;对于KPL-4T-DM1抗性细胞为每孔8000个细胞)并使其在37℃于5%CO2的潮湿气氛贴壁过夜。然后去除培养基,用含有T-DM1、GDC-0199或两者组合的新鲜培养基代替。在药物施用后3天将Cell Titer-Glo(Promega Corp.)添加至孔中,使用EnVision多标签酶标仪(PerkinElmer)测量发光信号。组合指数(C.I.)值使用CalcuSyn软件(Biosoft,Inc)产生。
如图2所示,T-DM1和GDC-0199的组合在KPL-4T-DM1抗性乳腺癌细胞中具有协同抗增殖作用。
实施例3
半胱天冬酶3/7活化发光测定-亲代和T-DM1抗性KPL-4乳腺癌细胞系
如前所述,Bcl-2家族蛋白调节由发育线索触发的程序性细胞死亡并响应于多重应激信号。当被活化时,它们可透化线粒体的外膜并释放活化拆散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 and Development 15(2001)2922-2933;(Adams,2003supra);Green,D.R.,and Kroemer,G.,Science 305(2004)626-629)。因此,半胱天冬酶诸如半胱天冬酶3和7的活化表明诱导细胞凋亡。
在本实验中,基本上按照制造商的说明使用Caspase-试剂(Promega)进行半胱天冬酶3/7活化发光测定。除药物温育时间是24小时且Caspase-Glo3/7(Promega)用于测量凋亡之外,以与活力测定相同的方式进行测定。
如图3右图所示,当用T-DM1+GDC-0199组合处理24小时,T-DM1抗性KPL-4(HER2+)乳腺癌细胞再次对T-DM1敏感,如凋亡增加(半胱天冬酶3/7活化增加)所示。相同的组合对亲代细胞没有影响。值得注意的是,处理后24小时评估结果,这对于亲代细胞系中单独的T-DM1诱导的凋亡而言过早(左图)。
图4A和4B示出半胱天冬酶3/7活化发光体外凋亡测定的结果,其在分别使用不同浓度的T-DM1和GDC-0199的KPL-4T-DM1抗性人乳腺癌细胞中测量相对于亲代细胞的半胱天冬酶3和7的活化。在添加渐增浓度的GDC-0199(1、2.5或5μM)至0.1或1μg/mL T-DM1后,在KPL-4T-DM1抗性细胞中观察到增加的凋亡。相比之下,T-DM1在KPL-4亲代细胞中诱导强烈的细胞凋亡,通过添加GDC-0199其未进一步增强。
图5A示出半胱天冬酶3/7活化发光体外凋亡测定的结果,其在用T-DM1、GDC-0199或T-DM1+GDC-0199处理的克隆#17T-DM1抗性KPL-4人乳腺癌细胞系中测量半胱天冬酶3和7的活化。与用KPL-4T-DM1抗性细胞库观察结果相似,在添加渐增浓度的GDC-0199后,克隆#17中凋亡的诱导增加。
图6A和6B示出半胱天冬酶3/7活化发光体外凋亡测定的结果,其在分别用0.1μg/mL和1μg/mL T-DM1浓度单独或与指定浓度的GDC-0199组合处理的克隆#8T-DM1抗性KPL-4人乳腺细胞系中测量半胱天冬酶3和7的活化。
如图4A、4B、5A、6A和6B所示,用T-DM1抗性KPL-4乳腺癌细胞系的不同克隆获得的结果证实各种浓度T-DM-1+GDC-0199组合增强促凋亡活性。
实施例4
异种移植物研究-KPL-4T-DM1抗乳腺癌细胞系
对于所有异种移植物研究,将300万T-DM1抗性KPL-4乳腺癌细胞植入雌性SCID-米色小鼠的#2/3***脂肪垫中。当肿瘤达到约200mm3的体积时,将小鼠随机分为治疗组(n=10只小鼠/组):5mg/kg T-DM1q3w、100mg/kg GDC-0199qd、两者的组合或媒介物。这些异种移植物研究用于T-DM1抗性KPL-4乳腺癌细胞的各种克隆的异种移植物的结果示于图5B和6C。结果表明,当组合使用T-DM1和GDC-0199时,相对于单一药剂活性,增强抗肿瘤作用。
