CN116585315A - 用于调节pd-1信号转导的组合物 - Google Patents
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Abstract
已发现了数种可调节经由PD‑1受体的信号转导的化合物。在某些实施方案中,所述化合物可促进或诱导经由PD‑1受体的可激活T细胞的激活信号。所述化合物可与PD‑1结合并抑制或阻止配体与PD‑1结合,从而压制经由PD‑1受体的抑制信号转导。
Description
本申请是申请号为201780082680.8、申请日为2017年12月1日、发明名称为“用于调节PD-1信号转导的组合物”的中国发明专利申请的分案申请,原申请为国际申请号为PCT/IB2017/057586的国家阶段申请,该国际申请要求申请日为2016年12月2日,申请号为62/429,126的美国申请的优先权。
技术领域
本发明整体涉及用于在有需要的受试者中调节免疫应答的化合物及其使用方法。
背景技术
T淋巴细胞对疾病状态(诸如感染和慢性疾病如癌症)的应答是复杂的并且涉及细胞间的相互作用和可溶性介质(称为细胞因子或淋巴因子)的产生。T细胞的活化通常取决于T细胞受体(TCR)与通过主要组织相容性复合物(MHC)呈递的抗原肽接触后的抗原特异性信号,而该反应的程度由各种共刺激分子发出的正和负的抗原非依赖性信号控制。后者通常是CD28/B7家族的成员。相反地,程序性死亡蛋白-1(Programmed Death-1,PD-1)是CD28受体家族的成员,当在T细胞上被诱导时,其传递负免疫应答。PD-1与其配体之一(PD-L1或PD-L2)之间的接触可诱导抑制性应答,该抑制性应答可降低T细胞增殖和/或T细胞应答的强度和/或持续时间。
PD-1/PD-1配体(PD-L)相互作用是肿瘤用于在外周和肿瘤微环境内抑制效应T细胞的重要机制之一。PD-1被其配体连接的主要结果是抑制T细胞受体(TCR)下游的信号传导。因此,经由PD-1的信号转导通常向T细胞提供压制或抑制信号,其导致T细胞增殖减少或T细胞活化的其它减少。PD-L1是主要的PD-1配体,其在T细胞中引起抑制性信号转导。迄今为止,已开发出阻断PD-1/PD-L相互作用的数种抗PD-1抗体和抗PD-L1抗体、抗PD-L2抗体以及ECD-Fc融合蛋白,这些药物已处于临床或已获得食品和药物监督管理局批准。在临床前研究和临床研究中都显示阻断这种抑制性相互作用是有效的。
负信号转导可能不是唯一从PD-1传送的信号,并且可能通过恰当的接合位点传送某些激活信号。
因此,本发明的一个目的是提供用于诱导T细胞活化的组合物和方法。
本发明的另一个目的是提供用于诱导或促进经由PD-1的T细胞活化信号的组合物和方法。
本发明的另一个目的是提供通过增加T细胞活性来治疗疾病,特别是癌症和传染病的治疗方案。
发明内容
已发现与PD-1受体接合并在T细胞中发送激活信号(诱导IFNγ产生)的数种化合物。一个实施方案提供了一种药物组合物,该药物组合物以一定的量含有一种或多种选自以下的化合物:1-(1H-苯并[d][1,2,3]三唑-1-基)蒽-9,10-二酮;1,1’-(氧基双(4,1-亚苯基))双(3-(2-氯苯基)脲);5,5’-二苯基-2,2’,3,3’-四氢-2,2’-二苯并[d]噁唑;2-(异喹啉-1-基)-5-苯基-4-(对甲苯基)噁唑;2’-((6-氧代-5,6-二氢菲啶-3-基)氨甲酰基)-[1,1’-联苯]-2-甲酸;2’-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1’-联苯]-2-甲酸;3-(4-氯-6-苯氧基-1,3,5-三嗪-2-基)-1-苯基-1H-吲哚;1,8-双(苯硫基)蒽-9,10-二酮;4-氯-2-(3-(苯硫基)苯基)喹啉-6-磺酰氟;双(2,2,4-三甲基-1,2-二氢喹啉-6-基)甲烷;2-硝基-4-((6-硝基喹啉-4-基)氨基)-N-(4-(吡啶-4-基氨基)苯基)苯甲酰胺;1,2-双(4-异丙基-6-(三氟甲基)嘧啶-2-基)肼;3-(苄硫基)菲并[9,10-e][1,2,4]三嗪;(4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(1H-咪唑-1-羰基)-4,4,6a,6b,11,11,14b-七甲基-3,13-二氧代-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-十八氢苉-2-腈(CDDO-Im);2-(1H-菲并[9,10-d]咪唑-2-基)苯酚;3-(4,5-二甲基苯并[h][1,6]萘啶-2-基)-2-甲基喹啉-4-胺;N-(4-溴萘-1-基)-1-羟基-2-萘甲酰胺;N-(3-(吡啶-2-基)异喹啉-1-基)吡啶-2-甲脒;2-(异喹啉-1-基)-4,5-二苯基噁唑;2,2'-((3,3'-二甲氧基-[1,1'-联苯]-4,4'-二基)双(氮烷二基))二苯甲酸;或它们的对映体、溶剂化物、药学上可接受的盐或衍生物,当施用给有需要的受试者时所述量的化合物可有效调节经由PD-1受体的信号转导。在某些实施方案中,这些化合物也称为PD-1调节化合物,并且组合物结合至PD-1受体的特定结构域,阻断和/或引发T细胞中的激活信号传导。因此,使PD-1受体的该位点与所公开的化合物接合可以阻断PD-1/PD-L1相互作用和/或可以刺激T细胞。所公开的化合物和组合物可用于治疗免疫障碍和癌症,因为它们通过原本抑制性的受体来刺激T细胞和/或阻断所述抑制性相互作用,从而克服与PD-1/PD-L途径相关的免疫耐受。
用于抗-PD1的当前方法是阻断其对T细胞的负信号,然后T细胞需要另一个信号来被激活。在某些实施方案中,所公开的PD-1调节化合物不仅1)阻止负信号,而且2)同时提供激活信号。
在一个实施方案中,所述一种或多种PD-1结合化合物在生理条件下与PD-1结合,并促进或诱导经由PD-1的可激活表达PD-1的T细胞的激活信号。在某些实施方案中,所述一种或多种PD-1结合化合物在生理条件下与PD-1受体结合并抑制、减少或阻止PD-1的配体与PD-1结合,从而抑制、减少或阻止经由PD-1受体的负信号转导。
另一个实施方案提供了通过向有需要的受试者施用一定量的一种或多种上面论述的化合物来在所述受试者中诱导或促进T细胞活化的方法,所述量的化合物可有效增加T细胞的抗原特异性增殖、增加或增强T细胞的细胞因子产生、刺激T细胞的分化和效应子功能和/或促进T细胞存活)或克服T细胞耗竭和/或失能。
另一个实施方案提供了通过向有需要的受试者施用有效量的一种或多种公开的化合物以诱导或促进T细胞活化,来在所述受试者中诱导或促进免疫应答的方法。
另一个实施方案提供了通过向受试者施用有效量的一种或多种PD-1调节化合物以诱导或促进T细胞活化来治疗癌症的方法。所述癌症可以是膀胱癌、脑癌、乳腺癌、宫颈癌、结肠直肠癌、食道癌、肾癌、肝癌、肺癌、鼻咽癌、胰腺癌、前列腺癌、皮肤癌、胃癌、子宫癌、卵巢癌、睾丸癌、血液癌、黑素瘤、肾癌、骨髓瘤、甲状腺癌、淋巴瘤、白血病或癌症的转移性病变。
一种方法提供了通过向有需要的受试者施用有效量的一种或多种PD-1调节化合物以在所述受试者中促进或诱导T细胞活化来治疗所述受试者的感染的方法。所述感染可以是微生物感染,例如细菌感染、真菌感染或病毒感染。在另一个实施方案中,所述感染是寄生虫感染。
具体实施方式
I.定义
术语“T细胞激活信号”或“活化信号”是指经由T细胞上的受体的可诱导或促进T细胞活化的信号转导。T细胞的活化包括但不限于T细胞的抗原特异性增殖的增加、增加或增强的T细胞的细胞因子产生、刺激T细胞的分化和效应子功能和/或促进T细胞存活或克服T细胞耗竭和/或失能。
