CN114907271A - 苯甲酰胺和活性化合物的组合物及其使用方法 - Google Patents
苯甲酰胺和活性化合物的组合物及其使用方法 Download PDFInfo
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及苯甲酰胺和活性化合物的组合物及其使用方法,特别描述了组合物,包括药物组合物,其包含PD‑1轴结合拮抗剂、CTLA4拮抗剂、或DNA脱甲基化试剂以及苯甲酰胺化合物,以及其用于例如治疗癌症的方法。在一些实施方案中,所述方法用于包括治疗需要增强的免疫原性的病症的方法,如增加用于治疗癌症的肿瘤免疫原性。
Description
本申请是申请号为201680042874.0,申请日为2016年5月23日,发明名称为“苯甲酰胺和活性化合物的组合物及其使用方法”的中国专利申请的分案申请。
相关申请的交叉引用
本申请要求2015年5月22日提交的美国临时专利申请号62/165,891、2015年5月28日提交的美国临时专利申请号62/167,790、2015年5月28日提交的美国临时专利申请号62/167,794、以及2016年3月2日提交的美国临时专利申请号62/302,781的优先权,其内容通过引用整体并入本文。
参考电子提交的序列表
序列表的官方拷贝通过EFS-Web以ASCII格式的序列表以电子方式提交,具有2016年5月23日创建的名为“11144_023_Seq_Listing_ST25.txt”的文件,具有68千字节的大小,并且与说明书同时提交。包含在该ASCII格式文件中的序列表是说明书的一部分,并且通过引用整体并入本文。
技术领域
本公开涉及包括治疗剂和苯甲酰胺化合物的联合的组合物及其使用方法。
背景技术
癌症是美国第二大死因。尽管新突破已经导致死亡率下降,而许多癌症仍然难以治疗。另外,典型的治疗如化学治疗、放射治疗和手术会引起广泛的不良副作用。另外,随着时间,许多癌症经常对目前的化学治疗产生抗性。显然,本领域非常需要减缓癌细胞扩增的新的化合物和方法,并且这些化合物和方法可用于治疗癌症。
由于目前观察到的多种癌症,已经开发了许多抗癌试剂来破坏体内的癌症。将这些化合物施用于癌症患者,目的是破坏或抑制恶性细胞的生长,同时保持正常的、健康的细胞不受干扰。抗癌剂根据其作用机制被分类。
一种类型的化学治疗剂被称为金属配位复合物。据信,这种类型的化学治疗剂主要在细胞核中形成链间(inter-strand)DNA交联,从而阻止细胞复制。结果是,肿瘤生长起初被抑制,然后被逆转。另一种类型的化学治疗剂被称为烷化剂。这些化合物通过将外来组合物或分子插入到分裂中的癌细胞的DNA中而起作用。这些外来部分的结果是,癌细胞的正常功能被破坏并且阻止了增殖。另一种类型的化学治疗剂是抗赘生剂。这种类型的试剂可以阻止、杀死或阻断癌细胞的生长和扩散。还有其它类型的抗癌剂包括非甾体类芳香化酶抑制剂、双功能烷化剂等。
化学免疫治疗是化学治疗剂和免疫治疗剂的联合,是治疗癌症的一种新的方法,它联合了直接攻击肿瘤细胞产生肿瘤细胞坏死或凋亡的试剂,以及调节宿主对肿瘤免疫应答的试剂的作用。化学治疗剂可以增强免疫治疗的作用,其通过产生由抗原呈递细胞呈递的肿瘤抗原,产生“多价”肿瘤细胞疫苗,并且通过使肿瘤结构变形(distort),因此促进免疫治疗剂的渗透以及扩大的免疫群。
发明内容
提供了组合物,包括药物组合物,以及使用组合物治疗癌症的方法,所述组合物包含苯甲酰胺化合物或其药学上可接受的盐或溶剂化物,以及PD-1轴结合拮抗剂。苯甲酰胺化合物具有式其中:X选自H、卤素、-OH、-CN、-NR’R”、-OR’、-SR’、-OC(O)R’、-NHC(O)R’、-NHC(O)NR’R”、-C(O)R’、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基、-Cl-C6烷基、芳基、-C3-C7环烷基、以及3至10元杂环,其中,-C1-C6烷基、芳基、-C3-C7环烷基或3至10元杂环中的任一个可以是未取代的或者被以下的一个或多个取代:卤素、-OH、-CN、-NR’R”、-OR’、-SR’、-OC(O)R’、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)R’、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基、-Cl-C6烷基、芳基、-C3-C7环烷基;Y选自H、-Cl-C6烷基、-C3-环烷基、芳基、3至10元杂环,其中,-Cl-C6烷基、-C3-C12环烷基、芳基、3至10元杂环中的任一个可以是未取代的或者被以下的一个或多个取代:-卤素、-Cl-C6烷基、-C3-C12环烷基、3至10元杂环、芳基、OH、-CN、-OR’、-SR’、-OC(O)、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)R’、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基;R’或R”可以是-H或-Cl-C6烷基;Z是NHOH;以及Q选自H、F、Cl、Br和I。在一些实施方案中,Y选自由环戊基、环己基和环庚基。在其它实施方案中,Y选自环戊基甲基、环己基甲基或环庚基甲基。
在一些实施方案中,PD-1轴结合拮抗剂选自PD-1结合拮抗剂、PD-L1结合拮抗剂和PD-L2结合拮抗剂。
PD-1结合拮抗剂可以选自抗PD-1抗体、针对PD-1的抗体的抗原结合片段、免疫粘附素、融合蛋白和抑制PD-1与PD-L1和/或PD-L2结合的寡肽。在一些方面,抗PD-1抗体可以包含重链可变区,所述重链可变区与SEQ ID NO:22所示的序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。SEQ ID NO:22如下所示:
在一些方面,抗PD-1抗体包含轻链可变区,所述轻链可变区与SEQ ID NO:19所示的序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。在一些实施方案中,抗PD-1抗体选自MDX-1106、Merck 3745和CT-011。
PD-L1结合拮抗剂可以选自抗PD-L1抗体、针对PD-L1的抗体的抗原结合片段、免疫粘附素、融合蛋白和抑制PD-L1与PD-1和/或B7-1结合的寡肽。在一些方面,抗PD-L1抗体包含具有至少一种序列的重链可变区,所述序列与选自以下的至少一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:GFTFS-X1-SWIH(SEQ ID NO:1)、AWI-X2-PYGGS-X3-YYADSVKG(SEQ ID NO:2)和RHWPGGFDY(SEQ ID NO:3),其中X1是D或G,X2是S或L,以及X3是T或S。在一些实施方案中,X1是D,X2是S,以及X3是T。在一些实施方案中,抗PD-L1抗体的重链可变区还包含至少一种序列,所述序列与选自以下的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4)、WVRQAPGKGLEWV(SEQ ID NO:5)、RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6)、WGQGTLVTVSA(SEQID NO:7)和WGQGTLVTVSS(SEQ ID NO:17)。
在一些实施方案中,PD-1轴结合拮抗剂选自PD-1结合拮抗剂、PD-L1结合拮抗剂和PD-L2结合拮抗剂。
PD-1结合拮抗剂可以选自抗PD-1抗体、针对PD-1的抗体的抗原结合片段、免疫粘附素、融合蛋白和抑制PD-1与PD-L1和/或PD-L2结合的寡肽。在一些方面,抗PD-1抗体可以包含重链可变区,所述重链可变区与SEQ ID NO:22所示的序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。在一些方面,抗PD-1抗体包含轻链可变区,所述轻链可变区与SEQ ID NO:19所示的序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。在一些实施方案中,抗PD-1抗体选自MDX-1106、Merck 3745和CT-011。
PD-L1结合拮抗剂可以选自抗PD-L1抗体、针对PD-L1的抗体的抗原结合片段、免疫粘附素、融合蛋白和抑制PD-L1与PD-1和/或B7-1结合的寡肽。在一些方面,抗PD-L1抗体包含具有至少一种序列的重链可变区,所述序列与选自以下的至少一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:GFTFS-X1-SWIH(SEQ ID NO:1)、AWI-X2-PYGGS-X3-YYADSVKG(SEQ ID NO:2)和RHWPGGFDY(SEQ ID NO:3),其中X1是D或G,X2是S或L,以及X3是T或S。在一些实施方案中,X1是D,X2是S,以及X3是T。在一些实施方案中,抗PD-L1抗体的重链可变区还包含至少一种序列,所述序列与选自以下的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4)、WVRQAPGKGLEWV(SEQ ID NO:5)、RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6)、WGQGTLVTVSA(SEQID NO:7)和WGQGTLVTVSS(SEQ ID NO:17)。
抗PD-L1抗体可以包含重链可变区,所述重链可变区与SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24中所示的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。在一些方面,抗PD-L1抗体包含具有至少一种序列的轻链可变区,所述序列与选自以下的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:RASQ-X4-X5-X6-T-X7-X8-A(SEQ ID NO:8)、SAS-X9-L-X10-S(SEQ ID NO:9)和QQ-X11-X12-X13-X14-P-X15-T(SEQ ID NO:10),其中X4是D或V;X5是V或I;X6是S或N;X7是A或F;X8是V或L;X9是F或T;X10是Y或A;X11是Y、G、F或S;X12是L、Y、F或W;X13是Y、N、A、T、G、F或I;X14是H、V、P、T或I;以及X15是A、W、R、P或T。在一些实施方案中,X4是D,X5是V,X6是S,X7是A,X8是V,X9是F,X10是Y,X11是Y,X12是L,X13是Y,X14是H,以及X15是A。在一些方面,抗PD-L1抗体的轻链可变区还包含至少一种序列,所述序列与选自以下的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11)、WYQQKPGKAPKLLIY(SEQ ID NO:12)、GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13)和FGQGTKVEIKR(SEQ ID NO:14)。在一些方面,抗PD-L1抗体包含轻链可变区,所述轻链可变区与SEQ ID NO:18、SEQ ID NO:19和SEQID NO:20中所示的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。在一些实施方案中,抗PD-L1抗体选自MDX-1105、YW243.55.S70和MPDL3280A。
PD-L2结合拮抗剂可以选自针对PD-L2的抗体、针对PD-L2的抗体的抗原结合片段、免疫粘附素、融合蛋白和抑制PD-L2与PD-1结合的寡肽。在一些实施方案中,PD-L2结合拮抗剂是AMP-224。
还提供了治疗增殖性疾病如癌症的方法。该方法包括向需要这种治疗的受试者施用治疗有效量的PD-1轴结合拮抗剂和治疗有效量的苯甲酰胺化合物或其药学上可接受的盐或溶剂化物的步骤。
在一些实施方案中,苯甲酰胺化合物的治疗有效量和PD-1轴结合拮抗剂的治疗有效量是足以延迟受试者中癌症进展的量。在一些实施方案中,治疗有效量是足以抑制癌症转移的量。根据本发明的方法可治疗的癌症的具体类型可以选自结直肠癌、黑素瘤、非小细胞肺癌、卵巢癌、乳癌、胰癌、血液恶性肿瘤和肾细胞癌。
治疗有效量也可以是足以增加受试者的免疫功能的量。在一些实施方案中,治疗有效量是相对于施用苯甲酰胺化合物和PD-1轴结合拮抗剂之前,足以增加受试者的CD8 T细胞的引发、活化、增殖和/或细胞毒活性的量。在一些方面,CD8 T细胞是抗原特异性CD8 T细胞。治疗有效量也可以是相对于施用苯甲酰胺化合物和PD-1轴结合拮抗剂之前,足以增加受试者中CD8 T细胞的群的量,其中CD8 T细胞的群是γIFN+的。在一些实施方案中,治疗有效量是相对于施用苯甲酰胺化合物和PD-1轴结合拮抗剂之前,足以增加MHC I类抗原表达的量。治疗有效量也可以是相对于施用苯甲酰胺化合物和PD-1轴结合拮抗剂之前,足以增加抗原呈递细胞的成熟和活化的量。在一些方面,增加抗原呈递细胞的成熟和活化包括增加的CD8+树突细胞的群。具体地,增加抗原呈递细胞的成熟和活化可以包括增加树突细胞上CD80和CD86的表达。
PD-1轴结合拮抗剂可以静脉内、肌肉内、皮下、局部、口服、经皮、腹膜内、眶内、植入、吸入、鞘内、心室内或鼻内施用。苯甲酰胺化合物可以连续地施用或间歇地施用。在一些实施方案中,苯甲酰胺化合物在施用PD-1轴结合拮抗剂之前施用。在其它实施方案中,苯甲酰胺化合物在施用PD-1轴结合拮抗剂之后施用。在一些实施方案中,苯甲酰胺化合物与PD-1轴结合拮抗剂共同施用。
提供了组合物,包括药物组合物,以及使用组合物治疗癌症的方法,所述组合物包含苯甲酰胺化合物或其药学上可接受的盐或溶剂化物,以及CTLA4拮抗剂。苯甲酰胺化合物具有式其中:X选自H、卤素、-OH、-CN、-NR’R”、-OR’、-SR’、-OC(O)R’、-NHC(O)R’、-NHC(O)NR’R”、-C(O)R’、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基、-Cl-C6烷基、芳基、-C3-C7环烷基、以及3至10元杂环,其中,-C1-C6烷基、芳基、-C3-C7环烷基或3至10元杂环中的任一个可以是未取代的或者被以下的一个或多个取代:卤素、-OH、-CN、-NR’R”、-OR’、-SR’、-OC(O)R’、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)R’、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基、-Cl-C6烷基、芳基、-C3-C7环烷基;Y选自H、-Cl-C6烷基、-C3-环烷基、芳基、3至10元杂环,其中,-Cl-C6烷基、-C3-C12环烷基、芳基、3至10元杂环中的任一个可以是未取代的或者被以下的一个或多个取代:-卤素、-Cl-C6烷基、-C3-C12环烷基、3至10元杂环、芳基、OH、-CN、-OR’、-SR’、-OC(O)、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)R’、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基;R’或R”可以是-H或-Cl-C6烷基;Z是NHOH;以及Q选自H、F、Cl、Br和I。在一些实施方案中,Y选自由环戊基、环己基和环庚基。在其它实施方案中,Y选自环戊基甲基、环己基甲基或环庚基甲基。
CTLA4拮抗剂可以选自激动共刺激通路的CTLA4抑制剂、破坏CD8结合其同源配体的能力的CD28抑制剂、破坏B7结合CD28和/或CTLA4能力的B7抑制剂、破坏CD80结合CD28和/或CTLA4能力的CD80抑制剂、破坏CD80结合CD28和/或CTLA4能力的CD86抑制剂。在一些实施方案中,CTLA4拮抗剂选自CD28、CD80、CD86和CTLA4的小分子抑制剂。CTLA4拮抗剂也可以选自针对CD28、CD80、CD86和CTLA4的反义分子。在其它实施方案中,CTLA4拮抗剂选自针对CD28、CD80、CD86和CTLA4的adnectin。CTLA4拮抗剂也可以选自CD28、CD80、CD86和CTLA4的单链和双链RNA干扰抑制剂。在一些实施方案中,CTLA4拮抗剂选自针对CD28、CD80、CD86和CTLA4的抗体。在一些方面,针对CTLA4的抗体选自易普利姆玛(ipilimumab)和tremelimumab。
该组合物还可以包含肽抗原,例如gp100。该组合物还可以包含选自烷化剂、抗代谢物、长春花生物碱、抗肿瘤抗生素、酶、淋巴因子、表鬼臼毒素、navelbene、CPT-11、阿那曲唑、来曲唑、卡培他滨、雷洛昔芬、环磷酰胺、异环磷酰胺和屈洛昔芬的抗增殖细胞毒性试剂。
在一些方面,烷化剂选自氮芥(nitrogen mustards)、乙撑亚胺衍生物、烷基磺酸盐、亚硝基脲和三氮烯。烷化剂也可以选自尿嘧啶氮芥(Uracil mustard)、盐酸氮芥(Chlormethine)、环磷酰胺、异环磷酰胺、Meiphalan、苯丁酸氮芥、哌酰溴烷、三乙撑蜜胺(Triethylene-melamine)、三乙烯硫代磷酸胺(Triethylenethiophosphoramine)、白消安、卡莫司汀、洛莫司汀、链脲菌素、达卡巴嗪和替莫唑胺。
抗代谢物选自叶酸拮抗剂、嘧啶类似物、嘌呤类似物和腺苷脱氨酶抑制剂。在一些方面,抗代谢物选自甲氨蝶呤、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-巯嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨、喷司他丁和吉西他滨。
治疗癌症的方法包括向有这种治疗需要的受试者施用治疗有效量的苯甲酰胺化合物,并且向有这种治疗需要的受试者施用治疗有效量的CTLA4拮抗剂。在一些实施方案中,治疗癌症的方法治疗实体瘤和/或难治性肿瘤。在一些实施方案中,苯甲酰胺化合物在施用CTLA4拮抗剂之前施用。在其它实施方案中,苯甲酰胺化合物与CTLA4拮抗剂共同施用。在一些方面,苯甲酰胺化合物静脉内施用。
在一些实施方案中,CTLA4拮抗剂静脉内施用。在一些实施方案中,CTLA4拮抗剂的治疗有效量为0.3至10mg/kg。在一些方面,CTLA4拮抗剂每三周施用。在一些实施方案中,CTLA4拮抗剂以递增的剂量施用。
本发明的一些方法还包括施用抗增殖细胞毒性试剂。在一些实施方案中,该方法还包括对受试者施用放射治疗。
提供了组合物,包括药物组合物,所述组合物包含苯甲酰胺化合物或其药学上可接受的盐或溶剂化物,以及DNA脱甲基化试剂。苯甲酰胺化合物具有式
其中:X选自H、卤素、-OH、-CN、-COOR’、-OR’、-SR’、-OC(O)R’、-NHR’、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)NR'R”、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基、-Cl-C6烷基、芳基、-C3-C7环烷基、以及3至10元杂环,其中,-C1-C6烷基、芳基、-C3-C7环烷基或3至10元杂环中的任一个可以是未取代的或者被以下的一个或多个取代:卤素、-OH、-CN、-COOR’、-OR’、-SR’、-OC(O)R'、-NHR'、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)NR’R”、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基、-Cl-C6烷基、芳基、-C3-C7环烷基;Y选自H、-Cl-C6烷基、-C3-C12环烷基、芳基、3至10元杂环,其中,-Cl-C6烷基、-C3-C12环烷基、芳基或3至10元杂环中的任一个可以是未取代的或者被以下的一个或多个取代:-卤素、-Cl-C6烷基、-C3-C12环烷基、3至10元杂环、芳基、OH、-CN、-COOR’、-OR’、-SR’、-OC(O)R’、-NHR’、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)NR’R”、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基;R’或R”可以是-H或-Cl-C6烷基;Z选自-NHOH;以及Q选自H和卤素。在一些实施方案中,苯甲酰胺化合物选自4-(1-(环己基甲基)-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺、4-(1-环己基-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺和4-(1-环庚基-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺。
还提供了治疗增殖性疾病如癌症的方法。该方法包括向有这种治疗需要的受试者施用治疗有效量的DNA脱甲基化试剂和治疗有效量的苯甲酰胺化合物或其药学上可接受的盐或溶剂化物的步骤。
在某些实施方案中,DNA脱甲基化试剂是DNA甲基转移酶抑制剂,如胞苷类似物。在一些实施方案中,胞苷类似物选自阿扎胞苷和地西他滨。
苯甲酰胺化合物和DNA脱甲基化试剂的治疗有效量是足以降低患者细胞中增生(hyperplasia)、化生(metaplasia)或发育异常的发生的量。在一个优选的实施方案中,苯甲酰胺化合物和DNA脱甲基化试剂是足以抑制患者的细胞的赘生、恶性或转移进展的量。
在具体的实施方案中,胞苷类似物的治疗有效量为每天约15、25、50、75或100mg/m2。胞苷类似物可以每天施用持续3至14天,之后21至25天休息。或者胞苷类似物可以周期施用,其中,胞苷类似物施用的周期为28天,从胞苷类似物施用3至14天开始,之后休息。
胞苷类似物和苯甲酰胺化合物可以系统性地施用。例如,胞苷类似物可以静脉内、皮下或口服施用。在具体实施方案中,胞苷类似物皮下施用,苯甲酰胺化合物口服施用。在另一个实施方案中,胞苷类似物口服施用,苯甲酰胺化合物静脉内施用。在另一个实施方案中,胞苷类似物静脉内施用,苯甲酰胺化合物口服施用。在一个实施方案中,胞苷类似物和苯甲酰胺化合物均口服施用。
附图说明
图1描绘单独的化合物ID#24、单独的PD-1轴结合拮抗剂和两种治疗剂的联合对4T1鼠乳肿瘤体积生长的作用。
图2描绘了单独的化合物ID#24、单独的CTLA4拮抗剂和两种治疗剂的联合对4T1鼠乳肿瘤体积生长的作用。
图3描绘单独的化合物ID#24、PD-1轴结合拮抗剂和CTLA4拮抗剂的联合以及所有三种治疗剂的联合对4T1鼠乳肿瘤体积生长的作用。
图4描绘单独的化合物ID#24、单独的PD-1轴结合拮抗剂和两种治疗剂的联合对4T1鼠乳肿瘤细胞移植形成的自发性肺转移的作用。
图5描绘单独的化合物ID#24、单独的CTLA4拮抗剂和两种治疗剂的联合对4T1鼠乳肿瘤细胞移植形成的自发性肺转移的作用。
图6描绘了单独的化合物ID#24、PD-1轴结合拮抗剂和CTLA4拮抗剂的联合以及所有三种治疗剂的联合对4T1鼠乳肿瘤细胞移植形成的自发性肺转移的作用。
具体实施方式
如本文所使用的,如在本说明书以及权利要求书中使用的动词“包含”及其词形变化以其非限制性含义使用,指包括在该词之后的项目,但是没有具体提及的项目不被排除。另外,通过不定冠词“一”或“一个”提及的元素并不排除存在多于一个的元素的可能性,除非上下文明确要求存在一个且仅有一个元素。因此,不定冠词“一”或“一个”通常指“至少一个”。
如本文所使用的,术语“受试者”或“患者”是指任何脊椎动物,包括但不限于人和其它灵长类动物(例如,猩猩和其它猿和猴物种)、农场动物(例如,牛、绵羊、猪、山羊和马)、驯养哺乳动物(例如,狗和猫)、实验用动物(例如,啮齿动物如小鼠、大鼠和豚鼠)和禽(例如,驯养、野生和猎禽,如鸡、火鸡和其它鹑鸡类禽、鸭、鹅等)。在一些实施方案中,受试者可以是哺乳动物。在其它实施方案中,受试者可以是人。
如本文所使用的,术语“治疗”是指全部或部分缓解与失调或疾病(例如,癌症或肿瘤综合征)相关的症状,或者减缓或停止那些症状的进一步进展或恶化。在包括但不限于哺乳动物(尤其是人)以及具有经济或社会重要性的其它哺乳动物(包括濒临灭绝状态的哺乳动物)的生命体中考虑治疗。进一步的示例包括通常饲养用于人消费的家畜或其它动物以及驯养伴侣动物。病症的治疗是这样的任何方法、过程或程序的实践,即其为了停止、抑制、减缓或逆转疾病、失调或病症的进展,实质上改善疾病、失调或病症的临床症状、或者实质上预防疾病、失调或病症的临床症状的出现,直至并且包括使患病实体返回到疾病发展之前的状态。
