CN114126624A - Hsp90结合缀合物及其联合疗法 - Google Patents
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Abstract
本公开总体上涉及一种治疗癌症的方法,包括施用HSP90结合缀合物或施用两种不同的治疗剂作为联合疗法。提供了联合疗法的组分和使用联合疗法的方法。
Description
相关申请的引用
本申请要求2019年6月25日提交的题为HSP90-BINDING CONJUGATES ANDCOMBINATION THERAPIES THEREOF(HSP90结合缀合物及其联合疗法)的美国临时专利申请号62/866,140,2019年9月13日提交的题为TARGETED THERAPEUTICS(靶向疗法)的美国临时专利申请号62/899,777,以及2020年6月5日提交的题为HSP90-BINDING CONJUGATES ANDCOMBINATION THERAPIES THEREOF(HSP90结合缀合物及其联合疗法)的美国临时专利申请号63/035,048的优先权,其各自内容通过引用整体并入本文。
公开领域
本公开总体上涉及用于治疗癌症的疗法。
背景
尽管已经在化学疗法中取得了巨大的进步,但是当前可用的治疗剂和疗法仍然不能令人满意,并且大多数被诊断出患有接受化学疗法治疗的疾病(例如癌症)的患者的预后仍然很差。通常,化学疗法以及采用潜在毒性部分的其他疗法和诊断的适用性和/或有效性受到不希望的副作用的限制。
许多疾病和病症的特征是特定类型的细胞中某些蛋白质的高存在水平。在某些情况下,蛋白质的这些高存在水平是由过度表达引起的。从历史上看,这些蛋白质中的一些一直是治疗分子的有用靶标,或被用作疾病检测的生物标志物。一类已经被识别为有用的治疗靶标的过度表达的细胞内蛋白质被称为热休克蛋白。
热休克蛋白(HSP)是响应于升高的温度和其他环境压力(例如紫外线、营养缺乏和氧缺乏)而被上调的一类蛋白质。HSP具有许多已知的功能,包括充当其他细胞蛋白(称为客户蛋白)的伴侣,以促进其正确折叠和修复,并帮助错误折叠的客户蛋白重新折叠。有几种已知的HSP家族,每个家族都有其自己的客户蛋白组。Hsp90是最丰富的HSP家族之一,在不受应激的细胞中约占蛋白质的1-2%,在受应激的细胞中增加到约4-6%。
Hsp90的抑制导致其客户蛋白通过泛素蛋白酶体途径降解。与其他伴侣蛋白不同,Hsp90的客户蛋白主要是与信号转导有关的蛋白激酶或转录因子,并且其许多客户蛋白已经显示与癌症的进展有关。通过突变分析已显示Hsp90对于正常真核细胞的存活是必需的。但是,Hsp90在许多肿瘤类型中过度表达,这表明它可能在癌细胞的存活中起重要作用,并且癌细胞可能比正常细胞对Hsp90的抑制更敏感。例如,癌细胞通常具有大量依赖于Hsp90进行折叠的突变和过度表达的癌蛋白。此外,由于肿瘤的环境通常由于缺氧、营养缺乏、酸中毒等而不利,因此肿瘤细胞的存活可能特别依赖于Hsp90。此外,Hsp90的抑制导致多种癌蛋白以及激素受体和转录因子的同时抑制,使其成为抗癌剂的有吸引力的靶标。鉴于此,Hsp90已经成为药物开发的有吸引力的靶标,包括诸如ganetespib、AUY-922和IPI-504的Hsp90抑制剂(Hsp90i)化合物。同时,显示出早期成功迹象的这些化合物中的某些(例如格尔德霉素)的进展因那些化合物的毒性作用而减慢了。据信迄今为止开发的Hsp90i化合物作为癌症药物显示出巨大的成功迹象,但是到目前为止,尚未研究出可能影响Hsp90在癌细胞中的普遍存在的其他方法。因此,需要选择性地靶向在与特定疾病或病症有关的细胞中过度表达的蛋白质如Hsp90的治疗性分子。
发明内容
本申请提供了一种治疗有需要的受试者的癌症的方法,包括以150mg/m2、175mg/m2或200mg/m2体表面积的剂量向受试者施用有效量的缀合物1(SDC-TRAP-0063)或其药学上可接受的盐。缀合物1或其药学上可接受的盐可以在第1天、第8天和第15天每周施用一次,持续3周,随后一周不进行治疗。癌症可以是***癌、乳腺癌、胆管癌、结肠癌、尤因肉瘤(Ewing sarcoma)、肝癌、肺癌、神经内分泌癌(未知原发性)、卵巢癌、胰腺癌、唾液腺癌或肉瘤。在一些实施方案中,癌症是胰腺癌、子宫内膜腺癌,或***、子宫颈或头颈部的鳞状细胞癌。
本申请还提供治疗有需要的受试者的癌症的方法,包括向受试者施用有效量的缀合物1或其药学上可接受的盐,其中受试者已接受至少一种先前的抗癌疗法。
本申请提供了一种治疗有需要的受试者的癌症的方法,包括向受试者施用有效量的缀合物1或其药学上可接受的盐,其中受试者在治疗后显示出部分缓解(partialresponse)或疾病稳定(stable disease)。
在一些实施方案中,在用缀合物1或其药学上可接受的盐对受试者进行治疗后,肿瘤缀合物1水平与血浆缀合物1水平之比大于5;肿瘤缀合物1水平大于300nM;肿瘤SN-38水平与血浆SN-38水平之比大于3;和/或肿瘤SN-38水平大于80nM。
本公开还涉及一种治疗患有过度增殖性疾病例如癌症的患者的方法,包括向患者施用:(A)第一组分,其包含缀合物1或其药学上可接受的盐作为活性剂;和任选的(B)第二组分,其包含组分II或其药学上可接受的盐作为活性剂;所述活性剂的量使得其组合在治疗所述过度增殖性疾病中是治疗有效的。组分I可包含靶向热休克蛋白90(HSP90)的缀合物。
本公开进一步涉及一种组合物,其包含:(A)第一组分,其包含缀合物1或其药学上可接受的盐作为活性剂;和(B)第二组分,其包含组分I或其药学上可接受的盐作为活性剂。
本公开还涉及一种试剂盒,其包含:(A)第一组分,其包含缀合物1或其药学上可接受的盐作为活性剂;和(B)第二组分,其包含组分II或其药学上可接受的盐作为活性剂。
此外,本公开涉及缀合物1或其药学上可接受的盐和组分II或其药学上可接受的盐在治疗过度增殖性疾病中的用途。
本公开的另一方面是缀合物1或其药学上可接受的盐和组分II或其药学上可接受的盐在制备用于治疗过度增殖性疾病的药物中的用途。
附图简要说明
图1A显示了在H1975模型中缀合物1以72和100mg/kg的每周剂量给药的功效。
图1B显示了在H1975模型中缀合物1以150mg/kg的每周剂量给药的功效。
图2显示了缀合物1和尼拉帕尼(niraparib)的血浆暴露量以及缀合物1的肿瘤异种移植物暴露量的估计值。
图3A显示了在用溶媒、他拉唑帕尼(talazoparib)、缀合物1和缀合物1/他拉唑帕尼联合疗法治疗后,携带SKOV3肿瘤的小鼠的平均肿瘤体积。
图3B显示了在用溶媒、他拉唑帕尼、缀合物1和缀合物1/他拉唑帕尼联合疗法治疗后,携带NCI-H460肿瘤的小鼠的平均肿瘤体积。
图3C显示了在用他拉唑帕尼、缀合物1和缀合物1/他拉唑帕尼联合疗法治疗后NCI-H460 NSCLC异种移植肿瘤中的pH2AX量。
详细描述
本公开涉及用于治疗过度增殖性疾病例如癌症的至少两种不同的治疗剂的联合疗法。每种不同的治疗剂均被称为联合疗法的“组分”。本公开的联合疗法在治疗各种类型的癌症中非常有效并且显示出与单独给药的每种组分的活性相比增强的作用。如本文所用的术语“联合疗法”或“联合治疗”或“组合”是指用至少两种不同的治疗剂同时或平行治疗的任何形式。过度增殖性疾病包括以不受控制的细胞增殖为特征的任何疾病或病症。
联合疗法的组分可以同时、顺序或以任何顺序给药。只要合适,组分可以以不同的剂量、以不同的给药频率或通过不同的途径来给药。
如本文所用的术语“同时给药”没有特别限制,并且是指联合疗法的组分基本上同时给药,例如作为混合物或以紧随其后的顺序。
如本文所用的术语“顺序给药”没有特别限制,并且是指联合疗法的组分不是同时给药,而是一个接一个或分组地给药,在给药之间有特定的时间间隔。联合疗法的组分的各自施用之间的时间间隔可以相同或不同,并且可以例如选自2分钟至96小时、1至7天或1、2或3周的范围。通常,给药之间的时间间隔可以在几分钟至数小时的范围内,例如在2分钟至72小时、30分钟至24小时或1至12小时的范围内。进一步的实例包括24至96小时、12至36小时、8至24小时和6至12小时范围内的时间间隔。在一些实施方案中,组分I在在组分II之前施用。在一些实施方案中,组分II在组分I之前施用。
组分的摩尔比没有特别限制。例如,当两种组分在组合物中组合时,两种组分之间的摩尔比可以在1:500至500:1、或1:100至100:1、或1:50至50:1、或1:20至20:1、或1:5至5:1、或1:1的范围内。当组合物中组合多于两种组分时,适用相似的摩尔比。每种组分可独立地包含组合物的约1%至10%、或约10%至约20%、或约20%至约30%、或约30%至40%、或约40%至50%、或约50%至60%、或约60%至70%、或约70%至80%、或约80%至90%、或约90%至99%的预定的摩尔重量百分比。
I.联合疗法中的组分
本公开的一个方面提供了一种用于治疗患有过度增殖性疾病例如癌症的受试者的联合疗法,其包括向患者施用:(A)第一组分,其包含组分I(或化合物I)或其前药、衍生物或药学上可接受的盐作为活性剂;和(B)第二成分,其包含组分II(或化合物II)或其前药、衍生物或药学上可接受的盐作为活性剂;所述活性剂的量使得其组合在治疗所述过度增殖性疾病中是治疗有效的。
在一些实施方案中,组分I是小分子缀合物,其包含附接至靶向部分的活性剂或其前药,其中靶向部分结合至热休克蛋白90(HSP90)。
组分II不同于组分I。在一些实施方案中,组分II包含治疗癌症的治疗剂,例如检查点抑制剂。如本文所用的检查点抑制剂是指在肿瘤微环境中阻断免疫抑制信号的活性剂。在一些实施方案中,活性剂可以是对共抑制检查点分子(例如CTLA-4、PD1、PD-L1)具有特异性的拮抗剂,其可以拮抗或减少对效应物免疫细胞的抑制信号。在一些实施方案中,活性剂可以是能够在肿瘤微环境中抑制和降低免疫抑制酶(例如ARG和IDO)和细胞因子(例如IL-10)、趋化因子和其他可溶性因子(例如TGF-β和VEGF)的活性的抑制剂。
如本文所用的术语“小分子”是指分子量小于2000g/mol、小于1500g/mol、小于1000g/mol、小于800g/mol或小于500g/mol的有机分子。小分子是非聚合的和/或非寡聚的。
如本文所用的术语“靶向部分”是指结合或定位于特定位置的部分。该部分可以是例如蛋白质、核酸、核酸类似物、碳水化合物或小分子。该位置可以是组织、特定的细胞类型或亚细胞区室。在一些实施方案中,靶向部分可以特异性结合至所选分子例如蛋白质。
在一些情况下,缀合物的分子量可小于约50,000Da、小于约40,000Da、小于约30,000Da、小于约20,000Da、小于约15,000Da、小于约10,000Da、小于约8,000Da,小于约5,000Da或小于约3,000Da。在一些情况下,缀合物的分子量可以为约1,000Da至约50,000Da、约1,000Da至约40,000Da,在一些实施方案中为约1,000Da至约30,000Da,在一些实施方案中为约1,000Da至约50,000Da、约1,000Da至约20,000Da,在一些实施方案中为约1,000Da至约15,000Da,在一些实施方案中为约1,000Da至约10,000Da,在一些实施方案中为约1,000Da至约8,000Da,在一些实施方案中为约1,000Da至约5,000Da,并且在一些实施方案中为约1,000Da至约3,000Da。缀合物的分子量可以计算为缀合物分子式中每种原子的原子量乘以每种原子的数目后的总和。也可以通过质谱法、NMR、色谱法、光散射、粘度和/或本领域已知的任何其他方法来测量。本领域中已知,分子量的单位可以是g/mol、道尔顿(Da)或原子质量单位(amu),其中1g/mol=1Da=1amu。
组分I和组分II可以同时、顺序或以任何顺序给药。只要合适,它们可以以不同的剂量、以不同的给药频率或通过不同的途径给药。
组分I
在一些实施方案中,组分I是缀合物,其包含附接至靶向部分的活性剂或其前药,其中靶向部分结合至热休克蛋白,例如HSP90。靶向部分可以选自ganetespib、格尔德霉素(geldanamycin)(坦螺旋霉素(tanespimycin))、IPI-493、麦克霉素类(macbecins)、雷公藤红素类(tripterins)、坦螺旋霉素类、17-AAG(阿螺旋霉素(alvespimycin))、KF-55823、根赤壳菌素类(radicicols)、KF-58333、KF-58332、17-DMAG、IPI-504、BIIB-021、BIIB-028、PU-H64、PU-H71、PU-DZ8、PU-HZ151、SNX-2112、SNX-2321、SNX-5422、SNX-7081、SNX-8891、SNX-0723、SAR-567530、ABI-287、ABI-328、AT-13387、NSC-113497、PF-3823863、PF-4470296、EC-102、EC-154、ARQ-250-RP、BC-274、VER-50589、KW-2478、BHI-001、AUY-922、EMD-614684、EMD-683671、XL-888、VER-51047、KOS-2484、KOS-2539、CUDC-305、MPC-3100、CH-5164840、PU-DZ13、PU-HZ151、PU-DZ13、VER-82576、VER-82160、VER-82576、VER-82160、NXD-30001、NVP-HSP990、SST-0201CL1、SST-0115AA1、SST-0221AA1、SST-0223AA1、新生霉素(novobiocin)、除莠霉素A(herbinmycin A)、根赤壳菌素(radicicol)、CCT018059、PU-H71、南蛇藤素(celastrol),或其互变异构体、类似物或衍生物。
在一些实例中,组分I包含SN-38或伊立替康(irinotecan)、来那度胺(lenalidomide)、伏立诺他(vorinostat)、5-氟尿嘧啶(5-Fluorouracil,5-FU)、阿比特龙(abiraterone)、苯达莫司汀(bendamustine)、克唑替尼(crizotinib)、阿霉素(doxorubicin)、培美曲塞(pemetrexed)、氟维司群(fulvestrant)、拓扑替康(topotecan)、血管阻断剂(Vascular Disrupting Agent,VDA),或其片段、衍生物或类似物作为活性剂。
