CN113891709A - 用于治疗疾病的转录抑制剂和免疫检验点抑制剂的组合 - Google Patents
用于治疗疾病的转录抑制剂和免疫检验点抑制剂的组合 Download PDFInfo
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Abstract
本申请提供了用转录抑制剂(例如,STAT3抑制剂)和免疫检验点阻断疗法(例如,抗PD‑1疗法、抗PD‑L1疗法、抗CTLA‑4疗法)的组合来治疗患者的方法。所述患者可能患有增殖性疾病,诸如癌症或银屑病。所述患者可能患有病原性感染。
Description
相关申请的引用
本申请要求2019年4月2日提交的美国临时申请号62/828,175的优先权权益,其整个内容通过引用并入本文。
背景
1.领域
本发明总体上涉及医学和肿瘤学领域。更具体地,本发明涉及用于治疗增殖性疾病的包含STAT3抑制剂和一种或多种免疫检验点抑制剂的组合疗法。
2.相关技术的描述
胰腺导管腺癌(PDAC)仍然是最致命的恶性肿瘤之一,其治疗选择有限,仅手术为唯一的治疗方式。周围的肿瘤微环境是非常复杂的,且主要由免疫抑制性细胞浸润的致密纤维炎性间质构成,这与肿瘤发生和对大多数疗法的应答缺乏相关。在过去十年中已经出现了几种免疫疗法方案,但尚未证明单一药剂免疫检验点抑制剂在治疗胰腺癌中是有效的。因此,迫切需要开发有利于抗肿瘤免疫的有效策略。
发明内容
因此,本文提供了通过抑制STAT3来提高免疫疗法的效力的方法,从而通过减少肿瘤诱导的免疫抑制来促进抗肿瘤免疫应答。这些可用于治疗增殖性疾病(诸如癌症)的方法包括使用两种治疗剂的组合治疗患者:1)STAT3抑制剂(例如,WP1066、WP1732等)和2)一种或多种免疫检验点抑制剂。
在一个实施方案中,本文提供了治疗患者中的疾病的方法,所述方法包括向所述患者施用组合有效量的转录抑制剂和免疫检验点抑制剂。在一些方面,所述转录抑制剂是STAT3抑制剂。在某些方面,所述转录抑制剂是α,β-不饱和氰基羧酰胺。在某些方面,所述转录抑制剂是WP1066或WP1732。在一些方面,所述免疫检验点抑制剂包括抗PD1疗法、抗PD-L1疗法和抗CTLA-4疗法中的一种或多种。在某些方面,所述抗PD1疗法包括纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、皮地利珠单抗(pidilizumab)、西米普利单抗(cemiplimab)、替雷利珠单抗(tislelizumab)、斯巴达珠单抗(spartalizumab)、PF-06801591、AK105、BCD-100、BI-754091、HLX10、JS001、LZM009、MEDI 0680、MGA012、Sym021、TSR-042、MGD013、AK104和/或XmAb20717。在某些方面,所述抗PD-L1疗法包括阿特朱单抗(atezolizumab)、阿维鲁单抗(avelumab)、度伐单抗(durvalumab)、FS118、BCD-135、BGB-A333、CBT502、CK-301、CS1001、FAZ053、KN035、MDX-1105、MSB2311、SHR-1316、M7824、LY3415244、CA-170和CX-072。在某些方面,所述抗CTLA-4疗法包括伊匹木单抗(ipilimumab)、曲美木单抗(tremelimumab)、BMS-986218、AK104和/或XmAb20717。
在一些方面,所述疾病是增殖性疾病。在某些方面,所述增殖性疾病是癌症。在某些方面,所述方法抑制癌细胞的存活或增殖。在某些方面,所述患者以前已经对施用的免疫检验点抑制剂应答失败。在某些方面,所述方法是克服对免疫检验点抑制剂疗法的抗性的方法。在某些方面,所述方法进一步包括向所述患者施用另一种抗癌疗法。在某些方面,所述另一种抗癌疗法是手术疗法、化学疗法、放射疗法、冷冻疗法、激素疗法、毒素疗法、免疫疗法或细胞因子疗法。在一些方面,所述另一种抗癌疗法包括吉西他滨(gemcitabine)、5-氟尿嘧啶、伊立替康(irinotecan)、奥沙利铂(oxaliplatin)、紫杉醇、卡培他滨(capecitabine)、顺铂或多西他赛(docetaxel)。
在一些方面,所述癌症是神经胶质瘤、胰腺癌、乳腺癌、黑素瘤、淋巴瘤或白血病。在一些方面,所述白血病是AML。在一些方面,所述患者以前已经经历至少一轮的抗癌疗法。在一些方面,所述增殖性疾病是银屑病。在某些方面,所述疾病是病原性感染。在一些方面,所述患者是人。
如本文中所使用的,就特定组分而言,“基本上不含”在本文中用于表示,没有任何特定组分被有意配制在组合物中和/或其仅作为污染物或以痕量存在。因此,组合物中的任何非预期污染产生的特定组分的总量远低于0.05%,优选地低于0.01%。最优选的是,组合物中该特定组分的量通过标准分析方法均检测不到。
如在此在说明书中使用的,“一个”或“一种”可以是指一个/种或多个/种。如在此在权利要求书中使用的,当与词语“包含”结合使用时,词语“一个”或“一种”可以是指一个/种或一个/种以上。
在权利要求书中使用的术语“或”用于表示“和/或”,除非明确表明仅仅表示替代方案或替代方案是相互排斥的,尽管本公开内容支持仅表示替代方案和“和/或”的定义。本文中使用的“另一种”可以是指至少第二种或更多。
贯穿本申请,术语“约”用于指示,值包括用于测定该值所采用的装置、方法的误差的固有变化,研究受试者之间存在的变化,或在规定值的10%内的值。
从下面的详细描述中,本发明的其它目的、特征和优点将更加明显。但是,应当理解,示出了本发明优选实施方式的详细描述和具体实施例虽然示出了仅以示例性的方式给出,本领域技术人员由该详细描述将清楚在本发明的精神和范围内的各种变化和修改。
附图说明
以下附图构成本说明书的一部分,并且被包括在内以进一步证实本发明的某些方面。通过参考这些附图中的一个或多个并结合本文中呈现的具体实施方案的详细描述,可以更好地理解本发明。
图1.胰腺癌的同源原位模型中的WP1066和抗PD-1/CTLA-4抗体组合疗法。
图2A至图2B.胰腺癌的同源原位模型中的WP1732和抗-PD-1/CTLA-4抗体联合疗法。图2A提供了示出每个治疗组的存活百分比的Kaplan-Meier曲线。图2B提供了每个治疗组中的小鼠随时间的生物发光图像。
具体实施方式
本发明提供了用转录抑制剂和免疫检验点抑制剂的组合来治疗患有增殖性障碍的患者的方法。这样的治疗也可以与另一种治疗方案(诸如化学疗法)组合。
I.转录抑制剂