如本文所使用的,术语“预防”是指全部或部分预防疾病或失调(例如,癌症)或其症状的发作、复发或扩散。
如本文所使用的,术语“肿瘤”是指所有赘生细胞生长和增殖,无论是恶性的或良性的,以及所有的癌前和癌细胞和组织。如本文所使用的,术语“赘生”是指任何形式的异常调节的(dysregulated)或未调节的(unregulated)细胞生长,无论是恶性的或良性的,这导致异常的组织生长。因此,“赘生细胞”包括具有异常调节的或未调节的细胞生长的恶性和良性细胞。
如本文所使用的,术语“癌症”包括但不限于实体瘤和血液源肿瘤。因此,术语“癌症”包括膀胱、骨或血液、脑、乳、子宫颈、胸、结肠、子宫内膜、食道、眼、头、肾脏、肝脏、淋巴结、肺、口、颈、卵巢、胰腺、前列腺、直肠、胃、睾丸、喉和子宫的癌症。
如本文所使用的,术语“增殖性”失调或疾病是指多细胞生物体中一种或多种细胞亚群的有害细胞增殖,导致对多细胞生物体的危害(即,不舒适或降低的预期寿命)。例如,如本文所使用的,增殖性失调或疾病包括赘生失调和其它增殖性失调。
如本文所使用的,术语“癌细胞”是指衍生自肿瘤、赘生、癌症、癌前、细胞系或任何其它最终能够潜在无限扩增和生长的细胞来源的任何细胞。癌细胞可以衍生自天然存在的来源,或者可以是人造的。当放入动物宿主时,癌细胞还能够侵入其它组织和转移。癌细胞还涵盖侵入其它组织和/或转移的任何恶性细胞。生物体情况下的一种或多种癌细胞也可以被称为癌症、肿瘤、赘生、生长、恶性肿瘤或本领域中用于描述癌性状态细胞的任何其它术语。
如本文所使用的,术语“复发”是指已经在治疗后获得癌症缓解的受试者具有癌细胞的返回的情况。
如本文所使用的,术语“难治性”或“抗性”是指即使在加强治疗之后,受试者体内具有残留癌细胞的情况。
如本文所使用的,术语“化学抗性癌症”是指这样一种癌症类型,即对化学治疗应答的癌症,因为癌细胞对化学治疗的作用不应答,突然开始生长。
如本文所使用的,术语“活性成分”和“活性物质”是指这样一种化合物,即单独或与一种或多种药学上可接受的赋形剂联合施用于受试者,用于治疗、预防或改善病症、失调或疾病的一种或多种症状。如本文所使用的,“活性成分”和“活性物质”可以是本文描述的化合物的光学活性异构体或同位素变体。
术语“药物”、“治疗剂”和“化学治疗剂”是指施用于受试者,用于治疗、预防或改善病症、失调或疾病的一种或多种症状的化合物或其药物组合物。
如本文所使用的,与苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂有关的术语“有效量”是指这样的量,即能够全部或部分缓解与失调相关的症状、或者减缓或停止那些症状的进一步进展或恶化、或者在有失调风险的受试者中预防或提供对失调的预防。苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的有效量(例如在药物组合物中),可以处于将实现所需作用的水平。例如,在癌症的情况下,有效量是这样的量,即能够全部或部分缓解与癌症例如癌症相关的症状、或者减缓或停止那些症状的进一步进展或恶化、或者在有癌症风险的受试者中预防或提供对癌症的预防。对于本领域技术人员来说显而易见的是,预期本文中苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的有效量可以根据待治疗的适应症的严重程度而变化。
如本文所使用的,术语“药学上可接受的”是指生理上可耐受的分子实体和组合物,并且当施用于受试者时通常不产生过敏或类似的不良反应,例如胃部不适、头晕等。
因此,术语“药学上可接受的载体”是指参与从一器官或身体的一部分的施用部位到另一器官或身体的一部分、或在体外测定系统中,携带或运输目标(subject)化合物的药学上可接受的材料、组合物或载体,如液体或固体填充剂、稀释剂、赋形剂、溶剂或包囊材料。每种载体在与制剂的其它成分相兼容的意义上必须是“可接受的”,并且不会对被施用的受试者有害。可接受的载体也不应该改变目的化合物的比活性(specific activity)。
如本文所使用的,术语“药学上可接受的盐”涵盖该术语所指化合物的无毒酸和碱加成盐。可接受的无毒酸加成盐包括衍生自有机和无机酸或碱的那些。这种盐的示例包括但不限于以下:氢溴酸、盐酸、硝酸、磷酸和硫酸的盐。有机酸加成盐包括例如醋酸、苯磺酸(benzenesulphonic acid)、苯甲酸、樟脑磺酸、柠檬酸、2-(4-氯苯氧基)-2-甲基丙酸、1,2-乙烷二磺酸、乙磺酸、乙二胺四乙酸(EDTA)、富马酸、葡庚糖酸、葡糖酸、谷氨酸、N-羟乙酰基阿散酸(N-glycolylarsanilic acid)、4-己基间苯二酚、马尿酸、2-(4-羟基苯甲酰基)苯甲酸、1-羟基-2-萘甲酸、3-羟基-2-萘甲酸、2-羟基乙磺酸、乳糖酸、正十二烷基硫酸、马来酸、苹果酸、扁桃酸、甲磺酸、甲基硫酸、粘酸、2-萘磺酸、双羟萘酸、泛酸、磷酸(phosphanilicacid)((4-氨基苯基)膦酸)、苦味酸、水杨酸、硬脂酸、琥珀酸、丹宁酸、酒石酸、对苯二甲酸、对甲苯磺酸、10-十一碳烯酸的盐或任何其它目前已知的或尚待公开的这种酸的盐。本领域技术人员将会理解,这种药学上可接受的盐可以用于药物组合物的制剂中。这种盐可以以本领域技术人员已知的方式,通过将苯甲酰胺化合物或PD-1轴结合拮抗剂、CTLA4拮抗剂、和/或DNA脱甲基化试剂与适合的酸反应来制备。
性质上为酸性的化合物能够与不同的药学上可接受的碱形成盐。可以用于制备这种酸性化合物的药学上可接受的碱加成盐的碱是形成无毒的碱加成盐的那些,即含有药理学上可接受的阳离子的盐,如但不限于碱金属或碱土金属盐,以及尤其是钙、镁、钠或钾盐。适合的有机碱包括但不限于N,N-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、甲葡胺(meglumaine)(N-甲基葡糖胺)、赖氨酸和普鲁卡因。
如本文所使用的,术语“前药”是指可在生物条件下(在体外或在体内)水解、氧化或以其它方式反应以提供化合物的化合物的衍生物。前药的示例包括但不限于包含可生物水解部分如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯/盐、可生物水解的碳酸酯/盐、可生物水解的酰脲和可生物水解的磷酸酯/盐类似物的本发明的免疫调节化合物的衍生物。前药的其它示例包括本发明的免疫调节化合物的衍生物,其包含-NO、-NO2、-ONO或-ONO2部分。通常可以使用熟知的方法制备前药,如Burger's MedicinalChemistry and Drug Discovery(Manfred E.Wolff编,第5版.1995)和Design ofProdrugs(H.Bundgaard编,Elselvier,纽约1985)中描述的那些。
如本文所使用的,当用于提及的治疗组合物时,术语“单位剂量”是指适合作为用于人的单一的剂量的物理离散单位,每单位含有预定量的活性物质,所述活性物质被计算为与所需的稀释剂(即,载体(carrier)或载体(vehicle))联合产生所需的治疗作用。
如本文所使用的,术语“单位剂型”是指适合施用于人和动物受试者的物理离散单位,并且如本领域已知的单独包装。每单位剂量含有与所需的药物载体或赋形剂联合的、足以产生所需治疗作用的预定量的一种或多种活性成分。单位剂型可以以其分数或倍数施用。单位剂型的示例包括安瓿、注射器和单独包装的片剂和胶囊。
如本文所使用的,术语“多剂型”是包装在单个容器中的多个相同的单位剂型,以分离的单位剂型施用。多剂型的示例包括小瓶、片剂或胶囊的瓶,或品脱或加仑的瓶。
如本文所使用的,并且除非另有说明,术语“组合物”、“制剂”和“剂型”旨在涵盖包含具体的一种或多种成分(如果指出的话,以具体的量)的产品,以及由具体的量的一种或多种具体的成分的组合直接或间接产生的任何一种或多种产品。
如本文所使用的,在免疫功能障碍的情况下,术语“功能障碍”是指对抗原刺激的免疫应答降低的状态。该术语包括抗原识别可以发生的耗竭和/或失能(anergy)的普通要素,但随后的免疫应答对控制感染或肿瘤生长是无效的。
如本文所使用的,术语“功能障碍的”还包括对抗原识别的不应性(refractory)或无应答,具体地,将抗原识别翻译成下游T细胞效应功能(如增殖、细胞因子产生(例如,IL-2)和/或靶细胞杀伤)的能力受损。
术语“失能”是指由于通过T细胞受体递送的信号不完整或不足(例如,在不存在ras活化的情况下细胞内Ca+2增加)而对抗原刺激无应答的状态。T细胞失能也可以在不存在共刺激的情况下用抗原刺激后产生,导致即使在共刺激的情况下,细胞变得难以被抗原随后活化。白细胞介素-2的存在经常可以克服(overridden)无应答的状态。失能的T细胞不经历克隆扩增和/或获得效应功能。
术语“耗竭”是指T细胞耗竭,其由于许多慢性感染和癌症期间发生的持续TCR信号传导而引起的T细胞功能障碍的状态。它与失能的区别在于它不是通过信号传导不完整或不足而产生的,而是由于持续的信号传导。其定义为效应功能差、抑制性受体的持续表达以及与功能效应或记忆T细胞不同的转录状态。耗竭无法对感染和肿瘤进行最佳控制。耗竭可由于外在负调节通路(例如,免疫调节细胞因子)以及细胞内在负调节(共刺激)通路(PD-1,B7-H3,B7-H4等)产生。
如本文所使用的,“增强T细胞功能”是指诱导、引起或刺激T细胞具有持续或放大的生物学功能,或者更新或重新活化耗竭或失活的T细胞。增强T细胞功能的示例包括:相对于干预之前的这种水平,增加CD8+T细胞的γ-干扰素分泌、增加的增殖、增加的抗原应答(例如,病毒、病原体或肿瘤清除)。在一个实施方案中,增强水平为至少50%,或者60%、70%、80%、90%、100%、120%、150%、200%。测量这种增强的方式是本领域普通技术人员已知的。
“T细胞功能障碍失调”是特征在于对抗原刺激的应答降低的T细胞的失调或病症。在一个具体的实施方案中,T细胞功能障碍失调是与通过PD-1的不适合增加的信号传导尤其相关的失调。在另一个实施方案中,T细胞功能障碍失调中的T细胞是失能的,或者具有降低的分泌细胞因子、增殖或执行细胞毒活性的能力。在具体的方面,降低应答导致对表达免疫原的病原体或肿瘤的无效控制。以T细胞功能障碍为特征的T细胞功能障碍失调的示例包括未解决的急性感染、慢性感染和肿瘤免疫。
“肿瘤免疫”是指肿瘤逃避免疫识别和清除的过程。因此,作为治疗概念,当这种逃避被减弱,并且肿瘤被免疫系统识别和攻击时,肿瘤免疫被“治疗”。肿瘤识别的示例包括肿瘤结合、肿瘤缩小和肿瘤清除。
“免疫原性”是指具体的物质激发免疫应答的能力。肿瘤是免疫原性的并且增强肿瘤免疫原性有助于通过免疫应答清除肿瘤细胞。增强肿瘤免疫原性的示例包括用抗PDL抗体和公开的苯甲酰胺化合物进行治疗。
“持续应答”是指在停止治疗后对降低肿瘤生长的持续作用。例如,与施用阶段开始时的尺寸相比,肿瘤尺寸可以保持相同或更小。在一些实施方案中,持续应答的持续时间至少与治疗持续时间相同、为治疗持续时间长度的至少1.5倍、2.0倍、2.5倍或3.0倍。
术语“抗体”包括单克隆抗体(包括具有免疫球蛋白Fc区的全长抗体)、具有多表位特异性的抗体组合物、多特异性抗体(例如,双特异性抗体、双体(diabodies)和单链分子,以及抗体片段(例如,Fab、F(ab’)2和Fv)。术语“免疫球蛋白”(Ig)在本文中可与“抗体”互换使用。
基本的4链抗体单元是由两条相同的轻(L)链和两条相同的重(H)链组成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元和称为J链的额外的多肽组成,并且含有10个抗原结合位点,而IgA抗体包含2-5个基本的4链单元,所述基本的4链单元与J链组合聚合形成多价集合体。在IgG的情况下,4链单元通常约为150,000道尔顿。每条L链通过一个共价二硫键与H链连接,而根据H链同种型,两条H链通过一个或多个二硫键相互连接。每条H和L链也具有规则间隔的链内(intrachain)二硫桥。每条H链在N末端具有可变结构域(VH),其后是α和γ链中的每条的三个恒定结构域(CH),以及1.1和E同种型的四个CH结构域。每条L链在N末端具有可变结构域(VL),其后是在另一端的恒定结构域。VL与VH对齐,并且CL与重链的第一恒定结构域(CH1)对齐。据信,具体的氨基酸残基在轻链和重链可变结构域之间形成界面。VH和VL的配对一起形成单个抗原结合位点。对于不同种类的抗体的结构和性质,参见例如,Basic and Clinical Immunology,第8版,Daniel P.Sties,Abba I.Terr和TristramG.Parsolw(编),Appleton&Lange,Norwalk,Conn.,1994,第71页和第6章。基于L链的恒定结构域的氨基酸序列,来自任何脊椎动物物种的L链可被分为两种明显不同的类型中的一种,称为κ和λ。根据免疫球蛋白的重链恒定结构域(CH)的氨基酸序列,可以将免疫球蛋白分为不同的类型或同种型。有五种类型的免疫球蛋白:IgA、IgD、IgE、IgG和IgM,分别具有指定为α、δ、ε、γ和pt的重链。基于CH序列和功能的相对小的差异,γ和α类型被进一步分成亚类,例如,人表达以下亚类:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgA2。
抗体的“可变区”或“可变结构域”是指抗体的重链或轻链的氨基末端结构域。重链和轻链的可变结构域可以分别称为“VH”和“VL”。这些结构域通常是抗体中最可变的部分(相对于相同类型的其它抗体)并含有抗原结合位点。
术语“可变”是指这样的事实,即可变结构域的某些区段在抗体中的序列差异很大。V结构域介导抗原结合并确定具体抗体对其具体抗原的特异性。然而,可变性并不是均匀分布在整个可变结构域的范围内。相反,它集中在轻链和重链可变结构域中称为高变区(HVR)的三个区段。可变结构域更高度保守的部分称为框架区(FR)。原生(native)重链和轻链的可变结构域各自包含四个FR区,大部分采用β-折叠构型,通过三个HVR连接,其形成环连接,并且在一些情况下形成β-折叠结构的一部分。每条链中的HVR通过FR区紧密邻近聚集在一起,并与来自另一条链的HVR促使抗体的抗原结合位点的形成(参见Kabat等人,Sequences of Immunological Interest,第5版,国立卫生研究院(National Instituteof Health),贝塞斯达,Md.(1991))。恒定结构域不直接参与抗体与抗原的结合,而是表现出不同的效应功能,如抗体依赖性细胞毒性中抗体的参与。
如本文所使用的,术语“单克隆抗体”是指从实质上同质的抗体的群获得的抗体,即,除了可能的天然存在的突变和/或翻译后修饰(例如异构化、酰胺化)可以以少量存在,包含该群的单独的抗体是相同的。针对单个抗原位点,单克隆抗体是高度特异性的。与通常包括针对不同决定簇(表位)的不同抗体的多克隆抗体制剂不同,每种单克隆抗体针对抗原上的单个决定簇。除了它们的特异性之外,单克隆抗体的优点在于它们由杂交瘤培养物合成,未被其它免疫球蛋白污染。修饰语“单克隆”表示从实质上同质的抗体的群获得的抗体的特征,并不被解释为需要通过任何具体方法产生抗体。例如,根据本发明使用的单克隆抗体可以通过多种技术来制备,包括例如杂交瘤方法(例如,Kohler和Milstein,Nature,256:495-97(1975);Hongo等人,Hybridoma,14(3):253-260(1995),Harlow等人,Antibodies:ALaboratory Manual,(Cold Spring Harbor Laboratory Press,第2版.1988);Hammerling等人,在Monoclonal Antibodies and T-Cell Hybridomas 563-681(Elsevier,N.Y.,1981)中)、重组DNA方法(参见,例如美国专利号4,816,567)、噬菌体展示技术(参见,例如Clackson等人,Nature,352:624-628(1991);Marks等人,J.Mol.Biol.222:581-597(1992);Sidhu等人,J.Mol.Biol.338(2):299-310(2004);Lee等人,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);以及Lee等人,J.Immunol.Methods 284(1-2):119-132(2004)、以及在具有部分或全部人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物中产生人或人样抗体的技术(参见,例如WO1998/24893;WO1996/34096;WO 1996/33735;WO 1991/10741;Jakobovits等人,Proc.Natl.Acad.Sci.USA 90:2551(1993);Jakobovits等人,Nature 362:255-258(1993);Bruggemann等人,Year in Immunol.7:33(1993);美国专利号5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;和5,661,016;Marks等人,Bio/Technology 10:779-783(1992);Lonberg等人,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild等人,Nature Biotechnol.14:845-851(1996);Neuberger,NatureBiotechnol.14:826(1996);以及Lonberg和Huszar,Intern.Rev.Immunol.13:65-93(1995)。
术语“裸抗体”是指不与细胞毒性部分或放射性标记缀合的抗体。
术语“全长抗体”、“完整抗体”或“全抗体”可互换使用,是指实质完整形式的抗体,与抗体片段不同。具体地,全抗体包括具有包括Fc区的重链和轻链的抗体。恒定结构域可以是原生序列恒定结构域(例如,人原生序列恒定结构域)或其氨基酸序列变体。在一些情况下,完整抗体可以具有一种或多种效应功能。
“抗体片段”包含完整抗体的一部分,优选完整抗体的抗原结合和/或可变区。抗体片段的示例包括Fab、Fab’、F(ab’)2和Fv片段;双体;线性抗体(参见美国专利号5,641,870,实施例2;Zapata等人,Protein Eng.8(10):1057-1062[1995]);单链抗体分子和由抗体片段形成的多特异性抗体。木瓜蛋白酶消化抗体产生称为“Fab”片段的两种相同的抗原结合片段和残留的“Fc”片段,一种反映容易结晶的能力的指定。Fab片段由整个L链连同H链的可变区结构域(VH)和一个重链的第一恒定结构域(CH1)组成。每个Fab片段相对于抗原结合是单价的,即,它具有单个抗原结合位点。胃蛋白酶处理抗体产生单个大的F(ab’)2片段,其大致对应于具有不同抗原结合活性并仍能够交联抗原的两个二硫连接的Fab片段。Fab'片段与Fab片段的不同在于在CH1结构域的羧基末端具有一些额外的残基,包括来自抗体铰链区的一个或多个半胱氨酸。Fab'-SH是本文对Fab'的指定,其中恒定结构域的半胱氨酸残基携带游离硫醇基。F(ab’)2抗体片段起初是作为Fab'片段对产生的,在所述Fab'片段对之间具有铰链半胱氨酸。其它抗体片段的化学偶联也是已知的。
Fc片段包含通过二硫化物结合在一起的两条H链的羧基末端部分。抗体的效应功能由Fc区中的序列确定,该区也被在某些类型的细胞上发现的Fc受体(FcR)识别。
“Fv”是含有完整抗原识别和结合位点的最小抗体片段。该片段由紧密非共价联合的一个重链和一个轻链可变区结构域的二聚体组成。从这两种结构域的折叠发出六个高变环(各来自H链和L链的三个环),其促使用于抗原结合的氨基酸残基并赋予抗体结合抗原的特异性。然而,甚至单个可变结构域(或Fv的一半,其仅包含三个抗原特异性的HVR)具有识别和结合抗原的能力,尽管其亲和力(affinity)低于整个结合位点。
“单链Fv”,也简写为“sFv”或“scFv”,是包含连接成单个多肽链的VH和VL抗体结构域的抗体片段。优选地,sFv多肽还包含VH和VL结构域之间的多肽接头,其使得sFv形成用于抗原结合的所需结构。关于sFv的综述,参见Pluckthun在The Pharmacology ofMonoclonal Antibodies,卷113,Rosenburg和Moore编,Springer-Verlag,纽约,第269-315页(1994)中。
本发明的抗体的“功能片段”包含完整抗体的一部分,通常包括完整抗体的抗原结合或可变区,或者保留或具有修饰的FcR结合能力的抗体的Fc区。抗体片段的示例包括线性抗体、单链抗体分子和由抗体片段形成的多特异性抗体。
“双体”是指通过在VH和VL结构域之间用短接头(约5-10个残基)构建sFv片段(参见前面的段落)制备的小抗体片段,使得V结构域的链间而不是链内配对,从而产生二价片段,即,具有两个抗原结合位点的片段。双特异性双体是两种“交叉”sFv片段的异二聚体,其中两种抗体的VH和VL结构域存在于不同的多肽链上。双体在例如EP 404,097;WO 93/11161;Hollinger等人,Proc.Natl.Acad.Sci.USA 90:6444-6448(1993)中更详细的描述。
本文中的单克隆抗体具体包括“嵌合”抗体(免疫球蛋白)以及这样的抗体的片段,只要它们表现出所需的生物学活性,其中重链和/或轻链的一部分与衍生自具体物种或属于具体抗体类型或亚类的抗体中的相应序列相同或同源,而链的其余部分与衍生自另一物种或者属于另一种抗体类型或亚类的抗体中的相应序列相同或同源(美国专利号4,816,567;Morrison等人,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984))。本文中感兴趣的嵌合抗体包括抗体,其中抗体的抗原结合区衍生自通过例如用感兴趣的抗原免疫猕猴产生的抗体。如本文所使用的,“人源化抗体”用作“嵌合抗体”的子集。
非人(例如,鼠)抗体的“人源化”形式是含有衍生自非人免疫球蛋白的最小序列的嵌合抗体。在一个实施方案中,人源化抗体是人免疫球蛋白(受体抗体),其中来自受体的HVR的残基(下文定义)被来自非人物种(供体抗体)(如小鼠、大鼠、兔或非人灵长类动物)的具有所需特异性、亲和力和/或能力的HVR的残基替换。在一些示例中,人免疫球蛋白的框架(“FR”)残基被相应的非人残基替换。此外,人源化抗体可以包含在受体抗体或供体抗体中未发现的残基。可以进行这些修饰以进一步改进抗体性能,例如结合亲和力。通常,人源化抗体将包含实质上全部的至少一种、通常两种可变结构域,其中全部或实质上全部的高变环对应于非人免疫球蛋白序列的高变环,并且全部或实质上全部的FR区是人免疫球蛋白序列的FR区,尽管FR区可以包括一种或多种单独的FR残基取代,其改善抗体性能,如结合亲和力、异构化、免疫原性等。FR中这些氨基酸取代的数量在H链中通常不超过6个,并且在L链中不超过3个。任选地,人源化抗体还将包含至少一部分免疫球蛋白恒定区(Fc),通常是人免疫球蛋白的恒定区。为了了解详情,参见,例如Jones等人,Nature 321:522-525(1986);Riechmann等人,Nature332:323-329(1988);以及Presta,Curr.Op.Struct.Biol.2:593-596(1992)。还参见,例如Vaswani和Hamilton,Ann.Allergy,Asthma&Immunol.1:105-115(1998);Harris,Biochem.Soc.Transactions 23:1035-1038(1995);Hurle和Gross,Curr.Op.Biotech.5:428-433(1994);以及美国专利号6,982,321和7,087,409。
“人抗体”是具有对应于由人产生的抗体的氨基酸序列的抗体,和/或使用本文公开的任何制备人抗体的技术制备的抗体。人抗体的该定义具体排除了包含非人抗原结合残基的人源化抗体。人抗体可以使用本领域已知的不同的技术产生,包括噬菌体展示文库。Hoogenboom和Winter,J.Mol.Biol.,227:381(1991);Marks等人,J.Mol.Biol.,222:581(1991)。也可用于制备人单克隆抗体的是在Cole等人,Monoclonal Antibodies andCancer Therapy,Alan R.Liss,p.77(1985);Boerner等人,J.Immunol.,147(1):86-95(1991)中描述的方法。还参见van Dijk和van de Winkel,Curr.Opin.Pharmacol.,5:368-74(2001)。人抗体可以通过将抗原施用于转基因动物来制备,所述转基因动物已经被修饰以产生对抗原攻击应答的这种抗体,但是其内源基因座是有缺陷的,例如免疫的xeno-小鼠(xenomice)(参见,例如美国专利号6,075,181和6,150,584关于XENOMOUSE.TM.技术)。还参见,例如Li等人,Proc.Natl.Acad.Sci.USA,103:3557-3562(2006)关于通过人B细胞杂交瘤技术产生的人抗体。
