CN115969854A - 用tg02治疗癌症 - Google Patents
用tg02治疗癌症 Download PDFInfo
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- CN115969854A CN115969854A CN202211276427.5A CN202211276427A CN115969854A CN 115969854 A CN115969854 A CN 115969854A CN 202211276427 A CN202211276427 A CN 202211276427A CN 115969854 A CN115969854 A CN 115969854A
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Abstract
本申请涉及用TG02治疗癌症。本公开内容提供了用TG02和第二治疗药物,例如TG02和免疫检查点抑制剂,TG02和COX‑2抑制剂,或TG02和免疫检查点抑制剂和COX‑2抑制剂治疗癌症患者的治疗方法。
Description
本申请是中国专利申请号201780032318.X的分案申请。
背景技术
发明领域
本公开内容提供了用TG02和第二治疗药物,例如TG02和免疫检查点抑制剂,TG02和COX-2抑制剂,以及TG02和免疫检查点抑制剂和COX2抑制剂治疗癌症患者的治疗方法。
背景
TG02是基于嘧啶的多激酶抑制剂,其与JAK2和FLT3一起抑制CDK 1,2,5,7和9。它剂量依赖性地抑制癌细胞中CDK,JAK2和FLT3下游的信号传导途径,主要靶标是CDK。TG02在广泛的肿瘤细胞系中是抗增殖的,诱导G1细胞周期停滞和细胞凋亡。源自急性髓性白血病(AML)和真性红细胞增多症患者的祖细胞的原代培养物对TG02非常敏感。与仅阻断TG02的主要靶标之一的参考抑制剂的比较证明了组合CDK和JAK2/FLT3抑制在细胞系以及原代细胞中的益处。参见Goh等,Leukemia 26:236-43(2012)。TG02也称为SB1317,化学名称为:(16E)-14-甲基-20-氧杂-5,7,14,26-四氮杂四环[19.3.1.1(2,6).1(8,12)]二十七碳-1(25),2(26),3,5,8(27),9,11,16,21,23-十烯。TG02在US 8,143,255中公开为化合物1。US9,120,815公开了各种盐,例如TG02柠檬酸盐,和TG02的结晶形式。TG02的化学结构是:
发明内容
在一个方面,本公开提供了治疗癌症患者的治疗方法,该方法包括向患者给予治疗有效量的TG02。在另一方面,患者的癌症的特征在于过表达MYC,MCL1或两者。
另一方面,本发明提供治疗癌症患者的治疗方法,该方法包括给予患者治疗有效量的TG02和免疫检查点抑制剂,例如PD-1抑制剂,PD-L1抑制剂,CTLA-4抑制剂,LAG3抑制剂,TIM3抑制剂或cd47抑制剂。
另一方面,本发明提供治疗癌症患者的治疗方法,该方法包括给予患者治疗有效量的TG02和COX抑制剂,例如,阿利考昔或6-溴-8-(甲基-D3)-2-(三氟甲基)-2H-色烯-3-羧酸。
另一方面,本发明提供了治疗癌症患者的治疗方法,该方法包括向患者给予治疗有效量的TG02,免疫检查点抑制剂和COX-2抑制剂。
另一方面,本发明提供治疗患有过表达MYC,MCL1或两者的肿瘤的癌症患者的治疗方法。
另一方面,本发明提供了试剂盒,其包含TG02,TG02和免疫检查点抑制剂,TG02和COX-2抑制剂,以及TG02和免疫检查点抑制剂和COX-2抑制剂。
另一方面,本发明提供药物组合物,其包含TG02,COX-2抑制剂,例如,阿利考昔或6-溴-8-(甲基-D3)-2-(三氟甲基)-2H-色烯-3-羧酸和药学上可接受的赋形剂。
附图说明
图1是柱状图,显示了TG02,TMZ(替莫唑胺),和TG02+TMZ在GSC923细胞中的体外活性。
图2是柱状图,显示了TG02,TMZ,和TG02+TMZ在LN18细胞中的体外活性。
图3是柱状图,显示了TG02,TMZ,和TG02+TMZ在T98G细胞中的体外活性。
图4是柱状图,显示了TG02,TMZ,和TG02+TMZ在U251细胞中的体外活性。
图5是柱状图,显示了TG02,TMZ,和TG02+TMZ在U87细胞中的体外活性。
图6是柱状图,显示了TG02,TMZ,和TG02+TMZ在LN299细胞中的体外活性。
图7是柱状图,显示了TG02,TMZ,和TG02+TMZ在GSC827细胞中的体外活性。
图8是柱状图,显示了TG02,TMZ,和TG02+TMZ(T+T)在GSC923细胞中的体外细胞毒性。
图9是柱状图,显示了TG02,TMZ,和TG02+TMZ(T+T)在U251细胞中的体外细胞毒性。
图10是柱状图,显示了TG02,TMZ,和TG02+TMZ(T+T)在人肺动脉内皮细胞中缺少体外活性。
图11是柱状图,显示了TG02,TMZ,和TG02+TMZ(T+T)在人星形胶质细胞中缺少体外活性。
图12是显示TG02和TG02+TMZ在GSC923细胞中的体外活性的剂量响应曲线。
图13是显示TMZ和TG02+TMZ在GSC923细胞中的体外活性的剂量响应曲线。
图14是显示TG02和TG02+TMZ在U251细胞中的体外活性的剂量响应曲线。
图15是显示TMZ和TG02+TMZ在U251细胞中的体外活性的剂量响应曲线。
图16是小鼠神经胶质瘤GL261细胞同种异体移植模型中TG02和TMZ给予的示意图。
图17是显示在小鼠神经胶质瘤GL261细胞同种异体移植模型中TG02,TMZ,和TG02+TMZ给予后存活百分比的线图。
图18是显示在小鼠神经胶质瘤GL261细胞同种异体移植模型中TG02,TMZ,和TG02+TMZ给予后肿瘤负荷的线图。
图19是显示TG02对肝细胞癌(HCC)细胞中MYC蛋白水平的影响的图示。
图20是显示TG02对HCC细胞中MYC蛋白水平的影响的剂量响应曲线。
图21是显示TG02对HCC肿瘤细胞中MYC蛋白水平的影响的图示。
图22是显示在HepG2 HCC异种移植物的原位模型中TG02和TG02+索拉非尼的体内活性的线图。
图23是显示在MYC诱导的T细胞急性淋巴细胞白血病的转基因小鼠模型中用TG02治疗后的PD-L1表达的柱状图。
图24是显示在MYC诱导的T细胞急性淋巴细胞白血病的转基因小鼠模型中用TG02治疗后的CD47表达的柱状图。
图25是显示在MYC诱导的T细胞急性淋巴细胞白血病的转基因小鼠模型中用TG02治疗后的BCL-xL表达的柱状图。
图26是显示在MYC诱导的T细胞急性淋巴细胞白血病的转基因小鼠模型中用TG02治疗后的MYC表达的柱状图。
图27是显示TG02联合抗PD1在小鼠同系GL261原位胶质母细胞瘤模型中的功效的线图。
图28是显示暴露于TG02的BT245肿瘤细胞显示对MYC和MCL-1表达的抑制的图示。
图29是柱状图,显示了胶质母细胞瘤(GBM)细胞中TG02诱导的抑制的曲线下面积(AUC)。
图30是散点图,显示高MYC表达与GBM细胞中的低AUC相关。
图31是一系列六个线图,显示了TG02联合放射在胶质母细胞瘤细胞系中的活性。
图32是显示TG02对26个源自患者的GBM干细胞系的活性的柱状图。
图33是显示用TG02治疗后患者来源的GBM干细胞系中CDK9,MYC和Mcl-1的表达水平的图示。
发明详述
在一个实施方式中,本公开内容提供了治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02,其中与取自另一表型状态的对象的生物样品相比,表1中列出的一种或多种基因(见下文)差异性地存在于取自患者的生物样品中。在另一个实施方式中,MYC过表达在取自患者的样品中差异性地存在。在另一个实施方式中,MCL1过表达在取自患者的样品中差异性地存在。
在另一个实施方式中,本公开内容提供了治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02和免疫检查点抑制剂,其中与取自另一表型状态的对象的生物样品相比,表1中列出的一种或多种基因(见下文)差异性地存在于取自患者的生物样品中。在另一个实施方式中,MYC过表达在取自患者的样品中差异性地存在。在另一个实施方式中,MCL1过表达在取自患者的样品中差异性地存在。在另一个实施方式中,在免疫检查点抑制剂之前将TG02给予患者。在另一个实施方式中,在免疫检查点抑制剂之后将TG02给予患者。在另一个实施方式中,将TG02与免疫检查点抑制剂同时给予患者。
在另一个实施方式中,本公开内容提供了治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02、免疫检查点抑制剂、和COX-2抑制剂,其中与取自另一表型状态的对象的生物样品相比,表1中列出的一种或多种基因(见下文)差异性地存在于取自患者的生物样品中。在另一个实施方式中,MYC过表达在取自患者的样品中差异性地存在。在另一个实施方式中,MCL1过表达在取自患者的样品中差异性地存在。在另一个实施方式中,在COX-2抑制剂之前将TG02给予患者。在另一个实施方式中,在COX-2抑制剂之后将TG02给予患者。在另一个实施方式中,将TG02与COX-2抑制剂同时给予患者。
在另一个实施方式中,本公开提供了治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02和免疫检查点抑制剂。在另一个实施方式中,在免疫检查点抑制剂之前将TG02给予患者。在另一个实施方式中,在免疫检查点抑制剂之后将TG02给予患者。在另一个实施方式中,将TG02与免疫检查点抑制剂同时给予患者。
在另一个实施方式中,本公开提供了治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02,免疫检查点抑制剂和COX-2抑制剂。在另一个实施方式中,在COX-2抑制剂之前将TG02给予患者。在另一个实施方式中,在COX-2抑制剂之后将TG02给予患者。在另一个实施方式中,将TG02与COX-2抑制剂同时给予患者。
在另一个实施方式中,本公开提供了包含TG02和免疫检查点抑制剂的试剂盒,以及将TG02和免疫检查点抑制剂给予于患有癌症的患者的说明书。在另一个实施方式中,试剂盒还包含COX-2抑制剂。
在另一个实施方式中,本公开提供了包含TG02和COX-2抑制剂的试剂盒,以及将TG02和COX-2抑制剂给予患有癌症的患者的说明书。
在另一个实施方式中,试剂盒以便于其用于实施本公开的方法的方式包装。
在另一个实施方式中,所述试剂盒包括包装在容器(例如密封的瓶子或器皿)中的TG02(或包含TG02的组合物),其中标签贴在容器上或包含在试剂盒中,其描述了使用TG02或组合物来实施本发明的方法。在一个实施方式中,TG02以单位剂型包装。该试剂盒还可包含适用于以预定给药途径给予该组合物的装置。
本公开内容提供了与癌症治疗有关的各种治疗方法,试剂盒和组合物。在一个实施方式中,癌症是实体瘤。在另一个实施方式中,癌症是血液恶性肿瘤。在另一个实施方式中,癌症选自肾上腺癌,腺泡细胞癌,听神经瘤,肢端黑色素瘤,肢端汗腺瘤,急性嗜酸性粒细胞白血病,急性红细胞白血病,急性淋巴细胞白血病,急性巨核细胞白血病,急性单核细胞白血病,急性早幼粒细胞白血病,腺癌,腺样囊性癌,腺瘤,齿原性腺瘤样瘤,腺鳞癌,脂肪组织肿瘤,肾上腺皮质癌,成人T细胞白血病/淋巴瘤,侵袭性NK细胞白血病,艾滋病相关淋巴瘤,肺泡状横纹肌肉瘤,肺泡状软组织肉瘤,成釉细胞纤维瘤,间变性大细胞淋巴瘤,甲状腺未分化癌,血管免疫母细胞性T细胞淋巴瘤,血管平滑肌脂肪瘤,血管肉瘤,星形细胞瘤,非典型畸胎瘤性横纹肌样瘤,B细胞慢性淋巴细胞白血病,B细胞前淋巴细胞白血病,B细胞淋巴瘤,基底细胞癌,胆道癌,膀胱癌,胚细胞瘤,骨癌,布伦纳瘤,布朗瘤,伯基特淋巴瘤,乳腺癌,脑癌,上皮癌,原位癌,癌肉瘤,软骨肿瘤,骨水泥瘤,骨髓瘤,软骨瘤,脊索瘤,绒毛膜癌,脉络丛乳头状瘤,肾透明细胞肉瘤,颅咽管瘤,皮肤T细胞淋巴瘤,宫颈癌,结直肠癌,德戈斯病,增生性小圆细胞瘤,弥漫性大B细胞淋巴瘤,胚胎发育不良性神经上皮肿瘤,无性细胞瘤,胚胎癌,内分泌腺肿瘤,内胚窦瘤,肠病相关T细胞淋巴瘤,食管癌,寄生胎,纤维瘤,纤维肉瘤,滤泡状淋巴瘤,滤泡状甲状腺癌,神经节细胞瘤,胃肠道癌,生殖细胞瘤,妊娠绒毛膜癌,巨细胞成纤维细胞瘤,骨巨细胞瘤,胶质瘤,胶质母细胞瘤,神经胶质瘤,脑胶质瘤,胰高血糖素瘤,性腺母细胞瘤,颗粒细胞瘤,两性胚细胞瘤,胆囊癌,胃癌,毛细胞白血病,血管母细胞瘤,头颈癌,血管外皮细胞瘤,血液系统恶性肿瘤,肝母细胞瘤,肝细胞癌,肝脾T细胞淋巴瘤,霍奇金淋巴瘤,非霍奇金淋巴瘤,浸润性小叶癌,肠癌,肾癌,喉癌,恶性小痣,致死性中线癌,白血病,睾丸间质细胞瘤,脂肪肉瘤,肺癌,淋巴管瘤,淋巴管肉瘤,淋巴上皮瘤,淋巴瘤,急性淋巴细胞白血病,急性髓系白血病,慢性淋巴细胞白血病,肝癌,小细胞肺癌,非小细胞肺癌,MALT淋巴瘤,恶性纤维组织细胞瘤,恶性周围神经鞘瘤,恶性蝾螈瘤,套细胞淋巴瘤,边缘区B细胞淋巴瘤,肥大细胞白血病,纵隔生殖细胞肿瘤,乳腺髓样癌,甲状腺髓样癌,成神经管细胞瘤,黑色素瘤,脑膜瘤,默克细胞癌,间皮瘤,转移性尿路上皮癌,混合苗勒氏肿瘤,粘液性肿瘤,多发性骨髓瘤,肌肉组织肿瘤,蕈样肉芽肿,粘液性脂肪肉瘤,粘液瘤,粘液肉瘤,鼻咽癌,神经鞘瘤,神经母细胞瘤,神经纤维瘤,神经瘤,结节性黑色素瘤,眼部癌,少突细胞瘤,少突神经胶质瘤,嗜酸细胞瘤,视神经鞘膜瘤,视神经肿瘤,口腔癌,骨肉瘤,卵巢癌,肺上沟癌,乳头状甲状腺癌,副神经节细胞瘤,松果体母细胞瘤,松果体细胞瘤,垂体细胞瘤,垂体腺瘤,垂体瘤,浆细胞瘤,多胚胎瘤,前驱T淋巴细胞淋巴瘤,原发性中枢神经系统淋巴瘤,原发性积液淋巴瘤,原发性腹膜癌,前列腺癌,胰腺癌,咽癌,腹膜假粘液瘤,肾细胞癌,肾髓样癌,视网膜母细胞瘤,横纹肌瘤,横纹肌肉瘤,里氏转化,直肠癌,肉瘤,神经鞘瘤病,精原细胞瘤,支持细胞瘤,性索-性腺间质瘤,印戒细胞癌,皮肤癌,小圆蓝细胞瘤,小细胞癌,软组织肉瘤,生长抑素瘤,煤烟疣,脊髓肿瘤,脾边缘区淋巴瘤,鳞状细胞癌,滑膜肉瘤,赛塞里病,小肠癌,鳞状细胞癌,胃癌,T细胞淋巴瘤,睾丸癌,卵泡膜细胞瘤,甲状腺癌,移行细胞癌,咽喉癌,脐尿管癌,泌尿生殖器癌,尿路上皮癌,葡萄膜黑色素瘤,子宫癌,疣状癌,视觉通路胶质瘤,外阴癌,阴道癌,华氏巨球蛋白血症,沃辛瘤,和维尔姆斯瘤。
在另一个实施方式中,癌症选自下组:头颈鳞状细胞癌,食管腺癌,胃腺癌,结肠腺癌,肝细胞癌,胆管系统胆管癌,胆囊腺癌,胰腺癌,乳腺原位导管癌,乳腺癌,肺腺癌,肺鳞状细胞癌,膀胱移行细胞癌,膀胱鳞状细胞癌,子宫颈鳞状细胞癌,子宫颈腺癌,子宫内膜癌,阴茎鳞状细胞癌和皮肤鳞状细胞癌。