在一些实例中,组分I可以是2013年4月16日提交的PCT申请号PCT/US13/36783(WO2013/158644)的任何缀合物,其内容通过引用并入本文。
在一个实例中,组分I是包含ganetespib或其互变异构体作为靶向部分和SN-38作为活性剂的缀合物。组分I可以是具有以下结构的缀合物1(也称为SDC-TRAP-0063):
((S)-4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]中氮茚并[1,2-b]喹啉-9-基4-(2-(5-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-***-4-基)-1H-吲哚-1-基)乙基)哌啶-1-羧酸酯)或其互变异构体。
缀合物1是可注射的、合成的小分子药物缀合物,其包含通过可裂解的连接基附接到SN-38(市售拓扑异构酶I抑制剂伊立替康的活性代谢产物)的ganetespib。该缀合物利用HSP90增强的肿瘤靶向性和优先的肿瘤保留特性来递送SN-38,从而导致广泛的临床前抗肿瘤活性。
在一些实施方案中,缀合物1可用于治疗癌症,例如肉瘤、胰腺癌、胆管癌、卵巢癌、小细胞肺癌(SCLC)、结肠癌、口腔癌、子宫内膜癌、***、头颈癌、鳞状细胞癌或***癌。在一些实施方案中,缀合物1可用于治疗由病毒引起的癌症,例如由乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、Epstein-Barr病毒(EBV)、人T细胞白血病病毒(HTLV)、Kaposi肉瘤相关疱疹病毒(KSHV)或人***瘤病毒(HPV)引起的癌症。在一些实施方案中,将缀合物1施用于HPV阳性患者。在一些实施方案中,将缀合物1施用于患有癌症且为HPV阳性的患者,其中癌症可以选自口腔癌、***、头颈癌或鳞状细胞癌。
组分II
在一些实施方案中,组分II包含与组分I不同的治疗癌症的治疗剂。
在一些实施方案中,组分II可以是化学治疗剂。在一些实施方案中,组分II可以是用于治疗***癌、乳腺癌、非小细胞肺癌(大细胞肺癌)、小细胞肺癌或卵巢癌的化学治疗剂。
在一些实施方案中,组分I和组分II一起引起合成致死并且可用于治疗癌症。癌症是由多个基因的突变和多个信号传导通路的异常引起的。如果两个靶(例如基因)中的任何一个中的突变不会改变细胞或生物体的生活力,但两个靶同时突变将导致致死表型,则这两个靶(例如基因)是合成致死的。合成致死性抗癌疗法可以包括针对BRCA1-和BRCA2-突变癌症的聚ADP-核糖聚合酶抑制剂、针对p53突变癌症的检查点抑制剂以及靶向RAS基因突变癌症的小分子药物。
在一些实施方案中,组分II可以是聚ADP核糖聚合酶(PARP)抑制剂。PARP是一组ADP-核糖转移酶,通过将ADP-核糖基团从供体底物烟酰胺腺嘌呤二核苷酸(NAD+)转移到受体蛋白中的谷氨酸、天冬氨酸和赖氨酸残基,来催化蛋白质的聚ADP-核糖基化,从而调节这些蛋白质的功能。PARP抑制剂可以抑制DNA损伤的修复,已被批准主要用于因BRCA1/2突变而导致DNA修复缺陷的肿瘤。由于毒性重叠,将PARP抑制剂与其他药物联合使用具有挑战性。一些癌症具有高BRCA1水平并且对PARP抑制不敏感。HSP90结合组分I可能具有DNA损伤作用,并可能使细胞对PARP抑制敏感。PARP抑制剂的非限制性实例可包括他拉唑帕尼(BMN-673)、奥拉帕尼(olaparib)(AZD-2281)、尼拉帕尼(MK-4827)、伊尼帕利(iniparib)(BSI201)、维利帕尼(veliparib)(ABT-888)、瑞卡帕尼(rucaparib)(AG014699,PF-01367338)、CEP 9722、氟唑帕利(Fluzoparib)(SHR3162)、Senaparib(IMP4297)、KU0058684、KU0058948、NU1025或AG14361。
在一些实施方案中,组分II可以为癌症患者提供支持性护理和/或减少组分I的副作用。在一些实施方案中,组分II是癌症症状缓解药物。症状缓解药物可减少腹泻或化学疗法或放射疗法的副作用。症状缓解药物的非限制性实例包括:奥曲肽(octreotide)或兰瑞肽(lanreotide);干扰素、塞庚啶(cypoheptadine)或任何其他抗组胺药;和/或用于类癌综合征的症状缓解药物,例如特罗司他(telotristat)或特罗司他马尿酸盐(telotristatetiprate,LX1032,)。
在一些实施方案中,组分II可以是5-氟尿嘧啶(5-FU)、亚叶酸(leucovorin,folinic acid)、伊立替康或奥沙利铂(oxaliplatin),或其衍生物或任何组合。在一些实施方案中,组分II是5-FU和亚叶酸的组合。
在一些实施方案中,组分II可以是沉默调节蛋白(sirtuin)调节剂例如US10590135中公开的取代桥连脲类似物、溴结构域抑制剂例如US10442786中公开的苯并咪唑衍生物、溴结构域抑制剂例如US10428026中公开的吡啶酮二甲酰胺、PAD4抑制剂例如US10407407中公开的苯并咪唑衍生物、NRF2调节剂例如US10364256中公开的联芳基吡唑、CXCR2抑制剂例如US10336719中公开的1-(环戊-2-烯-1-基)-3-(2-羟基-3-(芳基磺酰基)苯基)脲衍生物、US10336711中公开的脯氨酰羟化酶抑制剂、P13激酶抑制剂例如US8435988中公开的苯并咪唑衍生物、LSD1抑制剂例如US8853408中公开的环丙胺类、溴结构域抑制剂例如US10059699中公开的四氢喹啉衍生物、***受体抑制剂例如US9988376中公开的苯并噻吩衍生物、脂肪酸合酶抑制剂例如US8802864中公开的***酮类、PI3激酶抑制剂例如US8138347中公开的喹啉衍生物、US8138338中公开的极光激酶抑制剂、IGF-1R抑制剂例如US7981903中公开的2-[2-{苯基氨基}-1H-吡咯并[2,3-D]嘧啶-4-基)氨基]苯甲酰胺衍生物,ErbB激酶抑制剂例如US7807673中公开的2-嘧啶基吡唑并吡啶、p38抑制剂例如US7709506中公开的烟酰胺衍生物、激酶抑制剂例如US20200062735中公开的杂环酰胺、溴结构域抑制剂例如US20200009140中公开的吡啶基衍生物、PERK抑制剂例如US20190241573中公开的异喹啉衍生物,DNMT1抑制剂例如US20190194166中公开的取代的吡啶、蛋白酪氨酸激酶抑制剂例如US20150065527中公开的双环杂芳族化合物、咪唑并吡啶激酶抑制剂例如US20100216779中公开的那些、雄激素受体调节剂例如EP1725522中公开的苯胺衍生物、PLK调节剂例如EP1922316中公开的苯并咪唑噻吩化合物、二肽基肽酶抑制剂例如EP1862457中公开的氟吡咯烷类或肿瘤坏死因子抑制剂例如EP1284977中公开的噻吩并二苯并薁化合物。
在一些实施方案中,组分II可以是检查点抑制剂。肿瘤细胞可以诱导免疫抑制微环境,以帮助其逃避免疫监视。肿瘤微环境中的免疫抑制作用是通过固有的免疫抑制机制诱导的,或者是直接由肿瘤诱导的。联合疗法的组分II包含在肿瘤微环境中阻断这样的免疫抑制信号的检查点抑制剂。
在一些实施方案中,组分II可以是对共抑制检查点分子有特异性的拮抗剂,其可以拮抗或减少对效应物免疫细胞(例如细胞毒性T细胞和自然杀手细胞)的抑制信号。
在一些实施方案中,组分II可以是能够在肿瘤微环境中抑制和降低免疫抑制酶(例如ARG和IDO)和细胞因子(例如IL-10)、趋化因子和其他可溶性因子(例如TGF-β和VEGF)的活性的抑制剂。
肿瘤微环境
在用于消除肿瘤细胞的适应性免疫应答中,细胞毒性T细胞活化既需要来自特定抗原的初级信号(即第一信号)又需要一个或多个共刺激信号(即第二信号)。抗原呈递细胞(APC,例如树突状细胞(DC))加工肿瘤相关抗原(TAA),并在细胞表面上以肽/MHC分子(I/II类)(p/MHC)复合物的形式呈递源自TAA的抗原肽(即表位),并且T细胞经由识别p/MHC复合物的T细胞受体(TCR)与载有TAA的APC结合。该连接是激活癌症特异性细胞毒性T细胞的初级信号。此外,由T细胞上的共刺激受体及其APC上的配体(或共受体)提供次级共刺激信号。共刺激受体与其配体之间的相互作用可以调节T细胞活化并增强其活性。CD28、4-1BB(CD137)和OX40是T细胞上已被充分研究的共刺激受体,它们分别与APC上的B7-1/2(CD80/CD86)、4-1BB(CD137L)和OX-40L结合。在正常情况下,为了防止过度的T细胞增殖并平衡免疫力,共抑制信号例如CTLA-4可以被活化的T细胞诱导并表达,并与CD28竞争结合APC上的B7配体。在正常情况下,这可以减轻T细胞反应。然而,在某些癌症中,浸润肿瘤微环境的肿瘤细胞和调节性T细胞可以组成性地表达CTLA-4。该共抑制信号抑制共刺激信号,因此耗尽抗癌免疫应答。肿瘤细胞的这种免疫抑制机制被称为免疫检查点或检查点通路。
除了CTLA-4信号之外,还可以诱导活化的T细胞表达另一种抑制性受体PD-1(程序性死亡1)。在正常情况下,随着免疫应答的进行,CD4+和CD8+T淋巴细胞上调这些抑制性检查点受体(例如PD-1)的表达。炎症条件促使IFN释放,这将上调PD-1配体:PD-L1(也称为B7-H1)和PD-L2(也称为B7-DC)在外周组织中的表达,以维持免疫耐受,从而防止自身免疫。已证明许多人类癌症类型在肿瘤微环境中表达PD-L1(例如Zou和Chen,inhibitory B7-family in the tumor microenvironment.2008,Nat Rev Immunol,8:467-477)。PD-1/PD-L1相互作用在肿瘤微环境中具有很高的活性,抑制T细胞活化。
肿瘤微环境中其他已识别的共抑制信号包括TIM-3、LAG-3、BTLA、CD160、CD200R、TIGIT、KLRG-1、KIR、CD244/2B4、VISTA和Ara2R。
此外,肿瘤微环境包含抑制性要素,包括调节性T细胞(Treg)、骨髓来源的抑制性细胞(MDSC)和肿瘤相关巨噬细胞(TAM);可溶性因子,例如白介素6(IL-6)、IL-10、血管内皮生长因子(VEGF)和转化生长因子β(TGF-β)。IL-10、TGF-β和VEGF抵制抗癌免疫应答进展的重要机制是通过抑制树突状细胞(DC)分化、成熟、运输和抗原呈递(Gabrilovich D:Mechanisms and functional significance of tumour-induced dendritic-celldefects,Nat Rev Immunol,2004,4:941-952)。
调节性T细胞(Treg):CD4+CD25+Treg细胞代表源自胸腺的独特的淋巴细胞群。以叉头盒转录因子(Foxp3)为标志的CD4+CD25+Treg细胞在维持自身耐受性中起着关键的作用、抑制自身免疫性并调节器官移植和肿瘤免疫中的免疫应答。肿瘤进展通常将CD4+CD25+FoxP3+Treg细胞吸引到肿瘤区域。肿瘤浸润的调节性T细胞分泌抑制性细胞因子,例如IL-10和TGFβ,以抑制自身免疫和慢性炎症反应并维持肿瘤中的免疫耐受性(Unitt et al.,Compromised lymphocytes infiltrate hepatocellular carcinoma:the role of T-regulatory cells.Hepatology.2005;41(4):722–730)。
骨髓来源的抑制性细胞(MDSC):MDSC是一组异质细胞,其可以被视为恶性肿瘤相关炎症的标志以及在癌症中诱导T细胞抑制的主要介质。MDSC存在于许多恶性区域,在表型上分为粒细胞(G-MDSC)和单核细胞(Mo-MDSC)亚组。MDSC可以诱导T调节细胞,并产生T细胞耐受性。此外,MDSC在IFN-γ或活化的T细胞的存在下分泌TFG-β和IL-10,并产生一氧化氮(NO)。
肿瘤相关巨噬细胞(TAM):源自外周血单核细胞的TAM是多功能细胞,对来自肿瘤微环境的不同信号表现出不同的功能。在与肿瘤微环境相关的细胞类型中,TAM对肿瘤进展影响最大。响应于微环境刺激,例如肿瘤细胞外基质、缺氧环境和肿瘤细胞分泌的细胞因子,巨噬细胞经历M1(经典)或M2(替代)激活。在大多数恶性肿瘤中,TAM具有M2巨噬细胞的表型。
另一个免疫抑制机制涉及吲哚胺-2,3-双加氧酶(IDO)引起的色氨酸分解代谢。局部免疫抑制是由肿瘤微环境内和前哨***(SLN)内的恶性细胞诱导的活跃过程。(Gajewski et al.,Immune suppression in the tumor microenvironment.JImmunother,2006;29(3):233-240;和Zou W.,Immunosuppressive networks in thetumor environment and their therapeutic relevance,Nat Rev Cancer,2005;5(4):263-274)。研究表明,在肿瘤引流***内,作为区域免疫抑制中涉及的要素的一部分,T细胞受体ζ亚单位(TCR)被下调,吲哚胺2,3-双加氧酶(IDO)被上调。
除了通过浸润调节性免疫细胞所介导的抑制作用外,肿瘤细胞本身还可以分泌许多分子来主动抑制细胞毒性T细胞的活化和功能。
在一些肿瘤中,T细胞固有的无反应性和耗竭是常见的,这是在T细胞上没有结合共刺激受体例如CD28的情况下由TCR连接引起的。
在本公开中,联合疗法的组分II抑制一种或多种免疫抑制机制并增强用于消除肿瘤细胞的癌症特异性免疫应答。
检查点抑制剂
在一些实施方案中,组分II包含检查点抑制剂,例如阻断检查点通路的活性剂。
