CN105979958A - Cbp/ep300布罗莫结构域抑制剂用于癌症免疫疗法的用途 - Google Patents
Cbp/ep300布罗莫结构域抑制剂用于癌症免疫疗法的用途 Download PDFInfo
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Abstract
本发明涉及CBP/EP300布罗莫结构域抑制剂用于治疗癌症的用途。
Description
相关申请的交叉引用
本申请要求2013年10月11日提交的美国临时申请系列号61/890,041的权益和优先权,通过引用的方式将其整体并入。
序列表
本申请包含已以ASCII形式电子提交的序列表且通过引用的方式将其整体并入。所述2014年10月10日生成的ASCII拷贝命名为01075.004WO1_SL.txt且大小为53,084字节。
技术领域
本申请涉及CBP/EP300布罗莫结构域抑制剂用于治疗癌症的用途。
背景
染色质是组成染色体的DNA和蛋白的复杂组合。已发现其在真核细胞核内且分为异染色质(聚集)和常染色质(伸展)形式。染色质的主要组分为DNA和蛋白。组蛋白是染色质的主要蛋白组分,其作为DNA缠绕在其周围的卷轴发挥作用。染色质的功能是将DNA包装成为较小体积来适合细胞、强化DNA以允许有丝***和减数***并作为控制表达和DNA复制的机制发挥作用。染色质结构通过对组蛋白的一系列翻译后修饰控制,特别是组蛋白H3和H4,且大多在延伸超过核心核小体结构的"组蛋白尾"内。组蛋白尾倾向于无蛋白-蛋白相互作用且也是组蛋白最易于发生翻译后修饰的部分。这些修饰包括乙酰化、甲基化、磷酸化、泛素化、SUMO化。这些表观遗传标志物通过将标签置于组蛋白尾内特定残基上的特定酶写入和清除,由此形成表观遗传密码,其随后由细胞解读以允许对染色质进行基因特异性调节并由此进行转录。
对于全部种类的蛋白,组蛋白是对翻译后修饰最敏感的蛋白。组蛋白修饰是动态的,这是由于其可响应特定刺激进行添加或去除,且这些修饰指导染色质的结构变化以及在基因转录中的改变。不同种类的酶即组蛋白乙酰转移酶(HAT)和组蛋白脱乙酰酶(HDAC)乙酰化或脱乙酰化特定的组蛋白赖氨酸残基(Struhl K.,Genes Dev.,1989,12,5,599-606)。
组蛋白的共价修饰是控制基因表达的根本机制,且为真核细胞中起作用的主要表观遗传机制之一(Kouzarides,Cell,128,693-705(2007))。由于不同的转录状态限定根本的细胞过程,诸如细胞类型特异化、谱系承担、细胞活化和细胞死亡,因此其异常调节是一系列疾病的核心(Medzhitov等人,Nat.Rev.Immunol.,9,692-703(2009);Portela等人,Nat.Biotech.,28,1057-1068(2010))。基因表达表观遗传控制的根本部分是通过含有与这种修饰结合的特定基序的蛋白对组蛋白修饰进行解读。其中,布罗莫结构域演变为与乙酰化组蛋白结合且由此其表示染色质结构和基因转录间的根本连接(Fillipakoppoulos等人,Cell,149,214-231(2012))。
约110个氨基酸长的布罗莫结构域发现于大量的染色质-相关蛋白中且已在约70个人蛋白中得以识别,其经常邻近其他蛋白基序(Jeanmougin F.,等人,TrendsBiochem.Sci.,1997,22,5,151-153;和Tamkun J.W.,等人,Cell,1992,7,3,561-572)。布罗莫结构域和修饰的组蛋白间的相互作用可能是染色质结构改变和基因调节下的重要机制。包含布罗莫结构域的蛋白已牵涉包括癌症、炎症和病毒复制的疾病过程。参见例如Prinjha等人,Trends Pharm.Sci.,33(3):146-153(2012)和Muller等人,Expert Rev.,13(29):1-20(2011年9月)。
细胞类型特异性和适当的组织功能性需要受环境密切影响的不同转录程序的严密控制。该转录动态平衡的改变直接与多种疾病状态相关,尤其是癌症、免疫炎症、神经***病症和代谢性疾病。布罗莫结构域位于发挥控制不同疾病相关转录通路功能的核心染色质修饰复合物中。其通过包含布罗莫结构域的蛋白中的突变与癌症以及免疫和神经***功能异常相关而凸显。因此,贯穿该家族对布罗莫结构域的选择性抑制将创造作为人功能异常的新型治疗剂的各种机会。
对于癌症、免疫学病症和其他布罗莫结构域相关疾病的治疗存在需求。
发明概述
本发明一方面是用于在动物中治疗癌症的方法,其包括施用有效量的CBP/EP300布罗莫结构域抑制剂至动物。
本发明的另一方面是在个体中用于治疗癌症或延迟癌症进展的方法,其包括施用有效量的CBP/EP300布罗莫结构域抑制剂至所述个体。
本发明的一方面是在患有癌症的个体中增强免疫功能的方法,其包括施用有效量的CBP/EP300布罗莫结构域抑制剂。
在一些实施方案中,个体中的CD8 T细胞相对施用CBP/EP300布罗莫结构域抑制剂前具有增强的致敏、活化、增殖和/或细胞杀伤活性。
在一些实施方案中,CD8 T细胞的数目相对施用CBP/EP300布罗莫结构域抑制剂前有所升高。
在一些实施方案中,所述CD8 T细胞是抗原特异性CD8 T细胞。
在一些实施方案中,所述癌症具有升高的T-细胞浸润水平。
在一些实施方案中,所述癌症与增加的肿瘤内Treg细胞密度相关。
在一些实施方案中,所述癌症选自下组:听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性T-细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、子***、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞白血病、慢性髓细胞性白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、不良增生性改变、胚胎性癌、子宫内膜癌、内皮性肉瘤、室管膜瘤、上皮癌、红白血病、食道癌、***受体阳性乳腺癌、原发性血小板增多症、尤因氏瘤(Ewing'stumor)、纤维肉瘤、滤泡型淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、胶质肉瘤、重链病、头颈癌、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感性***癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、***内皮肉瘤、***肉瘤、成淋巴细胞白血病、淋巴瘤、T-细胞或B-细胞来源的淋巴***恶性肿瘤、髓样癌、成神经管细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、髓细胞性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌(NMC)、非小细胞肺癌(NSCLC)、少突神经胶质瘤、口腔癌、骨源性肉瘤、卵巢癌、胰腺癌、***状腺癌、***状癌、松果体瘤、真性红细胞增多症、***癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、***瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、瓦尔登斯特伦巨球蛋白血症(Waldenstrom'smacroglobulinemia)、睾丸肿瘤、子宫癌和维尔姆斯瘤(Wilms'tumor)。
在一些实施方案中,所述癌症是黑素瘤、NSCLC、肾癌、卵巢癌、结肠癌、胰腺癌、肝细胞癌或乳腺癌。
在一些实施方案中,所述癌症是NSCLC、卵巢癌、胰腺癌、肝细胞癌或乳腺癌。
在一些实施方案中,所述癌症是黑素瘤、NSCLC或肾细胞癌。
在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂抑制CBP。
在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂抑制EP300。
在一些实施方案中,所述方法抑制Treg功能。
在一些实施方案中,所述方法减少CD8+T细胞的T细胞衰竭。
在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂不与CBP和/或EP300的HAT结构域结合。
在一些实施方案中,所述个体是人,例如女性或男性。
本发明的一方面是CBP/EP300布罗莫结构域抑制剂,其用于包括疗法的医学治疗或诊断和/或治疗癌症。
本发明的一方面是用于选择抗癌化合物的方法,其包括确定受试化合物是否为CBP/EP300布罗莫结构域抑制剂化合物,其中将为CBP/EP300布罗莫结构域抑制剂的化合物的受试化合物选为抗癌化合物。
在一些实施方案中,本文公开的方法进一步包括确定受试化合物是否与CBP和/或EP300的HAT结构域结合,其中将不与CBP和/或EP300的HAT结构域结合的受试化合物选为抗癌化合物。
在一些实施方案中,所述方法进一步包括确定受试化合物是否抑制Treg功能,其中将抑制Treg功能的受试化合物选为抗癌化合物。
在一些实施方案中,所述方法进一步包括确定受试化合物是否减少CD8+T细胞的T细胞衰竭,其中将减少CD8+T细胞的T细胞衰竭的受试化合物选为抗癌化合物。
在一些实施方案中,CBP/EP300布罗莫结构域抑制剂化合物可包括式I的化合物、其异构体或异构体的混合物(例如,对映异构体)或其药学上可接受的盐、溶剂合物或前药。这种化合物、可用于制备该化合物的方法和中间体以及相应的支持信息描述于Angew.Chem.Int.Ed.,2014,v53,第1-6页。在一些实施方案中,式I的化合物包括:
其中:
X是NH或O;
m是1或2;
n是1或2;
R1独立地选自下组:取代或非取代的C1-C6烷基、取代或非取代的C2-6烯基、取代或非取代的C2-6炔基和取代或非取代的C3-6碳环基;
R2独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2-6烯基和取代或非取代的C2-6炔基;
R3独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2-6烯基和取代或非取代的C2-6炔基;
R4独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2-6烯基和取代或非取代的C2-6炔基;
R5独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基、取代或非取代的C2–6炔基和OC1-C6烷基;
R6独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基、取代或非取代的C2–6炔基和OC1-C6烷基;
R7独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基、取代或非取代的C2–6炔基和OC1-C6烷基;且
R8独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基、取代或非取代的C2–6炔基和OC1-C6烷基;
或其盐。
在一些实施方案中,式I的化合物选自下组:
或其盐。
附图简述
图1.未受过攻击的人T细胞在靶向CBP/EP300的布罗莫结构域的活性化合物或非活性对照化合物存在下于Treg-分化环境下培养。如图1所述,CBP/EP300抑制剂CBP/EP300(1)而不是非活性化合物CBP/EP300(A)减少了生成的FOXP3+细胞数目,如通过流式细胞术所见。
图2.剂量响应曲线使用来自不同化学骨架的示例性活性化合物CBP/EP300(1)和CBP/EP300(2)确定。这些活性化合物而不是非活性化合物CBP/EP300(A)和CBP/EP300(B)以剂量依赖性方式减少了FOXP3+细胞的数目(图2,上图)。活化标志物CD25未受到任何化合物处理的影响,表明这些细胞是功能性的,尽管不能分化成为Treg谱系(图2,下图)。
图3.如图3(上图)所示,人CD8细胞与CBP/EP300(1)而不是非活性化合物的温育导致LAG3、TIM3和CTLA4表达的剂量依赖性减少。使用CBP/EP300(1)抑制CBP/EP300布罗莫结构域未影响CD8细胞中的效应功能,这是由于编码穿孔蛋白、颗粒酶B和EOMES的基因在化合物处理时未发生显著变化(图3,下图)。
图4.如图4所示,效应细胞因子IFN-γ和TNFα的产生未受到化合物处理的影响。
图5.未受过攻击的T细胞的增殖通过染料基于FACS的量化监测。如图5中所示,~50%的未受过攻击的T细胞能够在Treg细胞不存下经CD3/CD28刺激时增殖。然而,当未受过攻击的T细胞与Treg细胞组合时,不足10%能够增殖。与CBP/EP300(1)的温育导致Treg抑制能力的剂量依赖性抑制,如通过相应的能够增殖的未受过攻击的T细胞百分比的增加所见。非活性化合物CBP/EP300(A)无影响,证明了特异性。
图6.抗肿瘤免疫性的生成和调节。肿瘤细胞可规避多种免疫校验点,且本文所述的免疫疗法的目的在于使免疫***再次抵抗癌细胞(参见例如Mellman等人.,Nature,480,480(2011))。
图7.CBP抑制剂CBP/EP300(3)和CBP/EP300(4)以剂量依赖性方式减少iTreg细胞中Foxp3表达。数据显示iTreg分化细胞中Foxp3表达与未刺激的未受过攻击的天然T细胞中相比的倍数变化。
图8.CBP抑制剂CBP/EP300(3)和CBP/EP300(4)减少iTreg细胞中Foxp3蛋白表达。数据显示刺激4天后,使用经DMSO单独作为对照(A)和不同浓度的CBP/EP300(4)(B)或CBP/EP300(3)(C)处理的iTreg分化细胞的Foxp3表达的流式细胞术斑马图。
图9.CBP抑制剂导致Lag3、CTLA4和TIM3表达的剂量依赖性减少。数据显示在经刺激的CD8+T细胞中Lag3、CTLA4和TIM3的表达与未刺激的CD8+T细胞中相比的倍数变化。
图10.CBP抑制剂CBP/EP300(3)和CBP/EP300(4)未影响CD8+T细胞的效应功能。数据显示经刺激的CD8+T细胞中GZMB表达与未刺激的CD8+T细胞中相比的倍数变化。
发明详述
本发明涉及通过使用下列蛋白中的一种或多种中所含的布罗莫结构域的药理学干扰治疗癌症和/或延迟癌症进展的方法:CBP和/或EP300,在本文也称为CBP/EP300。本发明的实施方案涉及对人免疫***的操纵以靶向和消除/减少癌细胞的数目,后文称为癌症免疫疗法。本文所述的发现特别聚焦于T淋巴细胞的两个亚群,即调节性CD4+T细胞(后文称为Treg细胞)和CD8+细胞毒性T细胞(后文称为CD8细胞),这是因为这些细胞被认作是免疫***抗肿瘤活性的核心调节剂。由此,本发明的一些实施方案提供用于在癌症的预防性或治疗性治疗中使用的CBP/EP300布罗莫结构域抑制剂。
定义
本文使用的术语“CBP/EP300布罗莫结构域抑制剂”指与CBP布罗莫结构域和/或EP300布罗莫结构域结合并抑制和/或减少CBP和/或EP300的生物学活性的化合物。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂主要(例如仅仅)通过与CBP布罗莫结构域和/或EP300布罗莫结构域接触和/或相互作用与CBP和/或EP300结合。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂通过与CBP布罗莫结构域和/或EP300布罗莫结构域以及额外的CBP和/或EP300残基和/或结构域接触和/或相互作用与CBP和/或EP300结合。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂基本上或完全抑制CBP和/或EP300的生物学活性。在一些实施方案中,生物学活性是CBP和/或EP300的布罗莫结构域与染色质(例如与DNA相关的组蛋白)和/或另一乙酰化蛋白的结合。在一些实施方案中,抑制剂具有少于约50μM、少于约1μM、少于约500nM、少于约100nM或少于约10nM的IC50或结合常数。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂阻断CBP/EP300活性进而通过由T-细胞的功能异常状态(例如增殖、细胞因子产生、靶细胞杀伤)至抗原刺激恢复功能性响应。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂与CBP布罗莫结构域结合并抑制CBP布罗莫结构域。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂与EP300布罗莫结构域结合并抑制EP300布罗莫结构域。
