CN113905764B - 用于治疗癌症的前体半胱天冬酶-3活化作用和免疫疗法 - Google Patents
用于治疗癌症的前体半胱天冬酶-3活化作用和免疫疗法 Download PDFInfo
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Abstract
血脑屏障渗透剂前体半胱天冬酶‑3(procaspase‑3)活化药物,PAC‑1,被确定用作诱导免疫刺激的摧毁癌细胞的有效途径。PAC‑1诱导癌细胞中MLH1的切割,而且研究表明,MLH1的灭活导致经由主要组织相容性复合物(MHC)产品增加突变的负担和新抗原的表达。本文描述了一种基于机制的战略,用以获得免疫疗法通过有效的方式治疗癌症的能力。
Description
申请相关
本申请根据35U.S.C.§119(e)规定要求下述在先申请的优先权:2019年5月30日提交的美国临时专利申请62/854,823以及2019年12月6日提交的美国临时专利申请62/944,404。上述在先申请在此通过引用纳入本文。
政府支持
本发明是通过美国National Institutes of Health提供拨款No.R01 CA120439的政府支持下完成的。美国政府对本发明享有某些权利。
背景技术
免疫治疗方式的成功应用使黑色素瘤、肺癌和膀胱癌的治疗发生了转变,并且对于其他几类肿瘤的治疗来说也具有相当的期望。对于部分患者能够看到显著的结果,例如即使在疾病晚期也呈现出持久反应,从而为其他顽固癌症的成功治疗带来了希望。肿瘤中的突变载荷与免疫检查点抑制剂的成功存在明显相关性。对于DNA错配修复缺陷或微卫星不稳定性(MSI)的患者,随着帕博利珠单抗(pembrolizumab)(Keytruda,一种对PD-1的抗体)的批准,上述观察结果成功发生转变。然而遗憾的是,对于突变载荷低的许多癌症,免疫治疗试验在很大程度上令人失望,并且少于10%的癌症具有MSI表型的事实表明显著扩大免疫治疗成功程度所具有的挑战性。胶质母细胞瘤(GBM)的免疫疗法所面临的挑战则更为显著,由于较低的新抗原表达,缺乏T细胞浸润进入肿瘤,以及大多数药物难于穿越血脑屏障(BBB)。
最近的一个重要进展是DNA微卫星不稳定性(MSI)作为生物标志物的临床批准,用于PD-1抑制(与帕博利珠单抗(pembrolizumab))无论致瘤起因的临床疗效。该批准是基于相当大的临床前和临床数据,其表明错配修复缺陷(dMMR)预测实体肿瘤对PD-1封闭的响应,由于已知,带有dMMR/MSI的肿瘤具有100s至1000s体细胞突变(somatic mutations)(10倍高于MMR表达癌症,图1A),可能导致新抗原的升高。然而,dMMR/MSI对应的癌症百分比较低,可能不到10%,包括<5%的GBM。零星的MSI由MLH1启动子的表观遗传沉默驱动,并且MLH1沉默通常用作MMR缺乏的标志。在许多研究中已经证明MLH1沉默和体细胞突变数量的相关性,其显著呈现于图1。
重要的是,最近的一份报告(Germano,G.,et al.,Nature 2017,552,116)验证了MLH1的失活(通过CRISPR/Cas9敲除)会导致较高的突变负荷和增加的新抗原谱。这种MLH1基因敲除诱导的表型导致癌细胞,其在小鼠体内最低限度地形成同系肿瘤,这表明dMMR足以增强免疫反应。此外,基因组MLH1敲除导致对免疫检查点抑制剂(即anti-PD-1+anti-CTLA-4)的相应急剧增加。这些结果表明,MLH1功能的丧失会导致由增加的突变负荷驱动的表型变化,最终导致更高的新抗原表达、免疫识别以及对体内免疫检查点封锁的敏感性增加。
如果MLH1功能丧失可以在癌细胞中被选择性诱导,就可以显著提高患者对免疫疗法的反应,包括检查点抑制剂和新抗原肽疫苗。令人兴奋的是,多项大型蛋白质组学研究表明,MLH1是半胱天冬酶-3(caspase-3)的顶级底物,其6小时后剩余0%的蛋白质。此外,MLH1只是活性caspase-3的底物,没有观察到其他活性caspase(即caspase-1,2,6,7,8)的蛋白水解。
前体半胱天冬酶-3(procaspase-3,PC-3)裂解为半胱天冬酶-3(caspase-3)是细胞凋亡的关键节点,因为这种杀手caspase催化数百种蛋白质底物的水解,导致细胞死亡。癌症的一个标志是肿瘤细胞通过凋亡蛋白的突变和失调来逃避凋亡的能力,并且几种抗癌药物的发现策略都集中在对这些突变蛋白的抑制上。一种补充的方式涉及促凋亡蛋白(如PC-3)的小分子介导活化。基于PC-3在凋亡级联中相对于频繁突变蛋白的下游位置、癌症中PC-3突变的低频率以及procaspase-3酶稳在多种类型癌症中的健表达,小分子介导的PC-3活化正被作为抗癌策略而积极探索,所述多种类型癌症包括淋巴瘤、白血病、多发性骨髓瘤、黑色素瘤、胶质母细胞瘤(GBM)、胰腺癌、肝癌、非小细胞肺癌(NSCLC)、乳腺癌、卵巢癌结肠癌、骨肉瘤和脑膜瘤。
问题是当新抗原表达低时,现有的治疗癌症的免疫疗法可能缺乏疗效。因此,需要一种可以选择性靶向癌细胞以增加其新抗原表达的药物,从而免疫疗法可以帮助消灭癌细胞。
发明内容
肿瘤中前体半胱天冬酶-3(procaspase-3)选择性活化为半胱天冬酶-3(caspase-3)引起MLH1的定量裂解,导致dMMR/MSI,从而显著提高免疫疗法的功效。此处PAC-1用于选择性诱导癌症中的免疫刺激,包括MLH1裂解,将MSS肿瘤转化为dMMR/MSI肿瘤,从而使肿瘤更容易接受免疫疗法的治疗。结果表明,PAC-1的免疫刺激促进了应激反应的诱导,从而改变了肿瘤微环境以增加免疫炎症的程度。这样的结果为更多的癌症患者带来免疫疗法的效力——急剧而持久的反应。
因此,本公开提供了一种组合物,其包含:
(a)procaspase-3活化剂;
(b)至少一种第二活性剂,其中所述第二活性剂是检查点抑制剂、癌症疫苗、代谢调节剂、巨噬细胞抑制剂或免疫刺激剂或调节剂;以及
(c)任选的药学上可接受的稀释剂、赋形剂或载体。
在各种实施方式中,前体半胱天冬酶-3(procaspase-3)活化剂是PAC-1:
本公开还提供了一种治疗癌症的方法,其包括向有需要的受试者同时或依次施用治疗有效量的procaspase-3活化剂和有效量的第二活性剂,其中所述第二活性剂是免疫治疗的;其中所述第二活性剂的作用通过procaspase-3活化剂的施用而得到增强。
治疗癌症的方法的一个特定实施方式包括向受试者施用PAC-1和anti-PD-1抗体,其中PAC-1是每天施用连续21天或更多天,使得PAC-1每天施用的总剂量为约100mg/kg至约125mg/kg,并且anti-PD-1抗体是连续21天或更多天内施用两次或四次,其中anti-PD-1抗体的剂量为约10mg/kg并且anti-PD-1抗体的各个剂量是在不同日子给药。
本发明提供了本文所述的组合物用于药物疗法的用途。所述药物疗法可以用于治疗癌症,例如乳腺癌、三阴性乳腺癌、卵巢癌、肺癌、子宫内膜癌、胰腺癌、前列腺癌、淋巴瘤、黑色素瘤、白血病、多发性骨髓瘤、胶质母细胞瘤、肝癌、非小细胞肺癌、骨肉瘤、脑膜瘤、肾癌、转移性肾细胞癌、甲状腺癌或结肠癌。本发明还提供了本文所述组合物在制备用于治疗哺乳动物疾病例如人类癌症的药物中的用途。所述药物可以包括药学上可接受的稀释剂,赋形剂或载体。
附图说明
下述附图属于说明书的一部分并且是用来对本发明的一些实施方式或不同方面作进一步的描述。在一些实例中,本发明的实施方式可以通过参照附图并结合本文提供的详细描述得到更好地理解。这些描述和附图可以突出某些具体的实施例或者本发明的某些方面。然而,本领域技术人员应当理解这些部分的实施例或方面也可用于结合本发明的其他实施例或方面。
图1:A)微卫星不稳定性(MSI)以及B)MLH1沉默与体细胞突变数量的增加密切相关,此处显示的结肠癌数据来自Vogelstein等人(Proc Natl Acad Sci U S A 2015,112,118),MSS,Microsatellite Stable。
图2:PAC-1加免疫疗法的协同作用。PAC-1诱导的半胱天冬酶-3(caspase-3)切割某些使癌症对各种免疫治疗方法敏感的蛋白质。
图3:PAC-1处理导致MLH1在没有凋亡死亡标志物的情况下裂解。将细胞系(cellline)与指定浓度的PAC-1孵育72小时,然后对MLH1蛋白水平以及PARP-1、裂解的PARP-1(c-PARP-1是一种凋亡标记)和β-肌动蛋白(β-actin)(加载对照)进行蛋白质印迹分析。细胞系的类型用正常细胞系(normal cell line)表示,特别突出显示HFF-1,表明癌细胞特异性MLH1裂解。
