CN115414351B - pladienolide B与PD-L1抗体组合在肿瘤免疫治疗领域的应用 - Google Patents
pladienolide B与PD-L1抗体组合在肿瘤免疫治疗领域的应用 Download PDFInfo
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Abstract
本发明涉及pladienolide B与PD‑L1抗体组合在肿瘤免疫治疗领域的应用。卵巢癌是目前研究威胁女性健康的恶性肿瘤，一线治疗复发率高，预后情况较差，单纯使用免疫治疗的效果不理想，采用标准化疗结合免疫治疗受到临床研究的重视。本发明发现SF3B1的抑制剂pladienolide B能够提高免疫细胞活性，本发明进一步提供了pladienolide B与PD‑L1抗体联合用药，可以显著增强免疫治疗的效果，有望应用于卵巢癌的临床治疗。
Description
技术领域
本发明属于肿瘤免疫治疗药物技术领域，具体涉及Pladienolide B作为免疫系统激活剂的应用及Pladienolide B与PD-L1的药物组合在肿瘤免疫治疗领域的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
卵巢癌，卵巢癌是常见的女性生殖器官恶性肿瘤之一。2020年世界卫生组织(World Health Organization，WHO)统计数据显示，全球每年新确诊卵巢癌病例约为31.4万例，发病率居妇科恶性肿瘤第3位；相关死亡病例约为20.7万例，死亡率仅次于宫颈癌，居第2位。大部分卵巢癌患者确诊时已为晚期，使用传统的一线标准化疗方案获益有限。一线治疗后复发的患者因缺少有效的二线治疗方案常预后较差。有数据显示，晚期卵巢癌患者的5年生存率仅为30％。因此，探讨新方案以改善晚期卵巢癌患者的生存和预后是临床和基础研究的重要课题。随着肿瘤分子学研究的深入，针对肿瘤相关分子通路的靶向药物已成为重要治疗策略。贝伐珠单抗是首个应用于卵巢癌的分子靶向药物，开启了免疫治疗在卵巢癌领域的应用，目前，以免疫检查点单抗为基础，联合化疗、其他分子靶向药物或抗肿瘤免疫药物治疗卵巢癌患者的新方案探讨日益受到研究者的重视。
SF3B1(splicing factor 3b subunit 1,剪接因子3b亚基1)基因突变引起的异常间接与多种恶性肿瘤相关，美国弗雷德哈金森癌症研究中心和纪念斯隆凯特琳癌症中心等研究机构的研究人员确定了SF3B1(splicing factor 3b subunit 1,剪接因子3b亚基1)基因突变如何促进很多癌症形成，其中SF3B1是最为频繁发生突变的剪接因子编码基因。pladienolide B是靶向SF3B1的剪接体抑制剂，以往研究表明，其可以诱导细胞凋亡，但细胞凋亡是非免疫原性的死亡，不能引起机体的免疫反应。
发明内容
基于上述技术背景，本发明目的在于提供一种适用于卵巢癌的免疫联合治疗方法及药物组合。现有研究表明Pladienolide B能够诱导卵巢癌细胞焦亡从而抑制肿瘤发展，本发明研究验证，Pladienolide B能够活化巨噬细胞，增强CD4+T细胞和CD8+T细胞在肿瘤中的浸润比例，通过激活免疫途径增强肿瘤免疫治疗效果。本发明进一步的，还提供了Pladienolide B与PD-L1的药物组合在肿瘤免疫治疗中的应用。
本发明第一方面，提供Pladienolide B作为免疫系统激活剂的应用。
上述Pladienolide B(CAS号445493-23-2)还包括其药学上可接受的盐，所述免疫系统激活剂施用目的为增强对肿瘤细胞具有杀伤活性的免疫细胞，如巨噬细胞、T细胞、NK细胞等。
本发明第二方面涉及一种药物组合物，所述组合物中至少包括：(a)SF3B1抑制剂，或其药学上可接受的盐；(b)免疫检查点的单克隆抗体。
优选的，所述SF3B1抑制剂为普拉地内酯类，如普拉地内酯A～G、E7107或H3B-8800。
优选的，所述免疫检查点包括但不限于PD-1、PD-L1、TIGIT、LAG3、TIM3中的一种或几种的组合。
本发明验证的一种效果较好的实施方式中，所述SF3B1抑制剂为剪接因子SF3B117的剪接体抑制剂pladienolide B，所述免疫检查点单克隆抗体为PD-L1抗体。
上述实施方式中，所述pladienolide B及PD-L1抗体的使用方式包括同时施用、分开或依序施用；所述药物组合物适用于预防、治疗或改善增生性疾病，所述增生性疾病为肿瘤，进一步的，为包括但不限于卵巢癌、乳腺癌、宫颈癌、肺癌、胰腺癌中的一种，包括上述类型肿瘤的实体瘤或转移瘤，可实现的效果包括肿瘤体积的降低或抑制病灶的生长、转移等。
优选的，所述药物组合物中，还包括至少一种药学上可接受的载体，所述载体的实例包括但不限于崩解剂、粘合剂、润滑剂、助流剂、稳定剂和填充剂、稀释剂、着色剂、调味剂和防腐剂。本领域普通技术人员可关于剂型的特定所需特性通过常规实验并且无任何不当负荷来选择一种或多种上述载体。所用的各载体的量可在本领域中的常规范围内变化。