在适应性免疫应答过程中,细胞毒性T细胞的激活由抗原呈递细胞上的抗原肽/MHC分子复合物与T细胞上的T细胞受体(TCR)之间的初级信号介导。次级共刺激信号对活跃的T细胞也很重要。在缺乏次级信号的情况下,抗原呈递不足以激活T细胞,例如CD4+T辅助细胞。众所周知的共刺激信号涉及T细胞上的共刺激受体CD28及其在抗原呈递细胞(APC)上的配体B7-1/CD80和B7-2/CD86。B7-1/2和CD28的相互作用可以增加抗原特异性T细胞增殖和细胞因子产生。为了严格调节免疫应答,T细胞还表达CTLA-4(抗细胞毒性T淋巴细胞抗原4),它是CD80和CD86介导的通过T细胞上的受体CD28的共刺激的共抑制性竞争者,其可以有效抑制T细胞的活化和功能。当CD28与APC表面上的B7-1/2相互作用时,经常诱导CTLA-4表达。与共刺激受体CD28相比,CTLA-4对共刺激配体B7-1/2(CD80/CD86)的结合亲和力更高,因此提示了从CD28和B7-1/2之间的T细胞活化相互作用到CTLA-4和B7-1/2之间的抑制性信号传导的平衡,这导致T细胞活化的抑制。CTLA-4上调主要发生在***中T细胞的初始活化过程中。
与CTLA-4特异性结合的抗体已被用来抑制该抑制性检查点。抗CTLA-4IgG1人源化抗体:易普利姆玛(ipilimumab)与CTLA-4结合并阻止CD28/B7刺激信号传导的抑制。它们可以降低淋巴器官中T细胞活化的阈值,也可以耗尽肿瘤微环境内的T调节细胞(Simpson etal.,Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4therapy against melanoma.J Exp.Med.,2013,210:1695-1710)。易普利姆玛最近被美国食品和药品管理局批准用于治疗患有转移性黑素瘤的患者。
在一些实施方案中,本公开的联合疗法的组分II可包含针对CTLA-4的拮抗剂,例如抗体、抗体的功能片段、多肽、或多肽的功能片段或肽,其能够以高亲和力与CTLA-4结合,并阻止B7-1/2(CD80/86)与CTLA-4的相互作用。在一个实例中,CTLA-4拮抗剂是拮抗性抗体或其功能片段。合适的抗CTLA-4拮抗性抗体包括但不限于抗CTLA-4抗体、人抗CTLA-4抗体、哺乳动物抗CTLA-4抗体、人源化抗CTLA-4抗体、单克隆抗CTLA-4抗体、多克隆抗CTLA-4抗体、嵌合抗CTLA-4抗体、MDX-010(易普利姆玛)、替西木单抗(tremelimumab)(完全人源化)、抗CD28抗体、抗CTLA-4adnectins、抗CTLA-4结构域抗体、单链抗CTLA-4抗体片段、重链抗CTLA-4片段、轻链抗CTLA-4片段以及在以下文献中公开的抗体:美国专利号8,748,815;8,529,902;8,318,916;8,017,114;7,744,875;7,605,238;7,465,446;7,109,003;7,132,281;6,984,720;6,682,736;6,207,156;5,977,318;和欧洲专利号EP1212422B1;和美国公开号US 2002/0039581和US2002/086014;和Hurwitz et al.,Proc.Natl.Acad.Sci.USA,1998,95(17):10067-10071;其全部内容均通过引用并入本文。
其他抗CTLA-4拮抗剂包括但不限于能够破坏CTLA-4与配体CD80/86结合的能力的任何抑制剂。
抑制性检查点受体PD-1(程序性死亡-1)在活化的T细胞上表达,并可以在通常在上皮细胞和内皮细胞和免疫细胞(例如DC、巨噬细胞和B细胞)上表达的程序性死亡配体1和2(PD-L1,也称为B7-H1、CD274)和PD-L2(也称为B7-DC、CD273)连接后诱导T细胞的抑制和凋亡。PD-1主要在周围组织(包括肿瘤组织)的效应期中调节T细胞功能。除了活化的T细胞外,PD-1还在B细胞和骨髓细胞上表达。许多人类肿瘤细胞可以表达PD-L1并劫持该调节功能,以逃避免疫识别和被细胞毒性T淋巴细胞破坏。肿瘤相关PD-L1已经显示出诱导效应T细胞的凋亡,并被认为有助于癌症的免疫逃避。
PD-1/PD-L1免疫检查点似乎涉及在多种肿瘤类型,例如黑素瘤中。PD-L1不仅为肿瘤细胞提供免疫逃逸,而且开启活化的T细胞上的凋亡开关。阻断该相互作用的疗法已在若干肿瘤类型中证明了有希望的临床活性。
组分II包含阻断PD-1通路的活性剂,其包括拮抗性肽/抗体和可溶性PD-L1/2配体。下面列出了阻断PD-1和PD-L1/2检查点通路的这种活性剂的非限制性实例。
根据本公开,组分II包含针对PD-1和PD-L1/2抑制性检查点通路的拮抗剂。在一个实施方案中,拮抗剂可以是以高亲和力与PD-1或PD-L1/L2特异性结合的拮抗性抗体或其功能片段。PD-1抗体可以是美国专利号8,779,105;8,168,757;8,008,449;7,488,802;6,808,710;和PCT公开号WO 2012/145493中教导的抗体;其全部内容通过引用并入本文。可以以高亲和力与PD-L1特异性结合的抗体可以是美国专利号8,552,154;8,217,149;7,943,743;7,635,757;美国公开号2009/0317368和PCT公开号WO 2011/066389和WO 2012/145493中公开的那些;其全部内容通过引用并入本文。在一些实例中,组分II包含选自美国专利号8,008,449中公开的17D8、2D3、4H1、5C4(也称为尼沃鲁单抗或BMS-936558)、4A11、7D3和5F4;AMP-224、Pidilizumab(CT-011)和派姆单抗的抗体。在其他实例中,抗PD-1抗体可以是人单克隆抗PD-1抗体的变体,例如“混合和匹配”的抗体变体,其中来自特定VH/VL配对的VH序列被结构相似的VH序列替换,或者来自特定VH/VL配对的VL序列被结构相似的VL序列替换,如美国公开号2015/125463中所公开的;其全部内容通过引用并入本文。
在一些实施方案中,组分II包含拮抗性抗体,其以高亲和力与PD-L1结合并破坏PD-1/PD-L1/2之间的相互作用。这样的抗体可以包括但不限于美国专利号7,943,743(其全部内容通过引用并入)中公开的3G10、12A4(也称为BMS-936559)、10A5、5F8、10H10、1B12、7H1、11E6、12B7和13G4;MPDL3280A、MEDI4736和MSB0010718。在另一个实例中,抗PD-L1抗体可以是人单克隆抗PD-L1抗体的变体,例如“混合和匹配”的抗体变体,其中来自特定VH/VL配对的VH序列被结构相似的VH序列替换,或者来自特定VH/VL配对的VL序列被结构相似的VL序列替换,如美国公开号2015/125463中所公开的;其全部内容通过引用并入。
在一些实施方案中,组分II包含拮抗性抗体,其以高亲和力与PD-L2结合并破坏PD-1/PD-L1/2之间的相互作用。示例性的抗PD-L2抗体可包括但不限于Rozali等人(Rozaliet al.,Programmed Death Ligand 2in Cancer-Induced Immune Suppression,Clinicaland Developmental Immunology,2012,Volume 2012(2012),Article ID 656340)所教导的抗体,以及在美国专利号8,552,154中公开的人抗PD-L2抗体(其全部内容通过引用并入本文)。
在一些实施方案中,组分II包含抑制由于PD-1、PD-L1和/或PD-L2诱导的免疫抑制信号的化合物,例如Sasikumar等人(Aurigene Discovery Tech.)的US9233940、Sasikumar等人的WO2015033303中公开的环状拟肽化合物;Sasikumar等人的WO2015036927中公开的免疫调节拟肽化合物;Govindan等人的US2015007302中公开的1,2,4-噁二唑衍生物;Sasikumar等人的WO2015033301中公开的1,3,4-噁二唑和1,3,4-噻二唑化合物;或者Sasikumar等人的WO2015044900中公开的治疗性免疫调节化合物和衍生物或式(I)的肽衍生物的药用盐或式(I)的肽衍生物的立体异构体,其各自的全部内容通过引用并入本文。
在其他实施方案中,组分II包含对PD-L1和PD-L2配体均具有结合亲和力的抗体,例如,PCT公开号WO2014/022758中公开的抗PD-L1和PD-L2抗体的单一药剂;其全部内容通过引用并入。
在一些实施方案中,组分II包含两种或更多种选自抗PD-1抗体、PD-L1抗体和PD-L2抗体的抗体。在一个实例中,抗PD-L1抗体和抗PD-L2抗体可通过连接基包含在单个缀合物中。
在一些实施方案中,组分II包含可同时阻断PD-1和PD-L1/2介导的负信号转导的调节剂。该调节剂可以是非抗体剂。在一些方面,非抗体剂可以是PD-L1蛋白、可溶性PD-L1片段,其变体和融合蛋白。非抗体剂可以是PD-L2蛋白、可溶性PD-L2片段,其变体和融合蛋白。PD-L1和PD-L2多肽、融合蛋白和可溶性片段可通过防止PD-1的内源性配体(即内源性PD-L1和PD-L2)与PD-1相互作用抑制或减少通过T细胞中的PD-1发生的抑制性信号转导。此外,非抗体剂可以是可溶性PD-1片段、PD-1融合蛋白,其与PD-1的配体结合并防止与T细胞上的内源性PD-1受体结合。在一个实例中,PD-L2融合蛋白是B7-DC-Ig,而PD-1融合蛋白是PD-1-Ig。在另一个实例中,PD-L1、PD-L2可溶性片段分别是PD-L1和PD-L2的细胞外结构域。在一个实施方案中,组分II包含在美国公开号2013/017199中公开的非抗体剂;其全部内容通过引用并入本文。
除了CTLA-4和PD-1,其他已知的免疫抑制性检查点包括TIM-3(T细胞免疫球蛋白和含有粘蛋白结构域的分子3)、LAG-3(淋巴细胞活化基因3,也称为CD223)、BTLA(B和T淋巴细胞衰减子)、CD200R、KRLG-1、2B4(CD244)、CD160、KIR(杀伤性免疫球蛋白受体)、TIGIT(具有免疫球蛋白和ITIM结构域的T细胞免疫受体)、VISTA(T细胞活化的V结构域免疫球蛋白抑制剂)和A2aR(A2a腺苷受体)(Ngiow et al.,Prospects for TIM3 targeted antitumorimmunotherapy,Cancer Res.,2011,71(21):6567-6571;Liu et al.,Immune-checkpointproteins VISTA and PD-1 nonredundantly regulate murine T-cell responses,PNAS,2015,112(21):6682-6687;和Baitsch et al.,Extended Co-Expression of InhibitoryReceptors by Human CD8 T-Cells Depending on Differentiation,Antigen-Specificity and Anatomical Localization.2012,Plos One,7(2):e30852)。这些类似地调节T细胞活化的分子被评估为癌症免疫疗法的靶标。
TIM-3是在分泌IFN-γ的T辅助1(Th1/Tc1)细胞(Monney et al.,Th1-specificcell surface protein Tim-3regulates macrophage activation and severity of anautoimmune disease.Nature.2002,415:536-541)、DC、单核细胞、CD8+T细胞和其他淋巴细胞子集上组成性表达的跨膜蛋白。TIM-3是一种抑制分子,其下调效应物Th1/Tc1细胞反应并通过与其配体半乳凝集素-9结合而诱导Th1细胞中的细胞死亡,并且还诱导周围耐受性(Fourcade et al.Upregulation of Tim-3and PD-1expression is associated withtumor antigen-specific CD8+T cell dysfunction in melanoma patients.Jexperimental medicine.2010;207:2175-2186)。阻断TIM-3可以增强癌症疫苗的功效(Leeet al.,The inhibition of the T cell immunoglobulin and mucin domain 3(Tim-3)pathway enhances the efficacy of tumor vaccine.Biochem.Biophys.Res Commun,2010,402:88-93)。
已经显示出在肿瘤微环境中由缺氧产生的细胞外腺苷与在各种免疫细胞和内皮细胞上表达的A2a受体结合。A2aR在免疫细胞上的活化诱导免疫抑制细胞因子(例如TGF-β、IL-10)的产生增加、其他免疫检查点通路受体(例如PD-1、LAG-3)的上调、驱动调节性T细胞表型的CD4+T细胞中FOXP3表达的增加以及效应T细胞无反应性的诱导。Beavis等人证明了A2aR阻断可以改善效应T细胞功能并抑制转移(Beavis et al.,Blockade ofA2Areceptors potently suppresses the metastasis of CD73+tumors.Proc Natl AcadSci USA,2013,110:14711–14716)。一些A2aR抑制剂用于阻断A2aR抑制信号,包括但不限于SCH58261、SYN115、ZM241365和FSPTP(Leone et al.,A2aR antagonists:Next generationcheckpoint blockade for cancer immunotherapy,Comput Struct Biotechnol.J 2015,13:265-272)。
LAG-3是一种I型跨膜蛋白,其在活化的CD4+和CD8+T细胞、γδT细胞的子集、NK细胞和调节性T细胞(Treg)上表达,并且可以负调节免疫应答(Jha et al.,LymphocyteActivation Gene-3(LAG-3)Negatively Regulates Environmentally-InducedAutoimmunity,PLos One,2014,9(8):e104484)。LAG-3通过抑制T细胞受体诱导的钙通量来负调节T细胞扩增,从而控制记忆T细胞池的大小。LAG-3信号传导对于自身免疫应答的CD4+调节性T细胞抑制很重要,并且LAG-3通过对CD8+T细胞的直接作用来维持对自身和肿瘤抗原的耐受性。最近的一项研究表明,在自身免疫性的小鼠模型中,阻断PD-1和LAG-3二者可引起免疫细胞活化,这支持LAG-3可能是检查点阻断的另一个重要潜在靶标。