图4:PAC-1治疗同系肿瘤小鼠会增加肿瘤浸润淋巴细胞的数量。A)具有GL261神经球原位移植的C57BL/6小鼠。允许肿瘤形成10天,然后用或不用PAC-1(100mg/kg PO x 10天)处理小鼠(n=3/组),然后灭杀。对肿瘤进行CD3(棕色)染色以鉴定T细胞TIL。数据表示为每4HPF/小鼠的平均CD3+。放大倍数l00x。B)皮下移植B16F10细胞的C57BL/6小鼠。允许肿瘤形成7天,然后用或不用PAC-1(100mg/kg IP x 2x 14天)处理小鼠(n=8/组),然后灭杀。对肿瘤进行CD3(棕色)染色以鉴定T细胞TIL。数据表示为每10HPF/小鼠的平均CD3+。放大倍数l00x。
图5:IHC研究的PD-L1和MLH1验证。(A)人扁桃体和(B)犬类淋巴结中的PD-L1阳性表达。犬类神经胶质瘤(C)H&E和(D)PD-L1 IHC。(E)人U87和(F-H)3种犬类神经胶质瘤细胞系的核MLH1 IHC。
图6:显示PAC-1与免疫疗法联合使用的功效的图表。PAC-1的剂量为100mg/kg,每天一次。1=载体+同型(vehicle+isotope);2=载体+anti-PD-1+anti-CTLA-4(vehicle+anti-PD-1+anti-CTLA-4);3=PAC-1+同型(PAC-1+isotope);4=PAC-1+anti-PD-1+anti-CTLA-4(PAC-1+anti-PD-1+anti-CTLA-4)。
图7:显示PAC-1与anti-PD-1抗体组合导致晚期K7M2转移模型存活期延长的图表。MST=中位生存时间(median survival time)。图中,PD1=anti-PD-1。
图8:BALB/c小鼠CT-26_WT皮下模型的开发。
图9:在2剂量(A)与4剂量(B)之后BALB/c小鼠中CT-26_WT的生长。其中,空心圆=载体+anti-IgG2A抗体;正方形=PAC-1(100mg/kg)+anti-IgG2a抗体;三角形=载体+anti-PD-1mAb;倒三角形=PAC-1(100mg/kg)+anti-PD-1mAb。
图10:使用PAC-1和anti-PDL1 mAb处理BALB/c小鼠的分析。其中,空心圆=载体+anti-IgG2A抗体;正方形=PAC-1(100mg/kg)+anti-IgG2a抗体;三角形=载体+anti-PD-1mAb;倒三角形=PAC-1(100mg/kg)+anti-PD-1mAb。
图11:BALB/C小鼠CT-26_TdTomato皮下肿瘤模型的开发。
图12:A)治疗方案示例。B)来自用PAC-1处理的BALB/c小鼠的血浆细胞因子阵列。
图13:肺、PBMC和脾脏肿瘤攻击后14天用PAC-1处理后的中性粒细胞和巨噬细胞群的分析。其中,空心圆=载体+anti-IgG2A抗体;正方形=PAC-1+anti-IgG2a抗体;三角形=载体+anti-PD-1mAb;倒三角形=PAC-1+anti-PD-1mAb。
图14:PAC-1和anti-PD-1组合治疗后26天,BALB/c小鼠肺、PBMC和脾脏中T细胞、B细胞和NK细胞群的分析。其中,空心圆=载体+anti-IgG2A抗体;正方形=PAC-1+anti-IgG2a抗体;三角形=载体+anti-PD-1mAb;倒三角形=PAC-1+anti-PD-1mAb。
图15:在肿瘤攻击后26天BALB/c小鼠的肺、PBMC和脾脏中的树突状细胞和CD45-肿瘤细胞表面的PD-L1表达。其中,空心圆=载体+anti-IgG2A抗体;正方形=PAC-1+anti-IgG2a抗体;三角形=载体+anti-PD-1mAb;倒三角形=PAC-1+anti-PD-1mAb。
图16:C57BL/6小鼠MC38肺转移模型的发展。1=载体(vehicle);2=PAC-1;3=anti-PD-1;4=PAC-1+anti-PD-1。PAC-1通过腹腔注射给药,剂量为100mg/kg,anti-PD-1通过腹腔注射给药,剂量为10mg/kg。
图17:根据MC38肺转移模型的生存曲线。1=载体;2=PAC-1;3=anti-PD-1;4=PAC-1+anti-PD-1。PAC-1通过腹腔注射给药,剂量为100mg/kg,anti-PD-1通过腹腔注射给药,剂量为10mg/kg。
具体实施方式
本文公开了一种新的基于机制的策略的开发,以选择性地将低突变负荷肿瘤转化为具有高突变负荷的肿瘤,使其成为免疫疗法治疗的理想选择。该策略的前提是靶向灭活肿瘤抑制因子MLH1。如本文所述,MLH1沉默与对anti-PD-1抗体的反应之间存在很强的相关性:MLH1的基因沉默与肿瘤中体细胞突变的数量之间的联系已被令人信服地证明,并且MLH1导致的DNA损伤功能丧失引起高度免疫原性应激反应。目标是通过药物介导的肿瘤选择性灭活MLH1,将免疫疗法的能量和潜力带给GBM。MLH1是caspase-3的主要细胞底物,并且所公开的方法可以用称为PAC-1的小分子在癌细胞中诱导选择性MLH1裂解,PAC-1选择性地将肿瘤细胞中的procaspase-3活化为caspase-3。
PAC-1是一种口服可用的BBB渗透实验性治疗剂,已被证明对人类癌症患者是安全的,目前正在对GBM进行临床评估(结合放射和替莫唑胺(temozolomide))。本申请的总体目标是在复杂的GBM模型中实现药物诱导的MLH1裂解与免疫疗法的基于机制的协同作用。主要假设是药物介导的MLH1裂解会诱导肿瘤选择性DNA损伤和MSI,从而增加潜在新抗原的数量(以及免疫原性)。此外,PAC-1的caspase-3诱导活性促进了炎症性肿瘤内环境,从而将“冷”GBM肿瘤转变为“热”肿瘤,这些肿瘤易受各种免疫治疗方式的影响(图2)。
定义
下面的定义是用来对说明书和权利要求书提供清晰和一致的理解。本文所采用的术语具有下述的含义。本说明书中所采用的其他术语和短语具有本领域技术人员所能理解的普通含义。这种普通含义可通过参考技术辞典获得,例如Hawley’s Condensed ChemicalDictionary 14th Edition,by R.J.Lewis,John Wiley&Sons,New York,N.Y.,2001。
本说明书中提及的“一种实施方式(one embodiment)"、“实施方式(anembodiment)”等表明所描述的实施方式可包含特定的方面、特征、结构、部分或特性,但并不是每个实施方式都必须包含这些特定的方面、特征、结构、部分或特点。此外,这些短语可能,但并不一定,适用于在本说明书其它部分提及的相同的实施方式。此外,当特定的方面、特征、结构、部分或特点是结合某种实施方式进行描述的,本领域技术人员应当能够知道将这些特定的方面、特征、结构、部分或特点应用到或关联到其它的实施方式,无论是否明确地表述出来。
单数形式的冠词"a,""an"和"the"包括复数含义,除非上下文存在明确的不同阐述。因此,例如,“化合物”可以是指包括多个这样的化合物,从而化合物X包括多个的化合物X。进一步值得注意的是,权利要求书可能被撰写为排除任何可选元素。因此,本声明旨在作为排除性术语使用的前置基础,例如"单独(solely)"、"仅仅(only)"等术语,与本文所描述的任何元素相关联和/或作为对权利要求所述要素的限定或者用作“负面”限制。
术语“和/或(and/or)”是指相关项目的任何一项、任何组合,或它们的全部。短语“一个或多个(one or more)"和“至少一个(at least one)"是本领域技术人员都能容易理解的,尤其是根据上下文理解。例如,这些短语可以是指一、二、三、四、五、六、十、一百,或大约比已经列举的下限高出10、100或1000倍的任何上限值。
本领域技术人员应当能够理解,包括表示成分含量、诸如分子量的性质、反应条件等等的任何数目都可以是近似的,并且在各种情下都能够采用术语“大约”进行修饰。取决与本领据技术人员通过本文所述方法所期望获得的性质,这些值是可以有变化的。还应当理解,这些值,由于测试中出现的标准偏差必然会导致其内在的可变化性。当使用先行词“约”表示近似值时,应当理解的是,不被“约”修饰的特定值也构成另外的方面。
术语“大约(about)”表示特定值可以具有±5%、±10%、±20%或±25%的变化。例如,“大约50”百分比在一些实施方式中可变化为45到55百分比。对于整数范围,术语“大约”可包含在所指范围各端相较于所列举的整数小或大一个或两个整数。除非文中另有说明,术语“大约”是用来包括对于成分、组合或实施例的功能来说等同的接近所列范围的数值。术语“大约”也能够用来对本段前述范围的端点进行调整。