术语“T细胞抑制信号”或“抑制信号”或“负信号转导”是指经由T细胞上的受体的可诱导或促进T细胞活性的压制的信号转导。示例性的抑制信号是PD-L1与PD-1受体的相互作用,其可降低T细胞增殖和/或T细胞应答的强度和/或持续时间。
在描述要求权利保护的本发明的上下文中(特别是在权利要求的上下文中)使用术语“一个”、“一种”、“该(所述)”和类似的指代物应被解释为涵盖单数和复数,除非本文另有说明或明确与上下文相矛盾。
除非本文另有说明,否则本文中对数值范围的描述仅旨在用作单独提及落入该范围内的每个单独值的简写方法,并且将每个单独的值并入本说明书中,就如同其在本文中单独引用一样。
术语“约”的使用旨在描述在大约+/-10%的范围内高于或低于所述值的值;在其它实施方案中,值的数值范围可以在大约+/-5%的范围内高于或低于所述值;在其它实施方案中,值的数值范围可以在大约+/-2%的范围内高于或低于所述值;在其它实施方案中,值的数值范围可以在大约+/-1%的范围内高于或低于所述值。前述范围旨在通过上下文解释清楚,并且不暗示进一步的限制。除非本文另有说明或上下文明显矛盾,否则本文所述的所有方法均可以任何合适的顺序进行。除非另有说明,否则本文提供的任何和所有实例或示例性语言(例如,“诸如”)的使用仅旨在更好地说明本发明,而不是对本发明的范围进行限制。说明书中的任何语言都不应被解释为表明任何未要求权利保护的要素对于本发明的实施是必不可少的。
首字母缩略词“ECD”是指胞外结构域。
如本文所用,术语“有效量”或“治疗有效量”意指足以治疗、抑制或减轻所治疗疾病状态的一种或多种症状或以其它方式提供所需的药理学和/或生理学效果的剂量。精确剂量将根据多种因素而变化,诸如受试者依赖性变量(例如,年龄、免疫系统健康状况等)、疾病以及所施用的治疗。
术语“个体”、“宿主”、“受试者”和“患者”在本文中可互换使用,并且是指哺乳动物,包括但不限于人、啮齿动物(诸如小鼠和大鼠)以及其它实验室动物。
术语“可溶性受体”是指涉及信号转导的跨膜蛋白的胞外结构域(ECD)。例如,可溶性PD-1是指PD-1受体的胞外结构域。可溶性受体可以是该跨膜蛋白的胞外结构域的片段,该片段保留了受体与该受体的配体相结合的能力。可溶性受体包括天然存在的可溶性受体和合成的(即非天然存在的)可溶性受体。
II.用于调节PD-1信号转导的组合物
A.PD-1调节化合物
已发现了数种可调节经由PD-1受体的信号转导的化合物。一个实施方案提供了在有需要的受试者中调节PD-1信号转导的药物制剂,其中所述药物制剂含有有效量的一种或多种图1A-1T的化合物。在一个实施方案中,图1A-1T的化合物与PD-1结合并促进或诱导经由PD-1受体的可激活T细胞的激活信号。在另一个实施方案中,一种或多种图1A-1T的化合物与PD-1结合并抑制配体(诸如PD-L1和PD-L2)与PD-1受体的结合,从而阻断经由PD-1受体的T细胞抑制信号的转导。在另一个实施方案中,图1A-1T的化合物与PD-1结合并阻断配体与PD-1的结合,以及促进或诱导经由PD-1的可激活T细胞的激活信号。
1.1-(1H-苯并[d][1,2,3]三唑-1-基)蒽-9,10-二酮
图1A示出了1-(1H-苯并[d][1,2,3]三唑-1-基)蒽-9,10-二酮的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,1-(1H-苯并[d][1,2,3]三唑-1-基)蒽-9,10-二酮与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,1-(1H-苯并[d][1,2,3]三唑-1-基)蒽-9,10-二酮与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受1-(1H-苯并[d][1,2,3]三唑-1-基)蒽-9,10-二酮阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,1-(1H-苯并[d][1,2,3]三唑-1-基)蒽-9,10-二酮与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
2.1,1’-(氧基双(4,1-亚苯基))双(3-(2-氯苯基)脲)
图1B示出了1,1’-(氧基双(4,1-亚苯基))双(3-(2-氯苯基)脲)的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,1,1’-(氧基双(4,1-亚苯基))双(3-(2-氯苯基)脲)与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在一个实施方案中,1,1’-(氧基双(4,1-亚苯基))双(3-(2-氯苯基)脲)与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受1,1’-(氧基双(4,1-亚苯基))双(3-(2-氯苯基)脲)阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,1,1’-(氧基双(4,1-亚苯基))双(3-(2-氯苯基)脲)与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
3.5,5’-二苯基-2,2’,3,3’-四氢-2,2’-二苯并[d]噁唑
图1C示出了5,5’-二苯基-2,2',3,3'-四氢-2,2'-二苯并[d]噁唑的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,5,5’-二苯基-2,2',3,3'-四氢-2,2'-二苯并[d]噁唑与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,5,5’-二苯基-2,2',3,3'-四氢-2,2'-二苯并[d]噁唑与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受5,5’-二苯基-2,2',3,3'-四氢-2,2'-二苯并[d]噁唑阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,5,5’-二苯基-2,2',3,3'-四氢-2,2'-二苯并[d]噁唑与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
4.2-(异喹啉-1-基)-5-苯基-4-(对甲苯基)噁唑
图1D示出了2-(异喹啉-1-基)-5-苯基-4-(对甲苯基)噁唑的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,2-(异喹啉-1-基)-5-苯基-4-(对甲苯基)噁唑与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,2-(异喹啉-1-基)-5-苯基-4-(对甲苯基)噁唑与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受2-(异喹啉-1-基)-5-苯基-4-(对甲苯基)噁唑阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,2-(异喹啉-1-基)-5-苯基-4-(对甲苯基)噁唑与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
5.2’-((6-氧代-5,6-二氢菲啶-3-基)氨甲酰基)-[1,1'-联苯]-2-甲酸