当在本文中使用时,术语“高变区”、“HVR”或“HV”是指抗体可变结构域的区域,其在序列中高变和/或形成结构上定义的环。通常,抗体包含六个HVR;VH中有三个(H1、H2、H3),VL中有三个(L1、L2、L3)。在原生抗体中,H3和L3在6个HVR中显示最多样化,尤其是认为H3在赋予抗体良好特异性方面发挥独特作用。参见,例如Xu等人,Immunity 13:37-45(2000);Johnson和Wu,在Methods in Molecular Biology 248:1-25(Lo,编,Human Press,Totowa,N.J.,2003)中。实际上,在不存在轻链的情况下,仅由重链组成的天然存在的骆驼抗体是有功能且稳定的。参见,例如Hamers-Casterman等人,Nature 363:446-448(1993);Sheriff等人,Nature Struct.Biol.3:733-736(1996)。
HVR的许多描述正在使用,并涵盖在本文。Kabat互补决定区(CDR)基于序列可变性,并且是最常使用的(Kabat等人,Sequences of Proteins of ImmunologicalInterest,第5版.Public Health Service,National Institutes of Health,Bethesda,Md.(1991))。而Chothia是指结构环的位置(Chothia和Lesk,J.Mol.Biol.196:901-917(1987))。AbM HVR代表Kabat HVR和Chothia结构环之间的折衷,并且通过OxfordMolecular's AbM抗体建模软件使用。“接触(contact)”HVR基于对可用的CompleX晶体结构的分析。
HVR可以包含如下的“延伸的HVR”:在VL中的24-36或24-34(L1)、46-56或50-56(L2)以及89-97或89-96(L3),以及在VH中的26-35(H1)、50-65或49-65(H2)以及93-102、94-102或95-102(H3)。对于这些定义中的每一个,可变结构域残基根据上文Kabat等人编号。
表述“如Kabat中的可变结构域残基编号”或“如Kabat中的氨基酸位置编号”及其变体,是指在上文Kabat等人中抗体汇编的用于重链可变结构域或轻链可变结构域的编号系统。使用该编号系统,实际的线性氨基酸序列可以含有更少或额外的氨基酸,其对应于可变结构域的FR或HVR的缩短或插入。例如,重链可变结构域可以包括在H2的残基52之后的单个氨基酸插入(根据Kabat的残基52a)和重链FR残基82之后插入的残基(例如根据Kabat的残基82a、82b和82c等)。可以通过在抗体序列与“标准”Kabat编号序列的同源区域比对来确定给定抗体的残基的Kabat编号。
“框架”或“FR”残基是除了本文定义的HVR残基以外的那些可变结构域残基。
“人一致框架”或“受体人框架”是代表选择的人免疫球蛋白VL或VH框架序列中最常出现的氨基酸残基的框架。通常,人免疫球蛋白VL或VH序列的选择来自可变结构域序列的亚组。通常,序列的亚组是如Kabat等人Sequences of Proteins of ImmunologicalInterest,第5版.Public Health Service,National Institutes of Health,Bethesda,Md.(1991)中的亚组。示例包括,对于VL的亚组可以是如上文Kabat等人中的亚组κI、κII、κIII或κIV。另外,对于VH,亚组可以是如上文Kabat等人中的亚组I、亚组II或亚组III。或者,衍生自上述的人一致框架,其中具体的残基,如当通过将供体框架序列与不同的人框架序列的集合进行比对,基于其与供体框架的同源性来选择人框架残基。“衍生自”人免疫球蛋白框架或人一致框架的受体人框架可以包含其相同的氨基酸序列,或者它可以包含预先存在的氨基酸序列改变。在一些实施方案中,预先存在的氨基酸改变的数量是10个或更少、9个或更少、8个或更少、7个或更少、6个或更少、5个或更少、4个或更少、3个或更少或2个或更少。
“VH亚组III一致框架”包含从上文Kabat等人的可变重亚组III中的氨基酸序列获得的一致序列。在一个实施方案中,VH亚组III一致框架氨基酸序列包含以下序列中每个的至少一部分或全部:EVQLVESGGGLVQPGGSLRLSCAAS(HC-FR1,SEQ ID NO:4)、WVRQAPGKGLEWV(HC-FR2,SEQ ID NO:5)、RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(HC-FR3,SEQ ID NO:6)、WGQGTLVTVSA(HC-FR4,SEQ ID NO:7)。
“VLκI一致框架”包含从上文Kabat等人的可变轻κ亚组I中的氨基酸序列获得的一致序列。在一个实施方案中,VH亚组I一致框架氨基酸序列包含以下序列中每个的至少一部分或全部:DIQMTQSPSSLSASVGDRVTITC(LC-FR1,SEQ ID NO:11)、WYQQKPGKAPKLLIY(LC-FR2,SEQ ID NO:12)、GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(LC-FR3,SEQ ID NO:13)、FGQGTKVEIKR(LC-FR4,SEQ ID NO:14)。
在具体位置(例如Fc区)的“氨基酸修饰”,是指具体残基的取代或缺失,或者邻近具体残基至少一个氨基酸残基的插入。“邻近”具体残基插入是指其插入1至2个残基内。插入可以是具体残基的N末端或C末端。本文优选的氨基酸修饰是取代。
“亲和力成熟的”抗体是在其一种或多种HVR中具有一种或多种改变的抗体,与不具有那些改变的亲本抗体相比,这导致抗体对抗原的亲和力改善。在一个实施方案中,亲和力成熟的抗体对靶抗原具有纳摩尔或者甚至皮摩尔亲和力。亲和力成熟的抗体通过本领域已知的程序产生。例如,Marks等人,Bio/Technology 10:779-783(1992)描述了通过VH和VL结构域重排(shuffling)的亲和力成熟。HVR和/或框架残基的随机诱变描述于例如:Barbas等人Proc Nat.Acad.Sci.USA91:3809-3813(1994);Schier等人Gene 169:147-155(1995);Yelton等人J.Immunol.155:1994-2004(1995);Jackson等人,J.Immunol.154(7):3310-9(1995);以及Hawkins等人,J.Mol.Biol.226:889-896(1992)。
如本文所使用的,术语“特异性结合”或“特异于”是指可测量的和可再现的相互作用,如靶与抗体之间的结合,所述抗体确定在存在包括生物分子的分子的异质群体中的靶的存在。例如,与靶(其可以是表位)特异性结合的抗体是这样一种抗体,其以比与其它靶结合更大的亲和力、亲合力(avidity)、更容易和/或更长持续时间结合该靶。在一个实施方案中,例如,通过放射免疫测定(RIA)测量的,抗体与无关靶的结合程度小于抗体与靶结合的约10%。在某些实施方案中,特异性结合靶的抗体具有≤1μM、≤100nM、≤10nM、≤1nM或≤0.1nM的解离常数(Kd)。在某些实施方案中,抗体特异性结合在来自不同物种的蛋白中保守的蛋白上的表位。在另一个实施方案中,特异性结合可以包括但不需要排他性结合。
如本文所使用的,术语“免疫粘附素”指定为将异源蛋白的结合特异性(“粘附素”)与免疫球蛋白恒定结构域的效应功能组合的抗体样分子。结构上,免疫粘附素包含氨基酸序列的融合物,其具有除了抗体的抗原识别和结合位点以外的所需结合特异性的氨基酸序列(即“异源的”)和免疫球蛋白恒定结构域序列。免疫粘附素分子的粘附素部分通常是连续的氨基酸序列,其至少包含受体或配体的结合位点。免疫粘附素中的免疫球蛋白恒定结构域序列可以从任何免疫球蛋白获得,如IgG-1、IgG-2(包括IgG2A和IgG2B)、IgG-3或IgG-4亚型、IgA(包括IgA-1和IgA-2)、IgE、IgD或IgM。Ig融合物优选包括本文描述的多肽或抗体的结构域代替Ig分子内的至少一个可变区的取代。在具体优选的实施方案中,免疫球蛋白融合物包括IgG1分子的铰链、CH2和CH3,或者铰链、CH1、CH2和CH3区。为了产生免疫球蛋白融合物,还参见颁布于1995年6月27日的美国专利号5,428,130。例如,作为可用于本文组合治疗的第二药物的有用的免疫粘附素包括包含PD-L1或PD-L2的细胞外或PD-1结合部分,或者PD-1的细胞外或PD-L1或PD-L2结合部分的多肽,分别与免疫球蛋白序列的恒定结构域融合,如PD-L1ECD Fc、PD-L2 ECD Fc和PD-1ECD-Fc。
Ig Fc和细胞表面受体的细胞外结构域的免疫粘附素组合有时被称为可溶性受体。
“融合蛋白”和“融合多肽”是指具有共价连接在一起的两个部分的多肽,其中每个部分是具有不同性质的多肽。该性质可以是生物学性质,如体外或体内活性。该性质还可以是简单的化学或物理性质,如与靶分子的结合、反应的催化作用等。这两个部分可以通过单个肽键直接连接,或者通过肽接头连接,但彼此处于阅读框中。
“PD-1寡肽”、“PD-L1寡肽”或“PD-L2寡肽”是分别结合、优选特异性结合PD-1、PD-L1或PD-L2负共刺激多肽的寡肽,分别包括如本文描述的受体、配体或信号传导组分。这种寡肽可以使用已知的寡肽合成方法来化学合成,或者可以使用重组技术来制备和纯化。这种寡肽通常至少约5个氨基酸的长度,或者至少约6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99或100个氨基酸的长度,或者更长。这种寡肽可以使用熟知的技术来鉴定。就此而言,应注意的是,用于筛选能够特异性结合多肽靶的寡肽的寡肽文库技术在本领域中是熟知的(参见,例如美国专利号5,556,762、5,750,373、4,708,871、4,833,092、5,223,409、5,403,484、5,571,689、5,663,143;PCT申请号WO 84/03506和WO84/03564;Geysen等人,Proc.Natl.Acad.Sci.USA.,81:3998-4002(1984);Geysen等人,Proc.Natl.Acad.Sci.U.S.A.,82:178-182(1985);Geysen等人,在Synthetic Peptides asAntigens,130-149(1986)中;Geysen等人,J Immunol.Meth.,102:259-274(1987);Schoofs等人,J.Immunol.,140:611-616(1988),Cwirla,S.E.等人Proc.Natl.Acad.Sci.USA,87:6378(1990);Lowman,H.B.等人Biochemistry,30:10832(1991);Clackson,T.等人Nature,352:624(1991);Marks,J.D.等人,J.Mol.Biol.,222:581(1991);Kang,A.S.等人Proc.Natl.Acad.Sci.USA,88:8363(1991),以及Smith,G.P.,Current Opin.Biotechnol.,2:668(1991)。
“阻断”抗体或“拮抗”抗体是抑制或降低其结合的抗原的生物学活性的抗体。在一些实施方案中,阻断抗体或拮抗抗体实质上或完全抑制抗原的生物学活性。本发明的抗PD-L1抗体阻断通过PD-1的信号传导,从而将T细胞的功能应答(例如,增殖、细胞因子产生,靶细胞杀伤)从功能障碍状态恢复到抗原刺激。
“激动”或活化抗体是通过与其结合的抗原增强或启动信号传导的抗体。在一些实施方案中,激动抗体在不存在天然配体的情况下引起或活化信号传导。
本文中的术语“Fc区”用于定义免疫球蛋白重链的C末端区域,包括原生序列Fc区和变体Fc区。虽然免疫球蛋白重链的Fc区的边界可以变化,但是人IgG重链Fc区通常被定义为从Cys226位置的氨基酸残基或Pro230延伸至其羧基末端。例如,在抗体的产生或纯化期间,或者通过重组工程化编码抗体重链的核酸,可以去除Fc区的C末端赖氨酸(根据EU编号系统的残基447)。因此,完整抗体的组合物可包含去除所有K447残基的抗体群、未去除K447残基的抗体群和具有和不具有K447残基的抗体混合物的抗体群。用于本发明抗体的适合的原生序列Fc区包括人IgG1、IgG2(IgG2A、IgG2B)、IgG3和IgG4。
“Fc受体”或“FcR”描述结合抗体的Fc区的受体。优选的FcR是原生序列人FcR。此外,优选的FcR是结合IgG抗体(γ受体)的FcR,包括FcγRI、FcγRII和FcγRIII亚类的受体,包括这些受体的等位基因变体以及可选地剪接形式,FcγRII受体包括FcγRIIA(“活化受体”)和FcγRIIB(“抑制受体”),它们有类似的氨基酸序列,主要不同在于它们的胞质结构域。活化受体FcγRIIA在其胞质结构域中含有基于免疫受体酪氨酸的活化基序(ITAM)。抑制受体FcγRIIB在其胞质结构域中含有基于免疫受体酪氨酸的抑制基序(ITIM)。(参见M.Daeron,Annu.Rev.Immunol.15:203-234(1997)。FcR在Ravetch和Kinet,Annu.Rev.Immunol.9:457-92(1991)中综述;Capel等人,Immunomethods 4:25-34(1994);以及de Haas等人,J.Lab.Clin.Med.126:330-41(1995)。其它FcR,包括将来鉴定的FcR,在本文中由术语“FcR”涵盖。
术语“Fc受体”或“FcR”还包括负责将母体IgG转移至胎儿的新生儿受体FcRn。Guyer等人,J.Immunol.117:587(1976)和Kim等人,J.Immunol.24:249(1994)。测量与FcRn结合的方法是已知的(参见,例如Ghetie和Ward,Immunol.Today 18:(12):592-8(1997);Ghetie等人,Nature Biotechnology 15(7):637-40(1997);Hinton等人,J.Biol.Chem.279(8):6213-6(2004);WO 2004/92219(Hinton等人)。可以测定体内结合FcRn,以及人FcRn高亲和力结合多肽的血清半衰期,例如,在转基因小鼠或表达人FcRn的转染的人细胞系中进行测定,或者在施用具有变体Fc区的多肽的灵长类动物中进行测定,WO 2004/42072(Presta)描述了改善或减少与FcR的结合的抗体变体。还参见,例如Shields等人,J.Biol.Chem.9(2):6591-6604(2001)。
如本文所使用的,短语“实质上降低”或“实质上不同”表示两个数值(通常一个与分子相关而另一个与参照/比较分子相关)之间的足够高的差异程度,使得本领域技术人员将认为在由所述值(例如,Kd值)测量的生物学特征的上下文中,两个值之间的差异具有统计显著性。所述两个值之间的差异例如是作为参照/比较分子的值的函数,大于约10%、大于约20%、大于约30%、大于约40%和/或大于约50%。
如本文所使用的,术语“实质上类似”或“实质上相同”表示两个数值(例如,一个与本发明的抗体相关和另一个与参照/比较抗体相关)之间的足够高的类似程度,使得本领域技术人员将认为在由所述值(例如,Kd值)测量的生物学特征的上下文中,两个值之间的差异很小、或者无生物学和/或统计学显著性。所述两个值之间的差异例如是作为参照/比较值的函数,小于约50%、小于约40%、小于约30%、小于约20%和/或小于约10%。
术语“协同”或“协同作用”可以定义为多于累加的作用(Chou,2006,PharmacologReviews,58:621-681)。药物联合之中的协同相互作用是高度需要和追求的,因为它们可以导致增加效力、降低剂量、降低副毒性、以及在临床上使用时最小化抗性的发展(Chou,2006)。用于评估联合治疗中药物相互作用的两种最流行的方法是等效图和联合指数(CI)(Zhao等人,2004,Clinical Cancer Res 10:7994-8004)。在癌症治疗领域有许多研究,其中评估药物联合以对抗抗药性的发展并最小化药物剂量,使用CI指数评估协同作用。CI基于Chou和Talalay1984(Adv.Enzyme Regul.22:27-55)的方法,并且依赖于中效原理和多个药物作用方程。可以使用CompuSyn(CompuSyn,Paramus,N.J.)程序容易地计算CI。如果CI值为0.85-0.9,则相互作用略有协同;如果CI值为0.7-0.85,则中度协同;如果CI值为0.3-0.7则协同;如果CI值为0.1-0.3则强协同;以及如果CI值<0.1非常强的协同(表1)(Chou2006)。然而,在癌症治疗文献中,定义协同的CI的值可以不同。例如在Lin等人,2007,Carcinogenesis 28:2521-2529中,药物之间的协同定义为CI<1,而在Fischel等人,2006,Preclinical Report 17:807-813中,协同定义为CI<0.8。然而,这些参考文献同意协同可以定义为CI<0.8。
表1:用联合指数方法分析的药物联合研究中的协同或拮抗的描述
联合指数范围 | 描述 |
<0.1 | 非常强协同 |
0.1-0.3 | 强协同 |
0.3-0.7 | 协同 |
0.7-0.85 | 中度协同 |
0.85-0.9 | 略有协同 |
0.9-1.1 | 几乎累加 |
1.1-1.2 | 略有拮抗 |
1.2-1.45 | 中度拮抗 |
1.45-3.3 | 拮抗 |
3.3-10 | 强拮抗 |
>10 | 非常强拮抗 |
本发明涉及PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂与苯甲酰胺化合物的联合产生协同治疗作用的发现。
治疗增殖性疾病如癌症的一个途径是癌症免疫治疗。这种治疗策略旨在改善免疫系统对在受试者中不健康细胞的识别。因此,诱导强细胞毒性T细胞应答是必要的。最佳T细胞活化需要两种信号(Lafferty 1975):1)T细胞受体和特异性抗原之间的相互作用(Bretscher 1970),以及2)T细胞表面上的共刺激受体与通过抗原呈递细胞(APC)表达的共刺激配体的结合(engagement)。该模型还提供了对自身和非自身以及免疫耐受之间的区分(discrimination)(Bretscher 1970、Bretscher 1999、Jenkins 1987)。在识别主要组织相容性复合体(MHC)的情况下呈递的外来抗原肽之后,主要信号或抗原特异性信号通过T细胞受体(TCR)转导。第二或共刺激信号通过抗原呈递细胞(APC)上表达的共刺激分子递送至T细胞,并诱导T细胞促进克隆扩增、细胞因子分泌和效应功能。(Lenschow 1996)。在不存在共刺激的情况下,T细胞可以对抗原刺激不响应,不会产生(mount)有效的免疫应答,并且还可以导致对外来抗原的耗竭或耐受。
在双信号模型中,T细胞接受正和负第二共刺激信号。这种正和负信号的调节对于最大化宿主的保护性免疫应答,同时保持免疫耐受和预防自身免疫至关重要。负第二信号对于诱导T细胞耐受似乎是必需的,而正信号促进T细胞活化。尽管简单的双信号模型仍然为原生淋巴细胞提供了有效的解释,但宿主的免疫应答是一个动态过程,共刺激信号也可以提供给抗原暴露的T细胞。共刺激的机制是治疗感兴趣的,因为已经显示共刺激信号的操作提供了增强或终止基于细胞的免疫应答的手段。最近,已经发现T细胞功能障碍或失能与抑制性受体、程序性死亡1多肽(PD-1)的诱导和持续表达同时发生。因此,治疗性地靶向PD-1以及通过与PD-1相互作用而进行信号传导的其它分子(如程序性死亡配体1(PD-L1)和程序性死亡配体2(PD-L2))是感兴趣的领域。
PD-L1在许多癌症中过度表达,经常与不良预后相关(Okazaki 2007、Thompson2006)。有趣的是,与正常组织的T淋巴细胞和外周血T淋巴细胞相比,大多数肿瘤浸润性T淋巴细胞主要表达PD-1,表明肿瘤反应性T细胞上PD-1的上调促使抗肿瘤免疫应答受损(Ahmadzadeh 2009)。这可以是由于利用表达PD-L1的肿瘤细胞与表达PD-1的T细胞相互作用介导的PD-L1信号传导,导致T细胞活化的减弱和免疫监视的逃避(Sharpe 2002、Keir 2008)。因此,抑制PD-L1/PD-1相互作用可以增强CD8+T细胞介导的肿瘤杀伤。
已经提出通过其直接配体(例如,PD-L1、PD-L2)抑制PD-1轴信号传导作为增强用于癌症治疗的T细胞免疫的手段(例如,肿瘤免疫)。此外,通过抑制PD-L1与结合配偶体B7-1的结合,已经观察到类似的T细胞免疫增强。此外,将PD-1信号传导抑制与在肿瘤细胞中失调的其它信号传导通路相联合还可以提高治疗效力。然而,最佳治疗性治疗将联合阻断PD-1受体/配体相互作用与直接抑制肿瘤生长的试剂,任选地还包括不单独由PD-1阻断提供的独特免疫增强性质。
因为CTLA4似乎破坏T细胞活化,已经尝试在癌症免疫治疗的鼠模型中阻断CTLA4活性。在植入免疫原性肿瘤的小鼠中,抗CTLA4抗体的施用增强了肿瘤排斥(Leach 1996),尽管用免疫原性差的肿瘤如SMI乳腺癌或B16黑素瘤可见很小的作用。当与粒细胞巨噬细胞集落刺激因子(GM-CSF)转导的B16细胞疫苗给予抗CTLA4抗体时,可见增强的抗肿瘤免疫,并且与脱色素相关,这表明至少部分抗肿瘤应答针对“自身”黑素细胞分化抗原是抗原特异性的(van Elsas 1999,van Elsas 2001)。在原发性前列腺癌的转基因鼠模型中,施用抗CTLA4抗体加表达GM-CSF的前列腺癌细胞降低了前列腺癌的发病率和组织学严重程度,并导致正常小鼠中的前列腺炎,再次表明在肿瘤排斥中针对自身抗原的抗原特异性免疫应答(Hurwitz 2000)。此外,由于许多人肿瘤抗原是正常的自身抗原,打破对自身的耐受可以对癌症免疫治疗的成功至关重要。在鼠模型中,来自CTLA4阻断的有利的肿瘤应答与肿瘤疫苗的联合,导致了在人癌症免疫治疗中使用CTLA4阻断的兴趣。
化学免疫治疗是化学治疗剂和免疫治疗剂的联合,是治疗癌症的一种新的方法,它联合了直接攻击肿瘤细胞产生肿瘤细胞坏死或凋亡的试剂,以及调节宿主对肿瘤免疫应答的试剂的作用。化学治疗剂可以增强免疫治疗的作用,其通过产生由抗原呈递细胞呈递的肿瘤抗原,产生“多价”肿瘤细胞疫苗,并且通过使肿瘤结构变形(distort),因此促进免疫治疗剂的渗透以及扩大的免疫群。
本发明涉及PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂与苯甲酰胺化合物的联合,在增殖性疾病包括癌症的治疗中产生协同治疗作用的发现。该联合还在减缓增殖性疾病进展中产生协同治疗作用。本发明提供联合组合物,包括药物组合物,其包含PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂以及苯甲酰胺化合物。该联合显示出优异的细胞毒性/抗肿瘤活性,例如抗转移活性。因此,该组合物和药物组合物可以用于治疗增殖性疾病包括癌症。在一些实施方案中,本发明的组合物和药物组合物的施用增强免疫原性,如增加用于治疗癌症的肿瘤免疫原性。在一个方面,将组合物和药物组合物施用于受试者增强了受试者的免疫功能。
因此,在一个优选的实施方案中,本发明的治疗方法包括将治疗有效量的苯甲酰胺化合物或其类似物与治疗有效量的PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的一种或多种联合施用。在一些实施方案中,所述方法涉及将治疗量的药物组合物施用于有需要的受试者,优选已经诊断出增殖性疾病的受试者,所述药物组合物包括苯甲酰胺化合物和/或其药学上可接受的盐,以及PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂。