本领域技术人员应当能够理解,出于任何各种目的,尤其是就提供文字描述来说,本文提供的任何范围还包括所有可能的子范围和这些子范围的组合,以及构成所述范围的单独值,尤其是整数值。因此,应当理解,两个特定单元之间的每个单元也被公开。例如,如果公开了10到15,则分别单独地公开了11、12、13和14,及其作为范围的一部分。所引述范围(例如重量百分比或碳基团)包括各个特定的数值、整数、小数或所述范围内的特性。应当易于理解,所列举的任何范围能够充分描述并能够使的相同的范围被分解为相等的二等份、三等分、四等分、五等分或十等分。作为非限制性例子,本文所述的每个范围都可容易地分解为下三分之一,中三分之一和上三分之一等等。本领域技术人员也应当能够理解,诸于“高至”、“至少”、“高于”、“低于”、“多于”、“或以上”或类似的术语包含所列举的数字,并且这种术语还指所述范围可随后分成上文述及的子范围。同样地,本文所列的任何比率也包含落在较宽比率之内的子比率。因此,自由基、取代基和范围的具体数值只是用来进行说明;其不排除自由基和取代基的其它指定数值或其它指定范围的数值。还将理解的是,每个范围的端点相对于另一个端点以及独立于另一个端点都是有意义的。
本领域技术人员还应当能够容易理解,当单元被按照通常的方式例如在马库什群组中被组合起来时,本发明不仅包括所列单元组合构成的整体,还包括所述群组单独的每个单元以及所述基本群组的任何可能的亚群组。另外,对于所有的目的,本发明不仅包括基本群组,还包括基本群组去掉一个或多个单元的群组。可见,本发明可以包括明确排除所引述群组的任何一个或多个单元。因此,有关约束条件可以附加于任何公开的范畴或实施方式,其中任何一个或多个单元、种类或实施方式,可从所述范畴或实施方式中排除出来,例如,用于明示负面限定的场合。
术语“接触(contacting)”是指触及、接触,或者邻接或紧密地靠近,例如,包括在细胞或分子水平,比如在溶液或反应混合物中,在体外或体内,发生生理反应、化学反应或物理变化。
术语“有效量(effective amount)"是指有效地治疗疾病、失调和/或病症,或者产生所描述效果的量。例如,有效量可以是有效地减缓所治疗的病症或症状的进展或程度的剂量。对治疗上有效量是在本领域技术人员能力范围内能够确定的。术语“有效量”是指包括本文所描述的化合物的量,或本文所描述的肽类的组合的量,比如,是用于针对受试者有效地治疗或预防疾病或失调,或者治疗疾病或失调的症状。因此,“有效量”通常是指能提供预期效果的量。
或者,本文中术语“有效量(effective amount)”或“治疗有效量(therapeutically effective amount)”是指足以在一定程度上缓解被治疗的疾病或病症的一种或多种症状的药剂或成分或成分的组合。结果可以是对疾病的体征、症状或根源的减轻和/或缓解,或生物系统的任何其他期望的改变。例如,用于治疗用途的“有效量”是包含本文所述化合物以提供临床上显著减轻疾病症状所需的量。在任何情况下,都可以使用诸如剂量递增研究之类的技术来确定适当的“有效”量。所述剂量可以通过一次或多次施用。然而,可以根据每个患者的个体因素来精确确定有效剂量,包括但不限于患者的年龄,个头,疾病类型或程度,疾病阶段,组合物的给药途径,所用补充疗法的类型或程度,当前疾病过程以及所需的治疗类型(例如,积极治疗与常规治疗)。
术语“治疗(treating,treat和treatment)”包括(i)防止疾病,病理或医学状况的发生(例如,预防);(ii)阻止疾病、病理或医学病症的发生或者控制其发展;(iii)缓解疾病、病理或医学病症;和/或(iv)减轻疾病、病理或医学病症。因此,术语“治疗”可以包括降低、阻止或逆转所治疗病症或症状的进展或程度。因此,术语“治疗”可以酌情包括医治、疗养和/或预防性用药。
如本文所用,“受试者(subject)”或“患者(patient)”是指具有疾病或其他恶性肿瘤的症状或处于危险中的个体。患者可以是人类或非人类,并且可以包括例如出于研究目的用作“模型系统”的动物品系或物种,例如本文所述的小鼠模型。同样,患者可以包括成人或青少年(例如,儿童)。此外,患者可以指可以从本文所述组合物的施用中受益的任何活生物体,优选哺乳类(例如人或非人)。哺乳类的例子包括但不限于哺乳动物类别的任何成员:人类,非人类灵长类动物(例如黑猩猩)以及其他猿类和猴类;牲畜,例如牛,马,绵羊,山羊,猪;家畜,例如兔子,狗和猫;实验动物包括啮齿动物,例如大鼠,小鼠和豚鼠等。非哺乳动物的例子包括但不限于鸟类,鱼类等。在本文提供的一种实施方式中,哺乳类是人。
如本文所用,术语“提供”,“施用”,“引入”在本文可交互使用,并且是指通过一定的方式或途径将本文所述的组合物置于受试者体内从而使得所述组合物至少部分地置于所需的部位。所述组合物可以通过递送到受试者中所需位置的任何合适的途径来施用。
本文所述的组合物可以与其它的组合物一起施用以延长组合物的稳定性和活性或者与其他治疗药物组合。
术语“抑制(inhibit,inhibiting和inhibition)”是指减缓、阻止或逆转疾病、感染、病况或细胞群的生长或进展。抑制作用可以大于约20%,40%,60%,80%,90%,95%或99%,例如,相比于发生在没有治疗或处理的情况下的生长或进展程度。
本文所使用的术语“基本上(substantially)”是广义的术语,并且以其通常的意义使用,包括但不限于很大程度上但不一定是所指定的全部。例如,该术语可以指不是整体数值的100%的数值。所述整体数值可以少约1%,约2%,约3%,约4%,约5%,约6%,约7%,约8%,约9%,约10%,约15%,约20%。
术语“免疫疗法(immunotherapy)”是指通过使用例如“免疫疗法的(immunotherapeutic)”活化或抑制免疫系统来治疗疾病。旨在引发或放大免疫反应的免疫疗法被归类为活化免疫疗法,而减少或抑制的免疫疗法被归类为抑制免疫疗法。免疫疗法是通过活化或抑制免疫系统来治疗疾病。这些旨在引发或放大免疫反应的免疫疗法被归类为活化免疫疗法,而减少或抑制的免疫疗法被归类为抑制免疫疗法。癌症免疫疗法试图刺激免疫系统以摧毁肿瘤。
术语“同型(isotype)”是指作为对靶标缺乏特异性但与应用中使用的初级抗体的类别和类型相匹配的初级抗体的对照。同型对照用作阴性对照,以帮助区分非特异性背景信号和特异性抗体信号。
本公开的实施例
本公开提供了一种组合物,其包含:
(a)procaspase-3活化剂;
(b)至少一种第二活性剂,其为检查点抑制剂、癌症疫苗、代谢调节剂、巨噬细胞抑制剂或免疫刺激剂或调节剂;以及
(c)任选的药学上可接受的稀释剂、赋形剂或载体。
在各种实施方式中,前体半胱天冬酶-3(procaspase-3)活化剂是PAC-1:
在各种另外的实施方式中,procaspase-3活化剂是公开于美国专利8,592,584;8,778,945;8,916,705;或9,249,116中的化合物;所述文献中的分子式和化合物通过引用并入本文。
在另外的实施方式中,所述第二活性剂在癌细胞中具有诱导细胞凋亡的作用并且PAC-1以大于加合作用的量增强所述第二活性剂的作用,其中PAC-1起动了癌细胞对所述第二活性剂的易受损性。
在各种其他实施方式中,所述组合物(例如procaspase-3活化剂)抑制错配修复(MMR)蛋白。在另外的实施方式中,所述组合物是MutL同源物1(MLH1)蛋白的半胱天冬酶-3(caspase-3)降解的中介物。在进一步的实施方式中,所述组合物诱导DNA微卫星不稳定性(MSI)。在其他实施方式中,所述组合物选择性地靶向癌细胞。
在一些进一步的实施方式中,MMR蛋白包含MutL同源物1(MLH1)蛋白,并且其中MMR蛋白(例如MLH1蛋白)的降解,通过经由procaspase-3活化剂的caspase-3活化介导,导致MMR蛋白的缺乏(即dMMR),并可以进一步诱导DNA微卫星不稳定性(MSI)和新抗原表达,从而增强免疫治疗的效果,其中procaspase-3活化剂增加癌症中的肿瘤浸润淋巴细胞。
在其他另外的实施方式中,至少一种第二活性剂是至少一种检查点抑制剂,其调节免疫响应,所述调节是通过程序性细胞死亡蛋白1(PD-1)、程序性死亡配体1(PD-L1)、细胞毒性T-淋巴细胞相关蛋白4(CTLA-4)、T细胞免疫球蛋白和含粘蛋白结构域3(TIM-3)、淋巴细胞活化基因3(LAG-3)、肿瘤坏死因子受体超家族成员4(TNFRSF4或OX40)、肿瘤坏死因子受体超家族成员9(TNFRSF9或4-1BB)、糖皮质激素诱导的TNFR相关蛋白(GITR)、诱导性T细胞共刺激剂(ICOS)或其组合进行的。
