CN110461324A - 用于治疗或预防肿瘤的联合疗法 - Google Patents
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Abstract
本发明涉及用于肿瘤的联合疗法,包含施用环氧巴豆萜烷化合物和免疫关卡抑制剂。在具体的实施方案中,提供使用该疗法治疗肿瘤和/或治疗或预防一种或多种旁观者肿瘤的方法。还描述了包含环氧巴豆萜烷化合物和免疫关卡抑制剂的药物组合物和药盒。
Description
技术领域
本发明涉及用于肿瘤的联合疗法,包含施用环氧巴豆萜烷(epoxytigliane)化合物和免疫关卡抑制剂。还描述了包含环氧巴豆萜烷化合物和免疫关卡(checkpoint)抑制剂的药物组合物和药盒。
背景技术
环氧巴豆萜烯酮(epoxytiglienone)化合物具有有效的抗肿瘤活性。当在肿瘤内施用时,环氧巴豆萜烯酮通过直接破坏肿瘤血管系统引发肿瘤块的快速出血性坏死(Boyle等人,2014)。迄今为止,没有证据表明局部施用环氧巴豆萜烯酮化合物对旁观者或更远距离的肿瘤具有全身作用,并且认为肿瘤内递送的环氧巴豆萜烯酮化合物主要在治疗部位起作用。因此,必须单独治疗每个肿瘤。
用于治疗癌症的免疫疗法在临床上得到广泛接受。特别地,免疫关卡抑制剂((immune checkpoint inhibitor,ICI)已经在一系列恶性肿瘤中显示出前景,包括晚期转移性黑素瘤,非小细胞肺癌,肾癌,膀胱癌和霍奇金淋巴瘤。ICI是阻断下述蛋白的作用的分子(典型地为单克隆抗体),所述蛋白允许肿瘤细胞规避、抑制或抵抗宿主免疫系统,尤其是对肿瘤抗原具有特异性的T细胞。目前批准的T细胞关卡抑制剂通过明显不同的作用机制增强抗肿瘤免疫应答。例如,细胞毒性T淋巴细胞相关抗原4(CTLA4)主要阻断在免疫应答的引发阶段期间增强T细胞活化,而程序性细胞死亡蛋白1(PD1)阻断显然释放耗尽但以其他方式激活的效应T细胞群并减少调节性T(Treg)细胞功能。
尽管ICI可以在晚期癌症患者中引起显著和持久的反应,但这些阳性反应仅限于总患者人群中的一小部分(Hu-Lieskovan等人,2017)。因此,将ICI与可刺激宿主免疫应答的其他治疗方式(例如放疗,化疗,溶瘤病毒,癌症疫苗)相结合的方法提供了一种有吸引力且临床可行的方法来克服对癌症免疫疗法的内在和获得性抗性,并且可能将临床成功扩展到更广泛的患者(Smyth等人2015)。
一种这样的方法是将ICI与小分子化疗剂组合(全身或肿瘤内递送),其可通过(1)减少总体肿瘤负荷来调节免疫应答,(2)通过在肿瘤坏死期间暴露新抗原来增强抗肿瘤应答,和/或(3)直接影响肿瘤基质细胞(Adams等人2015;Mahoney等人2015;O’Brien等人2014)。
本发明至少部分地基于以下发现:一些环氧巴豆萜烯-3-酮化合物可以刺激免疫应答,其可以与免疫关卡阻断协同作用,不仅为正在治疗的肿瘤而且为可能存在于被治疗的受试者中的其他肿瘤提供治疗。
发明内容
在一个方面,本发明涉及治疗受试者的至少一种肿瘤的方法,包含对受试者施用环氧巴豆萜烷(epoxytigliane)化合物或其药学上可接受的盐和免疫关卡(checkpoint)抑制剂。
本发明的另一个方面提供了治疗或预防受试者的旁观者肿瘤(bystandertumour)的方法,包含对有此需要的受试者施用环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂;其中将环氧巴豆萜烷化合物局部施用于除旁观者肿瘤之外的肿瘤。
本发明的另一个方面提供了环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂在制备用于治疗肿瘤的药物中的用途。
本发明的另一个方面提供了环氧巴豆萜烷化合物或其药学上可接受的盐在制备用于治疗肿瘤的药物中的用途,其中所述药物用于与免疫关卡抑制剂联合施用。
本发明的另一个方面提供了免疫关卡抑制剂在制备用于治疗肿瘤的药物中的用途,其中所述药物用于与环氧巴豆萜烷化合物或其药学上可接受的盐联合施用。
本发明的另一个方面提供了环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂在制备用于治疗或预防旁观者肿瘤的药物中的用途。
本发明的另一个方面提供了环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂在制备用于治疗或预防旁观者肿瘤的药物中的用途,其中所述药物用于与免疫关卡抑制剂联合施用。
本发明的另一个方面提供了免疫关卡抑制剂在制备用于治疗或预防旁观者肿瘤的药物中的用途,其中所述药物用于与环氧巴豆萜烷化合物或其药学上可接受的盐联合施用。
本发明的另一个方面提供了环氧巴豆萜烷化合物或其药学上可接受的盐与免疫关卡抑制剂相组合用于治疗或预防旁观者肿瘤。
本发明的另一个方面提供了药物组合物,其包含环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂,任选地与一种或多种药学上可接受的载体一起。
本发明的另一个方面提供了药盒,其包含环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂。
发明详述
定义
除非另外定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。尽管与本文描述的那些类似或等同的任何方法和材料可用于本发明的实践或测试,但描述了优选的方法和材料。出于本发明的目的,将以下术语定义如下。
如本文所用的冠词“一”和“一个”是指该冠词的一个或多于一个(即至少一个)语法对象。作为实例,“要素(an element)”表示一个要素或多于一个要素。
如本文所用,术语“约”是指相对于参比量、水平、数值、尺寸、大小或数量变化多达30%、25%、20%、15%或10%。
在本说明书的上下文中,除非上下文中另有要求,否则词语“包括”,“包含”和“含有”将被理解为暗示包括所述步骤或要素或者是步骤或元素组,但不排除任何其他步骤或要素或者是步骤或元素组。
术语“烷基”是指具有1-20个碳原子的任选取代的直链和支链烃基。适当时,烷基可具有指定数目的碳原子,例如,-C1-C6烷基包括在直链或支链排列上具有1、2、3、4、5或6个碳原子的烷基。烷基的非限制性实例包括甲基,乙基,丙基,异丙基,丁基,仲丁基和叔丁基,戊基,2-甲基丁基,3-甲基丁基,己基,2-甲基戊基,3-甲基戊基,4-甲基戊基,2-乙基丁基,3-乙基丁基,庚基,辛基,壬基,癸基,十一烷基,十二烷基,十三烷基,十四烷基和十五烷基。
术语“烯基”是指具有2-20个碳原子且具有至少一个双键的任选取代的不饱和直链或支链烃。适当时,烯基可具有指定数目的碳原子,例如,C2-C6烯基包括在直链或支链排列上具有2、3、4、5或6个碳原子的烯基。烯基的非限制性实例包括乙烯基,丙烯基,异丙烯基,丁烯基,仲丁烯基和叔丁烯基,戊烯基,己烯基,庚-1,3-二烯,己-1,3-二烯,壬-1,3,5-三烯等。
术语“炔基”是指具有2-20个碳原子且具有至少一个三键的任选取代的不饱和直链或支链烃。适当时,炔基可具有指定数目的碳原子,例如,C2-C6炔基包括在直链或支链排列上具有2、3、4、5或6个碳原子的炔基。非限制性实例包括乙炔基,丙炔基,丁炔基,戊炔基和己炔基。
术语"环烷基"和“碳环”是指任选取代的饱和或不饱和单环、双环或三环烃基。适当时,环烷基可具有指定数目的碳原子,例如,C3-C6环烷基为具有3、4、5或6个碳原子的碳环基。非限制性实例包括环丙基,环丁基,环戊基,环戊烯基,环己基,环己烯基,环己二烯基等。
"芳基"是指在每个环中具有至多7个原子的C6-C14元单环、双环或三环碳环环系,其中至少一个环是芳族的。芳基的实例包括但不限于苯基,萘基,四氢萘基,茚满基和联苯基。芳基可包含1-3个苯环。如果存在两个或更多个芳环,则环可以稠合在一起,使得相邻的环共享共同的键。
无论是单个实体还是作为更大实体的一部分,烷基、烯基、炔基、环烷基或芳基各自可任选地被一个或多个任选的取代基取代,所述取代基选自C1-6烷基、C2-6烯基、C3-6环烷基、氧代(=O)、-OH、-SH、C1-6烷基O-、C2-6烯基O-、C3-6环烷基O-、C1-6烷基S-、C2-6烯基S-、C3-6环烷基S-、-CO2H、-CO2C1-6烷基、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(苯基)、-N(苯基)2、-CN、-NO2、-卤素、-CF3、-OCF3、-SCF3、-CHF2、-OCHF2、-SCHF2、-苯基、-C1-6烷基苯基、-O苯基、-C(O)苯基、-C(O)C1-6烷基。适合的取代基的实例包括、但不限于甲基,乙基,丙基,异丙基,丁基,仲丁基,叔丁基,乙烯基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基,羟基,羟甲基,羟乙基,羟丙基,羟丁基,氟,氯,溴,碘,氰基,硝基,-CO2H,-CO2CH3,-C(O)CH3,三氟甲基,三氟甲氧基,三氟甲硫基,二氟甲基,二氟甲氧基,二氟甲硫基,吗啉代,氨基,甲氨基,二甲氨基,苯基,苯氧基,苯基羰基,苄基和乙酰基。
环氧巴豆萜烷化合物可以是药学上可接受的盐的形式。然而,应当理解,非药学上可接受的盐也属于本发明的范围,因为它们可以用作制备药学上可接受的盐的中间体,或者可以在储存或运输期间有用。适合的药学上可接受的盐包括但不限于药学上可接受的无机酸例如盐酸、硫酸、磷酸、硝酸、碳酸、硼酸、氨基磺酸和氢溴酸的盐;或药学上可接受的有机酸例如乙酸、丙酸、丁酸、酒石酸、马来酸、羟基马来酸、富马酸、马来酸、柠檬酸、乳酸、粘酸、葡糖酸、苯甲酸、琥珀酸、草酸、苯乙酸、甲磺酸、甲苯磺酸、苯磺酸、对氨基苯磺酸、天冬氨酸、谷氨酸、依地酸、硬脂酸、棕榈酸、油酸、月桂酸、泛酸、单宁酸、抗坏血酸和戊酸的盐。
碱的盐包括但不限于与药学上可接受的阳离子形成的那些,例如钠,钾,锂,钙,镁,铵和烷基铵。
含碱性氮的基团可用诸如低级烷基卤这样的试剂进行季铵化,例如甲基,乙基,丙基和丁基氯化物、溴化物和碘化物;二烷基硫酸盐如二甲基和二乙基硫酸盐等。
还应认识到,环氧巴豆萜烷化合物可具有不对称中心,因此能够以多于一种立体异构形式存在。因此,本发明还涉及在一个或多个不对称中心处基本上纯的异构形式的化合物,例如,大于约90%ee,例如约95%或97%ee或大于99%ee,及其混合物,包括外消旋混合物。这类异构体可以通过从天然来源分离,通过不对称合成,例如使用手性中间体,或通过手性拆分来获得。本发明的化合物可以几何异构体存在。本发明还涉及基本上纯的顺式(Z)或反式(E)形式或其混合物的化合物。
本发明化合物可以通过从植物或植物部分中分离,或通过所分离的化合物的衍生化,或通过相关化合物的衍生化来获得。分离方法和衍生化方法可以在WO 2007/070985和WO2014/169356中找到。
术语"环氧巴豆萜烷化合物"是指具有如下基础碳环结构的化合物:
该化合物具有三环[9.3.0.0]十四烷体系,其中稠合的环丙烷环连接在六元环上。环氧化物与6,7位上的七元环稠合。
环氧巴豆萜烷化合物的一个实例为环氧巴豆萜烯-3-酮化合物。术语"环氧巴豆萜烯-3-酮化合物"是指具有上述定义的环氧-巴豆萜烷结构的化合物,其中5元环具有1,2-烯-3-酮结构:
如本文所用,术语“旁观者肿瘤”是指除用环氧巴豆萜烷化合物治疗的肿瘤以外的肿瘤。旁观者肿瘤可以是原发性肿瘤或转移性肿瘤。
本文所用的术语“与...组合”是指环氧巴豆萜烷化合物和ICI以单一组合物形式施用,或者分别同时或依次施用。环氧巴豆萜烷化合物和ICI可以在不同的时间和以不同的频率施用,但是它们组合在一起同时或在重叠的时间发挥生物效应。例如,施用ICI使其在施用环氧巴豆萜烷化合物时对免疫应答有影响。