图1E示出了2’-((6-氧代-5,6-二氢菲啶-3-基)氨甲酰基)-[1,1’-联苯]-2-甲酸的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,2’-((6-氧代-5,6-二氢菲啶-3-基)氨甲酰基)-[1,1’-联苯]-2-甲酸与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,2’-((6-氧代-5,6-二氢菲啶-3-基)氨甲酰基)-[1,1’-联苯]-2-甲酸与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受2’-((6-氧代-5,6-二氢菲啶-3-基)氨甲酰基)-[1,1’-联苯]-2-甲酸阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,2’-((6-氧代-5,6-二氢菲啶-3-基)氨甲酰基)-[1,1’-联苯]-2-甲酸与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
6.2'-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1'-联苯]-2-甲酸
图1F示出了2’-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1’-联苯]-2-甲酸的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,2'-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1'-联苯]-2-甲酸与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,2’-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1’-联苯]-2-甲酸与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受2'-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1'-联苯]-2-甲酸阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,2'-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1'-联苯]-2-甲酸与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
7.3-(4-氯-6-苯氧基-1,3,5-三嗪-2-基)-1-苯基-1H-吲哚
图1G示出了3-(4-氯-6-苯氧基-1,3,5-三嗪-2-基)-1-苯基-1H-吲哚的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,3-(4-氯-6-苯氧基-1,3,5-三嗪-2-基)-1-苯基-1H-吲哚与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,3-(4-氯-6-苯氧基-1,3,5-三嗪-2-基)-1-苯基-1H-吲哚与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受2'-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1'-联苯]-2-甲酸阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,2'-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1'-联苯]-2-甲酸与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
8.1,8-双(苯硫基)蒽-9,10-二酮
图1H示出了1,8-双(苯硫基)蒽-9,10-二酮的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,1,8-双(苯硫基)蒽-9,10-二酮与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,1,8-双(苯硫基)蒽-9,10-二酮与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受1,8-双(苯硫基)蒽-9,10-二酮阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,1,8-双(苯硫基)蒽-9,10-二酮与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
9.4-氯-2-(3-(苯硫基)苯基)喹啉-6-磺酰氟
图1I示出了4-氯-2-(3-(苯硫基)苯基)喹啉-6-磺酰氟的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,4-氯-2-(3-(苯硫基)苯基)喹啉-6-磺酰氟与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,4-氯-2-(3-(苯硫基)苯基)喹啉-6-磺酰氟与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受4-氯-2-(3-(苯硫基)苯基)喹啉-6-磺酰氟阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,4-氯-2-(3-(苯硫基)苯基)喹啉-6-磺酰氟与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
10.双(2,2,4-三甲基-1,2-二氢喹啉-6-基)甲烷
图1J示出了双(2,2,4-三甲基-1,2-二氢喹啉-6-基)甲烷的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,双(2,2,4-三甲基-1,2-二氢喹啉-6-基)甲烷与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,双(2,2,4-三甲基-1,2-二氢喹啉-6-基)甲烷与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受双(2,2,4-三甲基-1,2-二氢喹啉-6-基)甲烷阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,双(2,2,4-三甲基-1,2-二氢喹啉-6-基)甲烷与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
11.2-硝基-4-((6-硝基喹啉-4-基)氨基)-N-(4-(吡啶-4-基氨基)苯基)苯甲酰胺