在一些实施方案中,受试者被诊断患有T细胞浸润水平提高的癌症。相对于施用PD-1轴结合拮抗剂和苯甲酰胺化合物之前,受试者还可以具有增强的个体中CD8 T细胞的引发、活化、增殖和/或细胞毒活性。CD8 T细胞引发的特征在于CD8T细胞中CD44表达提高和/或细胞毒活性增强。在一些实施方案中,CD8 T细胞活化的特征在于γIFN+CD8 T细胞的频率提高。在一些实施方案中,CD8 T细胞是抗原特异性T细胞。在一些实施方案中,通过PD-L1表面表达的信号传导的免疫逃避被抑制。
在一些实施方案中,相对于施用PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂以及本公开的苯甲酰胺化合物之前,受试者中的癌细胞可以具有MHC I类抗原表达的提高的表达。
在一些实施方案中,相对于在施用PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂以及苯甲酰胺化合物之前,个体中的抗原呈递细胞具有增强的成熟和活化。在一些实施方案中,其中抗原呈递细胞是树突细胞。在一些实施方案中,抗原呈递细胞的成熟的特征在于CD83+树突细胞频率增加。在一些实施方案中,抗原呈递细胞的活化的特征在于树突细胞上CD80和CD86的表达提高。
在一些实施方案中,相对于施用PD-1轴结合拮抗剂,如抗PD-L1抗体和苯甲酰胺化合物之前,个体中的细胞因子IL-10和/或趋化因子IL-8(鼠KC的人同源物)的血清水平降低。
治疗量是足以治疗增殖性疾病的量,其还包括预防增殖性疾病进展为赘生、恶性或转移状态,例如降低增生、化生或发育异常的发生,或者抑制受试者中细胞的赘生、恶性或转移进展。这种预防用途表示已知或怀疑进展为赘生或癌症之前的病症,具体地,由增生、化生组成的非赘生细胞生长,或者最具体的已经发生发育异常(对于这种异常生长病症的综述,参见Robbins和Angell 1976年,第68-79页)。增生是控制的细胞增殖的一种形式,涉及组织或器官中细胞数量的增加,而没有显著的结构或活性改变。例如,子宫内膜增生经常先于子宫内膜癌,而癌前结肠息肉经常转化为癌性病变。化生是受控的细胞生长的一种形式,其中一种成体或完全分化的细胞类型取代另一种成体细胞。上皮或结缔组织细胞中可以发生化生。典型的化生涉及稍微无序的化生上皮。发育异常通常是癌症的前身,主要见于上皮;它是非赘生细胞生长的最无序的形式,涉及个体细胞均一性和细胞结构取向的缺失。发育异常的细胞经常具有异常大的、核深染色,并呈现多形性。发育异常典型地发生在存在慢性刺激或炎症的位置,并且经常在子宫颈、呼吸道、口腔和胆囊中发现。
或者,或除了存在特征在于增生、化生或发育异常的异常细胞生长以外,在衍生自患者的细胞样本体内显示或体外显示的转化表型或恶性表型的一种或多种特征的存在,可以指示包括化合物的药物组合物的预防/治疗施用的可取性(desirability)。转化表型的这种特征包括形态变化、不牢固的底层附着、缺失接触抑制、缺失锚定依赖性、蛋白酶释放、糖转运增加、血清需求降低、胎儿抗原表达、250,000道尔顿细胞表面蛋白消失等(参见,Robbins和Angell,1976,第84-90页,关于与转化或恶性表型相关的特征)。进一步的示例包括白斑、良性外观增生或发育异常的上皮病变以及鲍温病(Bowen's disease)、原位癌,这些是指示预防干预的可取性的赘生前病变。在另一个示例中,包括囊性增生、乳腺发育异常、腺病或良性上皮增生的纤维囊性疾病指示预防干预的可取性。
癌细胞包括衍生自肿瘤、赘生、癌症、癌前、细胞系或任何其它最终能够潜在无限扩增和生长的细胞来源的任何细胞。癌细胞可以衍生自天然存在的来源,或者可以是人造的。当放入动物宿主时,癌细胞还能够侵入其它组织和转移。癌细胞还涵盖侵入其它组织和/或转移的任何恶性细胞。生物体情况下的一种或多种癌细胞也可以被称为癌症、肿瘤、赘生、生长、恶性肿瘤或本领域中用于描述癌性状态细胞的任何其它术语。
癌细胞的扩增包括导致衍生自癌细胞的个体细胞数量增加的任何过程。癌细胞的扩增可以由有丝分裂、增殖或癌细胞的任何其它形式的扩增引起,无论是在体外或在体内。癌细胞的扩增还包括侵入和转移。癌细胞可以在物理上邻近来自相同克隆的癌细胞或来自不同克隆的癌细胞,所述不同克隆的癌细胞可以与其遗传上相同或不同。这种聚集可以采取集落、肿瘤或转移的形式,其中任何一种可以在体内或体外发生。通过抑制促进扩增的细胞过程或通过引起抑制扩增的细胞过程,可以引起减缓癌细胞的扩增。抑制扩展的过程包括减缓有丝分裂的过程和促进细胞衰老或细胞死亡的过程。抑制扩增的具体过程的示例包括半胱天冬酶依赖和非依赖通路、自噬、坏死、凋亡和线粒体依赖和非依赖过程,并且还包括尚待公开的任何此类过程。
向癌细胞加入药物组合物包括实现药物组合物对癌细胞的作用的所有作用。选择的加入类型取决于癌细胞是在体内、离体或在体外,药物组合物的物理或化学性质,以及组合物对癌细胞的作用。加入的非限制性示例包括将包括药物组合物的溶液加入到组织培养介质中,体外癌细胞在其中生长;可以将药物组合物施用于动物的任何方法包括静脉内、口服、肠胃外或任何其它施用方法;或活化或抑制细胞,所述细胞继而对癌细胞具有作用,如免疫细胞(例如巨噬细胞和CD8+T细胞)或可在血管发生(angiogenesis)或血管生成(vasculogenesis)过程中分化成血管结构的内皮细胞。
在本发明的另一方面,显示一种或多种恶性诱发因素的受试者或疾病实体可以通过施用包括化合物的药物组合物进行治疗。这种诱发因素包括但不限于与恶性相关的染色体易位,如慢性骨髓性白血病的费城染色体和滤泡性淋巴瘤的t(14;18);息肉或加德纳氏综合征的发病是结肠癌的指示;良性单克隆丙种球蛋白病是多发性骨髓瘤的指示,与过去患有或目前患有癌症或癌前疾病的人的亲属关系,暴露于致癌物,或任何其它目前已知的或尚待公开的指示增加癌症发病的诱发因素。
确定所公开的组合物的有效量在本领域技术人员的能力内,尤其是根据本文提供的详细的公开。通过本领域技术人员目前已知的药物和毒理学程序或者通过尚待公开的任何类似的方法,可以在细胞培养或实验动物中确定用于达到具体目的以及其毒性、排泄和总体耐受的药物组合物的有效量。一个示例是确定在体外细胞系或靶分子中药物组合物的IC50(半数最大抑制浓度)。另一个示例是确定实验动物中药物组合物的LD50(引起50%的试验动物死亡的致死剂量)。用于确定有效量的准确技术将取决于这些因素,如药物组合物的类型和物理/化学性质、被试验的性质以及试验是否在体外或在体内进行。药物组合物的有效量的确定对于本领域技术人员而言将是熟知的,其将使用从任何试验获得的数据来进行该确定。确定用于加入至癌细胞的苯甲酰胺化合物或PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的有效量,还包括确定治疗有效量,包括体内(包括人)使用的制剂的有效剂量范围。
药物组合物的毒性和治疗效力可以通过细胞培养或动物中的标准药物程序来确定。示例包括确定目的化合物的IC50(半数最大抑制浓度)和LD50(引起50%的试验动物死亡的致死剂量)。从这些细胞培养测定和动物研究获得的数据可以用于配制用于人的剂量范围。剂量可以根据利用的剂型和使用的施用途径而变化。
导致癌细胞扩增减缓的苯甲酰胺化合物或PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的有效量,将优选导致在靶组织处或在靶组织附近聚集(concentration),其有效减缓赘生细胞中的细胞扩增,但对非赘生细胞,包括暴露于放射的非赘生细胞或化学治疗化学试剂识别的非赘生细胞具有最小的作用。产生这些作用的浓度可以使用例如凋亡标记物,如凋亡指数和/或半胱天冬酶活性,在体外或在体内确定。
加入治疗有效量的组合物涵盖任何化合物给药的方法。苯甲酰胺化合物或PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的给药,可以包括单次或多次施用许多药物组合物中的任何一种,所述药物组合物包括所公开的作为活性成分的组合物。示例包括缓释组合物的单次施用、涉及定期或不定期的几种治疗的治疗过程、多次施用一段时间直至达到疾病状态的减轻、在症状产生(instigation)之前应用预防治疗、或本领域已知的任何其它给药方案,或者尚未被公开、本领域技术人员将认识到潜在有效的方案。包括施用的规律性和模式的最终给药方案将取决于许多因素中的任何因素,包括但不限于待治疗的受试者;痛苦的严重程度;施用的方式;疾病发展阶段,一种或多种额外的病症的存在,如妊娠、婴儿期或存在一种或多种额外的疾病;或目前已知的或尚待公开的影响施用模式的选择、待施用剂量和施用剂量的时间段的任何其它因素。
包括所公开的组合物的药物组合物可以在施用第二药物组合物之前、与其同时(例如同时施用)、或之后施用,所述第二药物组合物可以包括或不包括化合物。组合物的苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂也可以同时施用,或者组合物的一种元素可以在其它元素之前施用。如果组合物或组合物的元素同时施用,则它们彼此在一分钟内施用。如果不同时施用,则可以在包括化合物的药物组合物之前或之后一或数分钟、小时、天、周或月的时间段,施用第二药物组合物。或者,可以周期地施用药物组合物的联合。周期治疗涉及持续一段时间地施用一种或多种药物组合物,之后持续一段时间地施用一种或多种不同的药物组合物,并重复该顺序施用,以降低对一种或多种组合物抗性的发展,以避免或降低一种或多种组合物的副作用,和/或改善治疗的效力。例如,在一个实施方案中,PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂以28天的周期施用,以每天采用PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂治疗3-14天开始,之后在剩余的周期中休息。在另一个实施方案中,PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂每天施用持续3-14天,之后休息21-25天。
本发明还涵盖促进将苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂施用于患病实体的试剂盒。这种试剂盒的示例包括一种或多种苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的单位剂量。单位剂量将被封装在优选无菌容器中,并且将由苯甲酰胺化合物或PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂以及药学上可接受的载体组成。另一方面,单位剂量将包含一种或多种苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的冻干物(lyophilates)。在本发明的这个方面,试剂盒可以包括另一种优选的无菌容器,其封装有能够溶解冻干物的溶液。然而,这种溶液不需要包括在试剂盒中,并且可以与冻干物分开获得。另一方面,试剂盒可以包括用于施用单位剂量或与化合物联合使用的药物组合物的一种或多种装置。这种装置的示例包括但不限于注射器、滴注袋、贴剂或灌肠剂。在本发明的一些方面,该装置包括封装单位剂量的容器。
本发明的组合物可根据许多因素采取任何必需的物理形式,所述因素包括所需的施用方法以及由苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂或其药学上可接受的盐采取的物理化学和立体化学形式。这种物理形式包括固体、液体、气体、溶胶、凝胶、气溶胶或目前已知的或尚待公开的任何其它物理形式。在一些方面,组合物包含PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的药学上可接受的盐和苯甲酰胺化合物的药学上可接受的盐。该组合物可以具有或不具有任何药学上可接受的添加剂。
在一些方面,组合物还可以包含药学上可接受的载体。载体包括可以与苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂施用的任何物质,目的是促进、协助或帮助化合物的施用或其它递送。载体包括可与苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂联合以有助于其施用的任何液体、固体、半固体、凝胶,气溶胶或任何其它。示例包括稀释剂、佐剂、赋形剂、水、油(包括石油、动物、植物或合成油)。这种载体包括颗粒如片剂或粉剂、液体如口服糖浆或注射液,以及可吸入气溶胶。其它示例包括盐水、阿拉伯树胶(gum acacia)、明胶、淀粉糊、滑石、角蛋白、硅溶胶(colloidal silica)和尿素。这种载体还可以包括粘合剂如乙基纤维素、羧甲基纤维素、微晶纤维素或明胶;赋形剂如淀粉、乳糖或糊精(dextrins);崩解剂如海藻酸、海藻酸钠、Primogel和玉米淀粉;润滑剂如硬脂酸镁或Sterotex;助流剂如胶体二氧化硅;甜味剂如蔗糖或糖精,调味剂如薄荷、水杨酸甲酯或橙香精,或着色剂。载体的其它示例包括聚乙二醇、环糊精、油或可配制成胶囊的任何其它类似的液体载体。载体的其它示例包括无菌稀释剂如注射用水、盐水溶液、生理盐水、林格氏液(Ringer's solution)、等渗氯化钠、固定油如合成的甘油单酯或甘油二酯、聚乙二醇、甘油、环糊精、丙二醇或其它溶剂;抗菌剂如苯甲醇或对羟基苯甲酸甲酯(methyl paraben);抗氧化剂如抗坏血酸或亚硫酸氢钠;螯合剂如乙二胺四乙酸;缓冲剂如醋酸盐、柠檬酸盐或磷酸盐,以及张力调节剂如氯化钠或右旋糖、增稠剂、润滑剂和着色剂。
根据组合物的物理化学形式和施用类型,本发明的组合物可以采取许多制剂中的任一种。这些形式包括溶液、悬液、乳剂、片剂、丸剂,微丸(pellets)、胶囊、包括液体的胶囊、粉剂,缓释制剂、定向释放制剂、冻干剂、栓剂、乳剂、气溶胶、喷雾剂、颗粒、粉剂、糖浆、酏剂或目前已知的或尚待公开的任何其它制剂。适合的药物载体的额外的示例在E.W.Martin的Remington's Pharmaceutical Sciences中描述,通过引用整体并入本文。在一些实施方案中,本发明的组合物可以包括来自苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的不同化学式或生物学结构的额外的有效化合物。在一些方面,额外的有效化合物可以具有与靶相同或类似的分子靶,或者其可以作用于和一种或多种生物化学通路相关的苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的分子靶的上游或下游。
额外的有效化合物的示例包括核酸结合组合物、止吐组合物、造血集落刺激因子、抗焦虑剂和止痛剂。
核酸结合组合物的示例包括但不限于顺-二胺二氯铂(II)(顺铂)、多柔比星、5-氟尿嘧啶、紫杉酚以及拓扑异构酶抑制剂,如依托泊苷、替尼泊苷、伊立替康和拓扑替康。止吐组合物的示例包括但不限于甲氧氯普胺(metoclopromide)、多潘立酮、丙氯拉嗪、异丙嗪、氯丙嗪,三甲苯甲酰胺、昂丹司琼、格拉司琼、羟嗪,乙酰亮氨酸单乙醇胺、阿立必利、阿扎司琼、苯喹胺、氨醇醋茶碱、溴必利、氯苯丁嗪、氯波必利、赛克利嗪、茶苯海明、地芬尼多、多拉司琼、氯苯甲嗪、美沙拉妥、美托哌丙嗪、大麻隆、oxyperndyl、哔哌马嗪、莨菪碱、舒必利、四氢大麻酚(tetrahydrocannabinols)、硫乙拉嗪、硫丙拉嗪和托烷司琼。造血集落刺激因子的示例包括但不限于非格司亭、沙格司亭、莫拉司亭和阿法依泊汀(epoietin alfa)。或者,包括苯甲酰胺化合物和DNA脱甲基化试剂的药物组合物可以与抗焦虑剂联合使用。抗焦虑剂的示例包括但不限于丁螺环酮和苯二氮卓类,如地西泮、劳拉西泮、奥沙西泮、氯氮卓、氯硝西泮、甲氨二氮草和阿普唑仑。
止痛剂可以是阿片或非阿片止痛剂。阿片止痛剂的非限制性示例包括吗啡、海洛因、氢吗啡酮、氢可酮、羟吗啡酮、羟考酮、美托酮、阿朴吗啡、去甲吗啡、埃托啡、丁丙诺啡、哌替啶、洛哌丁胺(lopermide)、氨苄哌替啶、ethoheptazine、piminidine、倍他罗定、苯乙哌啶、芬太尼、舒芬太尼、阿芬太尼、瑞芬太尼、左啡诺、右美沙芬、非那唑辛、喷他佐辛、环唑辛、美沙酮、异美沙酮和丙氧芬。适合的非阿片止痛剂包括但不限于阿司匹林、塞来昔布、罗非考昔、双氯芬酸、diflusinal、依托度酸、非诺洛芬、氟比洛芬、布洛芬、酮洛芬、吲哚美辛、酮咯酸、甲氯芬那酸、甲芬那酸、萘丁美酮、萘普生、吡罗昔康、舒林酸或目前已知的或尚待公开的任何其它止痛剂。
额外的有效化合物可以是化学治疗剂,其是用于治疗癌症的化学化合物。化学治疗剂的示例包括烷化剂如噻替派和环磷酰胺烷基磺酸盐,如白消安、英丙舒凡和哌泊舒凡;氮杂环丙烷,如苯并多巴(benzodopa)、卡波醌、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺(ethylenimines)和甲基蜜胺(methylamelamines),包括六甲蜜胺、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(trietylenephosphoramide)、三乙撑硫化磷酰胺(triethiylenethiophosphoramide)和三羟甲基蜜胺(trimethylolomelamine);番荔枝内酯(acetogenins)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone);Δ-9-四氢大麻酚(屈大麻酚,);β-拉帕醌;拉帕醇;秋水仙碱;桦木酸;喜树碱(包括合成类似物拓扑替康CPT-11(伊立替康,)、乙酰喜树碱、东莨菪内酯(scopolectin)和9-氨基喜树碱);苔藓抑素(bryostatin);培美曲塞;callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素;足叶草酸;替尼泊苷;隐藻素(cryptophycins)(尤其是隐藻素1和隐藻素8);多拉司他丁(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;TLK-286;CDP323,一种口服α-4整联蛋白抑制剂;sarcodictyin;海绵抑素;氮芥,如苯丁酸氮芥、萘氮芥、胆磷酰胺(cholophosphamide)、雌氮芥、异环磷酰胺、双氯乙基甲胺、盐酸氧氮芥、美法仑、新氮芥(novembichin)、苯芥胆甾醇、松龙苯芥(prednimustine)、三芥环磷酰胺(trofosfamide),尿嘧啶氮芥;亚硝基脲,如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀(ranimnustine);抗生素,如烯二炔类抗生素(例如,加利车霉素,尤其是加利车霉素γlI和加利车霉素ω11(参见,例如,Nicolaou等人,Angew.Chem.Intl.Ed.Engl.,33:183-186(1994));dynemicin,包括dynemicinA;埃斯波霉素(esperamicin);以及新抑癌菌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素、放线菌素、氨茴霉素(authramycin)、重氮丝氨酸、博来霉素、放线菌素、carabicin、caminomycin、嗜癌霉素、色霉素(chromomycinis)、更生霉素、道诺霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代多柔比星、氰基吗啉代阿霉素、2-吡咯啉多柔比星、盐酸多柔比星脂质体注射和脱氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素(marcellomycin)、丝裂霉素,如丝裂霉素C、霉酚酸、诺加霉素、橄榄霉素(olivomycin)、培洛霉素、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星、链黑菌素、链脲菌素、杀结核菌素(tubercidin)、乌苯美司、净司他丁(zinostatin),佐柔比星;抗代谢物,如甲氨蝶呤、吉西他滨替加氟卡培他滨埃坡霉素和5-氟尿嘧啶(5-FU);叶酸类似物,如二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物,如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、脱氧氟尿苷、依诺他滨、氟尿苷和伊马替尼(2-苯基氨基嘧啶衍生物)以及其它c-Kit抑制剂;抗肾上腺素如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂,如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;bestrabucil;比生群;依达曲沙(edatraxate);地弗胺(defofamine);地美可辛;地吖醌(diaziquone);elformithine;醋酸羟吡咔唑(elliptinium acetate);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidainine);美登木素生物碱,如美登素和安丝菌素;丙米腙(mitoguazone);米托蒽醌;莫匹达谋(mopidanmol);尼曲吖啶(nitraerine);喷司他丁;蛋氨氮芥(phenamet);吡柔比星;洛索蒽醌;2-乙基酰肼;甲基苄肼;多醣复合物(JHS Natural Products,Eugene,Oreg.);雷佐生;根霉素;西佐喃;锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2',2”-三氯代三乙胺;单端孢霉烯族毒素(尤其是T-2毒素、疣孢菌素A(verracurin A),杆孢菌素A(roridin A)和anguidine);乌拉坦;长春地辛达卡巴嗪;甘露醇氮芥;二溴甘露醇;二溴卫矛醇;哌酰溴烷;gacytosine;阿拉伯糖苷(“Ara-C”);噻替派;紫杉烷,例如紫杉醇紫杉醇的白蛋白工程化纳米颗粒制剂(ABRAXANE.TM.)和多西他赛(doxetaxel)苯丁酸氮芥(chloranbucil);6-硫鸟嘌呤;巯嘌呤;甲氨蝶呤;铂类似物如顺铂和卡铂;长春碱铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱奥沙利铂;亚叶酸(leucovovin);长春瑞滨诺消灵(novantrone);依达曲沙;柔红霉素;氨喋呤;伊班膦酸盐/酯;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄醇,如视黄酸;以上任一种的药学上可接受的盐、酸或衍生物;以及上述中的两种或更多种的联合,如CHOP,环磷酰胺、多柔比星、长春新碱和泼尼松龙的联合治疗的缩写,以及FOLFOX,奥沙利铂(ELOXATINTM)与5-FU和亚叶酸联合的治疗方案的缩写。
化学治疗剂的额外的示例包括作用于调节、降低、阻断或抑制可促进癌症生长的激素作用的抗激素试剂,并且经常以系统或全身治疗的形式。它们本身可以是激素。示例包括抗雌激素和选择性雌激素受体调节剂(SERM),包括,例如他莫昔芬(包括他莫昔芬)、雷洛昔芬屈洛昔芬,4-羟基他莫昔芬、曲沃昔芬、keoxifene、LY117018、奥那司酮和托瑞米芬抗黄体酮;下调雌激素受体(ERD);雌激素受体拮抗剂,如氟维司群抑制或关闭卵巢功能的试剂,例如,促黄体激素释放激素(LHRH)激动剂,如醋酸亮丙瑞林(和)、醋酸戈舍瑞林、醋酸布舍瑞林和曲普瑞林;抗雄激素,如氟他胺、尼鲁米特和比卡鲁胺;和抑制芳香化酶的芳香化酶抑制剂,其调节在肾上腺中雌激素的产生,如,例如4(5)-咪唑、氨鲁米特、醋酸甲地孕酮依西美坦福美坦(formestanie)、法倔唑、伏氯唑来曲唑(letrozole)和阿那曲唑另外,化学治疗剂的这种定义包括二膦酸盐,如氯膦酸盐(例如,或者)、依替膦酸盐(DIDROCAL8)、NE-58095、唑来膦酸/唑来膦酸盐阿仑膦酸盐帕米膦酸盐替鲁膦酸盐或者利塞膦酸盐以及曲沙他滨(1,3-二氧戊环核苷胞嘧啶类似物);反义寡核苷酸,尤其是涉及在异常细胞(abherant cell)增殖的信号传导通路中抑制基因表达的那些,如,例如PKC-α、Raf、H-Ras和表皮生长因子受体(EGF-R);疫苗如疫苗和基因治疗疫苗,例如疫苗,疫苗和疫苗;拓扑异构酶1抑制剂(例如,);抗雌激素,如氟维司群;Kit抑制剂,如伊马替尼或EXEL-0862(酪氨酸激酶抑制剂);EGFR抑制剂,如厄洛替尼或西妥昔单抗;抗VEGF抑制剂,如贝伐单抗;arinotecan;rmRH(例如,);拉帕替尼和二甲苯磺酸拉帕替尼(一种ErbB-2和EGFR双酪氨酸激酶小分子抑制剂,也称为GW572016);17AAG(格尔德霉素(geldanamycin)衍生物,其是一种热休克蛋白(Hsp)90毒素),以及以上任一种的药学上可接受的盐、酸或衍生物。