在另一个实施方式中,癌前肿瘤选自下组:头颈部白斑,巴雷特食道,胃化生,结肠腺瘤,慢性肝炎,胆管增生,胰腺上皮内瘤形成,肺非典型性腺瘤性增生,膀胱发育不良,颈部上皮内瘤形成,阴茎上皮内瘤形成,和皮肤光化性角化。
在另一个实施方式中,患者具有过表达MYC,MCL1或两者的肿瘤。可以通过本领域已知的方法确定肿瘤过表达MYC,MCL1或两者。
在另一个实施方式中,癌症选自下组:肝细胞癌,成胶质细胞瘤,肺癌,乳腺癌,头颈癌,前列腺癌,黑素瘤和结肠直肠癌。
在另一个实施方式中,癌症选自下组:成胶质细胞瘤,肝细胞癌,非小细胞和小细胞肺癌,头颈癌,结肠直肠癌和三阴性乳腺癌。
在另一个实施方式中,癌症已经变得对常规癌症治疗具有耐药性。本文所用的术语“常规癌症治疗”是指美国食品和药物管理局,欧洲药品管理局或类似的监管机构已经测试和/或批准用于人类治疗用途的任何癌症药物或生物制剂,或癌症药物和/或生物制剂的组合。
在另一个实施方式中,患者先前已经用不含TG02的免疫检查点抑制剂治疗。例如,先前的免疫检查点治疗可以是抗PD-1治疗。
在另一个实施方式中,患者先前已经用不含TG02的COX-2抑制剂治疗。
在另一个实施方式中,本公开提供了药物组合物,其包含TG02,COX-2抑制剂和药学上可接受的赋形剂。
在另一个实施方式中,本公开提供治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02,其中患者的表型状态是MYC的过表达,MCL1的过表达,或MYC和MCL1的过表达。在另一个实施方式中,癌症选自下组:肝细胞癌,成胶质细胞瘤,肺癌,乳腺癌,头颈癌,前列腺癌,黑素瘤和结肠直肠癌。
在另一个实施方式中,本公开提供了治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02和第二治疗剂,其中第二治疗剂既不是免疫检查点抑制剂也不是COX-2抑制剂。
在另一个实施方式中,本公开提供了治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02,免疫检查点抑制剂和第三治疗剂,其中第三治疗剂不是COX-2抑制剂。
在另一个实施方式中,本公开提供了治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02,COX-2抑制剂和第三治疗剂,其中第三治疗剂不是免疫检查点抑制剂。
在另一个实施方式中,本公开提供了治疗患有癌症的患者的治疗方法,该方法包括向患者给予治疗有效量的TG02,免疫检查点抑制剂,COX-2抑制剂和第四治疗剂,其中第四治疗剂既不是免疫检查点抑制剂也不是COX-2抑制剂。
在另一个实施方式中,本公开内容为癌症患者提供个性化药物,并且包括选择具有个体癌症患者成功结果的最高可能性的治疗选择。在另一个方面,本公开涉及用于预测患有癌症的患者的治疗结果(例如,有利响应或治疗成功的可能性)的测定用途。
在另一个实施方式中,本公开内容提供了选择患者(例如人对象)用于用TG02,和任选的免疫检查点抑制剂和/或COX-2抑制剂治疗癌症的方法,包括获得来自患者的生物样品,例如,血细胞,测试来自患者的生物样品中是否存在生物标志物,例如MYC的过表达,MCL1的过表达,或两者,并且如果生物样品含有该生物标志物则选择患者进行治疗。在另一个实施方式中,该方法还包括如果生物样品含有生物标志物,则向患者给予治疗有效量的TG02和任选的免疫检查点抑制剂和/或COX-2抑制剂。表1中提供了癌症生物标志物的实例。在另一个实施方式中,癌症是实体瘤。在另一个实施方式中,癌症是血液恶性肿瘤。在另一个实施方式中,癌症选自下组:肝细胞癌,成胶质细胞瘤,肺癌,乳腺癌,头颈癌,前列腺癌,黑素瘤和结肠直肠癌。
在另一个实施方式中,本公开内容提供了预测患有癌症的患者的治疗结果的方法,包括从患者获得生物样品,测试来自患者的生物样品中是否存在生物标志物,例如MYC的过表达,MCL1的过表达或两者,其中检测到生物标志物表明患者将对治疗有效量的TG02和任选的免疫检查点抑制剂和/或COX-2抑制剂的给药有利地响应。有利的响应包括但不限于肿瘤尺寸的减小和无进展或总体存活的增加。
在另一个实施方式中,本公开提供治疗癌症的方法,包括向患有癌症的患者(例如人对象)给予治疗有效量的TG02和任选的免疫检查点抑制剂和/或COX-2抑制剂,患者细胞中含有生物标志物。在另一个实施方式中,在确定患者细胞含有MYC的过表达后,选择患者用TG02和任选的免疫检查点抑制剂和/或COX-2抑制剂治疗。在另一个实施方式中,在确定患者细胞含有MCL1的过表达后,选择患者用TG02和任选的免疫检查点抑制剂和/或COX-2抑制剂治疗。在另一个实施方式中,在确定患者细胞含有MYC的过表达和MCL1的过表达后,选择患者用TG02和任选的免疫检查点抑制剂和/或COX-2抑制剂治疗。
在另一个实施方式中,治疗患有癌症的患者的方法包括从患者获得生物样品,确定生物样品是否含有生物标志物,例如MYC的过表达,MCL1的过表达,或两者,以及如果生物样品含有生物标志物,则给予患者治疗有效量的TG02和任选的免疫检查点抑制剂和/或COX-2抑制剂。在另一个实施方式中,本文提供的方法包括确定患者细胞是否含有MYC的过表达。在另一个实施方式中,本文提供的方法包括确定患者细胞是否含有MCL1的过表达。在另一个实施方式中,本文提供的方法包括确定患者细胞是否含有MYC和MCL1的过表达。
在另一个实施方式中,本公开内容提供了治疗患有癌症的对象的方法,该方法包括从对象获得生物样品,测定生物样品中MYC,MCL1或两者的表达水平;并且如果生物样品显示MYC,MCL1,或两者的过表达,则向对象给予治疗有效量的TG02和第二治疗剂,例如替莫唑胺,卡非佐米,索拉非尼,硼替佐米,多柔比星,顺铂,来那度胺,地塞米松或Ara-C。
在另一个实施方式中,患者先前仅用免疫检查点抑制剂治疗。例如,先前的免疫检查点治疗可以是抗PD-1治疗。
在另一个实施方式中,患者先前仅用COX-2抑制剂治疗。
I.免疫检验点抑制剂
免疫检查点抑制剂是阻断免疫系统抑制剂检查点的疗法。免疫检查点可以是刺激性的或抑制性的。阻断抑制性免疫检查点可以激活免疫系统功能,并可用于癌症免疫治疗。Pardoll,Nature Reviews.Cancer 12:252-64(2012)。当肿瘤细胞附着于特异性T细胞受体时,它们会关闭活化的T细胞。免疫检查点抑制剂防止肿瘤细胞附着于T细胞,从而导致T细胞保持活化。实际上,细胞和可溶性组分的协同作用可以抵抗癌症引起的病原体和损伤。免疫系统途径的调节可涉及改变途径的至少一种组分的表达或功能活性,然后调节免疫系统的响应。U.S.2015/0250853。免疫检查点抑制剂的实例包括PD-1抑制剂,PD-L1抑制剂,CTLA-4抑制剂,LAG3抑制剂,TIM3抑制剂,cd47抑制剂和B7-H1抑制剂。因此,在一个实施方式中,免疫检查点抑制剂选自PD-1抑制剂,PD-L1抑制剂,CTLA-4抑制剂,LAG3抑制剂,TIM3抑制剂和cd47抑制剂。
在另一个实施方式中,免疫检查点抑制剂是程序性细胞死亡(PD-1)抑制剂。PD-1是T细胞共抑制剂受体,其在肿瘤细胞逃避宿主免疫系统的能力中起关键作用。阻断PD-1和PD-L1(PD-1的配体)之间的相互作用增强免疫功能并介导抗肿瘤活性。PD-1抑制剂的实例包括特异性结合PD-1的抗体。具体的抗PD-1抗体包括但不限于尼莫单抗,彭美罗珠单抗,STI-1014和多替珠单抗。关于抗-PD-1抗体的可用性,生产方法,作用机制和临床研究的一般性讨论,参见U.S.2013/0309250,U.S.6,808,710,U.S.7,595,048,U.S.8,008,449,U.S.8,728,474,U.S.8,779,105,U.S.8,952,136,U.S.8,900,587,U.S.9,073,994,U.S.9,084,776,和Naido等,British Journal of Cancer 111:2214-19(2014)。
在另一个实施方式中,免疫检查点抑制剂是PD-L1(也称为B7-H1或CD274)抑制剂。PD-L1抑制剂的实例包括特异性结合PD-L1的抗体。具体的抗PD-L1抗体包括但不限于阿维单抗,阿特珠单抗,度伐鲁单抗和BMS-936559。关于可获得性,生产方法,作用机制和临床研究的一般性讨论,参见U.S.8,217,149,U.S.2014/0341917,U.S.2013/0071403,WO2015036499,和Naido等,British Journal of Cancer 111:2214-19(2014)。
在另一个实施方式中,免疫检查点抑制剂是CTLA-4抑制剂。CTLA-4,也称为细胞毒性T淋巴细胞抗原4,是一种下调免疫系统的蛋白质受体。CTLA-4的特征在于结合抗原呈递细胞上的共刺激分子的“制动”,其阻止与T细胞上的CD28相互作用并且还产生限制T细胞活化的明显抑制信号。CTLA-4抑制剂的实例包括特异性结合CTLA-4的抗体。特定的抗-CTLA-4抗体包括但不限于伊匹单抗和特姆单抗。关于可获得性,生产方法,作用机制和临床研究的一般性讨论,参见U.S.6,984,720,U.S.6,207,156,和Naido等,British Journal ofCancer 111:2214-19(2014)。
在另一个实施方式中,免疫检查点抑制剂是LAG3抑制剂。LAG3,淋巴细胞激活基因3,是一种负共同模拟受体,可调节T细胞的稳态,增殖和活化。此外,据报道LAG3参与调节性T细胞(Tregs)抑制功能。大部分LAG3分子保留在靠近微管组织中心的细胞中,并且仅在抗原特异性T细胞活化后被诱导。U.S.2014/0286935。LAG3抑制剂的实例包括特异性结合LAG3的抗体。特定的抗LAG3抗体包括但不限于GSK2831781。关于可获得性,生产方法,作用机制和研究的一般性讨论,参见U.S.2011/0150892,U.S.2014/0093511,U.S.20150259420,和Huang等,Immunity 21:503-13(2004)。
在另一个实施方式中,免疫检查点抑制剂是TIM3抑制剂。TIM3,T细胞免疫球蛋白和粘蛋白结构域3是免疫检查点受体,其功能是限制TH1和TC1 T细胞应答的持续时间和程度。TIM3途径被认为是抗癌免疫疗法的靶标,因为其在功能失调的CD8+ T细胞和Tregs上表达,这两种报道的免疫细胞群构成肿瘤组织中的免疫抑制。Anderson,Cancer ImmunologyResearch 2:393-98(2014)。TIM3抑制剂的实例包括特异性结合TIM3的抗体。关于TIM3抑制剂的可获得性,生产方法,作用机制和研究的一般性讨论,参见U.S.20150225457,U.S.20130022623,U.S.8,522,156,Ngiow等,Cancer Res 71:6567-71(2011),Ngiow等,Cancer Res 71:3540-51(2011),和Anderson,Cancer Immunology Res 2:393-98(2014)。
在另一个实施方式中,免疫检查点抑制剂是cd47抑制剂。参见Unanue,E.R.,PNAS110:10886-87(2013)。
术语“抗体”旨在包括完整的单克隆抗体、多克隆抗体、由至少两种完整抗体形成的多特异性抗体和抗体片段,前提是其具有所需生物活性。在另一个实施方式中,“抗体”意指包括不具有抗体Fc部分的可溶性受体。在一个实施方式中,抗体是人源化单克隆抗体及其片段,其通过重组基因工程改造制备。
另一类免疫检查点抑制剂包括结合并阻断T细胞上的PD-1受体而不触发抑制剂信号转导的多肽。这些肽包括B7-DC多肽,B7-H1多肽,B7-1多肽和B7-2多肽,及其可溶性片段,如美国专利号8,114,845中所公开的。
另一类免疫检查点抑制剂包括具有抑制PD-1信号传导的肽部分的化合物。这些化合物的实例公开于美国专利号8,907,053并具有以下结构:
或其药学上可接受的盐,其中所述化合物包含至少5个氨基酸,其可用作能够抑制PD-1信号传导途径的治疗剂。
另一类免疫检查点抑制剂包括某些代谢酶的抑制剂,例如吲哚胺2,3双加氧酶(IDO),其通过浸润骨髓细胞和肿瘤细胞表达。IDO酶通过消除T细胞中合成代谢功能所必需的氨基酸或通过合成能够改变淋巴细胞功能的细胞溶质受体的特定天然配体来抑制免疫应答。Pardoll,Nature Reviews.Cancer 12:252-64(2012);Cancer ImmunolImmunother 58:153-57(2009)。特定的IDO封闭剂包括但不限于左旋-1-甲基色氨酸(L-1MT)和1-甲基-色氨酸(1MT)。Qian等,Cancer Res 69:5498-504(2009);和等,CancerImmunol Immunother 58:153-7(2009)。
在一个实施方式中,免疫检查点抑制剂是尼莫单抗,彭美罗珠单抗,多替珠单抗,STI-1110,阿维单抗,阿特珠单抗,度伐鲁单抗,STI-1014,伊匹单抗,特姆单抗,GSK2831781,BMS-936559或MED14736。
II.COX-2抑制剂
环氧合酶-2(COX-2)是一种促进炎症并在肿瘤进展中起作用的酶。COX-2抑制剂包括非选择性抑制剂,如阿司匹林,布洛芬,舒林酸砜,舒林酸硫化物,双氯芬酸,萘丁酮,萘普生,吲哚美辛和吡罗昔康,选择性抑制剂如塞来考昔,罗非考昔,伐地考昔,ANS-398,Cay10404,SC-236和DUP697,以及美洛昔康和尼美舒利等优先抑制剂。其他COX-2抑制剂包括阿利考昔,替马考昔和西米考昔。预期任何COX-2抑制剂用于本公开的治疗方法。参见Sobolewski等,“环氧合酶-2在人类恶性肿瘤中细胞增殖和细胞死亡中的作用”,International Journal of Cell Biology,卷2010,文章号215158,21页,2010.doi:10.1155/2010/215158。
在另一个实施方式中,COX-2抑制剂是阿利考昔。参见Kirane等,Clin.CancerRes.18:5031-5042(2012)。
在另一实施方式中,COX-2抑制剂选自下组:
8-(乙基-D5)-6-(三氟甲氧基)-2-(三氟甲基)-2H-色烯-3-羧酸;
6-氯-8-(甲基-D3)-2-(三氟甲基)-2H-色烯-3-羧酸;
6-溴-8-(甲基-D3)-2-(三氟甲基)-2H-色烯-3-羧酸;
8-氯-6-(甲基-D3)-2-(三氟甲基)-2H-色烯-3-羧酸;
6,8-二溴-5,7-(二甲基-D6)-2-(三氟甲基)-2H-色烯-3-羧酸;
8-(1-甲基己基-D15)-2-(三氟甲基)-2H-色烯-3-羧酸;
6-氯-8-(1-甲基己基-D15)-2-(三氟甲基)-2H-色烯-3-羧酸;
8-(己基-D13)-2-(三氟甲基)-2H-色烯-3-羧酸;
