CN117729917A - 使用akr1c3活化化合物与免疫检查点抑制剂的组合疗法 - Google Patents
使用akr1c3活化化合物与免疫检查点抑制剂的组合疗法 Download PDFInfo
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- CN117729917A CN117729917A CN202180097625.2A CN202180097625A CN117729917A CN 117729917 A CN117729917 A CN 117729917A CN 202180097625 A CN202180097625 A CN 202180097625A CN 117729917 A CN117729917 A CN 117729917A
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Abstract
本发明提供一种医药组合物及其医疗用途。该医药组合物包括化合物1‑(3‑(3‑N,N‑二甲基胺基羰基)苯氧基‑4‑硝苯基)‑1‑乙基‑N,N′‑双(乙烯)胺基磷酸酯及至少一治疗剂,该治疗剂包括化学治疗剂或生物试剂。
Description
技术领域
本发明涉及一种组合物及其医疗用途,该组合物包括化合物1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯与至少一治疗剂的组合,该治疗剂包括化学治疗剂或生物试剂。
背景技术
癌症是人类罹病率及死亡率的主要原因之一。癌症治疗具有挑战性,此乃因难以在不损伤或杀死正常细胞的情形下杀死癌细胞。在癌症治疗期间损伤或杀死正常细胞是在患者中产生不利副作用的原因,且其限制向癌症患者投与的抗癌药物的量。
醛酮还原酶家族1成员C3(AKR1C3)是人类中由AKR1C3基因编码的酶。此基因编码醛/酮还原酶超家族的成员,该超家族由多于40种已知酶及蛋白质组成。该等酶通过利用NADH及/或NADPH作为辅因子来催化醛及酮转化为其相应醇。其亦被称为第5型,17β-羟基类固醇去氢酶(17β-hydroxysteroid dehydrogenase,17β-HSD)以及前列腺素F合成酶。AKR1C3为醛糖酮还原酶(aldo-keto reductases,AKRs)的15个基因家族的成员之一。AKR1C3最初是从人类前列腺(1)以及胎盘(2)的cDNA文库中选殖出来的。AKR1C3为一种单体、存在胞质液(cytosolic)中的NAD(P)(H)依赖性氧化还原酶,具有323个胺基酸,分子量为37kDa(1)。AKR1C3与其相关的人类AKR1C家族,包括AKR1C1、AKR1C2,以及AKR1C4,具有高度的序列同源性。AKR1C3催化雄性荷尔蒙、雌性荷尔蒙、孕酮(progesterone),以及前列腺素(prostaglandin,PG)代谢,随后参与核受体活性的调节(3,4)。AKR1C3在包括类固醇荷尔蒙依赖性以及类固醇荷尔蒙非依赖性细胞在内的正常组织中表现,其平均表现量低,除了在肝脏、肾脏,以及小肠以外(5)。许多研究显示,AKR1C3在许多恶性实体及血液系统肿瘤中异常过度表现。数据显示,以免疫组织化学评分(immunohistochemistry,IHC评分)0至6的评分范围内,检测到超过50%的肝癌、膀胱癌、肾癌,以及胃癌中AKR1C3的高度表现,其IHC评分≥4(6)。AKR1C3在非小细胞肺癌(non-small cell lung cancer,NSCLC)中高度表现,但在小细胞肺癌中则否(7)。
据报导,癌症中的AKR1C3上调与去势抗性前列腺癌(castrate-resistantprostate cancer,CRPC(8))以及直肠癌(colorectal cancer,CRC(9))的转移有关,且还与预后不良以及低存活率有关(10,11)。另外,许多类型的治疗抗性归因于AKR1C3的过度表现。据报导,对阿霉素(doxorubicin)(12,13)、恩杂鲁胺(enzalutamide)(14)、阿比特龙(abiraterone)(15)及氨甲蝶呤(methotrexate)(16)的化学疗法抗性与细胞中AKR1C3的高度表现直接相关。食道癌(17)、前列腺癌(18)以及NSCL癌细胞(19)中的放射线疗法抗性与AKR1C3过度表现有关。AKR1C3对抗电离辐射的主要作用机制为减少细胞中的活性含氧物(reactive oxygen species,ROS)、增加PGF2α,随后导致MAP激酶活化以及PPARγ的抑制,进而显著减少DNA损伤(18)。免疫治疗抗性也归因于AKR1C3的高度表现。一项研究显示,基于全基因组微阵列以及多重定量(q)RT-PCR基因表现分析(20),AKR1C3的高度表现与PD-L1阳性晚期肾细胞癌(renal cell carcinoma,RCC)患者的PD-1标靶治疗失败有关。由于AKR1C3的肿瘤特异性过度表现,设计AKR1C3活化的前药成为一种专门针对癌症的有吸引力的方法。其中一个例子为AKR1C3活化的前药PR104,尽管其最初被设计为一种低氧活化的前药(22-24),但其在体外及体内均表现出良好的抗肿瘤活性(6,21)。
本发明的式I-1的抗癌前药(在本发明中以OBI-3424表示)为一种化学合成的强氮芥(nitrogen mustard),其在NADPH的存在下被AKR1C3选择性裂解为细胞毒性氮丙啶(aziridine)(在本发明中以OBI-2660表示)。由OBI-3424释放的活性分子OBI-2660与标准化学治疗药物噻替哌(thiotepa)以及丝裂霉素C(mitomycin C)相似,后者导致DNA在鸟嘌呤(guanine)的N7(或O6)位置上的烷基化及交联。目前在亚洲,前药OBI-3424由深圳艾欣达伟医药科技有限公司(Ascentawits Pharmaceuticals,LTD.)开发,在亚洲以外的国家由OBI制药公司(OBIPharma,Inc.)开发(药物代码OBI-3424),以用于治疗恶性肿瘤。前药OBI-3424目前正在美国(NCT04315324以及NCT03592264)及中国(CXHL1900137以及CXHL2000263)进行多个临床第一期试验研究,以治疗超过14种的人类癌症,包括实体瘤以及血液系统恶性肿瘤。由于AKR1C3在肿瘤中的高度表现,前药OBI-3424被设计为在肿瘤中会被特异性活化,但在AKR1C3表现量低的正常细胞中不会被活化,以达到以肿瘤为特异性标靶的作用。此外,OBI-3424的肿瘤选择性活化与非选择性传统烷基化剂,例如环磷酰胺(cyclophosphamide)以及异环磷酰胺(ifosfamide)不同,这表示OBI-3424有潜力成为范围广、高选择性的抗肿瘤药物。据报导,前药OBI-3424在体外及体内对T-ALL的临床前模型均显示出强效功效(25,26)。
在NADPH存在的情况下,AKR1C3调节OBI-3424的还原作用,进而释放出细胞毒性部分体OBI-2660,其为一种氮丙啶双烷基化剂,可导致DNA在鸟嘌呤N7(或O6)位置的交联,并随后导致细胞死亡。
近年来,设计以癌细胞为标靶的前药已成为一种有吸引力的癌症治疗策略;然而,由于缺乏有效的生物标记物来选择患者,许多前药在临床第三期试验中失败了(27)。鉴于可使用RT-PCR或免疫组织化学来评估AKR1C3的表现,可通过选择具有较高AKR1C3表现且最可能对前药产生反应的患者,以临床有效的方式开发OBI-3424。AKR1C3被证明在获得化学抗性(13,14)、放射线抗性(19)以及免疫抗性(20)时过度表现。此外,已知具有同源重组缺陷(homologous recombination deficiency,HRD)的癌症,例如卵巢癌、乳癌,以及胰脏癌对DNA损伤剂敏感(28)。作为DNA烷基化剂,OBI-3424也可能是治疗具有AKR1C3表现的HRD癌症的良好候选药物。
仍然需要适合于治疗癌症患者的化合物,其为一种选择性的AKR1C3还原酶活化的前药,以及一种新颖、选择性且广泛的抗癌剂。本发明满足了此一需求。
程序性死亡1(PD-1)为表现在T细胞、B细胞、或单核球上的抑制性受体。PD-L1与PD-L2为PD-1的配体,其经确定在结合至PD-1时向下调节T细胞活化与细胞激素分泌。以PD-1配合PD-L1或PD-L2,导致免疫反应向下调节。因此,已知阻断PD-1/PD-L1途径可减弱对抗癌症时的中枢与周边免疫反应。在包括黑色素瘤、非小细胞肺癌(NSCLC)、肾细胞癌(RCC)、膀胱癌、及何杰金氏淋巴瘤(Hodgkin’slymphoma)等15种以上的癌症类型中,标靶PD-1与PD-L1途径显示临床功效。然而,仍有许多病患没有反应;一些病患出现最初的反应,但随时间推移产生抗药性。因此,迫切需要确定结合医疗的抗药性机制。
发明内容
基于如PCT专利申请号PCT/US2016/062114(WO2017087428A1)中公开的化合物或其医药上可接受的盐类或其溶剂化物,本发明提供该化合物的医疗用途,并提供包括该化合物或其医药上可接受的盐类、其同位素变体或其溶剂化物的组合物,及其抗癌医疗用途。
一方面,本发明提供由式I(于本发明中以OBI-2870表示)表示的化合物1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯(1-(3-(3-N,N-dimethylaminocarbonyl)phenoxyl-4-mtrophenyl)-1-ethyl-N,N'-bis(ethylene)phosphoramidate),或其医药上可接受的盐类、同位素变体或溶剂化物在制造用于治疗患者癌症的药物的用途,其中该癌症的AKR1C3还原酶含量由AKR1C3蛋白含量或RNA含量来表示,且等于或大于预定值。AKR1C3含量是根据本领域技术人员熟知的常规方法测量。
根据本发明的特定实施例,该化合物为式I-1(于本发明中以OBI-3424表示)表示的(S)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯,或为式I-2(于本发明中以OBI-3423表示)表示的(R)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基1-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯。
式I、式I-1或式I-2的化合物的制备公开于PCT专利申请号PCT/US2016/062114(WO2017087428A1)中,其公开内容通过引用整体并入本发明。于本发明中,化合物OBI-2870为外消旋混合物,包含1:1比例的R-镜像异构物3423以及S-镜像异构物OBI-3424。
于本发明中,该盐类可为碱性盐,包括该化合物与无机碱(例如,碱金属氢氧化物以及碱土金属氢氧化物)或与有机碱(例如,单乙醇胺、二乙醇胺或三乙醇胺)形成的盐类。或者,该盐可为酸盐,包括该化合物与无机酸(例如,盐酸、氢溴酸、氢碘酸、硝酸、过氯酸、硫酸或磷酸)或与有机酸(例如,甲磺酸、三氟甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、富马酸(fumaric acid)、草酸(oxalic acid)、马来酸以及柠檬酸)形成的盐类。选择并制备化合物的可接受的盐类、溶剂化物等为本领域熟知的技术。
根据本发明的特定实施例,式I-1或式I-2的化合物的镜像异构物过量不小于80%。优选地,该化合物的镜像异构物过量不小于90%,更优选不小于95%。
根据本发明的特定实施例,式I-1或式I-2的化合物为基本上纯的。
根据本发明的特定实施例,该癌症为肝癌、肝细胞癌(hepatocellularcarcinoma,HCC)、肺癌、黑色素瘤、前列腺癌、乳癌、血癌、食道癌、肾癌、胃癌、结肠癌、脑癌、膀胱癌、子宫颈癌、卵巢癌、头颈癌、子宫内膜癌、胰脏癌、肉瘤癌或直肠癌。