BTLA是Ig超家族的成员,其与肿瘤坏死因子受体超家族(TNFRSF)的成员HVEM(疱疹病毒进入介质;也称为TNFRSF14或CD270)结合(Watanabe et al.,BTLA is alymphocyte inhibitory receptor with similarities to CTLA-4and PD-1NatImmunol,2003,4670–679)。HVEM在T细胞(例如CD8+T细胞)上表达。HVEM-BTLA通路在调节T细胞增殖中起抑制作用(Wang et al.,The role of herpesvirus entry mediator as anegative regulator of T cell-mediated responses,J Clin Invest.,2005,115:74-77)。CD160是HVEM的另一种配体。CD160/HVEM的共抑制信号可以抑制CD4+辅助T细胞的活化(Cai et al.,CD160 inhibits activation of human CD4+T cells throughinteraction with herpesvirus entry mediator.Nat Immunol.2008;9:176–185)。
CD200R是在骨髓细胞上表达的CD200的受体。CD200(OX2)是在许多细胞上高度表达的膜糖蛋白。研究表明,CD200和CD200R相互作用可以扩增骨髓来源的抑制性细胞(MDSC)群(Holmannova et al.,CD200/CD200R paired potent inhibitory moleculesregulating immune and inflammatory responses;Part I:CD200/CD200R structure,activation,and function.Acta Medica(Hradec Kralove)2012,55(1):12–17;和Gorczynski,CD200 and its receptors as targets of immunoregulation,Curr OpinInvestig Drug,2005,6(5):483-488)。
TIGIT是一种共抑制受体,是高表达的肿瘤浸润T细胞。在肿瘤微环境中,TIGIT可以呈顺式与T细胞上的共刺激分子CD226相互作用,因此破坏CD226二聚。该抑制作用可以严重限制抗肿瘤和其他CD8+T细胞依赖性反应(Johnston et al.,The immunoreceptorTIGIT regulates antitumor and antiviral CD8(+)T cell effector function,Cancercell,2014,26(6):923-937)。
KIR是在自然杀手细胞(NK)上表达的细胞表面蛋白家族。它们通过与在任何细胞类型上表达的MHC I类分子相互作用来调节这些细胞的杀伤功能,允许检测被病毒感染的细胞或肿瘤细胞。大多数KIR具有抑制作用,这意味着它们对MHC分子的识别抑制其NK细胞的细胞毒性活性(Ivarsson et al.,Activating killer cell Ig-like receptor inhealth and disease,Frontier in Immu.,2014,5:1-9)。
影响T细胞活化的其他共抑制信号包括但不限于KLRG-1、2B4(也称为CD244)和VISTA(Lines et al.,VISTA is a novel broad-spectrum negative checkpointregulator for cancer immunotherapy,Cancer Immunol Res.,2014,2(6):510-517)。
根据本公开,组分II包含选自CTLA-4、PD-1、PD-L1、PD-L2、TIM-3、LAG-3(CD223)、BTLA、CD160、CD200R、TIGIT、KRLG-1、KIR、2B4(CD244)、VISTA、A2aR和其他免疫检查点的共抑制分子的拮抗剂或抑制剂。在一些方面,拮抗剂可以是针对选自CTLA-4、PD-1、PD-L1、PD-L2、TIM-3、LAG-3(CD223)、BTLA、CD160、CD200R、TIGIT、KRLG-1、KIR、2B4(CD244)、VISTA和A2aR的共抑制检查点分子的拮抗性抗体或其功能片段。
在一些实施方案中,组分II包含对LAG-3(CD223)具有特异性的拮抗性抗体和/或其功能片段。这样的拮抗性抗体可以与LAG-3(CD223)特异性结合,并抑制肿瘤中的调节性T细胞。在一个实例中,它可以是美国专利号9,005,629和8,551,481中公开的拮抗性抗LAG-3(CD223)抗体。组分II还可以包含使用美国专利号9,005,629和8,551,481(其各自的全部内容通过引用并入本文)中所公开的方法所识别的任何与LAG-3(CD223)细胞质结构域中的氨基酸基序KIEELE(其对于CD223功能是必不可少的)结合的抑制剂。对LAG-3(CD223)有特异性的其他拮抗性抗体可以包括美国公开号20130052642中公开的抗体;其全部内容通过引用并入本文。
在一些实施方案中,组分II包含对TIM-3具有特异性的拮抗性抗体和/或其功能片段。这样的拮抗性抗体与TIM-3特异性结合,并且可以被内化到表达TIM-3的细胞例如肿瘤细胞中以杀死肿瘤细胞。在其他方面,与TIM-3的细胞外结构域特异性结合的TIM-3特异性抗体可在结合后抑制表达TIM-3的细胞的增殖(例如,与不存在抗体时的增殖相比),并促进T细胞活化、效应物功能或运输到肿瘤部位。在一个实例中,拮抗性抗TIM-3抗体可以选自美国专利号8,841,418;8,709,412;8,697,069;8,647,623;8,586,038;和8,552,156中公开的任何抗体;其各自的全部内容通过引用并入本文。
此外,拮抗性TIM-3特异性抗体可以是如美国专利号8,697,069;8,101,176;和7,470,428中公开的单克隆抗体8B.2C12、25F.1D6;其各自的全部内容通过引用并入本文。
在其他实施方案中,组分II包含可与半乳凝集素9特异性结合并中和其与TIM-3的结合的药剂,包括PCT公开号2015/013389中公开的中和抗体;其全部内容通过引用并入。
在一些实施方案中,组分II包含对BTLA具有特异性的拮抗性抗体和/或其功能片段,包括但不限于美国专利号8,247,537;8,580,259中公开的抗体和抗体的抗原结合部分;美国专利号8,563,694中公开的全人类单克隆抗体;美国专利号8,188,232中公开的BTLA阻断抗体;其各自的全部内容通过引用并入本文。
可以抑制BTLA及其受体HVEM的其他另外的拮抗剂可以包括PCT公开号2014/184360;2014/183885;2010/006071和2007/010692中公开的药剂;其各自的全部内容通过引用并入本文。
在某些实施方案中,组分II包含对KIR具有特异性的拮抗性抗体和/或其功能片段,例如Benson等人(A phase I trial of the anti-KIR antibody IPH2101 andlenalidomide in patients with relapsed/refractory multiple myeloma,ClinCancer Res.,2015,May 21.pii:clincanres.0304.2015)教导的IPH2101;其全部内容通过引用并入。
在其他实施方案中,拮抗剂可以是能够抑制选自CTLA-4、PD-1、PD-L1、PD-L2、TIM-3、LAG-3(CD223)、BTLA、CD160、CD200R、TIGIT、KRLG-1、KIR、2B4(CD244)、VISTA和A2aR的共抑制检查点分子的抑制功能的任何化合物。
在一些实例中,拮抗剂可以是非抗体抑制剂,例如LAG-3-Ig融合蛋白(IMP321)(Romano et al.,J transl.Medicine,2014,12:97)和单纯疱疹病毒(HSV)-1糖蛋白D(gD)(其是BTLA)/CD160-HVEM)通路的拮抗剂)(Lasaro et al.,Mol Ther.2011;19(9):1727–1736)。
在一些实施方案中,组分II包含双特异性或多特异性药剂。如本文所用的术语“双特异性药剂”和“多特异性药剂”是指可以同时与两个靶标或多个靶标结合的任何药剂。在一些方面,双特异性药剂可以是双特异性肽药剂,其具有与第一靶标结合的第一肽序列和与第二不同靶标结合的第二肽序列。两种不同的靶标可以是选自CTLA-4、PD-1PD-L1、PD-L2、TIM-3、LAG-3(CD223)、BTLA、CD160、CD200R、TIGIT、KRLG-1、KIR、2B4(CD244)、VISTA和A2aR的两种不同抑制性检查点分子。双特异性肽药剂的非限制性实例是双特异性抗体或其抗原结合片段。类似地,多特异性药剂可以是具有多于一个特异性结合序列结构域以与多于一个靶标结合的多肽特异性药剂。例如,多特异性多肽可以与至少两个、至少三个、至少四个、至少五个、至少六个或更多个靶标结合。多特异性肽药剂的非限制性实例是多特异性抗体或其抗原结合片段。
在一个实例中,这种双特异性药剂是美国公开号2013/0156774中公开的用于靶向TIM-3和PD-1的双特异性多肽抗体变体;其全部内容通过引用并入本文。
在一些实施方案中,组分II包含缀合物,该缀合物具有在一个缀合物中经由连接基连接的一个、两个或更多个检查点拮抗剂/抑制剂。
在一些实施方案中,组分II包含任何结合并抑制检查点受体的药剂。检查点受体选自CTLA-4、PD-1、CD28、诱导型T细胞共刺激物(ICOS)、B和T淋巴细胞衰减子(BTLA)、杀手细胞免疫球蛋白样受体(KIR)、淋巴细胞活化基因3(LAG3)、CD137、OX40、CD27、CD40L、T细胞膜蛋白3(TIM3)和腺苷A2a受体(A2aR)。
在一个实例中,组分II包含CTLA-4拮抗剂。
在另一个实例中,组分II包含PD-1拮抗剂。
在另一个实例中,组分II包含PD-L1拮抗剂。
Zeste同系物增强子(EZH)抑制剂
Schlafen家族成员11(SLFN11)是一种与DNA修复缺陷有关的蛋白质,已显示其与DNA修复蛋白相互作用。根据临床前数据,它是对包括伊立替康在内的DNA损伤剂具有敏感性的潜在标志物。SLFN11的损失可以通过表观遗传沉默而发生,并且这种沉默有可能引起对导致DNA损伤的化学治疗药物的抗性。在对卡铂(carboplatin)/顺铂(cisplatin)具有抗性的卵巢癌、非小细胞肺癌(NSCLC)和乳腺癌细胞系中,通过甲基化使SLFN11基因座沉默。还发现,当在表达该蛋白的细胞中敲降SLFN11时,它增加以前对铂类药物敏感的细胞的抗性。在临床环境中,一些接受铂类药物的生存期较差的NSCLC和卵巢癌患者显示SLFN11基因座的沉默。对于具有化疗抗性的癌症患者,期望增加和/或恢复SLFN11表达。
已显示Zeste同系物增强子(EZH)蛋白质参与SLFN11沉默。EZH是一种组蛋白甲基化酶,并且抑制基因的转录,并且在癌细胞中能被过度表达和/或过度活跃。与敏感模型相比,已开发的对顺铂/依托泊苷(etoposide)具有抗性的SCLC临床前模型显示SLFN11的下调,并且在化学抗性细胞系中用EZH抑制剂治疗可以在体外和体内恢复敏感性。化学治疗剂与EZH抑制剂联用可预防癌细胞的化学疗法抗性。
在一些实施方案中,联合疗法的组分I是缀合物1,并且联合疗法的组分II是EZH抑制剂。任何EZH抑制剂(例如EZH 1和2抑制剂以及双重抑制剂)都可以用作组分II。EZH抑制剂的非限制性实例包括EPZ011989(游离碱CAS No.1598383-40-4)、EPZ005687(CASNo.1396772-26-1)、GSK126(CAS No.1346574-57-9)、GSK343(CAS No.1346704-33-3)、GSK503(CAS No.1346572-63-1)、他泽司他(tazemetostat)(EPZ-6438,CAS No.1403254-99-8)、3-去氮杂腺嘌呤A(3-deazaneplanocin A)(DZNeP,HCl盐CAS No.120964-45-6)、EI1(CAS No.1418308-27-6)、CPI-360(CAS No.1802175-06-9)、CPI-169(CAS No.1450655-76-1)、JQ-EZ-05(JQEZ5,CAS No.1913252-04-6)、PF-06726304(CAS No.1616287-82-1)、UNC1999(CAS No.1431612-23-5)和UNC2400(CAS 1433200-49-7)。
制剂和给药
可以使用一种或多种药学上可接受的赋形剂来配制本公开的联合疗法中的每种组分,以:(1)增加稳定性;(2)允许持续或延迟的释放(例如,从单马来酰亚胺的储库制剂中释放);(3)改变生物分布(例如,将单马来酰亚胺化合物靶向特定的组织或细胞类型);(4)改变单马来酰亚胺化合物在体内的释放特性。组分I和组分II可以各自以不同的组合物施用。
赋形剂的非限制性实例包括任何和所有溶剂、分散介质、稀释剂或其他液体溶媒、分散或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂和防腐剂。赋形剂还可包括但不限于类脂质、脂质体、脂质纳米颗粒、聚合物、脂质复合物(lipoplexes)、核-壳纳米颗粒、肽、蛋白质、透明质酸酶、纳米颗粒模拟物及其组合。因此,每种组分的制剂可以包含一种或多种赋形剂,每种赋形剂的量共同增加活性剂的稳定性。