7,8-(二甲基-D6)-2-(三氟甲基)-2H-色烯-3-羧酸;和
6-氯-8-(己基-D13)-2-(三氟甲基)-2H-色烯-3-羧酸。
参见US 2015/0133538。
在另一个实施方式中,COX-2抑制剂是6-溴-8-(甲基-D3)-2-(三氟甲基)-2H-色烯-3-羧酸。
III.任选治疗剂
在本公开的某些治疗方法中,第二治疗剂与TG02组合给予癌症患者,第三治疗剂与TG02和免疫检查点抑制剂组合或与TG02和COX-2抑制剂组合给予癌症患者,或第四治疗剂与TG02,免疫检查点抑制剂和COX-2抑制剂组合给予癌症患者。用于本公开的治疗方法的第二,第三和第四治疗剂被称为“任选治疗剂”。用于治疗癌症患者的此类任选治疗剂是本领域已知的。在一个实施方式中,任选治疗剂与TG02组合是抗癌剂,其既不是免疫检查点抑制剂也不是COX-2抑制剂。
任选治疗剂以一定量给予以提供其所需的治疗效果。各种任选治疗剂的有效剂量范围是本领域已知的,并在这类已建立的范围内将任选治疗剂给予有此需要的个体。
TG02,免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂可以作为单一单位剂量一起给予或作为多单位剂量分开给予,并且以任何顺序给予,例如,其中TG02在免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂之前给予,反之亦然。可以向患者给予一剂或多剂TG02,免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂。
在一个实施方式中,任选治疗剂是表观遗传药物。本文中,术语“表观遗传药物”指靶向表观遗传调控因子的治疗剂。表观遗传调控因子的示例包括组蛋白赖氨酸甲基转移酶、组蛋白精氨酸甲基转移酶、组蛋白去甲基化酶、组蛋白去乙酰化酶、组蛋白乙酰化酶和DNA甲基转移酶。组蛋白去乙酰化酶抑制剂包括但不限于伏立诺他。
在另一个实施方式中,任选治疗剂是化疗剂或其他抗增殖剂,其可以与TG02或其药学上可接受的盐组合给予,以治疗癌症。可与TG02或其药学上可接受的盐联用的治疗和抗癌剂的示例包括手术、放疗(例如γ-辐射、中子束辐射、电子束辐射、质子治疗、近程治疗和系统性放射性同位素)、内分泌治疗、生物应答改性剂(例如干扰素、白介素、肿瘤坏死因子(TNF))、高热和冷冻疗法、减弱任何不良作用的试剂(如止吐药)和任何其他批准的化疗药物。
抗增殖化合物的非限制性示例包括:芳香酶抑制剂;抗雌激素;抗雄激素;促性激素释放素激动剂;拓扑异构酶I抑制剂;拓扑异构酶II抑制剂;微管激活剂;烷化剂,例如替莫唑胺;类视黄醇、类胡萝卜素或生育酚;环加氧酶抑制剂;MMP抑制剂;mTOR抑制剂;抗代谢剂;铂化合物;甲硫氨酸氨基肽酶抑制剂;双磷酸盐;抗增殖性抗体;类肝素酶抑制剂;Ras癌基因同种型抑制剂;端粒酶抑制剂;蛋白酶体抑制剂;用于治疗血液恶性肿瘤的化合物;Flt-3抑制剂;Hsp90抑制剂;纺锤体驱动蛋白抑制剂;MEK抑制剂;抗肿瘤抗生素;亚硝基脲;靶向/降低蛋白质或脂质激酶活性的化合物;靶向/降低蛋白质或脂质磷酸酶活性的化合物,或任何其他抗血管原性化合物。
非限制性示例性芳香酶抑制剂包括:类固醇(如阿他美坦、依西美坦和福司曲星),以及非类固醇(如氨鲁米特(aminoglutethimide)、罗利米特(Roglethimide)、吡鲁米特、曲洛司坦、睾内酯、酮康唑、伏氯唑、法倔唑、阿那曲唑和来曲唑)。
非限制性抗雌激素包括他莫昔芬,氟维司群,雷洛昔芬和盐酸雷洛昔芬。抗雄激素包括但不限于比卡鲁胺。促性激素释放素激动剂包括但不限于阿巴瑞克、戈舍瑞林和乙酸戈舍瑞林。
非限制性示例性拓扑异构酶I抑制剂包括:拓扑替康、吉马替康、伊立替康、喜树碱及其类似物、9-硝基喜树碱和大分子喜树碱偶联物PNU-166148。拓扑异构酶II抑制剂包括但不限于:蒽环类抗生素(如阿霉素、柔红霉素、表柔比星、伊达比星和奈莫柔比星);蒽醌(如米托蒽醌和洛索蒽醌);以及鬼臼乙叉戒类(podophillotoxines)(如依托泊甙和替尼泊苷)。
微管活性剂包括微管稳定、微管去稳定化合物和微管聚合抑制剂,包括但不限于:紫杉烷(如紫杉醇和多西他赛);长春花生物碱(如长春花碱、硫酸长春花碱、长春新碱和硫酸长春新碱,以及长春瑞滨);淅皮海绵内酯;秋水仙素和埃博霉素及其衍生物。
非限制性示例性烷化剂包括环磷酰胺、异环磷酰胺、美法仑和亚硝基脲,如卡莫司汀和洛莫司汀。
非限制性示例性基质金属蛋白酶抑制剂(“MMP抑制剂”)包括胶原拟肽和非拟肽抑制剂、四环素衍生物、巴马司他、马立马司他、普啉司他、梅塔司他、BMS-279251、BAY 12-9566、TAA211、MMI270B和AAJ996。
非限制性示例性mTOR抑制剂包括抑制哺乳动物的雷帕霉素(mTOR)靶标并具有抗增殖活性的化合物,例如西罗莫司、依维莫司、CCI-779和ABT578。
非限制性示例性抗代谢物包括5-氟尿嘧啶(5-FU)、卡培他滨、吉西他滨、DNA去甲基化化合物(如5-氮杂胞苷和地西他滨)、氨甲蝶呤和依达曲沙以及叶酸拮抗剂(如培美曲塞)。
非限制性示例性铂化合物包括卡铂、顺-铂、顺铂和奥沙利铂。
非限制性示例性甲硫氨酸氨基肽酶抑制剂包括苯甲酰胺或其衍生物和PPI-2458。
非限制性示例性双磷酸盐包括埃区膦酸(etridonic acid)、氯屈膦酸、替鲁膦酸、帕米膦酸、阿仑膦酸、伊班膦酸、利塞膦酸和唑来膦酸。
非限制性示例性类肝素酶抑制剂包括靶向、降低或抑制硫酸肝素降解的化合物,例如PI-88和OGT2115。
靶向,降低或抑制Ras的致癌活性的非限制性示例性化合物包括法尼基转移酶抑制剂,例如L-744832,DK8G557,替比法尼和洛那芬尼。
非限制性示例性端粒酶抑制剂包括靶向、降低或抑制端粒酶活性的化合物,例如抑制端粒酶受体的化合物,如端粒抑素。
非限制性示例性蛋白酶体抑制剂包括靶向、降低或抑制端粒酶活性的化合物,包括但不限于硼替佐米。在一些实施方式中,蛋白酶体抑制剂是卡非佐米。
非限制性示例性FMS样酪氨酸激酶抑制剂,其是靶向、降低或抑制FMS样酪氨酸激酶受体(Flt-3R)的化合物,包括:干扰素、I-β-D-阿拉伯呋喃胞嘧啶(ara-c)和二硫酸酐(bisulfan);以及ALK抑制剂,其是靶向、降低或抑制间变性淋巴瘤激酶的化合物。
非限制性示例性Flt-3抑制剂包括PKC412、米哚妥林、十字孢碱衍生物、SU11248和MLN518。
非限制性示例性HSP90抑制剂包括靶向、降低或抑制HSP90的内源性ATP酶活性的化合物;或通过泛素蛋白酶体途径降解、靶向、降低或抑制HSP90客户蛋白(clientprotein)的化合物。靶向、降低或抑制HSP90的内源性ATP酶活性的化合物具体而言是抑制HSP90的ATP酶活性的化合物、蛋白质或抗体,例如17-烯丙基氨基,17-去甲氧格尔德霉素(17AAG),一种格尔德霉素衍生物;其他格尔德霉素相关化合物;根赤壳菌素和HDAC抑制剂。
非限制性示例性蛋白酪氨酸激酶和/或丝氨酸和/或苏氨酸激酶抑制剂或脂质激酶抑制剂包括a)靶向、降低或抑制血小板衍生的生长因子受体(PDGFR)的活性的化合物,如N-苯基-2-嘧啶-胺衍生物,如伊马替尼、SUlOl、SU6668和GFB111;b)靶向、降低或抑制成纤维细胞生长因子受体(FGFR)的活性的化合物;c)靶向、降低或抑制胰岛素样生长因子受体I(IGF-IR)的活性的化合物,如靶向、降低或抑制IGF-IR的活性的化合物;d)靶向、降低或抑制Trk受体酪氨酸激酶家族的活性的化合物,或肝配蛋白B4抑制剂;e)靶向、降低或抑制Axl受体酪氨酸激酶家族的活性的化合物;f)靶向、降低或抑制Ret受体酪氨酸激酶家族的活性的化合物;g)靶向、降低或抑制Kit/SCFR受体酪氨酸激酶家族的活性的化合物,如伊马替尼;h)靶向、降低或抑制c-Kit受体酪氨酸激酶家族的活性的化合物,如伊马替尼;i)靶向、降低或抑制c-Abl家族成员、其基因融合产物(如Bcr-Abl激酶)和突变体的活性的化合物,如N-苯基-2-嘧啶-胺衍生物,如伊马替尼或尼洛替尼;PD180970;AG957;NSC 680410;PD173955;或达沙替尼;j)靶向、降低或抑制丝氨酸/酪氨酸激酶的蛋白质激酶C(PKC)和Raf家族成员,MEK、SRC、JAK、FAK、PDK1、PKB/Akt和Ras/MAPK家族成员,和/或细胞周期素依赖性激酶家族(CDK)成员的活性的化合物,如美国专利号5,093,330公开的十字孢碱衍生物,如米哚妥林;其他化合物的示例包括:UCN-01、沙芬戈、BAY 43-9006、苔藓抑素1、哌立福辛;伊莫福新;RO 318220和RO 320432;GO 6976;lsis 3521;LY333531/LY379196;异喹啉化合物;法尼基转移酶抑制剂;PD184352或QAN697,或AT7519;k)靶向、降低或抑制蛋白质酪氨酸激酶的活性的化合物,如甲磺酸伊马替尼或酪氨酸磷酸化抑制剂,如酪氨酸磷酸化抑制剂A23/RG-50810;AG 99;酪氨酸磷酸化抑制剂AG 213;酪氨酸磷酸化抑制剂AG 1748;酪氨酸磷酸化抑制剂AG 490;酪氨酸磷酸化抑制剂B44;酪氨酸磷酸化抑制剂B44(+)对映异构体;酪氨酸磷酸化抑制剂AG 555;AG 494;酪氨酸磷酸化抑制剂AG 556、AG957和阿达斯廷(adaphostin)(4-{[(2,5-二羟基苯基)甲基]氨基}-苯甲酸金刚烷基酯;NSC 680410,阿达斯廷);1)靶向、降低或抑制受体酪氨酸激酶的表皮生长因子家族(同源二聚体和异源二聚体形式的EGFR、ErbB2、ErbB3、ErbB4)及其突变体的活性的化合物,例如CP 358774、ZD1839、ZM 105180;曲妥珠单抗、西妥昔单抗、吉非替尼、埃罗替尼、OSI-774、Cl-1033、EKB-569、GW-2016、抗体E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3和E7.6.3,以及7H-吡咯并[2,3-d]嘧啶衍生物;以及m)靶向、降低或抑制c-Met受体活性的化合物。
靶向、降低或抑制蛋白质或脂质磷酸酶的非限制性示例性化合物包括磷酸酶1、磷酸酶2A或CDC25的抑制剂,如冈田酸或其衍生物。
其他的抗血管原性化合物包括具有与蛋白质或脂质激酶抑制无关的其他活性机制的化合物,例如沙利度胺和TNP-470。
此外,一种或多种非限制性示例性化疗化合物可与TG02或其药学上可接受的盐联用,包括贝伐单抗、柔红霉素、阿霉素、Ara-C、VP-16、替尼泊苷、米托蒽醌、伊达比星、卡铂、PKC412、6-巯基嘌呤(6-MP)、磷酸氟达拉滨、奥曲肽、SOM230、FTY720、6-硫鸟嘌呤、克拉屈滨、6-巯基嘌呤、喷司他丁、羟基脲、2-羟基-1H-异吲哚-1,3-二酮衍生物、1-(4-氯苯胺基)-4-(4-吡啶甲基)酞嗪或其药学上可接受的盐、1-(4-氯苯胺基)-4-(4-吡啶甲基)酞嗪琥珀酸酯/盐、血管抑制素、内皮抑素、邻氨基苯甲酸酰胺、ZD4190、ZD6474、SU5416、SU6668、贝伐单抗、rhuMAb、rhuFab、马库刚(macugon);FLT-4抑制剂、FLT-3抑制剂、VEGFR-2 IgGI抗体、RPI 4610、贝伐单抗、卟吩姆钠、阿奈可他、去炎松、氢化可的松、11-a-泛氢皮质醇(epihydrocotisol)、皮质龙(cortex olone)、17a-羟孕酮、皮质酮、去氧皮质酮、睾酮、雌酮、地塞米松、氟轻松、植物生物碱、激素化合物和/或拮抗剂、生物应答改性剂如淋巴因子或干扰素、反义寡核苷酸或寡核苷酸衍生物、shRNA和siRNA。
预期许多合适的任选治疗剂,例如抗癌剂用于本文提供的治疗方法中。实际上,本文提供的方法可包括但不限于给予多种任选治疗剂,例如:诱导细胞凋亡的试剂;多核苷酸(例如,反义,核酶,siRNA);多肽(例如酶和抗体);生物模拟物(例如,棉酚或BH3模拟物);与Bcl-2家族蛋白如Bax结合(例如,寡聚化或复合)的试剂;生物碱;烷化剂;抗肿瘤抗生素;抗代谢药物;激素;铂化合物;单克隆或多克隆抗体(例如,与抗癌药物,毒素,防御素结合的抗体),毒素;放射性核素;生物反应调节剂(例如,干扰素(例如IFN-α)和白细胞介素(例如IL-2));过继免疫治疗剂;造血生长因子;诱导肿瘤细胞分化的试剂(例如全反式维甲酸);基因治疗试剂(例如,反义治疗试剂和核苷酸);肿瘤疫苗;血管生成抑制剂;蛋白酶体抑制剂:NF-KB调节剂;抗CDK化合物;HDAC抑制剂;等等。适合与所公开的化合物共同给予的任选治疗剂(例如化疗化合物和抗癌疗法)的许多其他示例是本领域技术人员已知的。
在某些实施方式中,抗癌剂包含诱导或刺激细胞凋亡的试剂。诱导或刺激细胞凋亡的试剂包括,例如,与DNA相互作用或修饰DNA的试剂,例如通过嵌入,交联,烷基化或以其它方式破坏或化学修饰DNA。诱导细胞凋亡的试剂包括但不限于放射(例如,X射线,γ射线,UV);肿瘤坏死因子(TNF)相关因子(例如,TNF家族受体蛋白,TNF家族配体,TRAIL,针对TRAIL-R1或TRAIL-R2的抗体);激酶抑制剂(如表皮生长因子受体(EGFR)激酶抑制剂。其他抗癌药物包括:血管生长因子受体(VGFR)激酶抑制剂,成纤维细胞生长因子受体(FGFR)激酶抑制剂,血小板衍生生长因子受体(PDGFR)激酶抑制剂和Bcr-Abl激酶抑制剂(如GLEEVEC));反义分子;抗体(例如HERCEPTIN,RITUXAN,ZEVALIN和AVASTIN);抗雌激素(如雷洛昔芬和他莫昔芬);抗雄激素(例如,氟他胺,比卡鲁胺,非那雄胺,氨基葡糖胺,酮康唑和皮质类固醇);环加氧酶2(COX-2)抑制剂(例如塞来考昔,美洛昔康,NS-398和非甾体抗炎药(NSAID));抗炎药(例如,丁唑烷,DECADRON,DELTASONE,地塞米松,地塞米松浓度,DEXONE,HEXADROL,羟氯喹,METICORTEN,ORADEXON,ORASONE,羟基保泰松,PEDIAPRED,保泰松,PLAQUENIL,泼尼松龙,泼尼松,PRELONE和TANDEARIL);和癌症化疗药物(如伊立替康(CAMPTOSAR),CPT-11,氟达拉滨(FLUDARA),达卡巴嗪(DTIC),地塞米松,米托蒽醌,MYLOTARG,VP-16,顺铂,卡铂,奥沙利铂,5-FU,多柔比星,吉西他滨,硼替佐米,吉非替尼,贝伐单抗,TAXOTERE或TAXOL);细胞信号传导分子;神经酰胺和细胞因子;十字孢碱等。
在其他实施方式中,本文提供的治疗方法包括向癌症患者给予治疗有效量的TG02和至少一种选自烷化剂,抗代谢物和天然产物(例如草药和其他植物和/或动物来源的化合物)的其他抗过度增殖或抗肿瘤剂。