除非另外表明,本文使用的术语“CBP”和“CREB结合蛋白”指来自任何脊椎动物来源的任何天然CBP,包括哺乳动物诸如灵长类动物(例如人)和啮齿类动物(例如小鼠和大鼠)。该术语涵盖“全长”未加工的CBP以及来自细胞中加工的任何CBP形式。该术语还涵盖天然存在的CBP变体,例如剪切变体或等位基因变体。在一些实施方案中,示例性的人CBP氨基酸序列是UNIPROT Q92793-1。在一些实施方案中,示例性的人CBP氨基酸序列是UNIPROTQ92793-2。在一些实施方案中,示例性的人CBP氨基酸序列示于SEQ ID NO:1。
除非另外表明,本文使用的术语“EP300”和“E1A结合蛋白p300”指来自任何脊椎动物来源的任何天然EP300,包括哺乳动物诸如灵长类动物(例如人)和啮齿类动物(例如小鼠和大鼠)。该术语涵盖“全长”未加工的EP300以及以及任何来自细胞中加工的EP300的形式。该术语还涵盖天然存在的EP300的变体,例如剪切变体或等位基因变体。在一些实施方案中,示例性的人EP300是UNIPROT Q09472。在一些实施方案中,示例性的人EP300的氨基酸序列示于SEQ ID NO:2。
本文使用的术语“可测量的亲和力”和“可测量地抑制”指下列样品间布罗莫结构域活性可测量的减少:(i)包含CBP/EP300布罗莫结构域抑制剂或其组合物和该布罗莫结构域的样品,和(ii)包含该布罗莫结构域而不存在该化合物或其组合物的等同样品。
“药学上可接受的盐”包括酸和碱加成盐两者。能够理解的是当化合物或本文实施例以特定的盐显示时,相应的游离碱以及其他相应的游离碱的盐(包括相应游离碱的药学上可接受的盐)是预期在内的。
“药学上可接受的酸加成盐”指保留游离碱的生物功效和性质且并非为生物学上或其他不期望的由无机酸诸如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸等形成的那些盐,且有机酸可选自脂族、环脂族、芳族、芳脂族、杂环、羧酸和磺酸类的有机酸诸如甲酸、乙酸、丙酸、乙醇酸、葡糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、双羟萘酸、苯乙酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、水杨酸等。
“药学上可接受的碱加成盐”包括源自无机碱诸如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等的那些。具体的碱加成盐为铵、钾、钠、钙和镁盐。源自药学上可接受的有机无毒碱的盐包括伯胺、仲胺和叔胺,包括天然存在的取代胺的取代胺、环胺和碱性离子交换树脂诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙基氨基乙醇、氨基丁三醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。具体的有机非毒性碱为异丙胺、二乙胺、乙醇胺、氨基丁三醇、二环己胺、胆碱和咖啡因。
“溶剂合物”指一种或多种溶剂分子与本发明化合物的缔合物或复合物。溶剂的实例包括水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语"水合物"指其中所述溶剂分子是水的复合物。
术语“药学上可接受的载体、佐剂或媒介物”指使用其配制化合物而不破坏化合物的药理学活性的非毒性的载体、佐剂或媒介物。可用于本发明组合物的药学上可接受的载体、佐剂或媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白诸如人血清白蛋白、缓冲物质诸如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
本文使用的短语“基本上相似”指两数值(一般而言与分子相关的一个和与参照/比较分子相关的另一个)间相似度足够高,由此本领域的技术人员将考虑两个值间的差异在由所述值测量的生物学特性内并非具有显著性差异(例如Kd值)。所述两个值间的差异作为参照/比较值的函数可举例来说少于约20%、少于约10%和/或小于约5%。短语“基本上正常”指与参照基本上相似(例如正常参照)。
短语“基本上不同”指两数值(一般而言与分子相关的一个和与参照/比较分子相关的另一个)间差异程度足够高,由此本领域的技术人员将考虑两个值间的差异在由所述值测量的生物学特性内具有显著性差异(例如Kd值)。所述两个值间的差异作为参照/比较值的函数可举例来说大于约10%、大于约20%、大于约30%、大于约40%和/或大于约50%。
与个体增加的临床益处相关的生物标志物的“存在”、"量"或"水平"是生物样品中可检测的水平。这些可通过本领域的技术人员已知以及本文公开的方法测量。评估的生物标志物的表达水平或量可用于确定对治疗的响应。
一般而言术语"表达的水平"或"表达水平"可交换使用且一般指生物样品中生物标志物的量。"表达"一般指通过其信息(例如基因编码的和/或表观遗传的)转化成为细胞中存在和操作的结构的过程。因此本文使用的"表达"可指转录成为多核苷酸、翻译成为多肽或甚至多核苷酸和/或多肽修饰(例如多肽的翻译后修饰)。还将转录的多核苷酸、翻译的多肽或多核苷酸和/或多肽修饰(例如多肽的翻译后修饰)的片段视作表达的,无论其源自通过选择性剪接或降解转录物或例如通过蛋白水解来自多肽的翻译后加工生成的转录物与否。"表达的基因"包括转录成为mRNA的多核苷酸且随后翻译成为多肽的那些,以及转录成为RNA但不翻译成为多肽的那些(例如转移和核糖体RNA)。
“升高的表达”、“升高的表达水平”或“升高的水平”指个体中相比对照(诸如未罹患疾病或病症(例如癌症)的个体或多个个体或内部对照(例如管家基因))生物标志物增加的表达或增加的水平。
“减少的表达”、“减少的表达水平”或“减少的水平”指个体中相比对照(诸如未罹患疾病或病症(例如癌症)的个体或多个个体或内部对照(例如管家基因))生物标志物减少的表达或减少的水平。
术语“管家生物标志物”指生物标志物或生物标志物组(例如多核苷酸和/或多肽),其通常在全部细胞类型中相似地存在。在一些实施方案中,管家生物标志物是“管家基因”。“管家基因”在本文指编码活性对于维持细胞功能为必需且通常在全部细胞类型中相似存在的蛋白的基因或基因组。
本文使用的术语“样品”指源自包含待表征和/或识别(例如基于物理、生化、化学和/或生理特性)的细胞和/或其他分子实体的感兴趣的受试者和/或个体或从其获得的组合物。举例来说,短语“疾病样品”和其变化指从预期或已知包含待表征的细胞和/或分子实体的感兴趣的受试者获得的任何样品。样品包括但不限于原代或培养的细胞或细胞系、细胞上清、细胞裂解物、血小板、血清、血浆、玻璃体液、淋巴液、滑液、滤泡液、***、羊膜液、乳、全血、源自血的细胞、尿、脑脊髓液、唾液、痰、泪液、汗液、粘液、肿瘤裂解物和组织培养基、组织提取物诸如匀浆的组织、肿瘤组织、细胞提取物及其组合。
"组织样品”或“细胞样品"意为从受试者或个体的组织获得的相似细胞的集合。组织或细胞样品的来源可以是实体组织如来自新鲜、冷冻和/或保存的器官、组织样品、活检和/或吸出物;血液或任何血液组分诸如血浆;体液诸如脑脊液、羊水、腹膜液或间质液;来自受试者妊娠或发育中任何时间的细胞。组织样品还可以是原代或培养的细胞或细胞系。任选地,所述组织或细胞样品从疾病组织/器官获得。所述组织样品可包含并非天然与组织原本混合的化合物诸如防腐剂、抗凝剂、缓冲剂、固定剂、营养物、抗生素等。
本文使用的“参照样品”、“参照细胞”、“参照组织”、“对照样品”、“对照细胞”或“对照组织”指用于比较目的的样品、细胞、组织、标准或水平。在一个实施方案中,参照样品、参照细胞、参照组织、对照样品、对照细胞或对照组织从相同受试者或个体机体的健康和/或非疾病部分(例如组织或细胞)获得。举例来说,与疾病细胞或组织邻近的健康和/或非疾病细胞或组织(例如与肿瘤邻近的细胞或组织)。在另一个实施方案中,参照样品从相同受试者或个体机体的未治疗组织和/或细胞获得。在另一实施方案中,参照样品、参照细胞、参照组织、对照细胞或对照组织从非受试者或个体的个体机体的健康和/或非疾病部分(例如组织或细胞)获得。在另一实施方案中,参照样品、参照细胞、参照组织、对照样品、对照细胞或对照组织从非受试者或个体的个体机体的未治疗组织和/或细胞获得。
就本文而言,组织样品“切片”意为组织样品的单一部分或片,例如从组织样品切下的组织或细胞薄片。假设理解组织样品的相同切片可在形态学和分子水平都进行分析,或对于多肽或多核苷酸进行分析,可以理解的是可取得组织样品的多重切片并对其进行分析。
“关联”或“相关”意为以任何方式对第一分析或方案的实施和/或结果与第二分析或方案的实施和/或结果进行比较。举例来说,实施者可将第一分析或方案的结果用于实施第二方案和/或实施者可使用第一分析或方案的结果以确定是否实施第二分析或方案。对于多核苷酸分析或方案的实施方案,实施者可使用多核苷酸表达分析或方案以确定是否实施特定的治疗方案。
药剂例如药物制剂的"有效量"指以剂量和持续所需时间的时段实现预期的治疗或预防结果的量。在一些实施方案中,有效量指(i)治疗特定疾病、病况或病症,(ii)衰减、改善或消除特定疾病、病况或病症的一种或多种症状或(iii)预防或延迟本文所述特定疾病、病况或病症的一种或多种症状发作的CBP/EP300布罗莫结构域抑制剂的量。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂的有效量可减少癌细胞的数目;减少肿瘤大小;抑制(即在某种程度上减缓且优选终止)癌细胞浸润至周边器官;抑制(即在某种程度上减缓且优选终止)肿瘤转移;在某种程度上抑制肿瘤生长和/或在某种程度上缓解一种或多种与癌症相关的症状。对于癌症疗法,效力可例如通过评估疾病进展的时间(TTP)和/或确定响应率(RR)进行测量。在免疫***病症的情况中,治疗有效量是足以减少或缓解过敏病症、自身免疫和/或炎症疾病的症状或急性炎症反应的症状(例如哮喘)的量。在一些实施方案中,有效量是足以显著减少耐药或持续耐药癌细胞的活性或数目的本文所述化学实体的量。
免疫功能障碍上下文中的术语"功能障碍"指对抗原性刺激减少的免疫响应状态。该术语包括衰竭(exhaustion)和/或无能(anergy)两者的共同元素,其中抗原识别可发生,但确保免疫响应不足以控制感染或肿瘤生长。
本文使用的术语"功能障碍的"还包括对抗原识别耐受或不响应,具体地,受损的将抗原识别翻译成下游T-细胞效应功能诸如分化、细胞因子产生(例如IL-2)和/或靶细胞杀伤的能力。
术语"无能"指由于通过T-细胞受体递送的不完全或不足信号导致的对抗原刺激不响应的状态(例如无ras-活化的细胞内Ca+2增加)。T细胞无能还可在当无共同刺激存在时施用抗原的刺激时发生,导致即使在共刺激存在背景下细胞对随后通过抗原的活化耐受。不响应状态可经常通过白细胞介素-2的存在而改写。无能T-细胞不经历克隆扩增和/或需要效应功能。
术语"衰竭"指T细胞衰竭,作为T细胞功能障碍的状态其由在许多慢性感染和癌症过程中发生的维持的TCR信号产生。衰竭与无能不同在于其不通过不完全或缺陷信号传导但由维持的信号传导产生。衰竭通过不良的效应功能、抑制受体的维持表达和不同于功能效应器或记忆T细胞的转录状态限定。衰竭阻止对感染和肿瘤的最佳控制。衰竭可由外在的负调节通路(例如免疫调节性细胞因子)以及细胞的内在负调节(共刺激)通路(PD-1、B7-H3、B7-H4等)两者导致。
“增强的T-细胞功能”意为诱导、引发或刺激T-细胞以具有维持的或扩大的生物学功能,或更新或再次活化的衰竭或非活化T-细胞。增强的T-细胞功能实例包括:相对干预前的这些水平增加的来自CD8+T-细胞的γ-干扰素的分泌、增加的增殖、增加的抗原响应(例如清除)。在一个实施方案中,增强的水平为至少50%,可替换地60%、70%、80%、90%、100%、120%、150%、200%。测量该增强的方式为本领域的普通技术人员已知。
“T细胞功能障碍病症”是T细胞的病症或病况,其通过对抗原性刺激减少的响应表征。在具体的实施方案中,T-细胞功能障碍病症是特异性与不适当的CBP和/或EP300活性相关的病症。在另一实施方案中,T-细胞功能障碍病症是一种其中T-细胞无能或具有减少的分泌增殖或执行细胞杀伤活性的细胞因子能力的病症。在特定的方面中,减少的响应导致表达免疫原的病原或肿瘤无效的控制。由T细胞功能障碍表征的T细胞功能障碍病症的实例包括肿瘤免疫力。
“肿瘤免疫力”指其中肿瘤规避免疫识别和清除的过程。因此,作为治疗概念,当该规避减弱时肿瘤免疫力“受到治疗”,且肿瘤由免疫***识别并攻击。肿瘤识别的实例包括肿瘤结合、肿瘤萎缩和肿瘤清除。
"免疫原性"指特定物质刺激免疫响应的能力。肿瘤是免疫原性的且增强肿瘤免疫原性有助于在通过免疫响应清除肿瘤细胞。
"持续响应"指治疗终止后持续的减少肿瘤生长的效应。举例来说,可保持肿瘤大小以与施用阶段初始时的大小相同或更小。在一些实施方案中,持续的响应具有至少与治疗持续时间相同、至少为治疗持续时间的1.5X、2.0X、2.5X或3.0X长的持续时间。
“治疗”(和变化诸如“进行治疗”或“进行的”)指尝试改变进行治疗的个体或细胞的天然过程的临床干预,且可用于预防或在临床病理过程中。治疗的预期效果包括一种或多种预防疾病发生或复发、减轻症状、消除任何直接或间接的疾病病理性后果、稳定疾病状态(即不使其恶化)、预防转移、减少疾病进展速率、改善或缓解疾病状态、与不接受治疗的预期生存率相比延长生存率和缓解或改善的预后。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂用于延迟疾病或病症的发展或减缓疾病或病症的进展。需要治疗的那些个体包括已患有病况或病症的那些以及易患有所述病况或病症的那些(例如通过基因突变或基因或蛋白的异常表达)或其中所述病况或病症有待预防的那些。
本文使用的"延迟疾病进展"意为推迟、阻碍、减缓、延缓、稳定和/或延迟疾病(诸如癌症)的发展。该延迟可以是不同的时间长度,取决于病史和/或待治疗的个体。对本领域技术人员显而易见的是,足够或显著的延迟可实际上涵盖在不发展所述疾病的个体中的预防。举例来说,晚期癌症诸如转移的发展可延迟。
本文使用的术语“患者”或“个体”指动物,诸如哺乳动物,诸如人。在一个实施方案中,患者或个体指人。
本文使用的术语"细胞毒性剂"指抑制或预防细胞功能和/或引起细胞死亡或毁灭的物质。细胞毒性剂包括但不限于放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素);化疗剂;生长抑制剂;酶及其片段诸如核酸水解;和毒素诸如小分子毒素或细菌、真菌、植物或动物来源的酶活性毒素,包括其片段和/或变体。示例性的细胞毒性剂可选自抗微管剂、铂配位复合物、烷化剂、抗生素剂、拓扑异构酶II抑制剂、抗代谢物、拓扑异构酶I抑制剂、激素和激素类似物、信号转导通路抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、LDH-A抑制剂;脂肪酸生物合成抑制剂;细胞周期信号传导抑制剂;HDAC抑制剂、蛋白酶体抑制剂;和癌症代谢抑制剂。
在一个实施方案中,细胞毒性剂选自抗微管剂、铂配位复合物、烷化剂、抗生素制剂、拓扑异构酶II抑制剂、抗代谢物、拓扑异构酶I抑制剂、激素和激素类似物、信号转导通路抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、LDH-A抑制剂;脂肪酸生物合成抑制剂;细胞周期信号传导抑制剂;HDAC抑制剂、蛋白酶体抑制剂;和癌症代谢抑制剂。在一个实施方案中,所述细胞毒性剂是紫杉烷。在一个实施方案中,所述紫杉烷是紫杉醇或多西紫杉醇。在一个实施方案中,所述细胞毒性剂是铂制剂。在一个实施方案中,所述细胞毒性剂是EGFR的拮抗剂。在一个实施方案中,所述EGFR的拮抗剂是N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺(例如厄洛替尼(erlotinib))。在一个实施方案中,所述细胞毒性剂是RAF抑制剂。在一个实施方案中,所述RAF抑制剂是BRAF和/或CRAF抑制剂。在一个实施方案中,所述RAF抑制剂是维罗非尼(vemurafenib)。在一个实施方案中,所述细胞毒性剂是PI3K抑制剂。