治疗方法
本发明涉及治疗肿瘤(包括旁观者肿瘤)的方法,该方法包含施用环氧巴豆萜烷化合物或其药学上可接受的盐与免疫关卡抑制剂(ICI)的组合。本发明还涉及预防旁观者肿瘤的方法,包含施用环氧巴豆萜烷化合物或其药学上可接受的盐与ICI的组合。
在一些实施方案中,所治疗的肿瘤是环氧巴豆萜烷化合物可以以局部方式直接递送至肿瘤的肿瘤。在具体的实施方案中,肿瘤是皮肤肿瘤或皮下肿瘤或可从身体外部进入的肿瘤,例如可触知的肿瘤。在其他实施方案中,肿瘤是体内肿瘤。在肿瘤是体内定位的肿瘤的一些实施方案中,当肿瘤暴露于并且能够注射环氧巴豆萜烷化合物时,在手术期间实现局部递送。在其他实施方案中,肿瘤位于体内,并且通过成像技术引导的注射递送环氧巴豆萜烷化合物,例如,通过内窥镜超声或通过立体定向成像引导。
在一些实施方案中,将环氧巴豆萜烷化合物全身递送至一个或多个肿瘤。
在一些实施方案中,肿瘤是良性肿瘤。在其他实施方案中,肿瘤是恶性肿瘤。在一些实施方案中,肿瘤是原发性肿瘤,而在其他实施方案中,肿瘤是转移性肿瘤。皮肤肿瘤的实例包括脂溢性角化病,光化性角化病,基底细胞癌(BCC),包括结节性BCC、浅表性BCC、浸润性BCC和小结节性BCC,鳞状细胞癌,包括原位鳞状细胞癌和浸润性鳞状细胞癌,黑色素瘤,包括浅表传播黑色素瘤、结节性黑色素瘤、恶性小痣黑色素瘤、肢端性黑色素瘤和促纤维增生/中性黑素瘤,皮肤B细胞淋巴瘤和皮肤T细胞淋巴瘤。皮下肿瘤的实例包括血管角化瘤,化脓性肉芽肿,樱桃状血管瘤,血管球瘤,血管肉瘤,卡波西肉瘤,尤因肉瘤,恶性纤维组织细胞瘤,平滑肌肉瘤,横纹肌肉瘤,脂肪肉瘤,滑膜肉瘤,间质肉瘤,胃肠道间质肉瘤,恶性外周神经鞘瘤,原始神经外胚层肿瘤,神经纤维瘤,Merkel细胞癌,皮肤纤维瘤,纤维肉瘤,上皮样肉瘤和肥大细胞瘤(肥大细胞瘤)。
体内肿瘤可以是在手术期间或通过引导注射可接受的任何肿瘤,或者可以用全身施用的环氧巴豆萜烷治疗的肿瘤,包括脑,肺,结肠,表皮样,鳞状细胞,膀胱,胃,胰腺,乳房,头部,颈部,肾脏系统,肾脏,肝脏,卵巢,前列腺,子宫,食道,睾丸,子宫颈,阴道,甲状腺或皮肤的肿瘤。
旁观者肿瘤可以是除用环氧巴豆萜烷化合物治疗的肿瘤之外的任何肿瘤。例如,旁观者肿瘤可以是多余(secoud)的皮肤或皮下肿瘤,或者它可以是另一器官或组织中的肿瘤。旁观者肿瘤的实例包括脑,肺,结肠,表皮样,鳞状细胞,膀胱,胃,胰腺,乳房,头部,颈部,肾系统,肾,肝,卵巢,前列腺,子宫,食道,睾丸,子宫颈,阴道,甲状腺或皮肤的肿瘤。
在一些实施方案中,旁观者肿瘤是另外的原发性肿瘤,并且在其他实施方案中,旁观者肿瘤是转移性肿瘤。
在一些实施方案中,用环氧巴豆萜烷化合物治疗的肿瘤是原发性肿瘤,旁观者肿瘤是转移性肿瘤。在一些实施方案中,用环氧巴豆萜烷化合物治疗的肿瘤是转移性肿瘤,旁观者肿瘤是原发性肿瘤。在一些实施方案中,用环氧巴豆萜烷化合物治疗的肿瘤和旁观者肿瘤都是原发性肿瘤。在一些实施方案中,用环氧巴豆萜烷化合物治疗的肿瘤和旁观者肿瘤都是转移性肿瘤。
在一些实施方案中,所述联合疗法防止旁观者肿瘤发生或延迟旁观者肿瘤的发生。在一些实施方案中,所述联合疗法减小旁观者肿瘤的大小。
环氧巴豆萜烷化合物
在一些实施方案中,环氧巴豆萜烷化合物为6,7-环氧巴豆萜烷化合物.在一些实施方案中,环氧巴豆萜烷化合物为环氧巴豆萜-1,2-烯-3-酮化合物。在一些实施方案中,环氧巴豆萜烷化合物为6,7-环氧巴豆萜-1,2-烯-3-酮化合物。
在一些实施方案中,环氧巴豆萜烷化合物为式(I)的化合物:
或几何异构体或立体异构体或其药学上可接受的盐;
其中
R1为氢或C1-6烷基;
R2为-OH或-OR9;
R3为-OH或-OR9;
R4和R5独立地选自氢和C1-6烷基;
R6为氢或-R10;
R7为羟基或-OR10;
R8为氢或C1-6烷基;
R9为-C1-20烷基、-C2-20烯基、-C2-20炔基、-C(O)C1-20烷基、-C(O)C2-20烯基、-C(O)C2-20炔基、-C(O)环烷基、-C(O)C1-10烷基环烷基;-C(O)C2-10烯基环烷基、-C(O)C2-10炔基环烷基、-C(O)芳基、-C(O)C1-10烷基芳基、-C(O)C2-10烯基芳基、-C(O)C2-10炔基芳基、-C(O)C1-10烷基C(O)R11、-C(O)C2-10烯基C(O)R11、-C(O)C2-10炔基C(O)R11、-C(O)C1-10烷基CH(OR11)(OR11)、-C(O)C2-10烯基CH(OR11)(OR11)、-C(O)C2-10炔基CH(OR11)(OR11)、-C(O)C1-10烷基SR11、-C(O)C2-10烯基SR11、-C(O)C2-10炔基SR11、-C(O)C1-10烷基C(O)OR11、-C(O)C2-10烯基C(O)OR11、-C(O)C2-10炔基C(O)OR11、-C(O)C1-10烷基C(O)SR11、-C(O)C2-10烯基C(O)SR11、-C(O)C2-10炔基C(O)SR11、
R10为-C1-6烷基、-C2-6烯基、-C2-6炔基、-C(O)C1-6烷基、-C(O)C2-6烯基、-C(O)C2-6炔基、-C(O)芳基、-C(O)C1-6烷基芳基、-C(O)C2-6烯基芳基、-C(O)C2-6炔基芳基;且
R11为氢、-C1-10烷基、-C2-10烯基、-C2-10炔基、环烷基或芳基;
其中烷基、烯基、炔基、环烷基或芳基各自任选地被取代。
在一些实施方案中,式(I)的环氧巴豆萜烷化合物为式(II)的化合物:
或几何异构体或立体异构体或其药学上可接受的盐;其中R6、R7和R9如对式(I)所定义。
在式(I)或(II)的具体的实施方案中,如下的一种或多种适用:
R1为-C1-3烷基,尤其是-CH3;
R2为-OC(O)C1-20烷基、-OC(O)C2-20烯基、-OC(O)C2-20炔基、-OC(O)环烷基、-OC(O)C1-10烷基环烷基;-OC(O)C2-10烯基环烷基、-OC(O)C2-10炔基环烷基、-OC(O)芳基、-OC(O)C1-10烷基芳基、-OC(O)C2-10烯基芳基、-OC(O)C2-10炔基芳基、-OC(O)C1-10烷基C(O)R11、-OC(O)C2-10烯基C(O)R11、-OC(O)C2-10炔基C(O)R11、-OC(O)C1-10烷基CH(OR11)(OR11)、-OC(O)C2-10烯基CH(OR11)(OR11)、-OC(O)C2-10炔基CH(OR11)(OR11)、-OC(O)C1-10烷基SR11、-OC(O)C2-10烯基SR11、-OC(O)C2-10炔基SR11、-OC(O)C1-10烷基C(O)OR11、-OC(O)C2-10烯基C(O)OR11、-OC(O)C2-10炔基C(O)OR11、-OC(O)C1-10烷基C(O)SR11、-OC(O)C2-10烯基C(O)SR11或-OC(O)C2-10炔基C(O)SR11;尤其是-OC(O)C1-20烷基、-OC(O)C2-20烯基、-OC(O)C2-20炔基、-OC(O)环烷基、-OC(O)C1-10烷基环烷基;-OC(O)C2-10烯基环烷基、-OC(O)C2-10炔基环烷基或-OC(O)芳基;更特别地为-OC(O)C1-20烷基、-OC(O)C2-20烯基或-OC(O)C2-20炔基;
R3为-OC(O)C1-20烷基、-OC(O)C2-20烯基、-OC(O)C2-20炔基、-OC(O)环烷基、-OC(O)C1-10烷基环烷基;-OC(O)C2-10烯基环烷基、-OC(O)C2-10炔基环烷基、-OC(O)芳基、-OC(O)C1-10烷基芳基、-OC(O)C2-10烯基芳基、-OC(O)C2-10炔基芳基、-OC(O)C1-10烷基C(O)R11、-OC(O)C2-10烯基C(O)R11、-OC(O)C2-10炔基C(O)R11、-OC(O)C1-10烷基CH(OR11)(OR11)、-OC(O)C2-10烯基CH(OR11)(OR11)、-OC(O)C2-10炔基CH(OR11)(OR11)、-OC(O)C1-10烷基SR11、-OC(O)C2-10烯基SR11、-OC(O)C2-10炔基SR11、-OC(O)C1-10烷基C(O)OR11、-OC(O)C2-10烯基C(O)OR11、-OC(O)C2-10炔基C(O)OR11、-OC(O)C1-10烷基C(O)SR11、-OC(O)C2-10烯基C(O)SR11或-OC(O)C2-10炔基C(O)SR11;尤其是-OC(O)C1-20烷基、-OC(O)C2-20烯基、-OC(O)C2-20炔基、-OC(O)环烷基、-OC(O)C1-10烷基环烷基;-OC(O)C2-10烯基环烷基、-OC(O)C2-10炔基环烷基或-OC(O)芳基;更特别地为-OC(O)C1-20烷基、-OC(O)C2-20烯基或-OC(O)C2-20炔基;
R4和R5独立地选自-C1-3烷基,尤其是-CH3;
R6为氢、-C(O)C1-6烷基、-C(O)C2-6烯基、-C(O)C2-6炔基或-C(O)芳基;尤其是氢、-C(O)C1-3烷基、-C(O)C2-3烯基或-C(O)C2-3炔基、更特别地为氢或-C(O)CH3;
R7为羟基、-OC(O)C1-6烷基、-OC(O)C2-6烯基或-OC(O)C2-6炔基,尤其是羟基、-OC(O)C1-3烷基、-OC(O)C2-3烯基或-OC(O)C2-3炔基、更特别地为羟基或-OC(O)CH3;且
R8为-C1-3烷基,尤其是-CH3。
在一些实施方案中,式(I)和/或(II)的化合物具有如下式(III)中所示的立体化学:
在一些实施方案中,6,7-位的环氧基团高于环系统的平面。在其他实施方案中,6,7-位的环氧基团低于环系统的平面。在一些实施方案中,12位的R2基团是S型,而在其他实施方案中,12位的R2基团是R型。
在具体的实施方案中,环氧巴豆萜烷化合物选自:
12-巴豆萜酰基(tigloyl)-13-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯(tiglien)-3-酮(化合物1);
12,13-di-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮(化合物2);
12-己酰基-13-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮(化合物3);
12,13-二己酰基-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮(化合物4);
12-肉豆蔻酰基-13-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮(化合物5);
12-巴豆萜酰基-13-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13-五羟基-20-乙酰氧基-1-巴豆萜烯-3-酮(化合物6);
12-肉豆蔻酰基-13-乙酰氧基-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮(化合物7);
12-丙酰基-13-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮(化合物8);
12,13-二巴豆萜酰基-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮(化合物9);且
12-(2-甲基丁酰基)-13-巴豆萜酰基-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮(化合物10).