转录抑制剂可以是STAT3抑制剂,诸如含有α,β-不饱和羧酰胺的化合物,例如,WP1066或WP1732。这些化合物是具有药物样性能的有效p-STAT3抑制剂。化合物WP1066目前作为口服施用药剂正在I期临床试验(NCT01904123)中进行评价。WP1732是适用于静脉内(IV)施用的WP1066类似物。信号传导和转录激活因子3(STAT3)在包括胰腺导管腺癌(PDAC)在内的多种恶性肿瘤的癌变、化学和放射敏感性、转移和免疫逃避中起着关键作用。它的激活会减少T细胞向肿瘤和肿瘤微环境的募集,并且增加免疫抑制性细胞(诸如Treg和MDSC)的活性和积累,从而促进免疫抑制性的肿瘤微环境。
WP1066、WP1732和其它含有α,β-不饱和氰基羧酰胺的化合物具有有效的抗肿瘤作用。WP1066、WP1732和类似化合物已在体内和体外的多种类型癌症显示出抗增殖作用。已经确定,炎症性和增殖性病症(诸如癌症)依赖于共同选择正常的信号通路,这些通路导致负责细胞生长、存活和细胞分化的因子的转录。WP1066和相关化合物的抗癌活性是通过抑制被称作信号传导和转录激活因子(称为“STAT”)的特定类型蛋白(更具体地STAT3)和相关的关键致癌转录因子(即c-Myc和HIF-1α)来介导的。
WP1066对激活形式的STAT3(p-STAT3—酪氨酸705磷酸化的STAT3)的作用已得到充分证明。p-STAT3在调节疾病细胞存活和增殖、血管生成和免疫系统功能的过程中起重要作用,并且在大量人类炎症过程中和以及在过度增殖性疾病中持续被激活。具体地,STAT3可以被许多不同的上游诱导剂中的任何一种激活,最终导致p-STAT3,然后形成进入细胞核并触发基因转录的二聚体。通过抑制p-STAT3的存在,WP1066通过抑制基因转录直接影响肿瘤细胞。
在本方法中考虑使用的含有α,β-不饱和羧酰胺的化合物的家族包括在记载于以下说明书中的那些:美国专利号7,745,468;8,119,827;8,143,412;8,450,337;8,648,102;8,779,151;9,096,499;8,809,377;和9,868,736;美国申请系列号16/185,669;美国专利申请公开号2016/0237082;2005/0277680;2011/0021805;2011/0053992;2010/0152143;2014/0329901;和2012/0214850;和国际(PCT)申请公开号WO2010/005,807和WO2015/187,427,它们中的每一篇通过引用整体并入本文。
II.免疫检验点抑制剂
免疫检验点要么调高信号(例如共刺激分子)要么调低信号。通过免疫检验点阻断可靶向的抑制性免疫检验点包括:腺苷A2A受体(A2AR)、B7-H3(也被称作CD276)、B和T淋巴细胞衰减因子(BTLA)、细胞毒性T淋巴细胞相关蛋白4(CTLA-4,也被称作CD152)、吲哚胺2,3-双加氧酶(IDO)、杀伤细胞免疫球蛋白(KIR)、淋巴细胞激活基因-3(LAG3)、程序性死亡1(PD-1)、程序性死亡-配体1(PD-L1)、T细胞免疫球蛋白结构域和粘蛋白结构域3(TIM-3)、以及T细胞活化的V-结构域Ig抑制因子(VISTA)。具体地,免疫检验点抑制剂靶向于PD-1轴和/或CTLA-4。
免疫检验点抑制剂可以是药物,诸如小分子,配体或受体的重组形式,或抗体,诸如人抗体(例如,国际专利公开WO2015/016718;Pardoll,Nat Rev Cancer,12(4):252-264,2012;这两篇通过引用并入本文)。可以使用免疫检验点蛋白的已知抑制剂或其类似物,尤其是可以使用嵌合形式、人源化形式或人形式的抗体。如技术人员所知晓的,本公开内容中提及的某些抗体可采用替代和/或等同名称。在本公开内容的上下文中,这样的替代和/或等同名称是可互换的。例如,已知的是,帕姆单抗(lambrolizumab)也以替代和等同名称MK-3475和派姆单抗(pembrolizumab)为人所知。
在一些实施方案中,PD-1结合拮抗剂是抑制PD-1与其配体结合配偶体相结合的分子。在一个具体的方面,PD-1配体结合配偶体是PD-L1和/或PD-L2。在另一个实施方案中,PD-L1结合拮抗剂是抑制PD-L1与其结合配偶体相结合的分子。在一个具体的方面,PD-L1结合配偶体是PD-1和/或B7-1。在另一个实施方案中,PD-L2结合拮抗剂是抑制PD-L2与其结合配偶体相结合的分子。在一个具体的方面,PD-L2结合配偶体是PD-1。所述拮抗剂可以是抗体、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。示例性抗体记载于美国专利号8,735,553、8,354,509和8,008,449中,它们都通过引用并入本文。用于本文提供的方法中的其它PD-1轴拮抗剂是本领域已知的,诸如记载于美国专利申请公开号2014/0294898、2014/022021和2011/0008369中的那些,它们都通过引用并入本文。
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,所述抗PD-1抗体选自由以下项组成的组:纳武单抗(也被称作MDX-1106-04、MDX-1106、MK-347、ONO-4538、BMS-936558和记载于WO2006/121168)、派姆单抗(也被称作MK-3475、Merck 3475、帕姆单抗、和SCH-900475;WO2009/114335)、皮地利珠单抗(也被称作CT-011、hBAT或hBAT-1;WO2009/101611)、西米普利单抗(也被称作REGN-2810、REGN2810、SAR-439684、SAR439684)、替雷利珠单抗(也被称作BGB-A317、hu317-1/IgG4mt2;美国专利号8,735,553)、斯巴达珠单抗(也被称作PDR001、PDR-001、NPV-PDR001、NPVPDR001;美国专利号9,683,048)、PF-06801591、AK105、BCD-100、BI-754091、HLX10、JS001、LZM009、MEDI 0680、MGA012、Sym021、TSR-042、MGD013、AK104(抗CTLA4,双特异性)和XmAb20717(抗CTLA4,双特异性)。
在一些实施方案中,所述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PD-L1或PD-L2的细胞外或PD-1结合部分的免疫粘附素)。例如,AMP-224(也被称作B7-DCIg)是在WO2010/027827和WO2011/066342中记载的PD-L2-Fc融合可溶性受体。