"化疗剂"包括治疗癌症中有效的化学化合物。化疗剂的实例包括厄洛替尼(Genentech/OSI Pharm.)、硼替佐米(bortezomib)(Millennium Pharm.)、双硫仑、儿茶素酸酯、salinosporamide A、卡菲偌米布(carfilzomib)、17-AAG(格尔德霉素(geldanamycin))、根赤壳菌素(radicicol)、乳酸脱氢酶A(LDH-A)、氟维司群(fulvestrant)(AstraZeneca)、舒尼替尼(sunitib)(Pfizer/Sugen)、来曲唑(letrozole)(Novartis)、甲磺酸伊马替尼(imatinib mesylate)(Novartis)、finasunate(Novartis)、奥沙利铂(oxaliplatin)(Sanofi)、5-FU(5-氟尿嘧啶)、亚叶酸钙、雷帕霉素(Sirolimus,Wyeth)、拉帕替尼(Lapatinib)(GSK572016,Glaxo Smith Kline)、Lonafamib(SCH 66336)、索拉非尼(sorafenib)(Bayer Labs)、gefitinib(AstraZeneca)、AG1478、烷化基诸如噻替哌和环磷酰胺;烷基磺酸盐诸如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶包括苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙烯亚胺和甲基蜜胺(methylamelamine)包括六甲密胺、三亚胺嗪、三亚乙基磷酰胺、三亚乙基硫化磷酰胺和三羟甲基蜜胺(trimethylomelamine);番荔枝内酯类化合物(尤其是布拉它辛和布拉它辛酮);喜树碱(包括拓扑替康和伊立替康);苔藓抑素;callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成性类似物);cryptophycin类化合物(特别是cryptophycin 1和cryptophycin 8);肾上腺皮质激素(包括***和***龙);乙酸环丙孕酮;5α-还原酶包括非那雄胺和度他雄胺);伏立诺他、罗米地辛、帕比司他、丙戊酸,mocetinostat dolastatin;阿地白介素(aldesleukin);talcduocarmycin(包括合成性类似物KW-2189和CB1-TM1);艾槽塞洛素;pancratistatin;sarcodictyin;spongistatin;氮芥类化合物诸如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、双氯乙基甲胺、盐酸氧氮芥、美法仑、新氮芥、苯芥胆留醇、泼尼莫司汀、曲磷胺、尿嘧啶氮芥;硝基脲类化合物诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫斯汀和雷莫司汀;抗生素诸如烯二炔抗生素(例如刺孢霉素尤其是刺孢霉素γ1I和刺孢霉素ω1I(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);蒽环类抗生素,包括dynemicin A;二膦酸盐诸如氯膦酸盐;埃斯培拉霉素;以及新抑癌蛋白生色团和相关色蛋白烯二炔抗生素生色团、aclacinomysin、放线菌素、authramycin、偶氮丝氨酸、博来霉素、放线菌素C、carabicin、去甲柔红霉素、嗜癌素、色霉素、放线菌素D、柔红霉素、地拖比星、6-重氮基-5-氧代-L-正亮氨酸、(多柔比星)、吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉子基-多柔比星和去氧多柔比星、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素诸如丝裂霉素C、麦考酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素、嘌罗霉素、三铁阿霉素、罗多比星、链黑霉素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢剂诸如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物诸如二甲叶酸、甲氨喋呤、喋罗呤、三甲曲沙;嘌呤类似物诸如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物诸如安西他滨、阿扎胞苷、6-氮鸟苷、卡莫氟、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、伊诺他滨、氟尿苷;雄激素诸如卡普睾酮、丙酸甲雄烷酮、环硫雄醇、美雄烷、睾内酯;抗肾上腺药物诸如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂诸如亚叶酸;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;伊达曲杀;地磷酰胺;秋水仙胺;地吖醌;elfomithine;依利醋铵;埃坡霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明;美登醇类化合物诸如美登素和安丝菌素;米托胍腙;米托蒽醌;mopidanmol;根瘤菌剂;喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基肼;丙卡巴肼;多糖复合物(JHSNatural Products,Eugene,OR);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”-三氯三乙胺;单端孢菌毒素(尤其是T-2毒素、verracurinΑ、杆孢菌素A和anguidine);乌拉坦;长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;gacytosine;阿糖胞苷(“Ara-C”);环磷酰胺;塞替派;紫杉烷例如(紫杉醇)(Bristol-Myers Squibb Oncology,Princeton,N.J.)、(不含Cremophor)、紫杉醇的白蛋白工程化纳米粒制剂(American Pharmaceutical Partners,Schaumberg,Ill.)和(多西紫杉醇)(Sanofi-Aventis);苯丁酸氮芥;(吉西他滨);6-硫代鸟嘌呤;巯嘌呤;甲氨喋呤;铂类似物诸如顺铂和卡铂;长春碱;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;(长春瑞滨);诺消灵;替尼泊苷;伊达曲杀;柔红霉素;氨基喋呤;卡培他滨伊班膦酸盐;CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄醇诸如视黄酸;及上述任何物质的药学上可接受的盐、酸和衍生物。
化疗剂还包括(i)调节或抑制激素对肿瘤作用的抗激素剂诸如抗***和选择性***受体调节剂(SERM),包括例如他莫昔芬(tamoxifen)(包括枸橼酸他莫昔芬)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、吲哚昔芬(iodoxyfene)、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、屈洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和(枸橼酸托瑞米芬);(ii)抑制芳香化酶的芳香化酶抑制剂,其在肾上腺中调节***的产生,如举例来说4(5)-咪唑、氨鲁米特、(乙酸甲地孕酮)、(依西美坦;Pfizer)、福美司坦(formestanie)、法倔唑(fadrozole)、(伏氯唑)、(来曲唑;Novartis)和(阿那曲唑;AstraZeneca);(iii)抗雄激素诸如氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、乙酸亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);布舍瑞林(buserelin)、tripterelin、乙酸甲羟孕酮(medroxyprogesteroneacetate)、己烯雌酚(diethylstilbestrol)、普力马(premarin)、氟***(fluoxymesterone)、全反维甲酸、芬维A胺(fenretinide)以及曲沙他滨(troxacitabine)(1,3-二氧六环胞嘧啶核苷类似物);(iv)蛋白激酶抑制剂;(v)脂质激酶抑制剂;(vi)反义寡核苷酸,特别是抑制参与异常细胞增殖信号传导通路的基因表达的那些,如举例来说PKC-α、Ralf和H-Ras;(vii)核酶诸如VEGF表达抑制剂(例如)和HER2表达抑制剂;(viii)疫苗诸如基因疗法疫苗,例如 和rIL-2;拓扑异构酶1抑制剂诸如rmRH;和(ix)上述任何的药学上可接受的盐、酸和衍生物。
化疗剂还包括抗体如阿仑珠单抗(alemtuzumab)(Campath)、贝伐珠单抗(Genentech);西妥昔单抗(Imclone);帕尼单抗(Amgen)、利妥昔单抗(Genentech/Biogen Idee)、帕妥珠单抗(2C4,Genentech)、曲妥珠单抗(Genentech)、托西莫单抗(Bexxaar,Corixia)和所述抗体的药物偶联物,吉妥珠单抗奥佐米星(Wyeth)。具有作为与本发明化合物组合的药剂的治疗潜力的其他人源化单克隆抗体包括:阿泊珠单抗(apolizumab)、阿塞珠单抗(aselizumab)、atlizumab、巴匹珠单抗(bapineuzumab)、bivatuzumab mertansine、莫坎妥珠单抗(cantuzumab mertansine)、西利珠单抗(cedeIizumab)、培舍珠单抗(certolizumab pegol)、cidfusituzumab、cidtuzumab、达克珠单抗(daclizumab)、依库珠单抗(eculizumab)、依法珠单抗(efalizumab)、依帕珠单抗(epratuzumab)、厄利珠单抗(erlizumab)、非维珠单抗(felvizumab)、芳妥珠单抗(fontolizumab)、吉妥珠单抗奥佐米星(gemtuzumabozogamicin)、英妥珠单抗奥佐米星(inotuzumab ozogamicin)、伊匹木单抗(ipilimumab)、拉贝珠单抗(labetuzumab)、林妥珠单抗(lintuzumab)、马妥珠单抗(matuzumab)、美泊利单抗(mepolizumab)、莫维珠单抗(motavizumab)、motovizumab、那他珠单抗(natalizumab)、尼妥珠单抗(nimotuzumab)、nolovizumab、numavizumab、ocrelizumab、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕考珠单抗(pascolizumab)、pecfusituzumab、pectuzumab、培克珠单抗(pexelizumab)、ralivizumab、雷珠单抗(ranibizumab)、reslivizumab、瑞利珠单抗(reslizumab)、resyvizumab、罗维珠单抗(rovelizumab)、卢利珠单抗(ruplizumab)、西罗珠单抗(sibrotuzumab)、西利珠单抗(siplizumab)、索土珠单抗(sontuzumab)、tacatuzumab tetraxetan、tadocizumab、他利珠单抗(talizumab)、特非珠单抗(tefibazumab)、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、tucotuzumab西莫白介素(tucotuzumab celmoleukin)、tucusituzumab、umavizumab、乌珠单抗(urtoxazumab)、优特克单抗(ustekinumab)、维西珠单抗(visilizumab),和抗白细胞介素-12(ABT-874/J695,Wyeth Research and Abbott Laboratories),其为经遗传修饰以识别白细胞介素-12p40蛋白的重组专有人序列全长IgG1λ抗体。
化疗剂还包括“EGFR抑制剂”,其指结合EGFR或以其他方式直接与EGFR相互作用并抑制或降低其信号传导活性的化合物,且其可替换地称为“EGFR拮抗剂”。这种药剂的实例包括结合EGFR的抗体和小分子。结合EGFR的抗体的实例包括MAb579(ATCC CRL HB8506)、MAb455(ATCC CRL HB8507)、MAb225(ATCC CRL8508)、MAb528(ATCCCRL8509)(参见美国专利号4,943,533,Mendelsohn等人)及其变体诸如嵌合的225(C225或西妥昔单抗;)和重构的人225(H225)(参见W096/40210,Imclone Systerms Inc.);MC-11F8,其为完全的人EGFR靶向抗体(Imclone);结合II型突变体EGFR的抗体(美国专利号5,212,290);结合EGFR的人源化和嵌合抗体,如美国专利号5,891,996中所述;和结合EGFR的人抗体,诸如ABX-EGF或帕尼单抗(Panitumumab)(参见WO98/50433,Abgenix/Amgen);EMD55900(Stragliotto等人,Eur.J.Cancer 32A:636-640(1996));EMD7200(matuzumab),其为针对EGFR且与EGF和TGF-α竞争EGFR结合的人源化EGFR抗体(EMD/Merck);人EGFR抗体,HuMax-EGFR(GenMab);称为E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3和E7.6.3且描述在6,235,883中的完全人抗体;MDX-447(Medarex Inc);和mAb806或人源化mAb806(Johns等人,J.Biol.Chem.279(29):30375-30384(2004))。抗EGFR抗体可与细胞毒性剂偶联,由此产生免疫偶联物(参见例如EP659,439A2,Merck Patent GmbH)。EGFR拮抗剂包括小分子,诸如美国专利号5,616,582、5,457,105、5,475,001、5,654,307、5,679,683、6,084,095、6,265,410、6,455,534、6,521,620、6,596,726、6,713,484、5,770,599、6,140,332、5,866,572、6,399,602、6,344,459、6,602,863、6,391,874、6,344,455、5,760,041、6,002,008和5,747,498以及下列PCT公开WO98/14451、WO98/50038、WO99/09016和WO99/24037中所述的化合物。具体的小分子EGFR拮抗剂包括OSI-774(CP-358774,厄洛替尼(erlotinib),(Genentech/OSI Pharmaceuticals);PD 183805(CI1033,2-丙烯酰胺,N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(4-吗啉基)丙氧基]-6-喹唑啉基]-,二盐酸盐,Pfizer Inc.);ZD1839、吉非替尼4-(3’-氯-4’-氟苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑琳,Zeneca);ZM105180((6-氨基-4-(3-甲基苯基-氨基)-喹唑啉,Zeneca);BIBX-1382(N8-(3-氯-4-氟-苯基)-N2-(1-甲基-哌啶-4-基)-嘧啶并[5,4-d]嘧啶-2,8-二胺,BoehringerIngelheim);PKI-166((R)-4-[4-[(1-苯基乙基)氨基]-1H-吡略并[2,3-d]嘧啶-6-基]-苯酚);(R)-6-(4-羟基苯基)-4-[(1-苯基乙基)氨基]-7H-吡咯并[2,3-d]嘧啶);CL-387785(N-[4-[(3-溴苯基)氨基]-6-喹唑啉基]-2-丁炔酰胺);EKB-569(N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]-4-(二甲氨基)-2-丁烯酰胺)(Wyeth);AG1478(Pfizer);AG1571(SU 5271;Pfizer);双重EGFR/HER2酪氨酸激酶抑制剂诸如拉帕替尼(lapatinib)(GSK572016或N-[3-氯-4-[(3-氟苯基)甲氧基]苯基]-6[5[[[2-甲基磺酰基)乙基]氨基]甲基]-2-呋喃基]-4-喹唑啉胺)。
