CN104066445A - 用mage-a3免疫治疗剂与braf抑制剂和/或mek抑制剂治疗癌症的方法 - Google Patents
用mage-a3免疫治疗剂与braf抑制剂和/或mek抑制剂治疗癌症的方法 Download PDFInfo
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Abstract
抗肿瘤剂的组合,所述组合相对单一疗法提供增加的活性,或者在一些情况下至少提供不利相互作用的预料不到的缺少。具体是,描述了包括MAGE-A3免疫治疗剂的药物组合,所述MAGE-A3免疫治疗剂组合B-Raf抑制剂,具体是N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺,或其药学可接受的盐,和/或MEK抑制剂,具体是N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺,或其药学可接受的盐或溶剂化物。
Description
技术领域
本发明涉及在哺乳动物中治疗癌症的方法,和涉及在这种治疗中有用的组合。具体是,该方法涉及包含MAGE-A3免疫治疗剂与B-Raf抑制剂,具体是N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺,或其药学可接受的盐,和/或MEK抑制剂,具体是N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺,或其药学可接受的盐或溶剂化物的新组合,包含该组合的药物组合物,和在其中B-Raf的抑制和MAGEA3特异性免疫应答的引起是有益的状况(例如癌症)的治疗中使用该组合和组合物的方法。
技术背景
过度增殖性疾病(包括癌症)的有效治疗在肿瘤学领域是持续的目标。一般地,癌症由控制细胞分裂、分化和凋亡性细胞死亡的正常过程的失调导致,并且其特征在于具有无限生长、局部扩张和全身转移的潜力的恶性细胞的增殖。正常过程的失调包括在信号转导途径和对与正常细胞中发现的因子不同的因子的应答中的异常。
最近,由于对Ras-Raf-MEK-ERK激酶途径(被称为MAPK途径)的了解增加,B-Raf抑制剂已被研究用于治疗癌症。具体是如下了解:响应于生长因子、激素、细胞因子等的Ras蛋白的激活刺激Raf激酶的磷酸化和激活,这进而磷酸化和激活MEK1和MEK2激酶,其然后磷酸化和激活ERK1和2激酶。
在MAPK替代激酶的突变被认为对该途径的生长信号的功能产生不利影响,从而导致各种人类癌症的建立、发展和进展。在显著百分比的人类黑色素瘤(Davies, H.,等, Nature (2002) 9:1-6;Garnett, M.J. & Marais, R., Cancer Cell (2004) 6:313-319)和甲状腺癌(Cohen 等 J. Nat. Cancer Inst. (2003) 95(8) 625-627 和Kimura 等 Cancer Res. (2003) 63(7) 1454-1457)中,以及在较低但仍然显著频率的一些其它癌症中,已观察到在B-Raf激酶中自然发生的突变。
最近还已研究了MEK抑制剂在癌症治疗中的使用。已知促分裂原活化蛋白(MAP)激酶/细胞外信号调节激酶(ERK)激酶(以下简称为MEK)作为介导Raf-MEK-ERK信号转导途径的激酶参与细胞增殖的调节,而Raf家族(B-Raf,C-Raf等)激活MEK家族(MEK-1,MEK-2等),且MEK家族激活ERK家族(ERK-1和ERK-2)。已经经常观察到Raf-MEK-ERK信号转导途径在癌症,特别是结肠直肠癌、胰腺癌、肺癌、乳腺癌等中的活化。
此外,由于通过信号分子如生长因子、细胞因子等的产生的信号汇集于MEK-ERK的激活,所以认为这些功能的抑制剂相比上游激酶如RTK、Ras和Raf的功能抑制,更有效地抑制Raf-MEK-ERK信号转导。
此外,也已知具有MEK抑制活性的化合物有效地诱导ERK1/2活性的抑制和细胞增殖的抑制(The Journal of Biological Chemistry, vol. 276, No. 4, pp. 2686-2692, 2001),并且预期该化合物对由不期望的细胞增殖导致的疾病,如肿瘤发生和/或癌症显示效果。
在激酶抑制剂之外的可能的癌症治疗中,针对肿瘤抗原的免疫疗法已经显示出希望。在肿瘤抗原的不同家族中,肿瘤/睾丸抗原(CT抗原)家族具有特别有意思的表达模式。该MAGE-A3基因属于这种癌症/睾丸抗原,并属于密切相关的MAGE基因家族,其位于染色体X并共享其编码序列的64-85%的同一性。
相应的MAGE-A3蛋白是最初通过其自身性黑素瘤细胞上被特异性细胞毒性T淋巴细胞(CTL)识别所定义的抗原(因此是术语MAGE,用于黑色素瘤抗原)。MAGE-A3在人体中是免疫原性的,并且已鉴定了几个MAGE-A3-衍生的表位[Cancer Immunome Database 2010]。该MAGE-A3基因是严格肿瘤特异性的。它不表达在正常成人体组织中,除了在睾丸中,并且其在胎儿发育中的一些点表达于胚胎组织或由胎盘滋养层细胞表达[DePlaen, 1994, De Smet, 1994, Takahashi, 1995, Chomez, 1996, De Smet, 1996]。该基因表达在在其表面不负载HLA分子的细胞(即睾丸中的精原细胞和胎盘中的滋养层细胞)的细胞质中[Haas, 1988, Bo?l, 1995, Chomez, 2001, Jungbluth, 2007];因此,MAGE-A3衍生的表位不能递呈给CD8+或CD4+ T细胞并由CD8+或CD4+ T细胞识别。因此,针对抗原MAGE-A3的免疫接种预期不会在人中诱导免疫相关的毒性,并将仅导致针对表达MAGE-A3的癌症细胞的免疫应答。MAGE-A3表达在某些百分比的不同组织学类型的许多不同的肿瘤中,包括65%;头颈癌,65%;膀胱癌,62%;肝癌,48%;食道癌,47%;非小细胞肺癌,35%;卵巢癌,30%;白血病,29%;和前列腺癌,18%[数据来自Van den Eynde, 1997]。
因此CT抗原,如MAGE-A3,是特定癌症免疫治疗的潜在目标,针对该抗原的引发免疫应答不应该影响正常组织,而只影响表达该抗原的癌细胞。在具有黑色素瘤和膀胱癌的对象中已通过这种基于CT抗原的免疫疗法展示了肿瘤消退(参见例如Nishiyama 等, Immunotherapy of Bladder Cancer Using Autologous Dendritic Cells Pulsed with Human Lymphocyte Antigen-A24-specific MAGE-3 Peptide 2001, Clin. Cancer Res., 7:23-31;Thurner 等, Vaccination with Mage-3A1 Peptide–Pulsed Mature, Monocyte-Derived Dendritic Cells Expands Specific Cytotoxic T Cells and Induces Regression of Some Metastases in Advanced Stage IV Melanoma 1999, J. Exp. Med., 190:1669-1678;Coulie 等, A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3, Proc Natl Acad Sci USA 98(18): 10290–10295 (2001))。已描述了超过50种癌/睾丸抗原,并且对于它们中的很多来说,已鉴定了被T淋巴细胞识别的特异性表位。
虽然在用化合物例如B-Raf的抑制剂、MEK抑制剂,和抗原如癌/睾丸抗原的癌症治疗中已有许多最近的进展,但对于遭受癌症影响的个体的更有效和/或增强的治疗仍然有需求。
发明概述
本发明人已鉴定了治疗剂的组合,所述组合相对单一疗法提供增加的活性,或者在一些情况下至少提供不利相互作用的预料不到的缺少。具体是,描述了使用MAGE-A3免疫治疗剂的药物组合的治疗方法,所述MAGE-A3免疫治疗剂组合B-Raf抑制剂 N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺, 或其药学可接受的盐,和/或组合MEK抑制剂:N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺,或其药学可接受的盐或溶剂化物。
根据本发明的一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,和
(ii)由式(I)的结构表示的B-Raf抑制剂:
或其药学可接受的盐(本文统称为“化合物A”)。
根据本发明的一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,和
(ii)由结构(II)表示的MEK抑制剂:
或其药学可接受的盐或溶剂化物(本文统称为“化合物B”)。
根据本发明的一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,
(ii)化合物A,和
(iii)化合物B。
根据本发明的另一个方面,提供了在有需要的人中治疗易患黑色素瘤的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,和
(ii)化合物A。
根据本发明的另一个方面,提供了在有需要的人中治疗易患黑色素瘤的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,和
(ii)化合物B。
根据本发明的另一个方面,提供了在有需要的人中治疗易患黑色素瘤的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,
(ii)化合物A,和
(iii)化合物B。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,和
N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸酯。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,和
(ii)N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基;-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺二甲亚砜。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,和
N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸酯,和