在一些实施方案中,PD-L1结合拮抗剂是抗PD-L1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,所述抗PD-L1抗体选自以下项组成的组:阿特朱单抗(也被称作Tencentriq、MPDL3280A;记载于美国专利号8,217,149)、阿维鲁单抗(也被称作MSB-0010718C、MSB0010718C)、度伐单抗(也被称作MEDI-4736、MEDI4736;记载于WO2011/066389)、FS118、BCD-135、BGB-A333、CBT502(也被称作TQB2450)、CK-301、CS1001(也被称作WBP3155)、FAZ053、KN035、MDX-1105、MSB2311、SHR-1316、M7824、LY3415244、CA-170和CX-072。
在本文提供的方法中可以靶向的另一种免疫检验点蛋白是细胞毒性T-淋巴细胞相关蛋白4(CTLA-4),也被称作CD152。人CTLA-4的完整cDNA序列具有Genbank登录号L15006。CTLA-4存在于T细胞表面上并且当与抗原呈递细胞表面上的CD80或CD86结合时充当“关闭”开关。CTLA-4类似于T-细胞共刺激性蛋白CD28,且这两种分子都结合在抗原呈递细胞上的CD80和CD86,分别也称为B7-1和B7-2。CTLA-4向T细胞传递抑制性信号,而CD28传递刺激信号。细胞内CTLA-4也存在于调节性T细胞中且对其功能可能是重要的。通过T细胞受体和CD28的T细胞激活会导致使CTLA-4(B7分子的抑制性受体)表达增加。
在一些实施方案中,所述免疫检验点抑制剂是抗CTLA-4抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。使用本领域众所周知的方法,可以产生适用于本发明方法的抗-人-CTLA-4抗体(或由此衍生出的VH和/或VL结构域)。可替换地,可以使用本领域公认的抗CTLA-4抗体。例如,在本文公开的方法中可以使用公开在以下文献中的抗CTLA-4抗体:美国专利号8,119,129;PCT公开号WO 01/14424、WO98/42752、WO 00/37504(CP675,206,也被称作曲美木单抗;以前称为替西木单抗);美国专利号6,207,156;Hurwitz等人(1998)Proc Natl Acad Sci USA,95(17):10067-10071;Camacho等人(2004)J Clin Oncology,22(145):摘要编号2505(抗体CP-675206);和Mokyr等人(1998)Cancer Res,58:5301-5304。每篇上述公开物的教导在此通过引用并入。也可以使用与这些本领域公知的抗体中的任一种竞争结合CTLA-4的抗体。例如,人源化CTLA-4抗体记载于国际专利申请号WO2001/014424、WO2000/037504和美国专利号8,017,114;这些均通过引用并入本文。
一种示例性的抗CTLA-4抗体是伊匹木单抗(也被称作10D1、MDX-010、MDX-101、MDX-CTLA4和)或其抗原结合片段及变体(参见,例如,WO 01/14424)。在其它实施方案中,所述抗体包含伊匹木单抗的重链和轻链CDR或VR。因此,在一个实施方案中,所述抗体包含伊匹木单抗的VH区域的CDR1、CDR2和CDR3结构域以及伊匹木单抗的VL区域的CDR1、CDR2和CDR3结构域。在另一个实施方案中,所述抗体与上述抗体竞争对CTLA-4上的相同表位的结合和/或结合CTLA-4上的相同表位。在另一个实施方案中,所述抗体与上述抗体具有至少约90%的可变区氨基酸序列同一性(例如,与伊匹木单抗具有至少约90%、95%或99%可变区同一性)。
在一些实施方案中,CTLA-4结合拮抗剂是抗CTLA-4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,所述抗CTLA-4抗体选自由以下项组成的组:伊匹木单抗(也被称作10D1、MDX-010、MDX-101、MDX-CTLA4和记载于WO 01/14424)、曲美木单抗(也被称作CP-675,206、CP-675、替西木单抗;记载于WO 00/37504)、BMS-986218、AK104(抗PD-1,双特异性)和XmAb20717(抗-PD-1,双特异性)。
用于调节CTLA-4的其它分子包括:CTLA-4配体和受体,诸如在美国专利号5844905、5885796和国际专利申请号WO1995001994和WO1998042752(都通过引用并入本文)中描述的那些;和免疫粘附素,诸如在美国专利号8329867(通过引用并入本文)中描述的那些。
在本文提供的方法中可以靶向的另一种免疫检验点蛋白是淋巴细胞-激活基因3(LAG-3),也被称作CD223。人LAG-3的完整蛋白序列具有Genbank登录号NP-002277。LAG-3存在于激活的T细胞、自然杀伤细胞、B细胞和浆细胞样树突细胞的表面上。当与抗原呈递细胞的表面上的MHC II类结合时,LAG-3充当“关闭”开关。LAG-3的抑制会激活效应T细胞和抑制剂调节性T细胞。在一些实施方案中,所述免疫检验点抑制剂是抗LAG-3抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。可以使用本领域众所周知的方法来生产适合用在本方法中的抗-人-LAG-3抗体(或从其衍生出的VH和/或VL结构域)。可替代地,可以使用本领域公知的抗LAG-3抗体。一种示例性的抗LAG-3抗体是瑞拉利单抗(也被称作BMS-986016)或其抗原结合片段及变体(参见,例如,WO 2015/116539)。其它示例性的抗LAG-3抗体包括TSR-033(参见,例如,WO 2018/201096)、MK-4280和REGN3767。MGD013是在WO 2017/019846中描述的抗LAG-3/PD-1双特异性抗体。FS118是在WO2017/220569中描述的抗LAG-3/PD-L1双特异性抗体。
在本文提供的方法中可以靶向的另一种免疫检验点蛋白是T细胞活化的V-结构域Ig抑制因子(VISTA),也被称作C10orf54。人VISTA的完整蛋白序列具有Genbank登录号NP_071436。VISTA存在于白血细胞上并抑制T细胞效应子功能。在一些实施方案中,所述免疫检验点抑制剂是抗VISTA3抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。可以使用本领域众所周知的方法来产生适合用在本方法中的抗-人-VISTA抗体(或从其衍生出的VH和/或VL结构域)。可替代地,可以使用本领域公知的抗VISTA抗体。一种示例性的抗VISTA抗体是JNJ-61610588(也被称作奥瓦利单抗)(参见,例如,WO 2015/097536、WO 2016/207717、WO 2017/137830、WO 2017/175058)。VISTA还可以用小分子CA-170抑制,其选择性地靶向PD-L1和VISTA两者(参见,例如,WO 2015/033299、WO2015/033301)。