化疗剂还包括“酪氨酸激酶抑制剂”,其包括前文中提到的EGFR靶向药物;小分子HER2酪氨酸激酶抑制剂,诸如可从Takeda获得的TAK165;CP-724,714,其为一种口服ErbB2受体酪氨酸激酶选择性抑制剂(Pfizer和OSI);优先结合EGFR但抑制HER2和EGFR过表达细胞的双重HER抑制剂,诸如EKB-569(可从Wyeth获得);拉帕替尼(lapatinib)(GSK572016;可从Glaxo-SmithKline获得),其为一种口服HER2和EGFR酪氨酸激酶抑制剂;PKI-166(可从Novartis获得);pan-HER抑制剂,诸如canertinib(C1-1033;Pharmacia);Raf-1抑制剂,如可从ISIS Pharmaceuticals获得的、抑制Raf-1信号传导的反义药剂ISIS-5132;非-HER靶向TK抑制剂,诸如甲磺酸伊马替尼(可从Glaxo SmithKline获得);多靶标酪氨酸激酶抑制剂诸如舒尼替尼(可从Pfizer获得);VEGF受体酪氨酸激酶抑制剂诸如瓦他拉尼(vatalanib)(PTK787/ZK222584,可从Novartis/Schering AG获得);MAPK胞外调控激酶I抑制剂C1-1040(可从Pharmacia获得);喹唑啉类,诸如PD153035,4-(3-氯苯胺基)喹唑啉;吡啶并嘧啶类;嘧啶并嘧啶类;吡咯并嘧啶类,诸如CGP 59326、CGP 60261和CGP 62706;吡唑并嘧啶类,4-(苯基氨基)-7H-吡咯并[2,3-d]嘧啶类;姜黄素(二阿魏酰甲烷,4,5-双(4-氟苯胺基)-酞酰亚胺);含tyrphostines的硝基噻吩部分;PD-0183805(Warner-Lamber);反义分子(例如那些与编码HER的核酸结合的反义分子);喹喔啉类(美国专利号5,804,396);tryphostins(美国专利号5,804,396);ZD6474(Astra Zeneca);PTK-787(Novartis/Schering AG);pan-HER抑制剂诸如C1-1033(Pfizer);Affinitac(ISIS3521;Isis/Lilly);甲磺酸伊马替尼PKI 166(Novartis);GW2016(Glaxo SmithKline);CI-1033(Pfizer);EKB-569(Wyeth);Semaxinib(Pfizer);ZD6474(Astra Zeneca);PTK-787(Novartis/Schering AG);INC-1C11(Imclone),雷帕霉素(西罗莫司,);或下列任何专利公开中所描述的药剂:美国专利号5,804,396;WO1999/09016(American Cyanamid);WO1998/43960(American Cyanamid);WO1997/38983(Warner Lambert);WO1999/06378(Warner Lambert);WO1999/06396(WarnerLambert);WO1996/30347(Pfizer,Inc);WO1996/33978(Zeneca);WO1996/3397(Zeneca)和WO1996/33980(Zeneca)。
化疗剂还包括***、干扰素、秋水仙素、氯苯氨啶(metoprine)、环孢菌素、两性霉素、甲硝唑、阿仑单抗(alemtuzumab)、阿利维A酸(alitretinoin)、别嘌呤醇、氨磷汀、三氧化二砷、天冬酰胺酶、活卡介苗(BCG live)、贝伐单抗(bevacuzimab)、贝沙罗汀(bexarotene)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、α达贝泊汀(darbepoetinalfa)、地尼白介(denileukin)、右雷佐生(dexrazoxane)、α依伯汀(epoetin alfa)、厄洛替尼(elotinib)、非格司亭(filgrastim)、乙酸组氨瑞林(histrelin acetate)、替伊莫单抗(ibritumomab)、干扰素α-2a、干扰素α-2b、来那度胺(lenalidomide)、左旋咪唑(levamisole)、美司钠(mesna)、甲氧沙林(methoxsalen)、诺龙(nandrolone)、奈拉滨(nelarabine)、若莫单抗(nofetumomab)、奥普瑞白介素(oprelvekin)、palifermin、帕米(pamidronate)、甲氧聚乙二醇琥珀酰胺腺苷脱氨酶(pegademase)、培门冬酶(pegaspargase)、培非司亭(pegfilgrastim)、培美曲塞二钠(pemetrexed disodium)、普卡霉素(plicamycin)、卟吩姆钠(porfimer sodium)、奎纳克林(quinacrine)、拉布立酶(quinacrine)、沙格司亭(sargramostim)、替莫唑胺(temozolomide)、VM-26、6-TG、托瑞米芬(toremifene)、维甲酸(tretinoin)、ATRA、戊柔比星(valrubicin)、唑来膦酸盐(zoledronate)和唑来膦酸(zoledronic acid),及其药学上可接受的盐。
化疗剂还包括氢化可的松、乙酸氢化可的松、乙酸可的松、戊酸替可的松新(tixocortol pivalate)、曲安奈德(triamcinolone acetonide)、曲安西龙醇(triamcinolone alcohol)、莫米松(mometasone)、安西缩松(amcinonide)、布***(budesonide)、***(desonide)、氟轻松乙酸酯(fluocinonide)、氟轻松(fluocinoloneacetonide)、倍他米松(betamethasone)、倍他米松磷酸钠(betamethasone sodiumphosphate)、***(dexamethasone)、***磷酸钠(dexamethasone sodiumphosphate)、氟可龙(fluocortolone)、氢化可的松-17-丁酸酯(hydrocortisone-17-butyrate)、氢化可的松-17-戊酸酯(hydrocortisone-17-valerate)、阿氯米松二丙酸酯(aclometasone dipropionate)、倍他米松戊酸酯(betamethasone valerate)、倍他米松二丙酸酯(betamethasone dipropionate)、***(prednicarbate)、氯倍他松-17-丁酸酯(clobetasone-17-butyrate)、氯倍他索-17-丙酸酯(clobetasol-17-propionate)、己酸氟可龙(fluocortolone caproate)、特戊酸氟可龙(fluocortolone pivalate)和乙酸氟泼尼定(fluprednidene acetate);免疫选择性抗炎症肽(ImSAID)诸如苯丙氨酸-谷氨酰胺-甘氨酸(FEG)及其D-异构体形式(feG)(IMULAN BioTherapeutics,LLC);抗风湿药诸如硫唑嘌呤、环孢素(环孢素A)、D-青霉胺、金盐、羟氯喹、来氟米特(leflunomide)米诺环素(minocycline)、柳氮磺胺吡啶(sulfasalazine)、肿瘤坏死因子α(TNFα)阻断剂诸如依那西普(etanercept)(Enbrel)、英利昔单抗(infliximab)(Remicade)、阿达木单抗(adalimumab)(Humira)、certolizumab pegol(Cimzia)、戈利木单抗(golimumab)(Simponi)、白细胞介素1(IL-1)阻断剂诸如阿那白滞素(anakinra)(Kineret)、T细胞共刺激阻断剂诸如阿贝西普(Orencia)、白细胞介素6(IL-6)阻断剂诸如托珠单抗(tocilizumab)白细胞介素13(IL-13)阻断剂诸如lebrikizumab;干扰素α(IFN)阻断剂诸如Rontalizumab;β7整合素阻断剂诸如rhuMAbβ7;IgE通路阻断剂诸如抗-M1';分泌的同源三聚体LTa3和膜结合异源三聚体LTa1/β2阻断剂诸如抗-淋巴毒素α(LTa);放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素);各类研究性药剂诸如thioplatin、PS-341、丁酸苯酯、ET-18-OCH3或法尼基转移酶抑制剂(L-739749、L-744832);多酚诸如槲皮素、白藜芦醇、白皮杉醇、表没食子儿茶素没食子酸酯(epigallocatechine gallate)、茶黄素、黄烷醇、原花青素、白桦脂酸及其衍生物;自吞噬抑制剂诸如喹;δ-9-四氢***酚(屈***酚,);β-拉帕醌(beta-lapachone);拉帕醇(lapachol);秋水仙素;桦木酸;乙酰喜树碱、scopolectin和9-氨基喜树碱);鬼臼毒素;替加氟(tegafur)蓓萨罗丁(bexarotene)双膦酸盐诸如氯膦酸盐(例如或)、依替膦酸钠NE-58095、唑来膦酸/唑来膦酸盐阿仑膦酸钠帕米膦酸二钠(pamidronate)替鲁膦酸钠(tiludronate)或利塞膦酸钠(risedronate)和表皮生长因子受体(EGF-R);疫苗诸如疫苗;哌立福辛(perifosine)、COX-2抑制剂(例如塞来昔布(celecoxib)或依托昔布(etoricoxib))、蛋白酶体抑制剂(例如PS341);CCI-779;tipifarnib(R11577);orafenib、ABT510;Bcl-2抑制剂诸如奥利默森钠(oblimersensodium)pixantrone;法尼基转移酶抑制剂诸如onafarnib(SCH 6636,SARASARTM)和上述任何的药学上可接受的盐、酸或衍生物;以及两种或多种上述药剂的组合,诸如CHOP(环磷酰胺、阿霉素、长春新碱和***龙组合疗法的缩写);和FOLFOX(奥沙利铂(ELOXATINTM)与5-FU和亚叶酸钙组合的治疗方案的缩写)。
化疗剂还包括具有镇痛、解热和抗炎作用的非甾体类抗炎药。NSAID包括环氧合酶的非选择性抑制剂。NSAID的具体实例包括阿司匹林;丙酸衍生物诸如布洛芬(ibuprofen)、非诺洛芬(fenoprofen)、酮洛芬(ketoprofen)、氟比洛芬(flurbiprofen)、奥沙普秦(oxaprozin)和萘普生(naproxen);乙酸衍生物诸如吲哚美辛(indomethacin)、舒林酸(sulindac)、依托度酸(etodolac)、双氯芬酸(diclofenac);烯醇酸衍生物诸如炎痛昔康(piroxicam)、美洛昔康(meloxicam)、替诺昔康(tenoxicam)、屈噁昔康(droxicam)、氯诺昔康(lornoxicam)和伊索昔康(isoxicam);灭酸衍生物诸如甲芬那酸(mefenamic acid)、甲氯芬那酸(meclofenamic acid)、氟芬那酸(flufenamic acid)、托芬那酸(tolfenamicacid);和COX-2抑制剂诸如塞来昔布(celecoxib)、依托昔布(etoricoxib)、罗美昔布(lumiracoxib)、帕瑞昔布(parecoxib)、罗非昔布(rofecoxib)、罗非昔布(rofecoxib)和伐地昔布(valdecoxib)。NSAID可适用于病况的症状性缓解,诸如类风湿关节炎、骨关节炎、炎性关节病、强直性脊柱炎、银屑病关节炎、莱特尔氏综合征(Reiter's syndrome)、急性痛风、痛经、转移性骨痛、头痛和偏头痛、手术后疼痛、由于炎症和组织损伤的轻度至中度疼痛、发热、肠梗阻和肾绞痛。
术语"PD-1轴结合拮抗剂"是抑制PD-1轴结合伴侣与一种或多种其结合伴侣的相互作用的分子,进而去除由对PD-1信号传导轴上的信号导致的T-细胞功能障碍—结果将恢复或增强T-细胞功能(例如增殖、细胞因子产生、靶细胞杀伤)。如本文使用,PD-1轴结合拮抗剂包括PD-1结合拮抗剂、PD-L1结合拮抗剂和PD-L2结合拮抗剂。
术语"PD-1结合拮抗剂"是减少、阻断、抑制、废除或干扰由PD-1与一种或多种其结合伴侣诸如PDL1、PDL2的相互作用导致的信号转导的分子。在一些实施方案中,所述PD-1结合拮抗剂是抑制PD-1与其结合伴侣结合的分子。在特定的方面中,所述PD-1结合拮抗剂抑制PD-1与PDL1和/或PDL2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、寡肽和其他减少、阻断、抑制、废除或干扰由PD-1与PDL1和/或PDL2相互作用导致的信号转导的分子。在一个实施方案中,PD-1结合拮抗剂减少通过PD-1减少阴性共刺激信号介导的信号传导进而赋予功能障碍性T-细胞较少的功能障碍(例如,增强对抗原识别的效应响应),其中所述阴性共刺激信号由或通过表达在T淋巴细胞上的细胞表面蛋白介导。在一些实施方案中,所述PD-1结合拮抗剂是抗-PD-1抗体。在特定方面中,PD-1结合拮抗剂是本文所述的纳武单抗(nivolumab)(也称为MDX-1106-04、MDX-1106、ONO-4538、BMS-936558和)。在另一特定方面中,PD-1结合拮抗剂是本文所述的哌姆单抗(pembrolizumab)(也称为MK-3475、Merck 3475、和SCH-900475)。在另一特定方面中,PD-1结合拮抗剂是本文所述的CT-011(也称为hBAT或hBAT-1)。在另一特定的方面中,PD-1结合拮抗剂是本文所述的AMP-224(也称为B7-DCIg)。
术语"PDL1结合拮抗剂"是减少、阻断、抑制、废除或干扰由PDL1与一种或多种其结合伴侣诸如PD-1、B7-1的相互作用导致的信号转导的分子。在一些实施方案中,PDL-1结合拮抗剂是抑制PDL-1与其结合伴侣结合的分子。在特定的方面中,PD-1结合拮抗剂抑制PDL1与PD-1和/或B7-1的结合。在一些实施方案中,PDL1结合拮抗剂包括抗-PDL1抗体、其抗原结合片段、免疫粘附素、融合蛋白、寡肽和其他减少、阻断、抑制、废除或干扰由PDL1与一种或多种其结合伴侣诸如如PD-1、B7-1的相互作用导致的信号转导的分子。在一个实施方案中,PDL1结合拮抗剂减少通过PDL-1减少阴性共刺激信号介导的信号传导进而赋予功能障碍性T-细胞较少的功能障碍(例如,增强对抗原识别的效应响应),其中所述阴性共刺激信号由或通过表达在T淋巴细胞上的细胞表面蛋白介导。在一些实施方案中,PDL1结合拮抗剂是抗-PDL1抗体。在特定的方面中,抗-PDL1抗体是本文所述的YW243.55.S70。在另一特定的方面中,抗-PDL1抗体是本文所述的MDX-1105(也称为BMS-936559)。在另一特定的方面中,抗-PDL1抗体是本文所述的MPDL3280A。在另一特定的方面中,抗-PDL1抗体是本文所述的MEDI4736。
术语"PDL2结合拮抗剂"是减少、阻断、抑制、废除或干扰由PD-L2与一种或多种其结合伴侣诸如PD-1的相互作用导致的信号转导的分子。在一些实施方案中,PD-L2结合拮抗剂是抑制PD-L2与其结合伴侣结合的分子。在特定的方面中,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、寡肽和其他减少、阻断、抑制、废除或干扰由PD-L2与一种或多种其结合伴侣诸如PD-1的相互作用导致的信号转导的分子。在一个实施方案中,PD-L2结合拮抗剂减少通过PD-L2减少阴性共刺激信号介导的信号进而赋予功能障碍性T-细胞较少的功能障碍(例如,增强对抗原识别的效应响应),其中所述阴性共刺激信号由或通过表达在T淋巴细胞上的细胞表面蛋白介导。在一些实施方案中,PD-L2结合拮抗剂是免疫粘附素。
除非本文另外表明,本文记载的数值范围仅意在作为单独指代每个单独落入该范围的不同值的简写方法,且如果在本文中单独记载,则每个不同的值都并入本说明书中。
本领域的技术人员可以理解的是,本文"约"某值或参数的提述包括(并描述)针对值或参数本身的实施方案。例如,"约X"的表述包括"X"的表述。
除非在本文另外表明或在上下文中明显不符,否则本发明所述的实施方案上下文中术语“一种”和“一个”及“所述”以及相似术语的使用应理解为包括单数和复数形式。除非另外表明,术语“包含”、“具有”、“包括”和“含有”应理解为开放式术语(即意为“包括但不限于”)。可以理解的是本文所述的本发明的方面和实施方案包括"组成"和/或"基本上组成"的方面和实施方案。
CBP/EP300布罗莫结构域抑制剂的用途
本文提供了使用CBP/EP300布罗莫结构域抑制剂用于抑制CBP/EP300布罗莫结构域(体外或体内)的方法。例如,本文提供了用于在个体中治疗布罗莫结构域介导的病症的方法,其包括施用CBP/EP300布罗莫结构域抑制剂至所述个体。在一些实施方案中,布罗莫结构域介导的病症为癌症。
本文提供了在个体中用于治疗癌症或延迟癌症进展的方法,其包括向个体施用有效量的CBP/EP300布罗莫结构域抑制剂。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与CBP的布罗莫结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与氨基酸序列SEQ ID NO:5的一个或多个残基结合(UniProt No.Q9279的氨基酸残基1082-1197)。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与氨基酸序列SEQ IDNO:3的一个或多个残基结合(UniProt No.Q92793的氨基酸残基1103-1175)。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与EP300的布罗莫结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与氨基酸序列SEQ ID NO:6的一个或多个残基结合(UniProt No.Q09472的氨基酸残基1040-1161)。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与氨基酸序列SEQ ID NO:4的一个或多个残基结合(UniProt No.Q09472的氨基酸残基1067-1139)。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与EP300的布罗莫结构域和CBP的布罗莫结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂结合SEQ ID NO:5和SEQ ID NO:6。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂结合SEQ ID NO:3和SEQ ID NO:4。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂抑制和/或减少CBP/EP300布罗莫结构域与染色质的结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂不抑制CBP/EP300的组蛋白乙酰转移酶活性。