根据本发明的特定实施例,该癌症为肝癌。
用于治疗癌症的药物剂量,或该药物中包含的化合物或其盐类、同位素变体或溶剂化物或其他化学治疗剂的剂量通常取决于所用的具体化合物、患者、具体疾病或状况及其严重性、给药途径及频率等,且需由主治医生根据具体情况来确定。为了本发明的目的,典型的日剂量可在约0.1μg/kg至1μg/kg、至10μg/kg、至100μg/kg、至1mg/kg、至10mg/kg、至100mg/kg或更高的任何范围内,具体取决于上述因素。针对几天或更长时间的重复给药,取决于病情,治疗持续到出现期望的症状抑制或直到达到足以减轻癌症或其症状的治疗程度。示例性的给药方案包括给予约0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg或更高的初始剂量,然后每周一次维持剂量。然而,取决于该行医者希望达到的药物动力学衰减的模式,其他剂量方案可能是有用的。例如,可考虑每周服用一至四次。于某些实施例中,给药频率为每周、每2周、每4周、每5周、每6周、每7周、每8周、每9周或每10周一次;或每月、每2个月或每3个月或更长时间一次。通过常规技术及分析很容易监测该疗法的进展。
药物可为用于临床给药的任何剂型,例如片剂、栓剂、分散片、肠溶片、咀嚼片、口腔崩解片、胶囊剂、糖衣剂、颗粒剂、干粉、口服溶液、注射用小针、注射用冻干粉或输注溶液。
根据本发明的特定实施例,该方法进一步包括以下步骤:使用AKR1C3抗体测量患者体内癌细胞的AKR1C3还原酶的含量,其中AKR1C3还原酶的含量被测量为等于或大于预定值,然后将该化合物施用于该患者。
另一方面,本发明提供一种抑制细胞生长的方法,包括使细胞与有效量的式I表示的化合物1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯,或其医药上可接受的盐类、同位素变体或溶剂化物接触的步骤;其中该细胞的AKR1C3还原酶含量由AKR1C3蛋白含量或RNA含量表示并且等于或大于预定值。
根据本发明的特定实施例,该方法进一步包括使用AKR1C3抗体测量细胞的AKR1C3还原酶含量的步骤,其中测得的AKR1C3还原酶的含量等于或大于该预定值,并使该化合物与该细胞接触。
另一方面,本发明提供式I表示的化合物1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯,或其医药上可接受的盐类、同位素变体或溶剂化物在制备用于抑制细胞生长的药物的用途;其中该细胞的AKR1C3还原酶含量由该AKR1C3蛋白含量或RNA含量表示并且等于或大于预定值。
根据本发明的特定实施例,该细胞为癌细胞。
另一方面,本发明提供一种组合物,包括:
(1)由式I表示的化合物1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯,或其医药上可接受的盐类、同位素变体或溶剂化物;以及
(2)至少一治疗剂,包括化学治疗剂或生物试剂。
根据本发明的特定实施例,该化合物为式I-1表示的(S)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯,或为式I-2表示的(R)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基1-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯。
根据本发明的特定实施例,该抗PD-1/PD-L1抗体为(阿维鲁单抗(avelumab))、/>(纳武利尤单抗(nivolumab))、/>(帕博利珠单抗(pembrolizumab))、/>(度伐利尤单抗(durvalumab)),及/或/>(阿替利珠单抗(atezolizumab))。
根据本发明的特定实施例,在该癌症为肝癌的情况下,该抗PD-1抗体为(帕博利珠单抗),且该抗PD-1抗体为/>(阿维鲁单抗)。
根据本发明的特定实施例,该组合物还包含医药上可接受的赋形剂。优选地,该赋形剂选自惰性稀释剂、分散剂及/或制粒剂、表面活性剂及/或乳化剂、崩解剂、粘合剂、防腐剂、缓冲剂、润滑剂及油类。
另一方面,本发明提供一种于有需要的患者中治疗癌症的方法,包括向该患者施用有效量的本发明的组合物的步骤。
根据本发明的特定实施例,该方法进一步包括使用AKR1C3抗体测量患者体内癌细胞的AKR1C3还原酶含量的步骤,当测得AKR1C3还原酶的含量等于或大于预定值时,将该组合物施用于该患者。
因此,本发明的实施例涉及包括式I(OBI-2870)、式I-1(OBI-3424)或式I-2(OBI-3423)的化合物以及至少一抑制性免疫检查点抗原的抑制剂的组合。于某些特定的实施例中,该免疫检查点抑制剂为抑制/阻断该抑制性免疫检查点抗原的抗免疫检查点抗体。
于一实施例中,该抑制性免疫检查点抗原是选自PD-1/PD-L1抗原、细胞毒性T淋巴细胞相关蛋白4(Cytotoxic T-lymphocyte-Associated Protein 4,CTLA-4)、淋巴细胞活化基因3(Lymphocyte Activation Gene 3,LAG-3)、基于T细胞免疫球蛋白与免疫受体酪胺酸的抑制性模体结构域(T-cell ImmunoGlobulin and Immunoreceptor Tyrosine-basedinhibitory motif domain,TIGIT)、癌胚抗原相关细胞粘附分子1(Carcinoembryonicantigen-related cell adhesion molecule 1,Ceacam 1)、白血球相关类免疫球蛋白受体-1(leucocyte-associated immunoglobulin-like receptor-1,LAIR-1)、T细胞免疫球蛋白及粘蛋白结构域3(T cell Immunoglobulin and Mucin domain-3,TIM-3)、T细胞活化的V结构域Ig抑制剂(V-domain Ig suppressor of T cell activation,VISTA)、杀伤细胞免疫球蛋白受体(Killer-cell Immunoglobulin-like Receptor,KIR)、吲哚胺-吡咯2,3-二氧酶(Indoleamine-pyrrole 2,3-dioxygenase,IDO)、B7-H3(CD276)、A2AR(腺苷A2A受体)或CD47。
于一实施例中,该抗免疫检查点抗体为抗PD-1/PD-L1抗体、抗CTLA-4(细胞毒性T淋巴细胞相关蛋白4)抗体、抗LAG-3(淋巴细胞活化基因3)抗体、抗TIGIT(基于T细胞免疫球蛋白与免疫受体酪胺酸的抑制性模体结构域)抗体、抗Ceacam 1(癌胚抗原相关细胞粘附分子1)抗体、抗LAIR-1(白血球相关类免疫球蛋白受体-1)抗体、抗TIM-3(T细胞免疫球蛋白及粘蛋白结构域3)抗体、抗VISTA(T细胞活化的V结构域Ig抑制剂)抗体、抗KIR(杀伤细胞免疫球蛋白受体)抗体、抗IDO(吲哚胺-吡咯2,3-二氧酶)抗体、抗B7-H3(抗CD276)抗体、抗A2AR(腺苷A2A受体)抗体或抗CD47抗体。
于一实施例中,该抗PD-1/PD-L1抗体为(阿维鲁单抗)、/>(纳武利尤单抗)、/>(帕博利珠单抗)、/>(度伐利尤单抗),及/或/>(阿替利珠单抗)。
附图说明
图1.实施例1各组的平均体重。每周两次记录载剂组、单一治疗组,以及组合治疗组的体重,直到第35天为止。在携带人类肝细胞癌HepG2肿瘤的人源化小鼠的所有治疗组中均未见体重减轻。数据显示为平均值±SEM(每组N=5)。通过司徒顿t检定(Student's ttest)进行统计分析。
图2.实施例1的每组中的平均肿瘤重量。在接种肿瘤细胞后第36天处死小鼠,并记录载剂组、单一治疗组,以及组合治疗组中小鼠的肿瘤重量。相较于载剂组(G1),OBI-3424(G2)以及OBI-3424+抗-hPD-1/抗-hPD-L1(G5/G6)组合治疗组的肿瘤重量得到显著抑制(p<0.001)。此外,相较于抗-hPD-1/抗-hPD-L1(G3/G4)治疗组,OBI-3424+抗-hPD-1/抗-hPD-L1(G5/G6)组合治疗组的肿瘤重量得到显著抑制(p<0.05)。数据显示为平均值±SEM(每组N=5)。通过司徒顿t检定进行统计分析。P值<0.05被认为是显著的。单星表示0.05<P<0.001,双星表示P<0.001。
图3.实施例1的各组中的平均肿瘤体积。每周两次记录载剂组、单一治疗组,以及组合治疗组的小鼠肿瘤体积,直到第35天为止。相较于载剂组(G1),OBI-3424(G2)以及OBI-3424+抗-hPD-1/抗-hPD-L1(G5/G6)组合治疗组的肿瘤体积得到显著抑制。数据显示为平均值±SEM(每组N=5)。通过司徒顿t检定进行统计分析。
图4.实施例2的每组中的平均体重。每周两次记录载剂组、OBI-3424低剂量及高剂量治疗组,以及OBI-3424加PD-1抗体组合治疗组的体重,直到第30天为止。在携带人类肝细胞癌HepG2肿瘤的人源化小鼠的载剂组、OBI-3424单剂量组或OBI-3424加PD-1抗体组合治疗组均未见体重减轻。数据显示为平均值±SEM(每组N=5)。通过司徒顿t检定进行统计分析。
图5.实施例2的各组中的平均肿瘤重量。施用试验品项后第30天处死小鼠,且相较于载剂组(G1),OBI-3424低剂量组(G2)、高剂量治疗组(G3)以及OBI-3424加PD-1抗体组合治疗组(G5~G7)中小鼠的肿瘤重量得到显著抑制(p<0.05)。此外,相较于高剂量OBI-3424单一治疗组(G3),高剂量OBI-3424加上PD-1抗体组合治疗组(G6)的肿瘤重量显著降低(p<0.05)。数据显示为平均值±SEM。通过司徒顿t检定进行统计分析。P值<0.05被认为是显著的。单星表示0.05<P<0.001,双星表示P<0.001。
图6.实施例2的各组中的平均肿瘤体积。每周两次记录载剂组、OBI-3424低剂量及高剂量治疗组,以及OBI-3424加PD-1抗体组合治疗组的小鼠肿瘤体积,直到第30天为止。相较于载剂组(G1),OBI-3424高剂量治疗组(G3)以及OBI-3424加抗hPD-1抗体(G5~G7)组合治疗组的肿瘤体积被显著抑制。数据显示为平均值±SEM(每组N=5)。透过司徒顿t检定进行统计分析。
具体实施方式
下面将参照具体实施例来描述本发明。本领域技术人员可以理解,这些实施例仅用于描述本发明,而不以任何方式限制其范围。
定义
提供以下定义以帮助读者。除非另有定义,否则本发明中使用的所有技术术语、符号以及其他科学或医学术语或词汇目的在于具有化学及医学领域技术人员通常理解的含义。于某些情况下,为了清楚及/或便于参考,本发明定义了具有通常理解的含义的术语,且不应将本发明中包括这样的定义解释为表示与本领域中通常理解的术语的定义实质性的差异。
所有数值标记,例如pH、温度、时间、浓度,以及重量,包括其范围,皆为近似值,通常可适当地以(+)或(-)为单位以0.1、1.0或10.0的增量变化。所有数字标记可理解为在术语“约”之后。本发明所述的试剂为示例性的,其等同物在本领域中为已知的。
除非上下文另外明确指出,否则术语“一”、“一个/种”以及“该”包括复数指示物。因此,例如,提及一化合物是指一种或多种化合物或至少一种化合物。如此,术语“一”(或“一个/种”)、“一或多个/种”以及“至少一”在本发明中可互换使用。
术语“大约”或“近似”是指由本领域技术人员确定的特定值的可接受误差,其部分取决于如何测量或确定该数值。于某些实施例中,术语“约”或“大约”是指在1、2、3或4个标准偏差之内。于某些实施例中,术语“约”或“大约”是指在一给定值或范围的50%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%或0.05%之内。