图1K示出了2-硝基-4-((6-硝基喹啉-4-基)氨基)-N-(4-(吡啶-4-基氨基)苯基)苯甲酰胺的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,2-硝基-4-((6-硝基喹啉-4-基)氨基)-N-(4-(吡啶-4-基氨基)苯基)苯甲酰胺与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,2-硝基-4-((6-硝基喹啉-4-基)氨基)-N-(4-(吡啶-4-基氨基)苯基)苯甲酰胺与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受2-硝基-4-((6-硝基喹啉-4-基)氨基)-N-(4-(吡啶-4-基氨基)苯基)苯甲酰胺阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,2-硝基-4-((6-硝基喹啉-4-基)氨基)-N-(4-(吡啶-4-基氨基)苯基)苯甲酰胺与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
12.1,2-双(4-异丙基-6-(三氟甲基)嘧啶-2-基)肼
图1L示出了1,2-双(4-异丙基-6-(三氟甲基)嘧啶-2-基)肼的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,1,2-双(4-异丙基-6-(三氟甲基)嘧啶-2-基)肼与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,1,2-双(4-异丙基-6-(三氟甲基)嘧啶-2-基)肼与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受1,2-双(4-异丙基-6-(三氟甲基)嘧啶-2-基)肼阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中1,2-双(4-异丙基-6-(三氟甲基)嘧啶-2-基)肼与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
13.3-(苄硫基)菲并[9,10-e][1,2,4]三嗪
图1M示出了3-(苄硫基)菲并[9,10-e][1,2,4]三嗪的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,3-(苄硫基)菲并[9,10-e][1,2,4]三嗪与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,3-(苄硫基)菲并[9,10-e][1,2,4]三嗪与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受3-(苄硫基)菲并[9,10-e][1,2,4]三嗪阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,3-(苄硫基)菲并[9,10-e][1,2,4]三嗪与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
14.(4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(1H-咪唑-1-羰基)-4,4,6a,6b,11,11,14b-七甲基-3,13-二氧代-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-十八氢苉-2-腈(CDDO-Im)
图1N示出了(4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(1H-咪唑-1-羰基)-4,4,6a,6b,11,11,14b-七甲基-3,13-二氧代-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-十八氢苉-2-腈(CDDO-Im)的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,(4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(1H-咪唑-1-羰基)-4,4,6a,6b,11,11,14b-七甲基-3,13-二氧代-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-十八氢苉-2-腈(CDDO-Im)与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,(4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(1H-咪唑-1-羰基)-4,4,6a,6b,11,11,14b-七甲基-3,13-二氧代-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-十八氢苉-2-腈(CDDO-Im)与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受(4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(1H-咪唑-1-羰基)-4,4,6a,6b,11,11,14b-七甲基-3,13-二氧代-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-十八氢苉-2-腈(CDDO-Im)阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,(4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(1H-咪唑-1-羰基)-4,4,6a,6b,11,11,14b-七甲基-3,13-二氧代-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-十八氢苉-2-腈(CDDO-Im)与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
15.2-(1H-菲并[9,10-d]咪唑-2-基)苯酚
图1O示出了2-(1H-菲并[9,10-d]咪唑-2-基)苯酚的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,2-(1H-菲并[9,10-d]咪唑-2-基)苯酚与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,2-(1H-菲并[9,10-d]咪唑-2-基)苯酚与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受2-(1H-菲并[9,10-d]咪唑-2-基)苯酚阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,2-(1H-菲并[9,10-d]咪唑-2-基)苯酚与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
16.3-(4,5-二甲基苯并[h][1,6]萘啶-2-基)-2-甲基喹啉-4-胺
图1P示出了2-(1H-菲并[9,10-d]咪唑-2-基)苯酚的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,2-(1H-菲并[9,10-d]咪唑-2-基)苯酚与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,2-(1H-菲并[9,10-d]咪唑-2-基)苯酚与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受2-(1H-菲并[9,10-d]咪唑-2-基)苯酚阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,2-(1H-菲并[9,10-d]咪唑-2-基)苯酚与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