实施例5
IHC研究-T-DM1抗性KPL-4异种移植物肿瘤
将FFPE(***固定的石蜡包埋的)异种移植物肿瘤切片,以供通过免疫组织化学(IHC)使用DAB检测方法分析Bcl-2和HER2(ErbB2)表达。Bcl-2抗体SP66获自Ventana。人扁桃体切片作为Bcl-2阳性对照。抗HER2抗体4D5获自Ventana。人乳腺癌细胞系作为阳性对照(作为3+的SK-BR-3;作为2+的MDA-MB-361;作为阴性对照的MBA-MB-231)。
图7A示出如上所述通过免疫组织化学(IHC)使用DAB检测方法确定的***固定的石蜡包埋的T-DM1抗性KPL-4异种移植物肿瘤样品(克隆#8和#17)中Bcl-2的表达。
图7B示出如上所述通过免疫组织化学(IHC)使用DAB检测方法确定的***固定的石蜡包埋的T-DM1抗性KPL-4异种移植物肿瘤样品(克隆#8和#17)中HER2(ErbB2)的表达。
抗Bcl-2抗体结果:每个克隆的媒介物组显示相似低频率的Bcl-2反应性细胞,最经常位于肿瘤小叶的周边(未显示)。T-DM1处理组中肿瘤小叶边缘Bcl-2信号的频率和强度增加或没有变化。
抗HER2抗体结果:在所有克隆中,媒介物和经T-DM1处理的肿瘤显示非常高频率的HER2 3+IHC。在一些经T-DM1处理的肿瘤中,存在较弱HER2染色的区域(克隆#17),最经常邻近肿瘤小叶周围的基质带(未显示)。
Bcl-2IHC结果表明,当作为异种移植物肿瘤生长时,Bcl-2表达在T-DM1抗性克隆#8和#17中保持(图7A;也参见实施例6,其在KPL-4亲代细胞通过Western印迹显示极少的Bcl-2表达)。经T-DM1处理的克隆#17中的Bcl-2表达高于相应的媒介物对照。图7B描绘了通过IHC评估的HER2表达。与在体外生长的细胞中观察到的相对较低的HER2表达相反,在媒介物和经T-DM1处理的肿瘤中,克隆#8和#17在2+和3+水平显示高HER2表达。所有克隆#8肿瘤被确定为85-95%HER2+或3+,具有非常低频率的2+或1+肿瘤细胞。克隆#17肿瘤更易变,媒介物组中有35-75%HER2 3+细胞和20-65%HER2 2+细胞。
实施例6
异种移植物研究-KPL-4T-DM1抗性乳腺肿瘤
图8示出用GDC-0199、T-DM1或T-DM-1+GDC-0199处理的KPL-4T-DM1抗性克隆#17异种移植物肿瘤中Bcl-2、HER2、Bcl-xL和Pgp的Western印迹表达数据。(泳道4-19上方的三位数字表示单个异种移植物肿瘤)。表达数据显示与在细胞培养物中体外生长的相应细胞相比,所有组都保持HER2和Bcl-2表达。
实施例7
半胱天冬酶3/7发光和荧光活化测定-T-DM1敏感性乳腺癌细胞系
如实施例3所述进行半胱天冬酶3/7活化发光测定。
使用IncuCyteTM试剂和设备进行半胱天冬酶3活化荧光体外凋亡测定,以基本上按照生产说明书测量随时间推移的半胱天冬酶活化(动力学分析)。
图9A示出半胱天冬酶3/7发光体外凋亡测定的结果,测试了5种不同浓度的GDC-0199(μM)与9种不同浓度的T-DM1的组合对HER2+MDA-MB-361乳腺癌细胞(对T-DM1敏感(未耐受))中半胱天冬酶活性的影响。结果表明,用T-DM1活化半胱天冬酶3和7,随着GDC-0199浓度的增加,其以剂量依赖性方式增强。
图9B示出半胱天冬酶3荧光体外凋亡测定的结果,单独或与T-DM1(0.1μg/mL)组合测试3种不同浓度的GDC-0199(0.63μM、1.25μM、2.5μM)对T-DM1敏感性(未耐受的)MDA-MB-361乳腺癌细胞中半胱天冬酶活性的影响。结果表明,GDC-0199以剂量和时间依赖性方式增强单独由T-DM1诱导的上述半胱天冬酶活化,并且因此导致使用所有组合均增强凋亡。