适用于本发明方法的烷化剂包括但不限于:1)氮芥(例如,双氯乙基甲胺,环磷酰胺,异环磷酰胺,美法仑(L-沙可来新);和苯丁酸氮芥);2)乙烯亚胺和甲基三聚氰胺(例如六甲基三聚氰胺和噻替哌);3)烷基磺酸盐(例如白消安);4)亚硝基脲(例如,卡莫司汀(BCNU);洛莫司汀(CCNU);司莫司汀(甲基-CCNU);和链脲佐菌素(链脲佐菌素));和5)三氮杂萘(例如,达卡巴嗪(DTIC;二甲基三氮烯基咪唑羧酰胺)。
在一些实施方式中,适用于本发明方法的抗代谢物包括但不限于:1)叶酸类似物(例如甲氨蝶呤(甲氨蝶呤));2)嘧啶类似物(例如氟尿嘧啶(5-氟尿嘧啶;5-FU),氟尿苷(氟代-氧尿苷;FudR)和阿糖胞苷(胞嘧啶阿拉伯糖苷));3)嘌呤类似物(例如,巯基嘌呤(6-巯基嘌呤;6-MP),硫鸟嘌呤(6-硫鸟嘌呤;TG)和喷司他丁(2′-脱氧同型霉素))。
在更进一步的实施方式中,适用于本公开内容的方法的化疗剂包括但不限于:1)长春花生物碱(例如,长春碱(VLB),长春新碱);2)表鬼臼毒素(例如依托泊苷和替尼泊苷);3)抗生素(例如,放线菌素(放线菌素D),柔红霉素(道诺霉素;铷霉素),多柔比星,博来霉素,普鲁霉素(光神霉素)和丝裂霉素(丝裂霉素C));4)酶(例如L-天冬酰胺酶);5)生物反应调节剂(例如,干扰素-α);6)铂配位络合物(例如,顺铂(顺式-DDP)和卡铂);7)蒽二酮(例如米托蒽醌);8)取代的脲(例如羟基脲);9)甲基肼衍生物(例如,丙卡巴肼(N-甲基肼;MIH));10)肾上腺皮质抑制剂(例如,米托坦(o,p′-DDD)和氨基戊二酰亚胺);11)肾上腺皮质激素(例如泼尼松);12)孕激素(例如己酸羟孕酮,醋酸甲羟孕酮和醋酸甲地孕酮);13)雌激素(例如,己烯雌酚和乙炔雌二醇);14)抗雌激素药(例如他莫昔芬);15)雄激素(例如,丙酸睾酮和氟甲睾酮);16)抗雄激素(例如氟他胺);和17)促性腺激素释放激素类似物(例如亮丙瑞林)。
常规用于癌症治疗背景的任何溶瘤剂可用于本公开的治疗方法中。例如,美国食品和药物管理局(FDA)维持批准在美国使用的溶瘤剂的处方集。FDA的国际对口机构维持类似的处方集。本领域技术人员将理解,所有美国批准的化疗剂所需的“产品标签”描述了示例性试剂的批准的适应症,剂量信息,毒性数据等。
抗癌剂还包括已经鉴定具有抗癌活性的化合物。示例包括但不限于3-AP,12-O-十四烷酰佛波醇-13-乙酸酯,17AAG,852A,ABI-007,ABR-217620,ABT-751,ADI-PEG 20,AE-941,AG-013736,AGRO100,阿拉诺新,AMG706,抗体G250,抗肿瘤药,AP23573,阿帕兹醌,APC8015,阿替莫德,ATN-161,阿曲斯汀(atrasenten),阿扎胞苷,BB-10901,BCX-1777,贝伐单抗,BG00001,比卡鲁胺,BMS 247550,硼替佐米,苔藓抑素-1,布舍瑞林,骨化三醇,CCI-779,CDB-2914,头孢克肟,西妥昔单抗,CG0070,西仑吉肽,氯法拉滨,考布他汀A4磷酸盐,CP-675,206,CP-724,714,CpG 7909,姜黄素,地西他滨,DENSPM,度骨化醇,E7070,E7389,海鞘素743,乙丙昔罗,依氟鸟氨酸,EKB-569,恩扎妥林,埃罗替尼,依昔舒林,芬维A胺,夫拉平度,氟达拉滨,氟他胺,福莫司汀,FR901228,G17DT,加利昔单抗,吉非替尼,染料木黄酮,葡磷酰胺,GTI-2040,组氨瑞林,HKI-272,高三尖杉酯碱,HSPPC-96,hu14.18-白细胞介素-2融合蛋白,HuMax-CD4,伊洛前列素,咪喹莫特,英夫利昔单抗,白细胞介素-12,IPI-504,依洛福芬,伊沙匹隆,拉帕替尼,来那度胺,来曲替尼,亮丙瑞林,LMB-9免疫毒素,洛那法尼,鲁昔单抗,马磷酰胺,MB07133,MDX-010,MLN2704,单克隆抗体3F8,单克隆抗体J591,莫特沙芬,MS-275,MVA-MUC1-IL2,尼罗替胺,硝基喜树碱,盐酸洛拉曲克,诺瓦得士,NS-9,O6-苄基鸟嘌呤,奥利默森钠,ONYX-015,奥米伏单抗,OSI-774,帕尼单抗,卡铂,PD-0325901,培美曲塞,PHY906,吡格列酮,吡非尼酮,匹杉琼,PS-341,PSC 833,PXD101,吡唑并吡啶,R115777,RAD001,豹蛙酶,蝴蝶霉素类似物,重组人血管生成抑制素蛋白,rhuMab 2C4,罗格列酮,卢比替康,S-1,S-8184,沙铂,SB-,15992,SGN-0010,SGN-40,索拉非尼,SR31747A,ST1571,SU011248,辛二酰苯胺异羟肟酸,苏拉明,他仑斯汀(talabostat),他仑帕奈,塔拉昆(tariquidar),坦西莫司,TGFa-PE38免疫毒素,沙利度胺,胸腺法新,替比法尼,替拉扎明,TLK286,曲贝替定,葡糖醛酸三甲曲沙,TroVax,UCN-1,丙戊酸,长春氟宁,VNP40101M,弗洛昔单抗,伏立诺他,VX-680,ZD1839,ZD6474,齐留通和三唑喹三盐酸盐。
对于抗癌剂和其他任选治疗剂的更详细描述,本领域技术人员可参考任何数量的指导性手册,包括但不限于《医师案头参考》(Physician′s Desk Reference)以及Goodman和Gilman的《治疗的药理学基础》(Pharmaceutical Basis of Therapeutics)第十版,Hardman等编,2002。
在一些实施方式中,本文提供的方法包括将TG02与放射疗法组合给予癌症患者。本文提供的方法不受用于向患者递送治疗剂量的放射的类型,量或递送和给药系统的限制。例如,患者可以接受光子放射疗法,粒子束放射疗法,其他类型的放射疗法,以及它们的组合。在一些实施方式中,使用线性加速器将放射递送至患者。在其他实施方式中,使用伽玛刀递送放射。
放射源可以在患者的外部或内部。外部放射疗法是最常见的并且涉及使用例如线性加速器将一束高能放射通过皮肤引导到肿瘤部位。虽然放射束定位于肿瘤部位,但几乎不可能避免正常健康组织的暴露。然而,患者通常可以很好地耐受外部放射。内部放射疗法涉及在肿瘤部位处或附近的体内植入发射放射的源,例如珠,线,丸,胶囊,颗粒等,包括使用特异性靶向癌细胞的递送系统(例如,使用附着于癌细胞结合配体的颗粒)。这种植入物可以在治疗后移除,或留在体内无活性。内部放射治疗的类型包括但不限于近距离放射治疗,间质照射,腔内照射,放射免疫治疗等。
患者可任选地接受放射增敏剂(例如,甲硝唑,咪唑,动脉内Budr,静脉内碘脱氧尿苷(IudR),硝基咪唑,5-取代-4-硝基咪唑,2H-异吲哚醌,[[(2-溴乙基)-氨基]甲基]-硝基-1H-咪唑-1-乙醇,硝基苯胺衍生物,DNA-亲和性缺氧选择性细胞毒素,卤代DNA配体,1,2,4-苯并三嗪氧化物,2-硝基咪唑衍生物,含氟硝基唑衍生物,苯甲酰胺,烟酰胺,吖啶-嵌入剂,5-硫代四唑衍生物,3-硝基-1,2,4-三唑,4,5-二硝基咪唑衍生物,羟基化特斯他林,顺铂,丝裂霉素,替拉扎明,亚硝基脲,巯嘌呤,甲氨蝶呤,氟尿嘧啶,博来霉素,长春新碱,卡铂,表柔比星,多柔比星,环磷酰胺,长春地辛,依托泊苷,紫杉醇,热(高热)等),放射防护剂(例如,半胱胺,氨基烷基二氢硫代磷酸酯,氨磷汀(WR 2721),IL-1,IL-6等)。放射增敏剂增强肿瘤细胞的杀伤作用。放射防护剂保护健康组织免受放射的有害影响。
可以向患者给予任何类型的放射,只要患者可以耐受放射剂量而没有不可接受的负面副作用。合适类型的放射疗法包括例如电离(电磁)放射疗法(例如,X射线或γ射线)或粒子束放射疗法(例如,高线性能量放射)。电离放射定义为包含粒子或光子的放射,所述粒子或光子具有足够的能量以产生电离,即电子的获得或损失(例如U.S.5,770,581中所述,其全部内容通过引用并入本文)。放射的影响可以至少部分地由临床医生控制。在一个实施方式中,对放射剂量进行分级以获得最大靶细胞暴露和降低的毒性。
在一个实施方式中,给予患者的放射的总剂量为约0.01戈瑞(Gy)至约100Gy。在另一个实施方式中,治疗过程中给予约10Gy至约65Gy(例如,约15Gy,20Gy,25Gy,30Gy,35Gy,40Gy,45Gy,50Gy,55Gy或60Gy)。虽然在一些实施方式中,可以在一天的过程中给予完整剂量的放射,但是理想地将总剂量分级并在数天内给予。理想地,放射疗法在至少约3天,例如,至少5、7、10、14、17、21、25、28、32、35、38、42、46、52或56天(约1-8周)的过程中给予。因此,每日放射剂量将包括约1-5Gy(例如,约1Gy,1.5Gy,1.8Gy,2Gy,2.5Gy,2.8Gy,3Gy,3.2Gy,3.5Gy,3.8Gy,4Gy,4.2Gy或4.5Gy),或1-2Gy(例如,1.5-2Gy)。每日放射剂量应足以诱导靶向的细胞的破坏。在一个实施方式中,如果延长一段时间,则不是每天给予放射,从而允许动物休息并且实现治疗的效果。例如,对于每周治疗,期望连续5天给予放射,而不是在2天给予,从而允许每周2天的休息。然而,放射可以1天/周,2天/周,3天/周,4天/周,5天/周,6天/周或全部7天/周给予,这取决于动物的反应性和任何潜在的副作用。放射治疗可以在治疗期的任何时间开始。在一个实施方式中,放射在第1周或第2周开始,并且在治疗期的剩余持续时间内给予。例如,在治疗期的第1-6周或第2-6周,包括6周给予放射,用于治疗例如实体瘤。或者,在治疗期的第1-5周或第2-5周,包括5周给予放射。然而,这些示例性放射治疗给予时间表并不旨在限制本文提供的方法。
IV.治疗方法
在本文提供的治疗方法中,TG02,免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂(例如抗癌剂)可以在以下一种或多种条件下给予癌症患者:在不同的周期下,在不同持续时间下,在不同浓度下,通过不同给药途径等。
在一些实施方式中,在免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂之前,例如在给予免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂之前0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,或1、2、3或4周给予TG02。
在一些实施方式中,在免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂之后,例如在给予免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂之后0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,或1、2、3或4周给予TG02。
在一些实施方式中,TG02,免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂同时给予,但是在不同的时间表上,例如,每天给予TG02,同时每周一次,每两周一次,每三周一次,或每四周一次给予免疫检查点抑制剂。在其他实施方式中,每天给予一次TG02,同时每周一次,每两周一次,每三周一次,或每四周一次给予免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂。
本文提供的治疗方法包括以有效实现其预期目的的量向癌症患者给予TG02。虽然个体需要不同,但本领域技术人员能够确定各组分有效量的最优范围。通常,可以约1mg/kg至约500mg/kg,约1mg/kg至约100mg/kg,或约1mg/kg至约50mg/kg的量给予TG02。组合物的剂量可以是任何剂量,包括但不限于30-600mg/天。具体剂量包括50、100、200、250、300、400、500和600mg/天。在一个实施方式中,在给予免疫检查点抑制剂之前3-7天连续每天一次给予TG02。在另一个实施方式中,给予250mg/天的TG02。在另一个实施方式中,每周两次给予250mg/天的TG02。在另一个实施方式中,TG02给予在免疫检查点抑制剂当天继续并持续另外数天直至疾病进展或直至TG02给予不再有益。这些剂量是平均情况的示例,但也存在应使用较高或较低剂量的单独情况,这类剂量也在本发明的范围内。实践中,医师确定最适用于个体患者的试剂剂量方案,其可随具体患者的年龄、体重和应答变化。
单位口服剂量的TG02可包含约0.01至约1000mg,例如约10至约500mg的TG02。在一个实施方式中,TG02的单位口服剂量是10mg,20mg,30mg,40mg,50mg,60mg,70mg,80mg,90mg,100mg,110mg,120mg,130mg,140mg,150mg,160mg,170mg,180mg,190mg,200mg,210mg,220mg,230mg,240mg,250mg,260mg,270mg,280mg,290mg,或300mg。单位剂量可以每天给予一次或多次,例如以一个或多个片剂或胶囊给予。
除了以原料化学品给予TG02外,它还可以作为药物制剂或组合物的一部分给药。在一些实施方式中,药物制剂或组合物可包含一种或多种药学上可接受的运载体,赋形剂和/或助剂。在一些实施方式中,一种或多种运载体,赋形剂和助剂有助于将TG02加工成可以在药学上使用的制剂或组合物。制剂,特别是那些可口服或局部给药并可用于一种给药方式的制剂,如片剂,糖衣丸,缓释锭剂和胶囊,漱口水和,凝胶,液体悬浮液,洗发水,发胶,香波以及可以直肠给药的制剂,例如栓剂,以及通过静脉内输注,注射,局部或口服给药的合适溶液,含有约0.01至99%,在一个实施方式中,约0.25至75%的活性化合物,与一种或多种运载体,赋形剂和/或助剂。
本文提供的药物组合物可以给予可能经历TG02有益效果的任何患者。这些患者中最重要的是哺乳动物,例如人,尽管本文提供的方法和组合物并不限于此。其他患者包括兽医动物(牛,羊,猪,马,狗,猫等)。
本文提供的药物制剂通过常规的混合,制粒,制糖衣,溶解或冻干方法制备。因此,口服使用的药物制剂可通过以下方法获得:将活性化合物与固体赋形剂混合,加入合适助剂(如果需要或必要)后任选研磨得到的混合物并加工颗粒混合物,获得片剂或糖锭芯。
合适赋形剂具体是:填料,如糖,如乳糖或蔗糖、甘露醇或山梨糖醇;纤维素制剂和/或磷酸钙,如磷酸三钙或磷酸氢钙;以及粘合剂,如使用玉米淀粉、小麦淀粉、水稻淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟基丙基甲基纤维素、羧甲基纤维素钠、和/或聚乙烯吡咯烷酮的淀粉糊。如果需要,可加入崩解剂,如上述淀粉,还可以是羧甲基-淀粉、交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐,如藻酸钠。助剂可以是合适的流动调节剂和润滑剂。合适的助剂包括,例如,二氧化硅,滑石,硬脂酸或其盐,如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。糖衣芯可被覆合适的包衣,如果需要,该包衣能耐受胃液。出于这种目的,可使用浓缩糖溶液,其中可任选地含有阿拉伯胶、滑石粉、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。为了产生能耐受胃液的包衣,使用合适纤维素制剂,如邻苯二甲酸乙酰基纤维素或邻苯二甲酸羟丙基甲基纤维素的溶液。可将染料或颜料加入片剂或糖锭包衣,以便鉴别或表征活性化合物剂量的组合。