17.N-(4-溴萘-1-基)-1-羟基-2-萘甲酰胺
图1Q示出了N-(4-溴萘-1-基)-1-羟基-2-萘甲酰胺的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,N-(4-溴萘-1-基)-1-羟基-2-萘甲酰胺与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,N-(4-溴萘-1-基)-1-羟基-2-萘甲酰胺与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受N-(4-溴萘-1-基)-1-羟基-2-萘甲酰胺阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,N-(4-溴萘-1-基)-1-羟基-2-萘甲酰胺与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
18.N-(3-(吡啶-2-基)异喹啉-1-基)吡啶-2-甲脒
图1R示出了N-(3-(吡啶-2-基)异喹啉-1-基)吡啶-2-甲脒的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,N-(3-(吡啶-2-基)异喹啉-1-基)吡啶-2-甲脒与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,N-(3-(吡啶-2-基)异喹啉-1-基)吡啶-2-甲脒与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受N-(3-(吡啶-2-基)异喹啉-1-基)吡啶-2-甲脒阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,N-(3-(吡啶-2-基)异喹啉-1-基)吡啶-2-甲脒与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
19.2-(异喹啉-1-基)-4,5-二苯基噁唑
图1S示出了2-(异喹啉-1-基)-4,5-二苯基噁唑的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,2-(异喹啉-1-基)-4,5-二苯基噁唑与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,2-(异喹啉-1-基)-4,5-二苯基噁唑与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受2-(异喹啉-1-基)-4,5-二苯基噁唑阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,2-(异喹啉-1-基)-4,5-二苯基噁唑与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
20.2,2'-((3,3'-二甲氧基-[1,1'-联苯]-4,4'-二基)双(氮烷二基))二苯甲酸
图1T示出了2,2'-((3,3'-二甲氧基-[1,1'-联苯]-4,4'-二基)双(氮烷二基))二苯甲酸的结构,其与PD-1结合并调节经由PD-1受体的信号转导。在一个实施方案中,2,2'-((3,3'-二甲氧基-[1,1'-联苯]-4,4'-二基)双(氮烷二基))二苯甲酸与PD-1结合并促进或诱导经由PD-1的激活信号以激活T细胞。在另一个实施方案中,2,2'-((3,3'-二甲氧基-[1,1'-联苯]-4,4'-二基)双(氮烷二基))二苯甲酸与PD-1结合并通过阻断PD-1的配体与PD-1受体的相互作用来阻断经由PD-1的信号转导。受2,2'-((3,3'-二甲氧基-[1,1'-联苯]-4,4'-二基)双(氮烷二基))二苯甲酸阻断的示例性PD-1配体包括但不限于PD-L1和PD-L2。在另一个实施方案中,2,2'-((3,3'-二甲氧基-[1,1'-联苯]-4,4'-二基)双(氮烷二基))二苯甲酸与PD-1结合并阻断配体与PD-1结合以及促进或诱导经由PD-1的可激活T细胞的激活信号。
III.治疗方法
A.调节PD-1信号转导
PD-1调节化合物及其药物组合物通常可在体内和体外用作免疫应答刺激治疗剂。通常,所公开的组合物可用于治疗患有或易患任何受试者的免疫系统可对其产生免疫应答的疾病或障碍的受试者。
1.促进经由PD-1的T细胞激活信号
在一个实施方案中,PD-1调节组合物通过与PD-1结合并且促进经由PD-1的T细胞激活信号来调节PD-1信号转导。该T细胞激活信号引起或促进T细胞活化,包括以下中的一者或多者:T细胞的抗原特异性增殖的增加、增加或增强的T细胞的细胞因子产生、刺激T细胞的分化和效应子功能和/或促进T细胞存活)、克服T细胞耗竭和/或失能或者它们的任何组合。在一些实施方案中,PD-1调节化合物和组合物结合PD-1并且引起或促进经由PD-1的可激活T细胞的信号转导,并且阻断其它配体与PD-1结合。
通过向受试者施用一定量的一种或多种PD-1调节组合物,所公开的PD-1调节组合物可用于刺激或增强宿主中的免疫应答以治疗癌症或感染,所述一定量的一种或多种PD-1调节组合物可有效激活所述受试者中的T细胞。可用所提供的组合物和方法治疗的癌症的类型包括但不限于以下:膀胱癌、脑癌、乳腺癌、宫颈癌、结肠直肠癌、食道癌、肾癌、肝癌、肺癌、鼻咽癌、胰腺癌、前列腺癌、皮肤癌、胃癌、子宫癌、卵巢癌、睾丸癌、血液癌、黑素瘤、肾癌、骨髓瘤、甲状腺癌、淋巴瘤、白血病或癌症的转移性病变。
可以治疗的恶性肿瘤在本文中根据肿瘤来源的组织的胚胎起源进行分类。癌是由内胚层或外胚层组织(诸如皮肤或内脏器官和腺体的上皮衬里)产生的肿瘤。较少出现的肉瘤来源于中胚层结缔组织,诸如骨骼、脂肪和软骨。白血病和淋巴瘤是骨髓造血细胞的恶性肿瘤。白血病作为单细胞增殖,而淋巴瘤往往作为肿瘤块生长。恶性肿瘤可能出现在身体的许多器官或组织中以确立癌症。
2.PD-1调节组合物在疫苗中的用途
所公开的PD-1调节组合物可以单独施用或与任何其它合适的治疗组合施用。在一个实施方案中,一种或多种PD-1调节组合物可以与疫苗组合物联合施用或作为疫苗组合物的组分施用。所公开的PD-1调节组合物可以在疫苗施用之前、同时或之后施用。在一个实施方案中,PD-1调节组合物在施用疫苗的同时施用。
所公开的PD-1调节组合物可以与预防性疫苗或治疗性疫苗联合施用,其可以用于引发或增强受试者对预先存在的抗原(诸如患有癌症的受试者中的肿瘤抗原)的免疫应答。
根据本领域熟知的原理,预防性、治疗性或脱敏免疫应答的期望结果可根据疾病而变化。类似地,针对癌症、变应原或感染因子的免疫应答可以完全治疗疾病、可以缓解症状、或者可以是针对疾病的总体治疗性干预中的一个方面。例如,刺激针对癌症的免疫应答可以与外科手术方法、化疗方法、放疗方法、激素方法和其它免疫学方法相结合以影响治疗。
3.辅助疗法
所公开的PD-1调节组合物可用于克服对抗原的耐受性,从而治疗癌症。适当地靶向共信号传导途径可导致T细胞活化并克服对肿瘤抗原的耐受性。一个实施方案提供了施用有效量的PD-1调节组合物以克服抗原耐受性。PD-1调节组合物还可以抑制或减少PD-1负信号传导,以在施用第一治疗剂或对免疫原性差的抗原(诸如肿瘤相关抗原)的应答后促进、增强或扩增T细胞应答和总体免疫力。另一个实施方案提供了在首选治疗、疫苗接种或肿瘤的杀灭(抗体介导的、使用化疗或放射或它们的任何组合)后PD-1调节组合物的被动施用。据信PD-1调节组合物可增强/强化初次应答,从而导致对肿瘤的稳健和持久的保护性应答。