在各种另外的实施方式中,所述第二活性剂调节吲哚胺-吡咯2,3-双加氧酶(IDO)、腺苷A2A受体(A2AR)、转化生长因子β(TGF-β)、CXC趋化因子受体4型(CXCR-4)、C-C趋化因子受体4型(CCR4)、肿瘤坏死因子受体(CD27)、白细胞介素2受体亚基β(CD122)、死亡受体5(DR5)、凋亡蛋白抑制剂(IAP)、谷氨酰胺酶、集落刺激因子1受体(CSF1R)、toll样受体(TLR)、树突细胞(DC)或其组合。
在更进一步的实施方式中,所述第二活性剂是ADXS11-001,ADXS31-142,AMP-224,AMP-514,阿特利姆单抗(atezolimumab),阿特利珠单抗(atezolizumab),阿维鲁单抗(avelumab),贝伐珠单抗(bevacizumab),西米普利单抗(cemiplimab),BLZ945,BMS-936559,BMS986016,BMS986156,BMS986205,CB839,CIMAvax,CMP001,CP870893,CPI-444,CRS207,CV301,DC疫苗,DNX2401,DS-8273a,德瓦鲁单抗(durvalumab),艾卡哚司他单抗(epacadostat),FAZ053,FPA008,GDC0919,GSK3174998,GVAX,GWN323,IMCgp100,IMP321,imprime PGG,因哚西单抗(indoximid),易普利姆单抗(ipilimumab),JTX-2011,LAG525,LCL161,LK-301,LY2157299,LY2510924,LY3022855,MBG453,MEDI0562,MEDI0680,MEDI6469,MEDI9447,MGN1703,莫格利珠单抗(mogamulizumab),MOXR0916,新抗原疫苗,NEO-PV-01,NIS793,纳武单抗(nivolumab),NKTR-214,PBF509,PDR001,帕博利珠单抗(pembrolizumab),多肽疫苗,培西达替尼(pexidartinib)(PLX3397),PF-04518600,PF-3512676,REGN2810,REGN3767,RO7009789,SD101,他利莫近-拉赫(talimogenelaherparepvec),TPIV200/huFR-1,曲美利木单抗(tremelimumab),TroVax,TSR022,乌洛鲁单抗(ulocuplumab),乌瑞芦单抗(urelumab),乌托鲁单抗(utomilumab),伐立鲁单抗(varlilumab),维阿基普-L(viagenpumatucel-L)(HS-110),或其组合。
在其他实施方式中,所述检查点抑制剂是anti-PD-1、anti-CTLA-4或其组合;其中anti-PD-1是纳武单抗(nivolumab)或帕博利珠单抗(pembrolizumab),anti-CTLA-4是易普利姆单抗(ipilimumab)或曲美利木单抗(tremelimumab),或其组合。
在一些实施方式中,所公开的组合物包含药学上可接受的稀释剂、赋形剂、载体或其组合。在所公开组合物的其他实施方式中,a)载体包含水、缓冲剂、糖、纤维素、环糊精、二甲亚砜、聚乙二醇、生育酚、脂质体、胶束或其组合,或b)赋形剂包括粘合剂、润滑剂、吸附剂、赋形剂、崩解剂、防腐剂或其组合。
在各种其他实施方式中,PAC-1的浓度为约0.1μM至约50μM。在其他实施例中,PAC-1的浓度为约0.1μM至约1μM、约1μM至约10μM、约2μM至约15μM、约3μM至约20μM,约4μM至约25μM,约5μM至约30μM,约10μM至约40μM,约15μM至约50μM,或约0.01μM至约100μM。
在另外的实施方式中,所述第二活性剂的浓度为约1nM至约100μM。在其他实施方式中,所述第二活性剂的浓度为约1nM至约100nM、约10nM至约1μM、约100nM至约1μM、约1μM至约5μM、约1μM至约10μM,约5μM至约15μM,约10μM至约20μM,约10μM至约30μM,约15μM至约40μM,约20μM至约50μM,或约50μM至约100μM。
在进一步的实施方式中,本文公开的组合物选择性靶向癌细胞,其中癌细胞是下述癌症的细胞:膀胱癌、乳腺癌、结肠癌、子宫内膜癌、胶质母细胞瘤、白血病、肝癌、肺癌、淋巴瘤、黑色素瘤、脑膜瘤、多发性骨髓瘤、卵巢癌、骨肉瘤、胰腺癌、前列腺癌、肾癌或甲状腺癌;其中乳腺癌任选地为三阴性乳腺癌,肺癌任选地为非小细胞肺癌,并且肾癌任选地为转移性肾细胞癌。
本公开还提供了一种抑制癌细胞生长或增殖的方法,包括使癌细胞与有效量的公开组合物接触,从而抑制癌细胞的生长或增殖。在其他实施方式中,通过抑制错配修复(MMR)蛋白来抑制癌细胞的生长或增殖。在进一步的实施方式中,癌细胞的生长或增殖受到半胱天冬酶3活化介导的MutL同源物1(MLH1)蛋白降解的抑制。在其他实施方式中,诱导了DNA微卫星不稳定性(MSI)。
本公开还提供了一种在癌细胞中诱导细胞凋亡的方法,包括使癌细胞与有效量的本文公开的组合物接触,其中通过抑制癌细胞中的错配修复(MMR)蛋白从而诱导细胞凋亡。在其他实施方式中,MutL同源物1(MLH1)蛋白的降解是经由procaspase-3活化剂的caspase-3活化介导,从而诱导癌细胞凋亡。
此外,本公开提供了一种治疗癌症的方法,包括向有需要的受试者同时或依次施用治疗有效量的procaspase-3活化剂和有效量的第二活性剂,其中所述第二活性剂是免疫治疗剂;其中所述第二活性剂的作用经由procaspase-3活化剂的施用而得以增强。
在其他另外的实施方式中,procaspase-3活化剂是PAC-1,或其中procaspase-3活化剂的分子量为约200至约800、约250至约550、约300至约600、约350至约550,或约350至约450,其中procaspase-3活化剂直接将procaspase-3活化为caspase-3。
在进一步的实施方式中,所述第二活性剂包括检查点抑制剂、癌症疫苗、代谢调节剂、巨噬细胞抑制剂、免疫刺激剂或调节剂,或其组合。
在各种实施方式中,MutL同源物1(MLH1)蛋白的caspase-3降解诱导DNA微卫星不稳定性(MSI)和新抗原表达,从而提高癌症治疗的有效性。在其他实施方式中,错配修复(MMR)蛋白被procaspase-3活化剂抑制。在进一步的实施方式中,procasepase-3活化剂,例如PAC-1,增加癌症(或癌细胞)中的肿瘤浸润淋巴细胞(TIL)。
在各种其他实施方式中,免疫治疗剂是检查点抑制剂,其调节免疫响应,所述调节是通过程序性细胞死亡蛋白1(PD-1)、程序性死亡配体1(PD-L1)、细胞毒性T-淋巴细胞相关蛋白4(CTLA-4)、T细胞免疫球蛋白和含粘蛋白结构域3(TIM-3)、淋巴细胞活化基因3(LAG-3)、肿瘤坏死因子受体超家族成员4(TNFRSF4或OX40)、肿瘤坏死因子受体超家族成员9(TNFRSF9或4-1BB)、糖皮质激素诱导的TNFR相关蛋白(GITR)、诱导性T细胞共刺激剂(ICOS)或其组合进行的。
在其他各种实施方式中,所述第二活性剂是阿特利姆单抗(atezolimumab)、阿维鲁单抗(avelumab)、贝伐珠单抗(bevacizumab)、BMS986016、BMS986156、CP870893、德瓦鲁单抗(durvalumab)、FAZ053、GSK3174998、GWN323、IMP321、伊匹单抗(ipilimumab)、JTX-2011,LAG525,MBG453,MEDI0562,MEDI0680,MEDI6469,MOXR0916,纳武单抗(nivolumab),PDR001,帕博利珠单抗(pembrolizumab),PF-04518600,REGN2810,REGN3767,RO7009789,曲美利木单抗(tremelimumab),TSR022,乌瑞芦单抗(urelumab),乌托鲁单抗(utomilumab),或其组合。
在各种另外的实施方式中,PAC-1的浓度为约0.1M至约50M,而且所述第二活性剂的浓度为约1nM至约100M。在进一步的实施方式中,PAC-1的浓度为约1至约10M。在其他实施例中,所述第二活性剂的浓度为约1nM至约1M。
在各种实施方式中,如本领域技术人员容易认识到的,本公开通篇所述的PAC-1和第二活性剂的浓度也可以被列举并解释为PAC-1与第二活性剂的比率,例如,通过将本文所述的浓度转化为相应的PAC-1与第二活性剂的摩尔比。