另外的有效化合物可以是抗增殖化合物,如抗增殖细胞毒性试剂。可以用作抗增殖细胞毒性试剂的化合物类别包括以下:
·烷化剂(包括但不限于氮芥、乙撑亚胺衍生物、烷基磺酸盐,亚硝基脲和三氮烯):尿嘧啶氮芥、盐酸氮芥、环磷酰胺异环磷酰胺、美法仑、苯丁酸氮芥、哌酰溴烷、三乙撑蜜胺、三乙烯硫代磷酸胺(Triethylenethiophosphoramine)、白消安、卡莫司汀、洛莫司汀、链脲菌素、达卡巴嗪和替莫唑胺;
·抗代谢物(包括但不限于叶酸拮抗剂、嘧啶类似物、嘌呤类似物和腺苷脱氨酶抑制剂):甲氨蝶呤、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-巯嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨、喷司他丁和吉西他滨;
·天然产物及其衍生物(例如,长春花生物碱、抗肿瘤抗生素、酶、淋巴因子(Iymphokines)和表鬼臼毒素):长春碱、长春新碱、长春地辛、博来霉素、更生霉素、道诺霉素、多柔比星、表柔比星、伊达比星、Ara-C、紫杉醇(紫杉醇可商购获得,如光神霉素、脱氧柯福霉素(Deoxy-coformycin)、丝裂霉素-C、L-天冬酰胺酶、干扰素(尤其是IFN-a)、依托泊苷和替尼泊苷;
·Navelbene;
·CPT-11;
·阿那曲唑;
·来曲唑;
·卡培他滨;
·雷洛昔芬;
·环磷酰胺;
·异环磷酰胺;和
·屈洛昔芬。
抗增殖化合物也可以是影响微管的试剂。影响微管的试剂干扰细胞有丝分裂,并且本领域熟知它们的抗增殖细胞毒性活性。用于本发明的影响微管的试剂包括但不限于,异秋水仙碱(allocolchicine)(NSC 406042)、软海绵素B(NSC 609395)、秋水仙碱(NSC757)、秋水仙碱衍生物(例如,NSC 33410)、多拉司他丁10(NSC376128)、美登素(NSC153858)、根霉素(NSC 332598)、紫杉醇(NSC 125973)、衍生物(例如,衍生物(例如,NSC 608832)、硫代秋水仙碱NSC 361792)、三苯甲基半胱氨酸(NSC 83265)、硫酸长春碱(NSC 49842)、硫酸长春新碱(NSC 67574)、天然和合成的埃坡霉素包括但不限于埃坡霉A、埃坡霉素B、埃坡霉素C、埃坡霉素D、脱氧埃坡霉素A、脱氧埃坡霉素B、[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7-11-二羟基-8,8,10,12,16-五甲基-3-[1-甲基-2-(2-甲基-4-噻唑基)乙烯基]-4-氮杂-17氧杂双环[14.1.0]十七烷-5,9-二酮、[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(氨基甲基)-4-噻唑基]-1-甲基乙烯基]-7,11-二羟基-8,8,10,12,16-五甲基-4-17-二氧杂双环[14.1.0]-十七烷-5,9-二酮(公开于2000年2月17日提交的美国序列号09/506,481)、及其衍生物;和其它微管破坏剂。额外的抗增殖化合物包括圆皮海绵内酯(discodermolide)、雌氮芥、诺考达唑、MAP4等。在科学和专利文献中也描述了这种试剂的示例,参见,例如Bulinski 1997、Panda 1997、Muhlradt1997Nicolaou 1997、Vasquez 1997、和Panda 1996。
抗增殖化合物的适合的候选物还有抗血管生成剂和抗血管剂,并且通过中断血液流向实体瘤,通过剥夺它们的营养使癌细胞静止。也可以使用也使雄激素依赖性的癌非增殖的阉割(castration)。通过除手术破坏血液流动之外的手段来饥饿是细胞生长抑制剂的另一示例。考布他汀是一类尤其优选的抗血管细胞生长抑制剂。其它示例性细胞生长抑制剂包括MET激酶抑制剂、MAP激酶抑制剂、非受体和受体酪氨酸激酶抑制剂、整联蛋白信号传导抑制剂和胰岛素样生长因子受体抑制剂。其它抗血管生成剂包括基质金属蛋白酶抑制剂。其它VEGF抑制剂也适合用于本发明的联合化学治疗方法,如抗VEGF抗体和小分子如ZD6474和SU6668。也可以使用来自Genentech的抗Her2抗体。适合的EGFR抑制剂是EKB-569(不可逆抑制剂)。还包括EGFR免疫特异性的Imclone抗体C225和src抑制剂。
额外的有效化合物还可以选自除CTLA4拮抗剂(例如免疫刺激剂)、微管蛋白稳定剂(例如,紫杉醇(pacitaxol)、埃坡霉素、紫杉烷等)以外的共刺激通路激动剂,IXEMPRATM、达卡巴嗪、伯尔定、多西他赛、一种或多种肽疫苗、MDX-1379黑素瘤肽疫苗、一种或多种gp100肽疫苗、禽痘-PSA-TRICOMTM疫苗、牛痘-PSA-TRICOMTM疫苗、MART-1抗原、沙格司亭、ticilimumab,联合雄激素消除治疗。共刺激通路调节剂的示例包括但不限于以下:agatolimod、博纳吐单抗(blinatumomab)、CD40配体、AG4263、依立托伦(eritoran)、抗OX40抗体、ISF-154和SGN-70。
肽抗原的非限制性示例是包含、或由选自IMDQVPFSV(SEQ ID NO:15)和YLEPGPVTV(SEQ ID NO:16)的序列组成的gp100肽。这种肽可以口服施用,或者优选地通过皮下注射,将不完全弗氏佐剂(IFA)中乳化的1mg皮下注射到一肢体,并且可以将1mg相同或不同的在IFA中乳化的肽注射到另一肢体。
包含PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂与苯甲酰胺衍生物的联合还可包括单独或与放射治疗(也称为放射疗法)联合的抗增殖细胞毒性试剂的加入。术语“放射治疗”包括但不限于来自外部施加的来源(如束)或通过植入小的放射源来递送的x射线或γ射线。
在需要与本发明的化学治疗方法治疗同时或在治疗之前使异常增殖细胞静止的情况下,也可将激素和类固醇(包括合成类似物)施用于患者。因此,额外的有效化合物还可以是选自以下的激素、类固醇或其合成类似物:17α-炔雌醇、己烯雌酚、睾酮、泼尼松、氟甲睾酮、屈他雄酮丙酸酯、睾内酯,醋酸甲地孕酮、甲基泼尼松龙、甲基睾酮、泼尼松龙、曲安西龙(Triamcinolone)、氯烯雌醚(Chlorotrianisene)、羟孕酮、氨鲁米特、雌氮芥、醋酸甲羟孕酮、亮丙瑞林,氟他胺、托瑞米芬和诺雷得。
还适合用作抗增殖细胞生长抑制剂的是使雄激素依赖性癌非增殖性的细胞生长抑制剂的另一个示例是抑制雌激素依赖性乳癌增殖或生长的抗雌激素他莫昔芬。细胞增殖信号转导的抑制剂是细胞生长抑制剂。示例是表皮生长因子抑制剂、Her-2抑制剂、MEK-1激酶抑制剂、MAPK激酶抑制剂、PI3抑制剂、Src激酶抑制剂和PDGF抑制剂。
药物组合物包括能够改变剂量单位的物理形式的物质。在一个非限制性示例中,组合物包括形成保持在化合物中的包衣的材料。可用于这种包衣的材料包括例如糖、虫胶、明胶或任何其它惰性包衣试剂。
药物组合物也可以制备成气体或气溶胶。气溶胶涵盖各种系统,包括胶质和密封包装。以这种形式递送组合物可以包括通过使用液化气体或其它压缩气体或通过适合的泵系统推进药物组合物。气溶胶可以在单相、双相或三相系统中递送。
在本发明的具体方面中,药物组合物是溶剂化物的形式。这种溶剂化物是通过将苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂溶解在药学上可接受的溶剂中而产生的。药学上可接受的溶剂包括多于一种溶剂的任何混合物。这种溶剂可以包括吡啶、氯仿、1丙醇(propan-1-ol)、油酸乙酯、乳酸乙酯、环氧乙烷、水、乙醇和任何其它溶剂,其将足够量的苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂递送以治疗痛苦,而在大多数患者中不具有使用溶剂而引起的严重并发症。
包括苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的药物组合物可以以促进局部或经皮施用的形式制备。这种制剂可以是溶液、乳剂、软膏、凝胶基质(base)、经皮贴剂或离子电渗装置的形式。在这种组合物中使用的基质的示例包括矿脂(opetrolatum)、羊毛脂、聚乙二醇、蜂蜡、矿物油、稀释剂如水和醇、以及乳化剂和稳定剂、增稠剂或目前已知的或尚待公开的任何其它适合的基质。
本发明还提供了治疗增殖性疾病包括癌症的方法,其包括向受试者施用治疗有效量的PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂,并向受试者施用治疗有效量的苯甲酰胺化合物。在本发明的优选实施方案中,提供了用于癌性肿瘤的协同治疗的方法。有利地,本发明的协同方法降低了肿瘤的发展、降低了肿瘤负荷,或者在哺乳动物宿主中产生了肿瘤消退。
可以通过药物组合物治疗的癌症包括但不限于以下:癌,包括膀胱癌(包括加速(accelerated)和转移膀胱癌)、乳癌、结肠癌(包括结肠直肠癌)、肾癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌和肺腺癌)、卵巢癌、前列腺癌、睾丸癌、泌尿生殖道癌、淋巴系统癌、直肠癌、喉癌,胰癌(包括外分泌胰癌)、食道癌、胃癌、胆囊癌、子宫颈癌、甲状腺癌和皮肤癌(包括鳞状细胞癌);淋巴谱系的造血肿瘤,包括白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤、组织细胞性淋巴瘤和Burketts淋巴瘤;骨髓谱系的造血肿瘤,包括急性和慢性骨髓性白血病、骨髓增生异常综合征、骨髓性白血病和早幼粒细胞白血病;中枢和外周神经系统的肿瘤,包括星形细胞瘤、神经母细胞瘤、神经胶质瘤和神经鞘瘤;间叶细胞起源的肿瘤,包括纤维肉瘤、横纹肌肉瘤(rhabdomyoscarcoma)和骨肉瘤;其它肿瘤包括黑素瘤、着色性干皮病(xenoderma pigmentosum)、角化棘皮瘤(keratoactanthoma)、精原细胞瘤、甲状腺滤泡癌和畸胎癌(teratocarcinoma);黑素瘤、不可切除阶段m或IV恶性黑素瘤、鳞状细胞癌,小细胞肺癌、非小细胞肺癌、神经胶质瘤、胃肠癌、肾癌、卵巢癌、肝癌、结肠直肠癌、子宫内膜癌、肾癌、前列腺癌、甲状腺癌、神经母细胞瘤、胰癌、多形性成胶质细胞瘤、子宫颈癌、胃癌、膀胱癌、肝癌、乳癌、结肠癌和头颈癌、胃部癌、生殖细胞瘤、骨癌、骨肿瘤、成人骨恶性纤维组织细胞瘤;儿童骨恶性纤维组织细胞瘤、肉瘤、小儿肉瘤、鼻窦自然杀伤、赘生、浆细胞赘生;骨髓增生异常综合征;神经母细胞瘤;睾丸生殖细胞肿瘤、眼内黑素瘤、骨髓增生异常综合征;骨髓增生异常综合征/骨髓增殖性疾病、滑膜肉瘤、慢性骨髓性白血病、急性成淋巴细胞性白血病、费城染色体阳性的急性成淋巴细胞性白血病(Ph+ALL)、多发性骨髓瘤、急性骨髓性白血病、慢性淋巴细胞性白血病、肥大细胞增多症和与肥大细胞增多症相关的任何症状,以及其任何转移。另外,失调包括色素性荨麻疹、肥大细胞增多症如弥漫性皮肤肥大细胞增多症、在人中的孤立性肥大细胞瘤以及狗肥大细胞瘤和一些罕见的亚型,如大疱性、红皮病性和毛细血管扩张性(teleangiectatic)肥大细胞增多症,具有相关血液失调的肥大细胞增多症,如骨髓增生性或骨髓增生异常综合征或急性白血病、与肥大细胞增多症相关的骨髓增生性失调、肥大细胞白血病,除其它癌症以外。其它癌症也包括在失调的范围内,包括但不限于以下:癌,包括膀胱癌、尿路上皮癌、乳癌、结肠癌、肾癌、肝癌、肺癌、卵巢癌、胰癌、胃癌、子宫颈癌、甲状腺癌症、睾丸癌(尤其是睾丸精原细胞瘤)、以及皮肤癌;包括鳞状细胞癌;胃肠道间质瘤(“GIST”);淋巴谱系的造血肿瘤,包括白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和Burketts淋巴瘤;骨髓谱系的造血肿瘤,包括急性和慢性骨髓性白血病和早幼粒细胞白血病;间叶细胞起源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;其它肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌(tetratocarcinoma)、神经母细胞瘤和神经胶质瘤;中枢和外周神经系统的肿瘤,包括星形细胞瘤、神经母细胞瘤、神经胶质瘤和神经鞘瘤;间叶细胞起源的肿瘤,包括纤维肉瘤、横纹肌肉瘤(rhabdomyoscaroma)和骨肉瘤,以及其它肿瘤,包括黑素瘤、着色性干皮病、角化棘皮瘤、精原细胞瘤、甲状腺滤泡癌、畸胎癌,化学治疗难治性非精原细胞生殖细胞肿瘤和卡波济氏肉瘤,及其任何转移。最优选地,本发明用于治疗加速或转移膀胱癌、胰癌、前列腺癌、黑素瘤、非小细胞肺癌、结肠直肠癌和乳癌。
本发明的药物组合物可用于治疗的癌症类型的其它示例包括血液源癌症,如急性成淋巴细胞性白血病(“ALL”)、急性成淋巴细胞性B细胞白血病、急性成淋巴细胞性T细胞白血病、急性髓细胞性白血病(“AML”)、急性早幼粒细胞白血病(“APL”)、急性单核细胞白血病、急性红细胞白血病(erythroleukemic leukemia)、急性成巨核细胞白血病、急性髓单核细胞白血病、急性非淋巴细胞性白血病、急性未分化性白血病、慢性粒细胞白血病(“CML”)、慢性髓单核细胞白血病(CMML)、慢性淋巴细胞性白血病(“CLL”)、毛细胞白血病、骨髓增生异常综合征、多发性骨髓瘤、成淋巴细胞性白血病、骨髓性白血病、淋巴细胞性白血病,粒细胞白血病、霍奇金病、非霍奇金淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom'smacroglobulinemia)、重链病和真性红细胞增多症。
苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的治疗有效量可以是协同有效量。苯甲酰胺化合物的协同有效少于如果苯甲酰胺化合物在没有PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的情况下施用以治疗增殖性疾病所需的量。类似地,PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的协同有效量小于治疗癌症所需的量,或者如果PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂在没有苯甲酰胺化合物的情况下施用所需的量。
苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的协同有效量可以由CI值表示的协同因子定义。当CI小于约0.8,或者小于约0.75、或者小于约0.7、或者小于约0.65、或者小于约0.6、或者小于约0.55、或者小于约0.5时、或者小于约0.45、或者小于约0.4、或者小于约0.35、或者小于约0.3、或者小于约0.25、或者小于约0.2、或者小于约0.15、或者小于约0.1,化合物之间存在协同作用。
施用PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂以及苯甲酰胺化合物的方法包括但不限于口服施用和肠胃外施用。肠胃外施用包括但不限于皮内、肌肉内、腹膜内、静脉内、皮下、鼻内、硬膜外、舌下、intramsal、脑内、心室内、鞘内、阴道内、经皮、直肠、吸入或局部至耳、鼻、眼或皮肤。其它施用方法包括但不限于包括输注或快速浓注(bolus injection)的输注技术,其通过经由上皮或皮肤粘膜衬里如口腔粘膜、直肠和肠粘膜的吸收。用于肠胃外施用的组合物可以封装在安瓿、一次性注射器或由玻璃、塑料或其它材料制成的多剂量小瓶中。为通过注射施用所配制的药物组合物,可以通过用水将苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂溶解以形成溶液来制备。另外,可加入表面活性剂以促进形成同质的溶液或悬液。表面活性剂包括能够与苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂非共价相互作用的任何复合物,以促进化合物的溶解或同质的悬液。
施用PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂以及苯甲酰胺化合物可以是系统的或局部的。局部施用是将苯甲酰胺化合物或PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂施用至需要治疗的部位。示例包括手术期间的局部输注;局部应用,通过局部注射;通过导管;通过栓剂;或通过植入。可以通过直接注射在癌症、肿瘤或癌前组织的位点(或先前的位点),或者通过任何适合的途径(包括心室内和鞘内注射)注射入中枢神经系统来施用。心室内注射可以通过例如附着到如Ommaya储液囊(reservoir)的储液囊的脑室内导管来促进。肺部施用可以通过本领域已知的许多方法中的任一种来实现。示例包括使用吸入器或喷雾器、采用气溶胶试剂的制剂、或通过在碳氟化合物或合成的肺表面活性剂中灌注。苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂可以在囊泡如脂质体或任何其它天然或合成囊泡的情况下递送。
在治疗增殖性疾病的方法的一些实施方案中,所述方法可以包括施用额外的治疗方式。这种治疗方式包括但不限于放射疗法(放射治疗)、手术(例如乳房肿瘤切除术和乳房切除术)、化学治疗、基因治疗、DNA治疗、病毒治疗、RNA治疗、免疫治疗、骨髓移植、纳米治疗、单克隆抗体治疗或前述的联合。联合治疗可以协同作用。也就是说,这些治疗的联合比单独施用任何一种治疗更有效。这导致两种治疗方式的较低剂量可有效使用的情况。这反过来降低了与任何一种施用方式相关的毒性和副作用(如果有的话),而没有降低效力。
在一个优选的实施方案中,本发明的组合物与治疗有效量的放射治疗联合施用。在一些方面,额外的治疗是γ照射。放射治疗可以在施用包括苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的药物组合物的同时、之前或之后施用。放射治疗可以与包括所述化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的药物组合物累加或协同作用。本发明的这个具体方面在已知对放射治疗应答的癌症中是最有效。已知对放射治疗应答的癌症包括但不限于非霍奇金淋巴瘤、霍奇金病、尤因氏肉瘤、睾丸癌、前列腺癌、卵巢癌、膀胱癌、喉癌、子宫颈癌、鼻咽癌、乳癌、结肠癌、胰癌、头颈癌、食管癌、直肠癌、小细胞肺癌、非小细胞肺癌、脑肿瘤、其它CNS赘生或任何其它目前已知的或尚待公开的这种肿瘤。
在其它实施方案中,与本发明的组合物联合施用的额外的治疗是手术。在一些方面,额外的治疗是放射治疗和手术的联合。在一些实施方案中,额外的治疗是靶向PI3K/AKT/mTOR通路、HSP90抑制剂、微管蛋白抑制剂、细胞凋亡抑制剂和/或化学预防剂的治疗。额外的治疗可以是上文所述的一种或多种化学治疗剂。
在治疗增殖性的方法的一些实施方案中,本发明的组合物可以与离体治疗癌症联合使用。这种治疗的一个示例是自体干细胞移植。在这种方法中,收集受试者或患病实体的自体造血干细胞并清除所有癌细胞。然后可以在通过加入患者自身或供体干细胞,恢复实体骨髓之前,将治疗量的包括苯甲酰胺化合物和PD-1轴结合拮抗剂、CTLA4拮抗剂和/或DNA脱甲基化试剂的药物组合物施用于受试者或患病实体。
PD-1轴结合拮抗剂
PD-1轴结合拮抗剂是抑制PD-1轴结合配偶体与其结合配偶体的一种或多种相互作用的分子,以去除由PD-1信号传导轴上的信号传导引起的T细胞功能障碍,其结果是恢复或增强T细胞功能(例如增殖、细胞因子产生、靶细胞杀伤)。PD-1轴结合拮抗剂包括但不限于PD-1结合拮抗剂、PD-L1结合拮抗剂和PD-L2结合拮抗剂。“PD-1”的替代名称包括CD279和SLEB2。“PD-L1”的替代名称包括B7-H1、B7-4、CD274和B7-H。“PD-L2”的替代名称包括B7-DC、Btdc和CD273。在一些实施方案中,PD-1、PD-L1和PD-L2是人PD-1、PD-L1和PD-L2。
PD-1结合拮抗剂是降低、阻断、抑制、消除或干扰由PD-1与其一种或多种结合配偶体(如PD-L1、PD-L2)相互作用产生的信号转导的分子。在一些实施方案中,PD-1结合拮抗剂是抑制PD-1与其结合配偶体的结合的分子。在一个具体方面,PD-1结合拮抗剂抑制PD-1与PD-L1和/或PD-L2的结合。例如,PD-1结合拮抗剂包括抗PD-1抗体、其抗原结合片段、免疫粘附素、融合蛋白、寡肽和降低、阻断、抑制、消除或干扰PD-1与PD-L1和/或PD-L2的相互作用产生的信号转导的其它分子。在一个实施方案中,PD-1结合拮抗剂降低负共刺激信号,从而使得功能障碍的T细胞更少的功能障碍(例如,增强对抗原识别效应应答),所述负共刺激信号通过或经由通过PD-1信号传导介导的T淋巴细胞上表达的细胞表面蛋白所介导。
在一些实施方案中,PD-1结合拮抗剂是抗PD-1抗体。例如,PD-1结合拮抗剂可以是选自MDX-1106(CAS登记号:946414-94-4;或者命名为MDX-1106-04、ONO-4538、BMS-936558或Nivolumab)、Merck 3745(或者称为MK-3475或SCH-900475)和CT-01(或者称为hBAT或hBAT-1)的抗PD-1抗体。
在一些实施方案中,PD-1结合拮抗剂是免疫粘附素,例如免疫粘附素,其包含与恒定区(例如,免疫球蛋白序列的Fc区)融合的PD-L1或PD-L2的细胞外或PD-1结合部分。在一些实施方案中,PD-1结合拮抗剂是AMP-224、AMP-224也称为B7-DCIg,是一种PD-L2-Fc融合可溶性受体。
在一些实施方案中,PD-1是分离的抗PD-1抗体,其包含含有来自SEQ ID NO:22的重链可变区氨基酸序列的重链可变区,和/或含有以下轻链可变区氨基酸序列的轻链可变区:
在另一个实施方案中,提供了包含重链和/或轻链序列的分离的抗PD-1抗体,其中重链序列与重链序列SEQ ID NO:22具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%,至少99%或100%的序列同一性;轻链序列与轻链序列SEQ ID NO:19具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。
PD-L1结合拮抗剂是降低、阻断、抑制、消除或干扰由PD-L1与其一种或多种结合配偶体(如PD-1、B7-1)相互作用产生的信号转导的分子。在一些实施方案中,PD-L1结合拮抗剂是抑制PD-L1与其结合配偶体的结合的分子。在一个具体方面,PD-L1结合拮抗剂抑制PD-L1与PD-1和/或B7-1的结合。在一些实施方案中,PD-L1结合拮抗剂包括抗PD-L1抗体、其抗原结合片段、免疫粘附素、融合蛋白、寡肽和降低、阻断、抑制、消除或干扰PD-L1与其一种或多种结合配偶体(如PD-1、B7-1)的相互作用产生的信号转导的其它分子。在一个实施方案中,PD-L1结合拮抗剂降低负共刺激信号,从而使得功能障碍的T细胞更少的功能障碍(例如,增强对抗原识别效应应答),所述负共刺激信号通过或经由通过PD-L1信号传导介导的T淋巴细胞上表达的细胞表面蛋白所介导。
在一些实施方案中,PD-L1结合拮抗剂是抗PD-L1抗体。在一些实施方案中,抗PD-L1抗体是人源化抗体。在一些实施方案中,抗PD-L1抗体是人抗体。在一些实施方案中,抗PD-L1抗体是选自Fab、Fab'-SH、Fv、scFv和(Fab’)2片段的抗体片段。
在一些方面,抗PD-L1抗体的重链可以包含具有至少一种序列的重链可变区,所述序列与选自以下的至少一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:GFTFS-X1-SWIH(SEQ ID NO:1)、AWI-X2-PYGGS-X3-YYADSVKG(SEQ ID NO:2)、和RHWPGGFDY(SEQ ID NO:3),其中X1是D或G,X2是S或L,以及X3是T或S。在优选的实施方案中X1是D,X2是S,以及X3是T。
或者,抗PD-L1抗体的重链可以包含具有至少一种序列的重链可变区,所述序列与选自以下的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:EVQLVESGGGLVQPGGSLRLSCAAS(SEQ ID NO:4)、WVRQAPGKGLEWV(SEQ ID NO:5)、RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(SEQ ID NO:6)、WGQGTLVTVSA(SEQ ID NO:7)、以及WGQGTLVTVSS(SEQ ID NO:17)。