除了用于根除肿瘤的第一治疗剂之外施用的治疗称为辅助疗法。给予辅助治疗以增强首选治疗(诸如外科手术或放疗)来减少癌症复发的机会。这种附加的治疗可以导致初次应答的扩增,如通过更有效和/或延长的应答所证明的。
有五种主要类型的辅助疗法(注意,其中一些也用作首选疗法/单一疗法):1.)使用药物杀死癌细胞的化学疗法,通过阻止它们增殖或者通过使细胞自我毁灭,2.)激素疗法以减少激素产生,阻止癌症的生长,3.)使用高能射线杀死癌细胞的放射疗法,4.)试图影响身体自身免疫系统以攻击和根除任何剩余的癌细胞的免疫疗法。免疫疗法可以刺激身体自身的防御(癌症疫苗)或补充它们(被动施用抗体或免疫细胞),或5.)针对癌细胞中存在的特定分子,从而放过正常、健康的细胞的靶向疗法。例如,许多乳腺癌病例是由产生过多称为HER2的蛋白质的肿瘤引起的。曲妥珠单抗用作靶向HER2阳性肿瘤的辅助疗法。
通常,辅助治疗与首选治疗共同施用或联合给予以诱导多种机制并增加根除肿瘤的机会。免疫疗法,特别是疫苗,提供诱导持续的抗肿瘤效果,具有精确的特异性以及具有规避现有免疫耐受的能力的独特优点。已经发现,延迟“辅助疗法”可使应答最大化并增加根除肿瘤的机会。
在一个实施方案中,在施用第一治疗剂诸如癌症治疗剂后施用如本文所述的PD-1调节组合物。施用所述辅助剂的时间可以在首选治疗后的第0天至第14天的范围内,并且可以包括单次或多次治疗。在某些实施方案中,在施用首选治疗后1、2、3、4、5、6、7、8、9、10、11、12、13或14天施用PD-1调节组合物。优选给患者系统性地施用(IV、IM或SQ)所述辅助剂。
用于增强免疫应答的PD-1调节组合物的选择可取决于初始的首选治疗模式。因此,可能需要治疗剂与PD-1调节组合物的特定组合以获得最佳功效。可针对癌症类型(例如实体瘤对液体瘤)优化PD-1调节组合物,例如利用亲和力成熟。
施用不限于治疗现有肿瘤或传染病,而是还可用于预防或降低个体发展此类疾病的风险,即用于预防用途。预防性疫苗接种的潜在候选者包括具有高的发展癌症风险(即具有某些类型癌症的病史或家族史)的个体。
另一个实施方案提供了通过向受试者施用有效量的PD-1调节组合物以增强所述受试者的T细胞活化来在所述受试者中增加肿瘤浸润性白细胞的群体的方法。
B.联合疗法
所公开的PD-1调节组合物可以单独施用给有需要的受试者或者与一种或多种附加的治疗剂或所述PD-1调节组合物的组合联合施用给有需要的受试者。所述附加的治疗剂是基于待治疗的病症、障碍或疾病选择。例如,PD-1调节组合物可与起到增强或促进免疫应答的作用的一种或多种附加药剂共同施用。
1.化疗剂
PD-1调节组合物还可以与一种或多种附加的治疗剂联合。代表性的治疗剂包括但不限于化疗剂和促凋亡剂。代表性的化疗剂包括但不限于安吖啶(amsacrine)、博来霉素、白消安、卡培他滨、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、克拉屈滨、氯法拉滨、克立他酶(crisantaspase)、环磷酰胺、阿糖胞苷、达卡巴嗪、更生霉素、柔红霉素、多烯紫杉醇(docetaxel)、阿霉素、表阿霉素、依托泊苷、氟达拉滨、氟尿嘧啶、吉西他滨、羟基脲、伊达比星、异环磷酰胺、伊立替康、甲酰四氢叶酸、脂质体阿霉素、脂质体柔红霉素、洛莫司汀、美法仑、巯嘌呤、美司钠、甲氨蝶呤、丝裂霉素、米托蒽醌、奥沙利铂、紫杉醇、培美曲塞、喷司他丁、丙卡巴肼、雷替曲塞、沙铂、链脲佐菌素、替加氟-尿嘧啶、替莫唑胺、替尼泊苷、塞替哌、硫鸟嘌呤、拓扑替康、苏消安、长春碱、长春新碱、长春地辛、长春瑞滨或它们的组合。代表性的促凋亡剂包括但不限于氟达拉滨、星状孢菌素、环己酰亚胺、放线菌素D、乳糖神经酰胺、15d-PGJ(2)以及它们的组合。
在某些实施方案中,可以联合使用不止一种多价免疫调节组合物以增加或增强受试者的免疫应答。
2.增强剂
所公开的PD-1调节化合物和组合物可以与促进或增强受试者的免疫应答的药剂联合或交替施用。这些附加的药剂统称为免疫增强剂。可与所公开的PD-1调节化合物一起使用的代表性免疫增强剂包括但不限于卡介苗(BCG)、杀死的短小棒杆菌(Corynebacterium parvum)、分枝杆菌细胞壁、CpG寡脱氧核苷酸、培非格司亭、非格司亭、tbo-非格司亭、沙格司亭、阿地白介素、奥普瑞白介素、干扰素β-1a、干扰素alfacon-1、干扰素γ-1b、干扰素α-n3、干扰素β-1b、聚乙二醇干扰素β-1a、格拉替雷、牛培加酶、普乐沙福、环磷酰胺、异环磷酰胺、培磷酰胺、曲磷胺(trophosphamide)以及它们的组合。
C.过继转移
过继性T细胞疗法是一种用于治疗已确立肿瘤的患者的有前景的策略,但是通常限于其中可以获得肿瘤浸润淋巴细胞(用于离体培养的T细胞的来源)的特定癌症。一个实施方案提供了通过施用有效量的PD-1调节组合物以抑制或减少T细胞中PD-1受体介导的抑制性信号转导并联合抗原特异性T细胞的过继性T细胞疗法来治疗癌症的方法。过继性T细胞转移可以在施用PD-1调节组合物之前或之后施用给受试者,或者加入离体细胞中。
抗原特异性T细胞系可以通过用抗原体外刺激、然后在CD3/CD28珠上非特异性扩增来产生。可以使用IFN-γ和颗粒酶B酶联免疫吸附斑来评估扩增抗原特异性T细胞的能力。可以通过流式细胞术评价所得的T细胞系的表型,包括表达FOXP3的CD4(+)T细胞的存在与否。通常通过在存在IL-2的情况下用最佳长度的抗原肽进行重复体外刺激来从外周血单核细胞(PBMC)扩增抗原特异性T细胞群体。传统上使用低剂量的IL-2(介于10U/ml至50U/ml之间)以避免淋巴因子激活的杀伤细胞的活化/扩增,如通常用于监测特异性T细胞扩增的铬释放测定法中所揭示的。抗原肽的浓度可以是0.1μM-10μM。
1.肿瘤特异性抗原和肿瘤相关抗原
可从来自待治疗受试者的肿瘤的活组织检查获得可用于扩增T细胞的抗原。可以从肿瘤活组检物中以生物化学方法纯化抗原。作为另外一种选择,抗原可以是重组多肽。肿瘤表达的抗原对肿瘤可以是特异性的,或者与非肿瘤细胞相比可以在肿瘤细胞上以较高的水平表达。抗原标志物诸如称为肿瘤相关抗原的血清学定义的标志物,其由癌细胞独特表达或相对于适当的对照在患有恶性病症的受试者中以明显更高的水平存在(例如,以统计学显著的方式升高),设想用于某些实施方案。
肿瘤相关抗原可包括,例如,细胞癌基因编码的产物或异常表达的原癌基因编码的产物(例如,由neu、ras、trk和kit基因编码的产物),或者生长因子受体的突变形式或受体样细胞表面分子(例如,由c-erb B基因编码的表面受体)。其它肿瘤相关抗原包括可直接参与转化事件的分子,或可能不直接参与致癌转化事件但由肿瘤细胞表达的分子(例如,癌胚抗原、CA-125、黑素瘤相关抗原等)(参见,例如美国专利No.6,699,475;Jager等人,Int.J.Cancer,106:817-20(2003);Kennedy等人,Int.Rev.Immunol.,22:141-72(2003);Scanlan等人,Cancer Immun.,4:1(2004))。
编码细胞肿瘤相关抗原的基因包括细胞癌基因和异常表达的原癌基因。通常,细胞癌基因编码与细胞转化直接相关的产物,因此,这些抗原是免疫疗法的特别优选的靶标。一个例子是致瘤neu基因,其编码参与致癌转化的细胞表面分子。其它例子包括ras、kit和trk基因。原癌基因(突变而形成癌基因的正常基因)的产物可能异常表达(例如,过表达),并且这种异常表达可能与细胞转化有关。因此,可以靶向由原癌基因编码的产物。一些癌基因编码在肿瘤细胞表面上表达的生长因子受体分子或生长因子受体样分子。一个例子是由c-erbB基因编码的细胞表面受体。其它肿瘤相关抗原可能或可能不直接参与恶性转化。然而,这些抗原由某些肿瘤细胞表达,因此可提供有效的靶标。一些例子是癌胚抗原(CEA)、CA125(与卵巢癌相关)和黑素瘤特异性抗原。