在本文提供的方法中可以靶向的另一种免疫检验点蛋白是CD38。人CD38的完整蛋白序列具有Genbank登录号NP_001766。在一些实施方案中,所述免疫检验点抑制剂是抗CD38抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。可以使用本领域众所周知的方法来生产适合用在本方法中的抗-人-CD38抗体(或从其衍生出的VH和/或VL结构域)。可替代地,可以使用本领域公知的抗CD38抗体。一种示例性的抗-CD38抗体是达雷木单抗(daratumumab)(参见,例如,美国专利号7,829,673)。
在本文提供的方法中可以靶向的另一种免疫检验点蛋白是具有Ig和ITIM结构域的T细胞免疫受体(TIGIT)。人TIGIT的完整蛋白序列具有Genbank登录号NP_776160。在一些实施方案中,所述免疫检验点抑制剂是抗TIGIT抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。可以使用本领域众所周知的方法来生产适合用在本方法中的抗-人-TIGIT抗体(或从其衍生出的VH和/或VL结构域)。可替代地,可以使用本领域公知的抗TIGIT抗体。一种示例性的抗TIGIT抗体是MK-7684(参见,例如,WO2017/030823、WO 2016/028656)。
共刺激性分子是与免疫细胞表面上的受体相互作用的配体,例如,CD28、4-1BB、OX40(也被称作CD134)、ICOS和GITR。作为示例,人OX40的完整蛋白序列具有Genbank登录号NP_003318。在一些实施方案中,所述免疫调节剂是抗OX40抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。可以使用本领域众所周知的方法来生产适合用在本方法中的抗-人-OX40抗体(或从其衍生出的VH和/或VL结构域)。可替代地,可以使用本领域公知的抗OX40抗体。一种示例性的抗OX40抗体是PF-04518600(参见,例如,WO 2017/130076)。ATOR-1015是靶向CTLA4和OX40的双特异性抗体(参见,例如,WO2017/182672、WO 2018/091740、WO 2018/202649、WO 2018/002339)。
在本文提供的方法中可以靶向的另一种共刺激性分子是ICOS,也被称作CD278。人ICOS的完整蛋白序列具有Genbank登录号NP_036224。在一些实施方案中,所述免疫检验点抑制剂是抗ICOS抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。可以使用本领域众所周知的方法来生产适合用在本方法中的抗-人-ICOS抗体(或从其衍生出的VH和/或VL结构域)。可替换地,可以使用本领域公知的抗-ICOS抗体。示例性的抗ICOS抗体包括JTX-2011(参见,例如,WO 2016/154177、WO 2018/187191)和GSK3359609(参见,例如,WO 2016/059602)。
在本文提供的方法中可以靶向的另一种共刺激性分子是糖皮质激素诱导的肿瘤坏死因子受体相关蛋白(GITR),也被称作TNFRSF18和AITR。人GITR的完整蛋白序列具有Genbank登录号NP_004186。在一些实施方案中,所述免疫调节剂是抗GITR抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。可以使用本领域众所周知的方法来生产适合用在本方法中的抗-人-GITR抗体(或从其衍生出的VH和/或VL结构域)。可替代地,可以使用本领域公知的抗GITR抗体。一种示例性的抗-GITR抗体是TRX518(参见,例如,WO 2006/105021)。
可以靶向用于免疫调节的其它免疫抑制性分子包括STAT3和吲哚胺2,3-双加氧酶(IDO)。作为示例,人IDO的完整蛋白序列具有Genbank登录号NP_002155。在一些实施方案中,所述免疫调节剂是小分子IDO抑制剂。示例性的小分子包括BMS-986205、艾卡哚司他(epacadostat)(INCB24360)和navoximod(GDC-0919)。
III.治疗方法
本文中使用的术语“受试者”或“患者”是指对其进行主题方法的任何个体。尽管本领域技术人员将知晓的是,患者可以是动物,但是通常患者是人。因此,在患者的定义中包括其它动物,该其它动物包括哺乳动物,诸如啮齿类动物(包括小鼠、大鼠、仓鼠和豚鼠)、猫、狗、兔,耕作动物包括牛、马、山羊、绵羊、猪等,以及灵长类动物(包括猴、黑猩猩、猩猩和大猩猩)。
“治疗(treatment)”和“治疗(treating)”是指为了获得疾病或健康相关状况的治疗益处的目的,向受试者施用或给予治疗剂或对受试者疗程或疗法。例如,治疗可以包括施用化学疗法、免疫疗法、放射疗法,实施手术,或其任何组合。
本文所述的方法可用于抑制细胞(例如,肿瘤细胞)的存活或增殖,治疗增殖性疾病(例如,癌症、银屑病),和治疗病原性感染。通常,术语“癌症”和“癌性的”是指或者描述哺乳动物中通常以不受控的细胞生长为特征的生理状况。更具体地,结合本文提供的方法治疗的癌症包括,但不限于实体瘤、转移性癌症或非转移性癌症。在某些实施方案中,所述癌症可以源于肺、肾、膀胱、血液、骨、骨髓、脑、乳房、结肠、食管、十二指肠、小肠、大肠、结肠、直肠、肛门、牙龈、头、肝、鼻咽、颈、卵巢、胰腺、前列腺、皮肤、胃、睾丸、舌或子宫。
所述癌症可以具体是以下组织学类型,不限于这些:恶性赘生物;恶性上皮肿瘤(carcinoma);非小细胞性肺癌;肾癌;肾细胞癌;透明细胞肾细胞癌;淋巴瘤;母细胞瘤;肉瘤;未分化的癌;脑膜瘤;脑癌;口咽癌;鼻咽癌;胆系癌;嗜铬细胞瘤;胰岛细胞癌;李弗劳明肿瘤;甲状腺癌;甲状旁腺癌;垂体瘤;肾上腺肿瘤;成骨性肉瘤肿瘤;神经内分泌肿瘤;乳腺癌;肺癌;头颈癌;前列腺癌;食管癌;气管癌;肝癌;膀胱癌;胃癌;胰腺癌;卵巢癌;子宫癌;宫颈癌;睾丸癌;结肠癌;直肠癌;皮肤癌;巨细胞和梭形细胞癌;小细胞癌;小细胞性肺癌;乳头状癌;口癌;口咽癌;鼻咽癌;呼吸道癌症;泌尿生殖器癌症;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌;移行细胞癌;乳头状移行细胞癌;腺癌;胃肠癌;恶性胃泌素瘤;胆管上皮癌;肝细胞癌;结合性肝细胞癌和胆管上皮癌;小梁腺癌;腺样囊性癌;腺瘤性息肉中的腺癌;腺癌,家族性结肠息肉症;实体癌;恶性类癌瘤;支气管-肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱性细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡状腺癌;乳头状和滤泡性腺癌;非包囊性硬化癌;肾上腺皮质癌;子宫内膜样癌;皮肤附件癌;大汗腺腺癌;皮脂腺癌;盯聍腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液性腺癌;印戒细胞癌;浸润性腺管癌;髓样癌;小叶癌;炎症性癌;乳房佩吉特病;腺泡细胞癌;腺鳞状癌;伴有鳞状组织转化的腺癌;恶性胸腺瘤;恶性卵巢间质瘤;恶性泡膜细胞瘤;恶性粒层细胞肿瘤;恶性雄激素母细胞瘤;塞尔托利细胞癌;恶性莱迪希细胞肿瘤;恶性脂质细胞肿瘤;恶性副神经节瘤;恶性乳房外副神经节瘤;嗜铬细胞瘤;血管球肉瘤;恶性黑素瘤;无黑色素性黑素瘤;浅表扩散性黑素瘤;巨大色素痣内恶性黑素瘤;恶性雀斑样黑素瘤;肢端雀斑样黑素瘤;结节性黑素瘤;上皮样细胞黑素瘤;恶性蓝痣;肉瘤;纤维肉瘤;恶性纤维组织细胞瘤;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎型横纹肌肉瘤;小泡型横纹肌肉瘤;间质肉瘤;恶性混合瘤;苗勒混合瘤;肾母细胞瘤;肝胚细胞瘤;癌肉瘤;恶性间叶瘤;恶性勃勒纳瘤;恶性叶状瘤;滑膜肉瘤;恶性间皮瘤;无性细胞瘤;胚胎癌;恶性畸胎瘤;恶性卵巢甲状腺肿;绒毛膜癌;恶性中肾瘤;血管肉瘤;恶性血管内皮瘤;卡波西肉瘤;恶性血管外皮细胞瘤;淋巴管肉瘤;骨肉瘤;皮质旁骨肉瘤;软骨肉瘤;恶性软骨母细胞瘤;间叶性软骨肉瘤;骨的巨细胞瘤;尤因肉瘤;恶性牙原性瘤;成釉细胞牙肉瘤;恶性成釉细胞瘤;成釉细胞纤维肉瘤;内分泌或神经内分泌癌或造血癌;恶性松果体瘤;脊索瘤;中枢或周围神经系统组织癌症;恶性神经胶质瘤;室管膜瘤;星形细胞瘤;原浆性星形细胞瘤;纤维性星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突神经胶质瘤;成少突神经胶质细胞瘤;原始神经外胚层瘤;小脑肉瘤;成神经节细胞瘤;神经母细胞瘤;视网膜母细胞瘤;嗅神经源性肿瘤;恶性脑膜瘤;神经纤维肉瘤;恶性神经鞘瘤;恶性颗粒细胞瘤;B-细胞淋巴瘤;恶性淋巴瘤;霍奇金病;霍奇金;低等级/滤泡非霍奇金淋巴瘤;副肉芽肿;小淋巴细胞性恶性淋巴瘤;弥漫性大细胞恶性淋巴瘤;滤泡性恶性淋巴瘤;蕈样肉芽肿病;套细胞淋巴瘤;沃尔登斯特伦巨球蛋白血症;其他特定的非霍奇金淋巴瘤;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠疾病;白血病;淋巴样白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓样白血病;嗜碱性粒细胞性白血病;嗜酸性粒细胞性白血病;单核细胞性白血病;肥大细胞白血病;巨核母细胞性白血病;髓样肉瘤;慢性淋巴细胞白血病(CLL);急性成淋巴细胞性白血病(ALL);毛细胞白血病;慢性成髓细胞白血病;和毛细胞白血病。
贯穿本申请使用的术语“治疗益处”或“治疗上有效的”是指促进或增强受试者在该病症的医学治疗方面的健康状况的任何事项。这包括、但不限于疾病的征象或症状的频率或严重程度的降低。例如,癌症的治疗可能涉及例如降低肿瘤的侵袭力、降低癌症的生长速率或防止转移。癌症的治疗还可以表示延长癌症受试者的生存期。
同样地,患者的有效应答或患者对治疗的“应答性”是指,为处于疾病或病症风险中或患有疾病或病症的患者提供的临床或治疗益处。这种益处可以包括细胞或生物应答、完全应答、部分应答、稳定的疾病(没有进展或复发)或推迟复发的应答。例如,有效应答可以是被诊断出患有癌症的患者中的减小的肿瘤大小或无进展生存期。
关于赘生性病症治疗,根据赘生性病症的阶段,赘生性病症治疗涉及以下疗法中的一种或疗法的组合:除去赘生性组织的手术,放射疗法,和化学疗法。其它治疗方案可以与施用抗癌剂(例如,治疗组合物和化学治疗剂)组合。例如,要用这样的抗癌剂治疗的患者也可以接受放射疗法和/或可以经历手术。
对于疾病的治疗,治疗组合物的适当剂量将取决于如上文所定义的待治疗疾病的类型、疾病的严重程度和病程、先前的疗法、患者的临床史和对药剂的应答、以及医师的判断。药剂可以一次性地或在一系列治疗中适当地施用给患者。
IV.组合治疗
包括组合疗法在内的方法和组合物增强了另一种抗癌或抗过度增殖疗法的治疗或保护作用,和/或增加了其治疗作用。治疗性和预防性方法和组合物可以以有效实现期望作用,诸如杀死癌细胞和/或抑制细胞的过度增殖的组合量提供。组织、肿瘤或细胞可以与一种或多种包含一种或多种药剂的组合物或药理学制剂接触,或者组织、肿瘤和/或细胞可以与两种或更多种不同的组合物或制剂接触。此外,可预期的是,此类联合疗法可以与放射疗法、手术疗法或免疫疗法结合使用。
组合施用可以包括在同一剂型中同时施加两种或更多种药剂,在独立剂型中同时施用,以及分开施用。也就是说,主题治疗组合物和另一种治疗剂可以一起配制在同一剂型中并同时施用。可替代地,主题治疗组合物和另一种治疗剂可以同时施用,其中两种药剂存在于独立制剂中。在另一个替代方案中,可以在施用治疗剂之后,紧接施用其它治疗剂,或反之亦然。在分开施用的方案中,主题治疗组合物和另一种治疗剂可以相隔几分钟、或相隔几小时、或相隔几天施用。
抗癌第一次治疗可以在第二次抗癌治疗之前、期间、之后或以各种组合的形式来施加。所述施加可以是在从同时至数分钟至数天至数周的间隔来进行。在第一次治疗与第二次治疗分开提供给患者的实施方案中,通常将确保在每次递送的时间之间不会存在很长的时段,使得两种化合物仍然能够对患者产生有利的组合效应。在这样的情况下,预期的是,可以在彼此间隔约12至24或72小时内,且更具体地在彼此间隔约6-12小时内,向患者提供第一疗法和第二疗法。在一些情况下,可能需要显著地延长治疗的时段,在各施用之间间隔数天(2天、3天、4天、5天、6天或7天)至间隔数周(1周、2周、3周、4周、5周、6周、7周或8周)。
在某些实施方案中,疗程将持续1天至90天或更长(该范围包括中间天数)。预期的是,可以在第1天至第90天(该范围包括中间天数)的任何一天或其任何组合施用一种药剂,并在第1天至第90天(该范围包括中间天数)的任何一天或其任何组合施用另一种药剂。在一天(24小时时段)内,可以给患者提供一次或多次药剂施用。此外,在疗程以后,预期的是,有一段时间不施用抗癌治疗。该时间段可能持续1至7天,和/或1至5周,和/或1至12个月或更长(该范围包括中间天数),取决于患者的状况,诸如他们的预后、强度、健康等。预见将根据需要重复治疗周期。
可以采用多种组合。对于下面的示例,转录抑制剂和免疫检验点抑制剂的组合是“A”,另一种抗癌疗法是“B”:
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A
B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