在各种其他实施方式中,所述癌症是膀胱癌、乳腺癌、结肠癌、子宫内膜癌、胶质母细胞瘤、白血病、肝癌、肺癌、淋巴瘤、黑色素瘤、脑膜瘤、多发性骨髓瘤、卵巢癌、骨肉瘤、胰腺癌、前列腺癌、肾癌或甲状腺癌;其中乳腺癌任选地为三阴性乳腺癌,肺癌任选地为非小细胞肺癌,并且肾癌任选地为转移性肾细胞癌。
在一些不同的实施方式中,化合物PAC-1和第二活性剂同时施用于受试者。在其他实施方式中,化合物PAC-1和第二活性剂依次施用于受试者。在另外的实施方式中,化合物PAC-1在第二活性剂之前施用于受试者。在进一步的实施方式中,化合物PAC-1在第二活性剂之后施用于受试者。
此外,本公开提供了一种用于制备用于治疗癌症的药物的组合物,该组合物包含:
(a)化合物PAC-1;
(b)至少一种第二活性剂,其中所述第二活性剂是检查点抑制剂、癌症疫苗、代谢调节剂、巨噬细胞抑制剂或免疫刺激剂或调节剂;以及
(c)任选的药学上可接受的稀释剂、赋形剂、载体或其组合;其中癌症由此得到治疗。
在另外的实施方式中,PAC-1的浓度为约0.1M至约500M,并且所述第二活性剂的浓度为约1nM至约1000M。在其他另外的实施方式中,所述第二活性剂是阿特利姆单抗(atezolimumab)、阿维鲁单抗(avelumab)、贝伐珠单抗(bevacizumab)、德瓦鲁单抗(durvalumab)、易普利姆单抗(ipilimumab)、纳武单抗(nivolumab)、帕博利珠单抗(pembrolizumab)、曲美利木单抗(tremelimumab)、乌瑞芦单抗(urelumab)、乌托鲁单抗(utomilumab)或其组合。在更进一步的实施方式中,癌症是淋巴瘤、黑色素瘤、白血病、多发性骨髓瘤、胶质母细胞瘤、胰腺癌、肝癌、非小细胞肺癌、乳腺癌、卵巢癌、结肠癌、骨肉瘤或脑膜瘤。
在各种实施方式中,化合物PAC-1和第二活性剂施用于受试者每天一次(q.d.),每天两次(b.i.d.),每天三次(t.i.d.)或每天四次(q.i.d.),其中PAC-1的每日总施用剂量为约1mg/kg至约150mg/kg,约10mg/kg至约125mg/kg,或约5mg/kg至约250mg/kg。在其他实施方式中,PAC-1(或第二活性剂)的各个施用剂量为约10mg,约25mg,约50mg,约60mg,约70mg,约75mg,约175mg,约250mg,约375mg,约450mg,约500mg,约625mg,约750mg,约1000mg,或者约10mg至约2000mg。在进一步的实施方式中,PAC-1(或第二活性剂)的各个施用剂量为约50mg/m2至约250mg/m2,或约10mg/m2至约500mg/m2。在一些其他实施方式中,第二活性剂的每日总施用剂量为约1mg/kg至约100mg/kg,或约5mg/kg至约150mg/kg。
在一些实施方式中,给予需要治疗癌症的患者的组合物包含PAC-1和α-PD-1,其中PAC-1的用量为约100mg/kg至约150mg/kg(或约125mg/kg)以及α-pd-1的用量为约150微克至约250微克(或约200微克);在各种实施方式中,与对照相比,患者的存活率延长。
本文描述了诸如体积、质量、百分比、比率等的变量的范围、极限和偏差。本领域普通技术人员应理解,诸如“数目1”至“数目2”的范围表示连续的数字范围,其包括整数和小数。例如,1到10表示1,2,3,4,5,……,9,10,它也表示1.0,1.1,1.2.1.3,……,9.8,9.9,10.0,还表示1.01,1.02,1.03,依此类推。如果所公开的变量是小于“数目10”的数字,则这意味着包括小于数目10的整数和分数的连续范围,如上所述。类似地,如果公开的变量是大于“数目10”的数字,则表示包含大于数目10的整数和分数的连续范围。这些范围可以由术语“约”修饰,其含义前面已有描述。
结果和讨论
涉及检查点抑制剂的免疫疗法已成为某些癌症(例如,黑色素瘤,NSCLC,尿路上皮)的有效治疗,具有诱导癌症患者亚群中的耐用反应的能力。现在有几十中涉及免疫检查点抑制剂和小分子药物的综合试验。直接procaspase-3活化的机制假设通过增强关键DNA错配修复蛋白MLH1的裂解而显著增强了免疫检查点抑制剂的功效,导致如本文所述对T细胞靶向的潜在新抗原的探讨的增加。
方法背景:涉及免疫检查点抑制剂的免疫疗法的相当程度的许诺已被许多临床试验中较低比率响应者以及失败而受到打击。最近的一个重要进展是DNA微卫星不稳定性(MSI)作为生物标志物的临床批准,用于PD-1抑制(与帕博利珠单抗(pembrolizumab))无论致瘤起因的临床疗效。该批准是基于相当大的临床前和临床数据,其表明错配修复缺陷(dMMR)预测实体肿瘤对PD-1封闭的响应,由于已知,带有dMMR/MSI的肿瘤具有100s至1000s体细胞突变(somatic mutations)(10倍高于MMR表达癌症,图1A),大概导致新抗原的升高和T细胞浸润的增强。然而,dMMR/MSI对应的癌症百分比较低,可能不到10%。零星的MSI由MLH1启动子的表观遗传沉默驱动,并且MLH1沉默通常用作MMR缺乏的标志。在许多研究中已经证明MLH1沉默和体细胞突变数量的相关性,其显著呈现于图1。
在癌细胞中选择性地诱导的MSI基本上升高了对免疫检查点抑制剂(例如,靶向PD-1和CTLA-4)的患者反应。具刺激性的,多个大的蛋白质组学研究表明,MLH1是用于caspase-3的顶级底物,其6小时后剩余0%的蛋白质(相较于MEK1/2,其在同一时间点留存70%)。此外,MLH1只是活性caspase-3的底物,没有观察到其他活性caspase(即caspase-1,2,6,7,8)的蛋白水解(即caspase-1,2,6,7,8)。该数据表明,肿瘤中PC-3的选择性活化可能导致MLH1的定量裂解,导致dMMR/MSI,从而显著增加了免疫检查点抑制剂的功效;如图2所概述的。
活动机理:本文内容显示,PAC-1可用于选择性地诱导癌症中的MLH1切割,从而使它们更容易用免疫检查点抑制剂治疗(图2)。此外,用PAC-1处理诱导应力响应,从而改变肿瘤微环境以增加免疫炎症的程度。这样就能使将免疫疗法的效力—急剧和持久的反应—带给更多的癌症患者。总之,通过caspase-3进行MLH1裂解和失活,可活化先天免疫系统,并导致两点突变和诱导(由衍生自新开放阅读框的新抗原),这将是免疫原性的。因此,这种化学诱导的MLH1降解增强了抗癌免疫应答。
结果:关于结肠癌细胞系的MSS/MSI状态已有报道(Ahmed,D.,et al.,Oncogenesis 2013,2,e71),允许选择HT-29,一种MSS结肠癌细胞系。迄今为止,专注于MLH1裂解的研究已经采用了广泛诱导高水平凋亡细胞死亡(即用星形孢菌素(staurosporine))的策略。HT-29细胞用亚致死PAC-1处理。如图3所示,PAC-1治疗HT-29细胞诱导PC-3活化和MLH1切割,但在这些时间和浓度下极少到完全没有PARP-1裂解。该结果进一步验证了MLH1作为Caspase-3的优异底物;重要的是,在这些实验中使用的PAC-1的浓度是在人类癌症患者中可持续几周(450mg,Cmin=3.2 M,Cmax=7.8M)。
此外,进行了在同系GL261和B16F10小鼠模型中的实验,其表明单药PAC-1增加了TILs(CD3+细胞)的数量(图4)。
有关PAC-1的大量数据表明它不会在体内诱导癌症。这可见于以下研究:a)对患有癌症的宠物狗进行治疗,其中一些已经用PAC-1治疗了>6个月,并在完成治疗后>12个月维持没有次发性恶性肿瘤,b)针对大鼠和犬类详细的IND启动毒理学研究,包括84天连续治疗犬的研究,c)来自人类临床试验的数据。多个患者服用PAC-1超出了试验的2个月窗口期,其中2个已经超过10个月(每日450mg),没有不利效果。应该注意的是,癌症药物可能诱导次发性癌症,例如,用单药威罗菲尼(vemureafenib)治疗的几乎1/3患者形成次发性恶性肿瘤;但到目前为止,PAC-1尚未观察到这一点。正如PAC-1在癌细胞中诱导PC-3选择性切割,所得的Caspase-3活性应导致在癌细胞中选择性MLH1切割。值得注意的是,胶质瘤息肉病综合征(Turcot综合征)是结构性错配修复缺陷(CMMRD)易患癌综合征,与MMR基因中的双态等位基因种系突变相关,导致GBM在年轻时的发展。Tutcot综合征和其他CMMRD综合征(即Lynch综合征)指向维持MMR蛋白功能的重要性,暗示在非靶向的泛生物方式中诱导MLH1切割/损失不是可行的治疗策略。然而,具有PAC-1的策略利用PC-3在癌细胞(包括GBM)中的众所周知的过表达,从而导致肿瘤中的靶向MLH1切割,使得MMR蛋白在正常细胞中的作用不受干扰。