(iii)N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基;-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺二甲亚砜。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,和
(ii)化合物A,连同药学可接受的稀释剂和/或载体。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,和
(ii)化合物B,连同药学可接受的稀释剂和/或载体。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)MAGE-A3免疫治疗剂,
(ii)化合物A,连同药学可接受的稀释剂和/或载体,
(iii)化合物B,连同药学可接受的稀释剂和/或载体。
根据本发明的另一个方面,提供了包含下列的组合用于在人中治疗易患癌症的用途:
(i)MAGE-A3免疫治疗剂,和
(ii)化合物A。
根据本发明的另一个方面,提供了包含下列的组合用于在人中治疗易患癌症的用途:
(i)MAGE-A3免疫治疗剂,和
(ii)化合物B。
根据本发明的另一个方面,提供了包含下列的组合用于在人中治疗易患癌症的用途:
(i)MAGE-A3免疫治疗剂,
(ii)化合物A,和
(iii)化合物B。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
(ii)化合物A。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
(ii)化合物B。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,
(ii)化合物A,和
(iii)化合物B。
根据本发明的另一个方面,提供了在有需要的人中治疗易患黑色素瘤的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
(ii)化合物A。
根据本发明的另一个方面,提供了在有需要的人中治疗易患黑色素瘤的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
(ii)化合物B。
根据本发明的另一个方面,提供了在有需要的人中治疗易患黑色素瘤的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,
(ii)化合物A,和
(iii)化合物B。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸酯。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
(ii)N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基;-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺二甲亚砜。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,
(ii)N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸酯,和
(iii)N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基;-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺二甲亚砜。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
(ii)化合物A,连同药学可接受的稀释剂和/或载体。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
(ii)化合物B,连同药学可接受的稀释剂和/或载体。
根据本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,
(ii)化合物A,连同药学可接受的稀释剂和/或载体,和
(iii)化合物B,连同药学可接受的稀释剂和/或载体。
根据本发明的另一个方面,提供了包含下列的组合用于在人中治疗易患癌症的用途:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
(ii)化合物A。
根据本发明的另一个方面,提供了包含下列的组合用于在人中治疗易患癌症的用途:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,和
(ii)化合物B。
根据本发明的另一个方面,提供了包含下列的组合用于在人中治疗易患癌症的用途:
(i)包含蛋白D-MAGE-A3融合蛋白的MAGEA3免疫治疗剂,
(ii)化合物A,和
(iii)化合物B。
在本发明的进一步的方面提供了在有需要的哺乳动物中治疗癌症的方法,其包括施用治疗有效量的本发明的组合,其中所述组合在特定期限内施用并施用一段时间。
附图说明
图1显示在用MAGE-A3 ASCI +/- BRAF或MEK抑制剂免疫两次的小鼠中产生细胞因子的CD4+ T细胞的百分比。
图2显示在用MAGE-A3 ASCI +/- B-RAF或MEK抑制剂免疫两次的小鼠中产生细胞因子的CD8+ T细胞的百分比。
图3显示在用MAGE-A3 ASCI +/- B-RAF或MEK抑制剂免疫两次的小鼠中抗体应答的平均滴度。
发明详述
MAGE蛋白和recMAGEA3
称为MAGE-A3的癌症-睾丸抗原属于MAGE-A亚家族,其包含11个已知成员(MAGE-A 1-6和8-12)。虽然已报道了其它“MAGE-A”(黑色素瘤抗原家族A)基因(例如MAGE-A7、A13-15),这些基因的表达模式表明它们是假基因(参见例如Chomez 等, Cancer Research, 61:5544 (2001))。WO 94/23031描述了MAGE-A3。已发现人MAGE-A3(也称为MAGE-3、MAGEA3或MAGE A3)在多种不相关的组织来源的人肿瘤类型,包括黑色素瘤、非小细胞肺癌(NSCLC)、膀胱癌、头颈部癌、鳞状食道癌和肝癌中表达。然而,不是所有具有特定肿瘤类型(如黑色素瘤)的个体都会具有表达MAGE-A3的肿瘤。此外,在单一肿瘤内,某些肿瘤细胞可以表达给定的癌症-睾丸抗原,而其它细胞则没有。
在一般术语中,MAGE-A蛋白可以被限定为包含位于朝向该蛋白C-末端的核心序列特征(例如,对于309个氨基酸的MAGE-A1蛋白,核心序列特征对应氨基酸195-279)。核心序列特征的共有模式描述如下(SEQ ID NO:1),其中x代表任何氨基酸,小写残基是保守的(允许的保守变体)并且大写残基是完全保守的。
MAGE-A核心序列特征:
保守取代是熟知的,并且在序列比对计算机程序中通常设置为默认的评分矩阵。这些程序包括PAM250 (Dayhoft M.O.等., (1978), “A model of evolutionary changes in proteins”, In “Atlas of Protein sequence and structure” 5(3) M.O.Dayhoft (ed.), 345-352), National Biomedical Research Foundation, Washington,和Blosum 62 (Steven Henikoft and Jorja G. Henikoft (1992), “Amino acid substitution matrices from protein blocks”), Proc.Natl.Acad.Sci.USA 89 (Biochemistry):10915-10919。
如本文所用,“佐剂”是指以下化合物或物质,其当与疫苗、免疫治疗剂或其它包含抗原或免疫原的组合物一起施用给对象时,增加或提高对象对所施用的抗原或免疫原的免疫应答(如相比在不存在佐剂的情况下获得的免疫应答)。这与“辅助治疗”不同,所述“辅助治疗”由美国国立卫生研究院国家癌症研究所定义为在癌症治疗的背景下在主要治疗后给予以降低癌症复发风险的额外治疗。
如本文所用,“易患癌症”是使用任何合适的方法评估的MAGEA3蛋白的表达阳性的癌症。参见,例如,Trefzer等,Melanoma Research, 20 (eSupplement A):e34-e35 (June 2010)。
适用于本发明的免疫治疗剂是那些能够引起MAGE-A3特异性免疫应答的免疫治疗剂(“MAGEA3免疫治疗剂”)。免疫治疗剂将包含MAGEA3抗原,其包括来自MAGEA3基因产物的至少一个表位。这样的表位可作为肽抗原存在。可选地,可以使用更大的蛋白片段或全长MAGEA3。然而当适当地呈递时该MAGEA3抗原必须能够引起MAGE-A3特异性免疫应答。该MAGEA3蛋白、肽或片段可连接至融合配偶体以提供融合蛋白。
所述MAGE-A3抗原和融合配偶体可以是化学缀合的,或可作为重组融合蛋白表达。在其中抗原和融合配偶体作为重组融合蛋白表达的实施方案中,这可以允许在表达系统中相比于非融合抗原产生水平增加。因此,融合配偶体可以协助提供T辅助表位(免疫融合配偶体),包括被人识别的T辅助表位,和/或协助以比天然重组蛋白更高的产量表达该蛋白(表达增强物)。在一个实施方案中,融合配偶体可以是免疫融合配偶体和表达增强配偶体两者。
在本发明的一个实施方案中,所述免疫融合配偶体衍生自蛋白D或其衍生物,所述蛋白D是革兰氏阴性菌流感嗜血杆菌B( Haemophilus influenza B)(WO91/18926)的表面蛋白。蛋白D被合成为具有18个残基长的信号序列的前体;未加工的蛋白D的19位氨基酸半胱氨酸残基在信号序列切割后变为氨基末端。(Janson等, Infection & Immunology 60(4):1336-42 (1992))。在一个实施方案中,蛋白D或其片段可被脂化。
在一个实施方案中,蛋白D衍生物包含经加工的蛋白的约前1/3,特别约N-末端前100-120个氨基酸,如前109-112个氨基酸,更具体地,前109个氨基酸(或其108个氨基酸)。在一个实施方案中,所述蛋白D衍生物可包括经加工的蛋白D的氨基酸20-127。脂蛋白D融合配偶体的前109个残基可以提供额外的外源T细胞表位,并增加在大肠杆菌中的表达水平(因此充当免疫融合配偶体和表达增强物两者)。在一个实施方案中,上述蛋白D的部分还包括18个氨基酸的信号序列。因此,免疫治疗剂融合蛋白可以包含如本文所述的融合MAGEA3抗原的N-末端或其免疫原性片段的蛋白D的N-末端部分。可能发生蛋白D和MAGEA3抗原的N-末端的融合,使得MAGEA3抗原替代切除的蛋白D的C-末端片段,并且蛋白D的N-末端变成融合蛋白的N-末端。