如本发明所用,术语“包含(comprising)”或“包括(including)”目的在于表示该组合物及方法包括所列举的要素,但不排除其他要素。当用于定义组合物及方法时,“基本上由...组成(consisting essentially of)”应表示排除对该组合物或方法具有任何重要意义的其他要素。“由...组成(consisting of)”是指排除所请求保护的组合物以及实质性方法步骤中其他成分的多于极微量的元素。由这些连接词中的每一个定义的实施例在本发明的范围内。因此,目的在于该方法及组合物可包括另外的步骤及组成分(包含/包括),或者可替代地包括不重要的步骤及组合物(基本上由其组成),或者目的仅在于所述的方法步骤或组合物(由...组成)。
术语对患者“施用(administering)”药物”或将药物“施用至(administrationof”患者(以及该短语的等同语法)是指直接施用,可由医疗专业人员对患者进行施用,或可为自我施用;以及/或间接施用,其可为开处方签的行为。例如,指示患者自我施用药物及/或对患者提供药物处方的医师正在对该患者施用药物。
术语“抗体”目的进一步涵盖抗体、消化片段、其特定部分及其变体,包括抗体模拟物(antibody mimetics)或包括模拟一抗癌抗体或其特定片段或部分的结构及/或功能的抗体部分,包括单链抗体及其片段,每个都包含至少一个衍生自本发明抗癌抗体的CDR。
术语“生物试剂”包括胜肽、蛋白质、抗体、荷尔蒙、细胞激素、趋化激素(chemokine)及其任何组合。
术语“癌症”是指血癌、淋巴瘤、上皮癌,以及其他恶性肿瘤,包括实体瘤,其潜在无限生长,可通过侵袭而局部扩散,并通过转移而全身扩散。癌症的实施例包括,但不限于,肾上腺癌、骨癌、脑癌、乳癌、支气管癌、结肠及/或直肠癌、胆囊癌、头颈癌、肾癌、喉癌、肝癌、肺癌、神经组织癌、胰脏癌、前列腺癌、副甲状腺癌、皮肤癌、胃癌,以及甲状腺癌。某些其他癌症实施例包括急性与慢性淋巴细胞与颗粒细胞性肿瘤、腺癌、腺瘤、基底细胞癌、子宫颈不典型增生及原位癌、Ewing氏肉瘤、表皮样癌、巨细胞瘤、多形性胶质母细胞瘤(glioblastoma multiforma)、毛细胞瘤、肠神经节细胞瘤、增生性角膜神经瘤、胰岛细胞癌、卡波西氏肉瘤(Kaposi’s sarcoma)、平滑肌瘤、血癌、淋巴瘤、恶性类癌、恶性黑色素瘤、恶性高钙血症、马凡氏体征肿瘤、髓质癌、转移性皮肤癌、粘膜神经瘤、骨髓瘤、蕈状肉芽肿、神经胚细胞瘤、骨肉瘤、骨原性肉瘤以及其他肉瘤、卵巢肿瘤、嗜铬细胞瘤、真性红血球增多症(polycythermia vera)、原发性脑肿瘤、小细胞肺肿瘤、溃疡及乳突型二者的鳞状细胞癌(squamous cell carcinoma of both ulcerating and papillary type)、增生、精原细胞瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞肿瘤、皮肤局部病变、网状细胞肉瘤(veticulum cell sarcoma),以及威尔姆氏瘤(Wilm’s tumor)。
如本发明所用,术语“化学治疗剂”为一种可用于治疗癌症的化合物。化学治疗剂的实施例包括单甲基澳瑞他汀E(Monomethyl auristatin E,MMAE)、单甲基澳瑞他汀F(MMAF)、美登木素生物碱(mertansine,DM1)、蒽环素(anthracycline)、吡咯并苯并二氮杂(pyrrolobenzodiazepine)、α-鹅膏蕈碱(α-amanitin)、微管溶素(tubulysin)、苯二氮平(benzodiazepine)、厄洛替尼(erlotinib)、硼替佐米(bortezomib)、氟维司群(fulvestrant)、舒尼替尼(sunitinib)、来曲唑(letrozole)、甲磺酸伊马替尼(imatinibmesylate)、PTK787/ZK 222584、奥沙利铂(oxaliplatin)、菊白叶酸(leucovorin)、雷帕霉素(rapamycin)、拉帕替尼(lapatinib)、洛那法尼(lonafarnib)(SCH66336)、索拉非尼(sorafenib)、吉非替尼(gefitinib)、AG1478、AG1571、烷基化试剂(alkylating agent)、烷基磺酸盐(alkyl sulfonate)、氮丙啶类(aziridines)、乙烯亚胺(ethylenimine)、甲基三聚氰胺(methylamelamine)、内酯(acetogenins)、喜树碱(camptothecin)、苔藓虫素(bryostatin)、卡利斯他汀(callystatin)、CC-1065、念珠藻素(cryptophycins)、尾海兔素(dolastatin)、杜卡霉素(duocarmycin)、艾榴塞洛素(eleutherobin)、胰抑素(pancratistatin)、珊瑚素(sarcodictyin)、海绵素(spongistatin)、氯芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、氯磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、甲氯乙胺(mechlorethamine)、盐酸甲氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard)、卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷诺氮芥(ranimustine)、卡奇霉素(calicheamicin)、达尼霉素(dynemicin)、氯磷酸盐(clodronate)、埃司帕霉素(esperamicin)、新卡司他汀发色团(neocarzinostatin chromophore)、阿克拉霉素(aclacinomysins)、放线菌霉素(actinomycin)、安曲霉素(authramycin)、重氮丝氨酸(azaserine)、博莱霉素(bleomycins)、放线菌素(cactinomycin)、卡拉霉素(carabicin)、卡氨霉素(caminomycin)、嗜癌菌素(carzinophilin)、色霉素(chromomycinis)、放线菌素(dactinomycin)、道诺霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正白胺酸(6-diazo-5-oxo-L-norleucine)、阿霉素(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycins)、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、喹纳霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲佐菌素(streptozocin)、结核菌素(tubercidin)、苯丁抑制素(ubenimex)、净司他丁(zinostatin)、红柔霉素(zorubicin)、氨甲蝶呤(methotrexate)、5-氟尿嘧啶(5-fluorouracil,5-FU)、二甲叶酸(denopterin)、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate)、氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine)、安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-硫唑脲嘧啶(6-azauridine)、卡莫呋(carmofur)、阿糖胞苷(cytarabine)、双去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、伊诺他滨(enocitabine)、氟尿苷(floxuridine)、卡鲁睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯酮(testolactone)、氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane)、醛叶酸(folinicacid)、醋葡醛内酯(aceglatone)、醛磷酰胺糖苷(aldophosphamide glycoside)、胺乙酰丙酸(aminolevulinic acid)、恩尿嘧啶(eniluracil)、安吖啶(amsacrine)、阿莫司汀(bestrabucil)、比生群(bisantrene)、依达曲沙(edatraxate)、地磷酰胺(defofamine)、秋水仙胺(demecolcine)、地吖醌(diaziquone)、艾福米辛(elformithine)、依利醋铵(elliptinium acetate)、埃博霉素(epothilone)、依托格鲁(etoglucid)、硝酸镓(galliumnitrate)、羟基脲(hydroxyurea)、香菇多醣(lentinan)、氯尼达明(lonidainine)、美登素(maytansine)、安丝菌素(ansamitocins)、米托脲腙(mitoguazone)、米托蒽醌(mitoxantrone)、莫哌达醇(mopidanmol)、硝拉维林(nitraerine)、喷司他丁(pentostatin)、蛋胺氮芥(phenamet)、吡柔比星(pirarubicin)、洛索蒽醌(losoxantrone)、鬼臼酸(podophyllinic acid)、2-乙基酰肼(ethylhydrazide)、甲基芐肼(procarbazine)、雷佐生(razoxane)、根霉素(rhizoxin)、西佐喃(sizofiran)、锗螺胺(spirogermanium)、细交链孢菌酮酸(tenuazonic acid)、三亚胺醌(Triaziquone)、2,2’,2”-三氯三乙胺(trichlorotriethylamine)、新月毒素(trichothecene)、乌拉坦(urethan)、长春地辛(vindesine)、达卡巴嗪(dacarbazine)、甘露醇氮芥(mannomustine)、二溴甘露醇(mitobronitol)、二溴卫矛醇(mitolactol)、溴丙哌嗪(pipobroman)、甲托辛(gacytosine)、阿拉伯醣苷(arabinoside)、环磷酰胺(cyclophosphamide)、噻替哌(thiotepa)、类紫杉醇(taxoid)、紫杉醇(paclitaxel)、欧洲紫杉醇(docetaxel)、苯丁酸氮芥(chloranbucil)、吉西他滨(gemcitabine)、6-硫鸟嘌呤(6-thioguanine)、巯基嘌呤(mercaptopurine)、氨甲蝶呤(methotrexate)、顺铂(cisplatin)、卡铂(carboplatin)、长春花碱(vinblastine)、铂(platinum)、依托泊苷(etoposide)、异环磷酰胺(ifosfamide)、米托葱醌(mitoxantrone)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、米托蒽醌(novantrone)、替尼泊苷(teniposide)、依达曲沙(edatrexate)、道诺霉素(daunomycin)、氨基蝶呤(aminopterin;)、截瘤达(xeloda)、伊班膦酸盐(ibandronate)、拓扑异构酶抑制剂、二氟甲基鸟氨酸(difluoromethylornithine,DMFO)、维他命A酸(retinoid),以及卡培他滨(capecitabine)。
术语“组合”是指组合治疗为OBI-3423/OBI-3424化合物的量及/或与其他生物或化学药物的量,在治疗周期期间的相同或不同日期依序地或同时地一起施用(共同施用及/或共同配制)时,具有在治疗上是有效的且多于治疗上的综合作用的协同作用。