此外,本文提供了在具有癌症的个体中增强免疫功能的方法,其包括施用有效量的CBP/EP300布罗莫结构域抑制剂。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与CBP的布罗莫结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与SEQ ID NO:3氨基酸序列的一个或多个残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与SEQ ID NO:5氨基酸序列的一个或多个残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与EP300的布罗莫结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与SEQ ID NO:4的氨基酸序列的一个或多个残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与SEQ ID NO:6的氨基酸序列的一个或多个残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与EP300的布罗莫结构域和CBP的布罗莫结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂结合SEQ ID NO:5和SEQ ID NO:6。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂结合SEQ ID NO:3和SEQ ID NO:4。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂抑制和/或减少CBP/EP300布罗莫结构域与染色质的结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂不抑制CBP/EP300的组蛋白乙酰转移酶活性。
在任何方法的一些实施方案中,个体中各CD8T细胞相比施用CBP/EP300布罗莫结构域抑制剂前具有增强的致敏、活化、增殖和/或杀伤活性。在一些实施方案中,CD8 T细胞的数目相对施用CBP/EP300布罗莫结构域抑制剂前有所增加。在一些实施方案中,CD8 T细胞相对施用CBP/EP300布罗莫结构域抑制剂前具有减少的一种或多种下列生物标志物的表达水平:IFNA17、IGF1、FSCN1、SUMO2、C1orf129、EIF2S2、TDGF1、AIDA、CCR4、CD160、MC4R、KRTAP2-2、MT1JP、OR4N2、KRTAP4-5、MT1L//MT1L、IL13、LCE1D、KIR2DL2、LOC158696、LIF、IL28A、TAS2R13、CTLA4和/或FOXP3。在一些实施方案中,CD8 T细胞相对施用CBP/EP300布罗莫结构域抑制剂前具有减少的CD160和/或KIR2DL2表达水平。
在任何方法的一些实施方案中,增强的免疫功能由相对施用CBP/EP300布罗莫结构域抑制剂前个体中(例如在一个或多个肿瘤位点)的Treg细胞具有减少的一种或多种下列标志物的表达水平表征:IL28A、GPR87、ANKRD37、CABLES1、RAPGEF2、TRIM69、MT1L//MT1L、FAM113B、FOXP3、CSF2、OCM2、GLIPR1、FGFBP2、CTLA4、CST7、GOLGA6L1、IFIT3、FAM13A、APOD、AK2、CLDN1、HSD11B1、DNAJC12、PHEX、IL2、FOXD4L3、GNA15、ZBTB32、RDH10、OR52E5、CYP2A6、GZMH、CCL20、ADM、LOC100131541、RNF122、FAM36A、AMY2B、GPR183、MYOF、IL29、AIDA、SPRY1、ENOPH1、IL1RN、SLAMF1、PGM2L1、SSBP3、MMP23B、HIST1H3J、MYO1B、BEND5、S1PR1、CDK6、GPR56、ZC3H12A、DOK5、DUSP1、CYB5R2、KCNAB2、LAG3、KLF10、GK、SHC4、IL12RB2、CD109、HAVCR2(TIM-3)、LTA、FAM40B、HMGCS1、HSPA1A、ZNF705A、CMAH、KIF3A、CHN1、KBTBD8、TNF、MOP-1、RASGRP4、INSIG1、SLAMF7、OR10H4、LPL、HIST1H2BJ、LIF、IGF1、IL18RAP、OR52N4、OR1D2、CCR4、CXCR5、IL1R1、MICAL2、NRN1、PICALM、B3GNT5、IFI44L、CXCR3、ICOS、IFIT2、NCR3、HSPA1B、CD80、GNG2、C7orf68、GPR171、RPS10P7、IL23A、LOC283174、PLK2、EMP1、FNBP1L、CD226、RBMS3、IL23R、PTGER4、GZMB、F5和/或HIST1H2BK。在一些实施方案中,Treg细胞生物标志物是LAG3、CTLA4和/或FOXP3中的一种或多种。
在任何方法的一些实施方案中,增强的免疫功能由Treg细胞存在的对CD3/CD28刺激增强的未受过攻击的T细胞响应表征。
在一些实施方案中,CD8 T细胞致敏由增加的T细胞增殖和/或CD8 T细胞中增强的杀伤活性表征。在一些实施方案中,CD8 T细胞活化由升高的γ-IFN+CD8 T细胞频率表征。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,抑制了免疫规避。
本文提供的方法可用于治疗其中预期用于治疗癌症的增强的免疫原性诸如增强的肿瘤免疫原性的病况。例如,本文提供可用于增强T细胞功能向上调细胞介导的免疫响应和用于治疗T细胞功能障碍性病症、肿瘤免疫力的CBP/EP300布罗莫结构域抑制剂。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂通过在慢性刺激的CD8+T细胞上抑制调节性T(Treg)细胞和/或缓解T细胞衰竭的抑制性功能促进抗肿瘤免疫力。
CBP/EP300布罗莫结构域抑制剂可进一步用于减少额外的胸腺Treg细胞分化过程中Foxp3的表达。持续的Foxp3表达对于在Treg细胞中维持抑制活性至关重要。在一些实施方案中,通过CBP/EP300布罗莫结构域的减少的Foxp3表达破坏了Treg细胞的抑制活性并刺激肿瘤的抗免疫力。Treg细胞在源自多种癌症适应症的肿瘤中富集,其包括黑素瘤、NSCLC、肾癌、卵巢癌、结肠癌、胰腺癌、肝细胞癌和乳腺癌。在这些适应症的亚组中,增加的肿瘤内Treg细胞密度与患者的不良预后相关。这些适应症包括NSCLC、卵巢癌、胰腺癌、肝细胞癌和乳腺癌。预测CBP/EP300布罗莫结构域抑制剂在这些癌症适应症中可破坏肿瘤内Treg细胞功能以增强效应T细胞活性。
T细胞衰竭由不存在抗原清除的慢性CD8+T细胞刺激表征。与未受过攻击的或活化的效应T细胞相比,衰竭的T细胞由于增加的抑制性受体(包括PD-1、LAG-3和TIM-3)的表达对T细胞受体刺激耐受。阻断这些抑制性受体的拮抗性抗体缓解T细胞抑制,由此促进肿瘤细胞杀伤。CBP/EP300布罗莫结构域抑制剂减少抑制性受体LAG-3和TIM-3的表达。
另一实施方案包括增加个体中癌症治疗(例如,癌症治疗包括第二治疗剂)效力的方法,其包括向个体施用有效量的CBP/EP300布罗莫结构域抑制剂。
另一实施方案包括在个体中延长对癌症疗法(例如第二治疗剂)响应持续时间的方法,其包括向经历癌症疗法的个体施用CBP/EP300布罗莫结构域抑制剂,其中当施用CBP/EP300布罗莫结构域抑制剂或其药学上可接受的盐时,对癌症疗法的响应持续时间相比未施用CBP/EP300布罗莫结构域抑制剂或其药学上可接受的盐对癌症疗法响应的持续时间延长。
另一实施方案包括在个体中治疗癌症的方法,其包括向个体施用(a)CBP/EP300布罗莫结构域抑制剂和(b)一种或多种第二治疗剂。本文进一步提供了在患有癌症的个体中延长响应持续时间的方法,其包括向个体施用(a)有效量的CBP/EP300布罗莫结构域抑制剂和(b)有效量的一种或多种第二治疗剂。在一些实施方案中,第二治疗剂是细胞毒性剂和/或化疗剂。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂和第二治疗剂同时施用。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂在一种或多种第二治疗剂之前和/或与其同时施用。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂和第二治疗剂共同施用。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂和第二治疗剂共同配制。
在组合疗法的任何方法的一些实施方案中,一种或多种第二治疗剂是阿仑单抗、屈***酚、达利珠单抗、米托蒽醌、盐酸扎利罗登(xaliproden)、氨吡啶、乙酸格拉替雷(glatiramer acetate)、那他珠单抗、sinnabidol、immunokine NNS03、ABR-215062、AnergiX.MS、趋化因子受体拮抗剂、BBR-2778、卡拉古林(calagualine)、CPI-1189、LEM(脂质体包封的米托蒽醌)、THC.CBD(***素激动剂)、MBP-8298、mesopram(PDE4抑制剂)、MNA-715、抗-IL-6受体抗体、neurovax、吡非尼酮(pirfenidone)allotrap 1258(RDP-1258)、sTNF-Rl、他仑帕奈(talampanel)、特立氟胺(teriflunomide)、TGF-β2、替利莫肽(tiplimotide)、VLA-4拮抗剂(例如TR-14035、VLA4Ultrahaler或Antegran-ELAN/Biogen),干扰素γ拮抗剂或IL-4激动剂。
在组合疗法的任何方法的一些实施方案中,一种或多种第二治疗剂是T细胞信号传导抑制剂(例如酪氨酸激酶抑制剂)或靶向T细胞活化的分子(例如CTLA-4-IgG、抗B7家族抗体或抗PD-1家族抗体)。举例来说,在个体中治疗癌症或延迟癌症进展的方法包括施用有效量的CBP/EP300布罗莫结构域抑制剂和靶向T细胞活化的分子。此外,本发明提供了在患有癌症的个体中增强免疫功能的方法,其包括向所述个体施用有效量的CBP/EP300布罗莫结构域抑制剂和有效量的靶向T细胞活化的分子。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂或其药学上可接受的盐和第二治疗剂同时施用。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂或其药学上可接受的盐和第二治疗剂共同施用。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂在一种或多种第二治疗剂之前和/或与其同时施用。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂或其药学上可接受的盐和第二治疗剂共同配制。
例如,本发明提供了使用CBP/EP300布罗莫结构域抑制剂与PD-1轴结合拮抗剂组合治疗癌症和/或延迟癌症进展的方法。本文还提供了在患有癌症的个体中增强免疫功能的方法,其包括向所述个体施用有效量的CBP/EP300布罗莫结构域抑制剂和有效量的PD-1轴结合拮抗剂。PD-1轴结合拮抗剂包括PD-1结合拮抗剂、PDL1结合拮抗剂和PDL2结合拮抗剂。“PD-1”可替换的名称包括CD279和SLEB2。“PDL1”可替换的名称包括B7-H1、B7-4、CD274和B7-H。“PDL2”可替换的名称包括B7-DC、Btdc和CD273。在一些实施方案中,PD-1、PDL1和PDL2是人PD-1、PDL1和PDL2。在一些实施方案中,PD-1结合拮抗剂是抑制PD-1与其配体结合伴侣结合的分子。在特定的方面中,PD-1配体结合伴侣是PDL1和/或PDL2。在另一实施方案中,PDL1结合拮抗剂是抑制PDL1与其结合伴侣结合的分子。在特定的方面中,PDL1结合伴侣是PD-1和/或B7-1。在另一实施方案中,PDL2结合拮抗剂是抑制PDL2与其结合伴侣结合的分子。在特定的方面中,PDL2结合伴侣是PD-1。拮抗剂可以是抗体、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。在一些实施方案中,PD-1结合拮抗剂是抗-PD-1抗体(例如人抗体、人源化抗体或嵌合抗体)。在一些实施方案中,抗-PD-1抗体选自下组:纳武单抗、哌姆单抗和CT-011。在一些实施方案中,PD-1结合拮抗剂是免疫粘附素(例如包含与恒定区(例如免疫球蛋白序列的Fc区)融合的PDL1或PDL2的胞外或PD-1结合部分的免疫粘附素。在一些实施方案中,PD-1结合拮抗剂是AMP-224。纳武单抗,也称为MDX-1106-04、MDX-1106、ONO-4538、BMS-936558和是描述于WO2006/121168的抗PD-1抗体。哌姆单抗也称为MK-3475、Merck 3475、lambrolizumab、和SCH-900475,是描述于WO2009/114335的抗PD-1抗体。CT-011,也称为hBAT或hBAT-1,是描述于WO2009/101611的抗PD-1抗体。AMP-224,也称为B7-DCIg,是描述于WO2010/027827和WO2011/066342的PDL2-Fc融合可溶性受体。在一些实施方案中,所述抗PD-1抗体是纳武单抗(CAS注册号:946414-94-4)。在一些实施方案中,所述癌症是黑素瘤、NSCLC和肾细胞癌。
在组合疗法的任何方法的一些实施方案中,一种或多种第二治疗剂是IL-11抗体、抗细胞因子抗体(例如fonotolizumab(抗IFNg抗体))或抗-受体受体抗体(例如抗-IL-6受体抗体或B细胞表面分子抗体)。
在组合疗法的任何方法的一些实施方案中,一种或多种第二治疗剂是下列一种或多种:LJP 394(阿贝莫司(abetimus))(其耗尽或灭活B-细胞(例如利妥昔单抗(Rituximab)(抗-CD20抗体)或lymphostat-B(抗-BlyS抗体))、TNF拮抗剂(例如抗-TNF抗体)、D2E7(阿达木单抗(adalimumab))、CA2(英利昔单抗(infliximab))、CDP 571、TNFR-Ig构建体、(p75TNFRigG(依那西普(etanercept))或p55TNFRigG(LENERCEPTTM)。
在组合疗法的任何方法的一些实施方案中,一种或多种第二治疗剂是靶向疗法。在一些实施方案中,所述靶向疗法是一种或多种EGFR拮抗剂、RAF抑制剂和/或PI3K抑制剂。
在组合疗法的任何方法的一些实施方案中,所述靶向疗法是EGFR拮抗剂。在任何方法的一些实施方案中,所述EGFR拮抗剂是N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)-4-喹唑啉胺和/或其药学上可接受的盐。在一些实施方案中,所述EGFR拮抗剂是N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)-4-喹唑啉胺。在一些实施方案中,所述EGFR拮抗剂是N-(4-(3-氟苄基氧基)-3-氯苯基)-6-(5-((2-(甲基磺酰基)乙基氨基)甲基)呋喃-2-基)喹唑啉-4-胺、二-4-甲基苯磺酸盐(例如拉帕替尼)。在任何方法的一些实施方案中,靶向疗法是RAF抑制剂。在一些实施方案中,所述RAF抑制剂是BRAF抑制剂。在一些实施方案中,所述RAF抑制剂是CRAF抑制剂。在一些实施方案中,所述BRAF抑制剂是维罗非尼。在一些实施方案中,所述RAF抑制剂是3-(2-氰基丙-2-基)-N-(4-甲基-3-(3-甲基-4-氧代-3,4-二氢喹唑啉-6-基氨基)苯基)苯甲酰胺(例如AZ628(CAS#878739-06-1))。在任何方法的一些实施方案中,所述靶向疗法是PI3K抑制剂。