免疫关卡抑制剂(ICI)
ICI可以是抑制免疫细胞或癌细胞蛋白的任何分子,所述蛋白阻断免疫细胞中的免疫应答,尤其是在免疫细胞是T细胞或天然杀伤细胞(NK细胞)的情况下。免疫细胞和肿瘤细胞蛋白的实例包括T细胞上的程序性死亡1(PD-1),其结合肿瘤细胞的PD-L1以阻断T细胞对肿瘤细胞的免疫应答,以及T细胞上的细胞毒性T-淋巴细胞相关蛋白4(CTLA-4)蛋白质,其在癌细胞上结合B7-1/B7-2蛋白质以阻断T细胞对肿瘤细胞的免疫应答。因此,ICI包括结合或阻断PD-1与PD-L1/PDL2或者是CTLA-4与B7-1/B7-2的相互作用的分子。阻断免疫细胞中的免疫应答并可能被调节以阻止其作用的其他免疫细胞蛋白包括腺苷A2A受体,B7-H3,B7-H4,吲哚胺2,3-双加氧酶(IDO),杀伤细胞免疫球蛋白样受体(KIR),淋巴细胞活化基因-3(LAG3),具有IG和ITIM结构域的T细胞免疫受体(TIGIT),含T-细胞免疫球蛋白和粘蛋白结构域的分子-3(TIM-3),CD96和T细胞激活的V结构域免疫球蛋白抑制剂(VISTA)。
ICI的实例包括但不限于PD-1、PD-L1、PD-L2、CTLA-4、B7-1/B7-2蛋白、腺苷A2A受体、B7-H3、B7-H4、IDO、KIR、LAG3、TIM-3、TIGIT、CD96和VISTA的拮抗剂,尤其是PD-1、PD-L1、CTLA-4或B7-1/B7-2蛋白的拮抗剂,更特别地为PD-1或CTLA-4的拮抗剂。在具体的实施方案中,所述拮抗剂为针对免疫关卡蛋白的抗体,例如抗-PD-1抗体或抗-CTLA-4抗体。在其他实施方案中,具体的拮抗剂为IDO拮抗剂。
组合物
尽管环氧巴豆萜烷化合物或其药学上可接受的盐和ICI可以以纯净的形式施用,但是以一种或多种各自与药学上可接受的载体、稀释剂和/或赋形剂的药物组合物的形式施用环氧巴豆萜烷化合物和ICI可能更方便。
用于药物用途和组合物的剂型和比率是本领域技术人员很容易确定的。
在具体的实施方案中,配制环氧巴豆萜烷化合物以用于直接施用在待治疗的肿瘤上或其中。在一些实施方案中,配制环氧巴豆萜烷化合物用于以凝胶、软膏剂、水剂、霜剂或透皮贴剂的形式局部施用,其可以直接施用于待治疗的肿瘤上。在其他实施方案中,配制环氧巴豆萜烷化合物用于注射,尤其是肿瘤内注射,其中将化合物注入肿瘤内的一个或多个位置。
ICI可以以能够全身或局部递送分子的任何方式施用。在具体的实施方案中,当ICI是抗体时,通过注射方便地递送分子,例如静脉内,关节内,肌肉内,皮内,皮下或腹膜内注射。ICI也可以配制用于通过注射局部递送,例如,肿瘤内。也可以将药学上可接受的载体和用于全身或局部施用的可接受的载体掺入ICI的组合物中。
在一些实施方案中,环氧巴豆萜烷化合物和ICI分别同时或依次递送。在其他实施方案中,环氧巴豆萜烷化合物和ICI以单一组合物递送,例如,适合于肿瘤内递送的单一组合物或配制成用于全身递送的单一组合物。
在本发明的另一个方面,提供了药物组合物,其包含环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂,任选地与一种或多种药学上可接受的载体一起。
适合地,药物组合物包含药学上可接受的赋形剂或可接受的赋形剂。“药学上可接受的赋形剂”是指可安全使用的固体或液体填充剂,稀释剂或包封物质。根据具体的施用途径的不同,可以使用本领域熟知的各种载体。这些载体或赋形剂可选自糖,淀粉,纤维素及其衍生物,环糊精,麦芽,明胶或其他胶凝剂,聚合物,滑石粉,硫酸钙,植物油,合成油,醇和/或多元醇,藻酸,磷酸盐缓冲溶液,乳化剂,等渗盐水和无热原水。
液体形式制剂包括溶液,悬浮液和乳液,例如水或水-丙二醇溶液。例如,可以将肠胃外注射液制剂配制成1,2-丙二醇水溶液,二甲亚砜(DMSO),γ-环糊精或2-羟丙基-β-环糊精的水溶液,盐水溶液或聚乙二醇溶液溶液,其中有或没有缓冲液。优选的pH范围是3.0-4.5。适合的缓冲液在pH 3.5-4.5下缓冲制剂,并且包括但不限于乙酸盐缓冲液和柠檬酸盐缓冲液。
因此,可以配制环氧巴豆萜烷化合物和/或ICI的组合物用于肠胃外施用(例如通过注射,例如推注或连续输注),并且可以以安瓿、预填充注射器、小体积输注液或加入防腐剂在多剂量容器中的单位剂量形式。该组合物可以采取诸如油性或水性媒介物中的悬浮液、溶液、凝胶或乳液的形式,并且可以含有配制剂,例如助悬剂、稳定剂和/或分散剂。或者,活性成分可以是通过无菌分离无菌固体或通过从溶液中冷冻干燥而获得的粉末形式,其用于在使用前用适合的媒介物(例如无菌、无热原的水)重构。
适于施用的环氧巴豆萜烷化合物和/或ICI的药物组合物可以以离散的单位存在,例如注射器,小瓶,管或小袋,它们各自含有预定量的一种或多种本发明的药物活性化合物或提取物,作为粉末或颗粒或作为水性液体中的溶液或悬浮液,环糊精溶液,非水液体,水包油型乳剂或油包水型乳剂或作为霜剂或凝胶中的溶液或悬浮液或作为掺入环氧巴豆萜烷化合物的微粒或纳米粒的悬浮液,包括但不限于二氧化硅或聚丙交酯微粒或纳米粒。此类组合物可通过任何药学方法制备,但所有方法包括使一种或多种本发明的药物活性化合物与构成一种或多种必需成分的载体结合的步骤。通常,通过将本发明的活性剂与液体载体或细碎的固体载体或两者均匀且紧密地混合来制备组合物,然后,如果必要,使产物成型为期望的形式。
对于表皮或其他器官的局部施用,可以将本发明的化合物配制成凝胶,软膏,乳液,糊剂,霜剂或水剂,或作为透皮贴剂。可以使用适合的增稠剂并将它们加入到化合物的水/醇组合物中制备凝胶。适合的增稠剂或胶凝剂是本领域已知的,例如聚乙烯基羧基聚合物卡波姆940。软膏和霜剂可以例如用水性或油性基质配制,同时加入适合的增稠剂和/或胶凝剂。水剂可以用水性或油性基质配制,并且通常还含有一种或多种乳化剂,稳定剂,分散剂,悬浮剂,增稠剂或着色剂。
适于局部施用的制剂还包括溶液或悬浮液,其可以以浴液或浸泡溶液或喷雾剂的形式、或者可以被吸收到敷料中局部施用。
当ICI是小分子时,它可以通过任何适合的方式递送,包括口服,局部,直肠,肠胃外,舌下,口腔,静脉内,关节内,肌肉内,皮内,皮下,吸入,眼内,腹膜内,脑室内,透皮等,如药学领域中已知的。
剂量方案
在一些实施方案中,将环氧巴豆萜烷化合物与ICI在相同的组合物中递送。然而,在具体的实施方案中,将ICI与环氧巴豆萜烷化合物在分开的组合物中施用。
在一些实施方案中,将环氧巴豆萜烷化合物直接施用于肿瘤,例如通过局部施用或通过肿瘤内注射。
在一些实施方案中,将环氧巴豆萜烷化合物一次施用于肿瘤。在其他实施方案中,监测治疗的肿瘤,并且如果肿瘤对治疗没有完全响应,则可能需要进一步施用环氧巴豆萜烷化合物。在局部治疗肿瘤的实施方案中,环氧巴豆萜烷化合物可以在一段时间期限内多次施用,例如每天施用持续一周,或者每周一次施用,持续4至10周。本领域技术人员监测受试者将能够确定适合的剂量方案,其可以根据对治疗的响应的不同而变化。
在一些实施方案中,ICI在环氧巴豆萜烷化合物之前或与之同时或与之依次施用至少一次。在具体的实施方案中,在施用环氧巴豆萜烷化合物之前或与之一起在一段时间内施用多次剂量的ICI,然后在施用环氧巴豆萜烷化合物之后继续施用。
在一些实施方案中,在施用环氧巴豆萜烷化合物之前和之后,将ICI施用一次以上且定期施用。在具体的实施方案中,ICI在施用氧巴豆萜烷化合物之前施用,与施用环氧巴豆萜烷化合物依次或同时施用,并且在施用环氧巴豆萜烷化合物之后施用至少一次。例如,ICI可以在施用环氧巴豆萜烷化合物之前1周至1天施用,尤其是在施用环氧巴豆萜烷化合物之前1至3天、更特别是约2天施用,然后在施用环氧巴豆萜烷化合物之前或之后立即依次或同时施用ICI,然后在施用环氧巴豆萜烷化合物后的下个月内将ICI施用一次或多次,例如,每周一次,每5天一次,每4天一次,每3天一次,每2天或每天一次,尤其是每1至3天,尤其是每2天一次。随后施用ICI可以持续至在施用环氧巴豆萜烷化合物后施用1-10个剂量的ICI,尤其是1-8个剂量,1-6个剂量,1-4个剂量,1-3个剂量或1-2个剂量。
在一个具体实施方案中,将ICI在环氧巴豆萜烷化合物施用前2天与环氧巴豆萜烷化合物依次(紧接在之前或之后)施用,然后在施用环氧巴豆萜烷化合物后每两天施用一次,持续6天。
环氧巴豆萜烷化合物以有效量施用。“有效量”是指至少部分地获得期望的反应所需的量,例如,减小肿瘤的大小或完全破坏肿瘤。该量取决于待治疗个体的健康和身体状况,待治疗个体的分类组,组合物的配方,肿瘤的大小,医学状况的评估和其他相关因素。预计该量将落在可通过常规试验确定的相对宽的范围内。例如,有效量可以在约0.1ng/kg体重-1g/kg体重/剂量的范围内。剂量优选为1μg-0.5g/kg体重/剂量,例如0.1μg-100mg/kg体重/剂量。在一个实施方案中,当将剂量在肿瘤内施用时,剂量在50ng-100mg/kg体重,例如0.1mg-5mg/kg体重,0.1-1mg/kg体重,例如0.25mg/kg体重。在另一个实施方案中,剂量为0.001mg-20mg/剂量,例如0.005mg-15mg/剂量,尤其是0.05-10mg/剂量,更特别地为约0.1-约5mg/剂量。可以调整剂量方案以提供最佳治疗反应。例如,在一些实施方案中,当施用在肿瘤内时,将环氧巴豆萜烷化合物施用一次并监测治疗进展。在一些实施方案中,如果肿瘤未完全消退或肿瘤复发,则可施用二次剂量。在一些实施方案中,当局部施用时,可以将局部化合物制剂以凝胶,霜剂,软膏或水剂的形式直接施用于肿瘤部位。治疗的频率取决于肿瘤,其大小,待治疗的受试者等。在一些实施方案中,可以每周施用局部制剂直至肿瘤消退。在其他实施方案中,治疗可以是单次治疗,并且仅在肿瘤未完全消退时才施用二次治疗。
ICI也可以以有效量施用。此外,被视为有效的ICI的量将取决于所治疗的受试者,他们的健康和身体状况,存在的旁观者肿瘤的数量,组合物的配方和医学状况的评估。预计ICI的量将在相当广泛的范围内。有效量可以在约0.1ng/kg-约500mg/kg体重,100μg/kg-100mg/kg体重,1mg/kg-50mg/kg体重,1mg/kg-20mg/kg体重范围内。在另一个实施方案中,实际剂量可以在1μg-1g,例如100μg-750mg/剂量范围内。