可口服使用的其它药物制剂包括明胶制成的推入配合(push-fit)胶囊,以及明胶和增塑剂(如甘油或山梨糖醇)制成的密封软胶囊。推入配合胶囊可含有颗粒形式的活性化合物,该化合物可与填充剂,如乳糖,粘合剂如淀粉,和/或润滑剂如滑石粉或硬脂酸镁,以及任选的稳定剂混合。在软胶囊中,在一个实施方式中,将活性化合物溶解或悬浮于合适液体,如脂肪油或液体石蜡中。此外可加入稳定剂。
可以直肠使用的可能药物制剂包括例如,由一种或多种活性化合物与栓剂基料组合而成的栓剂。合适的栓剂基料是,例如天然或合成的甘油三酯或石蜡烃。此外,也可能使用明胶直肠胶囊,它由活性化合物和基料组合而成。可能的基料包括例如,液体甘油三酯、聚乙二醇或石蜡烃。
合适的胃肠道外给药制剂包括水溶形式的活性化合物(例如水溶性盐)的水溶液和碱溶液。此外,可给予合适油性注射悬液形式的活性化合物悬液。合适的亲脂性溶剂或载剂包括脂肪油如芝麻油,或合成的脂肪酸酯,例如油酸乙酯或甘油三酯,或聚乙二醇-400。水性注射悬液还可包含增加悬液粘度的物质,例如,羧甲基纤维素钠、山梨糖醇和/或右旋糖苷。任选地,该悬液也可含有稳定剂。
本公开涵盖TG02的溶剂合物的用途。溶剂合物通常不会显著改变化合物的生理活性或毒性,因此可以起药理学等价物的作用。如本文所用的术语“溶剂合物”是TG02与溶剂分子的组合,物理缔合和/或溶剂化,例如,二溶剂合物,单溶剂合物或半溶剂合物,其中溶剂分子与TG02的比率分别为约2∶1,约1∶1或约1∶2。这种物理缔合涉及不同程度的离子和共价键,包括氢键。在某些情况下,溶剂合物将能够分离,例如当一个或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液相和可分离的溶剂化物。TG02可以与药学上可接受的溶剂(例如水,甲醇,乙醇等)的溶剂化形式存在,并且本公开内容旨在包括溶剂化和未溶剂化形式的TG02。一种溶剂合物是水合物。“水合物”涉及溶剂合物的特定亚组,其中溶剂分子是水。溶剂合物通常可以起药理学等价物的作用。溶剂合物的制备在本领域中是已知的。参见,例如,M.Caira等,J.Pharmaceut.Sci.,93(3):601-611(2004),其描述了氟康唑与乙酸乙酯和水的溶剂合物的制备。E.C.van Tonder等,AAPS Pharm.Sci.Tech.,5(1):Article 12(2004),和A.L.Bingham等,Chem.Commun.603-604(2001)描述了溶剂合物,半溶剂合物,水合物等的类似制备。制备溶剂合物的典型非限制性方法包括在高于20℃至约25℃的温度下将TG02溶解在所需溶剂(有机物,水或其混合物)中,然后以足以形成晶体的速率冷却溶液,并通过已知方法,例如过滤分离晶体。诸如红外光谱的分析技术可用于确认溶剂合物晶体中溶剂的存在。
将根据标准药学实践配制的治疗有效量的TG02和/或免疫检查点抑制剂和/或COX-2抑制剂和/或任选治疗剂给予有需要的人患者。是否指示这类治疗取决于个体病例并需要进行医疗评估(诊断),其考虑存在的迹象、症状和/或功能紊乱、发生特定迹象、症状和/或功能紊乱的风险,以及其他因素。
TG02,免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂可通过任何合适途径给予,例如通过口服、经颊、吸入、舌下、直肠、阴道、脑池内或鞘内(通过腰椎穿刺)、经尿道、经鼻、经皮(即透皮)或胃肠道外(包括静脉内、肌内、皮下、冠状动脉内、皮内、乳房内、腹膜内、关节腔内、鞘内、眼球后、肺内注射和/或外科植入特定位点)给药。可使用针或注射器或使用高压技术来实现胃肠道外给药。
药物组合物包括其中TG02,免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂以有效量给予以实现其预期目的的那些。可以由单个医师根据诊断的疾病或病症选择确切的制剂、给药途径和剂量。可以单独调整剂量和间隔以提供足以维持治疗效果的TG02,免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂的水平。
可在细胞培养物或实验动物中通过药学方法测定TG02,免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂的毒性和疗效,例如,用于确定某种化合物的最大耐受剂量(MTD),其定义为在患者中不导致毒性的最高剂量。最大耐受剂量和治疗效果(例如抑制肿瘤生长)之间的剂量比例是治疗指数。该剂量可根据所用的剂型和所用的给药途径在此范围内变化。治疗有效量的测定在本领域技术范围内,由其是在本发明的详细公开内容的教导下。
治疗所需的TG02,免疫检查点抑制剂,COX-2抑制剂和/或任选治疗剂的治疗有效量根据待治疗病症的性质、活性所需时间的长度和患者的年龄和状态而变化,并最终由参与的医师确定。例如,可单独调节剂量和间隔以提供足以维持所需疗效的TG02和免疫检查点抑制剂的血浆水平。所需剂量可容易地在单个剂量中给予,或以适当间隔作为多重剂量给予,例如每天1、2、3、4或更多次子剂量。通常需要多次剂量。例如,可按以下频率给予本发明的TG02和免疫检查点抑制剂:每天一次;以四天间隔每天一次剂量递送四次剂量(q4d x4);以三天间隔每天一次剂量递送四次剂量(q3d x 4);以五天间隔每天递送一次剂量(qdx 5);每周一次剂量持续三周(qwk3);五次每日剂量,间隔两天,再给予五次每日剂量(5/2/5);或根据实际情况确定的任何剂量方案。
免疫检查点抑制剂以治疗有效量给药。当免疫检查点抑制剂是单克隆抗体时,每2-4周静脉内输注1-20mg/kg。例如,可给予50mg,60mg,70mg,80mg,90mg,100mg,200mg,300mg,400mg,500mg,600mg,700mg,800mg,900mg,1000mg,1100mg,1200mg,1300mg,1400mg,1500mg,1600mg,1700mg,1800mg,1900mg和2000mg的抗体。
例如,当免疫检查点抑制剂是抗PD-1抗体尼莫单抗时,可以每两周60分钟通过静脉内输注给予3mg/kg。当免疫检查点抑制剂是抗PD-1抗体彭美罗珠单抗时,可以每两或三周30分钟通过静脉内输注给予2mg/kg。当免疫检查点抑制剂是抗PD-L1抗体阿维单抗时,可以每2周的频率通过静脉内输注给予10mg/kg。Disis等,J.Clin Oncol.33(2015)(增刊;abstr 5509)。当免疫检查点抑制剂是抗PD-L1抗体MPDL3280A时,可以每3周通过静脉内输注给予20mg/kg。Herbst等,Nature 515:563-80(2014)。当免疫检查点抑制剂是抗CTLA-4抗体伊匹单抗时,可以每三周90分钟通过静脉内输注给予3mg/kg。当免疫检查点抑制剂是抗CTLA-4抗体特姆单抗时,可以每12周通过静脉内输注给予15mg/kg。Naido等,BritishJournal of Cancer 111:2214-19(2014);Drugs R D,10:123-32(2010)。当免疫检查点抑制剂是抗LAG3抗体GSK2831781时,可以每2-4周通过静脉内输注120分钟以上给予1.5-5mg/kg。当免疫检查点抑制剂是抗TIM3抗体时,可以每2-4周通过静脉内输注30-90分钟以上给予1-5mg/kg。当吲哚胺2,3-双加氧酶(IDO)途径的抑制剂是抑制剂吲哚莫德与替莫唑胺组合时,吲哚莫德从18.5mg/kg/剂BID递增至27.7mg/kg/剂BID,每5天200mg/m2替莫唑胺。
COX-2抑制剂还以治疗有效量给药,例如约1mg/kg至约500mg/kg,约1mg/kg至约100mg/kg,或约1mg/kg至约50mg/kg。单位口服剂量的COX-2抑制剂可包含约0.01至约1000mg,例如约1至约250mg的COX-2抑制剂。在一个实施方式中,COX-2抑制剂的单位口服剂量是5mg,10mg,20mg,30mg,40mg,50mg,60mg,70mg,80mg,90mg,100mg,110mg,120mg,130mg,140mg,150mg,160mg,170mg,180mg,190mg,200mg,210mg,220mg,230mg,240mg,或250mg。单位剂量可以每天给予一次或多次,例如以一个或多个片剂或胶囊给予。
在一个实施方式中,免疫检查点抑制剂是抗体,并且每2-4周通过静脉内输注给予1-20mg/kg。在另一个实施方式中,每2-4周通过静脉内输注给予50-2000mg抗体。在另一个实施方式中,在给予抗体之前给予TG02。在另一个实施方式中,在给予抗体的当天之前3-7天给予TG02。在另一个实施方式中,TG02也在给予抗体的当天给予,并且在其后连续几天给予直至疾病进展或直到TG02给予不再有益。
在一个实施方式中,癌症患者具有带有生物标志物的肿瘤,例如MYC和/或MCL1的过表达,并且每三周通过静脉内输注给予2mg/kg的彭美罗珠单抗并在彭美罗珠单抗给药之前,在彭美罗珠单抗给药当天和此后给予30-600mg TG02持续3-7天,直到疾病进展或直到没有治疗益处。
在另一个实施方式中,癌症患者具有带有生物标志物的肿瘤,例如MYC和/或MCL1的过表达,并且每2周通过静脉内输注给予3mg/kg的尼莫单抗并在尼莫单抗给药之前,在尼莫单抗给药当天和此后口服给予30-600mg TG02持续3-7天,直到疾病进展或直到没有治疗益处。
在另一个实施方式中,癌症患者具有带有生物标志物的肿瘤,例如MYC和/或MCL1的过表达,并且每2周通过静脉内输注给予3mg/kg的尼莫单抗并在尼莫单抗给药之前,在尼莫单抗给药当天和此后每周两次口服给予30-600mg TG02,直到疾病进展或直到没有治疗益处。
在另一个实施方式中,用免疫检查点抑制剂和TG02治疗癌症患者比单独给予免疫检查点抑制剂时更快地诱导抗增殖响应。
在另一个实施方式中,用COX-2抑制剂和TG02治疗癌症患者比单独给予COX-2抑制剂时更快地诱导抗增殖响应。
V.生物标志物
如本文所用的术语“生物标志物”是指可以在癌症患者体内或从癌症患者获得的生物样品中检测和/或定量的任何生物化合物,例如基因,蛋白质,蛋白质片段,肽,多肽,核酸等。生物标志物可以是完整分子,或者它可以是其一部分或片段。在一个实施方式中,测量生物标志物的表达水平。生物标志物的表达水平可以例如通过检测生物标志物的蛋白质或RNA,例如mRNA水平来测量。在一些实施方式中,可以例如通过抗体或其他特异性结合剂检测或测量生物标志物的部分或片段。在一些实施方式中,生物标志物的可测量方面与患者的给定状态相关,例如癌症的特定阶段。对于在蛋白质或RNA水平检测的生物标志物,此类可测量方面可包括例如癌症患者,或从癌症患者获得的生物样品中生物标志物的存在,不存在或浓度(即表达水平)。对于在核酸水平检测的生物标志物,此类可测量方面可包括例如生物标志物的等位基因形式或生物标志物的类型,速率和/或突变程度,本文也称为突变状态。
对于基于蛋白质或RNA的表达水平检测的生物标志物,可以认为在不同表型状态之间测量的表达水平是不同的,例如,如果计算不同组中生物标志物的平均或中值表达水平是统计学显著的。统计学显著性的常见检验包含t检验、ANOVA、克-瓦二氏(Kruskal-Wallis)、威尔科克森(Wilcoxon)、曼-惠特尼(Mann-Whitney)微阵列重要性分析、让步比等。生物标志物单独或组合提供对象属于一种或另一种表型状态的相对可能性的测量。因此,它们尤其可用作疾病的标志物,并且作为特定治疗方案可能导致有益的患者结果的指标。
生物标志物包括但不限于表1中列出的基因。在一个实施方式中,生物标志物的可测量方面是其表达状态。在一个实施方式中,生物标志物的可测量方面是其突变状态。
表1
在一个实施方式中,生物标志物是MYC。在一个实施方式中,MYC的可测量方面是其表达状态。在一个实施方式中,生物标志物是MYC的过表达。
因此,在本公开的某些方面,生物标志物是MYC,与另一种表型状态,例如,正常未患病的对象或患有癌症但没有过表达MYC的患者相比,其在一种表型状态的对象中差异存在,例如患有癌症的患者,例如肝细胞癌(HCC),成胶质细胞瘤(GBM),肺癌,乳腺癌,头颈癌,前列腺癌,黑素瘤或结肠直肠癌。
生物标志物标准可以预先确定,同时确定,或在从对象获得生物样品后确定。与本文描述的方法一起使用的生物标志物标准可以例如包括来自没有癌症的对象的样品的数据;来自患有癌症的对象(例如GBM)的样品的数据,其不是进行性,复发性和/或转移性癌症;来自患有癌症的对象(例如GBM)的样品的数据,其是进行性,复发性和/或转移性癌症。可以进行比较以针对不同类别的对象(例如,患病对象与未患病对象)建立预定的阈值生物标志物标准。标准可以在相同的测定中进行,或者可以是先前测定的已知标准品。
在一个实施方式中,生物标志物是MCL1。在一个实施方式中,MCL1的可测量方面是其表达状态。在一个实施方式中,生物标志物是MCL1的过表达。
如果计算的不同表型状态的组之间的生物标志物的平均或中值表达或突变水平不同(即,较高/较低),则所述生物标志物在所述组间差异存在。因此,生物标志物提供了对象(例如癌症患者)属于一种表型状态或另一种表型状态的指示。
因此,在本公开的某些方面,生物标志物是MCL1,与另一种表型状态,例如,正常未患病的对象或没有过表达MCL1的癌症患者相比,其在一种表型状态的对象中差异存在,即过表达,例如患有癌症的患者,例如肝细胞癌(HCC),成胶质细胞瘤(GBM),肺癌,乳腺癌,头颈癌,前列腺癌,黑素瘤,结肠直肠癌,髓母细胞瘤或一般脑瘤。
除了单独的生物化合物,例如MYC或MCL1之外,本文所用的术语“生物标志物”意在包括多种生物化合物的基团,组或阵列。例如,MYC和MCL1的组合可包含生物标志物。术语“生物标志物”可包括一种,两种,三种,四种,五种,六种,七种,八种,九种,十种,十五种,二十种,二十五种,三十种或更多种生物化合物。