在组合疗法的任何方法的一些实施方案中,所述一种或多种第二治疗剂是紫杉烷。在一些实施方案中,所述紫杉烷是紫杉醇。在一些实施方案中,所述紫杉烷是多西紫杉醇。在组合疗法的任何方法的一些实施方案中,所述一种或多种第二治疗剂是铂制剂。在一些实施方案中,所述铂制剂是卡铂。在一些实施方案中,所述铂制剂是顺铂。在任何方法的一些实施方案中,所述细胞毒性剂是紫杉烷和铂制剂。在一些实施方案中,所述紫杉烷是紫杉醇。在一些实施方案中,所述紫杉烷是多西紫杉醇。在一些实施方案中,所述铂制剂是卡铂。在一些实施方案中,所述铂制剂是顺铂。在组合疗法的任何方法的一些实施方案中,所述一种或多种第二治疗剂是长春花生物碱。在一些实施方案中,所述长春花生物碱是长春瑞滨。在任何方法的一些实施方案中,所述化学疗法是核苷类似物。在一些实施方案中,所述核苷类似物是吉西他滨。在组合疗法的任何方法的一些实施方案中,所述一种或多种第二治疗剂是放射治疗。
在一些实施方案中,治疗可在一种或多种症状发展后施用。在其他实施方案中,治疗可在无症状时施用。例如,治疗可施用至症状发作前的易感个体(例如按照症状史和/或按照基因或其他易感因素)。治疗还可在症状解决后持续,例如以预防或延迟症状复发。
在任何方法的一些实施方案中,所述癌症具有升高的T-细胞浸润水平。在任何方法的一些实施方案中,所述癌症与增加的肿瘤内Treg细胞密度相关。在任何方法的一些实施方案中,与参照相比,所述癌症表达升高的一种或多种下列生物标志物的水平:IL28A、GPR87、ANKRD37、CABLES1、RAPGEF2、TRIM69、MT1L//MT1L、FAM113B、FOXP3、CSF2、OCM2、GLIPR1、FGFBP2、CTLA4、CST7、GOLGA6L1、IFIT3、FAM13A、APOD、AK2、CLDN1、HSD11B1、DNAJC12、PHEX、IL2、FOXD4L3、GNA15、ZBTB32、RDH10、OR52E5、CYP2A6、GZMH、CCL20、ADM、LOC100131541、RNF122、FAM36A、AMY2B、GPR183、MYOF、IL29、AIDA、SPRY1、ENOPH1、IL1RN、SLAMF1、PGM2L1、SSBP3、MMP23B、HIST1H3J、MYO1B、BEND5、S1PR1、CDK6、GPR56、ZC3H12A、DOK5、DUSP1、CYB5R2、KCNAB2、LAG3、KLF10、GK、SHC4、IL12RB2、CD109、HAVCR2(TIM-3)、LTA、FAM40B、HMGCS1、HSPA1A、ZNF705A、CMAH、KIF3A、CHN1、KBTBD8、TNF、MOP-1、RASGRP4、INSIG1、SLAMF7、OR10H4、LPL、HIST1H2BJ、LIF、IGF1、IL18RAP、OR52N4、OR1D2、CCR4、CXCR5、IL1R1、MICAL2、NRN1、PICALM、B3GNT5、IFI44L、CXCR3、ICOS、IFIT2、NCR3、HSPA1B、CD80、GNG2、C7orf68、GPR171、RPS10P7、IL23A、LOC283174、PLK2、EMP1、FNBP1L、CD226、RBMS3、IL23R、PTGER4、GZMB、F5和/或HIST1H2BK。在任何方法的一些实施方案中,与参照相比,所述癌症表达升高水平的一种或多种LAG3、CTLA4和/或FOXP3。在任何方法的一些实施方案中,与参照相比,所述癌症表达升高水平的一种或多种下列生物标志物:IFNA17、IGF1、FSCN1、SUMO2、C1orf129、EIF2S2、TDGF1、AIDA、CCR4、CD160、MC4R、KRTAP2-2、MT1JP、OR4N2、KRTAP4-5、MT1L//MT1L、IL13、LCE1D、KIR2DL2、LOC158696、LIF、IL28A、TAS2R13、CTLA4和/或FOXP3。在任何方法的一些实施方案中,与参照相比,所述癌症包含CD8细胞,其中所述CD8细胞表达升高水平的一种或多种下列生物标志物:IFNA17、IGF1、FSCN1、SUMO2、C1orf129、EIF2S2、TDGF1、AIDA、CCR4、CD160、MC4R、KRTAP2-2、MT1JP、OR4N2、KRTAP4-5、MT1L//MT1L、IL13、LCE1D、KIR2DL2、LOC158696、LIF、IL28A、TAS2R13、CTLA4和/或FOXP3。在任何方法的一些实施方案中,与参照相比,所述癌症包含CD8细胞,其中所述CD8细胞表达升高的CD160和/或KIR2DL2水平。在任何方法的一些实施方案中,所述参照是具有已知表达水平的的感兴趣的生物标志物的细胞或组织。在任何方法的一些实施方案中,所述组织是具有低T细胞浸润和/或低肿瘤内Treg细胞密度的癌症组织。
CBP/EP300布罗莫结构域介导的病症实例包括癌症,其包括但不限于听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞白血病(单核细胞性、成髓细胞性、腺癌、血管肉瘤、星形细胞瘤、骨髓单细胞性和早幼粒细胞性)、急性T-细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌癌、支气管癌、子***、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性(粒细胞性)白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、异常增殖性改变(发育异常和化生)、胚胎癌、子宫内膜癌、内皮瘤、室管膜瘤、上皮癌、红白血病、食道癌、***受体阳性乳腺癌、原发性血小板增多症、尤因氏瘤、纤维肉瘤、滤泡型淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、胶质肉瘤、重链病、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感性***癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、***内皮肉瘤、***肉瘤、成淋巴细胞白血病,淋巴瘤(霍奇金与非霍奇金淋巴瘤)、膀胱、乳腺、结肠、肺、卵巢、胰腺、***、皮肤和子宫的恶性和过度增殖性病症、T-细胞或B-细胞来源的淋巴恶性肿瘤、白血病、淋巴瘤、髓样癌、成神经管细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、髓细胞性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突神经胶质瘤、口腔癌、骨源性肉瘤、卵巢癌、胰腺癌、***状腺癌、***状癌、松果体瘤、真性红细胞增多症、***癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、***瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、子宫癌和维尔姆斯瘤。
在任何方法的一些实施方案中,所述癌症是肺癌、乳腺癌、胰腺癌、结肠直肠癌和/或黑素瘤。在一些实施方案中,所述癌症是肺癌。在一些实施方案中,所述肺癌是NSCLC。在一些实施方案中,所述癌症是乳腺癌。在一些实施方案中,所述癌症是黑素瘤。
生物标志物的存在和/或表达水平/量可以基于任何本领域已知的合适的标准定性和/或定量确定,包括但不限于DNA、mRNA、cDNA、蛋白、蛋白片段和/或基因拷贝数。在一些实施方案中,第一样品中生物标志物的存在和/或表达水平/量与第二样品中的存在/不存在和/或表达水平/量相比有所增加。在一些实施方案中,第一样品中生物标志物的存在/不存在和/或表达水平/量相比第二样品中的存在和/或表达水平/量有所减少。在一些实施方案中,第二样品是参照样品、参照细胞、参照组织、对照样品、对照细胞或对照组织。本文描述了其他用于确定基因存在/不存在和/或表达水平/量的内容。
在任何方法的一些实施方案中,升高的表达水平指与参照样品、参照细胞、参照组织、对照样品、对照细胞或对照组织相比,生物标志物(例如蛋白或核酸(例如基因或mRNA))水平整体增加约10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、96%、97%、98%、99%或更大中的任一种,其由本领域已知的标准方法诸如本文所述的那些方法检测。在一些实施方案中,升高的表达指样品中生物标志物表达水平/量的增加,其中所述增加是至少约参照样品、参照细胞、参照组织、对照样品、对照细胞或对照组织中对应的生物标志物的表达水平/量的1.5X、1.75X、2X、3X、4X、5X、6X、7X、8X、9X、10X、25X、50X、75X,或100X中的任一种。在一些实施方案中,升高的水平指与参照样品、参照细胞、参照组织、对照样品、对照细胞、对照组织或内部对照(例如管家基因)相比,整体增加多于约1.5倍、约1.75倍、约2倍、约2.25倍、约2.5倍、约2.75倍、约3.0倍或约3.25倍。
在任何方法的一些实施方案中,降低的表达指与参照样品、参照细胞、参照组织、对照样品、对照细胞或对照组织相比,生物标志物(例如蛋白或核酸(例如基因或mRNA))水平整体降低约10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、96%、97%、98%、99%或更大的任一种,其通过本领域已知的标准方法诸如本文所述的那些方法检测。在一些实施方案中,降低的表达指样品中生物标志物表达水平/量的减少,其中所述减少是至少约参照样品、参照细胞、参照组织、对照样品、对照细胞或对照组织中对应的生物标志物的表达水平/量的0.9X、0.8X、0.7X、0.6X、0.5X、0.4X、0.3X、0.2X、0.1X、0.05X或0.01X中的任一种。
样品中多种生物标志物的存在和/或表达可通过多种方法学分析,其中的许多为本领域技术人员已知和理解,包括但不限于免疫组化(“IHC”)、蛋白免疫印迹分析、免疫沉淀、分子结合测定、ELISA、ELIFA、荧光激活细胞分选(“FACS”)、MassARRAY、蛋白质组学、基于定量采血的测定(例如血清ELISA)、生化酶活性测定、原位杂交、Southern分析、Northern分析、全基因组测序、聚合酶链式反应(“PCR”)包括实时定量PCR(“qRT-PCR”)和其他扩展类型的检测方法,例如分支DNA、SISBA、TMA等)、RNA-Seq、FISH、微阵列分析、基于表达分布和/或基因表达的连续分析(“SAGE”)以及多种可通过蛋白、基因和/或组织阵列分析实施的测定中的任一种。例如在Ausubel等人,eds.,1995,Current Protocols In MolecularBiology,Units 2(Northern Blotting),4(Southern Blotting),15(Immunoblotting)和18(PCR Analysis)中发现了用于评价基因和基因产物状态的典型方案。也可使用多重复合免疫测定诸如可从Rules Based Medicine或Meso Scale Discovery(“MSD”)获得的那些。
取决于治疗的宿主和具体的施用模式,CBP/EP300布罗莫结构域抑制剂或其盐和可与载体材料组合以产生单一剂量形式的额外药剂(在包含如上文所述的其他治疗剂的那些组合物中)的量将发生变化。在一些实施方案中,配制本发明的组合物进而可施用0.01-100mg/kg体重/天的本发明剂量。
额外的治疗剂和CBP/EP300布罗莫结构域抑制剂可协调发挥作用。因此,这种组合物中额外的治疗剂的量可少于仅利用治疗剂的单一疗法中所需,或对于给予较低剂量的患者可能存在较少的副作用。在一些实施方案中,在这种组合物中可施用0.01-1,000μg/kg体重/天的额外治疗剂的剂量。
CBP/EP300布罗莫结构域抑制剂
已发现一些化合物是可与CBP和/或EP300的一种或多种中含有的布罗莫结构域基序特异性结合的CBP/EP300布罗莫结构域抑制剂。
在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与CBP的布罗莫结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与SEQ ID NO:5的氨基酸序列的一个或多种残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与SEQ IDNO:3的氨基酸序列的一个或多个残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与EP300的布罗莫结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与SEQ ID NO:6的氨基酸序列的一个或多个残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与SEQ ID NO:4的氨基酸序列的一个或多个残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与EP300的布罗莫结构域和CBP的布罗莫结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂结合SEQ ID NO:5和SEQID NO:6。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂结合SEQ ID NO:3和SEQID NO:4。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与至少一个(例如1、2、3、4、5、6、7、8、9、10、11、12或13个)下列CBP残基结合:LEU 1109、PRO 1110、PHE 1111、VAL1115、LEU 1120、ILE 1122、TYR 1125、ALA 1164、TYR 1167、ASN 1168、ARG 1173、VAL 1174或PHE 1177。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与至少一个(例如1、2、3、4、5、6、7、8、9、10、11、12或13个)下列EP300残基结合:LEU 1073、PRO 1074、PHE 1075、VAL 1079、LEU 1084、ILE 1086、TYR 1089、ALA1128、TYR 1131、ASN 1132、ARG 1137、VAL1138或TYR 1141。
在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂干扰CBP和/或EP300与组蛋白(特别是组蛋白中的乙酰化赖氨酸)的缔合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂抑制CBP和/或EP300与染色质(例如组蛋白相关DNA)的缔合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂抑制和/或减少CBP布罗莫结构域和/或EP300布罗莫结构域与染色质(例如组蛋白相关DNA)的缔合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂不影响CBP和/或EP300的其他结构域与染色质的缔合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂与CBP和/或EP300主要(例如仅仅)通过与CBP布罗莫结构域和/或EP300布罗莫结构域接触和/或相互作用结合。在一些实施方案中,CBP/EP300布罗莫结构域抑制剂与CBP和/或EP300通过与CBP布罗莫结构域和/或EP300布罗莫结构域以及额外的CBP和/或EP300残基和/或结构域接触和/或相互作用结合。与染色质相关的测定方法为本领域已知,包括但不限于染色质分级、BRET测定(Promega)、FRAP测定、染色质免疫沉淀(ChIP)、生物物理结合测定和/或组蛋白缔合测定。参见例如Das等人,BioTechniques37:961-969(2004)。
在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂不影响CD8细胞中的效应功能(即效应功能在CBP/EP300布罗莫结构域抑制剂存在和/或不存在时基本上相同)。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂不影响穿孔素、颗粒酶和/或EOMES的表达水平(即穿孔素、颗粒酶和/或EOMES中的一种或多种的表达水平在CBP/EP300布罗莫结构域抑制剂存在和/或不存在时基本上相同)。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂不影响效应细胞因子IFN-γ和/或TNFα的表达水平(即效应细胞因子IFN-γ和/或TNFα的表达水平在CBP/EP300布罗莫结构域抑制剂存在和/或不存在时基本上相同)。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂增强了Treg细胞存在时对CD3/CD28刺激的未受过攻击的T细胞响应。