可以用联合疗法治疗的受试者是哺乳动物,鸟类,水生动物,例如鱼类或爬行动物。在一些实施方案中,受试者是人,实验动物如小鼠、大鼠或家兔,伴侣动物如狗或猫,工作动物如马、驴等,家畜类动物如牛、公牛、猪、绵羊、山羊、鹿、美洲驼、羊驼等,或俘获的野生动物例如动物园或野生动物园内的那些,包括狮子、豹子、猎豹、大象、斑马、羚羊、长颈鹿、考拉、袋鼠,和爬行动物,如鳄鱼、蜥蜴、蛇等,鸟类,特别是俘获的鸟类,如澳洲长尾小鹦鹉或金丝雀、美冠鹦鹉、长尾鹦鹉、金刚鹦鹉、鹦鹉等,或鱼类,尤其是俘获的鱼,如热带鱼(斑马鱼、孔雀鱼、暹罗斗鱼、小丑鱼、红色南美产的热带鱼等),海豚,鲸鱼等。在具体的实施方案中,受试者是人或伴侣动物。
药盒
环氧巴豆萜烷化合物和ICI的组合物可以分别配制且合并一起以药盒或包装出售。药盒各自包含每种化合物的剂量以实现肿瘤的治疗并治疗或预防一种或多种旁观者肿瘤。
在一些实施方案中,将环氧巴豆萜烷组合物配制成用于局部施用的形式,例如在凝胶、水剂、霜剂或软膏中或浸渍到敷料中。在其他实施方案中,将环氧巴豆萜烷化合物环配制成用于注射,例如肿瘤内注射的形式。在该实施方案中,环氧巴豆萜烷制剂可以作为准备用于吸入到注射器中的液体、作为粉末或固体制剂存在于药盒中,其可以在注射前溶解在载体中或者可以以预先填充注射器的形式存在于药盒中。
药盒各自可以包含一个或多个剂量的环氧巴豆萜烷化合物。在一个实施方案中,药盒将在适于肿瘤内注射的制剂中含有单剂量的环氧巴豆萜烷化合物。在另一个实施方案中,药盒包含含有多剂量的环氧巴豆萜烷化合物的局部制剂,用于施用于肿瘤。
在一些实施方案中,ICI被配制用于以单次推注剂量或多剂量形式的肠胃外施用。例如,药盒可以在预填充注射器中包含ICI,作为准备用于注射到注射器中的小瓶中的液体,或者在摄取到注射器中之前作为固体准备溶解。液体或固体制剂可以是单剂量制剂或多剂量制剂。或者,药盒可以含有多个剂量的ICI,将ICI各自分别配制在预装注射器中,作为小瓶中的液体准备用于吸入到注射器中或作为固体用于溶解和摄取到注射器中。
所述药盒可进一步包含插页,其具有使用每种制剂的说明书,包括如果需要如何制备每种剂量,如何施用每种剂量以及何时施用每种剂量。
附图说明
图1提供A:用媒介物(Vehc.)或500nM化合物1(Comp 1),化合物3(Comp 3)和PMA处理后PKC-α、-βII、-γ、-δ和-θ易位的图像。这些图像也用于B中所示的定量。B:描绘响应于500、50和5nM化合物1和所示类似物的PKC同种型易位谱的热图(-α、-βI、-βII、-γ、-δ、-θ、-η和-ζ-显示EGFP易位至质膜的平均%细胞)。每个生物重复样品计数>150个细胞。n=3。
图2提供A:实验设计的示意图。B:通过化合物1处理(30μg)诱导选择在白细胞募集中起作用的宿主细胞因子/趋化因子。显示了所示细胞因子/趋化因子的基因表达的倍数变化。C:在t=8h时比较来自媒介物和化合物1基因表达谱的强度数据后产生热图。通过Ingenuity Pathway Analysis(IPA;Qiagen)分析随后的基因列表以鉴定受化合物1处理影响的途径。
图3提供A.从用化合物1处理的癌细胞系中的LDH释放。用指定浓度的化合物1或仅媒介物(Vehc.)处理A431、MM649和B16-OVA,并使用Pierce LDH细胞毒性检测试剂盒测定随时间释放的LDH。n=3。B.化合物1诱导胞内ATP水平的显著降低。此外,用化合物1或媒介物(Vehc.)处理细胞,并使用CellTiter-Glo测定试剂盒在指定的时间点测定胞内ATP水平。n=3。
图4提供A.响应于用化合物1处理的从癌细胞系的ATP释放的测定。用化合物1或媒介物(Vehc.)处理细胞指定的时间,并使用基于生物发光的ATP检测试剂盒测定来自细胞培养物上清液的ATP释放。确定平均RLU值+/-S.D.并绘制与时间的关系图。n=4。B.另外的环氧巴豆萜烷类似物(化合物2:Bi,化合物3:Bii和化合物4:Biii)也促进从A431、MM649和B16-OVA细胞系的ATP释放。n=4。C.用化合物1和环氧巴豆萜烷类似物处理的癌细胞系中HMGB1释放的测定。通过ELISA分析来自环氧巴豆萜烷或媒介物(Vehc.)处理的A431(Ci)、MM649(Cii)或B16-OVA(Ciii)的细胞培养物上清液的HMGB1释放。将来自化合物1处理的细胞的值相对于媒介物处理的细胞校准,以确定HMGB1释放的倍数增加。对于A431和MM649,n=2,而对于B16-OVA,n=3。(Civ)HMGB1释放也响应于用化合物2、3和4处理而发生。n=3。D.化合物1促进一系列癌细胞系中的钙网蛋白外化。将A431(Di)、MM649(Dii)和B16-OVA(Diii)仅用化合物1或媒介物(Vehc.)处理指定的时间,然后在流式细胞术之前用抗钙网蛋白/抗-家兔Alexa 488染色。对每个时间点指示平均荧光强度值(Ex:488nm,Em:530/530nm)+/-S.D.。
图5提供A和B.环氧巴豆萜烷处理的细胞在体外由CD11c+BMDC加工。将用化合物1或媒介物(Vehc.)处理的CMFDA标记的B16-OVA细胞与未成熟的BMDC一起温育4小时,然后在流式细胞术之前用抗CD11c-APC染色。实心灰色框-CD11c+BMDC细胞。虚线黑色框-已经摄取了死亡的B16-OVA细胞碎片的CD11c+BMDC(CD11c+CMFDAmid)。(CD11c+CMFDAmid)细胞的百分比在5A上显示,来自4个生物学重复样本的数据显示在图5B中。n=4。C.环氧巴豆萜烷类似物还诱导通过CD11c+BMDC摄取B16-OVA细胞。描述了使用化合物2、3和4获取的数据。n=3。
图6提供A:化合物1和ICI组合的实验方法的示意图。所有肿瘤均注射15/30μg化合物1或媒介物(Vehc.)。还描述了ICI治疗的剂量方案。B和C.Kaplan-Meier图显示在使用ICI、抗-PD-1(图6B)或抗-CTLA-4(图6C)的不同治疗条件下治疗的肿瘤保持在100mm3以下大小的%。还描述了响应于该组合的小鼠存活率。
图7提供A:联合疗法的示意图:指数和旁观者肿瘤与剂量方案一起显示;和B:联合疗法结果(肿瘤体积)的图形表示。在治疗的(白色圆圈)和旁观者(黑色圆圈)肿瘤中的同种型抗体+化合物1(点线),抗PD-1抗体或抗CTLA-4抗体+媒介物(虚线)和抗PD-1抗体或抗CTLA-4抗体+化合物1(实线)。
图8提供基于体积(左图)和Kaplan-Meier(右图)的肿瘤分析(%肿瘤<100mm3),其在wt和GCSF敲除背景情况下注射亚最佳剂量的化合物1(15μg)。
具体实施方案
本发明化合物可以通过从植物或植物部分中分离,或通过所分离的化合物的衍生化,或通过相关化合物的衍生化来获得。分离方法和衍生化方法可以在WO 2007/070985和WO2014/169356中找到。
化合物1的20-乙酰基衍生物化合物6可以通过在三乙胺存在下在二氯甲烷中用乙酸酐(1当量)乙酰化由化合物1制备。这些条件允许C-20羟基的选择性乙酰化而不会使仲羟基乙酰化。
化合物10虽然未在WO2014/169356中具体地合成,但可以使用获得WO2014/169356的第64-70页实施例1中所述的不对称酯的通用方法制备。
实施例1:环氧巴豆萜烷类似物活化PKC同种型
蛋白激酶C(PKC)是牵涉信号传导途径的关键酶家族,其特异性地在丝氨酸/苏氨酸残基处使底物磷酸化。通过PKC的磷酸化在调节多种细胞事件(如增殖和基因表达调节)中是重要的。PKC同种型(-θ,-η,-α,-β,-δ,-ε)直接参与免疫细胞反应,并且还可以促进关键免疫基因的表达。然而,这些PKC同种型中的每一种的表达模式和水平是细胞类型和背景特异性的(Lim等人2015;Anel等人2012;Pfeifhofer等人2006)。
为了鉴定环氧巴豆萜烷化合物的特异性PKC同种型激活谱(特异性和效能),用选择的PKC-EGFP载体(PKC-α、PKC-βI、PKC-βII、PKC-γ、PKC-δ、PK-Cθ、PKC-η、PKC-ζ-室内生成),使用Lipofectamine 2000(Invitrogen)按照Boyle等人(2014)描述的方法瞬时转染HeLa细胞。将相当于0.16μg PKC-EGFP和0.48μL Lipofectamine的体积与25μl Opti-MEM培养基(Invitrogen)混合,并在RT下温育5min。合并溶液并在RT下再温育20min(DNA:Lipofectamine 2000的比例为1:3)。将复合物(50μl)加入每个孔中,并在37℃温育3h后,加入另外50μl RPMI-1640,10%FCS至每孔100μl的总体积。在37℃温育24h后,用磷酸盐缓冲盐水(PBS)洗涤细胞,并用500、50和5nM的环氧巴豆萜烷处理。每个96-孔板可以测试三种化合物。每次实验运行需要五个96-孔板。处理1h后,用100μl PBS洗涤细胞两次,并用50μlPBS中2%甲醛/0.2%戊二醛固定10min。随后用100μl PBS将固定的细胞洗涤两次。为了染色细胞核,Hoechst 3342以1:10000稀释度使用。在黑暗中温育7min后,除去Hoechst并用PBS洗涤细胞。最后,用100μl PBS覆盖细胞,并在4℃下在黑暗中储存直至成像。使用GEInCell Analyzer 2000进行成像。使用Adobe Photoshop CS6手动计数PKC向质膜或其他亚细胞位置的易位。
显示在环氧巴豆萜烷化合物化合物1、化合物3和PMA(佛波醇-12-肉豆蔻酸酯-13-乙酸酯)存在下,选择的PKC同种型-α、-βII、-γ、-δ和-θ易位至细胞膜的图像如图1A所示。这些图像表明不同的环氧巴豆萜烷化合物可以激活不同的PKC同种型。
将显示化合物1-10的质膜转运的细胞百分比以及阳性对照PMA转化为热图,其描绘响应于每种化合物的500、50和5nM的PKC同种型易位谱。热图显示于图18。