可以使用本领域已知的许多方法中的任何一种来确定患者中生物标志物的表达水平或突变状态。本领域已知的用于定量特定蛋白质和/或检测MYC和/或MCL1表达,或患者或生物样品中任何其他生物标志物的表达或突变水平的任何方法可用于本公开的方法中。示例包括但不限于PCR(聚合酶链反应),或RT-PCR,Northern印迹,Western印迹,ELISA(酶联免疫吸附测定),RIA(放射免疫测定),RNA表达的基因芯片分析,免疫组织化学或免疫荧光。参见,例如,Slagle等,Cancer 83:1401(1998)。本公开的某些实施方式包括测定生物标志物RNA表达(转录)的方法。本公开的其他实施方式包括确定生物样品中蛋白质表达的方法。参见,例如,Harlow等,《抗体:实验室手册》(Antibodies:A Laboratory Manual),冷泉港实验室,纽约冷泉港,(1988)和Ausubel等,《新编分子生物学实验指南》(CurrentProtocols in Molecular Biology),John Wiley&Sons,纽约,第3版,(1995)。对于northern印迹或RT-PCR分析,使用无RNA酶技术从肿瘤组织样品中分离RNA。此类技术是本领域已知的。
在本公开的一个实施方式中,从患者获得生物样品,并测定活检中的细胞以确定生物标志物表达或突变状态。
在本公开的一个实施方式中,PET成像用于确定生物标志物表达。
在本公开的另一个实施方式中,进行肿瘤细胞样品中生物标志物转录的Northern印迹分析。Northern分析是用于检测和/或定量样品中mRNA水平的标准方法。最初,使用Northern印迹分析从待测样品中分离RNA。在分析中,首先通过在变性条件下在琼脂糖凝胶中电泳来根据大小分离RNA样品。然后将RNA转移到膜上,交联并与标记的探针杂交。通常,Northern杂交涉及在体外聚合放射性标记的或非同位素标记的DNA,或作为杂交探针产生寡核苷酸。通常,在探针杂交之前对保持RNA样品的膜进行预杂交或封闭,以防止探针包被膜,从而减少非特异性背景信号。杂交后,通常通过在几次更换缓冲液中洗涤除去未杂交的探针。洗涤和杂交条件的严格性可由本领域普通技术人员设计,选择和实施。使用可检测标记的探针和合适的检测方法完成检测。放射性标记和非放射性标记的探针及其用途是本领域熟知的。所测定的生物标志物的存在和/或相对表达水平可以使用例如光密度测定法来量化。
在本公开的另一个实施方式中,使用RT-PCR测定生物标志物表达和/或突变状态。RT-PCR允许实时检测靶基因的PCR扩增的进展。检测本公开的生物标志物的表达和/或突变状态所需的引物和探针的设计在本领域普通技术人员的技能范围内。RT-PCR可用于确定编码肿瘤组织样品中本公开的生物标志物的RNA的水平。在本公开的一个实施方式中,在无RNA酶条件下分离来自生物样品的RNA,而不是通过用逆转录酶处理转化成DNA。用于将RNA逆转录酶转化为DNA的方法是本领域熟知的。在以下参考文献中提供了PCR的描述:Mullis等,Cold Spring Harbor Symp.Quant.Biol.51:263(1986);EP 50,424;EP 84,796;EP258,017;EP 237,362;EP 201,184;美国专利号4,683,202;4,582,788;4,683,194。
RT-PCR探针取决于用于PCR的DNA聚合酶的5′-3′核酸酶水解与靶扩增子(生物标志物基因)杂交的寡核苷酸的活性。RT-PCR探针是寡核苷酸,其具有与5′末端连接的荧光报告染料和与3′末端偶联的猝灭剂部分(或反之亦然)。设计这些探针以与PCR产物的内部区域杂交。在未杂交状态下,氟和猝灭分子的接近阻止了探针的荧光信号的检测。在PCR扩增期间,当聚合酶复制其上结合有RT-PCR探针的模板时,聚合酶的5′-3′核酸酶活性切割探针。这使荧光和猝灭染料分离,并且不再发生FRET。因此,荧光在每个循环中以与探针切割量成比例的方式增加。可以使用常规和通用技术使用商购的设备随时间测量或跟踪反应发出的荧光信号。
在本公开的另一个实施方式中,通过western印迹分析检测由生物标志物编码的蛋白质的表达。Western印迹(也称为免疫印迹)是在给定的组织匀浆或提取物样品中检测蛋白质的方法。它使用凝胶电泳按质量分离变性蛋白质。然后将蛋白质从凝胶中转移到膜上(例如硝酸纤维素或聚偏二氟乙烯(PVDF)),在那里使用特异性结合蛋白质的一抗检测它们。然后可以通过与可检测标记(例如,生物素,辣根过氧化物酶或碱性磷酸酶)偶联的二抗检测结合的抗体。二级标记信号的检测表明存在蛋白质。
在本公开的另一个实施方式中,通过酶联免疫吸附测定(ELISA)检测由生物标志物编码的蛋白质的表达。在本公开的一个实施方式中,“夹心ELISA”包括用捕获抗体包被板;加入样品,其中存在的任何抗原与捕获抗体结合;添加也结合抗原的检测抗体;添加与检测抗体结合的酶联二抗;并且将由二抗上的酶转化的底物添加至可检测形式。检测到来自二抗的信号表明存在生物标志物抗原蛋白。
在本公开的另一个实施方式中,通过使用基因芯片或微阵列评估生物标志物的表达。这些技术在本领域普通技术人员的能力范围内。
VI.定义
本公开提供了各种治疗方法,试剂盒和包含TG02的药物组合物。如本文所使用的术语“TG02”是指任何结晶或无定形形式,或游离碱或药学上可接受的盐或溶剂合物的(16E)-14-甲基-20-氧杂5,7,14,26-四氮杂四环[19.3.1.1(2,6).1(8,12)]二十七碳-1(25),2(26),3,5,8(27),9,11,16,21,23-十烯。在一个实施例中,TG02是指(16E)-14-甲基-20-氧杂-5,7,14,26-四氮杂四环[19.3.1.1(2,6).1(8,12)]二十七碳-1(25),2(26),3,5,8(27),9,11,16,21,23-十烯的游离碱。在另一个实施方式中,TG02是指(16E)-14-甲基-20-氧杂-5,7,14,26-四氮杂四环[19.3.1.1(2,6).1(8,12)]二十七碳-1(25),2(26),3,5,8(27),9,11,16,21,23-十烯的药学上可接受的盐。TG02的药学上可接受的盐可以在TG02的最终分离和纯化期间制备,或者通过使TG02与药学上可接受的酸反应而单独制备。可用于形成药学上可接受的盐的酸的示例包括无机酸(如硝酸、硼酸、盐酸、氢溴酸、硫酸和磷酸)和有机酸(如草酸、马来酸、琥珀酸和柠檬酸)。TG02的盐的非限制性示例包括但不限于:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、2-羟乙磺酸盐、磷酸盐、磷酸氢盐、乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑烷磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、甲酸盐、琥珀酸盐、富马酸盐、马来酸盐、抗坏血酸盐、羟乙基磺酸盐、水杨酸盐、甲磺酸盐、均三甲基苯磺酸盐、亚萘基磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐、十一烷酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡萄糖酸盐、甲磺酸盐、乙二磺酸盐、苯磺酸盐和对甲苯磺酸盐。
在另一个实施方式中,TG02是指(16E)-14-甲基-20-氧杂-5,7,14,26-四氮杂四环[19.3.1.1(2,6).1(8,12)]二十七碳-1(25),2(26),3,5,8(27),9,11,16,21,23-十烯的柠檬酸盐。这被称为TG02柠檬酸盐或(16E)-14-甲基-20-氧杂-5,7,14,26-四氮杂四环[19.3.1.1(2,6).1(8,12)]二十七碳-1(25),2(26),3,5,8(27),9,11,16,21,23-十烯-柠檬酸。
如本文所用的术语“生物学样品”是指来自患者的任何组织或流体,其适于检测生物标志物,例如MYC和/或MCL1表达状态。有用的生物样品的示例包括但不限于活检组织和/或细胞,例如实体瘤,淋巴腺,发炎组织,涉及病症或疾病的组织和/或细胞,血液,血浆,血清,脑脊液,唾液,尿液,淋巴液,脑脊髓液等。其他合适的生物样品对于相关领域的普通技术人员来说是熟悉的。可以使用本领域已知的任何技术分析生物样品的生物标志物表达和/或突变,并且可以使用完全在临床实践者的普通知识范围内的技术获得生物样品。在本公开的一个实施方式中,生物样品包含血细胞。
描述本发明的内容时的术语“一个”、“一种”和“该”等类似表达(尤其在权利要求书的内容中)应解释为涵盖单数和复数,除非另有说明。本文中对数值范围的引用仅仅是一种速记方法,单独表示落在该范围内的各个独立的值,除非本文中另有说明,且各个独立的值包括在说明书范围内,如同它们被单独引用。本文涉及的任何和所有实施例,或者示例性的语言(例如,“例如”)的使用是为了更好地阐述本发明,而不是对本发明范围的限制,除非权利要求中另有说明。说明书中的所有语言都不应解释为指示对本发明实践所必需的非权利要求的要素。
在本文中,术语“约”包括列举的数字±10%。因此,约“10”表示9-11。
本文中,术语”治疗”、“处理”等表示消除、降低或缓解疾病或病症和/或其相关症状。虽然不是排除性的,但治疗疾病或病症不需要完全消除该疾病或病症或其相关症状。然而,在一个实施方式中,TG02和/或免疫检查点抑制剂和/或COX-2抑制剂的给予导致癌症的完全缓解。
如本文所用,术语“治疗有效量”是指治疗剂的量足以导致病症的一种或多种症状的改善,或预防病症的进展,或引起病症的消退。例如,关于癌症的治疗,在一个实施方式中,治疗有效量是指引起治疗响应的治疗剂的量,例如血细胞计数正常化,肿瘤生长速率降低,减少肿瘤质量减少,转移数量减少,肿瘤进展时间增加,和/或患者存活时间增加至少约2%,至少约5%,至少约10%,至少约15%,至少约20%,至少约25%,至少约30%,至少约35%,至少约40%,至少约45%,至少约50%,至少约55%,至少约60%,至少约65%,至少约70%,至少约75%,至少约80%,至少约85%,至少约90%,至少约95%,或至少约100%或更多。
术语“药学上可接受的运载体”或“药学上可接受的载剂”包括任何标准药物运载体,溶剂,表面活性剂或载剂。合适的药学上可接受的载剂包括含水载剂和非水载剂。标准药物运载体及其制剂描述于《雷明顿药物科学》(Remington′s PharmaceuticalSciences),马克出版公司(Mack Publishing Co.),宾西马尼亚州伊斯顿,第19版,1995。
术语“容器”指适用于储存、运输、分散和/或处理药物产品的任何接受器和封闭件。
术语“插入页”指药物产品附带的信息,其描述了如何给予该产品,以及所需安全性和效力数据以允许医师、药师和患者做出涉及产品使用的知情决定。包装插入页通常称作药物产品的“标签”。
“共同给予”、“组合给予”、“同时给予”和类似短语指将两种或更多种试剂共同给予正在治疗的患者。“共同”表示各试剂同时给予或在不同时间点处以任意顺序依次给予。然而,如果不是同时给予,其表示各试剂依次给予患者且在时间上足够接近以提供所需的治疗效果并能够一齐作用。例如,TG02可以作为免疫检查点抑制剂和/或COX-2抑制剂和/或任选治疗剂在不同的时间点同时或以任何顺序依次给予。TG02和免疫检查点抑制剂和/或COX-2抑制剂和/或任选治疗剂可以以任何适当的形式和通过任何合适的途径分开给予。当TG02和免疫检查点抑制剂和/或COX-2抑制剂和/或任选治疗剂不同时给药时,应理解它们可以以任何顺序给予有需要的患者。例如,可在向有此需要的个体给予免疫检查点抑制剂和/或COX-2抑制剂之前(如5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周前)、同时或之后(如5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周后)给予TG02。在多个实施方式中,TG02和免疫检查点抑制剂和/或COX-2抑制剂的给药之间相隔1分钟、相隔10分钟、相隔30分钟、相隔小于1小时、相隔1小时、相隔1-2小时、相隔2-3小时、相隔3-4小时、相隔4-5小时、相隔5-6小时、相隔6-7小时、相隔7-8小时、相隔8-9小时、相隔9-10小时、相隔10-11小时、相隔11-12小时、相隔不超过24小时,或相隔不超过48小时。在一个实施方式中,组合疗法的各组分的给药之间相隔约1分钟至约24小时。在一个实施方式中,在免疫检查点抑制剂的当天之前3-7天给予TG02。在另一个实施方式中,TG02也在给予免疫检查点抑制剂的当天给予,并且持续给予直至疾病进展或TG02治疗不再有益。
实施例
实施例1
正在进行这项研究,以比较使用彭美罗珠单抗(p)或尼莫单抗(n)与p或n联合TG02对于癌症参与者的无进展或总生存率,这些患者未经治疗或在先前治疗后已经进展并且已针对过表达MYC和/或MCL1状态选择。参与者将被随机接受标准抗PD-1治疗加安慰剂或标准抗PD-1治疗加TG02。
主要结果测量:无进展生存期(PFS)和/或总生存期(OS)
次要结果测量:总体响应率(ORR)和/或响应持续时间
资格
符合研究条件的年龄:一般18岁及以上
对于成神经管细胞瘤患者--6个月或以上
符合研究条件的性别:两者
纳入标准:
组织学或细胞学证实的癌症诊断不适合局部治疗
相关研究必须知情同意;必须提供新获得的组织/活检标本(或在同意后60天内获得的标本)
射线照相可测量的疾病
东部肿瘤协作组的表现状态为0或1
患者患有过表达MYC和/或MCL1的疾病
排除标准:
在第一剂研究药物之前四周内进行化疗,放射治疗或生物治疗,或者未从由于超过四周前给予的癌症治疗引起的AE中恢复
在第一剂研究药物后30天内参与或已参与研究试剂或使用研究装置的研究
在研究期间,预计需要任何其他形式的全身或局部抗肿瘤治疗
在第一剂随机治疗的计划日期之前两周内或任何其他形式的免疫抑制药物治疗前的慢性全身性类固醇治疗
除了充分治疗的皮肤基底或鳞状细胞癌,浅表性膀胱癌,原位宫颈癌,乳腺癌或其他原位癌症之外,除了目前的恶性肿瘤以外的任何其他已知病史
已知的活动性中枢神经系统(CNS)转移和/或癌性脑膜炎
活动性自身免疫性疾病或需要全身性类固醇或免疫抑制剂的自身免疫性疾病或综合征的病史记录
用任何其他抗程序性细胞死亡(PD)剂预先治疗
需要全身治疗的活动性感染
人类免疫缺陷病毒(HIV)的已知病史
活动性乙型肝炎或丙型肝炎
经常使用(包括娱乐性使用)非法药物或近期(最近一年内)药物(包括酒精)滥用
怀孕或哺乳,或期望在预计的研究期间内怀孕或生育孩子。
方案:
第一组患者每三周通过静脉内输注给予2-10mg/kg的彭美罗珠单抗(或平剂量当量),并且每天一次以100、200或300mg口服给予TG02直至疾病进展或不再有益。在开始彭美罗珠单抗治疗之前3-7天开始TG02给予,在彭美罗珠单抗给予当天继续给予,并持续至疾病进展或直至TG02治疗不再有益。对照患者每三周通过静脉内输注给予2-10mg/kg的彭美罗珠单抗(或平剂量当量)。