替代蛋白D或除了蛋白D之外,其它融合配偶体可以在本文所述的治疗性融合蛋白中使用。一种这样的融合配偶体是来自流感病毒的非结构蛋白,NS1(血凝素);典型地利用N末端81个氨基酸,虽然可以使用不同的片段,只要它们包括T辅助表位。
在另一个实施方案中,免疫融合配偶体是称为LytA的蛋白。LytA衍生自肺炎链球菌(Streptococcus pneumoniae),后者合成N-乙酰基-L-丙氨酸酰胺酶,酰胺酶LytA(由LytA基因{Garcia 等, Gene, 43 (1986) page 265-272}编码),其是特异性降解肽聚糖主链中某些键的自溶素。LytA蛋白的C-末端结构域负责对胆碱或一些胆碱类似物如DEAE的亲和力。已利用该属性用于大肠杆菌C-LytA表达质粒的开发,所述质粒可用于融合蛋白的表达。在其氨基末端包含C-LytA片段的杂交蛋白的纯化已有描述(Ortega,等, Biotechnology: 10, (1992) page 795-798)。在一个实施方案中,可以使用所述分子的C端部分。本实施方案可利用在从残基178开始的C末端中发现的LytA分子的重复部分。在一个实施方案中,所述LytA部分可以包含残基188-305。
用于本发明中使用的免疫治疗融合蛋白可包括亲和标签,例如,如包含5-9,例如6-7个组氨酸残基的组氨酸尾巴。这些残基可以,例如,在蛋白D的末端部分(如蛋白D的N-末端)和/或可被融合到MAGEA3抗原的末端部分。然而通常组氨酸尾巴将位于抗原的末端部分,如抗原的C-末端。组氨酸尾巴有利于帮助纯化。
在本发明中有用的MAGE-A3和其融合蛋白描述于WO99/40188、EP1053325、EP1659178。MAGE-A3免疫治疗剂与其它抗癌治疗,如手术、化疗和/或放疗组合的用途在WO2008/084040中描述。在本发明一个实施方案中,所述免疫治疗剂包括蛋白D和MAGE-A3的融合蛋白,其中所述融合蛋白包含未加工的蛋白D的约或恰好前127个氨基酸(用氨基酸D-2和P-3替代或不替代蛋白D的氨基酸K-2和L-3,参见下文;此编号用于包括18个氨基酸的信号序列的蛋白D的氨基酸序列)。在一个实施方案中,蛋白D-MAGE-A3融合蛋白不包括蛋白D的18个氨基酸的信号序列。所述融合蛋白在蛋白D序列和/或MAGE-A3序列前可以包括一个或多个接头氨基酸。该融合蛋白可以进一步包含任选的组氨酸尾巴,例如7个组氨酸残基,并且可以进一步在MAGE-3序列和所述组氨酸尾巴之间包含一个或两个接头氨基酸。一种这样的蛋白D-MAGE-A3融合蛋白具有下列序列(SEQ ID NO:2);此构建体在本文中称为recMAGEA3:
在SEQ ID NO:2中,前127个氨基酸是蛋白D,其包括最初18个氨基酸的信号序列并在残基2-3的Asp-Pro被取代;在残基128-129的Met-Asp在D蛋白序列和MAGE-A3序列之间;残基130-441是MAGE-A3的312个氨基酸;在残基442-443的Gly-Gly置于MAGE-A3序列和7组氨酸尾巴之间。参见例如WO 99/40188、EP1053325和EP1659178。可选地,recMAGEA3的氨基酸128-441可以描述为在第二个氨基酸位置具有Asp取代的全长(314个氨基酸)MAGE-A3。
在本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3,和
(ii)化合物A。
在本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3, 和
(ii)化合物B。
在本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3,
(ii)化合物A,和
(iii)化合物B。
在本发明的另一个方面,提供了在有需要的人中治疗易患黑色素瘤的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3,和
(ii)化合物A。
在本发明的另一个方面,提供了在有需要的人中治疗易患黑色素瘤的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3, 和
(ii)化合物B。
在本发明的另一个方面,提供了在有需要的人中治疗易患黑色素瘤的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3,
(ii)化合物A,和
(iii)化合物B。
在本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3, 和
(ii) N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸酯。
在本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3,和
(ii) N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基;-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺二甲亚砜。
在本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3,
(ii) N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺甲磺酸酯,和
(iii)N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基;-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺二甲亚砜。
在本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3,和
(ii)化合物A,连同药学可接受的稀释剂或载体。
在本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3,和
(ii)化合物B,连同药学可接受的稀释剂或载体。
在本发明的另一个方面,提供了在有需要的人中治疗易患癌症的方法,所述方法包括施用包含下列的组合:
(i) recMAGEA3,
(ii)化合物A,连同药学可接受的稀释剂或载体,和
(iii)化合物B,连同药学可接受的稀释剂或载体。
在另一个方面,提供了包含下列的组合用于在人中治疗易患癌症的用途:
(i) recMAGEA3 和
(ii)化合物A。
在另一个方面,提供了包含下列的组合用于在人中治疗易患癌症的用途:
(i) recMAGEA3和
(ii)化合物B。
在另一个方面,提供了包含下列的组合用于在人中治疗易患癌症的用途:
(i) recMAGEA3
(ii)化合物A,和
(iii)化合物B。
在本发明的一个实施方案中,所述MAGE-A3蛋白可以包含衍生的游离硫基。这类抗原和制备它们的方法已描述于WO99/40188。特别是可使用羧酰胺化或羧甲基化的衍生物。
还参见Kruit等, Immunization with recombinant MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with unresectable and progressive metastatic cutaneous melanoma: A randomized open-label phase II study of the EORTC Melanoma Group (16032- 18031), ASCO Meeting Abstracts 2008 J. Clinical Oncology 26(May 20 Suppl;Abstract 9065) (2008)。
可选地,可以施用包含编码免疫治疗蛋白的DNA的载体。可以生成针对携带所述编码DNA的载体的免疫应答,并且因此可以加强一般免疫应答(即,载体本身作为佐剂)。免疫治疗可以,例如作为初次加强方案施用。
因此,本发明可以用于治疗具有表达MAGE-A3的癌症,例如黑色素瘤、乳腺癌、膀胱癌、非小细胞肺癌(NSCLC)、结肠癌、食管癌和头颈部鳞状细胞癌的的人对象。
BRAF抑制剂
如本文所用,所述BRAF抑制剂N-{3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺酰胺或其药学可接受的盐,表示为化合物式(I):
或其药学可接受的盐。方便起见,可能的化合物和盐的组群统称为化合物A,意味着提及化合物A将指可选的任何化合物或其药学可接受的盐。
在PCT专利申请PCT/US09/42682中公开并要求保护化合物A连同其药学可接受的盐,由于其可用作BRAF活性的抑制剂,特别是在癌症治疗中。化合物A通过该申请的实施例58a至58e体现。该PCT申请公布于2009年11月12日,作为公开WO2009/137391,并在此通过引用并入。
通常,本发明的盐是药学可接受的盐。涵盖在术语“药学可接受的盐”中的盐是指本发明的化合物的无毒盐。本发明的化合物的盐可包含在本发明的化合物中取代基上的氮衍生的酸加成盐。代表性的盐包括下列盐:乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、乙二胺四乙酸钙、樟脑磺酸盐、碳酸盐、氯化物、克拉维酸盐、柠檬酸盐、二盐酸盐、乙二胺四乙酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、对羟乙酰氨基苯胂酸盐(glycollylarsanilate)、己基间苯二酚盐、哈胺盐、氢溴酸盐、盐酸盐、羟基萘酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐(methylnitrate)、甲基硫酸盐、马来酸单钾、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡糖胺、草酸盐、巴莫酸盐(双羟萘酸盐)、棕榈酸盐、泛酸盐、磷酸盐/磷酸氢盐、聚半乳糖醛酸盐、钾盐、水杨酸盐、钠盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐、三乙基碘化物、三甲基铵和戊酸盐。不是药学可接受的其它盐,可以在本发明的化合物的制备中是有用的,这些构成了本发明的进一步的方面。盐可通过本领域技术人员容易地制备。
化合物A可作为溶剂化物提供。如本文所用,术语“溶剂化物”是指由溶质(在本发明中,式(I)化合物或其盐)和溶剂形成的可变化学计量的复合物。用于本发明的目的这些溶剂不可以干扰溶质的生物活性。合适的溶剂的实例包括,但不限于,水、甲醇、二甲亚砜、乙醇和乙酸。在一个实施方案中,所使用的溶剂是药学可接受的溶剂。