在一些实施方案中,抗PD-L1抗体包含重链可变区,所述重链可变区与SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24中所示的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。SEQ ID NO:23如下所示:
SEQ ID NO:24如下所示:
在一些方面,抗PD-L1抗体的轻链可以包含具有至少一种序列的轻链可变区,所述序列与选自以下的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:RASQ-X4-X5-X6-T-X7-X8-A(SEQ ID NO:8)、SAS-X9-L-X10-S(SEQ ID NO:9)和QQ-X11-X12-X13-X14-P-X15-T(SEQ ID NO:10),其中X4是D或V;X5是V或I;X6是S或N;X7是A或F;X8是V或L;X9是F或T;X10是Y或A;X11是Y、G、F或S;X12是L、Y、F或W;X13是Y、N、A、T、G、F或I;X14是H、V、P、T或I;以及X15是A、W、R、P或T。在优选的实施方案中,X4是D,X5是V,X6是S,X7是A,X8是V,X9是F,X10是Y,X11是Y,X12是L,X13是Y,X14是H,以及X15是A。
或者,抗PD-L1抗体的轻链可以具有包含至少一种序列的轻链可变区,所述序列与选自以下的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性:DIQMTQSPSSLSASVGDRVTITC(SEQ ID NO:11)、WYQQKPGKAPKLLIY(SEQ ID NO:12)、GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(SEQ ID NO:13)和FGQGTKVEIKR(SEQ ID NO:14)。在优选的实施方案中,抗PD-1抗体包含轻链可变区,所述轻链可变区和选自SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:20的一种序列具有至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%的序列同一性。
SEQ ID NO:20如下所示:
在一些实施方案中,抗PD-L1抗体包含含有以下氨基酸序列的重链可变区:
和/或包含以下氨基酸序列的轻链可变区:
抗PD-L1结合拮抗剂还可选自YW243.55.S70(重链和轻链可变区序列分别显示于SEQ ID No.20和21中)、MPDL3280A和MDX-1105(还称为BMS-936559)。
PD-L2结合拮抗剂是降低、阻断、抑制、消除或干扰由PD-L2与其一种或多种结合配偶体(如PD-1)相互作用产生的信号转导的分子。在一些实施方案中,PD-L2结合拮抗剂是抑制PD-L2与其结合配偶体的结合的分子。在一个具体方面,PD-L2结合拮抗剂抑制PD-L2与PD-1的结合。在一些实施方案中,PD-L2拮抗剂包括抗PD-L2抗体、其抗原结合片段、免疫粘附素、融合蛋白、寡肽和降低、阻断、抑制、消除或干扰PD-L2与其一种或多种结合配偶体(如PD-1)的相互作用产生的信号转导的其它分子。在一个实施方案中,PD-L2结合拮抗剂降低负共刺激信号,从而使得功能障碍的T细胞更少的功能障碍(例如,增强对抗原识别效应应答),所述负共刺激信号通过或经由通过PD-L2信号传导介导的T淋巴细胞上表达的细胞表面蛋白所介导。在一些实施方案中,PD-L2结合拮抗剂是免疫粘附素。
在一些方面,本文描述的抗体(如抗PD-1抗体、抗PD-L1抗体或抗PD-L2抗体)可以包含人或鼠恒定区。在另一个方面,人恒定区选自IgG1、IgG2、IgG2、IgG3、IgG4。在另一个具体的方面,人恒定区是IgG1。在另一个方面,鼠恒定区选自IgG1、IgG2A、IgG2B、IgG3。在另一个方面,鼠恒定区是IgG2A。在另一个具体的方面,抗体具有降低的或最小的效应功能。在另一个具体的方面,最小的效应功能是由原核细胞的生产所产生。在另一个具体的方面,最小效应功能由“较小效应Fc突变”或无糖基化所产生。在另一个实施方案中,较小效应Fc突变是恒定区中的N297A或D265A/N297A取代。
在另一个实施方案中,本发明提供了一种组合物,其包含本文提供的抗PD-L1、抗PD-1或抗PD-L2抗体或其抗原结合片段,以及至少一种药学上可接受的载体。在一些实施方案中,施用于个体的抗PD-L1、抗PD-1或抗PD-L2抗体或其抗原结合片段是包含一种或多种药学上可接受的载体的组合物。可以使用本文描述的或本领域已知的任何药学上可接受的载体。
CTLA4拮抗剂
用于本发明的方法中的适合的抗CTLA4拮抗剂包括但不限于抗CTLA4抗体、人抗CTLA4抗体、小鼠抗CTLA4抗体、哺乳动物抗CTLA4抗体、人源化抗CTLA4抗体、单克隆抗CTLA4抗体、多克隆抗CTLA4抗体、嵌合抗CTLA4抗体、MDX-010(易普利姆玛)、tremelimumab、贝拉西普、抗CD28抗体、抗CTLA4 adnectins、抗CTLA4结构域抗体、单链抗CTLA4片段、重链抗CTLA4片段、轻链抗CTLA4片段、激动共刺激通路的CTLA4抑制剂、在PCT公开号WO 2001/014424中公开的抗体、在PCT公开号WO 2004/035607中公开的抗体、在美国公开号2005/0201994中公开的抗体和在授权的欧洲专利号EP1212422B1中公开的抗体。额外的CTLA4抗体描述于美国专利号5,811,097、5,855,887、6,051,227和6,984,720中;在PCT公开号WO01/14424和WO 00/37504中;以及在美国公开号2002/0039581和2002/086014中。可以在本发明的方法中使用的其它抗CTLA4抗体包括例如在以下中公开的那些:WO 98/42752;美国专利号5,977,318、6,207,156、6,682,736、7,109,003和7,132,281;Hurwitz 1998;Camacho2004(抗体CP-675206);和Mokyr1998。在一些优选的实施方案中,抗CTLA4抗体选自易普利姆玛和tremelimumab。
额外的CTLA4拮抗剂包括但不限于以下:任何能够破坏CD28抗原与其同源配体结合的能力的抑制剂、抑制CTLA4与其同源配体结合的能力的抑制剂、增加T细胞通过共刺激通路的应答的抑制剂、破坏B7与CD28和/或CTLA4结合的能力的抑制剂、破坏B7活化共刺激通路的能力的抑制剂、破坏CD80与CD28和/或CTLA4结合的能力的抑制剂、破坏CD80活化共刺激通路的能力的抑制剂、破坏CD86与CD28和/或CTLA4结合的能力的抑制剂、破坏CD86活化共刺激通路的能力的抑制剂、以及破坏共刺激通路的抑制剂,通常被活化。这必然包括CD28、CD80、CD86、CTLA4以及共同刺激通路的其它成员的小分子抑制剂;针对CD28、CD80、CD86、CTLA4以及共刺激通路的其它成员的抗体,针对CD28、CD80、CD86、CTLA4以及共刺激通路的其它成员的反义分子;针对CD28、CD80、CD86、CTLA4以及共刺激通路的其它成员的adnectins,CD28、CD80、CD86、CTLA4以及共刺激通路的其它成员的RNAi抑制剂(单链和双链)。在一些实施方案中,CTLA4拮抗剂可以是抗B7-1抗体、抗B7-2抗体、抗B7-H4抗体。
优选地,抗CTLA4抗体可以以约0.3-10mg/kg或最大耐受剂量施用。在本发明的一个实施方案中,约每三周施用一剂量的CTLA-4抗体。或者,CTLA-4抗体可以通过递增剂量方案施用,包括以约3mg/kg施用第一剂量的CTLA-4抗体,以约5mg/kg施用第二剂量的CTLA-4抗体,以及以约9mg/kg施用第三剂量的CTLA-4抗体。在另一个具体的实施方案中,递增的剂量方案包括以约5mg/kg施用第一剂量的CTLA-4抗体和以约9mg/kg施用第二剂量的CTLA-4抗体。
本发明还提供递增的剂量方案,其包括约每六周施用增加剂量的CTLA-4抗体。在本发明的一个方面中,提供逐步递增的剂量方案,其包括施用约3mg/kg的第一CTLA-4抗体剂量、约3mg/kg的第二CTLA-4抗体剂量、约5mg/kg的第三CTLA-4抗体剂量、约5mg/kg的第四CTLA-4抗体剂量和约9mg/kg的第五CTLA-4抗体剂量。在本发明的另一个方面,提供逐步递增的剂量方案,其包括施用5mg/kg的第一剂量、5mg/kg的第二剂量和9mg/kg的第三剂量。
实际使用的剂量可以根据患者的需要和待治疗病症的严重程度而变化。确定具体情况的适合的剂量在本领域的技术范围内。通常,治疗以小于化合物最佳剂量的较小剂量起始。此后,以小量增加剂量,直到在这种情况下达到最佳作用。为了方便起见,如果需要,可以将总的每天的剂量分开,并在一天中分批施用。也可以使用间歇性治疗(例如,三周中的一周或四周中的三周)。
DNA脱甲基化试剂
在组合物中使用的DNA脱甲基化试剂的示例包括DNA甲基转移酶抑制剂、其抑制甲基基团向DNA的转移。在一个具体的实施方案中,DNA甲基转移酶抑制剂是胞嘧啶的类似物。在与DNA甲基转移酶(DNMT)共价连接之前,这些胞嘧啶类似物在复制期间被并入DNA中,因此导致基因甲基化的全面缺失(Christman J.K.,Oncogene 21:5483-95,2002)。
在另一个实施方案中,DNA甲基转移酶抑制剂可以是胞苷的类似物。在一个具体的方面,胞苷类似物是与胞苷或脱氧胞苷在结构上相关并在功能上模拟和/或拮抗胞苷或脱氧胞苷的作用的任何化合物。胞苷类似物可以是5-氮杂胞苷(阿扎胞苷)、5-氮杂-2'-脱氧胞苷(地西他滨)、1-β-D-阿拉伯呋喃糖基胞嘧啶(阿糖胞苷或ara-C)、假胞苷(pseudoiso-cytidine,psi ICR)、5-氟-2'-脱氧胞苷(FCdR)、2'-脱氧-2',2'-二氟胞苷(吉西他滨)、5-氮杂-2'-脱氧-2',2'-二氟胞苷、5-氮杂-2'-脱氧-2'-氟胞苷、1-β-D-呋喃核糖基-2(1H)-嘧啶酮(Zebularine)、2',3'-二脱氧-5-氟-3'-硫代胞苷(thiacytidine)(恩曲他滨(Emtriva))、2'-环胞苷(安西他滨)、1-β-D-阿拉伯呋喃糖基-5-氮杂胞嘧啶(法扎拉滨(Fazarabine)或ara-AC)、6-氮杂胞苷(6-氮杂-CR)、5,6-二氢-5-氮杂胞苷(dH-氮杂-CR)、N4-戊氧基-羰基-5'-脱氧-5-氟胞苷(卡培他滨)、N4-十八烷基-阿糖胞苷或反油酸阿糖胞苷。
阿扎胞苷是4-氨基-1-β-D-呋喃核糖基-s-三嗪-2(1H)-酮,也称为其实验式为C8H12N4O5,分子量为244。阿扎胞苷是一种白色至灰白色固体,不溶于丙酮、乙醇和甲基酮;微溶于乙醇/水(50/50)、丙二醇和聚乙二醇;少量溶于水、水饱和辛醇、5%葡萄糖水溶液、N-甲基-2-吡咯烷酮、生理盐水和5%Tween 80水溶液,可溶于二甲基亚砜(DMSO)。被批准用于高风险MDS患者的治疗。以无菌形式提供,作为用于皮下注射的悬液的重建物,或作为用于静脉内输注的进一步稀释的溶液的重建物。小瓶含有作为无菌冻干粉剂的100mg阿扎胞苷和100mg甘露糖醇。
地西他滨是4-氨基-1-(2-脱氧-β-D-赤式-呋喃戊糖基)-1,3,5-三嗪-2(1H)酮,也称为其实验式为C8H12N4O4,分子量为228.21。地西他滨是一种精细的白色至几乎白色粉末,微溶于乙醇/水(50/50)、甲醇/水(50/50)和甲醇;少量溶于水,可溶于二甲基亚砜(DMSO)。用地西他滨治疗癌细胞模型导致通过重新表达沉默基因(Bender等人,Cancer Res 58:95-101,1998;Herman等人,N Engl J Med 349:2042-54,2003)以及通过p53和p21Waf1/Cip1的活化(Zhu等人,J Biol Chem 279:15161-6,2004)抑制生长和凋亡。最近的研究已经确定,地西他滨引起G2停滞、降低克隆的存活并且抑制细胞生长,同时引起DNA片段化并活化ATM和ATR DNA修复通路(Palii等人,Mol Cell Biol 28:752-71,2008)。被批准用于骨髓增生异常综合征患者的治疗。它是在一个透明无色玻璃小瓶中提供的用于注射的白色无菌冻干粉剂。每20mL作为单个剂量,玻璃小瓶含有地西他滨50mg、一价磷酸钾(monobasic potassium phosphate)(磷酸二氢钾)68mg和盐酸钠11.6mg。
如本文所使用的,除非另有说明,本文描述的DNA脱甲基化试剂的化合物旨在涵盖所有可能的立体异构体,除非指定了具体的立体化学。当化合物的结构异构体可通过低能障互相转化时,化合物可以以单种互变异构体或互变异构体的混合物存在。这可以采取质子互变异构的形式;或化合物中所谓的价互变异构,例如,含有芳族部分的化合物。
本文描述的DNA脱甲基化试剂的化合物可以涵盖同位素富集的类似物。例如,化合物中的一个或多个氢位置可以用氘和/或氚富集。可以在化合物的具体位置富集的其它适合的同位素包括但不限于C-13、C-14、N-15、O-17和/或O-18。在一个实施方案中,本文描述的化合物可以在多于一个位置上富集相同或不同的同位素。如本文所使用的,术语“胞嘧啶类似物”和“胞苷(cytdine)类似物”涵盖胞嘧啶类似物或胞苷类似物游离碱、或其盐、溶剂化物(例如水合物)、水合物、共晶体、复合物、前药、前体、代谢物和/或其衍生物。术语“胞嘧啶类似物”和“胞苷类似物”还可以指胞嘧啶类似物或胞苷类似物的游离碱或其盐、溶剂化物、水合物、共晶体或复合物。在某些实施方案中,本文涉及的胞苷类似物涵盖胞苷类似物的游离碱或其药学上可接受的盐、溶剂化物或水合物。在一个实施方案中,游离碱或药学上可接受的盐或溶剂化物是固体。在另一个实施方案中,游离碱或药学上可接受的盐或溶剂化物是无定形形式的固体。在另一个实施方案中,游离碱或药学上可接受的盐或溶剂化物是结晶形式的固体。
在一些方面,胞嘧啶类似物或胞苷类似物的药学上可接受的盐可以是醋酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(苯磺酸盐)、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐(camphorate)、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、1,2-乙二磺酸盐(乙二磺酸盐)、乙磺酸盐(乙磺酸盐)、甲酸盐、延胡索酸盐、葡庚糖酸盐(glucoheptanoate)、甘油磷酸盐、乙醇酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐,马来酸盐、丙二酸盐、甲磺酸盐(甲磺酸盐(mesylate))、2-萘磺酸盐(萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、棕榈酸盐(palmoate)、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐或十一烷酸盐。
在一个实施方案中,将阿扎胞苷配制成用于注射的无菌冻干粉剂,并将其提供在单次使用的小瓶中,其中含有100mg阿扎胞苷和100mg甘露糖醇。用于注射的阿扎胞苷旨在进一步采用稀释剂重建为溶液后用于静脉注射。用于注射的阿扎胞苷旨在重建为悬液后皮下注射。
在一个实施方案中,将地西他滨配制成用于注射的白色至几乎白色的无菌冻干粉剂,其提供在透明无色玻璃小瓶中。每小瓶(20mL的单剂量)含有地西他滨50mg、一价磷酸钾(磷酸二氢钾)68mg和氢氧化钠11.6mg。
苯甲酰胺化合物
优选地,用于本发明的组合物中的苯甲酰胺化合物是具有下式的化合物:
由X表示的基团可以是以下的任何一个:H、卤素、-OH、-CN、-COOR'、-OR’、-SR’、-OC(O)R'、-NHR'、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)NR’R”、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基、-C1-C6烷基、芳基、-C3-C7环烷基和3至10元杂环,其中,-C1-C6烷基、芳基、-C3-C7环烷基或3至10元杂环中的任一个可以是未取代的或者被以下的一个或多个取代:卤素、-OH、-CN、-COOR'、-OR’、-SR’、-OC(O)R'、-NHR'、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)NR'R”、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基、-C1-C6烷基、芳基、-C3-C7环烷基。
由Y表示的基团可以是以下的任何一个:H、-C1-C6烷基、-C3-C12环烷基、芳基、3至10元杂环,其中-C1-C6烷基、-C3-C12环烷基、芳基、3至10元杂环中的任一个可以是未取代的或者被以下的一个或多个取代:-卤素、-C1-C6烷基、-C3-C12环烷基、3至10元杂环、芳基、OH、-CN、-COOR’、-OR’、-SR’、-OC(O)R’、-NHR’、-NR’R”、-NHC(O)R’、-NHC(O)NR’R”、-C(O)NR'R”、-NS(O)2R’、-S(O)2NR’R”、-S(O)2R’、胍基、硝基、亚硝基。在一些方面,由Y表示的基团可以是环戊基、环己基、环庚基、环戊基甲基、环己基甲基或环庚基甲基中的任一个。
由Z表示的基团可以是-NHOH。
由Q表示的基团可以是H或卤素中的任何一个。卤素基团包括任何卤素。示例包括但不限于-F、-Cl、-Br或-I。
由R、R’或R”表示的基团可以是-H或-C1-C6烷基。在一些实施方案中,R’和/或R”可以附着到N或O原子上。在一些方面,R’和R”与它们所附着的原子一起形成3至8元或3至10元环状结构。
-C1-C6烷基基团包括由1至6个碳原子组成的任何直或支、饱和或不饱和的取代或未取代的碳氢化合物。-C1-C6烷基基团的示例包括但不限于甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基,异戊基、新戊基、己基、异己基、新己基、乙烯基、丙烯基、1-丁烯基、2-丁烯基、1-戊烯基、2-戊烯基、1-己烯基、2-己烯基、3-己烯基、乙炔基、戊炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基和3-己炔基基团。取代的-C1-C6烷基基团可以包括任何适合的化学部分。可以被取代到上述任何-C1-C6烷基基团上的基团的示例包括但不限于以下示例:-卤素、-C1-C6烷基、-O-(C1-C6烷基)、C3-C7环烷基、3至10元杂环、芳基、-OH、-CN、-COOR’、-OR’、-SR’、-OC(O)R’、-NHR’、-NR’R”、-NHC(O)R’、-C(O)NHR’、-NS(O)2R’、-S(O)2N(R’)2或-S(O)2R’基团。
芳基基团包括任何未取代或取代的苯基或萘(napthyl)基基团。可以被取代到芳基基团上的基团的示例包括但不限于:卤素、-C1-C6烷基、-O-(C1-C6烷基)、-C3-C7环烷基、3至10元杂环、芳基、-OH、-CN、-COOR’、-OR’、-SR’、-OC(O)R’、-NHR’、-NR’R”、-NHC(O)R’、-C(O)NHR’、-C(O)NEtR’、-NS(O)2R’、R’、-S(O)2N(R’)2或-S(O)2R’基团
-C3-C7环烷基基团包括任何3、4、5、6或7元取代或未取代的非芳族碳环,而-C3-C12环烷基基团包括任何3、4、5、6、7、8、9、10、11或12元取代或未取代的非芳族碳环。-C3-C7环烷基基团的示例包括但不限于环丙基、环丁基、环戊基、环戊二烯基、环己基、环己烯基、环庚基、环庚烷(cycloheptanyl)、1,3-环己二烯基、-1,4-环己二烯基、-1,3-环庚二烯基和-1,3,5-环庚三烯基基团。-C3-C12环烷基基团的示例包括但不限于环丙基、环丁基、环戊基、环戊二烯基、环己基、环己烯基、环庚基、环庚烷、1,3-环己二烯基、-1,4-环己二烯基、-1,3-环庚二烯基、-1,3,5-环庚三烯基基团、环辛基、环壬基和环癸基基团。C3-C7环烷基基团和C3-C12环烷基基团还包括取代或未取代的非芳族碳双环。双环的示例包括但不限于,双环[3.1.0]己基、双环[2.2.0]己基、双环[4.1.0]庚基、双环[3.2.0]庚基和双环[3.1.1]庚基。可以被取代到-C3-C7环烷基基团和-C3-C12环烷基基团上的基团的示例包括但不限于:-卤素、-C1-C6烷基、-C3-C7环烷基、3至10元杂环、芳基、-OH、-CN、-COOR’、-OR’、-SR’、-OC(O)R’、-NHR’、-NR’R”、-NHC(O)R’、-NRC(O)NR’R”、-C(O)NR’R”、-NRS(O)1-2R’、-S(O)1-2NR’R”或-S(O)1-2R’基团。其中R’和R”可以独立地为H、C1-C6烷基、芳基或3至10元杂环,或者R’和R”与它们所附着的原子一起形成3至10元环结构。
杂环可以是任何任选的取代的饱和、不饱和或芳族的环部分,其中所述环部分被选自O、S或N的至少一种杂原子间隔。杂环可以是单环或多环。例如,适合的取代基包括卤素、卤代C1-6烷基、卤代C1-6烷氧基、氨基,脒基、酰胺基、叠氮基、氰基、胍基、羟基、硝基、亚硝基、尿素、-OR、-NR’R”、-OS(O)2R’;-OS(O)2OR’、-S(O)2OR’、-S(O)0-2R’、-C(O)OR’、-C(O)N R’R”、-OP(O)OR、-P(O)OR、-SO2NR’R”、-NRS(O)2R’或-NRC(O)N R’R”,其中R’和R”可以独立地为H、C1-C6烷基、芳基或3至10元杂环,或者R’和R”与它们所附着的原子一起形成3至10元环结构。
杂环基团可能的取代基包括卤素(Br、Cl、I或F)、氰基、硝基、氧代、氨基、C1-4烷基(例如,CH3、C2H5、异丙基)C1-4烷氧基(例如,OCH3、OC2H5)、卤代C1-4烷基(例如,CF3、CHF2)、卤代C1-4烷氧基(例如,OCF3、OC2F5)、COOH、COO4C1-4烷基、CO4C1-4烷基、C1-4烷基-S-(例如,CH3S、C2H5S)、卤代C1-4烷基-S-(例如,CF3S、C2F5S)、苄氧基和吡唑基。
杂环的示例包括但不限于吖庚因基(azepinyl)、吖丙啶基、azetyl、氮杂环基(azetidinyl)、二氮杂基(diazepinyl)、二噻二嗪基(dithiadiazinyl)、二氧氮杂基(dioxazepinyl)、二氧杂环戊基(dioxolanyl)、二噻唑基、呋喃基、异噁唑基(isooxazolyl)、异噻唑基、咪唑基、吗啉基、吗啉代、氧杂环丁烷基(oxetanyl)、噁二唑基、环氧乙烷基、噁嗪基、噁唑基、哌嗪基、吡嗪基、哒嗪基、嘧啶基、哌啶(piperidyl)、哌啶基(piperidino)、吡啶基、吡喃基、吡唑基、吡咯基、吡咯烷基、噻三唑基(thiatriazolyl)、四唑基(tetrazolyl)、噻二唑基(thiadiazolyl)、三唑基(triazolyl)、噻唑基、噻吩基、四嗪基、噻二嗪基、三嗪基、噻嗪基、硫代吡喃基呋喃异噁唑基、咪唑噻唑基、噻吩并异噻唑基、噻吩并噻唑基、咪唑并吡唑基、环戊基吡唑基、吡咯并吡咯基、噻吩并噻吩基、噻二唑嘧啶基(thiadiazolopyrimidinyl)、噻唑噻嗪基、噻唑嘧啶基、噻唑吡啶基、噁唑嘧啶基、噁唑吡啶基、苯并噁唑基、苯并异噻唑基、苯并噻唑基、咪唑并吡嗪基、嘌呤基、吡唑并嘧啶基、咪唑并吡啶基、苯并咪唑基、吲唑基、苯并噻二唑基(benzoxathiolyl)、苯并二氧基(benzodioxolyl)、苯并二硫醇基(benzodithiolyl)、吲哚基(indolizinyl)、二氢吲哚基(indolinyl)、异二氢吲哚基、呋喃嘧啶基、呋喃吡啶基、苯并呋喃基、异苯并呋喃基、噻吩并嘧啶基、噻吩吡啶基(thienapyridyl)、苯并噻吩基、环戊基噁嗪基、环戊呋喃基、苯并噁嗪基、苯并噻嗪基、喹唑啉基、萘基吡啶基(naphthyridinyl)、喹啉基、异喹啉基、苯并吡喃基、吡啶并哒嗪基和吡啶并嘧啶基基团。