第二组患者每2周通过静脉内输注在60分钟内接受3mg/kg尼莫单抗,并且每天一次以100、200或300mg口服给予TG02。在开始尼莫单抗治疗之前3-7天开始TG02给予,在尼莫单抗给予当天继续给予,并持续至疾病进展或直至TG02治疗不再有益。对照患者每2周通过静脉输注在60分钟内接受3mg/kg尼莫单抗。
结果:
在肿瘤过表达MYC和/或MCL1的患者中,TG02与彭美罗珠单抗或尼莫单抗组合产生比单独的免疫检查点抑制剂更好的抗肿瘤临床活性。与仅使用(抗体)的历史对照相比,获得了与缺乏肿瘤进展和长期存活延长相关的意外客观响应。在一个实施方式中,接受TG02和免疫检查点抑制剂的患者实现至少2个月,至少4个月,至少6个月,至少8个月,至少10个月或至少12个月的进展时间(或无进展存活)延长。在另一个实施方式中,接受TG02和免疫检查点抑制剂的至少一些患者实现至少2个月,至少4个月,至少6个月,至少8个月,至少10个月或至少12个月的反应持续时间延长。
实施例2
开放标签2期研究评估对标准抗-PD-1疗法(p)或(n)复发或难治的患者中检查点阻断免疫疗法和TG02的组合。
一级终点:ORR
二级终点:PFS,OS,响应持续时间,安全性
纳入标准:
组织学证实的癌症诊断不适合局部治疗
东部肿瘤协作组(ECOG)的表现状态为0或1
至少一个可测量的病灶
足够的器官功能
先前用抗PD-1或抗PD-L1抗体治疗
患者患有过表达MYC和/或MCL1的疾病
排除标准:
化疗,靶向小分子治疗,放射治疗或生物癌症治疗(包括单克隆抗体),在第一剂试验治疗前4周内,或未从由于先前给药的药物引起的不良事件中恢复(<=1级或基线)。
在研究期间,预计需要任何其他形式的全身或局部抗肿瘤治疗
已知的活动性中枢神经系统(CNS)转移和/或癌性脑膜炎。
记录临床严重自身免疫疾病的历史,或需要全身性类固醇或免疫抑制剂的综合征。
在第一剂研究治疗之前1周内接受全身性类固醇治疗或任何其他形式的免疫抑制治疗。
在第一剂试验治疗前4周内接种活疫苗。
活动性肺炎的病史或证据。
人类免疫缺陷病毒(HIV)阳性。
活动性乙型肝炎或丙型肝炎。
在试验治疗到最后一剂研究药物后120天的预计持续时间内,怀孕,母乳喂养或期望怀孕或怀孕。
给药方案:
表1 TG02+检查点抑制剂组合给药和方案
*TG02每周给药(50-400mg),从开始检查点抑制剂治疗前至少5天开始,持续至疾病进展或研究者决定结果
在具有过表达的MYC和/或MCL1肿瘤的患者中将TG02与至少一种检查点抑制剂组合可以逆转免疫逃避并在先前对检查点抑制剂治疗无效或未通过治疗的患者或新发癌症患者中诱导临床相关反应。与仅使用(抗体)的历史对照相比,获得了与缺乏肿瘤进展和长期存活延长相关的意外客观响应。在一个实施方式中,接受TG02和至少一种免疫检查点抑制剂的患者实现至少2个月,至少4个月,至少6个月,至少8个月,至少10个月或至少12个月的反应持续时间(或无进展存活)延长。在另一个实施方式中,接受TG02和至少一种免疫检查点抑制剂的至少一些患者实现至少2个月,至少4个月,至少6个月,至少8个月,至少10个月或至少12个月的反应持续时间延长。
实施例3
表现出过度表达的MYC和/或MCL1状态的先前治疗过的局部晚期不可切除或转移性结直肠癌的参与者中安慰剂对照的随机2期彭美罗珠单抗+TG02与彭美罗珠单抗+安慰剂研究。
一级终点:PFS
二级终点:ORR,反应持续时间
纳入标准:
经组织学证实的局部晚期不可切除或转移性高结直肠癌
以前用至少两线经批准的标准疗法治疗,必须包括氟嘧啶,奥沙利铂,伊立替康,贝伐单抗和西妥昔单抗或帕尼单抗
东部肿瘤协作组的表现状态为0或1
患者患有过表达MYC和/或MCL1的疾病
预期寿命超过3个月
至少一个可测量的病灶
有生育能力的女性参与者应该愿意在研究过程直至最后一剂研究药物后120天内使用2种避孕方法或手术不育,或避免异性恋活动
男性参与者应同意从第一剂研究治疗开始到最后一剂研究药物后120天使用适当的避孕方法
足够的器官功能
排除标准:
目前正在参与另一项研究并接受试验治疗,参与了一项研究药物的研究,并在本研究第一剂药物治疗后4周内接受了试验治疗,或在本研究第一剂药物治疗后4周内使用了研究设备
在过去2年内需要全身治疗的活动性自身免疫性疾病
在第一剂研究药物治疗前7天内诊断免疫缺陷或接受全身性类固醇治疗或任何其他形式的免疫抑制治疗
已知的活动性中枢神经系统(CNS)转移和/或癌性脑膜炎
在研究第1天之前的2周内的先前单克隆抗体(mAb),化学疗法,靶向小分子疗法或放射疗法或未从由于先前给予的药物的不良事件中恢复(即,≤1级或基线)
先前使用抗程序性细胞死亡(PD)-1,抗PD-L1或抗PD-L2药物治疗或参与者之前曾参与过默克彭美罗珠单抗(MK-3475)临床试验
正在进展或需要积极治疗的已知其他恶性肿瘤,但皮肤基底细胞癌或经历过潜在治愈性治疗的皮肤鳞状细胞癌或原位宫颈癌除外
在计划开始研究药物后30天内接种活疫苗
人类免疫缺陷病毒(HIV)的已知病史
已知活动性乙型肝炎或丙型肝炎
任何间质性肺病或活动性非感染性肺炎的已知病史或证据
需要全身治疗的活动性感染
会干扰与试验要求的合作的已知精神疾病或药物滥用障碍
从筛选访视开始到最后一剂研究药物后120天的预计持续时间内,怀孕或母乳喂养、或期望怀孕或怀孕
给药方案:
患者每3周静脉输注2-10mg/kg彭美罗珠单抗,并且彭美罗珠单抗给药前3-7天,彭美罗珠单抗给药当天以1、2或3mg/kg口服给予TG02,此后持续至疾病进展或直到它不再有益。对照患者每三周通过静脉内输注接受2mg/kg彭美罗珠单抗。
结果:
当用于具有过表达MYC和/或MCL1的肿瘤的患者时,TG02与彭美罗珠单抗组合在相同患者中比单独的彭美罗珠单抗提供更好的临床活性。与仅使用(抗体)的历史对照相比,在患者中获得了与缺乏肿瘤进展和长期存活延长相关的意外客观响应。在一个实施方式中,接受TG02和彭美罗珠单抗的患者实现至少2个月,至少4个月,至少6个月,至少8个月,至少10个月或至少12个月的进展时间(或无进展存活)延长。在另一个实施方式中,接受TG02和彭美罗珠单抗的至少一些患者实现至少2个月,至少4个月,至少6个月,至少8个月,至少10个月或至少12个月的响应持续时间延长。
实施例4
TG02与卡非佐米组合用于卡非佐米(CFZ)难治性多发性骨髓瘤(MM)患者
方法
一项开放标签的1b期研究纳入了之前接受≥2线疗法治疗的MM患者。主要目的是确定TG02与卡非佐米组合(TG02/CFZ)的最大耐受剂量(MTD)。次要目的包括抗肿瘤活性和安全性。在28天的时间表(BIW)的第1、4、8、11、15、18天每天一次给予TG02。TG02起始剂量为150mg。TG02给药以50mg增量逐步增加至300mg。CFZ根据处方信息给药。使用标准标准评估响应。
结果
招募了14名患者进行剂量递增,招募了10名患者扩大MTD组。患者接受了大量预处理:中位数为6次先前治疗[最小3次;最大15次]并且92%的患者在之前的治疗方案中接受了CFZ。对先前治疗的最佳响应是46%患者的进行性疾病。MTD为250mg TG02与CFZ组合。在300mg组中观察到两种剂量限制性毒性(包括4级(Gr)败血症和Gr4中性粒细胞减少症)。最常见的药物相关不良事件(AE)是腹泻(Gr 1-2:71%,Gr 3:17%),恶心(Gr 1-2:79%),呕吐(Gr 1-2:50%),疲劳(Gr 1-2:38%,Gr 3:4%),厌食症(Gr 1:21%),贫血(Gr 1-2:4%,Gr 3:17%)和血小板减少症(Gr 3:8%,Gr 4:13%)。6名患者(25%)因AE而停止治疗。严重的AE发生在50%的患者中;只有急性肾功能衰竭和发热性中性粒细胞减少症发生在超过1名患者中(每种8%)。AE的严重程度与单一试剂TG02相似。TG02/CFZ给药时腹泻的发生率增加(88%对67%),但其他AE的发生率与单一药物TG02相似。可评估在MTD给予TG02的14名患者的响应。整体响应率(≥PR)为27%;临床受益率(≥MR)为45%(1个非常好的部分响应,2个部分响应和2个最小响应)。所有应答者(MR或更好)在先前的治疗方案中是CFZ难治的。27%的患者中观察到持久稳定的疾病。
结论
TG02 BIW/CFZ的安全性特征与单独的TG02相似。最常见的与药物有关的AE是腹泻,恶心和呕吐;4级AE不常见。在CFZ难治性患者中观察到客观响应。
实施例5
胶质瘤细胞和同种异体移植模型中的TG02活性
在72小时细胞增殖测定中,用TG02,替莫唑胺(TMZ),或TG02和TMZ的组合处理几种标准的多形性成胶质细胞瘤(GBM)细胞系和一种表达O6-甲基鸟嘌呤DNA甲基转移酶(MGMT)的干细胞系。见图1-3。还在没有MGMT表达的细胞系中测试了TG02,TMZ,和TG02+TMZ组合。见图4-7。将细胞接种到12孔板上,并用50nM TG02,100μM TMZ或TG02+TMZ处理72小时。通过细胞计数确定细胞活力。
通过GSC923和U251细胞中的集落形成测定检查TG02,TMZ,和TG02与TMZ组合的细胞毒性作用。见图8和9。
用50nM TG02,100μM TMZ,或TG02+TMZ测试肺动脉内皮细胞和人星形胶质细胞72小时。然后将细胞更换为正常培养基并再培养7天。通过细胞计数确定细胞活力。见图10和11。
将GSC923(图12和13)和U251(图14和15)细胞暴露于各种浓度的TG02,TMZ,和TG02+TMZ持续72小时,并通过细胞计数检查细胞活力。TG02+TMZ的协同效应通过组合指数(CI)确定。通过COMPUSYN软件计算CI值,并且对于GSC923细胞显示表2,对于U251细胞显示表3。CI<1是协同的,CI=1是添加剂,并且CI>1是两种化合物组合的拮抗作用。
表2
影响分数(Fa) | CI值 |
0.25 | 0.077 |
0.5 | 0.136 |
0.75 | 0.242 |
0.90 | 0.430 |
表3
影响分数(Fa) | CI值 |
0.25 | 0.029 |
0.5 | 0.104 |
0.75 | 0.376 |
0.90 | 1.333 |
图16是小鼠神经胶质瘤GL261细胞同种异体移植模型中药物给予的示意图。将小鼠神经胶质瘤GL261细胞立体定向注射到雌性C57BL/6白化小鼠(每组n=5-7)的纹状体中,然后进行载剂,TG02,TMZ,和TG02+TMZ组合治疗。观察到中位总生存期分别为24,24.5,27.5,和32天。见图17。使用对数秩检验分析结果,得到GraphPad Prism软件中的趋势(卡方=9.063,df=1,P值=0.0026**)。通过使用PerkinElmer Spectrum拍摄的生物发光成像(BLI)确定肿瘤负荷。计算BLI的强度并将其标准化至第5天的初始强度。见图18。
实施例6
肝细胞癌(HCC)细胞和异种移植模型中的TG02活性
研究了TG02对HCC细胞系中MYC表达的影响。用0.5μM TG02处理具有不同MYC表达水平的5个HCC细胞系24小时,并通过western印迹评估MYC表达。见图19。在HepG2,SNU398和HUH-1细胞系中通过TG02处理降低MYC表达水平,但在JHH-5细胞系中没有。Hep3B细胞不表达MYC。
然后在体外用TG02处理具有高或低MYC表达的8个HCC细胞系。TG02处理导致所有测试的HCC细胞系中细胞增殖的抑制。与具有低水平MYC表达的那些细胞相比,TG02在具有高水平MYC表达的细胞系中选择性地更有效,平均IC50值分别为524nM和84nM。见图20。
还在体内测量MYC表达的抑制。HepG2肝细胞癌异种移植物在Balb/c裸鼠中原位生长。TG02或载剂以50mg/kg口服给予5只小鼠;处理后8小时收集肿瘤,通过western印迹测量MYC蛋白表达水平。在每个对照肿瘤中观察到MYC表达。在TG02处理组中,5只动物中的4只中MYC表达水平降低,两只动物中MYC基本消耗,另外两只动物部分减少。见图21。
在BALB/c裸鼠中评估TG02作为单一试剂或与索拉非尼组合在治疗原位HepG2人肝癌异种移植模型中的治疗功效。在接种后第19天,基于追踪肝脏中肿瘤体积的基线血清AFP水平将小鼠随机分入治疗组。每周两次以50mg/kg口服给予TG02并降低至40mg/kg。索拉非尼每日口服15mg/kg。作为单一试剂的TG02对肿瘤体积具有适度影响。TG02与索拉非尼组合导致显著的抗肿瘤活性。见图22。
实施例7
TG02介导的CDK9抑制
用100或500μM的TG02处理过表达并依赖于MYC的MYC诱导的T细胞急性淋巴细胞白血病(MYC T-ALL)的Tet-off转基因小鼠模型。
MYC是一种转录因子,其调节参与细胞增殖,生长,分化和凋亡的多种基因产物的表达。MYC基因在许多人类癌症中被遗传激活并过表达,并且这种过表达与肿瘤发生有因果关系,导致恶性生长和免疫逃避。参见,例如,-Fernández等,Clin.CancerRes.Off.J.Am.Assoc.Cancer Res.19:2677-2687(2013);Carter等,Blood 105:4043-4050(2005);Casey等,Science 352:227-231(2016);Hannah,A.L.,Curr.Mol.Med.5:625-642(2005);和Parcells等,Stem Cells Dayt.Ohio 24:1174-1184(2006)。
如图23-26所示,当MYC“打开”时,通过RT-PCR检测表达的PD-L1(t=0小时)。但当MYC被“关闭”时,CD47和PD-L1表达均以时间依赖性方式显著降低。TG02导致MYC T-ALL细胞中PD-L1和CD47 mRNA表达的时间和剂量依赖性下调(分别为图23和24),并且BCL-xL和MYC表达均下调(分别为图25和26)。肿瘤细胞上CD47和PD-L1的表达降低可导致免疫逃逸减少和肿瘤细胞死亡增加。
实施例8
TG02与抗PD-1组合
在原位GL261神经胶质瘤模型中测试TG02和PD-1 mAb(抗PD-1)的组合。建立GL261同种异体移植物3天,然后基于生物发光肿瘤体积将小鼠随机分入6个治疗组(n=8)。
用载剂,单独的TG02(20或40mg/kg),单独的PD-1 mAb(500μg)以及TG02和抗PD-1的组合处理小鼠。小鼠的中位存活时间分别为27.5,26.5,33,32,78和超过95天(图27)。
与载剂组相比,40mg/kg的单独TG02(0.009),单独PD-1 mAb(0.003),TG02 20mg/kg+PD-1 mAb(0.0001)和TG02 40mg/kg+PD-1 mAb(0.0001)处理的小鼠有显著的生存获益。
实施例9
TG02诱导细胞死亡并与MYC驱动的胶质母细胞瘤中的放射协同作用
在一组源自患者的GBM细胞系(PDCL)中测试TG02抗肿瘤活性和MYC表达之间的关系。在IC50小于0.2μM时,TG02抑制12个PDCL中的6个。参见表4。
表4