术语“接触(contacting)”或“接触(contact)”是指将治疗剂与细胞或组织聚集在一起,使得由于这种接触而发生生理及/或化学作用。接触可在体外、离体或体内进行。于一实施例中,将治疗剂与细胞培养物中的细胞接触(体外)以确定该治疗剂对该细胞的作用。于另一实施例中,将治疗剂与细胞或组织的接触包括对一具有要接触的细胞或组织的受试者施用治疗剂。
术语“光学活性的(optically active)”是指分子的集合,其镜像异构物过量(enantiomeric excess)不少于约10%、不少于约20%、不少于约30%、不少于约40%、不少于约50%、不少于约60%、不少于约70%、不少于约80%、不少于约90%、不少于约91%、不少于约92%、不少于约93%、不少于约94%、不少于约95%、不少于约96%、不少于约97%、不少于约98%、不少于约99%、不少于约99.5%、不少于约99.8%或不少于约99.9%。于某些实施例中,光学活性化合物的镜像异构物过量不少于约90%、不少于约95%、不少于约98%或不少于约99%。化合物的镜像异构物过量可通过本领域技术人员使用的任何标准方法来确定,包括但不限于,使用光学活性固定相的对手性光学色谱法(chiropticalchromatography)(气相色谱法、高效液相色谱法,以及薄层色谱法)、同位素稀释、电泳、量热法、旋光测定法(polarimetry)、具有对手性衍生作用的NMR拆分方法(NMR resolutionmethods),以及具有对手性溶剂化剂(chiral solvating agent)或对手性转移剂的NMR方法。
在描述一光学活性化合物时,前缀R及S用于表示分子围绕其对手性中心的绝对构型。
术语“基本上纯的”是指足够均匀,以显示没有容易检测到的杂质,如通过本领域技术人员所使用的标准分析方法所确定的,包括但不限于,薄层色谱法(TLC)、凝胶电泳、高效液相色谱法(HPLC)、气相色谱法(GC)、核磁共振(NMR),以及质谱测定法(MS);或者足够纯净,以至于进一步纯化不会可检测地改变其物理、化学、生物学及/或药理特性,例如该物质的酶及生物活性。于某些实施例中,“基本上纯的”是指分子的集合,其中按重量计,至少约50%、至少约70%、至少约80%、至少约90%、至少约95%、至少约98%、至少约99%或至少约99.5%的分子为化合物的单一立体异构体,如通过标准分析方法所测定。
“患者”及“受试者”可互换使用,是指需要治疗癌症的哺乳动物。通常,该患者为人类。通常,该患者为被诊断出患有癌症的人类。于某些实施例中,“患者”或“受试者”可指用于筛选、描述特征,以及评估药物及疗法的非人类哺乳动物,例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
术语“前药”是指一化合物,其在给药后就至少一种性质而言被代谢或以其他方式转化为生物活性或更多活性的化合物(或药物)。相对于药物,前药以使其相对于药物较少活性或不活化的方式进行化学修饰,但是该化学修饰使得该相对应的药物是在施用该前药后,由代谢或其他生物学过程所产生。相对于活性药物,前药可能具有改变的代谢稳定性或转运特性、较少的副作用或较低的毒性,或改善的味道(例如,参阅参考文献Nogrady,1985年,Medicinal Chemistry A Biochemical Approach,牛津大学出版社,纽约,第388-392页,其通过引用并入本发明)。可使用除了该相应药物以外的反应物来合成前药。
术语“实体瘤”是指包括但不限于存在于骨、脑、肝、肺、淋巴结、胰腺、前列腺、皮肤,以及软组织(肉瘤)中的转移性肿瘤的实体瘤。
术语药物的“治疗有效量”是指当对一罹患癌症的患者施用时具有预期的治疗作用,例如减轻、改善、缓和或消除在该患者身上的一种或多种癌症表现的药物量。通过施用一剂量不一定产生治疗效果,且可能仅在施用一系列剂量之后才出现治疗效果。因此,治疗有效量可施用一次或多次。
术语“治疗”一病症或患者是指采取步骤以获得有益或期望的结果,包括临床结果。为了本发明的目的,有益的或期望的临床结果包括,但不限于:减轻或改善一种或多种癌症症状;疾病程度的减少;延缓或减缓疾病进展;减轻、缓和或稳定疾病状态;或其他有益的结果。于某些情况下,癌症的治疗可能会导致部分反应或疾病稳定。
术语“肿瘤细胞”是指任何适当种类的肿瘤细胞,例如哺乳动物,例如鼠、犬、猫、马或人类。
术语“同位素变体”是指在构成这样的化合物的一个或多个原子上含有非自然比例的同位素的化合物。于某些实施例中,化合物的“同位素变体”包含非自然比例的一种或多种同位素,包括但不限于,氢(1H)、氘(2H)、氚(3H)、碳11(11C)、碳12(12C)、碳13(13C)、碳14(14C)、氮13(13N)、氮14(14N)、氮15(15N)、氧14(14O)、氧15(15O)、氧16(16O)、氧17(17O)、氧18(18O)、氟17(17F)、氟18(18F)、磷31(31P)、磷32(32P)、磷33(33P)、硫32(32S)、硫33(33S)、硫34(34S)、硫35(35S)、硫36(36S)、氯35(35Cl)、氯36(36Cl)、氯37(37Cl)、溴79(79Br)、溴81(81Br)、碘123(123I)、碘125(125I)、碘127(127I)、碘129(129I),以及碘131(131I)。于某些实施例中,化合物的“同位素变体”为稳定形式,即非放射性的。于某些实施例中,化合物的“同位素变体”包含非自然比例的一种或多种同位素,包括但不限于,氢(1H)、氘(2H)、碳12(12C)、碳13(13C)、氮14(14N)、氮15(15N)、氧16(16O)、氧17(17O)、氧18(18O)、氟17(17F)、磷31(31P)、硫32(32S)、硫33(33S)、硫34(34S)、硫36(36S)、氯35(35Cl)、氯37(37Cl)、溴79(79Br)、溴81(81Br),以及碘127(127I)。于某些实施例中,化合物的“同位素变体”呈不稳定形式,即具有放射性。于某些实施例中,化合物的“同位素变体”包含非自然比例的一种或多种同位素,包括但不限于,氚(3H)、碳11(11C)、碳14(14C)、氮13(13N)、氧14(14O)、氧15(15O)、氟18(18F)、磷32(32P)、磷33(33P)、硫35(35S)、氯36(36Cl)、碘123(123I)、碘125(125I)、碘129(129I),以及碘131(131I)。应当理解的是,于可行的情况下,根据本领域技术人员的判断,在本发明提供的化合物中,例如,任何氢可为2H,或者任何碳可为例如13C,或者任何氮可为例如15N,且任何氧可为18O。于某些实施例中,化合物的“同位素变体”包含非自然比例的氘。
术语“溶剂化物”是指由一个或多个溶质分子,例如本发明提供的化合物,以及一个或多个溶剂分子形成的络合物或聚集体(aggregate),其以化学计量或非化学计量的量存在。合适的溶剂包括但不限于水、甲醇、乙醇、正丙醇、异丙醇,以及醋酸。于某些实施例中,该溶剂为医药上可接受的。于一实施例中,该络合物或聚集体为结晶形式。于另一实施例中,该络合物或聚集体为非结晶形式。当该溶剂为水时,该溶剂化物为水合物。水合物的实施例包括,但不限于,半水合物、单水合物、二水合物、三水合物、四水合物,以及五水合物。
术语“医药上可接受的赋形剂”是指医药上可接受的材料、组合物或载剂,例如液体或固体填充剂、稀释剂、溶剂或包囊材料(encapsulating material)。于一实施例中,在与一药物制剂的其他成分相容的意义上,每个成分都是“医药上可接受的”,且适合与人类及动物的组织或器官接触而没有过度的毒性、刺激性、过敏反应。
术语“免疫检查点抑制剂”为抑制/阻断抑制性免疫检查点系统的分子,已经成为晚期赘瘤形成(neoplasia)的有效疗法;其中包括阻断细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte associated antigen 4,CTLA4)以及程序性细胞死亡蛋白1(programmed cell death protein 1,PD-1)的治疗性抗体,已用于多种肿瘤(34)。PD-1(程序性细胞死亡蛋白,CD279),为B7/CD28受体家族的成员,为一种在活化的白血球(包括T、B、NK,以及骨髓来源的抑制细胞)的细胞表面表现的单体分子,其表现受到基因以及表观遗传(epigenetic)机制之间相互作用的良好调节。PD-1的已知配体为PD-L1以及和PD-L2(35)。
PD-L1(程序性细胞死亡蛋白配体1、B7H1、CD274)在包括T细胞、B细胞、骨髓细胞及树突状细胞的造血细胞,以及非造血细胞(如肺、心脏、内皮、胰岛细胞、角质细胞(keratinocyte))且特别是癌细胞上表现量低,并在细胞活化后上调。PD-L2(程序性细胞死亡蛋白配体2、B7-DC、CD273)在巨噬细胞、树突状细胞(dendritic cells,DCs)、活化的CD4+及CD8+淋巴细胞以及一些实体瘤(卵巢癌、小细胞肺癌、食道癌)上表现。在正常及与癌症相关的纤维母细胞上也检测到PD-L1以及PD-L2的表现。PD-L1与PD-L2均与其他受体相互作用:PD-L1与CD28配体CD80,而PD-L2与排斥导向分子(Repulsive Guidance Molecule,RGM)b,在巨噬细胞以及其他细胞类型上表现。PD-1的胞质尾部包含基于免疫受体酪胺酸的抑制模体(Immunoreceptor Tyrosine-based Inhibition Motif,ITIM)以及基于免疫受体酪胺酸的开关模体(immunoreceptor tyrosine-based switch motif,ITSM)。在T淋巴细胞中,PD-1及其配体的相互作用导致PD-1细胞内尾部的两个酪胺酸磷酸化;接着,将包含SH2结构域的蛋白酪胺酸磷酸酶(SHP-1及/或SHP-2)募集到PD-1的ITSM细胞质区域,然后抑制T细胞受体的下游讯号,进而抑制T细胞增殖及细胞激素的产生。PD-1对T细胞也有其他作用:例如,通过抑制Akt以及Ras途径,PD-1触发抑制了泛素连接酶组成分SKP2的转录:这导致SKP2调节的p27(kip1)的降解受损(p27为一种依赖细胞周期蛋白(cyclin-dependent)的激酶的抑制剂),进而阻断细胞周期进程。此外,PD-1可通过多种机制促进细胞雕亡。除了直接抑制T细胞活化外,由PD-L1触发的PD-1还可诱导T调节细胞(Treg)的发展,T调节细胞为周边耐受的关键调节者,可以有效抑制效应T细胞。由PD-1触发的Treg诱导是通过关键讯号分子(如磷酸化Akt(phospho-Akt))的调节所调节的,该关键讯号分子通过PD-1-诱导的PTEN活性而保持较低含量。几种类型的癌细胞确实表现PD-L1。此外,肿瘤微环境中的非肿瘤细胞(内皮细胞、白血球、纤维母细胞)亦可表现PD-L1。这表示它们可以耐受肿瘤浸润的PD-1+T淋巴细胞(TILs)及/或诱导Treg的发育;的确,有越来越多的证据显示,使用抗PD-1/PD-L1单株抗体(monoclonal antibodies,mAbs)治疗受某些癌症类型(黑色素瘤、肾癌、非小细胞肺癌等)影响的患者可减少肿瘤生长。