结果显示,化合物1-7均激活PKC-θ(达到不同程度),已知PKC同种型参与T细胞和NK细胞活化以及抑制Treg发育(Brezar等人,2015;Anel等人,2012)。所有环氧-巴豆萜烷化合物激活PKC-β,这在B细胞受体信号传导和抗原呈递中是关键的(例如Kang等人2001;Lim等人2015)。被环氧巴豆萜烷的一些或全部较弱地激活的另外三种PKC同种型(-η,-α,-δ)也直接参与免疫细胞反应(Lim等人2015;Pfeifhofer等人2006)。
实施例2:小鼠肿瘤基质中的基因表达变化与免疫细胞募集和诱导Th-1/M1样抗肿瘤免疫应答一致
抗肿瘤免疫中的Th1/M-1样响应.Th1/M1样免疫应答通过一系列机制诱导抗肿瘤细胞免疫,包括直接杀肿瘤活性,抗肿瘤细胞因子反应的改变和长期免疫记忆的增强。例如,几个品系的证据表明CD4+T辅助细胞1型(Th1)细胞即Th1免疫的驱动者可以通过分泌各种细胞因子来帮助支持清除肿瘤细胞,包括干扰素-γ(IFN-γ),白细胞介素-2(IL-2)和肿瘤坏死因子-α(TNF-α)(Knutson等人2005;DeNardo等人2010;Burkholder等人2014)。这些细胞因子促进几种细胞类型的活性,包括抗原呈递细胞(APC),细胞毒性T细胞,NK细胞和各种先天免疫细胞亚型(例如Cohen等人2000;Bos&Sherman 2010)。还已知IFN-γ和TNF对肿瘤细胞存活具有直接作用(Sugarman等人1985;Bayaert等人1994)。虽然IL-1和IL-6(由M1巨噬细胞产生)与肿瘤发育有关,但最近的证据启示它们实际上是急性抗肿瘤免疫反应的重要组成部分(Haabeth等人2011;Gabrilovich等人2012;Haabeth等人2016)。已经证实它们可增强B细胞增殖和抗体产生,增加抗原呈递细胞(APC)的活性,刺激抗原特异性细胞毒性细胞类型的增殖并促进Th1细胞分化(Haabeth等人2011;Burkholder等人2014)。Th1与M1细胞因子之间的组合也已显示在肿瘤免疫监视中是重要的。例如,IL-1和IFN-γ协同激活巨噬细胞的杀肿瘤活性(Hori等人1989;Haabeth等人2016)。重要的是,肿瘤中M1巨噬细胞和Th1淋巴细胞的出现与许多癌症中预后和生存时间的改善呈正相关(Pages等人2010;Fridman等人2012;Senovilla等人2012)。实际上,已经提出诱导Th1/M1型炎症以显著改善基于抗癌免疫疗法的方法(Haabeth等人,2012)。下面描述了化合物1在异种移植小鼠模型的基质中促进Th1/M1样抗肿瘤免疫应答中的作用。
来自小鼠的人肿瘤异种移植物中的小鼠基质.将SK-MEL-28人黑素瘤细胞系皮下(s.c)注射到每只BALB/c Foxn1nu小鼠的侧腹上的2个位点(2百万个细胞/位点),并使其生长至约7mm直径。然后向每个肿瘤注射50μl含有30μg化合物1的20%丙二醇或50μl的20%丙二醇。在注射后的不同时间,使小鼠安乐死并收集肿瘤,去除皮肤覆盖物,并将完整的肿瘤储存在-80℃。
RNA提取.根据制造商的说明,使用Qiagen RNeasy Plus Mini Kit从30mg冷冻肿瘤中提取RNA,然后用NanoDrop仪器定量,并在带有1kb DNA标记的变性琼脂糖凝胶上进行完整性验证,并用溴化乙锭染色。
RNA扩增和标记.用无核酸酶的水将约500ng总未标记的RNA调节至最终体积11μl。将RNA与9μl逆转录酶主混合物(1μl T7 Oligo(dT)引物、2μl 10x第一链缓冲液、4μl dNTP混合物、1μl RNase抑制剂和1μl ArrayScript)一起在42℃温育2h。接下来是第二链cDNA合成步骤,其中包括在16℃下与80μl第二链主混合物(63μl无核酸酶水、10μl 10X第二链缓冲液、4μl dNTP混合物、2μl DNA聚合酶和1μl RNaseH)进一步温育2小时。通过用250μl cDNA结合缓冲液通过cDNA过滤柱过滤并用500μl试剂盒中提供的洗涤缓冲液洗涤来纯化cDNA。用20μl 55℃无核酸酶的水洗脱纯化的cDNA。将每种cDNA样品与7.5μl IVT主混合物(2.5μlT7 10X反应缓冲液、2.5μl T7酶混合物和2.5μl生物素-NTP混合物)在37℃温育16h。通过向每个cRNA样品中添加75μl无核酸酶水来终止反应。生物素化的扩增的RNA通过cRNA过滤柱过滤cRNA样品来纯化,其中将350μl的cRNA结合缓冲液和250μl的100%乙醇混合在一起,然后加载到过滤器上。然后用650μl洗涤缓冲液洗涤带有附着RNA的cRNA过滤柱,然后用200μl55℃无核酸酶水洗脱纯化的cRNA。
Illumina表达BeadChip杂交.将cRNA样品在65℃加热5min并通过脉冲离心收集。在65℃加热5min后,将约750ng cRNA样品等分到分开的管中,向其中加入~5μl不含RNase的水和10μl的Hyb Mix。将约15μl制备的cRNA混合物上样到Illumina ExpressionBeadChips上。根据Illumina提供的全基因组基因表达直接杂交分析指南进行杂交和洗涤的后续步骤。HumanHT-12v4表达BeadChips涵盖人类转录组中超过47,000个转录物和已知的剪接变体。MouseRef-8 v2.0 Expression BeadChips涵盖大约25,600个注释良好的RefSeq(参比序列)转录物,其包含超过19,000个独特基因。
数据分析.BecanChips由iScan System读取,并通过GenomeStudio转移到GeneSpring GX v12.5(Agilent Technologies,Santa Clara,CA,USA)。使用具有默认设置的分位数归一化对表达值进行校准。基于GenomeStudio计算的检测分数过滤实体,其中p≤0.05被认为具有显著性。
结果显示在图2中。图2A显示响应化合物1处理,在肿瘤部位增量调节对免疫细胞募集/活化重要的几种宿主细胞因子/趋化因子。值得注意的是,已知化合物1显著增量调节的Cxcl1促进中性粒细胞募集和随后杀伤残留的癌细胞(Garg等人,2017)。此外,图2B显示化合物1诱导宿主中的基因表达变化,其与Th-1/M样反应的发生相关,即IFN-γ,TNF,IL-6和IL-1β诱导。该数据还启示可能存在TGFβ信号传导的减量调节(图2C),这是已知的免疫抑制信号传导途径(Neuzillet等人2015)。
实施例3:化合物1和其他环氧巴豆萜烷的治疗浓度诱导细胞的细胞胀亡的证实
细胞胀亡是一种坏死性细胞死亡,其特征在于亚细胞细胞器的肿胀和破裂以及随后的质膜透化,部分原因是由于维持渗透平衡的ATP驱动的离子泵活性的丧失。已经显示细胞胀亡实际上具有免疫原性,并且与一些溶瘤病毒和作为抗癌剂开发的小分子的效能相关(例如Dyer等人2016)。
细胞系、试剂和培养基.在RPMI-1640,10%FCS(完全培养基)中在37℃,5%CO2在加湿的温育箱中培养A431(人类表皮样癌),MM649(人黑素瘤),B16-OVA(用鸡卵白蛋白稳定转染的B16-F10小鼠黑素瘤细胞系),MM415(人黑素瘤)和FaDu(人咽喉癌)细胞。使用MycoAlert(Lonza)将本研究中使用的所有细胞系确认为支原体阴性。还进行STR分析以鉴别所用人细胞系。
IncuCyte细胞毒性测定.评估四种癌细胞系(A431,MM649(人黑色素瘤),FaDu(HNSCC)和MM415(人黑色素瘤)对环氧巴豆萜烷处理的反应。细胞以每孔10,000个细胞的密度接种(100μl完全培养基)进入透明底部黑色96-孔板(Corning,#3603)。温育24h后,抽吸出每个孔内的培养基并用50μl含有1μg/ml碘化丙啶(PI)的新鲜培养基替换。将四种环氧巴豆萜烷(化合物1、2、3和4)的储备溶液(乙醇中20mg/ml)在相同培养基中稀释至2×最终测定浓度(1mM),并插入U-形底96孔板中以准备转移。将50μl稀释液加入所需的孔中,并将所得的板插入Essen Biosciences IncuCyte中以准备成像。在不同时间点(30分钟,1h和每小时间隔)获取图像,总计24h。
乳酸脱氢酶(LDH)释放测定.测量LDH的释放是公认的用于评估质膜透化和检测坏死细胞死亡的测定(Chan等人,2013)。在这些测定中使用三种细胞系(A431,MM649和B16-OVA)。将细胞以每孔10,000个细胞的密度接种到透明的96-孔板(Corning,#3595;100μl完全培养基)中,并如前所述将所得平板温育过夜。第二天,从每个孔中抽吸出培养基并插入50μl新鲜培养基。将化合物1的储备溶液稀释至2×最终测定浓度(1mM和600μM),并将50μl这些稀释液加入所需孔中。还汇总和施用仅含乙醇的对照溶液。在指定的时间点,取出50μl培养基并使用Pierce LDH细胞毒性测定试剂盒(ThermoFisher Scientific)测定LDH释放。使用Hybrid Synergy H4读板仪记录每个样品的OD490nm和OD690nm读数。将来自药物处理的样品的吸光度读数对洗涤剂处理的对照品校准,以确定每孔的%LDH释放。
胞内ATP测定.CellTiter-2.0检测试剂盒(Promega Corporation)(一种基于发光的检测方法,用于定量细胞中ATP的含量)用于测定暴露于两种浓度(300μM和500μM)的化合物1在A431和MM649培养物中的细胞内ATP水平。此外,将细胞以每孔10,000个细胞的密度接种到透明的有底黑色96-孔板(在100μl完全培养基中)中,并在37℃,5%CO2下温育过夜。在测定时,从每个孔中抽吸出培养基并插入50μl新鲜培养基。将化合物1的储备溶液稀释至2×最终测定浓度(1mM和600μM),并将50μl这些稀释液加入所需孔中。还汇总和施用仅含乙醇的对照溶液。在指定的时间点,轻轻取出培养基,确保不打扰细胞,并加入100μlCellTiter-2.0试剂。将得到的平板在轨道振荡器上混合2min以诱导细胞裂解,之后将其在黑暗中温育10min。此后,确定每个孔中的发光信号。将来自化合物处理的孔的发光信号相对于媒介物处理的孔进行校准,并表示为%胞内ATP相对于时间的关系。