早在6小时,在MYC-扩增的BT245细胞系中观察到MYC和Mcl-1的下调,而在24小时时观察到完全下调,这与细胞凋亡的显著增加一致(图28)。在该细胞系组中计算TG02诱导的细胞活力抑制的AUC以与MYC表达水平相关(图29)。TG02是更有效的PDCL抑制剂,表现出高MYC表达(图30)。体外敏感性(AUC)与GBM细胞中MYC表达呈负相关(P值=0.02)
实施例10
放射是胶质母细胞瘤的有效治疗方法。但所有患者均出现肿瘤耐药和复发。
选择一组GBM PDCL,参见实施例9,用于评估TG02和放射疗法的组合,用于治疗胶质母细胞瘤(图31)。首先用增加浓度的TG02处理细胞。在30分钟内,用增加剂量的放射处理细胞,并在处理后72小时测量细胞增殖。单独的TG02在这些细胞系中具有抗增殖活性。TG02的添加以协同方式增强了放射效应。TG02和放射的组合超过了Bliss预测的模型(与Bliss预测的模型相比大于10%的变化),证明了TG02与多个PDCL中的放射之间的协同作用。
实施例11
TG02活性与胶质母细胞瘤细胞系中的MYC表达相关
在26个源自患者的GBM干细胞系的组中,评估了TG02对GBM干细胞增殖的活性(图32)。TG02在该组中是有效的,其中16个细胞系实现小于250nM的IC50。
测量CDK9和下游标志物(包括MYC和Mcl-1)的表达水平,以探究在该GBM组中蛋白质表达和IC50值之间是否存在相关性。发现高MYC表达与对TG02处理的更高敏感性相关(图33)。
现在已经完整地描述了本发明的方法、化合物和组合物,本领域普通技术人员应理解,可对本发明的条件、制剂和其它参数进行广泛等效改变,而不影响本发明的方法、化合物和组合物或其任意实施方式的范围。本文引用的所有专利、专利申请和发表物均通过引用全文纳入本文。
Claims (12)
1.TG02在制备用于治疗癌症患者的药物中的用途,其中TG02是(16E)-14-甲基-20-氧杂-5,7,14,26-四氮杂四环[19.3.1.1(2,6).1(8,12)]二十七碳-1(25),2(26),3,5,8(27),9,11,16,21,23-十烯或其药学上可接受的盐,其中TG02与治疗有效量的放射治疗一起向所述患者给予。
2.如权利要求1所述的用途,其中所述癌症的特征在于MYC过表达、MCL1过表达或两者。
3.如权利要求1所述的用途,其中所述癌症是实体瘤。
4.如权利要求1所述的用途,其中所述癌症是血液恶性肿瘤。
5.如权利要求1所述的用途,其中所述癌症选自:听神经瘤,急性淋巴细胞白血病,急性单核细胞白血病,急性早幼粒细胞白血病,腺癌,成人T细胞白血病/淋巴瘤,肺泡状横纹肌肉瘤,血管肉瘤,星形细胞瘤,B细胞慢性淋巴细胞白血病,B细胞前淋巴细胞白血病,B细胞淋巴瘤,基底细胞癌,膀胱癌,胚细胞瘤,伯基特淋巴瘤,乳腺癌,脑癌,上皮癌,原位癌,癌肉瘤,软骨瘤,脊索瘤,绒毛膜癌,颅咽管瘤,宫颈癌,结直肠癌,弥漫性大B细胞淋巴瘤,胚胎癌,食管癌,纤维肉瘤,滤泡状淋巴瘤,滤泡状甲状腺癌,神经节细胞瘤,生殖细胞瘤,妊娠绒毛膜癌,胶质母细胞瘤,神经胶质瘤,血管母细胞瘤,头颈癌,血液系统恶性肿瘤,肝母细胞瘤,肝细胞癌,霍奇金淋巴瘤,非霍奇金淋巴瘤,浸润性小叶癌,肠癌,肾癌,喉癌,恶性小痣,致死性中线癌,白血病,脂肪肉瘤,肺癌,淋巴管肉瘤,急性淋巴细胞白血病,急性髓性白血病,慢性淋巴细胞白血病,肝癌,小细胞肺癌,非小细胞肺癌,乳腺髓样癌,成神经管细胞瘤,黑色素瘤,脑膜瘤,间皮瘤,多发性骨髓瘤,粘液肉瘤,神经鞘瘤,神经母细胞瘤,神经瘤,结节性黑色素瘤,少突神经胶质瘤,口腔癌,骨肉瘤,卵巢癌,肺上沟瘤,甲状腺乳头状癌,松果体母细胞瘤,松果体细胞瘤,前列腺癌,胰腺癌,咽癌,腹膜假粘液瘤,肾细胞癌,视网膜母细胞瘤,横纹肌肉瘤,里氏转化,直肠癌,肉瘤,神经鞘瘤病,精原细胞瘤,皮肤癌,小细胞癌,生长抑素瘤,鳞状细胞癌,滑膜肉瘤,鳞状细胞癌,胃癌,T细胞淋巴瘤,睾丸癌,甲状腺癌,子宫癌,疣状癌,华氏巨球蛋白血症,沃辛瘤和维尔姆斯瘤。
6.如权利要求5所述的用途,其中所述癌症选自:肝细胞癌,成胶质细胞瘤,肺癌,乳腺癌,头颈癌,前列腺癌,黑素瘤和结肠直肠癌。
7.如权利要求5所述的用途,其中所述癌症是多发性骨髓瘤。
8.如权利要求5所述的用途,其中所述癌症是神经胶质瘤。
9.如权利要求5所述的用途,其中所述癌症是胶质母细胞瘤。
10.如权利要求5所述的用途,其中所述癌症是星形细胞瘤。
11.如权利要求1所述的用途,其中所述癌症已对常规治疗有耐药性。
12.如权利要求1-11中任一项所述的用途,其中所述TG02是(16E)-14-甲基-20-氧杂-5,7,14,26-四氮杂四环[19.3.1.1(2,6).1(8,12)]二十七碳-1(25),2(26),3,5,8(27),9,11,16,21,23-十烯的柠檬酸盐。
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JP (2) | JP7026299B2 (zh) |
KR (2) | KR20230020549A (zh) |
CN (2) | CN115969854A (zh) |
AU (1) | AU2017238647B2 (zh) |
CA (1) | CA3018875A1 (zh) |
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RU (1) | RU2749025C2 (zh) |
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TW202246349A (zh) | 2016-10-11 | 2022-12-01 | 美商艾吉納斯公司 | 抗lag-3抗體及其使用方法 |
KR20200037353A (ko) | 2017-08-07 | 2020-04-08 | 더 리전트 오브 더 유니버시티 오브 캘리포니아 | 안전한 세포 치료제를 생성하기 위한 플랫폼 |
SG11202001441WA (en) | 2017-08-18 | 2020-03-30 | Tragara Pharmaceuticals Inc | Polymorphic form of tg02 |
KR20220004025A (ko) * | 2019-03-18 | 2022-01-11 | 더 보드 오브 리젠츠 오브 더 유니버시티 오브 텍사스 시스템 | 종양-선택적 병용 요법 |
WO2020219603A1 (en) * | 2019-04-22 | 2020-10-29 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Use of tg02 for treating gliomas in pediatric subjects |
US20230287510A1 (en) * | 2020-08-10 | 2023-09-14 | The Broad Institute, Inc. | Compositions, panels, and methods for characterizing chronic lymphocytic leukemia |
WO2023092076A1 (en) * | 2021-11-18 | 2023-05-25 | Lantern Pharma Inc. | Method for treating cancer with acylfulvene and radiation |
CN114113051B (zh) * | 2021-12-16 | 2023-06-16 | 南京信息工程大学 | 一种psma电致化学发光传感器的制备方法及应用 |
EP4197525A1 (en) | 2021-12-20 | 2023-06-21 | Scandion Oncology A/S | Combination of drugs for the treatment of cancer |
CN114480639B (zh) * | 2021-12-24 | 2022-09-30 | 中国医学科学院北京协和医院 | 新靶点用于诊断和治疗垂体腺瘤 |
WO2023143608A1 (zh) * | 2022-01-30 | 2023-08-03 | 上海复东生物医药有限责任公司 | 一种组合物、其制备方法及应用 |
WO2023242235A1 (en) | 2022-06-14 | 2023-12-21 | Scandion Oncology A/S | Abcg2 inhibitor and nae inhibitor for the treatment of cancer |
CN115429793A (zh) * | 2022-08-15 | 2022-12-06 | 复旦大学附属中山医院 | 一种化合物在制备治疗肝细胞癌药物中的应用 |
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WO1982001011A1 (en) | 1980-09-24 | 1982-04-01 | Corp Cetus | Diagnostic method and probe |
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US4683194A (en) | 1984-05-29 | 1987-07-28 | Cetus Corporation | Method for detection of polymorphic restriction sites and nucleic acid sequences |
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CA1284931C (en) | 1986-03-13 | 1991-06-18 | Henry A. Erlich | Process for detecting specific nucleotide variations and genetic polymorphisms present in nucleic acids |
CA1338457C (en) | 1986-08-22 | 1996-07-16 | Henry A. Erlich | Purified thermostable enzyme |
US6605712B1 (en) | 1990-12-20 | 2003-08-12 | Arch Development Corporation | Gene transcription and ionizing radiation: methods and compositions |
KR101576159B1 (ko) * | 2005-11-16 | 2015-12-09 | 에스*바이오 피티이 리미티드 | 헤테로알킬이 결합된 피리미딘 유도체 |
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EP3010918B1 (en) | 2013-06-21 | 2018-08-15 | Zenith Epigenetics Ltd. | Novel substituted bicyclic compounds as bromodomain inhibitors |
JP6586087B2 (ja) | 2013-08-20 | 2019-10-02 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | Pd−1アンタゴニストとジナシクリブとの組合せでの癌治療 |
JP6678584B2 (ja) * | 2013-12-20 | 2020-04-22 | バイオメッド バレー ディスカバリーズ,インコーポレイティド | Cdk阻害剤およびerk阻害剤の組み合わせを使用するがん処置 |
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SG11202001441WA (en) | 2017-08-18 | 2020-03-30 | Tragara Pharmaceuticals Inc | Polymorphic form of tg02 |
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JP2019509354A (ja) | 2019-04-04 |
IL261959B2 (en) | 2023-08-01 |
JP2022050631A (ja) | 2022-03-30 |
SG10202005621WA (en) | 2020-07-29 |
KR20190006948A (ko) | 2019-01-21 |
EP3432888B1 (en) | 2022-10-05 |
JP7026299B2 (ja) | 2022-02-28 |
MX2021012977A (es) | 2022-10-03 |
IL261959B1 (en) | 2023-04-01 |
IL261959A (en) | 2018-10-31 |
CN109195603A (zh) | 2019-01-11 |
KR102491013B1 (ko) | 2023-01-31 |
EP3432888A4 (en) | 2019-11-13 |
EP3432888A1 (en) | 2019-01-30 |
RU2018137217A3 (zh) | 2020-05-29 |
RU2749025C2 (ru) | 2021-06-03 |
RU2018137217A (ru) | 2020-04-24 |
ES2941687T3 (es) | 2023-05-24 |
MX2022008868A (es) | 2022-08-11 |
CN109195603B (zh) | 2022-11-08 |
JP7459149B2 (ja) | 2024-04-01 |
US11865116B2 (en) | 2024-01-09 |
CA3018875A1 (en) | 2017-09-28 |
KR20230020549A (ko) | 2023-02-10 |
US20200323862A1 (en) | 2020-10-15 |
SG11201808306PA (en) | 2018-10-30 |
WO2017165732A1 (en) | 2017-09-28 |
AU2017238647B2 (en) | 2021-12-09 |
AU2017238647A1 (en) | 2018-10-25 |
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