苯甲酰胺化合物及其中间体可以以不同的互变异构形式存在。互变异构体包括具有低能障以互相转化的不同能量的任何结构异构体。一个示例是质子互变异构体(质子异变的互变异构体)。在这个示例中,相互转化通过质子迁移发生。质子异变的互变异构体的示例包括但不限于酮-烯醇和亚胺-烯胺异构化。在下面图示说明的另一个示例中,可以发生2-氨基苯并咪唑环的1-位、2-氨基和3-位氮原子之间的质子迁移。结果是,式Ia、Ib和Ic是彼此的互变异构形式:
苯甲酰胺化合物还涵盖所公开的苯甲酰胺化合物可能呈现的任何其它生理化学或立体化学形式。这种形式包括非对映异构体、外消旋体、分离的对映异构体、水合形式、溶剂化形式或任何其它已知的或尚待公开的结晶、多晶形结晶或无定形形式。无定形形式缺乏可区分的晶格,因此缺乏有序的结构单元排列。许多药物化合物具有无定形形式。产生这种化学形式的方法将是本领域技术人员所熟知的。
在一些方面,苯甲酰胺化合物是药学上可接受的盐的形式。药学上可接受的盐包括衍生自有机或无机酸的任何盐。这样的盐的示例包括但不限于以下:氢溴酸、盐酸、硝酸、磷酸和硫酸的盐。有机酸加成盐包括例如醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、2-(4-氯苯氧基)-2-甲基丙酸、1,2-乙烷二磺酸、乙磺酸、乙二胺四乙酸(EDTA)、富马酸、葡庚糖酸、葡糖酸、谷氨酸、N-羟乙酰基阿散酸、4-己基间苯二酚、马尿酸、2-(4-羟基苯甲酰基)苯甲酸、1-羟基-2-萘甲酸、3-羟基-2-萘甲酸、2-羟基乙磺酸、乳糖酸、正十二烷基硫酸、马来酸、苹果酸、扁桃酸、甲磺酸、甲基硫酸、粘酸、2-萘磺酸、双羟萘酸、泛酸、磷酸((4-氨基苯基)膦酸)、苦味酸、水杨酸、硬脂酸、琥珀酸、丹宁酸、酒石酸、对苯二甲酸、对甲苯磺酸、10-十一碳烯酸或任何其它目前已知的或尚待公开的这种酸的盐。本领域技术人员将会理解,这种药学上可接受的盐可以用于药物组合物的制剂中。这种盐可以以本领域技术人员已知的方式,通过将苯甲酰胺化合物与适合的酸反应来制备。
本发明还涵盖其中将保护基团加入到化合物的方面。本领域技术人员将认识到,在复合物分子的合成期间,苯甲酰胺化合物上的一种基团可以发生对包括化合物上的第二基团的预期反应的干扰。暂时掩盖或保护第一基团有利于(encourage)所需的反应。保护涉及将保护基团引入待保护的基团,进行所需的反应,并去除保护基团。保护基团的去除可称为脱保护。在一些合成中被保护的化合物的示例包括羟基基团、胺基基团、羰基基团、羧基基团和硫醇。
许多能够将它们引入到合成过程中的保护基团和试剂目前已经被发开,以及正在继续被开发。保护基团可以由任何化学合成产生,所述化学合成选择性地将对某些试剂具有抗性的基团附着到待保护的化学基团上,而对分子中的任何其它化学基团没有显著作用,在整个合成过程中保持稳定,并且可以通过这样的条件去除,即不会与受保护的基团发生不利反应,也不会与分子中的任何其它化学基团发生不利反应。可以在整个合成过程中加入多个保护基团,并且本领域技术人员将能够开发用于从待保护基团具体加入和去除的保护基团的策略。
保护基团、加入这些基团的试剂、这些试剂的制备、各种条件下的保护和脱保护策略,包括具有相互补充的保护基团的复合物合成,都是本领域熟知的。所有这些的非限制性示例可以在Green等人,Protective Groups in Organic Chemistry第2版,(Wiley 1991),以及Harrison等人,Compendium of Synthetic Organic Methods,卷1-8(Wiley,1971-1996)中发现,通过引用二者整体并入本文。
苯甲酰胺化合物的外消旋体、单独的对映异构体或非对映异构体可以通过目前已知的或尚待公开的任何方法的具体的合成或分离来制备。例如,可以通过使用光学活性酸,通过成盐形成非对映异构体对,将苯甲酰胺化合物分解成其对映异构体。对映异构体部分结晶,游离碱再生。在另一个示例中,对映异构体可以通过色谱分离。这样的色谱可以是目前已知的或尚待公开的任何适合的方法,其适用于在手性柱上分离对映异构体,如HPLC。
苯甲酰胺化合物的非限制性示例是:
N-羟基-4-(1-异丙基-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#1:
N-羟基-4-(1-甲基-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#2
4-(1-环丁基-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#3
N-羟基-4-(1-(2-甲氧基乙基)-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#4
4-(1-环戊基-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#5
4-(5-溴-1-异丙基-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#6
4-(6-溴-1-异丙基-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#7
N-羟基-4-(1-(2-甲氧基乙基)-5-苯基-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#8
N-羟基-4-(1-(3-甲氧基丙基)-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#9
4-(5-溴-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#10
N-羟基-4-(1-(2-羟乙基)-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#11
4-(5-氟代-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#12
N-羟基-4-(1-(2-异丙氧基乙基)-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#13
4-(5-(3-氟苯基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#14
N-羟基-4-(1-(2-甲氧基乙基)-5-(嘧啶-5-基)-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#15
4-(5-环丙基-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#16
4-(5-溴-1-(2-(二甲基氨基)乙基)-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#17
N-羟基-4-(1-异丙基-5-(嘧啶-5-基)-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#18
N-羟基-4-(1-异丙基-5-(吡啶-3-基)-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#19
N-羟基-4-(1-(戊-3-基)-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#20
4-(6-氟代-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#21
4-(4-氟代-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#22
N-羟基-4-(1-异丙基-5-(甲氧基甲基)-1H-苯并[d]咪唑-2-基氨基)苯甲酰胺ID#23
4-(1-(环己基甲基)-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#24
4-(1-环己基-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#25
4-(1-环庚基-1H-苯并[d]咪唑-2-基氨基)-N-羟基苯甲酰胺ID#26
额外的示例包括:
在某些方面,本发明涉及包含式(I)化合物的组合物:
和/或包含式(II)的化合物的组合物:
由X表示的基团可以是以下的任何一个:H、卤素、-Cl-C6烷基、芳基、-C3-C7环烷基或-3至10元杂环,其中的任一个可以是未取代的或者被以下的一个或多个取代:-卤素、-C1-C6烷基、-O-(C1-C6烷基)、-OH、-CN、-COOR'、-OC(O)R'、NHR'、N(R')2、-NHC(O)R'或-C(O)NHR'基团,其中R'可以是-H或-Cl-C6烷基。
由A表示的基团可以是任何键、-Cl-C6烷基或-C3-C7环烷基,其中的任一个可以是未取代的或者被以下的一个或多个取代:-卤素、-C1-C6烷基、-O-(C1-C6烷基)、-OH、-CN、-COOR'、-OC(O)R'、NHR'、N(R')2、-NHC(O)R'或-C(O)NHR'基团,其中R'可以是-H或-Cl-C6烷基。
由Y表示的基团可以是H、-Cl-C6烷基、-C3-C7环烷基、芳基或-3至10元杂环,其中的任一个可以是未取代的或者被以下的一个或多个取代:-卤素、-C1-C6烷基、-O-(C1-C6烷基)、-OH、-CN、-COOR'、-OC(O)R'、NHR'、N(R')2、-NHC(O)R'或-C(O)NHR'基团,其中R'可以是-H或-Cl-C6烷基。
由Q表示的基团可以是H、卤素、-C1-C6烷基、-O-(C1-C6烷基)、-OH、-CN、-COOR'、-OC(O)R’、NHR’、N(R’)2、-NHC(O)R’或-C(O)NHR’基团,其中R’可以是-H或-Cl-C6烷基。
-C1-C6烷基基团包括由1至6个碳原子组成的任何直或支、饱和或不饱和的取代或未取代的碳氢化合物。-C1-C6烷基基团的示例包括但不限于甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基,异戊基、新戊基、己基、异己基、新己基、乙烯基、丙烯基、1-丁烯基、2-丁烯基、1-戊烯基、2-戊烯基、1-己烯基、2-己烯基、3-己烯基、乙炔基、戊炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基和3-己炔基基团。取代的-C1-C6烷基基团可以包括任何适合的化学部分。可以被取代到上述任何-C1-C6烷基基团上的基团的示例包括但不限于以下示例:卤素、-Cl-C6烷基、-O-(Cl-C6烷基)、-OH、-CN、-COOR’、-OC(O)R’、-NHR’、N(R’)2、-NHC(O)R’或-C(O)NHR’基团。由R’表示的基团可以是-H或任何-Cl-C6烷基。
芳基基团包括任何未取代或取代的苯基或萘基基团。可以被取代到芳基基团上的基团的示例包括但不限于:卤素、-C1-C6烷基、-O-(C1-C6烷基)、-OH、-CN、-COOR’、-OC(O)R’、NHR’、N(R’)2、-NHC(O)、R’或-C(O)NEtR’。由R’表示的基团可以是-H或任何-Cl-C6烷基。
C3-C7环烷基基团包括任何3、4、5、6或7元取代或未取代的非芳族碳环。C3-C7环烷基基团的示例包括但不限于环丙基、环丁基、环戊基、环戊二烯基、环己基、环己烯基、环庚基、环庚烷、1,3-环己二烯基、-1,4-环己二烯基、-1,3-环庚二烯基和-1,3,5-环庚三烯基基团。可以被取代到C3-C7环烷基基团上的基团的示例包括但不限于:-卤素、-Cl-C6烷基、-O-(Cl-C6烷基)、-OH、-CN、-COOR’、-OC(O)R’、NHR’、N(R’)2、-NHC(O)R’或-C(O)NHR’基团。以上由R’表示的基团包括-H或任何未取代的-Cl-C6烷基,其示例如上所列。
卤素基团包括任何卤素。示例包括但不限于-F、-Cl、-Br或-I。
杂环可以是任何任选的取代的饱和、不饱和或芳族的环部分,其中所述环部分被选自氧(O)、硫(S)或氮(N)的至少一种杂原子间隔。杂环可以是单环或多环。例如,适合的取代基包括卤素、卤代C1-C6烷基、卤代C1-C6烷氧基、氨基,脒基、酰胺基、叠氮基、氰基、胍基、羟基、硝基、亚硝基、尿素、OS(O)2R;OS(O)2OR、S(O)2OR S(O)0-2R、C(O)OR,其中R可以是H、C1-C6烷基、芳基或3至10元杂环、OP(O)OR1OR2、P(O)OR1OR2、SO2NR1R2、NR1SO2R2 C(R1)NR2C(R1)NOR2,R1和R2可以独立地为H、C1-C6烷基、芳基或3至10元杂环、NR1C(O)R2、NR1C(O)OR2、NR3C(O)NR2R1、C(O)NR1R2、OC(O)NR1R2。对于这些基团,R1、R2和R3各自独立地选自H、C1-C6烷基、芳基或3至10元杂环,或者R1和R2与它们所附着的原子一起形成3至10元杂环。
杂环基团可能的取代基包括卤素(Br、Cl、I或F)、氰基、硝基、氧代、氨基、C1-4烷基(例如,CH3、C2H5、异丙基)、C1-4烷氧基(例如,OCH3、OC2H5)、卤代C1-4烷基(例如,CF3、CHF2)、卤代C1-4烷氧基(例如,OCF3、OC2F5)、COOH、COO4C1-4烷基、CO-C1-4烷基、C1-4烷基-S-(例如,CH3S、C2H5S)、卤代C1-4烷基-S-(例如,CF3S、C2F5S)、苄氧基和吡唑基。
杂环的示例包括但不限于吖庚因基(azepinyl)、吖丙啶基、azetyl、氮杂环基(azetidinyl)、二氮杂基(diazepinyl)、二噻二嗪基(dithiadiazinyl)、二氧氮杂基(dioxazepinyl)、二氧杂环戊基(dioxolanyl)、二噻唑基、呋喃基、异噁唑基(isooxazolyl)、异噻唑基、咪唑基、吗啉基、吗啉代、氧杂环丁烷基(oxetanyl)、噁二唑基、环氧乙烷基、噁嗪基、噁唑基、哌嗪基、吡嗪基、哒嗪基、嘧啶基、哌啶(piperidyl)、哌啶基(piperidino)、吡啶基、吡喃基、吡唑基、吡咯基、吡咯烷基、噻三唑基(thiatriazolyl)、四唑基(tetrazolyl)、噻二唑基(thiadiazolyl)、三唑基(triazolyl)、噻唑基、噻吩基、四嗪基、噻二嗪基、三嗪基、噻嗪基、硫代吡喃基呋喃异噁唑基、咪唑噻唑基、噻吩并异噻唑基、噻吩并噻唑基、咪唑并吡唑基、环戊基吡唑基、吡咯并吡咯基、噻吩并噻吩基、噻二唑嘧啶基(thiadiazolopyrimidinyl)、噻唑噻嗪基、噻唑嘧啶基、噻唑吡啶基、噁唑嘧啶基、噁唑吡啶基、苯并噁唑基、苯并异噻唑基、苯并噻唑基、咪唑并吡嗪基、嘌呤基、吡唑并嘧啶基、咪唑并吡啶基、苯并咪唑基、吲唑基、苯并噻二唑基(benzoxathiolyl)、苯并二氧基(benzodioxolyl)、苯并二硫醇基(benzodithiolyl)、吲哚基(indolizinyl)、二氢吲哚基(indolinyl)、异二氢吲哚基、呋喃嘧啶基、呋喃吡啶基、苯并呋喃基、异苯并呋喃基、噻吩并嘧啶基、噻吩吡啶基(thienσpyridyl)、苯并噻吩基、环戊基噁嗪基、环戊呋喃基、苯并噁嗪基、苯并噻嗪基、喹唑啉基、萘基吡啶基(naphthyridinyl)、喹啉基、异喹啉基、苯并吡喃基、吡啶并哒嗪基和吡啶并嘧啶基基团。
通过以下实施例进一步说明本发明,这些实施例不应被解释为限制性的。出于所有目的,本申请通篇引用的所有参考文献、专利和公开的专利申请以及附图的内容通过引用整体并入本文。
实施例
本实施例中的元素和行动旨在为了简单起见而说明本发明,并且不一定根据任何具体的顺序或实施方案来呈现。这些实施例还旨在确定发明人对本发明的所有。
实施例1:包含ID#24和抗PD-1抗体的组合物的抗转移活性
方法
六周龄雌性balb/c小鼠在右侧皮下接种0.1mL的含有4T1-luc2鼠乳肿瘤细胞(约1×106个细胞/小鼠)悬液的50%RPMI/50%MatrigelTM(BD Biosciences;Bedford,MA)混合物。4T1-luc2鼠乳肿瘤细胞是表达荧光素酶的腺癌细胞系的系,所述腺癌细胞系衍生自小鼠乳腺,采用萤火虫荧光素酶基因(luc2载体)稳定转染以产生加强的光。因此,荧光素酶诱导的发光可以是检测这些细胞的一种方式。
接种八天后,使用数字卡尺测量肿瘤。卡尺用于测量肿瘤的宽度直径和长度直径。使用动物研究管理软件,Study Director V.2.1.1(Study Log),将测量的值进行数字化记录。使用下式计算肿瘤体积:
其中“b”是最小的直径,“a”是最大的直径。通过随机平衡,将肿瘤体积为306-519mm3的小鼠随机分成每组8只小鼠的组,使得每组具有约450mm3的第1天平均肿瘤体积(使用Study Director计算)。当小鼠被随机化并且每周进行三次,记录肿瘤体积。
治疗从实验的第一天开始。每天通过口服填喂(oral gavage)给予化合物ID#24进行治疗,直至研究结束。每隔一天腹膜内给予抗小鼠PD-1(CD279,克隆J43)(PD-1抑制剂)抗体和抗小鼠CTLA4(CD152,克隆9H10)(CTLA4抑制剂)抗体,持续8天。实验中的治疗组是:
·第1组:化合物ID#24载体对照(PO)+同种型对照0.25mg/剂量(IP)
·第3组:PD-1抑制剂0.25mg/剂量(IP)
·第4组:化合物ID#24 50mg/kg(PO)+同种型对照0.25mg/剂量(IP)
·第6组:化合物ID#24 50mg/kg(PO)+PD-1抑制剂0.25mg/剂量(IP)
·第7组:CTLA4抑制剂0.25mg/剂量(IP)+PD-1抑制剂0.25mg/剂量(IP)
·第8组:化合物ID#24 50mg/kg(PO)+CTLA4抑制剂0.25mg/剂量(IP)+PD-1抑制剂0.25mg/剂量(IP)。
当对照肿瘤达到平均≥2300mm3时,使小鼠安乐死,收集肺组织并评估自发性肺转移(通过发光强度检测)。安乐死之前30分钟,小鼠腹膜内注射150mg/kg荧光素。将肺置于光度计,读取发光强度。
结果
如图1和图3所示,苯甲酰胺化合物(化合物ID#24)和PD-1抑制剂抗体的联合比单独治疗产生更高水平的肿瘤细胞生长抑制。因此,PD-1抑制剂和化合物ID#24的联合治疗对4T1肿瘤细胞具有协同的抗癌作用。
有趣的是,如图3所示,CTLA4抑制剂的加入产生了更大的协同的结果。PD-1抑制剂和CTLA4抑制剂的联合治疗损害了每种抑制剂对肿瘤生长的抑制,但化合物ID#24的加入恢复并增强了肿瘤细胞生长抑制的有效性。
在评估不同的治疗对自发性肺转移的存在的作用中,观察到类似的协同结果(参见图4和图6)。因此,苯甲酰胺化合物(化合物ID#24)和PD-1抑制剂的联合在抑制肿瘤细胞转移中具有协同性(图4)。
化合物ID#24、PD-1抑制剂和CTLA4抑制剂的联合也产生对肿瘤细胞转移的协同抑制(图6)。
实施例2:包含ID#24和CTLA4抑制剂的组合物的抗肿瘤细胞生长和抗转移活性
方法
六周龄雌性balb/c小鼠在右侧皮下接种0.1mL的含有4T1-luc2鼠乳肿瘤细胞(约1×106个细胞/小鼠)悬液的50%RPMI/50%MatrigelTM(BD Biosciences;Bedford,MA)混合物。4T1-luc2鼠乳肿瘤细胞是表达荧光素酶的腺癌细胞系的系,所述腺癌细胞系衍生自小鼠乳腺,采用萤火虫荧光素酶基因(luc2载体)稳定转染以产生加强的光。因此,荧光素酶诱导的发光可以是检测这些细胞的一种方式。
接种八天后,使用数字卡尺测量肿瘤。卡尺用于测量肿瘤的宽度直径和长度直径。使用动物研究管理软件,Study Director V.2.1.1(Study Log),将测量的值进行数字化记录。使用下式计算肿瘤体积:
其中“b”是最小的直径,“a”是最大的直径。通过随机平衡,将肿瘤体积为306-519mm3的小鼠随机分成每组8只小鼠的组,使得每组具有约450mm3的第1天平均肿瘤体积(使用Study Director计算)。当小鼠被随机化并且每周进行三次时,记录肿瘤体积。
治疗从实验的第一天开始。每天通过口服填喂给予化合物ID#24进行治疗,直至研究结束。每隔一天腹膜内给予抗小鼠CTLA4(CD152,克隆9H10)(CTLA4抑制剂)抗体和抗小鼠PD1(CD279,克隆J43)(PD1抑制剂)抗体,持续8天。实验中的治疗组是:
·第1组:化合物ID#24载体对照(PO)+同种型对照0.25mg/剂量(IP)
·第2组:CTLA抑制剂0.25mg/剂量(IP)
·第4组:化合物ID#24 50mg/kg(PO)+同种型对照0.25mg/剂量(IP)
·第5组:化合物ID#24 50mg/kg(PO)+CTLA4抑制剂0.25mg/剂量(IP)
·第7组:CTLA抑制剂0.25mg/剂量(IP)+PD1抑制剂0.25mg/剂量(IP)
·第8组:化合物ID#24 50mg/kg(PO)+CTLA4抑制剂0.25mg/剂量(IP)+PD1抑制剂0.25mg/剂量(IP)。
当对照肿瘤达到平均≥2300mm3时,使小鼠安乐死,收集肺组织并评估自发性肺转移(通过发光强度检测)。安乐死之前30分钟,小鼠腹膜内注射150mg/kg荧光素。将肺置于光度计,读取发光强度。
结果
如图2所示,苯甲酰胺化合物(化合物ID#24)和CTLA4抑制剂抗体的联合产生比单独治疗更高水平的肿瘤细胞生长抑制。因此,CTLA4抑制剂和化合物ID#24的联合治疗对4T1肿瘤细胞具有协同的抗癌作用。有趣的是,如图3所示,PD1抑制剂的加入产生了更大的协同的结果。CTLA4抑制剂和PD1抑制剂的联合治疗损害了每种抑制剂对肿瘤生长的抑制,但化合物ID#24的加入恢复并增强了肿瘤细胞生长抑制的有效性(图3)。
在评估不同的治疗对自发性肺转移的存在的作用中,观察到类似的协同结果(参见图5-6)。因此,苯甲酰胺化合物(化合物ID#24)和CTLA4抑制剂的联合在抑制肿瘤细胞转移中具有协同性(图5)。
化合物ID#24、CTLA4抑制剂和PD1抑制剂的联合也产生对肿瘤细胞转移的协同抑制。
实施例3:苯甲酰胺化合物对细胞活力的作用
在不同时间点,存在不同浓度的苯甲酰胺化合物时的细胞活力,用于评估化合物的细胞毒性和对细胞增殖的作用。表2总结了人急性白血病细胞系(HL-60)中苯甲酰胺化合物的IC50(或活力百分比)数据。
表2.单一试剂生长抑制结果
化合物 | IC<sub>50</sub>(μM) |
ID#24 | 1.15 |
ID#25 | 3.90 |
ID#26 | 0.66 |
细胞活力测定-细胞活力通过细胞活力测定Promega(Madison,Wis.)测量。发光细胞活力测定是基于对存在的ATP的定量来确定培养物中活细胞数量的同质的方法,ATP表示存在代谢活性细胞。处理后,将加入到处理孔中,并在37℃孵育。使用Molecular Devices Spectramax酶标仪测量发光值。
单一试剂研究—细胞生长至70%汇合,胰蛋白酶消化、计数,并以2.5×103-5×103细胞/孔(第0天)的终浓度接种于96孔平底板中。允许细胞在生长介质中孵育24小时以允许最大的粘附。在第1天开始用试验试剂或标准试剂处理,持续72小时。在72小时的时间点,含有介质的处理被去除。如上所述通过细胞活力测定来定量活细胞数量。以一式三份浓度进行实验以确定生长抑制活性。这些研究的结果用于计算每种化合物的IC50值(抑制对照的50%的细胞生长的药物浓度)。
数据收集-对于单一试剂和联合的研究,来自每实验的数据被收集并且表示为细胞生长%,使用以下计算:
细胞生长%=(f试验/f载体)×100
其中f试验是试验样品的发光,而f载体是溶解药物的载体的发光。使用Prism 6软件(GraphPad)产生剂量响应的图和IC50值。
实施例4:协同
为了试验苯甲酰胺化合物和DNA甲基转移酶抑制剂之间的协同,评价本发明的不同的苯甲酰胺化合物与5-氮杂胞苷的联合针对HL-60细胞的IC50。
对于每个实验,对药物联合计算ED50、ED75、ED90和ED95(产生作用的药物联合的剂量,例如降低50%、75%、90%和95%的细胞增殖)时的CI值。下表3总结了不同联合的协同因子(CI值)。使用CompuSyn程序(CompuSyn,Paramus,N.J.)计算CI值。CI值<0.90,显示苯甲酰胺化合物和DNA甲基转移酶抑制剂间的协同。
表3.在各个ED浓度下与5-氮杂胞苷联合的CI值:
参考文献
1.Lafferty等人,Aust.J.Exp.Biol.Med.ScL 53:27-42(1975).
2.Bretscher等人,Science 169:1042-1049(1970)
3.Bretscher,P.A.,P.N.A.S.USA 96:185-190(1999)
4.Jenkins等人,J.Exp.Med.165:302-319(1987).