本发明的向患者施用的任何化合物或疗法将遵循施用此类化合物的通用方案,考虑药剂的毒性(如果存在的话)。因此,在一些实施方案中,存在对归因于联合治疗的毒性进行监控的步骤。
A.化学疗法
根据本发明可以使用多种化学治疗剂。术语“化学疗法”是指使用药物来治疗癌症。“化学治疗剂”用于意指在癌症治疗中施用的化合物或组合物。这些药剂或药物通过其在细胞内的活性模式(例如,其是否影响细胞周期以及在何阶段影响细胞周期)进行分类。可替代地,可基于其直接交联DNA、嵌入到DNA中或通过影响核酸合成来诱导染色体和有丝分裂畸变的能力来表征药剂。
化学治疗剂的示例包括:烷化剂,诸如塞替派和环磷酰胺;烷基磺酸酯,诸如白消安、英丙舒凡和哌泊舒凡;氮丙啶类,诸如苯佐替派(benzodopa)、卡波醌、美妥替派(meturedopa)和乌瑞替派(uredopa);亚乙基亚胺和甲基密胺类,包括六甲蜜胺、三亚乙基密胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基密胺;番荔枝内酯(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(包括合成的类似物托泊替康);苔藓抑素;海绵多烯酮类化合物(callystatin);CC-1065(包括它的阿多来新、卡泽来新和比泽来新合成类似物);念珠藻环肽(尤其是念珠藻环肽1和念珠藻环肽8);多拉司他汀;多卡米星(包括合成类似物KW-2189和CB1-TM1);软珊瑚醇;水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑素;氮芥类,诸如苯丁酸氮芥、萘氮芥、胆磷酰胺(cholophosphamide)、雌莫司汀、异环磷酰胺、双氯乙基甲胺、盐酸氧化氮芥、美法仑、新氮芥、苯芥胆甾醇、泼尼莫司汀、曲磷胺和尿嘧啶氮芥;硝基脲类,诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素类,诸如烯二炔类抗生素(例如,卡奇霉素,尤其是卡奇霉素γlI和卡奇霉素ωI1);达内霉素,包括达内霉素A;二膦酸酯/盐类,诸如氯膦酸酯/盐;埃斯波霉素;以及新制癌菌素生色团和有关的色蛋白烯二炔类抗生素生色团、阿克拉霉素类(aclacinomysins)、放线菌素、氨茴霉素(authrarnycin)、偶氮丝氨酸、博来霉素类、放线菌素C、卡拉必星(carabicin)、洋红霉素、嗜癌霉素、色霉素、更生霉素、柔红霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉代-多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素类(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(potfiromycin)、嘌呤霉素、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、净司他丁和佐柔比星;抗代谢药类,诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸、蝶罗呤和三甲曲沙;嘌呤类似物,诸如氟达拉滨、6-巯基嘌呤、硫咪嘌呤和硫鸟嘌呤;嘧啶类似物,诸如安西他滨、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、依诺他滨和氟尿苷;雄激素类,诸如卡普睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷和睾内酪;抗-肾上腺类,诸如米托坦和曲洛司坦;叶酸补充剂,诸如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷;氨基酮戊酸;恩尿嘧啶;安吖啶;阿莫斯汀(bestrabucil);比生群;依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺;地吖醌;依氟鸟氨酸(elformithine);依利醋铵;埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidainine);美坦辛类,诸如美坦辛和安丝菌素类;米托胍腙;米托蒽醌;莫哌达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基酰肼;丙卡巴肼;PSK多糖复合物;雷佐生;根霉素;西佐喃;锗螺胺;替奴佐酸;三亚胺醌;2,2',2”-三氯三乙胺;单端孢霉烯类(特别是T-2毒素、疣孢菌素(verracurin)A、杆孢菌素A和蛇形菌素);尿烷(urethan);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;甲托辛(gacytosine);阿糖胞苷(“Ara-C”);环磷酰胺;紫杉烷类,例如,紫杉醇和多西他赛吉西他滨;6-硫鸟嘌呤;巯嘌呤;铂配位络合物,诸如顺铂、奥沙利铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨;诺肖林;替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;希罗达;伊班膦酸盐;伊立替康(例如,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DFMO);维A酸类(retinoids),诸如视黄酸;卡培他滨;卡铂、丙卡巴肼、普卡霉素、吉西他滨、诺维本、法呢基-蛋白转移酶抑制剂、反铂,和上述任一种的药学上可接受的盐、酸或衍生物。
B.放射疗法
造成DNA损伤并已广泛使用的其它因素包括通常被称为γ射线、X射线的那些和/或放射性同位素向肿瘤细胞的定向递送。还涵盖其它形式的DNA损伤因素,例如微波、质子束照射(美国专利5,760,395和4,870,287),和紫外光照射。最有可能的是,所有这些因素均对DNA、DNA前体、DNA的复制和修复以及染色体的组装和维持造成广泛范围的损害。对于X射线的剂量范围,其为从以50-200伦琴的日剂量持续较长时段(3至4周)至2000-6000伦琴的单次剂量。放射性同位素的剂量范围宽泛地变化,并且取决于同位素的半衰期、发射的辐射的强度和类型以及赘生性细胞的摄取。
C.免疫疗法
熟练的技术人员会理解,本发明的方法可以与另外的免疫疗法联合或结合使用。在治疗癌症的背景下,免疫治疗剂通常依赖于免疫效应细胞和分子的使用以靶向并破坏癌细胞。利妥昔单抗是这样的一个实例。免疫效应子可以是例如对肿瘤细胞表面上的一些标志物特异性的抗体。所述抗体单独地可以充当治疗的效应子,或者它可以募集其它细胞以实际影响细胞杀死。抗体也可以缀合至药物或毒素(化疗剂、放射性核素、蓖麻蛋白A链、霍乱毒素、百日咳毒素等)并仅仅用作靶向试剂。可替代地,效应子可以是携带直接地或间接地与肿瘤细胞靶标相互作用的表面分子的淋巴细胞。多种效应细胞包括细胞毒性T细胞和NK细胞。