在用500μM化合物1、2、3和4(A431,FaDu,MM649和MM415)处理的所有四种细胞系的大多数细胞中,从IncuCyte获得的图像在120分钟后显示强烈的红色染色。仅用媒介物处理的细胞没有染色,证实质膜完整性的丧失局限于用化合物1处理的细胞。此外,在用化合物1、2、3和4处理的所有细胞中也观察到显著的细胞质肿胀和“起泡”,不过,程度不同并且具有不同的起始动力学。
评估LDH释放和评估细胞内ATP水平的测定结果分别显示在图3A和3B中。与对照相比,在测试的两种浓度的化合物1(300μM和500μM)下处理的所有三种癌细胞系中均显著释放LDH(图3A)。用500μM化合物1处理后,胞内ATP水平非常迅速地下降,并且在60分钟后几乎检测不到(图3B)。在300μM化合物1下,与500μM浓度的化合物1时相比,胞内ATP下降得更慢并且更猛烈地下降,在120分钟后约为预处理水平的50%(图3B)。ATP的耗竭之前已经与诱导细胞胀亡有关(Kim等人2003)。
这些结果表明,环氧巴豆萜烷化合物在治疗相关浓度下(即在体内有效诱导出血性坏死的那些浓度)诱导细胞胀亡。
实施例4:化合物1和其他环氧巴豆萜烷诱导的细胞胀亡展示出免疫原性细胞死亡特征
免疫原性细胞死亡(ICD)是一种特定类型的受调节细胞死亡,其导致称为损伤相关分子模式(DAMP)的介质的释放或外化,其与树突细胞/巨噬细胞表达的受体相互作用以促进其募集并刺激肿瘤抗原摄取/将肿瘤抗原呈递给T细胞。ICD是激活免疫系统抵抗癌症的重要途径。ICD的生物化学标志包括钙蛋白(CALR)和其他内质网/线粒体蛋白在垂死细胞表面的暴露,以及大量ATP和高迁移率族蛋白1(HMGB1)释放到胞外环境中(Kroemer等人2013)。这些参数已被用于准确预测化疗药物(包括阿霉素,米托蒽醌,奥沙利铂和硼替佐米)诱导ICD的能力(Kroemer等人2013;Galluzzi等人2017)。环氧巴豆萜烷诱导这些特征的能力详述如下。
细胞系、试剂和培养基.在RPMI-1640,10%FCS(完全培养基)中于37℃,5%CO2加湿温育箱中培养A431(人表皮样癌),MM649(人黑色素瘤)和B16-OVA(用鸡卵清蛋白稳定转染的B16-F10小鼠黑色素瘤细胞系)。将BMDC在R10培养基(RPMI,10%FCS,2mM谷氨酰胺,50μMβ-巯基乙醇,Pen/Strep)中培养。使用MycoAlert(Lonza)将本研究中使用的所有细胞系确认为支原体阴性。还进行STR分析以确认所用人细胞系的身份。
ATP释放测定.将细胞系以每孔10,000个细胞的密度接种到透明的96-孔板(Corning,#3595;100μl完全培养基)中,并如前所述将所得平板温育过夜。第二天,从每个孔中抽吸出培养基并插入50μl新鲜培养基。将化合物1、2、3和4的储备溶液稀释至2×最终测定浓度(1mM和600μM),并将50μl这些稀释液加入所需孔中。还汇总和施用仅含乙醇的对照溶液。在指定的时间点,取出80μl培养基,以1,200rpm离心4分钟以沉淀细胞碎片,并使用基于生物发光的ATP测定试剂盒(FLAA,Sigma-Aldrich)测定50μl的ATP。使用HybridSynergy H4读板仪(BioTek)记录每个样品的相对发光单位。
HMGB1释放测定.将细胞系(A431,MM649和B16-OVA)置于T75cm2烧瓶(Nunc)中的10ml完全培养基中,并在37℃,5%CO2下培养直至它们达到90%汇合率。将化合物1、2、3和4在5ml相同的培养基中稀释至终浓度为500和300μM,然后施用于细胞。准备几个烧瓶,使得可以建立响应于药物处理的HMGB1释放的动力学曲线。进行了仅含乙醇的对照。在所需的时间点,将培养基从烧瓶中取出到10ml聚丙烯管中,将其置于冰上5min。将细胞培养物上清液以1,200rpm离心4min以除去细胞碎片,然后将4.5ml上清液插入浓缩器旋转柱(Ultra 50kDa截留膜,Merck)中以除去FCS。然后将来自该柱的流出物插入另一个浓缩器柱(Ultra 10kDa截留膜,Merck)中,并在通过ELISA(SEA399Hu/SEA399Mu,Cloud-Clone Corp)进行测定之前以3,500rpm离心以浓缩HMGB1。使用Hybr id Synergy H4读板仪(BioTek)测定OD 450nm值。将药物处理的样品的吸光度值相对于媒介物处理的样品校准,以确定响应于环氧巴豆萜烷处理的HMGB1释放的倍数增加。
钙网蛋白外化测定.如先前详述的那样测定钙网蛋白外化(Gomez-Cadena等人2016)。简言之,通过胰蛋白酶消化将在37℃,5%CO2的完全培养基中培养的细胞(A431,MM649,B16-OVA)分拆,以1,200rpm离心并用新鲜培养基洗涤×2。在另一轮离心后,将所得细胞沉淀以1×106个细胞/ml的浓度重悬,之后加入环氧巴豆萜烷至终浓度为500或300μM。也进行了仅含乙醇的对照。将细胞悬浮液在37℃,5%CO2下温育,并在指定的时间点,取出200μl样品,并与LIVE/DEAD可固定的远红色染料在冰上温育5min。然后,将细胞以1,200rpm沉淀4分钟并用PBS洗涤×1。然后向每个沉淀中加入500μl PBS,0.25%甲醛以进行光固定而不损害质膜完整性。此后,用PBS洗涤细胞×1并加入100μl含有抗钙网蛋白(ab2907,Abcam;1:50稀释)的PBS,1%BSA,2mM EDTA(FACs缓冲液)。在室温下温育1h后,将细胞以1,200rpm离心4min并用FAC缓冲液洗涤1次,然后在室温下用100μl含有抗家兔Alexa488的FAC缓冲液(1:750)再温育1小时。再次沉淀细胞,然后重悬于500μl FAC缓冲液中以准备流式细胞术。
首先通过FSC-H v FSC-A对样品进行门控以鉴定单个细胞,然后分析LIVE/DEAD染色(Ex:640nm,Em:670/14)阴性(完整细胞)群体的绿色荧光(Ex:488nm,Em:530/30;钙网蛋白外化)。随后测定平均荧光强度值并绘制与时间的关系图。
结果显示,由环氧巴豆萜烷化合物诱导的快速细胞胀亡也诱导了免疫原性细胞死亡的特征,其中关键DAMP的释放/外化包括ATP(图4A和4B),HMBG1(图4C)和钙网蛋白(图4D)。在用两种浓度的化合物1(图4A)和化合物2、3和4(图4B)处理的所有三种癌细胞系中,在60分钟内ATP显著释放。这些化合物还促进从癌细胞系释放HMGB1。在ELISA测定后,将处理细胞的值标准化为载体处理的细胞以确定倍数增加,显示化合物1在120分钟内使A341和MM649细胞的HMBG1释放增加高达40%(图4Ci和4Cii),并且对于B16-OVA细胞来说大于3倍(图4Ciii)。化合物2、3和4也对B16-OVA细胞进行了测定,并且在120分钟后显示出来自该细胞系的HMBG1释放最少增加2倍(图4Civ)。用化合物1处理3种细胞系后钙网蛋白外化的数据显示在处理60分钟内平均荧光强度显著增加(图4D)。已知这种DAMP释放/外化促进抗原呈递细胞的募集,刺激癌细胞相关抗原的有效摄取并刺激T细胞亚群的呈递(Kolaczkowska&Kubes,2013)。
实施例5:来自环氧巴豆萜烷处理的癌细胞的碎片被CD11c+骨髓衍生细胞群摄取
CD11c是DC/巨噬细胞的良好描述的标志物(Merad等人2013)。研究抗癌药物(以及它们诱导的相关死亡过程)促进免疫原性反应发展的潜力的一种方法是确定它们是否导致CD11c+树突细胞/巨噬细胞摄取细胞成分并随后成熟为真正的骨抗原呈递细胞(APC)(Guermonprez等,2002)。本文中,我们证明由化合物1和相关的环氧巴豆萜烷诱导的细胞胀亡导致这些细胞摄取垂死的癌细胞成分。
骨髓衍生细胞(BMDC)的分离和培养.首先在无菌条件下手术取出来自四只7-8周龄C57Bl/6小鼠的胫骨和纤维(fibias)。用10ml冰冷的R10培养基(使用27G针头/注射器注入50ml聚丙烯管)从骨腔冲洗骨髓。将细胞以1,500rpm沉淀5min并用冰冷的R10培养基洗涤×2。将沉淀重新悬浮于10ml冰冷的R10培养基中后,使用改进的血细胞计数器计数细胞,并以每个平板2×106个细胞(培养皿)的密度接种在10ml补充有20ng/ml鼠GM-CSF的R10中。将所有平板在37℃,5%CO2下温育,并在第3天,加入另外的10ml含有20ng/ml GM-CSF的R10。在第6天再次喂食细胞并在第7天用于下游测定。
BMDC摄取实验.在与BMDC共温育之前,用胰蛋白酶消化B16-OVA细胞,以1,200rpm离心4min以沉淀细胞并用完全培养基洗涤×2。然后将细胞用2μM Cell Tracker Green在完全培养基中染色45分钟,之后将它们沉淀并如上洗涤×2。标记的B16-OVA细胞随后用化合物1、2、3和4以两种浓度(500或300μM)在培养基中以1×106个细胞/ml的密度处理30和60min,此后通过离心沉淀细胞,通过抽吸除去上清液,用完全培养基洗涤细胞沉淀×1。洗涤后,将处理过的细胞重悬浮于R10培养基中,插入6-孔板(Corning,#3471。超低附着表面)的孔中,并加入BMDC。将共培养物温育4h,然后将细胞悬浮液转移至微量离心管中并以1,500rpm离心5min。将沉淀重悬于含有抗CD11c-APC的100μl FAC缓冲液中,并在4℃下温育10min。再次沉淀细胞,用FAC缓冲液洗涤×1,然后用PBS,1%甲醛固定10min。离心并除去上清液后,将细胞重悬于500μl FAC缓冲液中以准备流式细胞术。
首先通过FSC-H v FSC-A、然后SSC-H v SS-A对样品进行门控以鉴定单个细胞。然后对于处理和未处理细胞测定CD11c+细胞(Ex:640nm,Em:670/14)与CMFDAmid(Ex:488nm,Em:530/30)的比例作为全部CD11c+细胞的百分比。