药物制剂
本文所述的化合物可用于制备治疗性药物组合,例如,通过将所述化合物与药学上可接受的稀释剂、赋形剂或载体组合。所述化合物可以以盐或溶剂合物的形式加入到载体中。例如,在化合物具有足够碱性或酸性以形成稳定的无毒酸或碱盐的情况下,以盐形式施用所述化合物可能是合适的。药学上可接受的盐的实例为与形成生理学上可接受的阴离子的酸形成的有机酸加成盐,例如甲苯磺酸盐,甲磺酸盐,乙酸盐,柠檬酸盐,丙二酸盐,酒石酸盐,琥珀酸盐,苯甲酸盐,抗坏血酸盐,α-酮戊二酸盐和-甘油磷酸盐。也可以形成合适的无机盐,包括盐酸盐,卤化物,硫酸盐,硝酸盐,碳酸氢盐和碳酸盐。
药学上可接受的盐可以使用本领域公知的标准方法获得,例如通过使足够碱性的化合物例如胺与合适的酸反应以提供生理上可接受的离子化合物。羧酸的碱金属(例如钠,钾或锂)或碱土金属(例如钙)的盐也可以用类似的方法制备。
本文所述式的化合物可以配制成药物组合并以多种形式施用于哺乳动物宿主,例如人类患者。所述形式可以特别适合于选择的给药途径,例如口服或者通过静脉内、肌肉内、局部或皮下途径的肠胃外给药。
本文所述的化合物可以与药学上可接受的载体(例如惰性稀释剂或可吸收的可食用载体)一起全身给药。对于口服给药,可将化合物封装在硬或软壳胶囊中,压成片剂,或直接掺入患者饮食的食物中。所述化合物还可以与一种或多种赋形剂组合,并以可消化片剂,口腔片剂,锭剂,胶囊剂,酏剂,混悬剂,糖浆剂,糯米纸囊剂等的形式使用。这样的组合物和制剂通常含有至少0.1%的活性化合物。组合物和制剂的百分比可以变化,并且可以方便地为设定单位剂型重量的约0.5%至约60%,约1%至约25%或约2%至约10%。这种治疗上有用的组合物中的活性化合物的量可以是使得达到有效剂量水平。
片剂,锭剂,丸剂,胶囊剂等也可以含有一种或多种以下物质:粘合剂,如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,如磷酸二钙;崩解剂,如玉米淀粉、马铃薯淀粉、海藻酸等;;以及润滑剂,如硬脂酸镁。可以添加甜味剂,如蔗糖、果糖、乳糖或阿斯巴甜;或调味剂,如薄荷、冬青油或樱桃调味料。当单位剂型是胶囊时,除了上述类型的材料之外,它还可以含有液体载体,例如植物油或聚乙二醇。各种其他材料可作为包衣或以其他方式改变固态单位剂型的物理形式。例如,片剂、丸剂或胶囊剂可以包覆有明胶、蜡、虫胶或糖等。糖浆或酏剂可含有活性化合物,作为甜味剂的蔗糖或果糖,作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯,染料和诸如樱桃或橙调味料的调味剂。用于制备任何单位剂型的任何材料应该是药学上可接受的,并且在所述用量上基本上无毒。另外,可将活性化合物掺入缓释制剂和装置中。
所述活性化合物可通过输液或注射经静脉内或腹膜内给药。所述活性化合物或其盐的溶液可以在水中制备,可选择地与无毒表面活性剂混合。分散体可以在甘油、液体聚乙二醇、甘油三乙酸酯或其混合物中或在药学上可接受的油中制备。在普通的储存和使用条件下,制剂可含有防腐剂以防止微生物的生长。
适用于注射或输注的药物剂型可以包括无菌水溶液、分散体或无菌粉末,其包含适合即时制备无菌可注射或输注溶液或分散体的活性成分,可选择地包封在脂质体中。最终的剂型应该是无菌的、流体的以及在制造和储存的条件下稳定的。液体载体或赋形剂可以是溶剂或液态分散介质,包含例如水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油、无毒甘油酯和其合适的混合物。例如,适合的流动性能可以通过形成脂质体,通过在分散体的情况下维持所需的粒度,或通过使用表面活性剂来维持。对微生物作用的防止可以通过各种抗菌剂和/或抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等来实现。在许多情况下,优选地可以包括等渗剂,例如糖、缓冲剂或氯化钠。可注射组合物的延长吸收可通过使用延缓吸收的试剂,例如单硬脂酸铝和/或明胶。
无菌可注射溶液的制备可以是通过将所需量的活性化合物与上文列举的各种其它成分(如果需要)合并在适当的溶剂中,并且根据需要可选择地随后过滤除菌来进行。在采用制备无菌注射溶液的无菌粉末的情况下,制备方法可以包括真空干燥和冷冻干燥技术,其形成活性成分加上在溶液中需要的任何额外成分的粉末。
对于局部给药,所述化合物可以以纯净形式使用,例如当它们是液体时。然而,通常期望以例如与皮肤学上可接受的载体组合的组合物或制剂的形式将活性剂施用到皮肤,而所述载体可以是固体、液体、凝胶等。
可用的固体载体包括细碎的固体,如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。可用的液体载体包括水、二甲基亚砜(DMSO)、醇、二醇或水-醇/二醇混合物,其中化合物能够以有效的浓度溶解或分散,可选择地借助于无毒的表面活性剂。辅助剂如香料和其他抗微生物剂也可添加用以针对给定用途进行性能优化。所得的液体组合物可以从吸收垫施用,用于浸渍绷带和其它敷料,或者使用泵式或气溶胶喷雾器喷射到患处。
增稠剂,例如合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性矿物材料,也可与液体载体一起使用,以形成可涂抹的糊剂,凝胶剂,软膏剂,皂剂等,以直接施用到使用者的皮肤。
用于将活性剂递送至皮肤的皮肤病学组合物的实例是本领域已知的;例如,参见美国专利号4,992,478(Geria),4,820,508(Wortzman),4,608,392(Jacquet et al.),和4,559,157(Smith et al.)。此类皮肤病学组合物可以与本文所述的化合物组合使用,其中此类组合物的成分可以任选地被本文所述的化合物替代,或者可以将本文所述的化合物添加至所述组合物中。
本文所述化合物的有用剂量可通过比较其体外活性和动物模型中的体内活性来确定。用于将小鼠和其它动物中的有效剂量外推至人类的方法是本领域已知的;例如参见美国专利4,938,949(Borch et al.)。用于治疗所需的化合物或其活性盐或衍生物的量将不仅随着所选择的具体化合物或盐而变化,而且随着给药途径,被治疗的病症的性质以及患者的年龄和状况,最终由门诊医师或临床医师决定。
然而,通常活性剂的合适剂量可以是约0.5至约100mg/kg,例如约10至约75mg/kg体重每天,例如约3至约50mg每天每公斤接受者体重,优选6至90mg/kg/天,最优选15至60mg/kg/天。
所述化合物可以方便地施用为单位剂量形式,例如,每单位剂型含有活性成分5至1000mg,方便地10至750mg,最方便地50至500mg。在一种实施方式中,本发明提供了包含以这种单位剂型配制的本发明化合物的组合物。
所述化合物可以方便地施用为单位剂量形式,例如,每单位剂型含有活性成分5to1000mg/m2,方便地10to 750mg/m2,最方便地50to 500mg/m2。所需剂量可以方便地以单剂量或以适当间隔例如每天二、三、四或更多个亚剂量施用的分剂量存在。所述亚剂量本身可以进一步分为例如多个离散的松散间隔的给药。
期望的剂量可以方便地配制为单剂量,或者以分开剂量用于合适的时间间隔,例如每天二、三、四或更多个亚剂量。所述亚剂量本身还可以进一步分开,例如分成多个各自大致分隔的给药;例如从吹药器多次吸入或通过将多滴药液滴入眼中。
与单独的免疫疗法或其他癌症治疗相比,本文所述的化合物可以是有效的抗肿瘤剂,并且具有更高的效力和/或降低的毒性。
本发明提供了在哺乳动物中的癌症治疗方法,其包括对患有癌症的哺乳动物施用有效量的本文所述的化合物或组合物。所述哺乳动物包括灵长类动物,人类,啮齿动物,犬,猫,牛,羊,猪,猪,山羊,牛,脊椎动物等。所述癌症是指任何各种类型的恶性肿瘤,例如结肠癌,乳腺癌,卵巢癌,骨肉瘤,黑色素瘤和白血病,并且通常特征在于不良细胞增殖,例如细胞生长不受控制,分化不足,局部组织浸润和转移。
本发明化合物治疗癌症的能力可以通过使用本领域周知的测定法来确定。例如,治疗方案的设计,毒性评估,数据分析,肿瘤细胞杀伤的定量以及使用可移植肿瘤筛查的生物学意义是已知的。另外,化合物治疗癌症的能力可以使用如下所述的测试确定。
以下实施例是用来对上述发明内容进行说明,而不应被解释为缩小发明的范围。本领域技术人员应很容易的认识到所述实施例能够提示本发明可以通过很多其他方法来实施。应当理解,在本发明的范围内可以进行很多的变化和修改。
实施例
实施例1.有关4T1疗效模型的实验程序。