药物组合物可以每单位剂量含有预定量的活性成分的单位剂量形式提供。如本领域技术人员已知的,每剂量的活性成分的量将取决于所治疗的病症、施用途径和患者的年龄、体重和状况。优选的单位剂量组合物是那些含有活性成分的日剂量或亚剂量,或其适当部分的组合物。此外,这类药物组合物可以通过任何药学领域熟知的方法来制备。更具体的施用方法描述于PCT公开WO2009/137391。
合适地,作为根据本发明的组合的一部分施用的化合物A的量(基于未成盐/未溶剂化量的重量)将是选自约10mg至约600mg的量。合适地,所述量将选自约30mg至约300mg;合适地,所述量将选自约30mg至约280mg;合适地,所述量将选自约40mg至约260mg;合适地,所述量将选自约60mg至约240mg;合适地,所述量将选自约80mg至约220mg;合适地,所述量将选自约90mg至约210mg;合适地,所述量将选自约100mg至约200mg, 合适地,所述量将选自约110mg至约190mg, 合适地,所述量将选自约120mg至约180mg, 合适地,所述量将选自约130mg至约170mg, 合适地,所述量将选自约140mg至约160mg, 合适地,所述量将是150mg。因此,作为根据本发明的组合的一部分施用的化合物A的量将是选自约10mg至约300 mg的量。例如,作为根据本发明的组合的一部分施用的化合物A的量合适地选自 10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg和300mg。合适地,每天1-4次施用所选量的化合物A。合适地,每天2次施用所选量的化合物A。合适地,以150mg的量每天2次施用化合物A。合适地,每天1次施用所选量的化合物A。
MEK抑制剂
如本文所用,所述MEK抑制剂N-{3-[3-环丙基-5-(2-氟-4-碘-苯基氨基)6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙酰胺或其药学可接受的盐或溶剂化物,表示为化合物式(I):
或其药学可接受的盐或溶剂化物。方便起见,可能的化合物和/或盐和/或溶剂化物的组群统称为化合物B,意味着提及化合物B将指可选的任何化合物和/或其药学可接受的盐和/或溶剂化物。
在具有国际提交日期2005年6月10日,国际公开号WO 2005/121142和国际公开日期2005年12月22日的国际申请号PCT/JP2005/011082(其全部公开内容在此通过引用并入,化合物B是实施例4-1的化合物)中公开并要求保护化合物B连同其药学可接受的盐和溶剂化物,由于其可用作MEK活性的抑制剂,特别是在癌症治疗中。可以如国际申请号PCT/JP2005/011082所述制备化合物B。可以如公开于2006年1月19日的美国专利公开号US 2006/0014768(其全部公开内容在此通过引用并入)所述制备化合物B。
合适地,化合物B为二甲亚砜溶剂化物的形式。合适地,化合物B以钠盐的形式。合适地,化合物B为选自下列的溶剂化物的形式:水合物、乙酸、乙醇、硝基甲烷、氯苯、1-戊醇(1-pentanci)、异丙醇、乙二醇和3-甲基-1-丁醇。这些溶剂化物和盐形式可以由本领域技术人员根据国际申请号PCT/JP2005/011082或美国专利公开号US 2006/0014768所述制备。
通常,本发明的盐是药学可接受的盐。涵盖在术语“药学可接受的盐”中的盐是指本发明的化合物的无毒盐。本发明的化合物的盐可包含在本发明的化合物中取代基上的氮衍生的酸加成盐。不是药学可接受的其它盐,可以在本发明的化合物的制备中是有用的,这些构成了本发明的进一步的方面。盐可通过本领域技术人员容易地制备。
化合物B可作为溶剂化物提供。如本文所用,术语“溶剂化物”是指由溶质(在本发明中,结构(I)的化合物或其盐)和溶剂形成的可变化学计量的复合物。用于本发明的目的的这些溶剂不可以干扰溶质的生物活性。合适的溶剂的实例包括,但不限于,水、甲醇、二甲亚砜、乙醇和乙酸。在一个实施方案中,所使用的溶剂是药学可接受的溶剂。
药物组合物可以每单位剂量含有预定量的活性成分的单位剂量形式提供。如本领域技术人员已知的,每剂量的活性成分的量将取决于所治疗的病症、施用途径和患者的年龄、体重和状况。优选的单位剂量组合物是那些含有活性成分的日剂量或亚剂量,或其适当部分的组合物。此外,这类药物组合物可以通过任何药学领域熟知的方法来制备。更多具体施用方法描述于美国专利公开号US 2006/0014768。
合适地,作为根据本发明的组合的一部分施用的化合物B的量(基于未成盐/未溶剂化量的重量)将是选自约0.125mg至约10mg的量;合适地,所述量将选自约0.25mg至约9mg;合适地,所述量将选自约0.25mg至约8mg;合适地,所述量将选自约0.5mg至约8mg;合适地,所述量将选自约0.5mg至约7mg;合适地,所述量将选自约1mg至约7mg;合适地,所述量将是约5mg。因此,作为根据本发明的组合的一部分施用的化合物B的量将是选自约0.125mg至约10 mg的量。例如作为根据本发明的组合的一部分施用的化合物B的量可以是0.125mg、0.25mg、0.5mg、0.75mg、1mg、1.5mg、2mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、5.5mg、6mg、6.5mg、7mg、7.5mg、8mg、8.5mg、9mg、9.5mg、10mg。合适地,每天1-4次施用所选量的化合物B。合适地,每天2次施用所选量的化合物B。合适地,每天1次施用所选量的化合物B。
治疗方法
本发明的组合,在其中B-Raf和/或MEK活性的抑制和对MAGEA3的特异性免疫应答的引发是有益的疾病中被认为具有效用。因此,本发明还提供了本发明的组合,其用于治疗,特别是其中B-Raf和/或MEK活性的抑制和对MAGEA3的特异性免疫应答的引发是有益的疾病的治疗,特别是癌症的治疗。
本发明的进一步的方面提供了治疗其中B-Raf和/或MEK活性的抑制和对MAGEA3的特异性免疫应答的引发是有益的病症的方法,包括施用本发明的组合。
本发明的进一步的方面提供了本发明的组合在制备用于治疗其中B-Raf和/或MEK活性的抑制和对MAGEA3的特异性免疫应答的引发是有益的病症的药物中的用途。
如本文所用,“同时或伴随施用”是指两种(或更种)的疗法的施用,使得所述治疗部分同时被导入机体,或者以足够接近的时间导入机体以至于在施用后续一个或多个治疗时所述第一次施用的治疗仍然在对象的系统中(没有被代谢,排泄等)。可以通过不同途径施用。如本文所用,术语同时地和伴随地是可替代的。
如本文所用,“对治疗的响应”是指可以以任何如本领域已知且接受的方式测量的对抗癌治疗的响应,包括在肿瘤的响应后肿瘤完全消退(完全响应),肿瘤尺寸或体积减小(部分响应),没有明显的肿瘤生长或进展(稳定疾病),或混合的响应(一些肿瘤而非其它肿瘤的消退或稳定化)。可替代地,抗肿瘤治疗的效果可以通过跟进患者进行评估,例如,通过测量和比较存活时间,或疾病进展时间(无病存活)。响应的任何评估可以与没有接受治疗的个体相比,或与接受替代治疗的个体相比。
关于MAGE-A3免疫治疗剂,对治疗的响应可通过在待治疗的人体内基因信号的检测来预测。WO2010/029174、WO2009/068621和WO2007/140958描述了通过在治疗前检测在肿瘤微环境中某些基因(包括许多免疫相关基因)的表达水平或差异表达而将对象分类为对免疫治疗剂治疗的响应者或非响应者的方法。分类为响应者的对象更可能对用基于免疫疗法,如MAGEA3免疫疗法的治疗有响应。在一个实施方案中,这样的方法在当考虑用recMAGEA3治疗患有黑色素瘤的对象时是有用的。参见例如Louahed 等, Expression of defined genes identified by pretreatment tumor profiling:Association with clinical responses to the GSK MAGE- A3 immunotherapeutic in metastatic melanoma patients (EORTC 16032–18031), ASCO Meeting Abstracts 2008, J. Clinical Oncology 26(May 20 Suppl; Abstract 9045) (2008)。
本发明的组合适合用于治疗癌症,使得抑制B-Raf和/或MEK活性和对MAGEA3的特异性免疫应答的引发具有有益的效果。适合用于用本发明的组合治疗的癌症的实例包括,但不限于,原发性和转移性形式的头颈癌、乳腺癌、肺癌、非小细胞肺癌(NSCLC)、结肠癌、卵巢癌和前列腺癌。合适地,该癌症选自:脑癌(神经胶质瘤),成胶质细胞瘤、星形细胞瘤、多形性成胶质细胞瘤、Bannayan-Zonana综合征、考登病、小脑发育不良性节细胞瘤、乳腺癌、炎性乳腺癌、维尔姆斯瘤、尤因氏肉瘤、横纹肌肉瘤、室管膜瘤、髓母细胞瘤、结肠癌、头颈癌、肾癌、肺癌、肝癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌、肉瘤、骨肉瘤、骨巨细胞瘤、甲状腺癌、成淋巴细胞T细胞白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病、多毛细胞白血病、急性淋巴细胞白血病、急性髓细胞性白血病、AML、慢性中性粒细胞白血病、急性淋巴细胞T细胞白血病、浆细胞瘤、免疫大细胞性白血病、套细胞性白血病、多发性骨髓瘤巨核母细胞白血病、多发性骨髓瘤、急性巨核母细胞白血病、早幼粒细胞白血病、红白血病、恶性淋巴瘤、霍奇金氏淋巴瘤、非霍奇金淋巴瘤、淋巴母细胞性T细胞淋巴瘤、伯基特氏淋巴瘤、滤泡性淋巴瘤、成神经细胞瘤、膀胱癌、尿路上皮癌、肺癌、外阴癌、宫颈癌、子宫内膜癌、肾癌、间皮瘤、食道癌、唾液腺癌、肝细胞癌、胃癌、鼻咽癌、口癌(buccal cancer)、口腔癌(cancer of the mouth)、GIST(胃肠道间质瘤)和睾丸癌。
此外,待治疗的癌症的实例包括Barret腺癌;胆道癌;乳腺癌;子宫颈癌;胆管癌;中枢神经系统肿瘤,包括原发性CNS肿瘤如成胶质细胞瘤、星形细胞瘤(如多形性成胶质细胞瘤)和室管膜瘤,和继发性CNS肿瘤(即,源于中枢神经系统外的肿瘤转移至中枢神经系统);结直肠癌,包括大肠结肠癌;胃癌;头颈癌,包括头颈部鳞状细胞癌;血液系统癌症,包括白血病和淋巴瘤如急性淋巴细胞性白血病、急性髓性白血病(AML)、骨髓增生异常综合征、慢性骨髓性白血病、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、巨核细胞白血病、多发性骨髓瘤和红白血病;肝细胞癌;肺癌,包括小细胞肺癌和非小细胞肺癌;卵巢癌;子宫内膜癌;胰腺癌;垂体腺瘤;前列腺癌;肾癌;肉瘤;皮肤癌,包括黑素瘤;和甲状腺癌。
合适地,本发明涉及用于治疗或减轻选自BRAF V600突变的MAGE-A3阳性肿瘤的癌症的严重程度的方法,所述肿瘤如BRAF V600突变的MAGE-A3阳性脑癌(神经胶质瘤)、成胶质细胞瘤、Bannayan-Zonana综合征、考登病、小脑发育不良性节细胞瘤、乳腺癌、结肠癌、头颈癌、肾癌、肺癌、肝癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌、肉瘤和甲状腺癌。