5.Lenschow等人,Ann.Rev.Immunol.14:233(1996).
6.Okazaki T等人,Intern.Immun.19(7):813(2007).
7.Thompson R H等人,Cancer Res 66(7):3381(2006).
8.Ahmadzadeh等人,Blood 114(8):1537(2009).
9.Sharpe等人,Nat Rev 2002.
10.Keir M E等人,2008Annu.Rev.Immunol.26:677.
11.Long,B.H.等人,Cancer Res.,51:5275-5284(1991).
12.Giannakakou,P.等人,J.Biol.Chem.,272(27):17118-17125(1997).
13.Riss,T.L.等人,Mol.Biol.Cell,3(Suppl.):184a(1992).
14.Stephens,T.C.等人,“The evaluation of combinations of cytotoxicdrugs and radiation:Isobolograms and therapeutic synergism”,Rodent TumorModels in Experimental Cancer Therapy,第248页.Pergamon Press,NY,publ.,Kallman,R.F.,编.
15.Long,B.H.,Cancer Res.,54(16):4355-4361(1994).
16.Williams,R.C.等人,Meth.Enzymol.,85(Pt.D):376-385(1982).
17.Gehan,G.A.,“Biometrika,52:203-233(1985).
18.Walunas,T.L.等人,Immunity,1(5):405-413(1994年8月).
19.Linsley,P.S.等人,J.Exp.Med.,173:721-730(1991).
20.Linsley,P.S.等人,J.Exp.Med.,174:561-569(1991).
21.Brunet,J.F.等人,Nature,328:267-270(1987).
22.Gross,J.A.等人,J.Immunol.,149:380-388(1992).
23.Alegre,M.L.等人,Nat.Rev.Immunol.,1:220-228(2002).
24.Lindsten,T.等人,J.Immunol.,151:3489-3499(1993).
25.Walunas,T.L.等人,Immunity,1:405-413(1994).
26.Linsley,P.S.等人,Immunity,1:793-801(1994).
27.Walunas,T.L.等人,J.Exp.Med.,183:2541-2550(1996).
28.Krummel,M.F.等人,J.Exp.Med.,183:2533-2540(1996).
29.Brunner,M.C.等人,J.Immunol.,162:5813-5820(1999).
30.Greenwald,R.J.等人,Eur.J.Immunol.,32:366-373(2002).
31.Leach,D.R.等人,Science,271:1734-1736(1996).
32.van Elsas,A.等人,J.Exp.Med.,190:355-366(1999).
33.van Elsas,A.等人,J.Exp.Med.,194:481-489(2001).
34.Hurwitz,A.A.等人,Cancer Res.,60:2444-2448(2000).
35.Robbins and Angell,1976,Basic Pathology,第2版,W.B.Saunders Co.,Philadelphia.
36.Bulinski,J.Cell Sci.,110:3055-3064(1997).
37.Panda,Proc.Natl.Acad.Sci.USA,94:10560-10564(1997).
38.Muhlradt,Cancer Res.,57:3344-3346(1997).
39.Nicolaou,Nature,387:268-272(1997).
40.Vasquez,Mol.Biol.Cell.,8:973-985(1997).
41.Panda,J.Biol.Chem.,271:29807-29812(1996).
42.Schwartz,R.H.,Science,248:1349-1356(1990)。
序列表
<110> 转化药物开发有限责任公司
<120> 苯甲酰胺和活性化合物的组合物及其使用方法
<130> 11144.023
<150> US 62/165,891
<151> 2015-05-22
<150> US 62/167,790
<151> 2015-05-28
<150> US 62/167,794
<151> 2015-05-28
<150> US 62/302,781
<151> 2016-03-18
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Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
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Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
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Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
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Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
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Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
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Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
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Claims (10)
2.根据权利要求1所述的化合物,其中A为未取代的-Cl-C6烷基,且Y为-C3-C7环烷基、芳基或-3至10元杂环,其中的任一个是未取代的或者被一个或多个-卤素取代。
4.根据权利要求3所述的化合物,其中所述化合物为4-(1-(环己基甲基)-1H-苯并[d]咪唑-2-基)氨基)-N-羟基苯甲酰胺。
5.一种药物组合物,其包含前述权利要求中任一项所述的化合物和药学上可接受的载体。
6.根据权利要求1至4中任一项所述的化合物或者根据权利要求5所述的药物组合物,其用于在受试者中治疗癌症的用途。
7.根据权利要求6所述的用途的化合物或药物组合物,其中所述受试者展现出恶性诱发因素,所述诱发因素选自与恶性相关的染色体易位,息肉,良性单克隆丙种球蛋白病,与过去患有或目前患有癌症或癌前疾病的人的亲属关系,暴露于致癌物。
8.根据权利要求7所述的用途的化合物或药物组合物,其中所述染色体易位选自费城染色体和t(14;18)。
9.根据权利要求1至4中任一项所述的化合物或者根据权利要求5所述的药物组合物,其用于预防细胞的赘生、恶性和/或转移进展的用途。
10.根据权利要求9所述的用途的化合物或药物组合物,其中所述细胞具有特征在于增生、化生或发育异常的异常细胞生长。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10441654B2 (en) | 2014-01-24 | 2019-10-15 | Children's Hospital Of Eastern Ontario Research Institute Inc. | SMC combination therapy for the treatment of cancer |
JP6688735B2 (ja) | 2014-02-11 | 2020-04-28 | バイエル・ファルマ・アクティエンゲゼルシャフト | mIDH1阻害剤としてのベンズイミダゾール−2−アミン |
US9957235B2 (en) | 2014-02-11 | 2018-05-01 | Bayer Pharma Aktiengesellschaft | Benzimidazol-2-amines as mIDH1 inhibitors |
WO2019051125A1 (en) | 2017-09-06 | 2019-03-14 | Translational Drug Development, Llc | AMINOBENZIMIDAZOLE DERIVATIVES, TREATMENTS AND METHODS FOR INHIBITING HISTONE DEACETYLASE |
AU2016394945A1 (en) * | 2016-03-02 | 2018-10-11 | Translational Drug Development Llc | Aminobenzimidazole derivatives |
IL300095A (en) * | 2016-11-23 | 2023-03-01 | Translational Drug Dev Llc | Compositions of benzamide and an agonist for the cancer necrosis factor receptor superfamily and uses thereof |
SG11202106963YA (en) * | 2019-01-11 | 2021-07-29 | Omeros Corp | Methods and compositions for treating cancer |
WO2020149712A1 (ko) * | 2019-01-17 | 2020-07-23 | 오토텔릭바이오 주식회사 | 암 치료용 조성물 |
WO2023203249A1 (en) * | 2022-04-22 | 2023-10-26 | Universität Heidelberg | Composition comprising cytidine analogs and uses and methods thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101379060A (zh) * | 2006-02-10 | 2009-03-04 | 转化技术制药公司 | 作为Aurora激酶抑制剂的苯并唑系衍生物、组合物和使用方法 |
US20140341902A1 (en) * | 2011-08-01 | 2014-11-20 | Genentech, Inc. | Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors |
CN104219954A (zh) * | 2009-06-23 | 2014-12-17 | 翻译基因组学研究院 | 苯甲酰胺衍生物 |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ207394A (en) | 1983-03-08 | 1987-03-06 | Commw Serum Lab Commission | Detecting or determining sequence of amino acids |
WO1984003506A1 (en) | 1983-03-08 | 1984-09-13 | Commw Serum Lab Commission | Antigenically active amino acid sequences |
CA1247080A (en) | 1983-03-08 | 1988-12-20 | Commonwealth Serum Laboratories Commission | Antigenically active amino acid sequences |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
NZ215865A (en) | 1985-04-22 | 1988-10-28 | Commw Serum Lab Commission | Method of determining the active site of a receptor-binding analogue |
US6548640B1 (en) | 1986-03-27 | 2003-04-15 | Btg International Limited | Altered antibodies |
US5571689A (en) | 1988-06-16 | 1996-11-05 | Washington University | Method of N-acylating peptide and proteins with diheteroatom substituted analogs of myristic acid |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
US5663143A (en) | 1988-09-02 | 1997-09-02 | Dyax Corp. | Engineered human-derived kunitz domains that inhibit human neutrophil elastase |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
US5225538A (en) | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
JPH06759B2 (ja) * | 1989-09-22 | 1994-01-05 | ファイザー製薬株式会社 | 新規なベンゾイミダゾール化合物 |
US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
ES2087997T3 (es) | 1990-01-12 | 1996-08-01 | Cell Genesys Inc | Generacion de anticuerpos xenogenicos. |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
DK0546073T3 (da) | 1990-08-29 | 1998-02-02 | Genpharm Int | Frembringelse og anvendelse af transgene, ikke-humane dyr, der er i stand til at danne heterologe antistoffer |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
EP0558671B1 (en) | 1990-11-21 | 1999-01-27 | Iterex Pharmaceuticals Ltd. Partnership | Synthesis of equimolar multiple oligomer mixtures, especially of oligopeptide mixtures |
ATE164395T1 (de) | 1990-12-03 | 1998-04-15 | Genentech Inc | Verfahren zur anreicherung von proteinvarianten mit geänderten bindungseigenschaften |
US5851795A (en) | 1991-06-27 | 1998-12-22 | Bristol-Myers Squibb Company | Soluble CTLA4 molecules and uses thereof |
DE69232137T2 (de) | 1991-11-25 | 2002-05-29 | Enzon Inc | Multivalente antigen-bindende proteine |
US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
KR100654645B1 (ko) | 1995-04-27 | 2007-04-04 | 아브게닉스, 인크. | 면역화된 제노마우스 유래의 인간 항체 |
CA2219486A1 (en) | 1995-04-28 | 1996-10-31 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5855887A (en) | 1995-07-25 | 1999-01-05 | The Regents Of The University Of California | Blockade of lymphocyte down-regulation associated with CTLA-4 signaling |
US6051227A (en) | 1995-07-25 | 2000-04-18 | The Regents Of The University Of California, Office Of Technology Transfer | Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling |
US5811097A (en) | 1995-07-25 | 1998-09-22 | The Regents Of The University Of California | Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling |
CA2722378C (en) | 1996-12-03 | 2015-02-03 | Amgen Fremont Inc. | Human antibodies that bind tnf.alpha. |
JP2001523958A (ja) | 1997-03-21 | 2001-11-27 | ブライハム アンド ウィミンズ ホスピタル,インコーポレイテッド | 免疫療法のctla−4結合ペプチド |
JP4460155B2 (ja) | 1997-12-05 | 2010-05-12 | ザ・スクリプス・リサーチ・インステイチユート | マウス抗体のヒト化 |
ID29991A (id) | 1998-12-23 | 2001-10-25 | Pfizer Inc Cs | Antibodi monoklonal manusia pada ctla-4 |
US6682736B1 (en) | 1998-12-23 | 2004-01-27 | Abgenix, Inc. | Human monoclonal antibodies to CTLA-4 |
US7109003B2 (en) | 1998-12-23 | 2006-09-19 | Abgenix, Inc. | Methods for expressing and recovering human monoclonal antibodies to CTLA-4 |
NZ517202A (en) | 1999-08-24 | 2004-05-28 | Medarex Inc | Human CTLA-4 antibodies and their uses |
US7605238B2 (en) | 1999-08-24 | 2009-10-20 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
US7034121B2 (en) | 2000-01-27 | 2006-04-25 | Genetics Institue, Llc | Antibodies against CTLA4 |
US7217797B2 (en) | 2002-10-15 | 2007-05-15 | Pdl Biopharma, Inc. | Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis |
NZ568769A (en) | 2002-10-17 | 2010-04-30 | Genmab As | Human monoclonal antibodies against CD20 |
JP2006504971A (ja) | 2002-11-01 | 2006-02-09 | ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・コロラド,ア・ボディー・コーポレイト | マトリックス支援レーザー脱離イオン化−飛行時間型質量分析によるタンパク質アイソフォームの定量的解析 |
EP3530736A3 (en) | 2005-05-09 | 2019-11-06 | ONO Pharmaceutical Co., Ltd. | Human monoclonal antibodies to programmed death 1 (pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics |
EP1993536A4 (en) * | 2006-03-02 | 2010-05-19 | Glaxosmithkline Llc | THIAZOLONES AS INHIBITORS OF P13-KINASES |
EP2914112A4 (en) * | 2012-11-05 | 2016-06-15 | Celgene Corp | TREATMENT OF CANCER BY POMALIDOMIDE IN A SUBJECT WITH RENAL FAILURE |
US9506481B1 (en) | 2013-01-31 | 2016-11-29 | Daniel Theobald | High force hydraulic actuator |
US9339565B2 (en) | 2013-09-25 | 2016-05-17 | Mallinckrodt Llc | Process for the preparation of radioiodinated 3-fluoropropyl-nor-β-CIT |
PT3049441T (pt) * | 2013-09-27 | 2020-01-21 | Hoffmann La Roche | Formulações de anticorpos anti-pdl1 |
WO2019051125A1 (en) * | 2017-09-06 | 2019-03-14 | Translational Drug Development, Llc | AMINOBENZIMIDAZOLE DERIVATIVES, TREATMENTS AND METHODS FOR INHIBITING HISTONE DEACETYLASE |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101379060A (zh) * | 2006-02-10 | 2009-03-04 | 转化技术制药公司 | 作为Aurora激酶抑制剂的苯并唑系衍生物、组合物和使用方法 |
CN104219954A (zh) * | 2009-06-23 | 2014-12-17 | 翻译基因组学研究院 | 苯甲酰胺衍生物 |
US20140341902A1 (en) * | 2011-08-01 | 2014-11-20 | Genentech, Inc. | Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors |
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