结果(图5A和5B)显示化合物1诱导的细胞胀亡促进CD11c+树突细胞/巨噬细胞对垂死的癌细胞碎片的摄取(即有效摄取)。该摄取显然取决于化合物1浓度和处理时间,使得与使用300μM相比,在更短的处理时间后,500μM的化合物1抗原摄取发生的程度更大。这与实施例3中观察到的细胞胀亡的动力学一致。图5C表明化合物2、3和4也能够诱导体外免疫原性的细胞死亡反应,即促进CD11c+BMDC的摄取。
实施例6:化合物1与免疫关卡抑制剂的组合
免疫关卡抑制剂疗法,特别是那些靶向牵涉T细胞免疫抑制的受体(例如细胞毒性T-淋巴细胞相关蛋白4(CTLA-4)或程序性死亡1(PD-1)及其配体PD-L1)的疗法显著改善了患者几种类型的晚期癌症的结果,包括黑素瘤,肾细胞癌,膀胱癌和头颈部鳞状细胞癌(HNSCC)(Msaouel&Massarelli 2016;Sharma&Allison 2015)。然而,对这些ICI药物的原发性和新生抗性是一个重要的临床问题。此外,广泛的临床随访已经证实,一些黑色素瘤患者正在发展对治疗的抵抗力并且正在经历疾病复发(O'Donnell等人,2017)。将ICI与可能通过促进免疫原性细胞死亡(特别是通过导致免疫细胞浸润到肿瘤旁瘤和抗原摄取/呈递中增加)作为辅助的化合物相结合的疗法有望克服ICI的一些局限性并改善总体临床结果(Workenhe等人2014;Ribas等人2017)。本文中,并且在实施例7中,数据检验了ICI与化合物1的病灶内注射的组合。
实验方法的示意图可以在图6A中看到。简言之,将6-7周龄C57BL/6小鼠皮下(s.c.)注射到两侧,采用B16-F10-OVA小鼠黑色素瘤细胞(每个位点2×105个细胞,100μl)。允许肿瘤发育至约5-50mm3,此后将200μg抗PD-1(RMP1-14,BioXCell),抗-CTLA-4(9H10,BioXCell)或同种型对照抗体(2A3和Syrian Hamster IgG,BioXCell)i.p.注射/小鼠(第-2天)。在第0天,两个肿瘤均I.T.注射仅含化合物1(50μl中15μg)或媒介物(Vehc.)。在第-2天每只小鼠接受额外的i.p.注射施用的相同抗体(再次,200μg)。通过每2天i.p.注射一次施用抗体另外3次。如先前详述(Boyle等人2014)使用卡尺测量治疗肿瘤的体积,并确定随时间变化的小鼠存活率。
图6B和6C中显示的结果显示化合物1可以与抗PD-1和抗-CTLA-4结合以限制肿瘤生长并且比单一活性剂处理更大程度地改善小鼠存活。对于每种化合物1/ICI组合,该效果似乎是浓度依赖性的。例如,与单独使用30μg化合物1相比,注射30μg化合物1和抗PD-1导致存活率提高/肿瘤生长减少(图6Biii,iv)。当15μg化合物1以相同组合使用时,未观察到存活或肿瘤生长的改善(图6Bi,ii)。当使用抗-CTLA4时,情况相反,其中组合治疗中的15μg化合物1(图6Ci,ii)得到最佳响应,而30μg化合物1未得到(图6Ciii,iv)。
实施例7:当使用化合物1与免疫关卡抑制剂组合时Abscopal效应的观察
实验方法的示意图可以在图7A中看到。简言之,皮下注射6-7周龄的C57BL/6小鼠,采用B16-F10-OVA小鼠黑素瘤细胞注射到两侧上(每个位点2×105个细胞,100μl)。使肿瘤发育至约5-50mm3,此后将200μg抗-PD-1(RMP1-14,BioXCell),抗-CTLA-4(9H10,BioXCell)或同种型对照抗体(2A3,BioXCell)通过i.p.注入每只小鼠(第-2天)。在第0天,给两个肿瘤中的最大肿瘤(约50-75mm3)I.T.注射仅化合物1(50μl中15μg)或媒介物(Vehc.)。剩余的肿瘤未经处理,每只小鼠接受额外的i.p.注射(在第-2天)施用的相同抗体(进一步200μg)。通过每2天i.p.注射一次施用抗体另外3次。如前详述,在实验过程中测量治疗和未治疗肿瘤的体积。
结果显示在图7B中。结果显示,不仅用抗体和化合物1的组合治疗的肿瘤被有效消融,而且一些未治疗的邻近肿瘤也显示出对联合疗法的反应,这是单独使用任一种活性剂均未观察到的。
实施例8:髓细胞样衍生抑制细胞可以影响化合物1的低剂量效能
髓源性抑制细胞(MDSCs)是未成熟的髓样细胞,其可通过多种途径抑制宿主对肿瘤的免疫应答(Qu等人2016)。我们使用粒细胞集落刺激因子(GCSF)敲除C57BL/6小鼠提供了一个模型,其用于评估化合物1与抑制或阻断蛋白质的分子(例如吲哚胺2,3-双加氧酶(IDO))的可能联合治疗的未来潜力与MDSC招募和功能相关。GCSF是中性粒细胞生成和运输的重要调节因子,其在MDSC的迁移和增殖中也起着关键作用(Li等人2016)。使用我们的GCSFR敲除模型,检验了粒细胞衍生的MSDC在限制化合物1针对MC38结肠直肠腺癌的单一疗法(在次优剂量下)的效能中的可能作用。
简言之,给6-7周龄的C57BL/6和gcsfr-/-小鼠两侧s.c.注射MC38小鼠结肠直肠癌细胞(每个位点1×106个细胞,100μl)。使肿瘤发育至约5-50mm3,此后,I.T.注射15μg化合物1或媒介物(Vehc.)(50μl)。遵循如先前在实施例6和7中详述的经处理的肿瘤的体积。在图8中可以看到野生型(wt)和GCSFR敲除小鼠中化合物1注射的肿瘤之间的肿瘤大小和存活率比较。
考虑到GCSFR在粒细胞募集中的作用,这些数据启示这种免疫细胞浸润可能限制化合物1在已知次优剂量(15μg)下的抗癌效能。化合物1或类似物与阻止这种免疫抑制细胞群发育的化合物(例如IDO抑制剂)的组合因此可以产生更好的抗癌效能并改善患者存活率。
本发明所属领域的技术人员将理解,在不脱离本发明的精神和范围的情况下,可以进行许多变型。
参考文献
应当理解,在澳大利亚或任何其他国家,如果本文涉及任何现有技术出版物,则这类参考文献并不构成该出版物形成本领域公知常识的组成部分的允许。
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Claims (29)
1.治疗肿瘤的方法,包含对有此需要的受试者施用环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂。
2.治疗或预防受试者的一种或多种旁观者肿瘤的方法,包含对有此需要的受试者施用环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂;其中将环氧巴豆萜烷化合物局部施用于除了所述一种或多种旁观者肿瘤之外的肿瘤。
3.权利要求1或权利要求2的方法,其中将环氧巴豆萜烷化合物局部施用于肿瘤。
4.权利要求1-3任一项的方法,其中通过肿瘤内注射施用环氧巴豆萜烷化合物。
5.权利要求1-4任一项的方法,其中全身施用免疫关卡抑制剂。
6.权利要求5的方法,其中通过胃肠外注射施用免疫关卡抑制剂。
7.权利要求1-6任一项的方法,其中环氧巴豆萜烷化合物为式(I)的化合物:
或其几何异构体或立体异构体或药学上可接受的盐;
其中
R1为氢或C1-6烷基;
R2为-OH或-OR9;
R3为-OH或-OR9;
R4和R5独立地选自氢和C1-6烷基;
R6为氢或-R10;
R7为羟基或OR10;
R8为氢或C1-6烷基;
R9为-C1-20烷基、-C2-20烯基、-C2-20炔基、-C(O)C1-20烷基、-C(O)C2-20烯基、-C(O)C2-20炔基、-C(O)环烷基、-C(O)C1-10烷基环烷基;-C(O)C2-10烯基环烷基、-C(O)C2-10炔基环烷基、-C(O)芳基、-C(O)C1-10烷基芳基、-C(O)C2-10烯基芳基、-C(O)C2-10炔基芳基、-C(O)C1-10烷基C(O)R11、-C(O)C2-10烯基C(O)R11、-C(O)C2-10炔基C(O)R11、-C(O)C1-10烷基CH(OR11)(OR11)、-C(O)C2-10烯基CH(OR11)(OR11)、-C(O)C2-10炔基CH(OR11)(OR11)、-C(O)C1-10烷基SR11、-C(O)C2-10烯基SR11、-C(O)C2-10炔基SR11、-C(O)C1-10烷基C(O)OR11、-C(O)C2-10烯基C(O)OR11、-C(O)C2-10炔基C(O)OR11、-C(O)C1-10烷基C(O)SR11、-C(O)C2-10烯基C(O)SR11、-C(O)C2-10炔基C(O)SR11、
或
R10为-C1-6烷基、-C2-6烯基、-C2-6炔基、-C(O)C1-6烷基、-C(O)C2-6烯基、-C(O)C2-6炔基、-C(O)芳基、-C(O)C1-6烷基芳基、-C(O)C2-6烯基芳基,或-C(O)C2-6炔基芳基;且
R11为氢、-C1-10烷基、-C2-10烯基、-C2-10炔基、环烷基或芳基;
其中烷基、烯基、炔基、环烷基或芳基各自任选地被取代。
8.权利要求7的方法,其中R1为-CH3。
9.权利要求7或权利要求8的方法,其中R2和R3独立地选自-OC(O)C1-20烷基、-OC(O)C2-20烯基、-OC(O)C2-20炔基、-OC(O)环烷基、-OC(O)C1-10烷基环烷基;-OC(O)C2-10烯基环烷基、-OC(O)C2-10炔基环烷基、-OC(O)芳基、-OC(O)C1-10烷基芳基、-OC(O)C2-10烯基芳基、-OC(O)C2-10炔基芳基、-OC(O)C1-10烷基C(O)R11、-OC(O)C2-10烯基C(O)R11、-OC(O)C2-10炔基C(O)R11、-OC(O)C1-10烷基CH(OR11)(OR11)、-OC(O)C2-10烯基CH(OR11)(OR11)、-OC(O)C2-10炔基CH(OR11)(OR11)、-OC(O)C1-10烷基SR11、-OC(O)C2-10烯基SR11、-OC(O)C2-10炔基SR11、-OC(O)C1-10烷基C(O)OR11、-OC(O)C2-10烯基C(O)OR11、-OC(O)C2-10炔基C(O)OR11、-OC(O)C1-10烷基C(O)SR11、-OC(O)C2-10烯基C(O)SR11和-OC(O)C2-10炔基C(O)SR11。