此外,本发明涉及用于治疗或减轻选自BRAF V600E突变的MAGE-A3阳性肿瘤的癌症的严重程度的方法,所述肿瘤如BRAF V600E突变的MAGE-A3阳性脑癌(神经胶质瘤)、成胶质细胞瘤、Bannayan-Zonana综合征、考登病、小脑发育不良性节细胞瘤、乳腺癌、结肠癌、头颈癌、肾癌、肺癌、肝癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌、肉瘤和甲状腺癌。
合适地,本发明涉及用于治疗或减轻黑色素瘤,特别是BRAF V600突变的MAGE-A3阳性黑色素瘤,更特别是BRAF V600E突变的MAGE-A3阳性黑色素瘤的严重程度的方法。
除非另有定义,在本文所述的所有给药方案中,组合的B-Raf和/或MEK抑制剂化合物和MAGEA3免疫治疗剂的方案不一定在治疗开始时进行和在治疗结束时终止。它仅要求在治疗期间的某一点在同一天施用B-Raf和/或MEK抑制剂和MAGEA3免疫治疗剂。B-Raf抑制剂可以以每日剂量施用,然而,MAGEA3免疫治疗剂的施用可以以几周的间隔发生,随后是每隔几个月的额外施用(参见,例如,WO2007/137986)。
如本文所用,术语“肿瘤”指细胞或组织的异常生长,并理解为包括良性的,即非癌性生长,和恶性的,即癌性生长。术语“肿瘤的”是指肿瘤或肿瘤相关的。
如本文所用,术语“剂”理解为是指在组织、系统、动物、哺乳动物、人或其它对象中产生所希望的效果的物质。因此,术语“抗肿瘤剂”理解为是指在组织、系统、动物、哺乳动物、人或其它对象中产生抗肿瘤效果的物质。其也可以理解为“剂”可以是单一化合物、单一抗原或两种或更多种化合物或抗原的组合或组合物。
如本文所用,术语“治疗”和其衍生物,是指治疗性治疗。关于具体状况,治疗是指:(1)改善该状况或该状况的一种或多种生物学表现,(2)干扰(a)导致或负责该状况的生物级联中的一个或多个点,或(b)该状况的一种或多种生物学表现,(3)缓解一种或多种与所述状况相关联的症状、作用或副作用或一种或多种与该状况或其治疗相关联的症状、作用或副作用,或(4)减缓该状况或该状况的一种或多种生物学表现的进展。
如本文所用,“预防”理解为是指药物的预防性施用以基本上消除状况或其生物学表现的可能性或严重性,或延迟该状况或其生物学表现的发作。本领域技术人员将了解,“预防”并不是绝对的术语。预防性治疗是适当的,例如,当对象被认为具有发展癌症的高风险,例如,当对象具有强的癌症家族史或当对象已经暴露于致癌物质时。
如本文所用,术语“有效量”是指药物或药剂的量,其将引发如研究人员或临床医师所寻求的组织、系统、动物或人的生物学或医学响应。此外,术语“治疗有效量”是指任何的量,相比没有接受该量的相应的对象,其导致疾病、病症或副作用的改进的治疗、治愈、预防或改善或疾病或病症的进展速度的下降。该术语在其范围内还包括有效增强正常生理功能的量。
化合物A和/或化合物B和MAGE-A3免疫治疗剂可以在同时或伴随施用中采用。因此,在一个实施方案中,化合物A的一个或多个剂量同时或分开地与MAGE-A3融合蛋白的一个或多个剂量一起施用。
如本文所用,术语“负荷剂量”将理解为是指化合物A、化合物B和/或MAGE-A3免疫治疗剂的单一剂量或短持续时间方案,其剂量高于维持剂量高,所述剂量施用给对象以例如,迅速提高药物的血药浓度水平。如本文所用,术语“维持剂量”将理解为是指系列施用(例如,至少两次)的剂量,并且其意在缓慢地升高该化合物的血药浓度水平到治疗有效的水平,或保持这样的治疗有效水平。维持剂量一般每天施用一次,并且维持剂量的每日剂量低于负荷剂量的总每日剂量。
在一个实施方案中,本发明的方法和用途中的哺乳动物是人。
合适地,本发明涉及治疗或减轻对于Raf、RAS、MEK和PI3K/PTEN各自是野生型或突变的癌症的严重性的方法。这包括但不限于具有下列癌症的患者,对于RAF是突变的,对于RAS是野生型,对于MEK是野生型,和对于PI3K/PTEN是野生型;对于RAF是突变的,对于RAS是突变的,对于MEK是野生型和对于PI3K/PTEN是野生型;对于RAF是突变的,对于RAS是突变的,对于MEK是突变的和对于PI3K/PTEN是野生型;以及对于RAF是突变的,对于RAS是野生型,对于MEK是突变的和对于PI3K/PTEN是野生型。
术语“野生型”如在本领域中理解为指存在于天然群体中没有遗传修饰的多肽或多核苷酸序列。还如在本领域中所理解,“突变”包括相比在野生型多肽或多核苷酸中发现的相应的氨基酸或核酸分别具有对氨基酸或核酸的至少一个修饰的多肽或多核苷酸序列。包括在术语突变中的是单核苷酸多态性(SNP),其中相比最为普遍发现(野生型)的核酸链,核酸链的序列中存在单一碱基对差异。
通过已知方法鉴定对于Raf、Raf、MEK是野生型或突变的,或对于PI3K/PTEN是突变的癌症。例如,可通过DNA扩增和测序技术、DNA和RNA检测技术,分别包括但不限于Northern和Southern印迹,和/或各种生物芯片和阵列技术鉴定野生型或突变的肿瘤细胞。野生型和突变多肽可以通过多种技术检测,包括但不限于免疫诊断技术,如ELISA、Western印迹或免疫细胞化学。合适地,可以使用焦磷酸解活化的聚合(PAP)和/或PCR方法。Liu, Q 等; Human Mutation 23:426-436 (2004)。
如所指示的,上文讨论了化合物A的治疗有效量。本发明的进一步的治疗剂的治疗有效量将取决于许多因素,包括,例如,哺乳动物的年龄和体重、需要治疗的确切的状况、状况的严重程度,制剂的性质和施用途径。最终,所述治疗有效量将根据主治医师或兽医的判断。将选择施用的相对时机以实现所希望的联合治疗效果。
组合
在一个实施方案中,本发明的治疗方法包括施用所公开的BRaf抑制剂和/或MEK抑制剂和MAGE-A3免疫治疗剂,和至少一种额外的抗肿瘤剂。
典型地,在本发明中,对于被治疗的易患肿瘤具有活性的任何抗肿瘤剂可以在癌症治疗中共同施用。这类试剂的实例可以见于V.T. Devita and S. Hellman (编辑)的Cancer Principles and Practice of Oncology,第6版(2001年2月15日),Lippincott Williams & Wilkins Publishers。可用于与上面讨论的BRaf和MEK抑制剂组合的典型的抗肿瘤剂包括,但不限于,抗微管剂,如二萜类化合物和长春花生物碱类;铂配位络合物;烷化剂如氮芥类、氧氮磷环类、烷基磺酸盐、亚硝基脲和三氮烯;抗生素剂如蒽环类、放线菌素类和博来霉素类;拓扑异构酶II抑制剂如表鬼臼毒素类;抗代谢物如嘌呤和嘧啶类似物和抗叶酸化合物;拓扑异构酶I抑制剂,如喜树碱;激素和激素类似物;信号转导途径抑制剂;受体酪氨酸激酶抑制剂;丝氨酸-苏氨酸激酶抑制剂;非受体酪氨酸激酶抑制剂;血管生成抑制剂、免疫治疗剂;促凋亡剂;和细胞周期信号传导抑制剂。
抗微管或抗有丝分裂剂,如二萜类化合物和长春花生物碱(如长春碱、长春新碱和长春瑞滨);二萜类化合物,如紫杉醇(TAXOL?)和其类似物多西他赛;铂配位络合物,如顺铂和卡铂;烷化剂,如环磷酰胺、美法仑和苯丁酸氮芥;烷基磺酸盐如白消安;亚硝基脲如卡莫司汀;和三氮烯如达卡巴嗪。
可与本发明组合使用的另外的抗肿瘤剂包括抗生素类抗肿瘤药,如放线菌素类如放线菌素D、蒽环类例如柔红霉素和多柔比星;和博来霉素;拓扑异构酶II抑制剂,如表鬼臼毒素类如依托泊苷和替尼泊苷。
可与本发明组合使用的另外的抗肿瘤剂包括抗代谢物肿瘤剂,如氟尿嘧啶(5-氟-2,4-(1H,3H)嘧啶二酮、5-氟脱氧尿苷(氟尿苷)和5-氟脱氧尿苷单磷酸)、甲氨蝶呤、阿糖胞苷、巯基嘌呤(PURINETHOL?)、硫鸟嘌呤(TABLOID?)和吉西他滨(GEMZAR?)。
可与本发明组合使用的另外的抗肿瘤剂包括喜树碱类,包括作为拓扑异构酶I抑制剂可用的或正在开发的喜树碱和喜树碱衍生物,例如伊立替康、拓扑替康和7-(4-甲基哌嗪-亚甲基)-10,11-亚乙二氧基-20-喜树碱的各种光学形式;盐酸伊立替康(CAMPTOSAR?);伊立替康和盐酸拓扑替康(HYCAMTIN?)。
可与本发明组合使用其它抗肿瘤剂,包括利妥昔单抗(RITUXAN?和MABTHERA?);奥法木单抗(ARZERRA?);mTOR抑制剂包括但不限于雷帕霉素和雷帕霉素类似物(rapalogs)、RAD001或依维莫司(Afinitor)、CCI-779或西罗莫司脂化物、AP23573、AZD8055、WYE-354、WYE-600、WYE-687和PP121;蓓萨罗丁(Targretin?);索拉非尼(Nexavar?)。
本发明的组合可以与治疗癌症有用的激素组合使用。在癌症治疗中有用的激素和激素类似物的实例包括,但不限于,肾上腺皮质类固醇类如泼尼松和泼尼松龙;氨鲁米特和其它芳香化酶抑制剂如阿那曲唑、来曲唑、伏氯唑和依西美坦;孕酮类如醋酸甲地孕酮;雌激素、雄激素和抗雄激素类如氟他胺、尼鲁米特、比卡鲁胺、醋酸环丙孕酮和5α-还原酶,例如非那雄胺和度他雄胺;抗雌激素类如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬、iodoxyfene,以及选择性雌激素受体调节剂(SERM),例如描述于美国专利号5681835、5877219和6207716中的那些;和促性腺素释放激素(GnRH)及其类似物(其刺激促黄体生成激素(LH)和/或促卵泡激素(FSH)的释放用于治疗前列腺癌),例如LHRH激动剂和拮抗剂如醋酸戈舍瑞林和luprolide。
本发明的组合可进一步与信号转导途径抑制剂组合使用,如下列的抑制剂:受体酪氨酸激酶、非受体酪氨酸激酶、SH2/SH3结构域阻断剂、丝氨酸/苏氨酸激酶、磷脂酰肌醇-3激酶、肌醇信号传导和Ras癌基因,包括生长因子受体包括例如表皮生长因子受体(EGFR)、血小板衍生生长因子受体(PDGFR)、erbB2、erbB4、ret、血管内皮生长因子受体(VEGFR)、具有免疫球蛋白样和表皮生长因子同源性结构域的酪氨酸激酶(TIE-2)、胰岛素生长因子-I(IGFI)受体、巨噬细胞集落刺激因子(cfms)、BTK、ckit、cmet、成纤维细胞生长因子(FGF)受体、Trk受体(TrkA、TrkB和TrkC)、肝配蛋白(eph)受体和RET原癌基因。示例性的信号转导途径抑制剂是拉帕替尼(Tykerb/Tyverb?),双EGFR/ErbB2抑制剂。
不是生长因子受体激酶的酪氨酸激酶被称为非受体酪氨酸激酶。可用于本发明的非受体酪氨酸激酶,其是抗癌药物的目标或潜在目标,包括cSrc、Lck、Fyn、Yes、Jak、cAbl、FAK (粘着斑激酶)、Brutons酪氨酸激酶和Bcr-Abl。这些非受体激酶和抑制非受体酪氨酸激酶功能的试剂描述于Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research8 (5): 465 – 80;和Bolen, J.B., Brugge, J.S., (1997) Annual review of Immunology. 15: 371-404。