进一步的，所述药学上可接受的崩解剂的实例包括但不限于淀粉；粘土；纤维素；海藻酸盐；胶；交联聚合物，例如交联聚乙烯吡咯烷酮或交联聚维酮，例如来自International Specialty Products(Wayne,NJ)的POLYPLASDONE XL；交联羧甲基纤维素钠(cross-linked sodium carboxymethylcellulose)或交联羧甲基纤维素钠(croscarmellose sodium)，例如来自FMC的AC-DI-SOL；和交联羧甲基纤维素钙；大豆多糖；和瓜尔胶。崩解剂可以所述组合物的约0重量％至约10重量％的量存在。在一个实施方案中，崩解剂是以组合物的约0.1重量％至约5重量％的量存在。
药学上可接受的粘合剂的实例包括但不限于淀粉；纤维素和其衍生物，例如微晶纤维素，例如来自FMC(Philadelphia,PA)的AVICEL PH、来自Dow Chemical Corp.(Midland,MI)的羟基丙基纤维素、羟基乙基纤维素和羟基丙基甲基纤维素METHOCEL；蔗糖；右旋糖；玉米糖浆；多糖；和明胶。粘合剂可以所述组合物的约0重量％至约50重量％，例如2-20重量％的量存在。
药学上可接受的润滑剂和药学上可接受的助流剂的实例包括但不限于胶状二氧化硅、三硅酸镁、淀粉、滑石、磷酸三钙、硬脂酸镁、硬脂酸铝、硬脂酸钙、碳酸镁、氧化镁、聚乙二醇、粉末状纤维素和微晶纤维素。润滑剂可以所述组合物的约0重量％至约10重量％的量存在。在一个实施方案中，润滑剂可以组合物的约0.1重量％至约1.5重量％的量存在。助流剂可以约0.1重量％至约10重量％的量存在。
药学上可接受的填充剂和药学上可接受的稀释剂的实例包括但不限于糖粉、可压缩糖、葡萄糖结合剂(dextrate)、糊精、右旋糖、乳糖、甘露醇、微晶纤维素、粉末状纤维素、山梨醇、蔗糖和滑石。填充剂和/或稀释剂例如可以所述组合物的约0重量％至约80重量％的量存在。
本发明第三方面，提供第二方面所述药物组合物在制备抗肿瘤药剂中的应用。
所述抗肿瘤制剂包括但不限于用于预防、改善或治疗肿瘤相关疾病的药物、医用器械或模型药剂；优选的，上述抗肿瘤药物中，含有、可含有约0.1％至约99.9％，优选地约1％至约60％的药物组合物。
本发明第四方面，提供一种抗肿瘤药物，所述抗肿瘤药物中，第二方面所述药物组合物作为活性治疗剂。
所述抗肿瘤药物包括经肠或不经肠的单位剂型，具体的制剂形式如包覆糖衣的片剂、片剂、胶囊或栓剂或安瓿。如果未另外指示，那么这些组合物是以本身已知的方式，例如借助于各种常规混合、粉碎、直接压缩、粒化、包覆糖衣、溶解、冻干工艺或本领域技术人员显而易知的制造技术来制备；更为优选的实施方式中，所述抗肿瘤药物为注射剂。
本发明第五方面，提供一种肿瘤治疗方法，所述治疗方法包括将第一方面所述药物组合物或第四方面所述抗肿瘤药物施用于有治疗需求的个体。
优选的，所述施用方式包括注射方式或通过手术介入等方式将上述药物组合物或抗肿瘤药物施用于病灶部位。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1为实施例1中体外实验结果；
图2为实施例1中小鼠体内实验肿瘤抑制结果；
图3为实施例1中各实验组肿瘤组织染色结果。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本发明的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例详细说明本发明的技术方案。
实施例1
小鼠体外模型实验：
Pladienolide B处理肿瘤细胞72小时，取上清液，与小鼠巨噬细胞共培养24小时，检测巨噬细胞对肿瘤的杀伤效果，结果如附图1所示，纵轴表示处理后巨噬细胞对肿瘤细胞的杀伤能力。结果发现与正常肿瘤细胞上清相比，Pladienolide B处理后的肿瘤细胞上清(即图1中tumor cell+pladienolideB组)能显著增加巨噬细胞的肿瘤杀伤能力，而单独Pladienolide B处理对巨噬细胞活性无明显影响。
小鼠体内模型实验：
实验方法：将小鼠卵巢癌ID8细胞接种到C57/BL小鼠体内，当肿瘤体积达到50-100mm3时，将小鼠随机分为4组，分别给予对照处理、pladienolide B(0.5mg/kg，每3天一次，腹腔注射)、PD-L1抗体(200μg/小鼠，每3天一次，腹腔注射，共6次)和pladienolide B+PD-L1抗体联合(先用pladienolide B 0.5mg/kg，每3天一次，腹腔注射，3次，然后PD-L1抗体200μg/小鼠，每3天一次，腹腔注射，3次)。
结果如附图2及下表1所示，结合肿瘤抑制结果可以看出，pladienolide B的加入能够有效增强PD-L1抗体抗肿瘤效果。图3为上述实验组肿瘤组织的免疫组化结果，从图2中可以看出，联合用药组中CD8+T细胞浸润比例明显提升。
表1图1中各实验组肿瘤平均重量(mg)
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.Pladienolide B在体外用肿瘤细胞中显著增加巨噬细胞的肿瘤杀伤能力的应用；
上述应用在体外环境中进行，且所述应用不包含疾病诊断和治疗用途。
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