在免疫疗法的一个方面,肿瘤细胞必须带有一些适合靶向(即,不存在于大多数其它细胞上)的标志物。存在许多肿瘤标志物且这些中的任一种可以适合用于在本发明的上下文中的靶向。常见的肿瘤标志物包括CD20、癌胚抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸基Lewis抗原、MucA、MucB、PLAP、层粘连蛋白受体、erb B和p155。免疫疗法的一个替代方面是组合抗癌效应与免疫刺激效应。还存在免疫刺激分子,包括:细胞因子,诸如IL-2、IL-4、IL-12、GM-CSF、γ-IFN,趋化因子,诸如MIP-1、MCP-1、IL-8,和生长因子,诸如FLT3配体。
目前在研究中或在使用中的免疫疗法的实例是免疫佐剂,例如牛分枝杆菌、恶性疟原虫、二硝基氯苯和芳族化合物(美国专利5,801,005和5,739,169;Hui和Hashimoto,Infection Immun.,66(11):5329-5336,1998;Christodoulides等人,Microbiology,144(Pt 11):3027-3037,1998);细胞因子疗法,例如干扰素α、β和γ、IL-1、GM-CSF和TNF(Bukowski等人,Clinical Cancer Res.,4(10):2337-2347,1998;Davidson等人,J.Immunother.,21(5):389-398,1998;Hellstrand等人,Acta Oncologica,37(4):347-353,1998);基因疗法,例如TNF、IL-1、IL-2和p53(Qin等人,Proc.Natl.Acad.Sci.USA,95(24):14411-14416,1998;Austin-Ward和Villaseca,Revista Medica de Chile,126(7):838-845,1998;美国专利5,830,880和5,846,945);和单克隆抗体,例如抗-CD20、抗-神经节苷脂GM2和抗-p185(Hanibuchi等人,Int.J.Cancer,78(4):480-485,1998;美国专利5,824,311)。预期的是,一种或更多种抗癌疗法可以与本文所述的抗体疗法一起使用。
在一些实施方案中,免疫疗法可以是过继免疫疗法,其涉及离体产生的自体抗原特异性T细胞的转移。通过抗原特异性T细胞的扩增或通过基因工程对T细胞重定向,可以产生用于过继免疫疗法的T细胞。已证明,肿瘤特异性T细胞的分离和转移可成功治疗黑素瘤。通过转基因T细胞受体或嵌合抗原受体(CAR)的遗传转移,已经在T细胞中成功产生了新特异性。CAR是由在单个融合分子中与一个或多个信号传递结构域结合的靶向部分组成的合成受体。一般而言,CAR的结合部分由单链抗体(scFv)的抗原结合结构域组成,其包含通过柔性接头连接的单克隆抗体的轻且可变片段。也已经成功使用基于受体或配体结构域的结合部分。第一代CAR的信号传递结构域源自CD3zeta的细胞质区域或Fc受体γ链。CAR已经成功地使T细胞能够针对在来自各种恶性肿瘤(包括淋巴瘤和实体瘤)的肿瘤细胞的表面上表达的抗原进行重定向。
在一个实施方案中,本申请提供了用于治疗癌症的组合疗法,其中该组合疗法包含过继性T细胞疗法和检验点抑制剂。在一个方面,过继性T细胞疗法包含自体和/或同种异体T-细胞。在另一个方面,自体和/或同种异体T-细胞靶向肿瘤抗原。
D.手术
大约60%的癌症患者会经历一些类型的手术,这包括预防性、诊断性或分期、治愈性和姑息性手术。治愈性手术包括将全部或部分癌性组织物理移除、切离和/或破坏的切除术,并可与其它疗法,诸如本发明的治疗、化学疗法、放射疗法、激素疗法、基因疗法、免疫疗法和/或替代疗法联合使用。肿瘤切除术是指物理去除肿瘤的至少一部分的。除肿瘤切除术外,手术治疗还包括激光手术、冷冻手术、电外科手术,和在显微镜控制的手术(莫氏手术)。
在切除部分或全部癌细胞、组织或肿瘤后,可能在体内形成空腔。可以通过给该区域灌注、直接注射或局部施用其它抗癌疗法来完成治疗。可以重复这样的治疗,例如每隔1、2、3、4、5、6或7天,或每隔1、2、3、4和5周,或每隔1、2、3、4、5、6、7、8、9、10、11或12个月。这些治疗也可以具有不同的剂量。
E.其它药剂
预期的是,其它药剂可以与本发明的某些方面组合使用以改善治疗的治疗效果。这些另外的药剂包括影响细胞表面受体和GAP连接的上调的药剂、细胞生长抑制剂和分化剂、细胞粘附抑制剂、增加过度增殖性细胞对细胞凋亡诱导物的敏感性的药剂、或其它生物药剂。通过升高GAP连接的数目来增加细胞间信号传递会增加对相邻过度增殖性细胞群体的抗过度增殖作用。在其它实施方案中,细胞生长抑制剂或分化剂可以与本发明的某些方面组合使用以改善治疗的抗过度增殖效力。预期的是,细胞粘附抑制剂改进本发明的效力。细胞粘附抑制剂的实例是粘着斑激酶(FAK)抑制剂和洛伐他汀。进一步预期的是,增加过度增殖性细胞对细胞凋亡的敏感性的其它药剂,诸如抗体c225,可以与本发明的某些方面组合使用以提高治疗效力。
V.试剂盒
在本发明的多个方面,设想了含有诊断剂、治疗剂和/或递送剂的试剂盒。在某些实施方案中,本发明考虑用于制备和/或施用本发明的疗法的试剂盒。试剂盒可以包含能够用于施用本发明的活性或有效药剂的试剂。试剂盒的试剂可以包括组合疗法的一种或多种抗癌组分,以及用于制备、配制和/或施用本发明的组分或执行本发明方法的一个或多个步骤的试剂。在一些实施方案中,试剂盒还可以包含合适的容器装置,所述容器装置是不会与试剂盒的组分反应的容器,诸如埃彭道夫管、测定板、注射器、瓶或试管。容器可以由可灭菌的材料(诸如塑料或玻璃)制成。试剂盒可以进一步包括概述方法的程序步骤的指令页,并且将基本上遵循与本文所述或普通技术人员已知的相同方案。
VI.实施例
包括以下实施例来证实本发明的优选实施方案。本领域技术人员应该理解,在以下的实施例中公开的技术代表发明人发现的在本发明的实践中运行良好的技术,并且因而可以视为构成其实践的优选模式。但是,本领域技术人员根据本公开内容,应该理解,在不背离本发明的精神和范围的情况下,可以对所公开的具体实施方案中进行多种改变且仍然获得类似或相似的结果。
实施例1-胰腺癌的同源原位模型中的WP1066和抗PD-1/CTLA-4抗体组合疗法