已知免疫检查点抑制剂可在人体内提供某些抗肿瘤活性,且这种部分抗肿瘤活性仅在一部分接受治疗的受试者中观察到。检查点抑制剂可包括或不包括蛋白质、多胜肽(包括胺基酸残基)以及单株或多株抗体。本发明所述的组合物可包括或与多于一种的检查点抑制剂一起施用。于一些实施例中,检查点抑制剂结合在任何T细胞调节剂家族中发现的配体或蛋白质,包括CD28/CTLA-4。检查点抑制剂的标靶可包括或排除在免疫系统效应子或调节细胞(例如,T细胞)上表现的受体或共受体(例如CTLA-4;CD8);抗原呈现细胞表面表现的蛋白质(亦即,在活化的T细胞表面表现,可包括或不包括PD-1、PD-2、PD-L1,以及PD-L2);肿瘤及肿瘤浸润细胞均表现的代谢酶(例如,吲哚胺-吡咯2,3-二氧酶(Indoleamine-pyrrole2,3-dioxygenase,IDO),包括同功型(isoform),例如IDO1以及IDO2);属于免疫球蛋白超级家族的蛋白质(例如,淋巴细胞活化基因3,亦称为LAG3);属于B7超级家族的蛋白质(例如,B7-H3/CD276或其同源物)。在活化的抗原呈现细胞以及T细胞上均可发现B7蛋白。于一些实施例中,可以将两种或更多种检查点抑制剂组合或配对。例如,可将在抗原呈现细胞上发现的B7家族检查点抑制剂与在T细胞表面表现的CD28或CTLA-4抑制剂配对,以产生共同抑制讯号,进而降低这两种细胞之间的活性。共同受体是指位于同一细胞上的两个不同受体,它们与外部配体结合后可以调节内部细胞过程。共同受体可为刺激性的或抑制性的。共同受体有时被称为辅助受体或共同讯号受体。如本发明所用,术语“共同抑制”是指不止一个分子与细胞表面上的它们各自的受体结合进而减慢或防止细胞内过程发生的结果。
于某些实施例中,免疫检查点抑制剂可包括抑制PD-1或CTLA-4途径的抑制性受体的拮抗剂,例如抗PD-1、抗PD-L1或抗CTLA-4抗体或抑制剂。PD-1或PD-L1抑制剂的实施例可包括,但不限于,阻断人类PD-1的人源化抗体,例如派姆单抗(lambrolizumab)(抗PD-1抗体,商品名)或匹地珠单抗(pidilizumab)(抗PD-1抗体)、/>(抗PD-L1抗体,阿维鲁单抗(avelumab))、/>(抗PD-L1抗体,度伐利尤单抗(durvalumab)),以及(抗PD-L1抗体,阿替利珠单抗(atezolizumab)),以及完全人类抗体,例如纳武利尤单抗(nivolumab)(抗PD-1抗体,商品名/>)。其他PD-1抑制剂可包括可溶性PD-1配体的呈现,包括,但不限于亦称为B7-DC-Ig或AMP-244的PD-L2 Fc融合蛋白以及目前正在研究及/或开发用于治疗的其他PD-1抑制剂。此外,免疫检查点抑制剂可包括,但不限于阻断PD-L1的人源化或完全人源抗体,例如度伐利尤单抗(durvalumab)与MIH1以及目前正在研究的其他PD-L1抑制剂。于一些实施例中,免疫检查点抑制剂为CTLA-4、PD-L1或PD-1抗体。于一些实施例中,PD-1或CTLA-4抑制剂包括,但不限于阻断人类PD-1的人源化抗体,例如派姆单抗(lambrolizumab)(抗PD-1抗体,商品名/>)或匹地珠单抗(pidilizumab)(抗PD-1抗体)、纳武利尤单抗(nivolumab)(抗PD-1抗体,商品名/>)、替利木单抗(ticilimumab)(抗CTLA-4抗体)、易普利姆单抗(ipilimumab)(抗CTLA-4抗体)、MPDL3280A、BMS-936559、AMP-224、IMP321(ImmuFact公司)、MGA271、Indoximod,以及INCB024360。
实施例
实施例1.OBI-3424+抗PD-1抗体(帕博利珠单抗(pembrolizumab))或抗PD-L1抗体(阿维鲁单抗(avelumab))在HepG2肿瘤人源化小鼠模型中的功效性评估
研究的目的为在HepG2肿瘤人源化小鼠模型中评估测试品OBI-3424单一治疗或在抗hPD-1抗体或抗hPD-L1抗体存在下组合治疗的功效。
材料
1.OBI-3424-DP
批号:FLC-INJ-1711-01
测试品数:2个小瓶/每个小瓶1mL
成分:DNA烷基化剂
浓度:10mg/mL
物理外观:透明液体
储存条件:-20℃
2.抗人类PD-1抗体,帕博利珠单抗(pembrolizumab),默克公司(Merck&Co.,Inc.)。
批号:7302614A13
测试品数:1瓶/每瓶1.2mL
成分:抗体
浓度:25mg/mL
物理外观:透明液体
储存条件:2~8℃
3.抗人类PD-L1抗体,阿维鲁单抗(avelumab),默克公司。
批号:AU024788
测试品数:1管/每管1.5mL
成分:抗体
浓度:20mg/mL
物理外观:透明液体
储存条件:2~8℃
4.无菌生理食盐水(信东生技股份有限公司)
批号:1PD2A054
测试品数:6管20mL试管
浓度:0.9%氯化钠
物理外观:透明液体
溶解度:未提供
储存条件:室温
5.基质胶(Matrigel)(Corning公司,型号:354248,批号:8228001)
6.人类PBMC(批号:PBMC102219D,Zenbio公司,美国)
7.胶原酶(Sigma Aldrich公司,C5138)、DNA水解酶I(Sigma Aldrich公司,D5025)、玻尿酸酶(Sigma Aldrich公司,H6254)
8.RBC红血球裂解缓冲液(Biolegend公司,420302)
9.细胞染色缓冲液(Biolegend公司,420201)
10.人类TruStain FcXTM(Fc受体阻隔溶液)(Biolegend公司,422302)
11.抗体:
抗人类CD45抗体(Beckman公司,IM0782U)、抗人类CD8抗体(Beckman公司,IM0452U以及Biolegend公司,300911)、抗人类CD4抗体(Beckman公司,B16491)、抗人类CD56抗体(Beckman公司,IM2474U)、抗人类CD16抗体(Beckman公司,IM1238U)、抗人类CD25抗体(Beckman公司,IM0479U)。
小鼠
1.物种:小鼠(Mus musculus)
品系:晚期免疫缺陷小鼠。
(NOD.Cg-Prkdcscid Il2rg)
来源:三华生物科技股份有限公司
性别:雌
研究开始时的年龄:6~8周
研究开始时的体重范围:17~28克
2.编号与识别:每只小鼠以耳标编号。通过笼卡识别住笼,其中包括研究编号、笼编号、动物编号、性别、剂量含量等资讯。
动物分组:小鼠分为6组:G1(载剂)、G2(OBI-3424)、G3(抗hPD-1抗体)、G4(抗hPD-L1抗体)、G5(OBI-3424+抗hPD-1抗体),以及G6(OBI-3424+抗hPD-L1抗体)。每组包含五只小鼠。将人类肝癌细胞株HepG2皮下接种至晚期免疫缺陷小鼠。本项研究含括共30只小鼠。
3.选择动物的原因:根据卫生福利部食品药物管理署公告的非临床药物安全性研究建议中的抗癌药物非临床研究指南,可将动物异种移植肿瘤模型用于评估新药或新抗癌药的疗效。常用的小鼠品系包括BALB/c、C57BL/6,而通常选择BALB/c Nude、Nu/Nu以及NOD/SCID小鼠来评估目标药物的抗肿瘤作用。这些品系是在全球的基础下进行管理的,具有众所周知的遗传及品种背景,可提供对人体适当反应的功能性意义。
4.适应期:在随机分组之前,使小鼠适应至少3天。在适应期间进行临床观察并测量体重。在此期间,这些动物没有表现出任何疾病迹象或行为改变。
5.动物的居住条件:将小鼠饲养在单独的通风笼(individually ventilatedcages,IVC)中,该笼中装有无菌垫层(10054,Andersons公司,美国),在受控环境中,温度为22±3℃,相对湿度为50±20%,光照/黑暗周期为12/12小时。在整个研究期间,小鼠可随意取用食物(LabDiet 5010,PMI公司,美国)及水(无菌逆渗透水)。
6.随机化:将所有动物称重,并在研究前观察健康状况。在实验中选择没有异常临床征状的动物。将健康的动物随机分为不同的组别,各组之间的体重没有显著差异。动物的体重变化不应超过平均体重的±20%。该程序遵循实验室动物操作标准。
7.IACUC核准号:IACUC-2020-SH-016
设备
细胞培养培养箱(Shel Lab公司/3552)
生物安全柜(BAKER公司/SG604)
电子天平(PRECISA公司/XS225A-SCS)
吸量管(Thermo公司/Finnpipette F1)
隔离正/负压验证的笼式住房系统(Allentown公司/NEXGEN)
分析天平(PRECISA公司/XS3250C-SCS)
动物安乐死设备(联台国际科技有限公司)
流式细胞仪(Beckman Coulter公司/Navios EX)
游标尺(Mitutoyo公司/CD-6”ASX)
方法
实验设计
1.取样:实验设计、实验组、注射剂量与体积、施用途径以及动物数量列于表1。
表1.剂量方案及取样
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*从第15天开始,腹膜内注射剂量更改为20mg/kg。
2.异种移植小鼠模型的建立
2.1.动物除毛:在注射人类肝癌细胞株HepG2之前,仅剪除右侧腹部的毛发。
2.2.皮下接种肿瘤细胞:将1x107个HepG2细胞与0.25x107个hPBMC(细胞数比为4:1)预混合,然后再与基质胶混合(体积比1:1)(Corning公司,型号:354248,批号:8228001)。皮下注射体积为200μL/小鼠。
3.测试物品的施用途径:
3.1.在接种肿瘤细胞后的第8天,将测试品抗hPD-1抗体或参照品以腹膜内注射施用于小鼠。使用胰岛素注射器以10mg/kg的剂量进行注射,注射量为10mL/kg(从第15天起将注射剂量更改为20mg/kg)。针对G3及G5,在第8、11、15、18、22、25、29及32天连续给予测试品抗hPD-1抗体。G1组施用该参照品。该程序遵循样品施用的标准。
3.2.在接种肿瘤细胞后第8天,将测试品抗hPD-L1抗体或参照品以腹膜内注射施用于小鼠。使用胰岛素注射器以10mg/kg的剂量进行注射,注射量为10mL/kg(从第15天起将注射剂量更改为20mg/kg)。针对G4及G6,在第8、11、15、18、22、25、29及32天连续给予测试品抗hPD-L1抗体。G1组施用该参照品。该程序遵循样品施用的标准。
3.3.在接种肿瘤细胞后第14天,将测试品OBI-3424、参照品以静脉内注射施用于小鼠。使用胰岛素注射器以1mg/kg的剂量以及5mL/kg的注射体积进行注射。针对G2、G5及G6,在第14、21、28及35天连续给予OBI-3424测试品。G1组施用该参照品。该程序遵循样品施用的标准。
3.4.测试品或参照品的准备:
施用前,将测试品以参照品稀释。测试品OBI-3424的溶液浓度为0.2mg/mL,测试品抗hPD-1抗体及测试品抗hPD-L1抗体为1mg/mL(从第15天起为2mg/mL)。
4.体重测量:
从接种的第二天开始进行测量。测量动物体重,每周记录两次。
5.肿瘤直径测量:
从接种的第二天开始进行测量。每周两次测量并记录肿瘤体积(周一、周四)。根据记录,通过椭圆方程式算出肿瘤体积(长轴×短轴×短轴)×(π/6)。
6.肿瘤生长抑制率的计算:
根据以下公式,将肿瘤体积用于计算肿瘤生长抑制(tumor growth inhibition,TGI)速率:TGI(%)=[1-(Ti-T0)/(Ci-C0)]×100,其中Ti及Ci表示实验结束时(第35天)治疗组以及载剂组的平均肿瘤体积。而T0及C0表示实验开始(第1天)时治疗组及载剂组的平均肿瘤体积。
7.血液采样:
在实验终点收集颌下(Submandibular)血液样本。处死动物时,可使用心脏穿刺收集血液样本。将收集的血液样本于4±2℃下以1500xg离心15分钟以分离血清及沉淀物。收集上层血清,并保存在低于-70℃的温度下。该程序遵循动物血液采样的标准。
8.确定研究的终点:
该研究在第36天结束。
9.肿瘤切除:
在研究结束时,以二氧化碳安乐死方式将小鼠处死,并切除肿瘤周围的结缔组织。然后取出肿瘤样品并称重。将一半的组织固定在10%甲醛中,然后包埋在石蜡中;另一半准备用于分离肿瘤浸润淋巴细胞(tumor-infiltrating lymphocytes,TILs)。
10.肿瘤浸润淋巴细胞(TILs)的分离:
以手术刀将一半的小鼠肿瘤切成较小的碎片,然后以胶原酶、DNA水解酶I,以及玻尿酸酶(胶原酶,型号C5138,DNA水解酶I,型号D5025,玻尿酸酶,型号H6254,Sigma Aldrich公司)的混合物消化至少2小时。然后使用注射器柱塞将肿瘤消化物通过70μm筛孔细胞过滤器(Falcon公司,型号352350),并以PBS洗涤。以RBC红血球裂解缓冲液(Biolegend公司,型号420302)处理细胞,并制备用于流式细胞仪的单细胞悬浮液。
11.TIL族群的流式细胞仪分析:
以染色缓冲液(Biolegend公司,型号420201)洗涤细胞,重新悬浮于含有Fc受体阻隔溶液(Biolegend公司,型号422302)的染色缓冲液中,并于4℃下作用15分钟。以荧光共轭的表面抗体对细胞进行染色,并于4℃下作用30分钟,然后将其重新悬浮于染色缓冲液中以进行流式细胞仪分析。使用Navios EX流式细胞仪(Beckman Coulter公司)进行流式细胞仪分析。使用Kaluza分析软体(BeckmanCoulter公司)分析数据。
12.统计分析:
结果表示为平均值与平均值的标准误差(Mean±SEM)。使用司徒顿t检定(Microsoft Excel,2007年)计算每个治疗组收集的所有数据与同时出现的阴性对照数据的比较。P≤0.05被认为具有显著差异。
结果
表2列出各组体重的总结。在研究开始时,各组之间的平均体重没有统计学上的显著差异。在研究结束时,相较于其他组别,G5(OBI-3424+抗hPD-1抗体)以及G6(OBI-3424+抗hPD-L1抗体)的体重略有增加(图1及表2)。从不同的测试品检查肿瘤反应,在第1、4、7、11、14、18、21、25、28、32以及35天记录平均肿瘤反应(图3及表3)。
表2.体重总结
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*:于第34天发现MI052死亡。
表3.肿瘤体积及重量的总结
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*于第34天发现MI052死亡,并记录其肿瘤重量。平均肿瘤重量统计计算中不包括MI052。
首先,我们检查来自G1(载剂)、G2(OBI-3424)、G3(抗hPD-1抗体),以及G4(抗hPD-L1抗体)的所有测试品对肿瘤反应的效果。于第35天时,在存在OBI-3424的情况下,观察到平均肿瘤体积显著减少(G1载剂:1538.51±195.78mm3;G2 OBI-3424:590.62±164.32mm3,p=0.003<0.05)。在第35天以抗hPD-1抗体及抗hPD-L1的治疗未观察到统计学上的显著差异(G1载剂:1538.51±195.78mm3;G3抗hPD-1抗体:1613.37±338.07mm3;G4抗hPD-L1抗体:1148.64±193.00mm3)。
此外,组合治疗G5(抗hPD-1抗体+OBI-3424)及G6(抗hPD-L1抗体+OBI-3424)的结果显示第35天的平均肿瘤体积显著减少(G1载剂:1538.51±195.78mm3;G5抗hPD-1抗体+OBI-3424:267.43±32.10mm3,p=0.0001<0.001;G6抗hPD-L1抗体+OBI-3424:452.75±80.72mm3,p=0.0005<0.001),同时,在第35天G3与G5之间的平均肿瘤体积显著减少(G3抗-hPD-1抗体:1613.37±338.07mm3;G5抗-hPD-1抗体+OBI-3424:267.43±32.10mm3,p=0.002<0.05)。此外,在第35天G4与G6之间的平均肿瘤体积显著减少(G4抗hPD-L1抗体:1148.64±193.00mm3;G6抗hPD-L1抗体+OBI-3424:452.75±80.72mm3,p=0.004<0.05)(图3以及表3)。在肿瘤重量上观察到类似的趋势(图2及表3)。此外,在第34天发现一只G4(抗-hPD-L1抗体)小鼠死亡,并在同一天记录肿瘤重量。
从新鲜肿瘤组织中分离出肿瘤浸润淋巴细胞(TILs),并通过流式细胞仪检测各组之间表面标记物CD45、CD4、CD8、CD56、CD16、CD25、PD-1及PD-L1的表现量。表4~7提供了个别小鼠的数值数据。这表示相较于载剂,OBI-3424治疗(G2)后肿瘤中的CD8+细胞毒性T细胞(cytotoxic T cells,CTL)细胞数量显著增加,但在抗PD-1抗体(G3)或抗PD-L1抗体(G4)治疗后的肿瘤中未观察到这种增加。然而,在OBI-3424+抗PD-1抗体(G5)以及OBI-3424+抗PD-L1抗体(G6)治疗后的肿瘤中,这两组中的CTL族群数量均显著升高。这表示增加的CTL族群是由OBI-3424而非抗PD-1抗体或抗PD-L1抗体治疗所引起的。此外,在G5及G6的肿瘤中,CD4+T辅助细胞的数量显著增加。载剂以及每个治疗组之间的NK细胞数量没有显著差异。
表4.TILs中CTL细胞百分比的总结
CD45+圈选(Gated)%=圈选的CD45+细胞
细胞计数(x104)=细胞总数x总数%x 10
CTL圈选%=圈选的CD45+CD8+细胞
5.TILs中TH细胞的百分比的总结
CD45+圈选%=圈选的CD45+细胞
细胞计数(x104)=细胞总数x总数%x 10
TH圈选%=圈选的CD45+CD4+细胞
表6.TILs中NK细胞百分比的总结
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CD45+圈选%=圈选的CD45+细胞
细胞计数(x104)=细胞总数x总数%x 10
NK圈选%=圈选的CD45+CD56+细胞
表7.TILs中PD-L1细胞百分比的总结
结果显示施用抗-hPD-1抗体或抗-hPD-L1抗体对肿瘤生长没有影响。相较之下,在HepG2人源化小鼠模型中,OBI-3424的施用、OBI-3424与抗hPD-1抗体的组合治疗,或OBI-3424与抗hPD-L1抗体的组合治疗证明对肿瘤生长具有有效的抗肿瘤作用。
实施例2.OBI-3424+抗PD-1抗体(帕博利珠单抗(pembrolizumab))在HepG2肿瘤人源化小鼠模型中的功效性评估
研究的目的为评估在HepG2人源化小鼠模型中存在抗PD-1抗体(帕博利珠单抗(pembrolizumab))的情况下,不同剂量的OBI-3424测试品对肿瘤生长的功效,以及CD8+T细胞耗竭对组合治疗(OBI-3424/抗PD-1抗体)的抗肿瘤作用的影响。
材料
1.OBI-3424-DP
批号:FLC-INJ-1711-01
测试品数:2小瓶/每小瓶1mL
成分:DNA烷基化剂
浓度:10mg/mL
物理外观:透明液体
储存条件:-20℃
2.抗人类PD-1抗体,帕博利珠单抗(pembrolizumab),默克公司。
批号:7006846900
测试品数:1瓶/每瓶100mg
成分:抗体
浓度:25mg/mL
物理外观:透明液体
储存条件:2~8℃
3.等渗透压氯化钠溶液(信东生技股份有限公司)
批号:1OP2A092
浓度:0.9%氯化钠
物理外观:透明液体
溶解度:未提供
储存条件:室温
4.基质胶(Corning公司,型号:354248,批号:0261002)
5.人类PBMC(批号:PBMC102219D,Zenbio公司,美国)
6.胶原酶(Sigma Aldrich公司,型号:C5138),DNA水解酶I(Sigma Aldrich公司,型号:D5025),玻尿酸酶(Sigma Aldrich公司,型号:H6254)
7.RBC红血球裂解缓冲液(Biolegend公司,型号:420302)
8.细胞染色缓冲液(Biolegend公司,型号:420201)
9.人类TruStain FcXTM(Fc受体阻隔溶液)(Biolegend公司,型号:422302)
10.抗体:
抗人类CD45抗体(Biolegend公司,型号:368508)、抗人类CD8抗体(Biolegend公司,型号:344710)、抗人类CD4抗体(Biolegend公司,型号:317429)、抗人类CD56抗体(Biolegend公司,型号:318332)、抗人类CD11c抗体(Biolegend公司,型号:301614)、抗人类CD25抗体(Biolegend公司,型号:302610)、抗人类CD69抗体(Biolegend公司,型号:310914)、抗人类CD86抗体(Biolegend公司,型号:305406)、抗人类CD91抗体(Invitrogen、46-0919-42)、抗人类Foxp3抗体(Biolegend公司,型号:320108)、抗人类IFN-γ抗体(Biolegend公司,型号:506507)、抗人类颗粒酶B抗体(Biolegend公司,型号:372204)、抗人类钙网蛋白抗体(Abcam公司,型号:ab209577)、抗人类PD-1抗体(Biolegend公司,型号:329907)、抗人类PD-L1抗体(Biolegend公司,型号:329738)以及ViaKrome 405(Biolegend公司,型号:302610)。
小鼠
1.物种:小鼠(Mus musculus)
品是:晚期免疫缺陷小鼠。
(NOD.Cg-Prkdcscid Il2rg)
来源:三华生物科技股份有限公司
性别:雌
研究开始时的年龄:6~8周
研究开始时的体重范围:17~30克
2.编号与识别:每只小鼠以耳标编号。通过笼卡识别住笼,其中包括研究编号、笼编号、动物编号、性别、剂量含量等资讯。
动物分组:小鼠分为9组:G1(载剂)、G2(OBI-3424 0.3mg/kg)、G3(OBI-34241mg/kg)、G4(抗hPD-1抗体)、G5(OBI-3424 0.3mg/kg+抗hPD-1抗体)、G6(OBI-3424 1mg/kg+抗-hPD-1抗体),以及G7(OBI-3424 1mg/kg+抗hPD-1抗体,不包括CD8+PBMC组)。每组包含六只小鼠。将人类肝癌细胞株HepG2皮下接种至晚期免疫缺陷小鼠。本项研究含括共42只小鼠。
3.选择动物的原因:根据卫生福利部食品药物管理署公告的非临床药物安全性研究建议中的抗癌药物非临床研究指南,可将动物异种移植肿瘤模型用于评估新药或新抗癌药的疗效。常用的小鼠品系包括BALB/c、C57BL/6,而通常选择BALB/c Nude、Nu/Nu以及NOD/SCID小鼠来评估目标药物的抗肿瘤作用。这些品系是在全球的基础下进行管理的,具有众所周知的遗传及品种背景,可提供对人体适当反应的功能性意义。
4.适应期:在随机分组之前,使小鼠适应至少3天。在适应期间进行临床观察并测量体重。在此期间,这些动物没有表现出任何疾病迹象或行为改变。
5.动物的居住条件:将小鼠饲养在单独的通风笼(individually ventilatedcages,IVC)中,该笼中装有无菌垫层(10054,Andersons公司,美国),在受控环境中,温度为22±3℃,相对湿度为50±20%,光照/黑暗周期为12/12小时。在整个研究期间,小鼠可随意取用食物(LabDiet 5010,PMI公司,美国)及水(无菌逆渗透水)。
6.随机化:将所有动物称重,并在研究前观察健康状况。在实验中选择没有异常临床征状的动物。将健康的动物随机分为不同的组别,各组之间的体重没有显著差异。动物的体重变化不应超过平均体重的±20%。该程序遵循实验室动物操作标准。
7.IACUC核准号:IACUC-2020-SH-024
设备
细胞培养培养箱(Shel Lab公司/3552)
生物安全柜(BAKER公司/SG604)
电子天平(PRECISA公司/XS225A-SCS)
吸量管(Thermo公司/Finnpipette F1)
隔离正/负压验证的笼式住房系统(Allentown公司/NEXGEN)
分析天平(PRECISA公司/XS3250C-SCS)
动物安乐死设备(联台国际科技有限公司)
流式细胞仪(Beckman Coulter公司/Navios EX)
游标尺(Mitutoyo公司/CD-6”ASX)
方法
实验设计
取样:实验设计、实验组、注射剂量与体积、施用途径以及动物数量列于表8。