10.权利要求9的方法,其中R2和R3独立地选自-OC(O)C1-20烷基、-OC(O)C2-20烯基、-OC(O)C2-20炔基、-OC(O)环烷基、-OC(O)C1-10烷基环烷基;-OC(O)C2-10烯基环烷基、-OC(O)C2-10炔基环烷基和-OC(O)芳基。
11.权利要求9或权利要求10的方法,其中R2和R3独立地选自-OC(O)C1-20烷基、-OC(O)C2-20烯基和-OC(O)C2-20炔基。
12.权利要求7-11任一项的方法,其中R4和R5各自独立地选自H和-CH3。
13.权利要求7-12任一项的方法,其中R6为氢、-C(O)C1-6烷基、-C(O)C2-6烯基、-C(O)C2-6炔基或-C(O)芳基。
14.权利要求7-13任一项的方法,其中R7为羟基、-OC(O)C1-6烷基、-OC(O)C2-6烯基或-OC(O)C2-6炔基。
15.权利要求7-14任一项的方法,其中R8为H或-CH3。
16.权利要求7的方法,其中式(I)的化合物为式(II)的化合物:
或其几何异构体或立体异构体或药学上可接受的盐;
其中R6,R7和R9如权利要求7中所定义。
17.权利要求7-16任一项的方法,其中式(II)的环氧巴豆萜烷化合物选自下列化合物:
12-巴豆萜酰基-13-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮;
12,13-二-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮;
12-己酰基-13-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮;
12,13-二己酰基-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮;
12-肉豆蔻酰基-13-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮;
12-巴豆萜酰基-13-(2-甲基丁酰基)-6,7-环氧-4,5,9,12,13-五羟基-20-乙酰氧基-1-巴豆萜烯-3-酮;
12-肉豆蔻酰基-13-乙酰氧基-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮;
12-丙酰基-13-2-甲基丁酰基)-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮;12,13-二巴豆萜酰基-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮;和
12-(2-甲基丁酰基)-13-巴豆萜酰基-6,7-环氧-4,5,9,12,13,20-六羟基-1-巴豆萜烯-3-酮;
或其药学上可接受的盐。
18.权利要求1-17任一项的方法,其中免疫关卡抑制剂为下列物质的拮抗剂:程序性死亡1(PD-1)受体、细胞毒性T-淋巴细胞相关蛋白4(CTLA-4)、腺苷A2A受体、B7-H3,B7-H4、吲哚胺2,3-双加氧酶、杀伤细胞免疫球蛋白样受体(KIR)、淋巴细胞活化基因-3(LAG3)、具有IG和ITIM结构域的T细胞免疫受体(TIGIT)、含T-细胞免疫球蛋白和粘蛋白-结构域的分子-3(TIM-3)、CD96和T细胞活化的V-结构域免疫球蛋白抑制剂(VISTA)。
19.权利要求18的方法,其中免疫关卡抑制剂为程序性死亡1(PD-1)受体或细胞毒性T-淋巴细胞相关蛋白4(CTLA-4)的拮抗剂。
20.权利要求1-19任一项的方法,其中以多剂量施用免疫关卡抑制剂。
21.权利要求20的方法,其中在施用环氧巴豆萜烷化合物之前、与之同时和/或随后施用多剂量。
22.权利要求21的方法,其中在施用环氧巴豆萜烷化合物之前施用免疫关卡抑制剂的首剂量。
23.权利要求21或22的方法,其中与环氧巴豆萜烷化合物同时施用免疫关卡抑制剂的剂量。
24.权利要求21-23任一项的方法,其中在施用环氧巴豆萜烷化合物之后施用一个或多个剂量的免疫关卡抑制剂。
25.药物组合物,包含环氧巴豆萜烷化合物或其药学上可接受的盐和免疫关卡抑制剂,且任选地包含药学上可接受的载体。
26.药盒,包含含有环氧巴豆萜烷化合物的组合物和含有免疫关卡抑制剂的组合物。
27.权利要求26的药盒,包含一个或多个剂量的环氧巴豆萜烷化合物和一个或多个剂量的免疫关卡抑制剂。
28.权利要求26或27的药盒,包含一个或多个剂量的配制成用于局部施用形式的环氧巴豆萜烷化合物和一个或多个剂量的配制成用于通过注射施用的免疫关卡抑制剂。
29.权利要求26或27的药盒,包含一个剂量的配制成用于肿瘤内注射形式的环氧巴豆萜烷化合物和一个或多个剂量的配制成用于通过注射施用的免疫关卡抑制剂。
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CA2975852A1 (en) | 2015-02-04 | 2016-08-11 | Twist Bioscience Corporation | Methods and devices for de novo oligonucleic acid assembly |
WO2016172377A1 (en) | 2015-04-21 | 2016-10-27 | Twist Bioscience Corporation | Devices and methods for oligonucleic acid library synthesis |
CN108368482A (zh) | 2015-09-18 | 2018-08-03 | 特韦斯特生物科学公司 | 寡核酸变体文库及其合成 |
KR20180058772A (ko) | 2015-09-22 | 2018-06-01 | 트위스트 바이오사이언스 코포레이션 | 핵산 합성을 위한 가요성 기판 |
KR102217487B1 (ko) | 2016-09-21 | 2021-02-23 | 트위스트 바이오사이언스 코포레이션 | 핵산 기반 데이터 저장 |
EP3586255A4 (en) | 2017-02-22 | 2021-03-31 | Twist Bioscience Corporation | NUCLEIC ACID-BASED DATA STORAGE |
CA3066744A1 (en) | 2017-06-12 | 2018-12-20 | Twist Bioscience Corporation | Methods for seamless nucleic acid assembly |
WO2018231864A1 (en) | 2017-06-12 | 2018-12-20 | Twist Bioscience Corporation | Methods for seamless nucleic acid assembly |
CA3075505A1 (en) | 2017-09-11 | 2019-03-14 | Twist Bioscience Corporation | Gpcr binding proteins and synthesis thereof |
GB2583590A (en) | 2017-10-20 | 2020-11-04 | Twist Bioscience Corp | Heated nanowells for polynucleotide synthesis |
AU2019270243A1 (en) | 2018-05-18 | 2021-01-07 | Twist Bioscience Corporation | Polynucleotides, reagents, and methods for nucleic acid hybridization |
SG11202109283UA (en) | 2019-02-26 | 2021-09-29 | Twist Bioscience Corp | Variant nucleic acid libraries for antibody optimization |
US20220193023A1 (en) | 2019-04-12 | 2022-06-23 | QBiotics Pty Ltd | Method of treating tumours |
MX2021015673A (es) * | 2019-06-19 | 2022-02-03 | QBiotics Pty Ltd | Alteracion de biopelicula. |
CN114729342A (zh) | 2019-06-21 | 2022-07-08 | 特韦斯特生物科学公司 | 基于条形码的核酸序列装配 |
MX2022006995A (es) * | 2019-12-09 | 2022-10-27 | Twist Bioscience Corp | Bibliotecas de acidos nucleicos variantes para receptores de adenosina. |
KR20220151333A (ko) | 2021-05-06 | 2022-11-15 | 한국과학기술연구원 | 가시광선에 의해 활성화되는 항암 면역치료용 나노입자 및 이의 용도 |
WO2023115123A1 (en) * | 2021-12-21 | 2023-06-29 | QBiotics Pty Ltd | Crystalline intermediates |
WO2023154984A1 (en) * | 2022-02-17 | 2023-08-24 | QBiotics Pty Ltd | Combination therapies |
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