Remington’s The Science and Practice of Pharmacy(雷明顿:药剂学科学与技术),第21版,A.R.Gennaro(Lippincott,Williams&Wilkins,Baltimore,MD,2006;通过引用全部并入本文)公开了用于配制药物组合物的各种赋形剂以及用于其制备的已知技术。除非任何常规的赋形剂介质与物质或其衍生物不相容,例如通过产生任何不希望的生物学作用或以有害的方式与药物组合物的任何其他组分相互作用,否则预期其使用在本公开的范围内。
根据本公开的药物组合物中的活性成分、药学上可接受的赋形剂和/或任何其他成分的相对量将根据所治疗的受试者的身份、大小和/或状况并进一步根据施用该组合物的途径而变化。举例来说,组合物可包含0.1%至100%,例如0.5至50%、1-30%、5-80%、至少80%(w/w)的活性成分。
在一些实施方案中,药学上可接受的赋形剂为至少95%、至少96%、至少97%、至少98%、至少99%或100%纯。在一些实施方案中,赋形剂被批准用于人类和兽医用途。在一些实施方案中,赋形剂得到了美国食品和药品管理局的批准。在一些实施方案中,赋形剂是药物级的。在一些实施方案中,赋形剂符合美国药典(USP)、欧洲药典(EP)、英国药典和/或国际药典的标准。
在一些实施方案中,将缀合物1在药物组合物中向患者给药,其中所述药物组合物的pH为约4.0至约5.0。在一些实施方案中,药物组合物包含pH为约4.0至约4.8的乙酸盐缓冲液(乙酸钠和乙酸)。在一些实施方案中,药物组合物还包含甘露醇和聚乙二醇15羟基硬脂酸酯。
在一个实施方案中,提供了用于注射用溶液的组合物,用于施用缀合物1。该溶液包含缀合物1、甘露醇、聚乙二醇15羟基硬脂酸酯和乙酸盐缓冲水溶液。该组合物可以静脉内输注(IV)。
给药/施用
可以通过导致治疗有效结果的任何途径施用联合疗法的组分。这些包括但不限于肠内、胃肠内、硬膜外(epidural)、口服、透皮、硬膜外(epidural/peridural)、脑内(进入大脑)、脑室内(进入脑室)、表皮(应用于皮肤)、真皮内(进入皮肤本身)、皮下(皮肤下)、鼻腔给药(通过鼻)、静脉内(进入静脉)、动脉内(进入动脉)、肌内(进入肌肉)、心内(进入心脏)、骨内输注(进入骨髓)、鞘内(进入椎管)、腹膜内(输注或注射入腹膜)、膀胱内输注、玻璃体内(通过眼睛)、海绵窦内注射(进入阴***部)、***内给药、子宫内、羊膜外给药、透皮(通过完整皮肤的扩散进行全身分布)、透粘膜(通过粘膜扩散)、吹入(鼻吸)、舌下、唇下、灌肠、滴眼液(在结膜上)或滴耳液。在特定的实施方案中,组合物可以以允许它们穿过血脑屏障、血管屏障或其他上皮屏障的方式施用。
本文所述的制剂包含在适合于向有需要的患者给药的药物载体中的有效量的组分。制剂可以肠胃外给药(例如通过注射或输注)。制剂或其变化形式可以以任何方式给药,包括肠内、局部(例如向眼睛)或通过肺部给药。在一些实施方案中,局部施用制剂。
剂量
患者对每种组分所需的确切量将因受试者而异,取决于受试者的物种、年龄和一般状况、疾病的严重程度、特定的组合物、其给药方式、其活动方式等等。
为了易于给药和剂量均匀,联合疗法的组分通常以剂量单位形式配制。然而,应当理解,本公开的组合物的每日总用量可以由主治医师在合理的医学判断范围内决定。对于任何特定患者而言,具体的治疗有效的、预防有效的或适当的剂量水平将取决于多种因素,包括正在治疗的疾病和疾病的严重程度;所用的具体化合物的活性;使用的具体组合物;患者的年龄、体重、总体健康状况、性别和饮食;给药时间、给药途径和所用具体化合物的***速率;治疗的持续时间;与所使用的具体化合物组合或同时使用的药物;以及医学领域众所周知的类似因素。
在一些实施方案中,可以以足以递送每天约0.0001mg/kg至约100mg/kg、约0.001mg/kg至约0.05mg/kg、约0.005mg/kg至约0.05mg/kg、约0.001mg/kg至约0.005mg/kg、约0.05mg/kg至约0.5mg/kg、约0.01mg/kg至约50mg/kg、约0.1mg/kg至约40mg/kg、约0.5mg/kg至约30mg/kg、约0.01mg/kg至约10mg/kg、约0.1mg/kg至约10mg/kg或约1mg/kg至约25mg/kg受试者体重的剂量水平每天一次或多次施用根据本发明的联合疗法的组分,以获得所需的治疗、诊断、预防或成像效果。
所需剂量可以一天三次、一天两次、一天一次、隔天一次、每三天一次、每周一次、每两周一次、每三周一次或每四周一次递送。在一些实施方案中,可以使用多次给药(例如,两次、三次、四次、五次、六次、七次、八次、九次、十次、十一次、十二次、十三次、十四次或更多次给药)来递送所需剂量。当采用多次给药时,可以使用分次给药方案,例如本文所述的那些。
组分在药物组合物中的浓度可以为约0.01mg/mL至约50mg/mL、约0.1mg/mL至约25mg/mL、约0.5mg/mL至约10mg/mL或约1mg/mL至约5mg/mL。
如本文所用的“分次剂量”是将单个单位剂量或每日总剂量分成两个或更多个剂量,例如单个单位剂量的两次或更多次给药。如本文所用的“单个单位剂量”是以一个剂量/一次/单个途径/单个接触点(即单个给药事件)施用的任何治疗剂的剂量。如本文所用的“每日总剂量”是24小时内给予或处方的量。它可以作为单个单位剂量给药。在一个实施方案中,本公开的单马来酰亚胺化合物以分次剂量向受试者给药。单马来酰亚胺化合物可以仅在缓冲液中或在本文所述的制剂中配制。
受试者可以接受联合疗法持续任何合适的时间长度,例如一周、2周、3周、4周、一个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、一年或直到达到预定的目标(例如,TGI%为高于90%、95%或99%)。
在一些实施方案中,组分I是缀合物1并且以约30mg、60mg、120mg、240mg或360mg的剂量施用于有需要的受试者。任选地,施用于有需要的受试者的缀合物1的剂量是基于受试者的体表面积(BSA)。如本文所用,BSA(平方米)是身高(以厘米计)乘以体重(以千克计)除以3600后的平方根。例如,缀合物1的剂量可以是至少约150mg/m2,例如约175mg/m2、200mg/m2、225mg/m2、250mg/m2、275mg/m2或300mg/m2。缀合物1可在28天周期的第1、8和15天施用。
在一些实施方案中,组分II是PARP抑制剂。PARP抑制剂可以在7天周期的第2、3、4、5和6天施用。
如实施例中所讨论的,在临床前小鼠模型中安排缀合物1和PARP抑制剂的施用实现了疗效,同时降低了潜在的重叠毒性。将最佳方案转化为人类取决于缀合物1和具体PARP抑制剂的药代动力学和毒性。对PK和施用天数的估计值取决于所考虑的PARPi。图2显示了基于7天方案的缀合物1和尼拉帕尼的血浆暴露量以及缀合物1的肿瘤异种移植物暴露量的估计,以最大限度地提高疗效和/或使毒性最小化。缀合物1数据来自小鼠血浆和小鼠肿瘤异种移植物。PARP抑制剂血浆浓度是根据已发表的尼拉帕尼人类数据估计/外推的。
在一些实施方案中,组分I是缀合物1并且在28天周期的第1、8和15天以至少150mg/m2的剂量向有需要的受试者施用;组分II是PARP抑制剂并且在7天周期的第2、3、4、5和6天施用于受试者。受试者可以患有SCLC,接受不超过1种在先线治疗(prior line oftherapy),活动状态(PS)0/1,未接受过伊立替康治疗和/或具有PARP野生型。
II.使用缀合物1和/或联合疗法的方法
本公开的一方面提供了用缀合物1治疗多种不同疾病状况的方法。疾病状况包括细胞增殖性疾病,例如肿瘤性疾病、自身免疫性疾病、中枢神经***或神经变性疾病、心血管疾病、激素异常疾病、传染性疾病等。
“治疗”是指至少改善与困扰主体的疾病状况相关的症状,其中改善以广义使用,是指至少降低与正在治疗的病理状况相关的参数(例如症状),例如与其相关的炎症和疼痛的程度。因此,治疗还包括以下情况:病理状况或至少与其相关的症状被完全抑制(例如防止其发生)或停止(例如终止),使得主体不再具有病理状况或至少是表征病理状况的症状。
根据本公开可以治疗多种主体。通常,此类主体是“哺乳动物”或“哺乳动物的”,其中这些术语广泛用于描述属于哺乳动物纲的生物,包括食肉目(例如,狗和猫)、啮齿目(例如,小鼠、豚鼠和大鼠)和灵长类动物(例如人类、黑猩猩和猴)。在许多实施方案中,主体是人类。
本发明还提供了治疗疾病或病症的方法,其中基于特定蛋白质的存在或过度表达来选择待治疗的受试者进行治疗。例如,可以基于高于正常水平的Hsp90的存在来选择受试者来治疗癌症。HSP90可以是肿瘤细胞上的细胞外HSP90(eHSP90)或体液(例如血浆或血清)中的循环HSP90。该方法包括从患者获得样品并测量样品中人细胞外Hsp90或循环HSP90的表达。
eHSP90的表达可以使用本领域已知的方法测量,例如ELISA、RIA、EIA、夹心测定、蛋白质印迹分析、免疫染色、流式细胞术和免疫组织学染色。
可以在患者的血清样品中测量循环HSP90。在一些实施方案中,可以收集患者的血清样品并在-20℃冷冻直至分析。HSP90 ELISA使用双抗体夹心酶联免疫吸附测定来确定样品中人HSP90的水平。
在一些实施方案中,循环HSP90是HSP90α。根据US8580519(马里兰大学,其内容通过引用整体并入),患者血浆或血清中HSP90α的量或浓度可用于确定癌症进展。可以使用与HSP90α多肽相互作用的物质来检测HSP90α多肽。例如,该物质可以是结合HSP90α或HSP90α片段的抗体。该物质可包含用于检测的标记,例如化学发光标记、比色标记、荧光标记或放射性标记。
在一些实施方案中,使用WO2007096194(Novartis;其内容通过引用整体并入本文)中公开的放射性标记的异噁唑衍生物来使用分子成像方式探测HSP90。在一些实施方案中,使用在US7834181(Sloan-Kettering Institute;其内容通过引用整体并入本文)中公开的具有放射性标记(例如124I、131I或123I)的芳基取代的基于腺嘌呤的HSP90抑制剂来进行肿瘤组织的放射成像并确定HSP90水平。
在一些实施方案中,进行HSP90小分子抑制剂作为造影剂的核磁共振成像以测量HSP90的表达。该步骤包括(a)提供包含与靶组织中的HSP90结合的小分子的造影增强剂;(b)将造影增强剂引入靶组织;和(c)使用磁共振成像扫描靶组织,从而非侵入性地生成靶组织的可见图像。可以使用US2009/0088578(Haystead et al.)中公开的HSP90结合造影增强小分子,其内容通过引用整体并入本文。
在一些实施方案中,提供了一种治疗患者的癌症的方法,其中该方法包括以下步骤:
1).测量患者的HSP90水平,以及
2).向患者施用治疗有效量的缀合物1。
作为非限制性实例,可以治疗的癌症可以是急性粒细胞白血病、急性淋巴细胞白血病、急性髓性白血病、腺癌、腺肉瘤、肾上腺癌、肾上腺皮质癌、***癌、间变性星形细胞瘤(Anaplastic astrocytoma)、血管肉瘤、阑尾癌、星形细胞瘤、基底细胞癌、B细胞淋巴瘤)、胆管癌、膀胱癌、骨癌、肠癌、脑癌、脑干胶质瘤、脑肿瘤、乳腺癌、类癌肿瘤、***、胆管癌、软骨肉瘤、慢性淋巴细胞白血病、慢性髓性白血病、结肠癌、结直肠癌、颅咽管瘤、皮肤淋巴瘤、皮肤黑色素瘤、弥漫性星形细胞瘤、导管原位癌、子宫内膜癌、室管膜瘤、上皮样肉瘤、食管癌、尤因肉瘤、肝外胆管癌、眼癌、输卵管癌、纤维肉瘤、胆囊癌、胃癌、胃肠癌、胃肠类癌、胃肠道间质瘤、一般、生殖细胞肿瘤、多形性成胶质细胞瘤、胶质瘤、毛细胞白血病、头颈癌、血管内皮瘤、霍奇金淋巴瘤、霍奇金氏病、霍奇金氏淋巴瘤、下咽癌、浸润性导管癌、浸润性小叶癌、炎性乳腺癌、肠癌、肝内胆管癌、侵袭性/浸润性乳腺癌、胰岛细胞癌、颌骨癌、Kaposi肉瘤、肾癌、喉癌、平滑肌肉瘤、软脑膜转移瘤(Leptomeningeal metastase)、白血病、唇癌、脂肪肉瘤、肝癌、小叶原位癌、低级星形细胞瘤、肺癌、***癌、淋巴瘤、男性乳腺癌、髓样癌、成髓细胞瘤、黑素瘤、脑膜瘤、Merkel细胞癌、间充质软骨肉瘤、间充质(Mesenchymous)、间皮瘤、转移性乳腺癌、转移性黑素瘤、转移性鳞状颈癌、混合性胶质瘤、口腔癌、粘液癌、黏膜黑素瘤、多发性骨髓瘤、鼻腔癌、鼻咽癌、颈癌、成神经细胞瘤、神经内分泌肿瘤、非霍奇金淋巴瘤、非霍奇金氏淋巴瘤、非小细胞肺癌、燕麦细胞癌、眼癌、眼黑素瘤、少突胶质瘤、口癌、口腔癌、口咽癌、成骨肉瘤、骨肉瘤、卵巢癌、卵巢上皮癌、卵巢生殖细胞肿瘤、卵巢原发性腹膜癌、卵巢性索间质瘤、佩吉特氏病(Paget's disease)、胰腺癌、***状癌、鼻旁窦癌(Paranasal sinus cancer)、甲状旁腺癌、盆腔癌、***癌、外周神经癌、腹膜癌、咽癌、嗜铬细胞瘤、毛细胞星形细胞瘤、松果体区肿瘤、成松果体细胞瘤、垂体癌、原发性中枢神经***淋巴瘤、***癌、直肠癌、肾细胞癌、肾盂癌、横纹肌肉瘤、唾液腺癌、肉瘤、骨肉瘤(Sarcoma,bone)、软组织肉瘤(Sarcoma,soft tissue)、子宫肉瘤(Sarcoma,uterine)、窦癌、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、脊髓癌、脊柱癌、脊髓癌、脊髓肿瘤、鳞状细胞癌、胃癌、滑膜肉瘤、T细胞淋巴瘤)、睾丸癌、喉癌、胸腺瘤/胸腺癌、甲状腺癌、舌癌、扁桃体癌、移行细胞癌、移行细胞癌、移行细胞癌、三阴性乳腺癌、输卵管癌、管状癌、输尿管癌、输尿管癌、尿道癌、子宫腺癌、子宫癌、子宫肉瘤、***癌和外阴癌。
在一些实施方案中,将缀合物1施用于患有癌症的受试者,其中所述癌症选自小细胞肺癌(SCLC)、胃癌或胃食管交界(GEJ)癌、胰腺导管腺癌(PDAC)、卵巢癌、子宫内膜癌、小细胞癌(SCC),或***、宫颈、外阴或***的鳞状细胞癌、尤因肉瘤和横纹肌肉瘤。
在一些实施方案中,将缀合物1施用于患有肿瘤的受试者,其中所述肿瘤选自***肿瘤、乳腺肿瘤、胆管癌、结肠肿瘤、十二指肠肿瘤、食管肿瘤、肝细胞肿瘤、肺(小细胞)肿瘤、神经内分泌肿瘤、卵巢肿瘤、胰腺肿瘤、***肿瘤或肉瘤。
在一些实施方案中,将缀合物1施用于患有癌症的受试者,其中所述癌症选自鳞状癌、胰腺腺癌、胰腺的腺泡细胞癌和脂肪肉瘤。
在一些实施方案中,将缀合物1施用于患有癌症的受试者,其中该受试者已接受至少一种先前的抗癌疗法。抗癌疗法的非限制性实例包括:
在一个实例中,提供了包含有效量的缀合物1钠、其互变异构体或其药学上可接受的盐和5%甘露醇的药物组合物。药物组合物的pH值在约9.4至约10.3的范围内。缀合物1钠、其互变异构体或其药学上可接受的盐的浓度在约1mg/mL至约20mg/mL的范围内,例如为约3mg/mL、6mg/mL或12mg/mL。
本公开的另一个方面提供了用于治疗患有过度增殖性疾病例如癌症的受试者的方法,其中该方法包括至少两种不同的治疗剂的联合疗法。在一些实施方案中,该方法包括向患者施用:(A)第一组分,其包含化合物I或其前药、衍生物或药学上可接受的盐作为活性剂;和(B)第二成分,其包含化合物II或其前药、衍生物或药学上可接受的盐作为活性剂。
根据本公开,癌症的特征可以在于肿瘤,例如实体瘤或任何肿瘤。在一些实施方案中,癌症是实体瘤。大的药物分子在实体瘤中的渗透有限。大的药物分子的渗透很慢。另一方面,诸如小分子缀合物的小分子可能迅速且更深地渗透实体瘤。关于药物的渗透深度,较大的分子尽管具有更持久的药代动力学,但渗透较少。
在一些实施方案中,联合疗法抑制癌症和/或肿瘤生长。联合疗法还可以减少包括细胞增殖、侵袭性和/或转移,从而使它们可用于治疗癌症。
在一些实施方案中,联合疗法可用于预防肿瘤或癌症的生长和/或预防肿瘤或癌症的转移。在一些实施方案中,联合疗法可用于缩小或破坏癌症。
在一些实施方案中,联合疗法可用于抑制癌细胞的增殖。在一些实施方案中,联合疗法可用于抑制细胞增殖,例如抑制细胞增殖的速率、防止细胞增殖和/或诱导细胞死亡。通常,联合疗法可以抑制癌细胞的细胞增殖或者同时抑制癌细胞的增殖和/或诱导癌细胞的死亡。在一些实施方案中,在用本公开的联合疗法治疗后,与未经治疗的细胞相比,细胞增殖减少了至少约25%、约50%、约75%或约90%。在一些实施方案中,在用联合疗法治疗后,与未经治疗的细胞相比,细胞周期停滞标志物磷酸组蛋白H3(phospho histone H3,PH3或PHH3)增加了至少约50%、约75%、约100%、约200%、约400%或约600%。在一些实施方案中,在用联合疗法治疗后,与未经治疗的细胞相比,细胞凋亡标志物裂解的半胱氨酸天冬氨酸蛋白酶3(cleaved caspase-3,CC3)增加了至少50%、约75%、约100%、约200%、约400%或约600%。
此外,在一些实施方案中,无论是以大小(重量、表面积或体积)的净值还是以随时间变化的速率测量,联合疗法对于抑制多种类型的肿瘤中的肿瘤生长都是有效的。
在一些实施方案中,在用联合疗法治疗后,肿瘤的大小减少了约60%或更多。在一些实施方案中,通过测量重量和/或面积和/或体积,肿瘤的大小减少了至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%、至少约100%。
在一些实施方案中,接受联合疗法的受试者的肿瘤生长抑制率(TGI)可以为至少约80%、85%、90%、95%或99%。
通过本公开的联合疗法可治疗的癌症通常发生在哺乳动物中。哺乳动物包括例如人、非人灵长类、狗、猫、大鼠、小鼠、兔、雪貂、豚鼠、马、猪、绵羊、山羊和牛。在各种实施方案中,癌症是肺癌、乳腺癌例如突变体BRCA1和/或突变体BRCA2乳腺癌、非BRCA相关乳腺癌、结肠直肠癌、卵巢癌、胰腺癌、结肠直肠癌、膀胱癌、***癌、***、肾癌、白血病、中枢神经***癌症、骨髓瘤和黑素瘤。
在一些实施方案中,癌症是神经内分泌癌,例如但不限于小细胞肺癌(SCLC)、肾上腺髓质肿瘤(例如嗜铬细胞瘤、成神经细胞瘤、神经节瘤或副神经节瘤)、胃肠胰神经内分泌肿瘤(例如类癌、胃泌素瘤、胰升糖素瘤、分泌血管活性肠多肽的肿瘤、分泌胰多肽的肿瘤或无功能的胃肠胰肿瘤)、甲状腺髓样癌、皮肤Merkel细胞瘤、垂体腺瘤和胰腺癌。在一些实施方案中,神经内分泌癌是原发性神经内分泌癌。在一些实施方案中,神经内分泌癌是神经内分泌转移。神经内分泌转移可以在受试者的肝、肺、骨或脑中。在某些实施方案中,癌症是脑癌、人肺癌、卵巢癌、胰腺癌或结肠直肠癌。
在一个实施方案中,本公开的联合疗法用于治疗小细胞肺癌。约12%至15%的肺癌患者患有小细胞肺癌。转移性小细胞肺癌的存活率很低。诊断后五年的存活率低于5%。美国小细胞肺癌的发病率为约26K-30K。在这些患者中,约40%-80%为SSTR2阳性。
在一个实施方案中,本公开的联合疗法用于治疗患有组织学证实的局部晚期或转移性高级别神经内分泌癌(NEC)的患者。在一些实施方案中,患者可能患有未知原发性或任何肺外部位的小细胞和大细胞神经内分泌癌。在一些实施方案中,如果Ki-67>30%,则患者可能患有分化良好的G3神经内分泌肿瘤。在一些实施方案中,如果是小细胞或大细胞组织学,则患者可能患有***的神经内分泌***癌(从头或治疗中出现的)。在一些实施方案中,如果高级别(小细胞或大细胞)NEC组分占原始样品或后续活检样品的>50%,则患者可能患有混合瘤,例如,混合性腺神经内分泌癌(MANEC)或混合性鳞状或腺泡细胞NEC。在一些实施方案中,患者可能患有去势抵抗性***癌(CRPC)。
联合疗法的组分的特征是对生物体的毒性相对低,同时保持抑制例如减慢或停止肿瘤生长的功效。如本文所用的“毒性”是指物质或组合物对细胞、组织生物体或细胞环境有害或有毒的能力。低毒性是指物质或组合物对细胞、组织生物体或细胞环境有害或有毒的能力降低。这种降低的毒性或低毒性可以是相对于标准措施、相对于治疗或相对于不存在治疗而言。例如,包含SN-38作为活性剂的缀合物1的毒性低于单独给药的SN-38。
可以进一步相对于受试者的体重减轻来测量毒性,其中体重减轻超过体重的15%、超过20%或超过30%表示毒性。也可以测量其他毒性指标,例如患者表现指标,包括嗜睡和全身不适。中性粒细胞减少、血小板减少、白细胞(WBC)计数、全血细胞(CBC)计数也可以是毒性的指标。毒性的药理学指标包括转氨酶(AST/ALT)水平升高、神经毒性、肾脏损伤、GI损伤等。在一个实施方案中,本公开的联合疗法不引起受试者体重的显著变化。在用本公开的联合疗法治疗后,受试者的体重减轻小于约30%、约20%、约15%、约10%或约5%。在另一个实施方案中,本公开的联合疗法不引起受试者的AST/ALT水平的显著增加。在用本公开的联合疗法治疗后,受试者的AST或ALT水平增加小于约30%、约20%、约15%、约10%或约5%。在又一个实施方案中,在用本公开的联合疗法治疗后,本公开的联合疗法不引起受试者的CBC或WBC计数的显著变化。在用本公开的联合疗法治疗后,受试者的CBC或WBC水平降低小于约30%、约20%、约15%、约10%或约5%。
III.试剂盒和装置
本公开的一个方面提供了用于方便和/或有效地实施本公开的方法的多种试剂盒和装置。通常,试剂盒将包含足够量和/或数目的组分,以允许使用者对受试者进行多次治疗和/或进行多次实验。
在一个实施方案中,本公开提供了用于在体外或体内抑制肿瘤细胞生长的试剂盒,其包含至少两种不同的治疗剂。在一些实施方案中,用于抑制肿瘤细胞生长的试剂盒包括:(A)第一组分,其包含化合物I或其前药、衍生物或药学上可接受的盐作为活性剂;和(B)第二成分,其包含化合物II或其前药、衍生物或药学上可接受的盐作为活性剂。
试剂盒可进一步包括包装和说明书和/或形成制剂组合物的递送剂。递送剂可以包括盐水、缓冲溶液或本文公开的任何递送剂。每种药剂的量可以变化,以实现一致的、可再现的更高浓度的盐水或仅缓冲液制剂。为了在一段时间内和/或在各种条件下增加联合疗法的组分的稳定性,药剂也可以变化。
本公开提供了可以结合联合疗法的组分的装置。这些装置含有稳定的制剂,其可用于立即递送给有需要的受试者,例如人类患者。在一些实施方案中,受试者患有癌症。
装置的非限制性实例包括泵、导管、针、透皮贴剂、加压的嗅觉递送装置、离子电渗疗法装置、多层微流体装置。装置可用于根据单次、多次或分次给药方案来递送联合疗法的组分。装置可用于跨生物组织、皮内、皮下或肌肉内递送联合疗法的组分。
IV.定义
如本文所用的术语“化合物”是指包括所描述结构的所有立体异构体、几何异构体、互变异构体和同位素。在本申请中,化合物与缀合物可互换使用。因此,本文所用的缀合物还意在包括所描述结构的所有立体异构体、几何异构体、互变异构体和同位素。
本文所述的化合物可以是不对称的(例如,具有一个或多个立体中心)。除非另外指明,否则所有立体异构体,例如对映异构体和非对映异构体都是预期的。可以以旋光的或外消旋的形式分离含有不对称取代的碳原子的本公开的化合物。如何从旋光起始原料制备旋光形式的方法是本领域已知的,例如通过外消旋混合物的拆分或通过立体选择性合成。本文所述的化合物中也可以存在烯烃、C=N双键等的许多几何异构体,并且所有这些稳定的异构体均在本公开中考虑。描述了本公开的化合物的顺式和反式几何异构体,并且可以分离为异构体的混合物或分离的异构体形式。
本公开的化合物还包括互变异构形式。互变异构形式是由单键与相邻双键的交换以及伴随的质子迁移引起的。互变异构形式包括质子移变互变异构体,其是具有相同经验式和总电荷的异构质子化状态。质子移变互变异构体的实例包括酮-烯醇对、酰胺-亚胺酸对、内酰胺-内酰亚胺对、酰胺-亚胺酸对、烯胺-亚胺对以及环状形式,其中质子可占据杂环体系的两个或多个位置,例如,1H-和3H-咪唑、1H-、2H-和4H-1,2,4-***、1H-和2H-异吲哚以及1H-和2H-吡唑。互变异构形式可以处于平衡或通过适当的取代而空间锁定成一种形式。
本公开的化合物还包括存在于中间或最终化合物中的原子的所有同位素。“同位素”是指具有相同原子序数但由于原子核中的中子数不同而导致的不同质量数的原子。例如,氢的同位素包括氚和氘。
可以通过常规方法将本公开的化合物和盐与溶剂或水分子组合制备,以形成溶剂化物和水合物。
如本文所用的术语“受试者”或“患者”是指可以例如出于实验、治疗、诊断和/或预防目的而向其施用联合疗法的任何生物体。典型的受试者包括动物(例如哺乳动物,例如小鼠、大鼠、兔、豚鼠、牛、猪、绵羊、马、狗、猫、仓鼠、羊驼、非人类灵长类动物和人类)。
如本文所用的术语“治疗”或“预防”可包括防止疾病、病症或状况在可能易患该疾病、病症和/或状况但尚未被诊断出患有该疾病、病症或状况的动物中发生;抑制疾病、病症或状况,例如阻碍其进展;和减轻疾病、病症或状况,例如引起疾病、病症和/或状况的消退。治疗疾病、病症或状况可以包括改善特定疾病、病症或状况的至少一种症状,即使根本的病理生理学不受影响,例如通过施用镇痛剂来治疗受试者的疼痛,即使该药剂并不治疗疼痛的起因。
如本文所用的“靶标”应指所靶向的构建体结合的位点。靶标可以是体内或体外的。在某些实施方案中,靶标可以是在白血病或肿瘤(例如脑、肺(小细胞和非小细胞)、卵巢、***、乳腺和结肠的肿瘤以及其他癌和肉瘤)中发现的癌细胞。在其他实施方案中,靶标可以指靶向部分或配体结合的分子结构,例如半抗原、表位、受体、dsDNA片段、碳水化合物或酶。靶标可以是组织类型,例如神经元组织、肠组织、胰腺组织、肝、肾、***、卵巢、肺、骨髓或乳腺组织。
可以作为联合疗法的靶标的“靶细胞”通常是动物细胞,例如哺乳动物细胞。本发明的方法可用于在体外(即在细胞培养物中)或在体内(其中细胞形成动物组织的一部分或存在于动物组织中)修饰活细胞的细胞功能。因此,靶细胞可以包括例如血液、淋巴组织、消化道(如口和咽粘膜)内衬的细胞、形成小肠绒毛的细胞、大肠衬里的细胞、动物的呼吸***(鼻道/肺)衬里的细胞(其可以通过本公开的吸入而被接触)、真皮/表皮细胞、***和直肠细胞、内脏细胞(包括胎盘细胞)和所谓的血/脑屏障等。通常,靶细胞表达至少一种类型的SSTR。在一些实施方案中,靶细胞可以是表达SSTR并被本文所述的缀合物靶向的细胞,并且靠近受缀合物的活性剂释放影响的细胞。例如,在肿瘤附近的表达SSTR的血管可能是靶标,而在该部位释放的活性剂将影响肿瘤。
术语“治疗作用”是本领域公认的,并且是指由药理活性物质引起的在动物,特别是哺乳动物,尤其是人类中的局部或全身作用。因此,该术语是指旨在用于在动物(例如人)中增强期望的身体或精神发育和状况的诊断、治愈、缓解、治疗或预防疾病、病症或状况的任何物质。
术语“调节”是本领域公认的,并且是指反应的上调(即激活或刺激)、下调(即抑制或压抑),或两者结合或分开。通常将调节与可以在被治疗的个体内部或外部的基线或参考进行比较。
本文可互换使用的术语“足够”和“有效”是指达到一个或多个期望的结果所需的量(例如质量、体积、剂量、浓度和/或时间段)。“治疗有效量”至少是影响特定状况或病症的至少一种症状的可测量的改善或预防、实现预期寿命的可测量的提高或总体上改善患者生活质量所需的最小浓度。因此,治疗有效量取决于具体的生物活性分子和要治疗的具体状况或病症。许多活性剂例如抗体的治疗有效量是本领域已知的。本文描述的化合物和组合物例如用于治疗具体病症的治疗有效量可以通过熟练的技术人员例如医师的能力范围内的技术来确定。
本文可互换使用的术语“生物活性剂”和“活性剂”包括但不限于在体内局部或全身起作用的生理或药理活性物质。生物活性剂是用于治疗(例如治疗剂)、预防(例如预防剂)、诊断(例如诊断剂)、治愈或缓解疾病或病症的物质;影响身体结构或功能的物质;或前药(在将它们置于预定的生理环境中之后变得具有生物活性或活性更强)。