WP1066和WP1732是p-STAT3的抑制剂,具有经证实的对PDAC肿瘤模型的体外和体内活性。在U.T.MD Anderson Cancer Center进行了WP1066和WP1732的化学合成及表征。使用增殖和细胞凋亡诱导测定在一组患者衍生的和市售的PDAC细胞系中评估两种抑制剂的体外效力。使用蛋白质印迹(WB)和免疫荧光研究p-STAT3的抑制。在所有测试的PDAC细胞系中,WP1066和WP1732均证实诱导细胞凋亡并抑制p-STAT3及其核定位。观察到的IC50值范围为0.5-2μM。
在CD-1小鼠中测试了WP1732的急性和多剂量毒性。小鼠对WP1732具有良好耐受性(静脉内施用,LD50 85mg/kg)。使用质谱法LC/MS/MS在原初CD-1小鼠中,或使用放射性标记的试剂通过液体闪烁计数(LSC)在大鼠中,评价了在静脉内施用后WP1732的药代动力学参数。药代动力学和生物分布研究表明,在药物的单次快速推注以后,药物的高血浆水平和WP1732在小鼠和大鼠的胰腺中的显著积累。在PDAC肿瘤模型中测试了单独的或与免疫检验点抑制剂组合的两种药剂的效力。
使用稳定表达荧火虫萤光素酶的Panc02细胞在胰腺导管腺癌的同基因常位小鼠模型中测试口服施用的WP1066 40mg/kg(图1)。一组小鼠施用载剂,一组通过腹膜内(IP)注射施用100和250μg/小鼠的抗CTLA-4/PD-1抗体,一组口服施用40mg/kg的WP1066,一组施用所述组合。药物施用按照7天时间表进行3周,其中在每周的第1天和第5天施用药物。4周后,接受载剂的小鼠和接受单一药剂疗法的小鼠显示出的肿瘤生物发光是在2周时测量的基线的2至4倍。这意味着,肿瘤随着每种单一疗法而生长。接受组合疗法的小鼠平均显示出低于基线的生物发光(图1)。因此,在免疫活性的小鼠的Panc02肿瘤的常位模型中观察到WP1066与抗-PD-1/CTLA-4抗体的组合的叠加/协同作用。
实施例2-胰腺癌的同源原位MT04-Lyt2模型中,WP1732(次优剂量)作为单一药剂和与免疫检验点抑制剂组合中的活性
使用稳定表达荧火虫萤光素酶的MT04-Lyt2细胞和WP1732 20mg/kg IP在不同类型的胰腺癌的同基因常位小鼠模型中进行类似的实验。给BL6 albino雄性小鼠通过手术植入2.5×105个表达萤光素酶的MT04-Lyt2小鼠胰腺癌细胞。施用计划在手术后第10天开始。药物施用按7天计划进行,共三周。在施用计划的第1和5天腹膜内施用免疫检验点抗体混合液(抗CTLA4,100μg/小鼠;和抗PD-1,250μg/小鼠),并在施用计划的第1-5天腹膜内施用WP1732(20mg/kg)。从手术后第7、14、21和28天开始,使用IVIS Spectrum成像仪每周用萤光素对小鼠进行成像,并分析光亮度(总计数/秒)。使用Kaplan-Meier方法和Gehan-Breslow-Wilcoxon统计分析在GraphPad Prism中分析存活数据。未治疗小鼠的生存中值为18天,WP1732单一疗法小鼠为21.5天,检验点抑制剂小鼠为26天,且联合疗法WP1732和检验点抑制剂(CTLA4和PD-1抗体)小鼠为40天(图2A-B)。本体内试验证实,WP1066和WP1732以非常显著的方式增强了免疫检验点抑制剂的抗肿瘤活性。
***
根据本公开内容,无需过多实验可以实现和执行在本文中公开并要求保护的所有方法。虽然已经以优选实施方案的方式描述了本发明的组合物和方法,但是本领域技术人员显而易见,在不偏离本发明的概念、精神和范围的情况下,可以对本文中所述方法以及本文所述方法的步骤或步骤顺序作出改变。更具体地,显而易见,可以用在化学上和生理学上均相关的某些药剂替代本文所述的药剂,并实现相同或类似的结果。本领域技术人员显而易见的所有这样的类似的替代和修改均被认为落入由所附权利要求书限定的本发明的精神、范围和概念内。
Claims (22)
1.一种治疗患者中的疾病的方法,所述方法包括向所述患者施用组合有效量的转录抑制剂和免疫检验点抑制剂。
2.根据权利要求1所述的方法,其中,所述转录抑制剂是STAT3抑制剂。
3.根据权利要求2所述的方法,其中,所述转录抑制剂是α,β-不饱和氰基羧酰胺。
4.根据权利要求2所述的方法,其中,所述转录抑制剂是WP1066或WP1732。
5.根据权利要求1至4中的任一项所述的方法,其中,所述免疫检验点抑制剂包括抗PD1疗法、抗PD-L1疗法和抗CTLA-4疗法中的一种或多种。
6.根据权利要求5所述的方法,其中所述抗PD1疗法包括纳武单抗、派姆单抗、皮地利珠单抗、西米普利单抗、替雷利珠单抗、斯巴达珠单抗、PF-06801591、AK105、BCD-100、BI-754091、HLX10、JS001、LZM009、MEDI 0680、MGA012、Sym021、TSR-042、MGD013、AK104和/或XmAb20717。
7.根据权利要求5所述的方法,其中,所述抗PD-L1疗法包括阿特朱单抗、阿维鲁单抗、度伐单抗、FS118、BCD-135、BGB-A333、CBT502、CK-301、CS1001、FAZ053、KN035、MDX-1105、MSB2311、SHR-1316、M7824、LY3415244、CA-170和CX-072。
8.根据权利要求5所述的方法,其中,所述抗CTLA-4疗法包括伊匹木单抗、曲美木单抗、BMS-986218、AK104和/或XmAb20717。
9.根据权利要求1-8中的任一项所述的方法,其中,所述疾病是增殖性疾病。
10.根据权利要求9所述的方法,其中,所述增殖性疾病是癌症。
11.根据权利要求9所述的方法,其中,所述方法抑制癌细胞的存活或增殖。
12.根据权利要求10或11所述的方法,其中,所述患者以前已经对施用的免疫检验点抑制剂应答失败。
13.根据权利要求12所述的方法,其中,所述方法是克服对免疫检验点抑制剂疗法的抗性的方法。
14.根据权利要求9至13中的任一项所述的方法,所述方法进一步包括向所述患者施用另一种抗癌疗法。
15.根据权利要求14所述的方法,其中,所述另一种抗癌疗法是手术疗法、化学疗法、放射疗法、冷冻疗法、激素疗法、毒素疗法、免疫疗法或细胞因子疗法。
16.根据权利要求14所述的方法,其中,所述另一种抗癌疗法包括吉西他滨、5-氟尿嘧啶、伊立替康、奥沙利铂、紫杉醇、卡培他滨、顺铂或多西他赛。
17.根据权利要求10至16中的任一项所述的方法,其中,所述癌症是神经胶质瘤、胰腺癌、乳腺癌、黑素瘤、淋巴瘤或白血病。
18.根据权利要求17所述的方法,其中,所述白血病是AML。
19.根据权利要求10至18中的任一项所述的方法,其中,所述患者以前已经经历至少一轮的抗癌疗法。
20.根据权利要求9所述的方法,其中,所述增殖性疾病是银屑病。
21.根据权利要求1所述的方法,其中,所述疾病是病原性感染。
22.根据权利要求1至21中的任一项所述的方法,其中,所述患者是人。
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