在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂基本上不(例如并不)与CBP和/或EP300的HAT结构域结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂基本上不(例如并不)与CBP和/或EP300的HAT结构域结合,如在Delvecchio等人,Nat.Struct.&Mol.Biol.20:1040-1046(2013)中所鉴定,通过的方式将其整体并入。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂基本上不与氨基酸序列SEQ ID NO:8(UniProt No.Q92793的氨基酸残基1321-1701)的一个或多个残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂基本上不与氨基酸序列SEQ ID NO:7(UniProtNo.Q09472的氨基酸残基1285-1664)的一个或多个残基结合。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂不抑制CBP和/或EP300的组蛋白乙酰转移酶(HAT)催化活性。
预期为CBP/EP300布罗莫结构域抑制剂的化合物将具有相比其他化合物改善的和/或不同的性质,诸如“HAT”抑制剂化合物。HAT抑制预期将导致蛋白(组蛋白和非组蛋白)乙酰化的整体减少,可能以显著的方式影响细胞活力。在一些实施方案中,CBP/EP300布罗莫结构域抑制保持这些蛋白的HAT活性同时导致靶基因相对小的亚组的转录活性的降低,如在表2和表3中所示(Treg细胞中的244个基因和CD8细胞中的25个基因减少了2倍或更多)。
在一些实施方案中,所述CBP和/或EP300抑制剂在靶调节位点抑制转录的转录激活。在一些实施方案中,所述CBP/EP300布罗莫结构域在Treg细胞和CD8细胞中于一个或多个靶位点消除或减少CBP和/或EP300的结合。在一些实施方案中,Treg细胞和CD8细胞中的靶位点是一个或多个下列基因座:IL28A、GPR87、ANKRD37、CABLES1、RAPGEF2、TRIM69、MT1L//MT1L、FAM113B、FOXP3、CSF2、OCM2、GLIPR1、FGFBP2、CTLA4、CST7、GOLGA6L1、IFIT3、FAM13A、APOD、AK2、CLDN1、HSD11B1、DNAJC12、PHEX、IL2、FOXD4L3、GNA15、ZBTB32、RDH10、OR52E5、CYP2A6、GZMH、CCL20、ADM、LOC100131541、RNF122、FAM36A、AMY2B、GPR183、MYOF、IL29、AIDA、SPRY1、ENOPH1、IL1RN、SLAMF1、PGM2L1、SSBP3、MMP23B、HIST1H3J、MYO1B、BEND5、S1PR1、CDK6、GPR56、ZC3H12A、DOK5、DUSP1、CYB5R2、KCNAB2、LAG3、KLF10、GK、SHC4、IL12RB2、CD109、HAVCR2(TIM-3)、LTA、FAM40B、HMGCS1、HSPA1A、ZNF705A、CMAH、KIF3A、CHN1、KBTBD8、TNF、MOP-1、RASGRP4、INSIG1、SLAMF7、OR10H4、LPL、HIST1H2BJ、LIF、IGF1、IL18RAP、OR52N4、OR1D2、CCR4、CXCR5、IL1R1、MICAL2、NRN1、PICALM、B3GNT5、IFI44L、CXCR3、ICOS、IFIT2、NCR3、HSPA1B、CD80、GNG2、C7orf68、GPR171、RPS10P7、IL23A、LOC283174、PLK2、EMP1、FNBP1L、CD226、RBMS3、IL23R、PTGER4、GZMB、F5、HIST1H2BK、IFNA17、IGF1、FSCN1、SUMO2、C1orf129、EIF2S2、TDGF1、AIDA、CCR4、CD160、MC4R、KRTAP2-2、MT1JP、OR4N2、KRTAP4-5、IL13、LCE1D、KIR2DL2、LOC158696、IL28A和/或TAS2R13。在一些实施方案中,所述靶位点是FOXP3、LAG3、TIM3和CTLA4基因座中的一个或多个。在一些实施方案中,所述CBP/EP300布罗莫结构域抑制剂通过减少FOXP3处CBP和/或EP300的结合抑制CBP和/或EP300-介导的FOXP3乙酰化且不影响组蛋白乙酰转移酶催化活性。
CBP和EP300(也称为p300)的描述可在Chrivia等人,Nature,365,855(1993)和Teufel等人,PNAS,104,7009(2007)中发现。可用于一些实施方案实践中的CBP/EP300布罗莫结构域抑制剂化合物的实例包括式I的化合物、其异构体或异构体的混合物(例如对映异构体)或其药学上可接受的盐、溶剂合物或前药。这些化合物和可用于制备这些化合物的方法和中间体描述于Angew.Chem.Int.Ed.,2014,v53,pages 1-6和相应的支持性信息。这些化合物与CBP/EP300的布罗莫结构域结合,与CBP布罗莫结构域的R1173残基形成阳离子-π相互作用
其中:
X是NH或O;
M是1或2;
N是1或2;
R1独立地选自下组:取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基、取代或非取代的C2–6炔基和取代或非取代的C3–6碳环基;
R2独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基和取代或非取代的C2–6炔基;
R3独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基和取代或非取代的C2–6炔基;
R4独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基和取代或非取代的C2–6炔基;
R5独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基和取代或非取代的C2–6炔基和OC1-C6烷基;
R6独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基和取代或非取代的C2–6炔基和OC1-C6烷基;
R7独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基和取代或非取代的C2–6炔基和OC1-C6烷基;且
R8独立地选自下组:氢、卤素、取代或非取代的C1-C6烷基、取代或非取代的C2–6烯基和取代或非取代的C2–6炔基和OC1-C6烷基;
或其盐。
在一些实施方案中,式I的化合物选自下组:
或其盐。
在一些实施方案中,本发明的方法和用途排除全部下列这些化合物:
药物组合物和施用方法
本文进一步提供了药物组合物,其包含用于本文所述的方法的CBP/EP300布罗莫结构域抑制剂。在一个实施方案中,所述组合物进一步包含药学上可接受的载体、佐剂或媒介物。在另一实施方案中,所述组合物进一步包含有效可测量地抑制CBP/EP300布罗莫结构域的量的化合物。在一些实施方案中,配制所述组合物用于施用至有此需要的患者。
包含CBP/EP300布罗莫结构域抑制剂或其盐的组合物可口服、肠胃外、通过吸入喷雾、局部、经皮、直肠、经鼻、口腔、舌下、经***、腹膜内、肺内、皮内、硬膜外或经由植入容器施用。本文使用的术语"肠胃外"包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术施用。
在一个实施方案中,将包含CBP/EP300布罗莫结构域抑制剂或其盐的组合物配制为固体剂型用于口服施用。用于口服施用的固体剂型包括胶囊、片剂、丸剂、粉末和颗粒。在一些实施方案中,包含CBP/EP300布罗莫结构域抑制剂或其盐的固体口服剂型进一步包含一种或多种下列物质:(i)惰性的、药学上可接受的赋形剂或载体,诸如柠檬酸钠或磷酸氢二钙;和(ii)填充剂或增容剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇或硅酸;(iii)粘合剂,诸如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖或***胶;(iv)湿润剂,诸如甘油;(v)崩解剂,诸如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐或碳酸钠;(vi)溶液阻滞剂,诸如石蜡;(vii)吸收促进剂,诸如季铵盐;(viii)湿润剂,诸如鲸蜡醇或单硬脂酸甘油酯;(ix)吸收剂,诸如高岭土或膨润土粘土;和(x)润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、聚乙二醇或月桂基硫酸钠。在一些实施方案中,将固体口服剂型配制为胶囊、片剂或丸剂。在一些实施方案中,所述固体口服剂型进一步包含缓冲剂。在一些实施方案中,用于固体口服剂型的这种组合物可进一步配制为软或硬的填充明胶胶囊中的填充物,其包含一种或多种赋形剂诸如乳糖(lactose)或奶糖(milksugar)、聚乙二醇等。
在一些实施方案中,包含CBP/EP300布罗莫结构域抑制剂或其盐的组合物的片剂、糖锭剂、胶囊、丸剂和颗粒任选地包含包衣或壳体,诸如肠溶包衣。它们可任选地包含遮光剂且可以任选地以延迟的方式优选在肠道的某些部分仅释放活性成分的组合物。包埋组合物的实例包括聚合物质和蜡状物,其还可以在使用如乳糖或奶糖以及高分子量聚乙二醇等赋形剂的软和硬的填充明胶胶囊中用作填充物。
在另一实施方案中,组合物包含微囊包封的CBP/EP300布罗莫结构域抑制剂或其盐,且任选地进一步包含一种或多种赋形剂。
在另一实施方案中,组合物包含液体剂量制剂,其包含用于口服的CBP/EP300布罗莫结构域抑制剂或其盐,且任选地进一步包含一种或多种药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。在一些实施方案中,所述液体剂型任选地进一步包含一种或多种惰性稀释剂诸如水或其他溶剂、增溶剂和乳化剂诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(具体地,棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇或山梨醇酐的脂肪酸酯及其混合物。在一些实施方案中,液体口服组合物任选地进一步包含一种或多种佐剂,诸如润湿剂、悬浮剂、增甜剂、矫味剂和芳香剂。
可根据本领域已知的方法使用适当的分散剂或润湿剂和悬浮剂配制可注射的制剂例如无菌可注射的水性或油性悬浮液。无菌可注射的制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的可注射的溶液、悬浮液或乳液,例如,作为在1,3-丁二醇中的溶液。可使用的可接受的媒介物和溶剂为水、林格氏溶液,U.S.P.和等渗氯化钠溶液。此外,无菌的不挥发性油可方便地用作溶剂或悬浮培介质。出于该目的,可使用任何温和的不挥发性油(包括合成的单或甘油二酯)。此外,脂肪酸诸如油酸可用于可注射物的制备。
可注射的制剂可通过以下方式灭菌:例如,在使用前经细菌保留过滤器过滤,或将掺入呈可溶解或分散于无菌水或其他无菌可注射介质中的无菌固体组合物形式的灭菌剂。
为延长CBP/EP300布罗莫结构域抑制剂的效果,经常预期减缓化合物从皮下或肌肉注射的吸收。该方式可通过使用具有不良水溶解度的结晶或无定形物质的液体悬浮液实现。化合物的吸收率则取决于其溶解速率,其反过来将取决于晶体大小和晶形。可替换地,肠胃外施用的化合物形式的延迟吸收通过将化合物溶解或悬浮于油媒介物中实现。可注射的贮存形式通过在生物可降解的聚合物诸如聚乳酸-聚乙醇酸中形成化合物的微胶囊基质制备。取决于化合物与聚合物的比率和采用的具体聚合物的特性,可控制化合物释放的速率。其他可降解聚合物的实例包括聚(原酸酯)和聚(酐)。贮存的可注射配制物也可通过将化合物包埋于与机体组织兼容的脂质体或微乳液制备。
在一些实施方案中,将用于直肠或***施用的组合物配制为栓剂,其可通过将CBP/EP300布罗莫结构域抑制剂或其盐与适当的无刺激性的赋形剂或载体诸如可可脂、聚乙二醇或栓剂用蜡(例如在环境温度为固体但在体温为液体且因此在直肠或***腔内溶解并释放CBP/EP300布罗莫结构域抑制剂的那些)混合制备。
用于局部或透皮施用的CBP/EP300布罗莫结构域抑制剂示例性的剂型包括软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、粉剂、溶液、喷雾剂、吸入剂或贴剂。所述CBP/EP300布罗莫结构域抑制剂或其盐在无菌条件下与药学上可接受的载体和任选的防腐剂或缓冲剂混合。额外的制剂实例包括眼用制剂、滴耳剂、滴眼剂、透皮贴剂。透皮剂型可通过将CBP/EP300布罗莫结构域抑制剂或其盐溶解或分散于介质例如乙醇或二甲亚砜制备。吸收增强剂还可用于增加化合物穿透皮肤的通量。速率可由提供速率控制膜或通过将化合物分散于聚合物基质或凝胶控制。
CBP/EP300布罗莫结构域抑制剂或其盐的鼻气雾剂或吸入制剂可作为盐水中的溶液、采用苄醇或其它合适的防腐剂、增强生物利用度的吸收促进剂、氟碳化合物和/或其他常规增溶剂或分散剂制备。
在一些实施方案中,药物组合物与食物一起或不与食物一起施用。在一些实施方案中,药学上可接受的组合物不与食物一起施用。在一些实施方案中,本发明的药学上可接受的组合物与食物一起施用。
用于任何具体患者的特定剂量和治疗方案将取决于多种因素,包括年龄、体重、一般健康状况、性别、饮食、施用时间、***速率、药物组合、治疗医师的判断和待治疗具体疾病的严重性。组合物中提供的CBP/EP300布罗莫结构域抑制剂或其盐的量将取决于组合物中的特定化合物。
在一个实施方案中,肠胃外施用的每剂量的本发明化合物的有效量范围将为约0.01-100mg/kg患者体重/天,可替换地约0.1-20mg/kg患者体重/天,其中使用的化合物的典型初始范围为0.3-15mg/kg/天。在另一实施方案中,口服单位剂型诸如片剂和胶囊包含约5mg至约100mg本发明化合物。
示例性的片剂口服剂型包含约2mg、5mg、25mg、50mg、100mg、250mg或500mg的CBP/EP300布罗莫结构域抑制剂或其盐,且进一步包含约5-30mg的无水乳糖、约5-40mg羧甲基纤维素钠、约5-30mg聚乙烯吡咯烷酮(PVP)K30和约1-10mg硬脂酸镁。配制片剂的过程包括将粉末成分共同混合且进一步用PVP溶液混合。可将获得的组合物干燥、颗粒化、与硬脂酸镁混合并使用常规设备压成片剂形式。气雾制剂的实例可通过以下方式制备:将约2-500mg式I的化合物或其盐溶解于适当的缓冲溶液(例如盐酸盐缓冲液)中并添加张力剂(例如盐,诸如氯化钠)。可使用例如0.2微米过滤器过滤溶液以去除杂质和污染物。
所述CBP/EP300布罗莫结构域抑制剂或其盐可单独使用或与其他上文所述的用于治疗的药剂组合使用。例如药物组合配制物或给药方案的第二药剂可具有与CBP/EP300布罗莫结构域抑制剂互补的活性进而其彼此不造成不利影响。化合物可在单一药物组合物中共同施用或分别施用。在一个实施方案中,化合物或药学上可接受的盐可与细胞毒性剂共同施用以治疗增殖性疾病或癌症。
术语"共同施用"指CBP/EP300布罗莫结构域抑制剂或其盐和一种或多种其他活性药物成分(包括细胞毒性剂和放射治疗)的同时施用或以任何方式的分开依序施用。如果施用不是同时的,则化合物以彼此接近的时间施用。此外,化合物是否以相同的剂型施用无关紧要,例如,一种化合物可局部施用而另一种化合物可口服施用。
通常,任何对于待治疗的疾病或病况具有活性的药剂可共同施用。这些药剂的实例可在Cancer Principles and Practice of Oncology by V.T.Devita and S.Hellman(editors),6th edition(February 15,2001),Lippincott Williams & WilkinsPublishers中获得。基于涉及的药物和疾病的具体特性,本领域技术人员将能够辨别哪些药剂的组合可能是有用的。
实施例
下列是本发明方法和组合物的实施例。可以理解的是,鉴于上文提供的一般性描述,可实践多种其他实施方案。
实施例1:作为用于癌症免疫疗法的小分子靶标的CBP/EP300