例如,在卵巢癌和其它癌中,肿瘤相关抗原可在易于获得的生物流体诸如血清或粘膜分泌物的样品中检测到。一种这样的标记物是CA125,其为一种癌相关抗原,其也脱落进血流中,可在血清中检测到(例如,Bast等人,N.Eng.J.Med.,309:883(1983);Lloyd等人,Int.J.Canc.,71:842(1997))。已测量了血清和其它生物流体中的CA125水平以及其它标志物的水平,例如癌胚抗原(CEA)、鳞状细胞癌抗原(SCC)、组织多肽特异性抗原(TPS)、唾液酸TN粘蛋白(STN)和胎盘碱性磷酸酶(PLAP),试图提供卵巢癌和其它癌的诊断和/或预后概况(例如,Sarandakou等人,Acta Oncol.,36:755(1997);Sarandakou等人,Eur.J.Gynaecol.Oncol.,19:73(1998);Meier等,人Anticancer Res.,17(4B):2945(1997);Kudoh等人,Gynecol.Obstet.Invest.,47:52(1999))。升高的血清CA125也可伴随神经母细胞瘤(例如,Hirokawa等人,Surg.Today,28:349(1998)),而升高的CEA和SCC等可伴随结肠直肠癌(Gebauer等人,Anticancer Res.,17(4B):2939(1997))。
通过与单克隆抗体K-1的反应性定义的肿瘤相关抗原间皮素存在于大多数鳞状细胞癌(包括上皮卵巢肿瘤、宫颈肿瘤和食道肿瘤)上,以及间皮瘤上(Chang等人,CancerRes.,52:181(1992);Chang等人,Int.J.Cancer,50:373(1992);Chang等人,Int.J.Cancer,51:548(1992);Chang等人,Proc.Natl.Acad.Sci.USA,93:136(1996);Chowdhury等人,Proc.Natl.Acad.Sci.USA,95:669(1998))。使用MAb K-1,间皮素仅作为细胞相关肿瘤标志物可检测到,并且在卵巢癌患者的血清中或在OVCAR-3细胞调整的培养基中未发现可溶形式(Chang等人,Int.J.Cancer,50:373(1992))。然而,结构上相关的人间皮素多肽还包括肿瘤相关抗原多肽,诸如独特的间皮素相关抗原(MRA)多肽,其在来自患有恶性肿瘤的患者的生物流体中作为天然存在的可溶性抗原可检测到。
肿瘤抗原可包括细胞表面分子。已知结构并具有已知或已述功能的肿瘤抗原(见上文)。
2.与肿瘤新生血管相关的抗原
蛋白质治疗剂在治疗肿瘤方面可能无效,因为它们在肿瘤穿透方面效率低。
抗原对肿瘤新血管系统可以是特异性,或者当与正常血管系统相比时,可以在肿瘤新血管系统中以较高的水平表达。与正常血管系统相比,由肿瘤相关新血管系统过表达的示例性抗原包括但不限于VEGF/KDR、Tie2、血管细胞粘附分子(VCAM)、内皮糖蛋白(Endoglin)和α5β3整联蛋白/玻连蛋白。与正常血管系统相比,肿瘤相关新血管系统过表达的其它抗原是本领域技术人员已知的并且适于通过所公开的融合蛋白进行靶向。
D.感染的治疗
所公开的PD-1调节化合物和组合物可用于治疗感染,包括但不限于微生物感染,诸如细菌感染、真菌感染、病毒感染和支原体感染。PD-1调节组合物也可用于治疗寄生虫感染。一个实施方案提供了通过向受试者施用一定量的一种或多种PD-1调节化合物或组合物来治疗受试者感染的方法,所述量的化合物或组合物可在受试者中有效促进或诱导经由PD-1受体的可激活T细胞的激活信号。
IV.制剂和施用
所公开的PD-1调节化合物可以配制成供通过肠胃外(肌内、腹膜内、静脉内(IV)或皮下注射)、透皮(被动地或利用离子导入(iontophoresis)或电穿孔)或经粘膜(鼻、阴道、直肠或舌下)施用途径或通过使用生物溶蚀性插入物来施用的药物组合物,并且可以配制成适合于每种施用途径的剂型。
在一些体内方法中,将本文公开的组合物以治疗有效量施用给受试者。如本文所用,术语“有效量”或“治疗有效量”意指足以治疗、抑制或减轻所治疗障碍的一种或多种症状或以其它方式提供所需的药理学和/或生理学效果的剂量。精确剂量将根据多种因素而变化,诸如受试者依赖性变量(例如,年龄、免疫系统健康状况等)、疾病以及所实施的治疗。
随着进行进一步的研究,将出现关于用于治疗各种患者的各种病症的适当剂量水平的信息,并且考虑到接受者的治疗背景、年龄和一般健康状况,普通技术人员将能够确定适当的剂量。所选剂量取决于所需的治疗效果、施用途径和所需的治疗持续时间。一般来讲,每天向哺乳动物施用0.001mg/kg体重至10mg/kg体重的剂量水平。一般来讲,对于静脉内注射或输注,剂量可以更低。
在某些实施方案中,局部施用PD-1调节组合物,例如通过直接注射到待治疗的部位。通常,注射会引起PD-1调节组合物的局部浓度增加,该浓度大于通过全身施用可实现的浓度。可将PD-1调节组合物与基质组合,以通过减少化合物从待治疗部位被动扩散出去来帮助产生增加的PD-1调节组合物的局部浓度。
A.用于肠胃外施用的制剂
在一个实施方案中,通过肠胃外注射以水溶液施用PD-1调节组合物。制剂也可以是悬浮液或乳液的形式。一般来讲,提供包含有效量的PD-1调节化合物的药物组合物,并且药物组合物任选包含药学上可接受的稀释剂、防腐剂、增溶剂、乳化剂、佐剂和/或载体。这些组合物包含稀释剂,诸如无菌水、具有各种缓冲剂内容物的缓冲盐水(例如Tris-HCl、醋酸盐、磷酸盐)、pH和离子强度调节剂;以及任选地,添加剂诸如去垢剂和增溶剂(例如,20、/>80,也称为聚山梨醇酯20或80)、抗氧化剂(例如抗坏血酸、焦亚硫酸钠),以及防腐剂(例如,硫柳汞、苯甲醇)和填充物质(例如乳糖、甘露醇)。非水溶剂或媒介物的实例是丙二醇、糊精、聚乙二醇、植物油诸如橄榄油和玉米油、明胶以及可注射的有机酯诸如油酸乙酯。可以将制剂冻干并在即将使用前重新溶解/重悬。制剂可以通过例如滤过细菌截留过滤器、通过将灭菌剂掺入组合物中、通过照射组合物或通过加热组合物来灭菌。
B.用于局部施用的制剂
可局部施用PD-1调节组合物,包括施加至肺、鼻、口(舌下、口颊)、阴道或直肠粘膜。当组合物作为气溶胶或喷雾干燥的颗粒(具有小于约5微米的空气动力学直径)递送时,组合物可以在吸入时递送到肺部并穿过肺上皮衬里到达血流。
可以使用设计用于治疗产品的肺部递送的各种机械装置,包括但不限于喷雾器、定量吸入器和粉末吸入器,所有这些都是本领域技术人员所熟悉的。市售装置的一些具体实例是Ultravent喷雾器(密苏里州圣路易斯市的马林克罗公司(Mallinckrodt Inc.,St.Louis,Mo.));Acorn II喷雾器(科罗拉多州恩格尔伍德市的Marquest医疗产品公司(Marquest Medical Products,Englewood,Colo.);Ventolin计量吸入器(北卡罗来纳州三角科技园的葛兰素史克公司(Glaxo Inc.,Research Triangle Park,N.C.));以及Spinhaler粉末吸入器(马萨诸塞州贝德福德市的菲森斯公司(Fisons Corp.,Bedford,Mass.))。内克塔公司(Nektar)、阿尔凯默斯公司(Alkermes)和曼恩凯德公司(Mannkind)都有已批准或处于临床试验中的可吸入胰岛素粉末制剂,其中该技术可适用于本文所述的制剂。