图10A示出半胱天冬酶3/7发光体外凋亡测定的结果,测试了5种不同浓度的GDC-0199(μM)与9种不同浓度的T-DM1对T-DM1未耐受HER2+HCC1569乳腺癌细胞中半胱天冬酶活性的影响。结果表明,单独的T-DM1不诱导细胞凋亡,但是添加GDC-0199导致半胱天冬酶活性增强,并且因此在所有组合中均增强凋亡。
图10B示出半胱天冬酶3荧光体外凋亡测定的结果,单独或与T-DM1(0.1μg/mL)组合测试3种不同浓度的GDC-0199(0.63μM、1.25μM、2.5μM)对HER2+HCC1569乳腺癌细胞中半胱天冬酶活性的影响。结果表明,GDC-0199以剂量和时间依赖性方式增强单独由T-DM1诱导的上述半胱天冬酶活化,并且因此导致使用所有组合均增强凋亡。
这些结果显示,T-DM1/GDC-0199组合在T-DM1未耐受(即非T-DM1抗性)细胞系中也是有效的。
实施例8
异种移植物研究-TDM-1敏感性(未耐受的)MDA-MB-361乳腺肿瘤
植入60天释放17β-***丸剂后一天,将1000万个MDA-MB-361乳腺癌细胞植入雌性NOD/SCID小鼠的右侧***脂肪垫中。当肿瘤达到大约200-300mm3的体积时,将小鼠随机分为治疗组(n=10只小鼠/组)和施用T-DM1(1、3或7mg/kg静脉内每天一次(i.v.once))、GDC-0199(100mg/kg qd x 21)或T-DM1与GDC-0199的组合,如图11所示。结果表明,与单一药剂活性相比,GDC-0199与7mg/kg T-DM1具有增强的抗肿瘤活性。
实施例9
Western分析:T-DM1+/-GDC-0199对HER2+乳腺癌细胞系中Bcl-2家族成员蛋白的影响
研究了单独或与GDC-0199(1.25μM)组合的T-DM1(1.25μg/mL)处理对各种T-DM1未耐受HER2+乳腺癌细胞系的影响。结果如图12所示。测试的8种HER2+乳腺癌细胞系中的4种(BT-474、HCC1569、MDA-361和ZR-75-30)表达Bcl-2;所有8种乳腺癌细胞系均表达所评估的其他Bcl-2家族成员Bcl-xL和Mcl-1。3种细胞系(BT-474、MDA_361和ZR-75-30)在T-DM1处理后显示Bcl-2的磷酸化,这是暴露于抗有丝***剂诸如T-DM1的已知作用。如图9A、9B、10A和10B所示,当用T-DM1和GDC-0199的组合处理时,MDA-MB-361和HCC1569显示增强的凋亡。
T-DM1在治疗患者的癌症方面展现出明显的临床益处,诸如在HER2靶向治疗(诸如用曲妥珠单抗治疗)之前已经进展的乳腺癌患者。美国食品和药物管理局批准(ado-曲妥珠单抗美坦新偶联物)治疗先前接受使用曲妥珠单抗和紫杉醇的治疗的HER2阳性转移性乳腺癌患者。本申请示出的数据表明用Bcl(例如Bcl-2)抑制剂和T-DM1的组合治疗显著改善作为单一药剂施用的T-DM1的功效。结果还表明,用T-DM1和Bcl-2抑制剂的这种组合治疗在治疗T-DM1敏感性(未耐受的)HER2阳性癌症(例如乳腺癌)和对使用T-DM1的治疗具有抗性的HER2阳性癌症(例如乳腺癌)两者中均是有效的。
本说明书中引用的所有出版物和专利申请通过引用并入本申请,如同每个单独的出版物或专利申请被具体地和单独地指出通过引用并入。尽管为了清楚理解的目的,已经通过举例说明和实施例的方式详细描述了上述发明,但是根据本发明的教导,对于本领域普通技术人员来说显而易见的是,可在不脱离所附权利要求的精神或范围的情况下进行某些改变和修改。
序列表
<110> 基因泰克公司(GENENTECH, INC.)