表8.剂量方案及取样
2.异种移植小鼠模型的建立
2.1.动物除毛:在注射人类肝癌细胞株HepG2之前,仅剪除右侧腹部的毛发。
2.2.皮下接种肿瘤细胞:将1x107个HepG2细胞与0.25x107个hPBMC(细胞数比为4:1)预混合,然后再与基质胶混合(体积比1:1)(Corning公司,型号:354248,批号:8228001)。皮下注射体积为200μL/小鼠。
将肿瘤细胞注射的日期表示为潜伏期的第一天(L0)。
3.测试物品的施用途径:
3.1.在第0天将测试品OBI-3424或参照品以静脉内注射施用于小鼠。使用胰岛素注射器以0.3mg/kg或1mg/kg的剂量进行注射,且注射体积为5mL/kg。针对G2、G3、G5、G6及G7,在第7、14、21及28天连续给予OBI-3424测试品。G1组施用该参照品。该程序遵循样品施用的标准。给予试验品项的开始日为第一个实验日(D0)。
3.2.于第2天将测试品抗hPD-1抗体以腹膜内注射施用于小鼠。使用胰岛素注射器以20mg/kg的剂量以及10mL/kg的注射体积进行注射。针对G4、G5、G6及G7,在第5、9、12、16、19、23及26天连续给予测试品抗hPD-1抗体。该程序遵循样品施用的标准。
3.3.测试品或参照品的准备:
施用前,将测试品以参照品稀释。测试品OBI-3424的溶液浓度为0.06mg/mL及0.2mg/mL,测试品抗hPD-1抗体为2mg/mL。
4.体重测量:
从接种的第二天开始进行测量。测量动物体重,每周记录两次。
5.肿瘤直径测量:
从接种的第二天开始进行测量。每周两次测量并记录肿瘤体积(周一、周四)。根据记录,通过椭圆方程式算出肿瘤体积(长轴×短轴×短轴)×(π/6)。
6.肿瘤生长抑制率的计算:
根据以下公式,将肿瘤体积用于计算肿瘤生长抑制(TGI)速率:TGI(%)=[1-(Ti-T0)/(Ci-C0)]×100,其中Ti及Ci表示实验结束时(第30天)治疗组以及载剂组的平均肿瘤体积。而T0及C0表示实验开始(第0天)时治疗组及载剂组的平均肿瘤体积。
7.血液采样:
在实验终点收集颌下血液样本。处死动物时,可使用心脏穿刺收集血液样本。将收集的血液样本于4±2℃下以1500xg离心15分钟以分离血清及沉淀物。收集上层血清,并保存在低于-70℃的温度下。该程序遵循动物血液采样的标准。
8.确定研究的终点:
该研究在第30天结束。
9.肿瘤切除:
在研究结束时,以二氧化碳安乐死方式将小鼠处死,并切除肿瘤周围的结缔组织。然后取出肿瘤样品并称重,如果肿瘤重量超过400mg,则将其均等地切成三段。准备肿瘤组织以分离肿瘤浸润淋巴细胞(TILs)。一段的其余部分以10%甲醛固定并包埋在石蜡中;其他的则存放在低于-70℃的温度下。
10.肿瘤浸润淋巴细胞(TILs)的分离:
以手术刀将肿瘤样品切成较小的碎片,然后以胶原酶、DNA水解酶I,以及玻尿酸酶(胶原酶,型号C5138,DNA水解酶I,型号D5025,玻尿酸酶,型号H6254,Sigma Aldrich公司)的混合物消化至少2小时。然后使用注射器柱塞将肿瘤消化物通过70μm筛孔细胞过滤器(Falcon公司,型号352350),并以PBS洗涤。以RBC红血球裂解缓冲液(Biolegend公司,型号420302)处理细胞,并制备用于流式细胞仪的单细胞悬浮液。
11.TIL族群的流式细胞仪分析:
以染色缓冲液(Biolegend公司,型号420201)洗涤细胞,重新悬浮于含有Fc受体阻隔溶液(Biolegend公司,型号422302)的染色缓冲液中,并于4℃下作用15分钟。以荧光共轭的表面抗体对细胞进行染色,并于4℃下作用30分钟,然后将其重新悬浮于染色缓冲液中以进行流式细胞仪分析。使用Navios EX流式细胞仪(Beckman Coulter公司)进行流式细胞仪分析。使用Kaluza分析软体(Beckman Coulter公司)分析数据。
12.统计分析:
结果表示为平均值与平均值的标准误差(Mean±SEM)。使用司徒顿t检定(Microsoft Excel,2007年)计算每个治疗组收集的所有数据与同时出现的阴性对照数据的比较。P≤0.05被认为具有显著差异。
结果
表9列出各组体重的总结。在研究开始或处死时,G1~G7组之间的平均体重没有统计学上的显著差异(图4及表9)。
表9.体重总结
从不同的测试品检查肿瘤反应,在注射肿瘤细胞后的L1、L3及L7天记录平均肿瘤反应,在施用测试品后的D0、D2、D6、D9、D13、D16、D20、D23、D27及D30天记录平均肿瘤反应(图6及表10)。
首先,我们检查自G1(载剂)、G2(OBI-3424 0.3mg/kg)、G3(OBI-3424 1mg/kg)及G4(抗hPD-1抗体,20mg/kg)测试品对肿瘤反应的效果。在第30天,在存在OBI-3424(0.3mg/kg及1mg/kg)的情况下,观察到与剂量相关的平均肿瘤体积减少(G1载体:882.92±158.14mm3;G2 OBI-3424 0.3mg/kg:716.44±31.12mm3;G3OBI-3424 1mg/kg:216.90±22.20mm3,p=0.00096<0.001)。于第30天,抗hPD-1抗体的治疗中未观察到统计学上的显著差异(G1载剂:882.92±158.14mm3;G4抗hPD-1抗体:983.84±266.44mm3)。
组合治疗G5(OBI-3424 0.3mg/kg+抗hPD-1抗体20mg/kg)、G6(OBI-3424 1mg/kg+抗hPD-1抗体20mg/kg)及G7(OBI-3424 1mg/kg+抗hPD-1抗体20mg/kg,不包括CD8+PBMC)的结果显示,于D30天相较于载剂组,所有这些组别的平均肿瘤体积均显著减少(G1载剂:882.92±158.14mm3;G5 OBI-3424 0.3mg/kg+抗hPD-1抗体:429.41±106.14mm3,p=0.0193<0.05;G6 OBI-3424 1mg/kg+抗hPD-1抗体:197.74±19.62mm3,p=0.00078<0.001;G7OBI-3424 1mg/kg+抗-hPD-1抗体,不包括CD8+PBMC:374.44±36.97mm3,p=0.0053<0.05)。
相较于单一治疗,于D30天时,组合治疗倾向于改善G2与G5之间以及G3与G6之间对平均肿瘤体积的抑制作用,但是这些减少并不显著(G2 OBI-3424 0.3mg/kg:716.44±31.12mm3;G5 OBI-3424 0.3mg/kg+抗hPD-1抗体:429.41±106.14mm3;G3OBI-3424 1mg/kg:216.90±22.20mm3;G6 OBI-3424 1mg/kg+抗hPD-1抗体:197.74±19.62mm3)。此外,计算肿瘤生长抑制(TGI)的百分比以量化治疗效果。低剂量与高剂量OBI-3424的单一治疗分别产生的TGI为27.82%及113.27%。抗-hPD-1抗体与低剂量及高剂量OBI-3424的组合治疗分别产生的TGI为77.22%及117.66%(图6及表10)。
不过,针对G6(OBI-3424 1mg/kg+抗hPD-1抗体)以及G7(OBI-3424 1mg/kg+抗hPD-1抗体,不包括CD8+PBMC)进行比较,CD8+细胞的耗竭导致在D30天的平均肿瘤体积显著增加(G6 OBI-3424 1mg/kg+抗hPD-1抗体:197.74±19.62mm3,G7 OBI-3424 1mg/kg+抗hPD-1抗体,不包括CD8+PBMC:374.44±36.97mm3,p=0.00088<0.001),尽管采用相同剂量的组合治疗,TGI的百分比仍从117.66%降至87.35%(图6及表10)。在肿瘤重量上也观察到类似趋势(图5及表10)。
表10.肿瘤体积及重量的总结
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从新鲜肿瘤组织中分离出肿瘤浸润淋巴细胞(TILs),并以流式细胞仪测量各组之间的表面标记物CD45、CD4、CD8、CD56、CD11c、CD69、CD25、CD86、CD91、颗粒酶B、IFN-γ、Foxp3、钙网蛋白(Calreticulin)、PD-1,以及PD-L1的表现量。表11~16中提供个别小鼠的数值数据。相较于载剂组,高剂量OBI-3424治疗不论是单独治疗或与抗hPD-1抗体组合治疗时,细胞毒性淋巴细胞(CTL)细胞(CD45+CD8+T细胞)以及T辅助细胞(T helper,TH)(CD45+CD4+T细胞)的数量显著增加(CTL细胞:G1载剂:15.53±5.66%;G3 OBI-3424 1mg/kg:33.50±3.38%,p=0.0107<0.05;G6 OBI-3424 1mg/kg+抗hPD-1抗体:38.46±2.63%,p=0.00215<0.05。TH细胞:G1载体:14.59±2.00%,G3 OBI-3424 1mg/kg:25.05±2.08%,p=0.0023<0.05;G6OBI-3424 1mg/kg+抗hPD-1抗体:30.62±2.07%,p=0.00012<0.001)(表13~14)。
表11.TILs中钙网蛋白细胞百分比的总结
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CD45-圈选%=圈选的CD45-细胞活细胞圈选%=圈选的CD45-ViaKrome405弱细胞细胞计数(x105)=细胞总数x总数%x 10
表12.TILs中PD-L1+细胞的百分比的总结
CD45-圈选%=圈选的CD45-细胞细胞计数(x105)=细胞总数x总数%x 10
表13.TILs中CTL细胞百分比的总结
CD45-圈选%=圈选的CD45-细胞
CTL圈选%=圈选的CD45+CD8+细胞细胞计数(x105)=细胞总数x总数%x 10
表14.TILs中TH细胞的百分比的总结
CD45-圈选%=圈选的CD45-细胞
TH圈选百分比=圈选的CD45+CD4+细胞细胞计数(x105)=细胞总数x总数%x 10
表15.TILs中NK细胞百分比的总结
CD45+圈选%=圈选的CD45+细胞
NK圈选%=圈选的CD45+CD56+细胞细胞计数(x105)=细胞总数x总数%x 10
表16.TILs中树突状细胞百分比的总结
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CD45+圈选%=圈选的CD45+细胞
DC圈选%=圈选的CD45+CD11c+细胞
细胞计数(x105)=细胞总数x总数%x 10
结果显示,施用OBI-3424可显著更大程度地抑制肿瘤生长,并显示出具有抗肿瘤活性的剂量依赖性趋势。此外,高剂量OBI-3424结合抗hPD-1抗体治疗在HepG2人源化小鼠模型中显示出对肿瘤生长最有效的抗肿瘤作用。但是,CD8+细胞的耗竭导致组合治疗的抗肿瘤功效大幅降低。
本发明实施例的以上描述并不限制本发明。本领域技术人员可根据本发明做出各种修改及改变,且在本发明的精神内的任何修改及改变都应包括在本发明所附申请专利范围的范围内。
本发明引用的所有参考文献均在法律允许的范围内通过引用并入本发明。这些参考文献的讨论目的仅在于总结其作者提出的主张。不承认任何参考文献(或任何参考文献的一部分)为相关的现有技术。申请人保留质疑任何引用文献的准确性及相关性的权利。
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Claims (20)
1.一种医药组合物,包含:
(1)由式I表示的化合物1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯,
或其医药上可接受的盐类、同位素变体或溶剂化物;以及
(2)至少一治疗剂,包括化学治疗剂或生物试剂。
2.如权利要求1所述的医药组合物,其中该化合物为式I-1表示的(S)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯,或