供施用于粘膜的制剂通常会是喷雾干燥的PD-1调节化合物颗粒,其可以掺入片剂、凝胶剂、胶囊剂、混悬剂或乳剂中。标准的药用赋形剂可从任何配方设计师处获得。口服制剂可以是口香糖、凝胶条、片剂或锭剂的形式。
也可以制备透皮制剂。这些通常会是软膏剂、洗剂、喷剂或贴剂,所有这些都可以使用标准技术制备。透皮制剂将需要包含渗透促进剂。
C.受控递送聚合物基质
PD-1调节组合物也可以以控释制剂施用。控释聚合物装置可以在植入聚合物装置(棒、圆筒、薄膜、圆盘)或注入(微粒)后系统地长期释放。基质可以是微粒的形式,诸如微球,其中肽分散在固体聚合物基质内,或者微胶囊,其中芯是与聚合物外壳不同的材料,并且肽分散或悬浮在芯中,其性质可以是液体或固体。除非本文具体地限定,否则微粒、微球和微胶囊可互换使用。作为另外一种选择,聚合物可以浇铸成薄板或薄膜(范围从数纳米到4厘米),可以是通过研磨或其它标准技术生产的粉末,或者甚至是凝胶,诸如水凝胶。
不可生物降解的或可生物降解的基质都可用于递送PD-1调节组合物,但可生物降解的基质是优选的。这些可以是天然的或合成的聚合物,但是由于降解和释放曲线得到更好表征,合成聚合物是优选的。基于期望的释放时段来选择聚合物。在某些情况下,线性释放可能是最有用的,但在其它情况下,脉冲释放或“大量释放(bulk release)”可能提供更有效的结果。聚合物可以是水凝胶的形式(通常吸收高达约90重量%的水),并且可以任选地与多价离子或聚合物交联。
基质可以通过溶剂蒸发、喷雾干燥、溶剂提取和本领域技术人员已知的其它方法形成。生物溶蚀性微球可以使用开发用于制备供药物递送的微球的任何方法来制备,例如,如以下文献所述的:Mathiowitz和Langer,J.Controlled Release,5:13-22(1987);Mathiowitz等人,Reactive Polymers,6:275-283(1987);以及Mathiowitz等人,J.Appl.Polymer Sci.,35:755-774(1988)。
装置可以配制用于局部释放以治疗植入或注入的区域(其通常会递送远小于用于治疗整个身体的剂量的剂量),或用于全身递送。这些可以皮下植入或注入进入肌肉、脂肪中,或可吞咽。
Claims (11)
1.一种药物组合物,其包含有效量的一种或多种PD-1调节化合物,所述化合物选自2'-((6-氧代-5,6-二氢菲啶-3-基)氨甲酰基)-[1,1'-联苯]-2-甲酸;2'-((6-氧代-6H-苯并[c]色烯-2-基)氨甲酰基)-[1,1'-联苯]-2-甲酸;5,5'-二苯基-2,2',3,3'-四氢-2,2'-二苯并[d]噁唑;2-硝基-4-((6-硝基喹啉-4-基)氨基)-N-(4-(吡啶-4-基氨基)苯基)苯甲酰胺;1,2-双(4-异丙基-6-(三氟甲基)嘧啶-2-基)肼;1-(1H-苯并[d][1,2,3]三唑-1-基)蒽-9,10-二酮;
1,1'-(氧基双(4,1-亚苯基))双(3-(2-氯苯基)脲);2-(异喹啉-1-基)-5-苯基-4-(对甲苯基)噁唑;3-(4-氯-6-苯氧基-1,3,5-三嗪-2-基)-1-苯基-1H-吲哚;1,8-双(苯硫基)蒽-9,10-二酮;4-氯-2-(3-(苯硫基)苯基)喹啉-6-磺酰氟;双(2,2,4-三甲基-1,2-二氢喹啉-6-基)甲烷;3-(苄硫基)菲并[9,10-e][1,2,4]三嗪;(4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(1H-咪唑-1-羰基)-4,4,6a,6b,11,11,14b-七甲基-3,13-二氧代
-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-十八氢苉-2-腈(CDDO-Im);2-(1H-菲并[9,10-d]咪唑-2-基)苯酚;3-(4,5-二甲基苯并[h][1,6]萘啶-2-基)-2-甲基喹啉-4-胺;N-(4-溴萘-1-基)-1-羟基-2-萘甲酰胺;
N-(3-(吡啶-2-基)异喹啉-1-基)吡啶-2-甲脒;2-(异喹啉-1-基)-4,5-二苯基噁唑;2,2'-((3,3'-二甲氧基-[1,1'-联苯]-4,4'-二基)双(氮烷二基))二苯甲酸;或它们的对映体、溶剂化物、药学上可接受的盐或衍生物,当施用给有需要的受试者时所述量的化合物可有效调节经由PD-1受体的信号转导。
2.根据权利要求1所述的药物组合物,其中所述一种或多种PD-1调节化合物在生理条件下与PD-1结合并促进或诱导经由PD-1的可激活表达PD-1的T细胞的激活信号。
3.根据权利要求1或2所述的药物组合物,其中所述一种或多种PD-1调节化合物在生理条件下与PD-1结合并抑制、减少或阻止PD-1的配体与PD-1结合,从而抑制、减少或阻止经由PD-1受体的负信号转导。
4.一种在有需要的受试者中诱导或促进T细胞活化的方法,包括向所述受试者施用一定量的一种或多种根据权利要求1所述的化合物,所述量的化合物可有效增加T细胞的抗原特异性增殖、增加或增强T细胞的细胞因子产生、刺激T细胞的分化和效应子功能和/或促进T细胞存活)或克服T细胞耗竭和/或失能。
5.一种在有需要的受试者中诱导或促进免疫应答的方法,包括向所述受试者施用有效量的一种或多种根据权利要求1所述的化合物以诱导或促进T细胞活化。
6.一种治疗癌症的方法,其包括向所述受试者施用有效量的一种或多种根据权利要求1所述的化合物以诱导或促进T细胞活化。
7.根据权利要求6所述的方法,其中所述癌症选自膀胱癌、脑癌、乳腺癌、宫颈癌、结肠直肠癌、食道癌、肾癌、肝癌、肺癌、鼻咽癌、胰腺癌、前列腺癌、皮肤癌、胃癌、子宫癌、卵巢癌、睾丸癌、血液癌、黑素瘤、肾癌、骨髓瘤、甲状腺癌、淋巴瘤、白血病或所述癌症的转移性病变。
8.一种在有需要的受试者中治疗感染的方法,包括向所述受试者施用有效量的一种或多种根据权利要求1所述的化合物以在所述受试者中促进或诱导T细胞活化。
9.根据权利要求8所述的方法,其中所述感染是微生物感染。
10.根据权利要求9所述的方法,其中所述感染是细菌、真菌或病毒感染。
11.根据权利要求8所述的方法,其中所述感染是寄生虫感染。
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US20190192501A1 (en) * | 2016-08-23 | 2019-06-27 | Icahn School Of Medicine At Mount Sinai | Methods for treating pten-mutant tumors |
WO2019050890A1 (en) * | 2017-09-05 | 2019-03-14 | President And Fellows Of Harvard College | METHODS AND COMPOSITIONS FOR THE TREATMENT OF TUBERCULOSIS |
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AU2017370002B2 (en) | 2022-04-21 |
CN110177552A (zh) | 2019-08-27 |
AU2022204549A1 (en) | 2022-07-21 |
JP2023012536A (ja) | 2023-01-25 |
EP4302833A2 (en) | 2024-01-10 |
EP3548022A4 (en) | 2020-06-03 |
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