SH2/SH3结构域阻断剂是破坏多种酶或接头蛋白(包括PI3-K p85亚基、Src家族激酶、接头分子(Shc、Crk、Nck、Grb2)和Ras-GAP)中的SH2或SH3结构域结合的试剂。作为抗癌药物目标的SH2/SH3结构域在Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32中进行讨论。
丝氨酸/苏氨酸激酶抑制剂,包括MAP激酶级联阻断剂,其包括Raf激酶(rafk)、有丝分裂原或细胞外调节激酶(MEKs)和细胞外信号调节激酶(ERKs)的阻断剂;和蛋白激酶C家族成员阻断剂,包括PKC(α、β、γ、ε、μ、λ、ι、ζ)的阻断剂。IkB激酶家族(IKKa,IKKb)、PKB家族激酶、akt激酶家族成员和TGFβ受体激酶。这样的丝氨酸/苏氨酸激酶及其抑制剂描述于Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803;Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107;Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64;Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27;Lackey, K. 等 Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226;美国专利号6,268,391;和Martinez-Iacaci, L., 等, Int. J. Cancer (2000), 88(1), 44-52。
磷脂酰肌醇-3激酶家族成员抑制剂,包括PI3-激酶、ATM、DNA-PK和Ku的阻断剂也可用于本发明。这些激酶在Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8;Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308;Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8;和Zhong, H. 等, Cancer res, (2000) 60(6), 1541-1545中讨论。
还可用于本发明的是肌醇信号传导抑制剂,如磷脂酶C阻断剂和肌醇类似物。这些信号抑制剂描述于Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London。
另一组信号传导途径抑制剂是Ras癌基因的抑制剂。这类抑制剂包括法尼基转移酶、香叶基-香叶基转移酶和CAAX蛋白酶的抑制剂以及反义寡核苷酸、核酶和免疫治疗。这样的抑制剂已显示在含有野生型突变ras的细胞中阻断ras激活,由此充当抗增殖剂。Ras癌基因抑制剂在Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8;Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 – 102和BioChim. Biophys. Acta, (19899) 1423(3):19-30中进行讨论。
如上所述,针对受体激酶配体结合的抗体拮抗剂也可以充当信号转导抑制剂。这组信号转导途径抑制剂包括使用针对受体酪氨酸激酶的细胞外配体结合结构域的人源化抗体。例如,Imclone C225 EGFR特异性抗体(参见Green, M.C. 等, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286);Herceptin ? erbB2 抗体(参见Tyrosine Kinase Signalling in Breast cancer:erbB Family Receptor Tyrosine Kinases, Breast cancer Res., 2000, 2(3), 176-183);和2CB VEGFR2特异性抗体(参见Brekken, R.A. 等, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124)。
包括非受体MEK血管生成抑制剂的抗血管生成剂也可以是有用的。抗血管生成剂,例如那些抑制血管内皮细胞生长因子的作用的抗血管生成剂,(例如抗血管内皮细胞生长因子抗体贝伐单抗[阿瓦斯汀?],和通过其它机制起作用的化合物(例如利诺胺,整合素αvβ3功能抑制剂、内皮抑素和血管抑素);
在免疫治疗方案中使用的试剂也可以与本发明的化合物组合使用。免疫治疗方法,包括例如提高患者肿瘤细胞免疫原性的从体外到体内和体内方法(例如用细胞因子如白介素2、白介素4或粒细胞-巨噬细胞集落刺激因子转染),降低T细胞无反应性的方法,使用转染的免疫细胞如转染细胞因子的树突状细胞的方法,使用转染细胞因子的肿瘤细胞系的方法和使用抗独特型抗体的方法。
在促凋亡方案中使用的试剂(例如,bcl-2反义寡核苷酸)也可在本发明的组合中使用。
细胞周期信号传导抑制剂,包括CDK2、CDK4和CDK6及其抑制剂描述于,例如Rosania 等, Exp. Opin. Ther. Patents (2000) 10(2):215-230。
佐剂
当在本说明书中使用术语“佐剂”提及免疫疗法的组分时,它是指结合免疫治疗施用以加强患者对免疫疗法的免疫原性组分的免疫应答的物质(参见,例如,WO02/32450)。这与“辅助治疗”不同,后者如上所讨论的是在用于癌症的主要治疗之后给予的额外治疗。因此免疫疗法可以是辅助治疗;所述免疫治疗组合物可包含佐剂化合物,例如在下文讨论的那些。这些佐剂是本领域熟知的,并且可以在单独的制剂中施用,或者可以是包含免疫疗法的免疫原性组分的制剂的组分。因此如本文所述的免疫治疗剂还可以包括疫苗佐剂,和/或免疫刺激性细胞因子或趋化因子。
用于本发明的合适的疫苗佐剂是可商购获得的,例如,如,弗氏不完全佐剂和完全佐剂(Difco Laboratories, Detroit, MI); Merck Adjuvant 65 (Merck and Company, Inc., Rahway, NJ);AS02(在水包油乳液中包含MPL和QS21的佐剂系统;SmithKline Beecham, Philadelphia, PA);AS15(包含MPL、QS21、CpG和脂质体的佐剂系统);铝盐例如氢氧化铝凝胶(alum)或磷酸铝;钙、铁或锌盐;酰化酪氨酸的不溶性悬浮液;酰化糖;阳离子或阴离子衍生的多糖;聚磷腈;可生物降解微球;单磷酰脂质A和奎尔A。细胞因子,如GM-CSF或白介素-2、-7或-12和趋化因子也可以用作佐剂。
在本发明的制剂中,可能希望该佐剂组合物诱导主要为Th1型的免疫应答。高水平的Th1型细胞因子(如IFN-γ、TNFα、IL-2和IL-12)倾向于促进针对所施用抗原的细胞介导的免疫应答的诱导。根据一个实施方案,其中应答主要是Th1型,Th1型细胞因子的水平将增加至高于Th2型细胞因子的水平的程度。这些细胞因子的水平可通过标准测定容易地评估。对于细胞因子家族的综述,参见Mosmann and Coffman, Ann. Rev. Immunol. 7:145-173, 1989。
因此,可以用于引发主要是Th1型应答的合适的佐剂包括例如单磷酰脂质A(MPL)(例如3-O-脱酰基-4'-单磷酰脂质A)连同铝盐的组合。如公开于WO9850399、WO0134617和WO03065806的,MPL或其它Toll样受体4(TLR4)配体,如氨烷基氨基葡糖苷磷酸酯(AGP)也可单独使用,以产生主要为Th1型的应答。
可优先诱导Th1型免疫应答的其它已知的佐剂,包括TLR9拮抗剂,如含有非甲基化CpG基序(CpG或含CpG的寡脱氧核苷酸)的合成的寡脱氧核苷酸(ODN)。此类寡核苷酸是熟知的,并且描述于,例如WO96/02555。
含CpG的寡脱氧核苷酸,也可以单独使用或与其它佐剂组合使用。例如,增强的系统包括:含CpG的寡脱氧核苷酸和皂苷衍生物的组合,尤其是如公开于WO00/09159和WO00/62800的CpG和QS21的组合(石碱木(Quillaja Saponaria Molina), 级分21;Antigenics, New York, NY, USA)。
所述制剂可另外包含水包油乳液和/或生育酚。
另一种合适的佐剂是皂苷,例如QS21,其可单独使用或与其它佐剂组合使用。例如,增强的系统包括单磷酰脂质A和皂苷衍生物的组合,例如如WO94/00153中所述的QS21和MPL的组合,或如WO 96/33739中所述的低反应原性组合物,其中QS21用胆固醇淬灭。其它合适的制剂包含水包油乳液和α-生育酚。特别有效的包括在水包油乳液中QS21、MPL和α-生育酚的佐剂制剂描述于WO 95/17210。
在另一个实施方案中,佐剂可以配制在脂质体组合物中。
所使用的MPL的量通常是小的,但取决于免疫治疗制剂可在每剂量1-1000μg、每剂量1-500μg或每剂量1-100μg的范围内。
在一个实施方案中,该佐剂系统包括三种免疫刺激剂:含CpG的寡核苷酸、MPL和QS21,提供在脂质体制剂中或水包油乳液中,例如WO 95/17210中所述。
在本发明的佐剂或免疫治疗剂中含CpG的寡脱氧核苷酸,或免疫刺激寡核苷酸的量通常较小,但取决于免疫治疗制剂可在每剂量1-1000μg、每剂量1-500μg或每剂量1-100μg的范围内。
在本发明的佐剂中使用的皂苷的量可在每剂量1-1000μg、每剂量1-500μg、每剂量1-250μg或每剂量1-100μg的范围内。
通常,每个人剂量可包括1-1000μg的蛋白抗原。在一个实施方案中,所述剂量可包括30-300μg的蛋白抗原。用于特定的免疫治疗剂和/或用于治疗特定肿瘤类型的有用的剂量,可以通过涉及观察接种对象中适当的免疫应答的标准研究确定。在最初的疫苗接种后,对象会接受足够间隔的一次或几次加强免疫。
在一个实施方案中,佐剂可以包括MPL、QS21和免疫刺激性含CpG的寡脱氧核苷酸的一种或多种。在一个实施方案中,所有三种免疫刺激剂都存在。在另一个实施方案中,MPL和QS21在水包油乳液中提供,并不存在含CpG的寡脱氧核苷酸。
实施例
黑素瘤中BRAF V600突变与MAGE表达的患病率
在临床研究期间将53个新鲜肿瘤组织的DNA收集在RNAlaterDNA用Maxwell组织DNA纯化试剂盒(Promega)提取并通过光谱法进行定量。然后用Response Genetics (RGI)开发的等位基因特异性PCR测定法测试BRAF突变状态。简而言之,使用对照测定通过扩增BRAF基因中外显子13的无多态性区域,来评估样品中的总DNA。平行地,使用开发用于特异性检测BRAF V600E、V600K和V600D*变体的三种BRAF变体特异性突变测定法来确定BRAF突变状态。样品被认为是:
BRAF V600E突变,如果ΔCt[(BRAF V600E CT)-(BRAF EX13 CT)]劣于6.5;
BRAF V600K突变,如果ΔCt[(BRAF V600K CT)-(BRAF EX13 CT)]劣于6.5;
BRAF V600D突变,如果ΔCt[(BRAF V600D CT)-(BRAF EX13 CT)]劣于6.7;
BRAF野生型,如果三个上述ΔCt优于它们各自的截止值。
通过qRTPCR对相同的活组织检查样本确定MAGEA3表达水平。
表1显示所获得的MAGEA3表达状态和BRAF基因型
表1:
BRAF抑制剂或MEK抑制剂对小鼠MAGE免疫疗法无有害影响
7组22只CB6F1雌性小鼠接受如下– 1) PBS, 2)MAGE-A3/AS15, 3) 媒介物, 4) BRAF 抑制剂(GSK436), 5) MEK 抑制剂(GSK212), 6) 组合的ASCI + GSK 436, 和7) 组合的 ASCI + GSK 212。在第0和14天肌内(IM)给予MAGE-A3/AS15。从第0天至第14天通过每天灌胃(IG)给予B-RAF和MEK抑制剂。
第二次免疫后两周(第28天),在12只小鼠/组(3只小鼠的4次合并)的脾细胞上分析所述CD4+和CD8+ T细胞应答=主要终点,并且在12只小鼠/组上测量抗体应答。
T细胞应答
认为T细胞应答的分析是主要终点并且实验得到了相应支持。在对来自12只小鼠/组(3只小鼠的4次合并)的脾细胞进行最后一次免疫后2周进行所述测定,所述小鼠以2周的时间间隔用MAGE-A3 ASCI免疫两次,并包括通过流式细胞术(ICS)的细胞内细胞因子染色,评估能够产生细胞因子(IFNg和/或TNFa)的CD4 +或CD8+ T细胞的百分比。
在96W板中用介质(无刺激)或覆盖MAGE-A3整个序列的重叠10AA的57、15聚体肽的混合物(1μg/ml/肽),在37℃下再刺激免疫动物的脾细胞2小时,所述肽在含共刺激抗体(各2μg/ml的抗CD49d和抗CD28)的RPMI 5% FCS的200μl的终体积中。培养后,通过添加50μl在RPMI5%FCS中的布雷菲德菌素(1/1000)阻断细胞因子的分泌。
然后将细胞转移在96W(锥孔)板中,离心(1000rpm 5分钟,4℃),用250μl FACS缓冲液(PBS 1%FCS)洗涤。细胞沉淀物与50μl 1/50X稀释在FACS缓冲液中的2.4G2在4℃下孵育10分钟以阻断对Fc受体的非特异性结合。CD4 +和CD8+ T细胞通过添加50μl在FACS缓冲液中的含有荧光抗体(CD4-PE mAb:1/100和CD8PerCP mAb:6/100)的预混物进行染色(30分钟,4℃)。
在FACS缓冲液中洗涤细胞,离心(1200rpm,10分钟)。加入200μl cytoFix-cytoPerm4℃持续20分钟,离心细胞。添加在无菌水中1X浓缩的透化溶液(permWASH),并将细胞离心(1000RPM-5分钟)。沉淀在4℃与50μl在permWASH1X溶液中的抗IFNg APC(mAb:1/50)和TNFa FITC(mAb: 1/50)的荧光抗体的混合物孵育2小时。洗涤细胞,离心(1000RPM)并重悬浮于FACS缓冲液,然后FACS分析(LSR2来自Becton Dickinson)。
对活的T细胞(1)进行门控后,获得总共约20000个CD4+ T细胞和约10000个CD8+ T细胞(2)并且数据表示为这些产生细胞因子的CD4+或CD8+ T细胞的百分比(3)。
从用MAGE-A3肽刺激的细胞所获得的数据中减去用未刺激细胞(介质)获得的数据。背景水平通常检测不到或非常低,在接受磷酸盐缓冲盐水(PBS)的小鼠的对照组中占0.01-0.05%。取决于背景,0.1百分比可被视为阳性应答。
为实现应答的正态分布和方差齐性,数据首先在log10的基础上转化。应用单向方差分析和多重比较(Tukey检验)以揭示组间的显著性差异。
2次免疫后14天,使用细胞内细胞因子染色测定在免疫动物的脾细胞上测量T细胞应答。作为每组3只小鼠的4个合并分析数据。CD4+ T细胞应答显示于图1。CD8+ T细胞应答显示于图2。
对于CD4+ T细胞应答,ASCI和ASCI+B-RAF抑制剂之间的几何平均比例为0.9,具有[0.7-1.16]的95% CI,完全包含在[0.3-3]中,并且ASCI和ASCI+MEK抑制剂之间的几何平均比例为0.71,具有[0.55-0.92]的95% CI,完全包含在[0.3-3]中。
对于CD8+ T细胞应答,ASCI和ASCI+B-RAF抑制剂之间的几何平均比例为0.97,具有[0.53-1.78]的95% CI,完全包含在[0.3-3]中。ASCI和ASCI+MEK抑制剂之间的几何平均比例为0.64,具有[0.35-1.16]的95% CI,完全包含在[0.3-3]中。
抗体应答
对每组12只小鼠在最后一次免疫后2周评价抗体应答。在2次免疫后14天通过ELISA测试小鼠血清是否存在MAGE-A3特异性抗体。
添加血清前,免疫板用在杆状病毒中产生的MAGE3抗原在4℃包被过夜。在37℃与血清反应90分钟后,添加抗小鼠免疫球蛋白的生物素化的绵羊全抗体,在37℃持续90分钟。通过与链霉亲和素-生物素化的过氧化物酶复合物在37℃孵育30分钟揭示抗原-抗体复合物。此复合物然后通过添加四甲基联苯胺(TMB)在室温下10分钟揭示复合物,并且用0.2M H2SO4终止反应。在450nm记录光密度。
通过参考用标准血清(来自用MAGE-A3 ASCI – LIMS 20100152免疫的小鼠的血清混合物)建立的标准曲线计算单个小鼠的抗MAGE-A3低速,并且对每组计算平均值。
为实现应答的正态分布和方差齐性,数据首先基于log10进行转化。应用单向方差分析和多重比较(Tukey检验)以揭示组间的显著性差异。
通过ELISA使用在杆状病毒表达系统中产生的纯化的重组MAGE-A3蛋白作为包被抗原测量抗体应答。单独测试来自每组12只小鼠的血清。图3表示每组12只小鼠的平均滴度+/-标准偏差。
ASCI和ASCI+MEK抑制剂之间的抗体滴度的几何平均比例为1.08,具有[0.91-1.3]的95% CI,完全包含在[0.3-3]中。ASCI和ASCI+MEK抑制剂之间的几何平均比例为1.07,具有[0.9-1.3]的95% CI,完全包含在[0.3-3]中。
用BRAF抑制剂治疗的癌症患者的整体免疫能力不被削弱
对13例具有携带BRAF突变的肿瘤的接受用GSK2118436(式(I)的化合物),V600突变的BRAF特异性抑制剂治疗的患者进行了研究,以评估突变的BRAF抑制对全身免疫的效果。在一个或两个28天的治疗周期前后进行外周血免疫监视。
结果是,GSK2118436治疗对大部分测试的免疫参数,包括血清细胞因子水平、外周血细胞计数、白细胞子集频率和记忆CD4+和CD8+ T细胞回忆应答没有可检测的影响。观察到血清TNF-α随着治疗过程略有增加。此外,四分之三的人白细胞抗原-A2阳性患者在BRAF(V600)抑制剂治疗后经历了循环肿瘤抗原特异性CD8+ T细胞的适度增加。
结论是,GSK2118436治疗导致对现有系统免疫或肿瘤特异性T细胞的从头产生没有可检测到的负面影响。
基础分析和结果的更详细的报告提供于Hong DS, Vence L, Falchook G, Radvanyi LG, Liu C, Goodman V, 等BRAF(V600) Inhibitor GSK2118436 Targeted Inhibition of Mutant BRAF in Cancer Patients Does Not Impair Overall Immune Competency. Clinical cancer research: an official journal of the American Association for Cancer Research. 2012;18:2326-35,其通过引用并入本文。
序列表
<110> 葛兰素史克有限责任公司
C. M. G. 格拉尔
S. 拉奎雷
P. F. 勒鲍维茨
F. F. E. 勒曼
J. 卢阿赫
<120> 用MAGE-A3免疫治疗剂与BRAF抑制剂和/或MEK抑制剂治疗癌症的方法
<130> PR65074WO
<150> 61/579028
<151> 2011-12-22
<150> 61/578943
<151> 2011-12-22
<160> 2
<170> PatentIn版本3.5
<210> 1
<211> 85
<212> PRT
人工
<220>
<223> MAGE核心特征序列-共有序列
<220>
<221> 尚未归类的特征
<223> 残基 2, 4, 12, 15, 16, 20, 22, 24, 27, 34, 39, 41, 44, 45,
46, 51, 53, 59, 63, 68, 69, 74, 75, 80, 84和85可以是
所示氨基酸的保守变体。
<220>
<221> 尚未归类的特征
<222> (3)..(3)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (6)..(7)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (9)..(11)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (13)..(14)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (19)..(19)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (23)..(23)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (25)..(26)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (28)..(31)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (33)..(33)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (35)..(38)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (40)..(40)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (42)..(43)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (47)..(49)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (53)..(53)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (56)..(56)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (58)..(58)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (62)..(62)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (64)..(64)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (66)..(67)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (77)..(78)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> 尚未归类的特征