式I-2表示的(R)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N'-双(乙烯)胺基磷酸酯
3.如权利要求1所述的医药组合物,其中该化学治疗剂选自单甲基澳瑞他汀E(Monomethyl auristatin E,MMAE)、单甲基澳瑞他汀F(MMAF)、美登木素生物碱(mertansine,DM1)、蒽环素(anthracycline)、吡咯并苯并二氮杂(pyrrolobenzodiazepine)、α-鹅膏蕈碱(α-amanitin)、微管溶素(tubulysin)、苯二氮平(benzodiazepine)、厄洛替尼(erlotinib)、硼替佐米(bortezomib)、氟维司群(fulvestrant)、舒尼替尼(sunitinib)、来曲唑(letrozole)、甲磺酸伊马替尼(imatinibmesylate)、PTK787/ZK 222584、奥沙利铂(oxaliplatin)、菊白叶酸(leucovorin)、雷帕霉素(rapamycin)、拉帕替尼(lapatinib)、洛那法尼(lonafarnib)、索拉非尼(sorafenib)、吉非替尼(gefitinib)、AG1478、AG1571、烷基化试剂(alkylating agent)、烷基磺酸盐(alkylsulfonate)、氮丙啶类(aziridines)、乙烯亚胺(ethylenimine)、甲基三聚氰胺(methylamelamine)、内酯(acetogenins)、喜树碱(camptothecin)、苔藓虫素(bryostatin)、卡利斯他汀(callystatin)、CC-1065、念珠藻素(cryptophycins)、尾海兔素(dolastatin)、杜卡霉素(duocarmycin)、艾榴塞洛素(eleutherobin)、胰抑素(pancratistatin)、珊瑚素(sarcodictyin)、海绵素(spongistatin)、氯芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、氯磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、甲氯乙胺(mechlorethamine)、盐酸甲氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard)、卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷诺氮芥(ranimustine)、卡奇霉素(calicheamicin)、达尼霉素(dynemicin)、氯磷酸盐(clodronate)、埃司帕霉素(esperamicin)、新卡司他汀发色团(neocarzinostatin chromophore)、阿克拉霉素(aclacinomysins)、放线菌霉素(actinomycin)、安曲霉素(authramycin)、重氮丝氨酸(azaserine)、博莱霉素(bleomycins)、放线菌素(cactinomycin)、卡拉霉素(carabicin)、卡氨霉素(caminomycin)、嗜癌菌素(carzinophilin)、色霉素(chromomycinis)、放线菌素(dactinomycin)、道诺霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正白胺酸(6-diazo-5-oxo-L-norleucine)、阿霉素(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycins)、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、喹纳霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲佐菌素(streptozocin)、结核菌素(tubercidin)、苯丁抑制素(ubenimex)、净司他丁(zinostatin)、红柔霉素(zorubicin)、氨甲蝶呤(methotrexate)、5-氟尿嘧啶(5-fluorouracil,5-FU)、二甲叶酸(denopterin)、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate)、氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine)、安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-硫唑脲嘧啶(6-azauridine)、卡莫呋(carmofur)、阿糖胞苷(cytarabine)、双去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、伊诺他滨(enocitabine)、氟尿苷(floxuridine)、卡鲁睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯酮(testolactone)、氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane)、醛叶酸(folinicacid)、醋葡醛内酯(aceglatone)、醛磷酰胺糖苷(aldophosphamide glycoside)、胺乙酰丙酸(aminolevulinic acid)、恩尿嘧啶(eniluracil)、安吖啶(amsacrine)、阿莫司汀(bestrabucil)、比生群(bisantrene)、依达曲沙(edatraxate)、地磷酰胺(defofamine)、秋水仙胺(demecolcine)、地吖醌(diaziquone)、艾福米辛(elformithine)、依利醋铵(elliptinium acetate)、埃博霉素(epothilone)、依托格鲁(etoglucid)、硝酸镓(galliumnitrate)、羟基脲(hydroxyurea)、香菇多醣(lentinan)、氯尼达明(lonidainine)、美登素(maytansine)、安丝菌素(ansamitocins)、米托脲腙(mitoguazone)、米托蒽醌(mitoxantrone)、莫哌达醇(mopidanmol)、硝拉维林(nitraerine)、喷司他丁(pentostatin)、蛋胺氮芥(phenamet)、吡柔比星(pirarubicin)、洛索蒽醌(losoxantrone)、鬼臼酸(podophyllinic acid)、2-乙基酰肼(ethylhydrazide)、甲基芐肼(procarbazine)、雷佐生(razoxane)、根霉素(rhizoxin)、西佐喃(sizofiran)、锗螺胺(spirogermanium)、细交链孢菌酮酸(tenuazonic acid)、三亚胺醌(Triaziquone)、2,2’,2”-三氯三乙胺(trichlorotriethylamine)、新月毒素(trichothecene)、乌拉坦(urethan)、长春地辛(vindesine)、达卡巴嗪(dacarbazine)、甘露醇氮芥(mannomustine)、二溴甘露醇(mitobronitol)、二溴卫矛醇(mitolactol)、溴丙哌嗪(pipobroman)、甲托辛(gacytosine)、阿拉伯醣苷(arabinoside)、环磷酰胺(cyclophosphamide)、噻替哌(thiotepa)、类紫杉醇(taxoid)、紫杉醇(paclitaxel)、欧洲紫杉醇(docetaxel)、苯丁酸氮芥(chloranbucil)、吉西他滨(gemcitabine)、6-硫鸟嘌呤(6-thioguanine)、巯基嘌呤(mercaptopurine)、氨甲蝶呤(methotrexate)、顺铂(cisplatin)、卡铂(carboplatin)、长春花碱(vinblastine)、铂(platinum)、依托泊苷(etoposide)、异环磷酰胺(ifosfamide)、米托葱醌(mitoxantrone)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、米托蒽醌(novantrone)、替尼泊苷(teniposide)、依达曲沙(edatrexate)、道诺霉素(daunomycin)、氨基蝶呤(aminopterin)、截瘤达(xeloda)、伊班膦酸盐(ibandronate)、拓扑异构酶抑制剂(topoisomerase inhibitor)、二氟甲基鸟氨酸(difluoromethylornithine,DMFO)、维他命A酸(retinoid)及卡培他滨(capecitabine)。
4.如权利要求1所述的医药组合物,其中该生物试剂选自胜肽、蛋白质、抗体、荷尔蒙、细胞激素或趋化激素。
5.如权利要求4所述的医药组合物,其中该抗体为抑制/阻断抑制性免疫检查点抗原的抗免疫检查点抗体。
6.如权利要求5所述的医药组合物,其中该抗免疫检查点抗体为抗PD-1/PD-L1抗体、抗CTLA-4抗体、抗LAG-3抗体、抗TIGIT抗体、抗Ceacam 1抗体、抗LAIR-1抗体、抗TIM-3抗体、抗VISTA抗体、抗KIR抗体、抗IDO抗体、抗CD276抗体、抗A2AR抗体或抗CD47抗体。
7.如权利要求6所述的医药组合物,其中该抗PD-1/PD-L1抗体为阿维鲁单抗(avelumab)、纳武利尤单抗(nivolumab)、帕博利珠单抗(pembrolizumab)、度伐利尤单抗(durvalumab)及/或阿替利珠单抗(atezolizumab)。
8.如权利要求1所述的医药组合物,进一步包含医药上可接受的赋形剂。
9.一种如权利要求1至8中任一项所述的医药组合物在制备用于治疗患者癌症的药物的用途。
10.如权利要求9所述的用途,其中该癌症为AKR1C3还原酶过度表现的癌症。
11.如权利要求9所述的用途,其中该癌症为肝癌、肝细胞癌(hepatocellularcarcinoma,HCC)、肺癌、黑色素瘤、前列腺癌、乳癌、血癌、食道癌、肾癌、胃癌、结肠癌、脑癌、膀胱癌、子宫颈癌、卵巢癌、头颈癌、子宫内膜癌、胰脏癌、肉瘤癌或直肠癌。
12.一种在一有其需要之患者中治疗癌症之方法,包含对该患者施用治疗有效量的如权利要求1至8中任一项所述之医药组合物的步骤。
13.如权利要求12所述之方法,其中该治疗有效量为0.1mg/kg至100mg/kg。
14.如权利要求12所述之方法,其中该癌症为AKR1C3还原酶过度表现的癌症。
15.如权利要求12所述之方法,其中该癌症为肝癌、肝细胞癌(HCC)、肺癌、黑色素瘤、前列腺癌、乳癌、血癌、食道癌、肾癌、胃癌、结肠癌、脑癌、膀胱癌、子宫颈癌、卵巢癌、头颈癌、子宫内膜癌、胰脏癌、肉瘤癌或直肠癌。
16.一种抑制癌细胞生长的方法,包含对一有此需要的患者施用治疗有效量的医药组合物,该医药组合物包含由式I-1或式I-2表示的化合物与免疫检查点抑制剂的组合
17.如权利要求16所述的方法,其中该化合物与该免疫检查点抑制剂的组合共同或协同地进行阻断作用以拯救T细胞不活化作用并改善治疗功效。
18.如权利要求16所述的方法,其中该免疫检查点抑制剂为抗PD-1/PD-L1抗体。
19.如权利要求16所述的方法,其中该癌症为AKR1C3还原酶过度表现的癌症。
20.如权利要求16所述的方法,其中该癌症为肝癌、肝细胞癌(HCC)、肺癌、黑色素瘤、前列腺癌、乳癌、血癌、食道癌、肾癌、胃癌、结肠癌、脑癌、膀胱癌、子宫颈癌、卵巢癌、头颈癌、子宫内膜癌、胰脏癌、肉瘤癌或直肠癌。
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