为发现CBP/EP300布罗莫结构域如何可用作治疗癌症的靶标,研究了使用经设计以与CBP/EP300布罗莫结构域结合的强效和选择性的小分子抑制剂化合物的功能性影响,因此阻止其与染色质中乙酰化的组蛋白缔合。由于小分子抑制剂可具有脱靶效应,检验了来自不同化学骨架的具有一系列生化效力的化合物的组合(活性化合物,表1)以排除这些脱靶效应。此外,将活性化合物享有相同骨架但不具有针对CBP/EP300的布罗莫结构域的活性的化合物(非活性化合物,表1)用作阴性对照。
表1
化合物 | 效力(IC50,uM) | |
CBP/EP300(1) | 0.5 | 活性的 |
CBP/EP300(2) | 0.27 | 活性的 |
CBP/EP300(A) | >20 | 非活性的 |
CBP/EP300(B) | >20 | 非活性的 |
在第一组实验中,制备了来自纯化的未受过攻击的人CD4+T细胞的Treg细胞。这些未受过攻击的T细胞可通过标志物CD45RA在其表面的表达识别,且随后如方法部分所述使用标准和业已确立的细胞因子混合物在体外分化成为Treg细胞。Treg细胞可通过其FOXP3(一种这些细胞分化和功能所需的转录因子)的表达容易地识别(Josefowicz等人,Immunity,30,616-625(2009))。将未受过攻击的人T细胞在靶向CBP/EP300的布罗莫结构域的活性化合物或非活性对照化合物存在时的Treg-分化条件下培养。如图1所示,CBP/EP300抑制剂CBP/EP300(1)而不是非活性化合物CBP/EP300(A)展示了减少在这些实验中生成的FOXP3+细胞的数目,如通过流式细胞术可见。这些观察通过在如上文所述相同的培养条件下使用来自不同化学骨架的两种典型活性化合物CBP/EP300(1)和CBP/EP300(2)产生的剂量响应曲线确认并扩大。这些活性化合物而不是非活性化合物CBP/EP300(A)和CBP/EP300(B)的确以剂量依赖方式减少了FOXP3+细胞的数目(图2,上图)。重要的是,活化标志物CD25未受任何化合物处理影响,表明这些细胞是功能性的,尽管不能分化成为Treg谱系(图2,下图)。从这些组实验中,可以得出的结论是CBP/EP300布罗莫结构域抑制导致未受过攻击的T细胞分化成为Treg细胞的损伤。
进一步研究了CBP/EP300布罗莫结构域抑制在Treg细胞基因表达中的影响。为了该目标,实施了全基因组转录分析,与在与图1所述相同的条件下培养的样品进行了比较,与活性化合物CBP/EP300(1)或DMSO(化合物媒介物,对照)温育。作为额外对照,未受过攻击的T细胞在无分化细胞因子下培养,此后称为TH0(参见方法部分)。244个基因在转录水平下调2倍或更多。下调的基因包括FOXP3(如从图1和图2中所示的数据所预测),但还有其他认为在Treg细胞功能中起重要作用的基因,诸如LAG3、TIM3和CTLA4。由这些结果,可以得出的结论是CPB/EP300布罗莫结构域抑制导致在很大程度上定义Treg细胞的基因网络及其生物学功能的抑制(包括常规T细胞的增殖的抑制)。
表2 CBP/EP300布罗莫结构域抑制导致Treg细胞中244个基因转录活性减少2倍或更多倍
表3 CBP/EP300布罗莫结构域抑制导致CD8细胞中25个基因转录活性减少2倍或更多倍
通过癌细胞的免疫***规避的一种主要机制已知为T细胞衰竭。在该状态中,癌细胞在T细胞,特别是CD8+T细胞中诱导使这些细胞不响应且不能发挥细胞毒性功能的转录状态。该过程的核心特性是这些CD8细胞表面上抑制性受体的表达,诸如PD-1、LAG3、TIM3和CTLA4(Wherry,Nat.Immunol.,12,492-499(2011)。如上文所述,由于发现了LAG3、TIM3和CTLA4在CBP/EP300布罗莫结构域的转录控制下,还研究了导致CD8细胞中这些基因抑制的CBP/EP300布罗莫结构域是否可作为这样的方法:其用CBP/EP300抑制剂抑制其表达进而逆转CD8衰竭。如图3中所示(上图),人CD8细胞与CBP/EP300(1)而不是非活性化合物CBP/EP300(A)的温育导致LAG3、TIM3和CTLA4表达的剂量依赖性减少。相似地,如图9中所示,CBP/EP300(3)和CBP/EP300(4)都导致LAG3、TIM3和CTLA4的剂量依赖性减少。有趣的是,用CBP/EP300(1)抑制CBP/EP300布罗莫结构域未影响CD8细胞中的效应功能,这是由于编码穿孔素、颗粒酶B和EOMES的基因随化合物处理未显著改变(图3,下图)。此外,效应细胞因子IFN-γ和TNFα的产生(图4)未受化合物处理的影响。如图10所示,对于CBP/EP300(3)和CBP/EP300(4)观察到相似的趋势。此外,当用CBP/EP300(1)处理时CD8细胞的整体基因组的转录分析表明参与衰竭的其他基因,诸如CD160和KIR2DL2也有所减少。从这些结果,可以得出的结论是CBP/EP300布罗莫结构域抑制导致对于调节CD 8细胞衰竭至关重要的关键抑制受体的选择性阻断。
为研究CBP/EP300布罗莫结构域抑制对Treg细胞的影响是否导致这些细胞抑制常规T细胞增殖的功能性损伤,实施了结合Treg和CFSE-标记的未受过攻击的T细胞的抑制测定。由于细胞随每个细胞***循环稀释,在这些研究中通过基于FACS的染料量化监测了未受过攻击的T细胞的增殖。如图5所示,~50%的未受过攻击的T细胞能够在Treg细胞不存在时在CD3/CD28的刺激下增殖。然而,当未受过攻击的T细胞与Treg细胞组合时,少于10%能够增殖。用CBP/EP300(1)的温育导致Treg抑制能力的剂量依赖性抑制,如能够增殖的未受过攻击的T细胞百分数的相应增加所见。非活性的化合物CBP/EP300(A)无影响,证明了特异性。
总之,CBP/EP300布罗莫结构域在Treg细胞和CD8+T细胞中起到意想不到但至关重要的作用。CBP/EP300布罗莫结构域控制Treg细胞的分化并控制在Treg细胞中控制关键生物学功能的重要基因。此外,CBP/EP300布罗莫结构域抑制导致Treg细胞抑制能力的损伤。在CD8+T细胞中,CBP/EP300布罗莫结构域控制包括控制衰竭的重要基因的基因的亚组。因此,通过对协调功能的抑制Treg功能并逆转CD8+T细胞衰竭的协调,CBP/EP300布罗莫结构域抑制在通过癌症免疫疗法的人癌症治疗中具有益处。
方法
图1-6中给出的数据的方法
人T细胞培养:使用Miltenyi未受过攻击的人T细胞分离试剂盒(Cat#130-094-131)从健康人供体leukopak分离未受过攻击的CD4+CD45RA+T细胞至纯度>95%。分离的细胞以10^6个细胞/mL使用人T活化Dynabead(以1:1的珠/细胞比率)(Invitrogen;Cat#11132D)在iTreg-极化条件下培养,其中人TGFβ为10ng/mL且人IL-2为10U/mL(R&D Cat#分别为100-B和202-IL)。活化后16h添加化合物;培养物中DMSO终浓度为0.5%。对于"未极化的"Th0培养物,仅使用Dynabead培养分离的细胞,而不添加外源性细胞因子。从健康人供体leukopak使用Miltenyi人T细胞分离试剂盒(Cat#130-095-236)分离CD8 T细胞并在100U/mL人IL-2存在下使用人T活化Dynabead(以1:1的珠/细胞比率)以10^6个细胞/mL培养。
FACS:来自iTreg培养物的细胞首先用CD25:PE(eBioscience;Cat#12-0259-42)染色;随后为固定/透化步骤并使用人FOXP3染色试剂盒(eBioscience;Cat#77-5774-40)根据制造商的方案对细胞内FOXP3染色。通过FACS的FOXP3表达通常在活化后4天测量。
表达分析:使用RNeasy Plus试剂盒(Qiagen;Cat#74136)分离RNA。其随后为cDNA合成和使用Taqman引物和探针(Invitrogen)的qPCR。一式两份或三份运行反应,且结果通过deldelCT方法分析,针对DMSO对照标准化;将葡萄糖-6-磷酸脱氢酶(G6PD)用作管家基因(Roche;Cat#05 046 246 001)。对于整体转录分析,处理样品并在Affymetrix外显子阵列上杂交化,并在ALMAC Diagnostics获得数据。CEL文件在核心探针集上使用Affymetrix’Expression Console软件用RMA算法处理。平均化并扣除重复的log2表达值以获得log倍数变化。对于加热图谱,选择具有至少2倍改变的基因和未调整斯氏T检验p值<0.10。
抑制试验:按说明培养iTreg细胞84小时并以1:1的比率添加已用CFSE(MolecularProbes;Cat#C34554;制造商的方法)染色的未受过攻击的CD4T细胞。在圆底96孔圆底板中200uL终体积内使用Dynabead活化细胞。活化后16小时在培养物中添加化合物,DMSO终浓度为0.5%的。如通过CFSE稀释的测定和较低密度峰值的出现,在活化后60小时测量增殖。
图7-10所示数据的方法
人T细胞培养:从健康人PBMC使用Miltenyi Biotec未受过攻击的人T细胞分离试剂盒(cat#130-094-131)分离未受过攻击的CD4+CD45RA+T细胞。分离的细胞以10e6个细胞/mL使用Dynabead(Invitrogen;Cat#11132D)(以1:1的珠/细胞比率)+人重组IL-2(10ng/ml)(R&D,cat#202-IL-010)+人重组TGFb(10ng/ml)(Invitrogen;cat#PHG9204)在iTreg-分化条件下培养。16小时后,使用DMSO作为对照添加CBP抑制剂CBP/EP300(3)和CBP/EP300(4)。从健康人PBMC使用Miltenyi Biotec人T细胞分离试剂盒(cat#130-095-236)分离CD8+T细胞并以10e6个细胞/mL添加10ng/ml重组人IL-2使用人T活化Dynabead(以1:1的细胞/细胞的比率)培养。CD8+T细胞刺激3天后,收集上清液并通过Luminex分析CD8+T细胞相关效应功能细胞因子IFNγ和TNFα。图10中的数据显示使用DMSO作为对照用化合物CBP/EP300(3)和CBP/EP300(4)刺激的CD8+T细胞的上清液中分泌的IFNγ(A)和TNFα(B)(pg/ml)。CBP抑制剂最小地影响由CD8+T细胞产生的细胞因子。
FACS:首先使用CD4APC-CY7和CD25太平洋蓝(都来自BD pharmigen,cat#分别为557811和560355)对来自iTreg培养物的细胞染色;其随后为固定/透化步骤并根据制造商的方案使用人Foxp3染色试剂盒(eBioscience;cat#77-5774-40)对细胞内的Foxp3FITC进行染色。通过FACS的FOXP3表达通常在活化后4天测量。
表达分析:CD8+T细胞刺激3天后,使用mRNA CatcherTM PLUS纯化试剂盒(Invitrogen;K1570-02)提取mRNA。在CBP/p300的转录控制下通过q-RT-PCR分析了编码CD8+T细胞表面上抑制性受体Lag3、CTLA4和TIM3的基因表达。Foxp3表达和颗粒酶B(GZMB)表达(编码CD8+T细胞效应功能的基因)还通过q-RT-PCR进行了分析。将β-2-微球蛋白(B2M)用作管家基因。CBP抑制剂导致Lag3、CTLA4和TIM3表达的剂量依赖性减少。
CBP/EP300布罗莫结构域抑制剂:
CBP/EP300(3)具有如下结构:
CBP/EP300(4)具有如下结构:
除本文详细描述的次序,除非在本文清楚表明或换而言之在上下文明显矛盾的情况下,本文所述的方法可以任何适当的次序实施。本文提供的任一和全部实施例或示例性语言的使用仅意在更好地理解本发明的实施方案且无需理解为是对本发明的范围强加限制,除非在权利要求中具体记载。说明书中的语言不应理解为表明了任何非权利要求的元素对本发明的实践是至关重要的。
通过引用的方式将本文引用的全部文件并入。
尽管描述了多个实施方案,但这些实施例可发生变化以提供利用本文所述的化合物和方法的其他实施方案。因此,本发明的保护范围应通过附加的权利要求而不是由实施例的方式给出的具体实施方案进行限定。
Claims (22)
1.用于在个体中治疗癌症或延迟癌症进展的方法,其包括施用有效量的CBP/EP300布罗莫结构域抑制剂至所述个体。
2.在患有癌症的个体中增强免疫功能的方法,其包括施用有效量的CBP/EP300布罗莫结构域抑制剂至所述个体。
3.权利要求1或2的方法,其中所述个体中的CD8T细胞相对施用CBP/EP300布罗莫结构域抑制剂前具有增强的致敏、活化、增殖和/或细胞杀伤活性。
4.权利要求3的方法,其中所述CD8T细胞的数目相对施用CBP/EP300布罗莫结构域抑制剂前是升高的。
5.权利要求3-4中任一项的方法,其中所述CD8T细胞是抗原特异性CD8T细胞。
6.权利要求1-5中任一项的方法,其中所述癌症具有升高的T-细胞浸润水平。
7.权利要求1-6中任一项的方法,其中所述癌症与增加的肿瘤内Treg细胞密度相关。
8.权利要求1-7中任一项的方法,其中所述癌症选自下组:听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性T-细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、子***、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞白血病、慢性髓细胞性白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、不良增生性改变、胚胎性癌、子宫内膜癌、内皮性肉瘤、室管膜瘤、上皮癌、红白血病、食道癌、***受体阳性乳腺癌、原发性血小板增多症、尤因氏瘤、纤维肉瘤、滤泡型淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、胶质肉瘤、重链病、头颈癌、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感性***癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、***内皮肉瘤、***肉瘤、成淋巴细胞白血病、淋巴瘤、T-细胞或B-细胞来源的淋巴***恶性肿瘤、髓样癌、成神经管细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、髓细胞性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌(NMC)、非小细胞肺癌(NSCLC)、少突神经胶质瘤、口腔癌、骨源性肉瘤、卵巢癌、胰腺癌、***状腺癌、***状癌、松果体瘤、真性红细胞增多症、***癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、***瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、子宫癌和维尔姆斯瘤。
9.权利要求1-8中任一项的方法,其中所述癌症是黑素瘤、NSCLC、肾癌、卵巢癌、结肠癌、胰腺癌、肝细胞癌或乳腺癌。
10.权利要求1-9中任一项的方法,其中所述癌症是NSCLC、卵巢癌、胰腺癌、肝细胞癌或乳腺癌。
11.权利要求1-8中任一项的方法,其中所述癌症是黑素瘤、NSCLC或肾细胞癌。
12.权利要求1-11中任一项的方法,其中所述CBP/EP300布罗莫结构域抑制剂抑制CBP。
13.权利要求1-11中任一项的方法,其中所述CBP/EP300布罗莫结构域抑制剂抑制EP300。
14.权利要求1-13中任一项的方法,其中所述方法抑制Treg功能。
15.权利要求1-14中任一项的方法,其中所述方法减少CD8+T细胞的T细胞衰竭。
16.权利要求1-15中任一项的方法,其中所述CBP/EP300布罗莫结构域抑制剂不与CBP和/或EP300的HAT结构域结合。
17.权利要求1-16中任一项的方法,其中所述个体是人。
18.CBP/EP300布罗莫结构域抑制剂,其用于包括疗法的药物治疗或诊断和/或治疗癌症。
19.用于选择抗癌化合物的方法,其包括确定受试化合物是否为CBP/EP300布罗莫结构域抑制剂化合物,其中将为CBP/EP300布罗莫结构域抑制剂化合物的受试化合物选为抗癌化合物。
20.权利要求19的方法,其进一步包括确定受试化合物是否与CBP和/或EP300的HAT结构域结合,其中将不与CBP和/或EP300的HAT结构域结合的受试化合物选为抗癌化合物。
21.权利要求19或20的方法,其进一步包括确定受试化合物是否抑制Treg功能,其中将抑制Treg功能的受试化合物选为抗癌化合物。
22.权利要求19-21中任一项的方法,其进一步包括确定受试化合物是否减少CD8+T细胞的T细胞衰竭,其中将减少CD8+T细胞的T细胞衰竭的受试化合物选为抗癌化合物。
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