试剂:从Bio X Cell购得以下抗体:抗小鼠CTLA-4单克隆抗体(anti-mouse CTLA-4monoclonal antibody,9H10),抗小鼠PD-1单克隆抗体(anti-mouse PD-1monoclonalantibody,RMP1-14),大鼠IgG2A同型对照(rat IgG2a isotype control,2A3)以及多克隆Syrian仓鼠IgG(polyclonal Syrian hamster IgG)。
细胞系:从ATCC获得4T1鼠乳腺癌细胞系,并在CO2培养箱中于37℃在含有10%FBS、100U/mL青霉素、100μg/mL链霉素的完全RPMI1640中培养。
4T1原位肿瘤模型:所有的实验程序均获得the Institutional Animal Care andUse Committee at the University of Illinois at Urbana-Champaign的批准。6-8周龄的雌性BALB/c小鼠从Charles River购买,允许适应7天。用羟嗪(16mg/kg)和氯胺酮(100mg/kg)腹腔注射对小鼠进行轻度镇静。镇静后,将冷冻过的HBSS(1000万细胞/mL)中的100μL 4T1细胞注入小鼠右第二乳腺。一周后原位生长肿瘤建立。接种4T1细胞后12天,荷瘤小鼠随机分为4个治疗组:载体+同型(vehicle+isotypes)、载体+anti-PD-1/anti-CTLA-4、PAC-1+同型、PAC-1+anti-PD-1/anti-CTLA-4(n=6)。PAC-1是用HPβCD(10mg/mL在200mg/mLHPβCD中,pH 5.5)配制。
所有抗体在无菌PBS(pH 7.0)中稀释至适当浓度。载体或100mg/kg PAC-1连续5天腹膜内施用,持续3周。在肿瘤植入后第13、16、20和23天,在PAC-1后4小时腹膜内施用同型或10mg/kg anti-PD-1+10mg/kg anti-CTLA-4抗体。使用卡尺每2或3天进行一次肿瘤测量,并使用公式(0.5×l×w2)计算肿瘤体积。在4T1细胞接种后第30天,灭杀小鼠。然后切除肿瘤,并测量它们的质量。所有统计分析均使用未配对的双尾Student’s检验进行,p值<0.05被认为具有统计学意义(见图6)。
实施例2.肿瘤研究
PAC-1治疗的GL261肿瘤中增加的免疫细胞浸润:除了数据显示PAC-1诱导癌细胞中caspase-3介导的MLH1裂解外,还有许多其他证据支持PAC-1与免疫治疗策略(包括检查点抑制剂和新抗原疫苗)的协同组合:1)PAC-1处理的癌细胞的转录谱显示关键基因包括TNFα、先天免疫系统激动剂IL-1和IL-8的上调,并且与anti-PD-1抗性相关的标志物没有上调疗法(IPRES:例如CCL2、CCL7、CCL8、CCL13等)。2)另一研究组的工作表明,PAC-1可以通过与免疫细胞因子TRAIL的组合研究来增强培养物中的外在细胞死亡。3)PAC-1在具有完整免疫系统的体内环境中有效,包括同系小鼠(EL4、K7M2、GL261)(图7)和大鼠(9L)模型,以及犬类癌症患者。4)MD Anderson的Gandhi研究组(Blood2015,125,1126)表明PAC-1及其衍生物对PMBC的毒性最小。5)尚未观察到PAC-1诱导骨髓抑制(在小鼠、大鼠、狗或人类中),即使在IND启用的大鼠和狗的研究中以非常高的剂量使用。6)PAC-1选择性地在癌细胞中引起DNA损伤,进一步验证研究表明caspase-3活化可导致显著的基因组不稳定性。作为探索PAC-1刺激免疫反应潜力的开始,在同基因GL261小鼠模型中进行了一项实验,该实验表明单药PAC-1增加了TIL(CD3+细胞)的数量(图4)。
犬类神经胶质瘤免疫检查点的相关性:最近的研究已经确定了PD-L1在各种犬类肿瘤类型中的表达。然而,没有已发表的研究描述了犬类神经胶质瘤中的PD-L1。使用存档的犬类神经胶质瘤肿瘤,验证了商用小鼠单克隆抗人PD-L1抗体(Abcam,克隆ABM4E54)(图5)的交叉反应性,并证明PD-L1在75%的肿瘤中表达;这个频率与人类GBM相当,其中PD-L1分别在88%和72%的原发和复发样本中被识别出来。除PD-L1外,抗体已被证实与人类和犬类神经胶质瘤细胞系中的核靶标MLH1发生交叉反应,并允许人们在PAC-1治疗后定量评估MLH1裂解。
实施例3.同系结肠癌模型(CT-26细胞)中的PAC-1和免疫疗法
图8说明了CT-26WT皮下疾病模型在BALB/c小鼠中的发展。在第0天,BALB/c小鼠被皮下注射1x106 CT-26_WT细胞。在不同的天数间隔内,对选定的小鼠注射(i.p.)空白载体、PAC-1(100mg/kg)、anti-PD-1抗体(10mg/kg;2剂)、anti-PD-1抗体(10mg/kg;4剂),或PAC-1(100mg/kg)和anti-PD-1抗体(10mg/kg)的组合,如表1所示。
表1.BALB/c小鼠治疗方案(表中:Ear tag(耳标),Treatment comb’n(治疗组合),#of mice(小鼠数量))
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图9显示单一药剂PAC-1在控制BALB/c小鼠的sc CT-26_WT生长方面表现出很大的变化。此外,相较于载体+anti-IgG对照(vehicle+anti-IgG control),PAC-1和anti-PD-1mAb的组合显著降低了BALB/c小鼠中CT-26_WT的生长。图10说明相较于对照小鼠(注射空载体+anti-IgG抗体,即empty vehicle+anti-IgG antibody),PAC-1和anti-PD-1单克隆抗体(monoclonal antibody,mAb)的组合降低了BALB/c小鼠中CT-26_WT细胞的生长。当anti-PD-1mAb的剂量从4剂减少到2剂时,PAC-1在这种联合治疗中的相对贡献更加明显。这些实验还表明,第14天和第21天是进行TIL分析的好时间点。
图11描述BALB/c小鼠中CT-26_TdTomato皮下肿瘤模型的发展。在小鼠后胁部皮下接种1x106CT-26_TdTomato细胞。接种后十天(肿瘤体积~150mm3),小鼠接受以下处理:
第1组:3只小鼠-载体+大鼠IgG同型mAb(10mg/kg)(vehicle+rat IgG isotypemAb)
第2组:3只小鼠-PAC-1(125mg/kg)+大鼠IgG同型mAb(10mg/kg)(PAC-1(125mg/kg)+rat IgG isotype mAb(10mg/kg))
第3组:3只小鼠-载体+anti-PD1 mAb(10mg/kg)(vehicle+anti-PD1 mAb(10mg/kg))
第4组:3只小鼠-PAC-1(125mg/kg)+anti-PD1 mAb(10mg/kg)(PAC-1(125mg/kg)+anti-PD1 mAb(10mg/kg))
第4组(PAC-1+anti-PD1 mAb)中的BALB/C小鼠在连续5天的PAC-1治疗和2次anti-PD1给药后能够排斥CT-26-TdT。在第47天,小鼠仍然没有肿瘤。anti-PD1治疗组在注射3次anti-PD1 mAb后能够清除肿瘤。在第47天,小鼠仍然没有肿瘤。在第47天,仍无肿瘤的小鼠再次受到1x106 CT-26_TdTomato细胞的攻击。再次攻击后未观察到肿瘤体积的显著增加。
图12A描述细胞因子阵列,表明PAC-1具有免疫原性并导致促进巨噬细胞分化以及B细胞和T细胞增殖的细胞因子增加。如图12B所示,通过眼眶后血液提取在肝素化小瓶中收集了~100ul的血液。白细胞以8000g离心10分钟,血浆/血清被转移到新管中。使用来自2-3只小鼠的混合样本对4组进行细胞因子阵列操作:
无瘤+载体
无瘤+PAC-1(x5剂量)
荷瘤+载体
荷瘤+PAC-1(x5剂量)
信号是采用ImageJ进行量化。如图所示,通过计算PAC-1/载体平均像素密度的比率对数据进行标准化。
图13描述在肿瘤攻击后第14天,PAC-1治疗后肺肿瘤微环境中的嗜中性粒细胞和巨噬细胞显示增加。在第26天,肿瘤微环境中的巨噬细胞和树突细胞数量减少了。
图14描述在联合PAC-1和anti-PD-1治疗后第26天肺肿瘤微环境中CD4+Th细胞的增加。肺中FoxP3+Treg的百分比在联合治疗组中最低。
图15说明了树突状细胞和CD45-(肿瘤)细胞上的PD-L1表达在肿瘤攻击后第26天增加,并且可能导致T细胞耗竭。
实施例4.同系结肠癌模型(MC-38细胞)中的PAC-1和免疫疗法