豪夫迈·罗氏有限公司(F. HOFFMANN-LA ROCHE AG)
<120> 抗HER2抗体-药物缀合物和Bcl-2抑制剂的组合疗法
<130> GNE-0416-WO
<140>
<141>
<150> 62/189,610
<151> 2015-07-07
<160> 2
<170> PatentIn version 3.5
<210> 1
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<212> PRT
<213> 人工序列
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<223> 人工序列的描述:合成的多肽
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Claims (22)
1.曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐在制备用于治疗HER2阳性癌症的药物中的用途。
2.权利要求1的用途,其中所述癌症为HER2阳性乳腺癌或胃癌。
3.权利要求2的用途,其中所述HER2阳性乳腺癌或胃癌具有2+或3+的免疫组织化学(IHC)评分和/或≥2.0的原位杂交(ISH)扩增率。
4.权利要求1至3中任一项的用途,其中所述HER2阳性癌症对使用作为单一药剂施用的所述曲妥珠单抗-MCC-DM1的治疗具有抗性。
5.权利要求1至3中任一项的用途,其中所述HER2阳性癌症对使用作为单一药剂施用的所述曲妥珠单抗-MCC-DM1的治疗具有敏感性。
6.权利要求1至3中任一项的用途,其中所述曲妥珠单抗-MCC-DM1和所述2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐显示协同活性。
7.权利要求1至3中任一项的用途,其中所述曲妥珠单抗-MCC-DM1和所述2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐共同施用。
8.权利要求7的用途,其中所述曲妥珠单抗-MCC-DM1和所述2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐在一个制剂中或交替施用。
9.权利要求8的用途,其中所述曲妥珠单抗-MCC-DM1和所述2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐同时施用。
10.权利要求8的用途,其中所述曲妥珠单抗-MCC-DM1和所述2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐连续施用。
11.曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺或其药学上可接受的盐的组合,其用于治疗癌症。
12.权利要求11的组合,其为药物组合物。
13.权利要求11或12的组合,其中所述癌症为HER2阳性癌症。
14.权利要求13的组合,其中所述癌症为HER2阳性乳腺癌或胃癌。
15.权利要求13的组合,其中当作为单一药剂施用时,所述癌症对使用所述曲妥珠单抗-MCC-DM1的治疗具有抗性。
16.权利要求13的组合,其中当作为单一药剂施用时,所述癌症对使用所述曲妥珠单抗-MCC-DM1的治疗具有敏感性。
17.一种试剂盒,其包含用于治疗具有表达HER2的癌症的人的曲妥珠单抗-MCC-DM1和2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺的组合。
18.权利要求17的试剂盒,其中所述曲妥珠单抗-MCC-DM1和所述2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺为单独制剂的形式。
19.权利要求17的试剂盒,其中所述曲妥珠单抗-MCC-DM1和所述2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺为同一制剂的形式。
20.权利要求17至19中任一项的试剂盒,其还包括包装说明书,所述说明书指导向具有表达HER2的癌症的人施用所述曲妥珠单抗-MCC-DM1和所述2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基环己-1-烯基)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)苯甲酰胺。
21.权利要求20的试剂盒,其中当作为单一药剂施用时,所述癌症对使用所述曲妥珠单抗-MCC-DM1的治疗具有抗性。
22.权利要求20的试剂盒,其中当作为单一药剂施用时,所述癌症对使用所述曲妥珠单抗-MCC-DM1的治疗具有敏感性。
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