术语“前药”是指包括小有机分子、肽、核酸或蛋白质的药剂,其在体外和/或体内转化为生物活性形式。前药之所以有用,是因为在某些情况下,它们可能比母体化合物(活性化合物)更容易给药。例如,前药可以通过口服给药而生物利用,而母体化合物不能。与母体药物相比,前药还可以在药物组合物中具有改善的溶解度。前药的毒性也可能比母体低。前药可以通过多种机制转化为母体药物,包括酶促过程和代谢水解。Harper,N.J.(1962)Drug Latentiation,Jucker,ed.Progress in Drug Research,4:221-294;Morozowich etal.(1977)Application of Physical Organic Principles to Prodrug Design,E.B.Roche ed.Design of Biopharmaceutical Properties through Prodrugs andAnalogs,APhA;Acad.Pharm.Sci.;E.B.Roche,ed.(1977)Bioreversible Carriers inDrug in Drug Design,Theory and Application,APhA;H.Bundgaard,ed.(1985)Designof Prodrugs,Elsevier;Wang et al.(1999)Prodrug approaches to the improveddelivery of peptide drug,Curr.Pharm.Design.5(4):265-287;Pauletti et al.(1997)Improvement in peptide bioavailability:Peptidomimetics and ProdrugStrategies,Adv.Drug.Delivery Rev.27:235-256;Mizen et al.(1998).The Use ofEsters as Prodrugs for Oral Delivery ofβ-Lactam antibiotics,Pharm.Biotech.11:345-365;Gaignault et al.(1996)Designing Prodrugs and Bioprecursors I.CarrierProdrugs,Pract.Med.Chem.671-696;M.Asgharnejad(2000).Improving Oral DrugTransport Via Prodrugs,G.L.Amidon,P.I.Lee和E.M.Topp,Eds.,Transport Processesin Pharmaceutical Systems,Marcell Dekker,p.185-218;Balant et al.(1990)Prodrugs for the improvement of drug absorption via different routes ofadministration,Eur.J.Drug Metab.Pharmacokinet.,15(2):143-53;Balimane和Sinko(1999).Involvement of multiple transporters in the oral absorption ofnucleoside analogues,Adv.Drug Delivery Rev.,39(1-3):183-209;Browne(1997).Fosphenytoin(Cerebyx),Clin.Neuropharmacol.20(1):1-12;Bundgaard(1979).Bioreversible derivatization of drugs--principle and applicability toimprove the therapeutic effects of drugs,Arch.Pharm.Chemi.86(1):1-39;H.Bundgaard,ed.(1985)Design of Prodrugs,New York:Elsevier;Fleisher et al.(1996)Improved oral drug delivery:solubility limitations overcome by the useof prodrugs,Adv.Drug Delivery Rev.19(2):115-130;Fleisher et al.(1985)Designof prodrugs for improved gastrointestinal absorption by intestinal enzymetargeting,Methods Enzymol.112:360-81;Farquhar D,et al.(1983)BiologicallyReversible Phosphate-Protective Groups,J.Pharm.Sci.,72(3):324-325;Han,H.K.etal.(2000)Targeted prodrug design to optimize drug delivery,AAPS PharmSci.,2(1):E6;Sadzuka Y.(2000)Effective prodrug liposome and conversion to activemetabolite,Curr.Drug Metab.,1(1):31-48;D.M.Lambert(2000)Rationale andapplications of lipids as prodrug carriers,Eur.J.Pharm.Sci.,11Suppl.2:S15-27;Wang,W.et al.(1999)Prodrug approaches to the improved delivery of peptidedrugs.Curr.Pharm.Des.,5(4):265-87。
如本文所用的术语“生物相容的”是指通常对接受者无毒并且不对接受者造成任何重大不良作用的物质以及其任何代谢产物或降解产物。一般来说,生物相容的物质是当施用于患者时不引起明显的炎症或免疫应答的物质。
如本文所用的术语“可生物降解的”通常是指将在生理条件下降解或侵蚀为能够被受试者代谢、消除或***的较小单位或化学物质的物质。降解时间是组成和形态的函数。降解时间可能从几小时到几周。
如本文所用的术语“药学上可接受的”是指化合物、物质、组合物和/或剂型,根据诸如美国食品和药品管理局的机构的指南,其在合理的医学判断范围内,适用于与人和动物的组织接触而没有过多的毒性、刺激性、过敏性反应或其他问题或并发症,与合理的获益/风险比相称。如本文所用的“药学上可接受的载体”是指药物制剂中促进组合物在体内递送的所有组分。药学上可接受的载体包括但不限于稀释剂、防腐剂、粘合剂、润滑剂、崩解剂、溶胀剂、填充剂、稳定剂及其组合。
如本文所用的术语“分子量”通常是指物质的质量或平均质量。如果是聚合物或低聚物,则分子量可以指本体聚合物的相对平均链长或相对链质量。在实践中,聚合物和低聚物的分子量可以以各种方式估算或表征,包括凝胶渗透色谱法(GPC)或毛细管粘度测定法。GPC分子量报告为重均分子量(Mw),而不是数均分子量(Mn)。毛细管粘度测定法通过使用特定的一组浓度、温度和溶剂条件,从稀聚合物溶液中测得的特性粘度来估算分子量。
本文所用的术语“小分子”通常是指分子量小于2000g/mol、小于1500g/mol、小于1000g/mol、小于800g/mol、或小于500g/mol的有机分子。小分子是非聚合的和/或非寡聚的。
术语“多肽”、“肽”和“蛋白质”通常是指氨基酸残基的聚合物。如本文所用,该术语还适用于氨基酸聚合物,其中一种或多种氨基酸是相应的天然存在的氨基酸的化学类似物或修饰的衍生物,或者是非天然的氨基酸。如本文中一般性使用的术语“蛋白质”是指通过肽键彼此连接以形成多肽的氨基酸的聚合物,其链长足以产生三级和/或四级结构。术语“蛋白质”从定义上排除了小肽,小肽缺乏被认为是蛋白质所必需的高级结构。
术语“核酸”、“多核苷酸”和“寡核苷酸”可互换使用,是指呈线性或环状构型且呈单链或双链形式的脱氧核糖核苷酸或核糖核苷酸聚合物。这些术语不应被解释为对聚合物长度的限制。该术语可涵盖天然核苷酸的已知类似物,以及在碱基、糖和/或磷酸部分(例如硫代磷酸酯主链)中修饰的核苷酸。通常且除非另外指明,否则特定核苷酸的类似物具有相同的碱基配对特异性;即,A的类似物将与T碱基配对。术语“核酸”是本领域的术语,其是指一串至少两个碱基-糖-磷酸酯单体单元。核苷酸是核酸聚合物的单体单元。该术语包括以信使RNA、反义、质粒DNA、质粒DNA的一部分或衍生自病毒的遗传物质形式的脱氧核糖核酸(DNA)和核糖核酸(RNA)。反义核酸是干扰DNA和/或RNA序列表达的多核苷酸。术语核酸是指一串至少两个碱基-糖-磷酸酯组合。天然核酸具有磷酸酯主链。人工核酸可以含有其他类型的主链,但含有与天然核酸相同的碱基。该术语还包括PNA(肽核酸)、硫代磷酸酯和天然核酸的磷酸酯主链的其他变体。
如本文所用的术语“连接基”是指可以包含杂原子(例如氮、氧、硫等)并且长度可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50个原子的碳链。连接基可以被各种取代基取代,这些取代基包括但不限于氢原子、烷基、烯基、炔基、氨基、烷基氨基、二烷基氨基、三烷基氨基、羟基、烷氧基、卤素、芳基、杂环基、芳族杂环基、氰基、酰胺、氨基甲酰基、羧酸、酯、硫醚、烷基硫醚、硫醇和脲基。本领域技术人员将认识到,这些基团中的每一个也可以被取代。连接基的实例包括但不限于pH敏感的连接基、蛋白酶可裂解的肽连接基、核酸酶敏感的核酸连接基、脂酶敏感的脂质连接基、糖苷酶敏感的碳水化合物连接基、缺氧敏感的连接基、光可裂解的连接基、热不稳定的连接基、酶可裂解的连接基(例如酯酶可裂解的连接基)、超声敏感的连接基和X射线可裂解的连接基。
术语“药学上可接受的盐”是指可以存在于本发明组合物中使用的化合物中的酸性或碱性基团的盐。本发明组合物中包括的本质上是碱性的化合物能够与各种无机和有机酸形成各种盐。可用于制备这样的碱性化合物的药学上可接受的酸加成盐的酸是形成无毒酸加成盐的那些酸,所述无毒酸加成盐即含有药学上可接受的阴离子的盐,包括但不限于硫酸盐、柠檬酸盐、苹果酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡萄糖酸盐、葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1,1’-亚甲基-双-(2-羟基-3-萘甲酸盐))。除了上述酸以外,本发明组合物中包括的包含氨基部分的化合物还可与各种氨基酸形成药学上可接受的盐。包括在本发明组合物中的本质上是酸性的化合物能够与各种药理学上可接受的阳离子形成碱式盐。这种盐的实例包括碱金属或碱土金属盐,特别是钙、镁、钠、锂、锌、钾和铁盐。
如果本文所述的化合物以酸加成盐的形式获得,则可以通过碱化该酸式盐的溶液来获得游离碱。相反,如果产物是游离碱,则可以按照用于从碱性化合物制备酸加成盐的常规方法,通过将游离碱溶解在合适的有机溶剂中并用酸处理该溶液来制备加成盐,特别是药学上可接受的加成盐。本领域技术人员将认识到各种可用于制备无毒的药学上可接受的加成盐的合成方法。
药学上可接受的盐可衍生自选自以下的酸:1-羟基-2-萘甲酸、2,2-二氯乙酸、2-羟基乙烷磺酸、2-氧戊二酸、4-乙酰氨基苯甲酸、4-氨基水杨酸、乙酸、己二酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸(十碳酸)、己酸(六碳酸)、辛酸(八碳酸)、碳酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、戊二酸、甘油磷酸、乙醇酸、马尿酸、氢溴酸、盐酸、羟乙磺酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、粘液酸、萘-1,5-二磺酸、萘-2-磺酸、烟酸、硝酸、油酸、草酸、棕榈酸、双羟萘酸、泛酸、磷酸、丙酸、焦谷氨酸、水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、酒石酸、硫氰酸、甲苯磺酸、三氟乙酸和十一碳烯酸。
术语“生物可利用的”是本领域公认的,并且是指本公开的形式,其允许其或所施用的量的一部分被其所施用的受试者或患者吸收、并入或以其他方式生理上可用。
应当理解,以下实施例旨在说明而非限制本公开。在不脱离本公开的精神和范围的情况下,在阅读本公开之后,前述描述和实例的各种其他实例和修改对于本领域技术人员将是显而易见的,并且意图将所有这些实例或修改均包括在所附权利要求的范围内。本文引用的所有出版物和专利均通过引用全文并入本文。
实施例
实施例1:缀合物1的合成
缀合物1(SDC-TRAP-0063)
((S)-4,11-二乙基-4-羟基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]中氮茚并[1,2-b]喹啉-9-基4-(2-(5-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-***-4-基)-1H-吲哚-1-基)乙基)哌啶-1-羧酸酯)或其互变异构体。
合成SDC-TRAP-0063的合成方案在PCT申请号PCT/US2013/036783的实施例6中提供。本领域技术人员无需过多实验就能够调整该合成方案以制备本发明范围内的其他靶向分子缀合物。
实施例2:HSP90结合药物缀合物的盐形式和制剂
在溶液中,缀合物1在pH依赖性平衡时包含内酯环与相应的开链羧酸形式。在高pH值(pH值高于9.3,pKa值)时,平衡向开环羧酸形式移动,在低pH值时,平衡向闭环内酯形式移动,如下所示:
开环羧酸形式可以与阳离子形成盐,包括但不限于锂、铝、钙、镁、钾、钠、锌、钡、铋、苯乙苄胺(benethamine)、二乙胺、氨丁三醇、benzathid、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺或普鲁卡因。
缀合物1(SDC-TRAP-0063)的钠盐衍生物
该羧酸衍生物的钠盐(SDC-TRAP-0063钠或SDC-TRAP-0063Na)具有以下结构:
((S)-2-(2-((4-(2-(5-(3-(2,4-二羟基-5-异丙基苯基)-5-羟基-4H-1,2,4-***-4-基)-1H-吲哚-1-基)乙基)哌啶-l-羰基)氧基)-12-乙基-8-(羟甲基)-9-氧代-9,11-二氢中氮茚并[1,2-b]喹啉-7-基)-2-羟基丁酸钠)或其互变异构体:
内酯和钠盐形式的SDC-TRAP-0063的结构:
以内酯形式分离和储存SDC-TRAP-0063原料药,以羧酸钠盐形式转化和储存SDC-TRAP-0063钠药物产品。