图16描述C57BL/6小鼠中MC-38转移模型的发展和PAC-1与anti-PD-1抗体的组合治疗。MC-38细胞通过尾静脉注射,1x106细胞/小鼠。在MC38注射后的23天内,PAC-1以100mg/kg注射(i.p.),anti-PD-1以10mg/kg注射(i.p.)。注射PAC-1/anti-PD-1治疗组合的小鼠的体重从大约第24天开始显著恢复,一直增加到第32天。
图17示出了用MC-38细胞攻击后的小鼠的存活曲线,后来注射空载体对照、PAC-1、anti-PD-1抗体或PAC-1和anti-PD-1抗体的组合。这些结果表明,对于注射PAC-1和anti-PD-1抗体的小鼠约32天后表明了稳定的存活概率。
实施例5.药物剂型
下述制剂描述了能够用于本文所述化合物组合,本文具体公开的化合物或其药学上可接受的盐(下文称为“组合物X”):
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这些制剂可以通过制药领域公知的常规方法制备。应当理解,上述药物组合可根据公知的制药技术进行改变,以适应不同量和不同类型的活性成分“化合物X”。气雾剂(vi)可以与标准计量喷雾器结合使用。另外,具体的成分和比例只是用来进行说明。根据需要的剂型的期望的性质,具体成分可以用合适的等价物(例如上述成分)替代,并且比例也可以改变。
文中描述了上述的一些实施方式和实施例,但这些描述都只是示意和说明性的,对本发明的范围不产生限制作用。根据本领域的普通技术可能进行一些改变和修饰,然而并不脱离本发明由下列权利要求所定义的较为宽泛的范围。
所有的出版物、授权专利和专利申请文献均通过参考纳入文本,就如各自单独通过参考纳入本文那样。由这些公开物,应当不会引入与本文公开内容不一致的限制。本发明的描述引述了各种特定和优选的实施方式和技术方案。应当理解,还有许多变化和修饰可被采纳,仍然都应属于本发明的精神和范围。
Claims (11)
1.一种组合物,包括:
(a) PAC-1;
(b) anti-PD-1抗体,其为RMP1-14;以及
(c)任选的药学上可接受的稀释剂、赋形剂或载体;
其中PAC-1的浓度为1µM至10µM,所述anti-PD-1抗体的浓度为1nM至1µM。
2. 根据权利要求1所述的组合物,其包含药学上可接受的稀释剂、赋形剂或载体,其中a)所述载体包括水、缓冲剂、糖、纤维素、环糊精、二甲亚砜、聚乙二醇、生育酚、脂质体、 胶束或其组合,或者 b) 所述赋形剂包括粘合剂、润滑剂、吸附剂、溶媒辅剂、崩解剂、防腐剂,或其组合。
3.根据权利要求1所述的组合物,其中所述组合物选择性靶向癌细胞,其中所述癌细胞是下述癌症的细胞:结肠癌或骨肉瘤。
4.一种组合物在制备抑制癌细胞生长或增殖的药物中的用途,其中所述药物是用来使癌细胞与有效量的组合物接触,从而抑制结肠癌或骨肉瘤癌细胞的生长或增殖,其中所述组合物包含治疗有效量的PAC-1和治疗有效量的第二活性剂,其中所述第二活性试剂是anti-PD-1抗体,其中所述anti-PD-1抗体的作用是通过施用所述PAC-1增强,并且其中所述PAC-1与所述anti-PD1抗体协同作用,所述PAC-1的浓度为1µM至10µM,所述anti-PD-1抗体的浓度为1nM至1µM。
5.一种组合物在制备诱导结肠癌或骨肉瘤癌细胞凋亡的药物中的用途,其中所述药物是用来使癌细胞与有效量的组合物接触,其中所述组合物包含治疗有效量的PAC-1和治疗有效量的anti-PD-1抗体,其中所述anti-PD-1抗体的作用是通过施用所述PAC-1增强,并且其中所述PAC-1与所述anti-PD1抗体协同作用,所述PAC-1的浓度为1µM至10µM,所述anti-PD-1抗体的浓度为1nM至1µM。
6. 一种组合物在制备治疗结肠癌或骨肉瘤的药物中的用途,其中所述药物是用来向有需要的受试者施用所述组合物,从而能够同时或依次施用治疗有效量的PAC-1和治疗有效量的anti-PD-1 抗体, 其中anti-PD-1 抗体的作用经由PAC-1的施用而得以增强,并且其中PAC-1与所述anti-PD-1 抗体协同作用,PAC-1的浓度为1µM至10µM,所述anti-PD-1 抗体的浓度为1nM至1µM。
7. 根据权利要求6所述的用途,其中, PAC-1的每日总给药剂量为约10mg/kg至约125mg/kg,并且anti-PD-1 抗体的每日总给药剂量为约1mg/kg至约100mg/kg。
8. 根据权利要求6所述的用途,其中所述anti-PD-1 抗体是RMP1-14,阿特利姆单抗(atezolimumab),阿维鲁单抗(avelumab),德瓦鲁单抗(durvalumab),纳武单抗(nivolumab),帕博利珠单抗(pembrolizumab),或其组合。
9.根据权利要求6-8任一项所述的用途,其中:
将化合物PAC-1和anti-PD-1 抗体同时施用于受试者; 或者
将化合物PAC-1和anti-PD-1 抗体依次施用于受试者,其中化合物PAC-1是在anti-PD-1 抗体之前施用于受试者或化合物PAC-1是在anti-PD-1 抗体之后施用于受试者。
10. 根据权利要求6-8任一项所述的用途,其中将化合物PAC-1和anti-PD-1 抗体施用于受试者每日一次(q.d.),每日两次(b.i.d.),每日三次(t.i.d.)或 每日四次(q.i.d.),其中PAC-1的每日总给药剂量为约1mg/kg至约150mg/kg。
11. 一种组合物在制备治疗结肠癌或骨肉瘤的药物中的用途,其中所述药物是用来向有需要的受试者施用所述组合物,从而能够施用治疗有效量的 PAC-1 和治疗有效量的anti-PD-1 抗体,其中PAC-1是每天施用连续 21 天或更多天,使得PAC-1每天施用的总剂量为约100mg/kg至约125mg/kg,并且anti-PD-1抗体在连续21天或更长时间内施用两次或四次,其中anti-PD-1抗体的剂量约为 10 mg/kg,并且anti-PD-1 抗体各个剂量均在不同的日子施用。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20120067715A (ko) * | 2010-12-16 | 2012-06-26 | 학교법인 동의학원 | 나린제닌 및 trail을 포함하는 폐암 치료 및 예방용 조성물 |
CN104507479A (zh) * | 2012-03-06 | 2015-04-08 | 伊利诺伊大学评议会 | 通过联合治疗的半胱天冬酶-3酶原激活 |
CN108135896A (zh) * | 2015-06-05 | 2018-06-08 | 伊利诺伊大学董事会 | Pac-1联合疗法 |
WO2018213631A1 (en) * | 2017-05-18 | 2018-11-22 | The Regents Of The University Of California | Nano-enabled immunotherapy in cancer |
CN108884159A (zh) * | 2015-11-07 | 2018-11-23 | 茂体外尔公司 | 用于癌症治疗的包含肿瘤抑制基因治疗和免疫检查点阻断的组合物 |
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IN2014MN01944A (zh) * | 2012-03-06 | 2015-07-10 | Univ Illinois | |
US20170037004A1 (en) * | 2015-07-13 | 2017-02-09 | Arvinas, Inc. | Alanine-based modulators of proteolysis and associated methods of use |
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CN104507479A (zh) * | 2012-03-06 | 2015-04-08 | 伊利诺伊大学评议会 | 通过联合治疗的半胱天冬酶-3酶原激活 |
CN108135896A (zh) * | 2015-06-05 | 2018-06-08 | 伊利诺伊大学董事会 | Pac-1联合疗法 |
CN108884159A (zh) * | 2015-11-07 | 2018-11-23 | 茂体外尔公司 | 用于癌症治疗的包含肿瘤抑制基因治疗和免疫检查点阻断的组合物 |
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