<222> (81)..(83)
<223> Xaa可以是任何天然存在的氨基酸
<400> 1
Leu Ile Xaa Val Leu Xaa Xaa Ile Xaa Xaa Xaa Gly Xaa Xaa Ala Pro
1 5 10 15
Glu Glu Xaa Ile Trp Glu Xaa Leu Xaa Xaa Met Xaa Xaa Xaa Xaa Gly
20 25 30
Xaa Glu Xaa Xaa Xaa Xaa Gly Xaa Pro Xaa Xaa Leu Leu Thr Xaa Xaa
35 40 45
Xaa Val Gln Glu Xaa Tyr Leu Xaa Tyr Xaa Gln Val Pro Xaa Ser Xaa
50 55 60
Pro Xaa Xaa Tyr Glu Phe Leu Trp Gly Pro Arg Ala Xaa Xaa Glu Thr
65 70 75 80
Xaa Xaa Xaa Lys Val
85
<210> 2
<211> 450
<212> PRT
人工
<220>
<223> 脂蛋白D片段、Mage3片段和组氨酸尾巴的融合蛋白
<400> 2
Met Asp Pro Lys Thr Leu Ala Leu Ser Leu Leu Ala Ala Gly Val Leu
1 5 10 15
Ala Gly Cys Ser Ser His Ser Ser Asn Met Ala Asn Thr Gln Met Lys
20 25 30
Ser Asp Lys Ile Ile Ile Ala His Arg Gly Ala Ser Gly Tyr Leu Pro
35 40 45
Glu His Thr Leu Glu Ser Lys Ala Leu Ala Phe Ala Gln Gln Ala Asp
50 55 60
Tyr Leu Glu Gln Asp Leu Ala Met Thr Lys Asp Gly Arg Leu Val Val
65 70 75 80
Ile His Asp His Phe Leu Asp Gly Leu Thr Asp Val Ala Lys Lys Phe
85 90 95
Pro His Arg His Arg Lys Asp Gly Arg Tyr Tyr Val Ile Asp Phe Thr
100 105 110
Leu Lys Glu Ile Gln Ser Leu Glu Met Thr Glu Asn Phe Glu Thr Met
115 120 125
Asp Leu Glu Gln Arg Ser Gln His Cys Lys Pro Glu Glu Gly Leu Glu
130 135 140
Ala Arg Gly Glu Ala Leu Gly Leu Val Gly Ala Gln Ala Pro Ala Thr
145 150 155 160
Glu Glu Gln Glu Ala Ala Ser Ser Ser Ser Thr Leu Val Glu Val Thr
165 170 175
Leu Gly Glu Val Pro Ala Ala Glu Ser Pro Asp Pro Pro Gln Ser Pro
180 185 190
Gln Gly Ala Ser Ser Leu Pro Thr Thr Met Asn Tyr Pro Leu Trp Ser
195 200 205
Gln Ser Tyr Glu Asp Ser Ser Asn Gln Glu Glu Glu Gly Pro Ser Thr
210 215 220
Phe Pro Asp Leu Glu Ser Glu Phe Gln Ala Ala Leu Ser Arg Lys Val
225 230 235 240
Ala Glu Leu Val His Phe Leu Leu Leu Lys Tyr Arg Ala Arg Glu Pro
245 250 255
Val Thr Lys Ala Glu Met Leu Gly Ser Val Val Gly Asn Trp Gln Tyr
260 265 270
Phe Phe Pro Val Ile Phe Ser Lys Ala Ser Ser Ser Leu Gln Leu Val
275 280 285
Phe Gly Ile Glu Leu Met Glu Val Asp Pro Ile Gly His Leu Tyr Ile
290 295 300
Phe Ala Thr Cys Leu Gly Leu Ser Tyr Asp Gly Leu Leu Gly Asp Asn
305 310 315 320
Gln Ile Met Pro Lys Ala Gly Leu Leu Ile Ile Val Leu Ala Ile Ile
325 330 335
Ala Arg Glu Gly Asp Cys Ala Pro Glu Glu Lys Ile Trp Glu Glu Leu
340 345 350
Ser Val Leu Glu Val Phe Glu Gly Arg Glu Asp Ser Ile Leu Gly Asp
355 360 365
Pro Lys Lys Leu Leu Thr Gln His Phe Val Gln Glu Asn Tyr Leu Glu
370 375 380
Tyr Arg Gln Val Pro Gly Ser Asp Pro Ala Cys Tyr Glu Phe Leu Trp
385 390 395 400
Gly Pro Arg Ala Leu Val Glu Thr Ser Tyr Val Lys Val Leu His His
405 410 415
Met Val Lys Ile Ser Gly Gly Pro His Ile Ser Tyr Pro Pro Leu His
420 425 430
Glu Trp Val Leu Arg Glu Gly Glu Glu Gly Gly His His His His His
435 440 445
His His
450
Claims (9)
1.用于在有需要的人中治疗易患癌症的方法,所述方法包括施用治疗有效量的
(i)MAGE-A3免疫治疗剂,和以下中的一种或两种
(a)式(I)的化合物
或其药学可接受的盐,和
(b)结构(II)的化合物
或其药学可接受的盐或溶剂化物。
2.权利要求1的方法,其中所述式(I)化合物或其药学可接受的盐为甲磺酸盐的形式。
3.权利要求1或2的方法,其中所述结构(I)的化合物为二甲基亚砜溶剂化物的形式。
4.权利要求1-3任一项的方法,其中所述MAGE-A3免疫治疗剂是蛋白D-MAGE-A3融合蛋白。
5.权利要求1-4任一项的方法,其中所述MAGE-A3免疫治疗剂是包含SEQ ID NO:2的融合蛋白。
6.权利要求1-5任一项的方法,其中所述MAGE-A3免疫治疗剂包含佐剂。
7.权利要求1-6任一项的方法,其中所述式(I)和/或(II)的化合物或其药学可接受的盐进一步包含药学可接受的稀释剂或载体。
8.权利要求1-7任一项的方法,其中所述癌症选自:头颈癌、乳腺癌、肺癌、结肠癌、卵巢癌、前列腺癌、 非小细胞肺癌(NSCLC) 、神经胶质瘤、成胶质细胞瘤、星形细胞瘤、多形性成胶质细胞瘤、Bannayan-Zonana综合征、考登病、小脑发育不良性节细胞瘤、炎性乳腺癌、维尔姆斯瘤、尤因氏肉瘤、横纹肌肉瘤、室管膜瘤、髓母细胞瘤、肾癌、肝癌、黑色素瘤、胰腺癌、肉瘤、骨肉瘤、骨巨细胞瘤、甲状腺癌、成淋巴细胞T细胞白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病、多毛细胞白血病、急性淋巴细胞白血病、急性髓细胞性白血病、AML、慢性中性粒细胞白血病、急性淋巴细胞T细胞白血病、浆细胞瘤、免疫大细胞性白血病、套细胞性白血病、多发性骨髓瘤巨核母细胞白血病、多发性骨髓瘤、急性巨核母细胞白血病、早幼粒细胞白血病、红白血病、恶性淋巴瘤、霍奇金氏淋巴瘤、非霍奇金淋巴瘤、淋巴母细胞性T细胞淋巴瘤、伯基特氏淋巴瘤、滤泡性淋巴瘤、成神经细胞瘤、膀胱癌、尿路上皮癌、肺癌、外阴癌、宫颈癌、子宫内膜癌、肾癌、间皮瘤、食道癌、唾液腺癌、肝细胞癌、胃癌、鼻咽癌、口癌、口腔癌、GIST(胃肠道间质瘤)和睾丸癌。
9.根据权利要求1-8任一项的方法,其中所述癌症是黑色素瘤。
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PCT/US2012/070582 WO2013096430A1 (en) | 2011-12-22 | 2012-12-19 | Method of treating cancer with magea3 immunotherapeutic with braf inhibitor and/or mek inhibitor |
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ASCIERTO ET AL.: "Future perspectives in melanoma research.Meeting report from the "Melanoma Research: a bridge Naples-USA. Naples, December 6th-7 th2010"", 《JOURNAL OF TRANSLATIONAL MEDICINE》, vol. 9, no. 32, 26 March 2011 (2011-03-26), pages 1 - 12 * |
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