SDC-TRAP-0063可以通过以下过程制备:一部分叔丁醇在28-32℃下熔化并分配到一个8升的带有夹套的玻璃混合容器中,夹套温度为28-32℃。将SDC-TRAP-0063粉末缓慢加入搅拌的叔丁醇中并混合至少20分钟。通过重量分析测定SDC-TRAP-0063的添加量,并计算目标药物产品的批量大小。然后按照足够数量的(Q.S.或QS)重量加入的第二部分叔丁醇,并用~6”磁力搅拌棒混合至少15分钟以使它充分润湿和悬浮。然后缓慢加入0.3当量氢氧化钠水溶液并再混合至少1小时。SDC-TRAP-0063粉末的完全溶解通过在混合时和混合器停止时的目视观察来确认。然后将注射用水(WFI)分配至目标总批次体积的~95%并混合20分钟。取样并测量以确保pH值大于或等于9.8,必要时可选择通过增量添加5克的0.3当量氢氧化钠水溶液等分试样并混合至少15分钟来进行调节。再次加入注射用水至QS重量并混合15分钟以完成原料药溶液的混合。然后将8升玻璃混合容器夹套温度降低到20-25℃。产品灭菌是通过一个至少两个串联的Millipore Opticap XL3 0.2μm过滤器进行过滤来实现的,并且在即将进入预过滤器之前采集样品进行微生物计数测试。然后,向去热原的10毫升标称尺寸硼硅酸盐玻璃小瓶无菌填充每小瓶1.1毫升原料药溶液。将小瓶加塞到冻干位置并装入冻干机中。按照表1中的方法冻干小瓶,并完全塞住。将小瓶从冻干机中无菌取出并拧紧瓶盖以密封小瓶。进行外部小瓶清洗和目视检查以完成药物产品在其一级外壳中的生产。
表1:冻干步骤和条件
步骤# | 步骤描述 | 温度 | 压力 | 持续时间 |
1 | 装填 | 5℃ | 大气 | 不适用 |
2 | 冷冻 | 5℃ | 大气 | 120分钟 |
3 | 梯度冷冻 | 5℃至-50℃ | 大气 | 120分钟 |
4 | 冷冻 | -50℃ | 大气 | 210分钟 |
5 | 梯度冷冻 | -50℃至-40℃ | 大气 | 15分钟 |
6 | 抽空 | -40℃ | 80μbar | 不适用 |
7 | 一级梯度干燥 | -40℃至-15℃ | 80μbar | 50分钟 |
8 | 一级干燥 | -15℃ | 80μbar | 2,520分钟 |
9 | 二级梯度干燥 | -15℃至25℃ | 80μbar | 156分钟 |
10 | 二级干燥 | 25℃ | 80μbar | 960分钟 |
11 | 用氮气预曝气 | 25℃ | 800μbar | 不适用 |
12 | 加塞 | 25℃ | 800μbar | 不适用 |
13 | 用氮气曝气 | 25℃ | 大气 | 不适用 |
14 | 卸载* | 25℃ | 大气 | 不适用 |
*如果不是立即卸载,请将架子保持在5℃;开始卸载前,将架子温度调至卸载温度。
在制造过程中,SDC-TRAP-0063转化为SDC-TRAP-0063钠,这是pH值高于9.3时的主要形式。SDC-TRAP-0063钠药物产品是无菌生产为冻干的无菌过滤溶液。冻干的药物产品的组成如下所示:
成分 | 作用 | 量(mg/小瓶) |
SDC-TRAP-0063钠 | 活性物质 | 105 |
填充该溶液以将105mg/小瓶递送到由USP 1型透明玻璃小瓶、塞子和外密封件组成的容器密闭***中。药物产品储存于2℃至8℃,避光。在施用之前,将冻干粉用注射用水复溶,然后在使用前用5%甘露醇USP进一步稀释至目标浓度。SDC-TRAP-0063钠的浓度可为约20至约25mg/mL、约25至约50mg/mL、约50至约100mg/mL、约100至约150mg/mL、或约150至200mg/mL。该药物产品旨在通过输注进行静脉施用。
SDC-TRAP-0063钠的复溶溶液的pH值为约10.0。该溶液在5%甘露醇USP中稀释至目标剂量。输注溶液的pH值取决于稀释的输注溶液中SDC-TRAP-0063钠的浓度。在临床研究方案中采用的剂量范围内,所施用的稀释的输注溶液的体积范围为50至500mL,pH范围为8.1至9.6。为了降低在IV施用期间注射部位疼痛和/或静脉内皮损伤的潜在风险,使用中心静脉通路线来施用稀释的SDC-TRAP-0063钠。
实施例3:针对晚期实体瘤患者的缀合物1的首次人体1/2a期研究:1期结果
在缀合物1的1/2a期研究中,患者在28天的周期中每周一次接受缀合物1治疗,持续4周中的3周。患者具有经组织学或细胞学证实的晚期实体瘤。他们的肿瘤类型包括***肿瘤、乳腺肿瘤、胆管癌、结肠肿瘤、尤因肉瘤、肝肿瘤、肺肿瘤、神经内分泌(未知原发性)肿瘤、卵巢肿瘤、胰腺肿瘤、唾液腺肿瘤和肉瘤。他们已经接受了一种或多种在先线抗癌疗法。患者接受固定剂量或基于体表面积(BSA)的剂量。剂量包括30mg、60mg、120mg、240mg、360mg、175mg/m2和200mg/m2。缀合物1单一疗法的最大耐受剂量(MTD)确定为175mg/m2。未来的研究将使用基于BSA的剂量。
为了研究药代动力学(PK)曲线,收集多个血浆样品以测量缀合物1和SN-38的浓度。如表2所示,缀合物1在较低剂量下表现出非线性PK,但在较高剂量下观察到更大的成比例性。在所有剂量范围中,消除半衰期为~10小时。游离的SN-38水平总体较低。AUC小于缀合物(缀合物1)AUC的2%。在通常与BSA相关的固定剂量下观察到患者间PK差异性。PK分析显示连接基在循环中是稳定的,并且游离SN-28的全身暴露量低。
表2.药代动力学参数(周期1第1天)
在接受缀合物1治疗的17名患者中,1名患者实现了部分缓解(PR;肿瘤大小减少了30%或更多),5名患者病情稳定(SD;肿瘤有反应且大小没有增长)。120-360mg固定剂量和175mg/m2 BSA剂量与病情稳定维持≥12周有关。
总的来说,缀合物1是安全的并且具有预期的不良(AE)事件特性。通过剂量调整可以很好地控制AE。最常见的AE是恶心、疲劳、腹泻、呕吐和脱发。
缀合物1将在3个2a期扩展疾病队列中进行评价:先前治疗的胰腺腺癌;子宫内膜腺癌;以及***、子宫颈或头颈部的鳞状细胞癌。
实施例4:肿瘤和血浆中缀合物1和SN-38的水平
胰腺癌患者接受了剂量为150mg/m2的缀合物1并进行了肿瘤活检以确定肿瘤和血浆中的缀合物1和SN-38水平。在第二剂150mg/m2缀合物1后24小时从肝转移中取样。
如表3所示,在24小时时,在肿瘤中观察到显著水平的缀合物1和SN-38,而在血浆中观察到该浓度的一部分(与以175mg/m2给药的5名其他患者相比)。肿瘤中缀合物1和SN-38的水平远高于血浆中的水平。这些数据表明,随着时间的推移,正在进行的缓慢连接基裂解导致集中的肿瘤摄取、缀合物(缀合物1)的保留和有效载荷(SN-38)的肿瘤内释放。这些数据也与临床前数据一致,临床前数据显示保留的缀合物1在多日内在癌细胞中缓慢释放SN-38有效载荷。
表3. 24小时时患者活检中缀合物1和SN-38的水平
血浆中的量(nM) | 肿瘤中的量(nM) | 肿瘤水平/血浆水平之比 | |
缀合物1 | 52.3* | 318 | 约6.1 |
SN-38 | 25.5* | 86.6 | 约3.4 |
*以175mg/m2给药的5名患者的平均值
还将胰腺患者在24小时时的SN-38暴露量与接受Onivyde(伊立替康)治疗的患者(13名患者)在72小时时的SN-38暴露量进行比较,数据如表4所示。接受缀合物1治疗的患者在肿瘤中具有86.6nM的SN-38,约为接受Onivyde治疗的患者的SN-38肿瘤水平(24.5nM)的3.5倍。
表4. Onivyde治疗72小时后患者活检中伊立替康和SN-38的水平
血浆中的量(nM) | 肿瘤中的量(nM) | 肿瘤水平/血浆水平之比 | |
伊立替康 | 7921 | 4043 | 约0.5 |
SN-38 | 5.9 | 24.5 | 约4.2 |
对于接受Onivyde治疗的患者,肿瘤中SN-38水平低和循环中依立替康水平随时间推移变高与伊立替康的非靶向脂质体制剂在循环中花费很长时间的事实一致。
对于接受Onivyde治疗的患者,伊立替康的肿瘤水平仅为血浆水平的约1/2,说明缺乏肿瘤靶向性,这与接受靶向缀合物缀合物1治疗并相对于血浆在肿瘤中具有更高水平的缀合物和有效载荷的患者形成对比。
Onivyde肿瘤伊立替康水平由于非常高的血浆水平和包封的伊立替康在脉管***中的水平混淆实际肿瘤细胞内水平而升高。Onyvide的非靶向方法导致肿瘤中SN-38水平较低。
实施例5:小鼠异种移植物模型中的有效肿瘤暴露
在H1975(NSCLC)小鼠异种移植物模型中给药的缀合物1显示缀合物1和SN-38的24小时肿瘤暴露量与实施例4中患者活检中测量的水平相似。图1A和图1B中显示了以72、100和150mg/kg的每周剂量给药的缀合物1在H1975模型中的功效。
在肿瘤PK(虽然可变)中50mg/kg和100mg/kg剂量的暴露量与患者活检暴露量相似,72mg/kg和100mg/kg的每周剂量在异种移植物模型中产生显著的功效。150mg/kg的剂量导致肿瘤消退,与患者活检数据相比,缀合物1的24小时肿瘤暴露量显著更高,但SN-38仅略高。
表5. 24小时时H1975模型中PEN-866和SN-38的水平
实施例6:缀合物1与他拉唑帕尼联合的抗肿瘤功效
携带SKOV3(卵巢癌)肿瘤的小鼠接受以下治疗:
1).溶媒对照;
2).75mg/kg缀合物1每周一次(第1天),通过静脉内施用(IV),持续6周;
3).每天0.33mg/kg他拉唑帕尼,服药4天/停药3天(一周的第2-5天),口服施用(PO),持续6周;
4).75mg/kg缀合物1每周一次,静脉内施用,以及每天0.33mpk他拉唑帕尼,服药4天/停药3天,从缀合物1给药后24小时开始,持续6周。
在治疗后测量肿瘤体积。如图3A所示,与单独的缀合物1治疗和单独的他拉唑帕尼治疗相比,联合治疗观察到了统计学上显著的功效改善。
在一项类似的研究中,在携带NCI-H460(非小细胞肺癌(NSCLC))的小鼠模型中研究了缀合物1和他拉唑帕利联合治疗。携带SKOV3(卵巢癌)肿瘤的小鼠接受以下治疗:
1).溶媒对照;
2).100mg/kg缀合物1每周一次(第1天),通过静脉内施用(IV),持续2周;
3).每天0.33mg/kg他拉唑帕尼,服药4天/停药3天(一周的第2-5天),口服施用(PO),持续2周;
4).100mg/kg缀合物1每周一次,静脉内施用,每天0.33mpk他拉唑帕尼,服药4天/停药3天,从缀合物1给药后24小时开始,持续2周。
在治疗后测量肿瘤体积。如图3B所示,与单独的缀合物1治疗和单独的他拉唑帕尼治疗相比,联合治疗观察到了统计学上显著的功效改善。图3C中的pH2AX定量数据表明,用缀合物1与他拉唑帕尼联合治疗在给药后7天产生持续和协同的DNA损伤。
在另一项类似的研究中,在小鼠模型中评价了缀合物1和维利帕尼联合治疗。
本公开的范围不限于上文的描述,而是如所附权利要求书中所给出。
在权利要求中,诸如“一”、“一个”和“该”的冠词可以表示一个或多于一个,除非相反地指出或从上下文中明显看出其他含义。如果一个、多于一个或所有组成员在给定的产品或过程中存在、使用或以其他方式与给定的产品或过程相关,则在该组中的一个或多个成员之间包含“或”的权利要求或说明将被认为是满足的,除非相反地指出或从上下文中明显看出其他含义。本公开包括这样的实施方案:其中恰好一个组成员在给定的产品或过程中存在、使用或以其他方式与给定的产品或过程相关。本公开包括这样的实施方案:其中多于一个或所有组成员在给定的产品或方法中存在、采用或以其他方式与给定的产品或方法相关。
还应注意,术语“包含”旨在是开放的并且允许但不要求包括附加的要素或步骤。因此,当在本文中使用术语“包含”时,也涵盖和公开术语“由……组成”。
在给出范围的情况下,包括端点。此外,应理解,除非另外指明或从上下文和本领域普通技术人员的理解中明显看出其他含义,否则表示为范围的值可以假定为在本公开的不同实施方案中所述的范围内的任何特定值或子范围,至范围的下限的单位的十分之一,除非上下文另外明确指明。
此外,应该理解,落入现有技术范围内的本公开的任何特定实施方案可以明确地从任何一项或多项权利要求中排除。由于这样的实施方案被认为是本领域普通技术人员已知的,因此可以将它们排除,即使在此未明确提出排除。出于任何原因,无论是否与现有技术的存在有关,本公开的组合物的任何特定实施方案都可以从任何一项或多项权利要求中排除。
所有引用的来源,例如,本文引用的参考文献、出版物、数据库、数据库条目和技术,都以引用方式并入本申请,即使在引用中未明确说明。如果引用的来源与本申请的表述存在冲突,则以本申请中的表述为准。
章节和表格的标题并非旨在进行限制。
Claims (17)
1.一种治疗有需要的受试者的癌症的方法,包括以150mg/m2、175mg/m2或200mg/m2体表面积的剂量向受试者施用有效量的缀合物1或其药学上可接受的盐。
2.一种治疗有需要的受试者的癌症的方法,包括向受试者施用有效量的缀合物1或其药学上可接受的盐,其中受试者先前已接受至少一种抗癌疗法。
3.一种治疗有需要的受试者的癌症的方法,包括向受试者施用有效量的缀合物1或其药学上可接受的盐,其中受试者在治疗后显示部分缓解或疾病稳定。
4.如权利要求1、2或3中任一项所述的方法,其中缀合物1或其药学上可接受的盐的剂量为175mg/m2。
5.如权利要求4所述的方法,其中在第1天、第8天和第15天每周一次施用缀合物1或其药学上可接受的盐,持续3周,随后一周不进行治疗。
6.如权利要求1、2或3中任一项所述的方法,其中所述癌症选自***癌、乳腺癌、胆管癌、结肠癌、尤因肉瘤、肝癌、肺癌、神经内分泌癌、卵巢癌、胰腺癌、唾液腺癌和肉瘤。
7.如权利要求1、2或3中任一项所述的方法,其中所述癌症是胰腺腺癌、子宫内膜腺癌、脂肪肉瘤或***、子宫颈或头颈部的鳞状细胞癌。
8.如权利要求1、2或3中任一项所述的方法,其中肿瘤缀合物1水平与血浆缀合物1水平之比为大于5。
9.如权利要求1、2或3中任一项所述的方法,其中肿瘤缀合物1水平为大于300nM。
10.如权利要求1、2或3中任一项所述的方法,其中肿瘤SN-38水平与血浆SN-38水平之比为大于3。
11.如权利要求1、2或3中任一项所述的方法,其中肿瘤SN-38水平大于80nM。
12.如权利要求1所述的方法,其中所述受试者还接受至少一种PARP抑制剂治疗。
13.如权利要求12所述的方法,其中在7天周期的第2、3、4、5和6天施用所述PARP抑制剂。
14.如权利要求12所述的方法,其中所述PARP抑制剂是他拉唑帕尼。
15.如权利要求12所述的方法,其中所述癌症是小细胞肺癌。
16.如权利要求12所述的方法,其中所述受试者为HPV阳性。
17.如权利要求1所述的方法,其中所述受试者还接受5-FU、亚叶酸或5-FU和亚叶酸的组合。
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