CN114681609A - 抗il-6抗体组合物在制备治疗肝细胞癌药物中的应用 - Google Patents
抗il-6抗体组合物在制备治疗肝细胞癌药物中的应用 Download PDFInfo
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Abstract
本发明提供抗IL‑6抗体组合物在制备治疗肝细胞癌药物中的应用，所述组合物由抗IL‑6抗体与磷酸肌醇‑3‑激酶‑雷帕霉素靶点小分子抑制剂(NVP‑BEZ235)组合。本发明基于NVP‑BEZ235用药后会引起促炎性细胞因子IL‑6表达水平升高的发现，经实验证明，组合物组治疗后显著延缓了肿瘤进程并延长了荷瘤小鼠的生存时间。更进一步，本发明组合有望制备提高NVP‑BEZ235的治疗效果的可应用于肝细胞癌的治疗的药物。
Description
技术领域
本发明属于生物医学领域，涉及抗IL-6抗体组合物在制备治疗肝细胞癌药物中的应用，是抗IL-6抗体与NVP-BEZ235(磷酸肌醇-3-激酶-雷帕霉素靶点小分子抑制剂)组合物在制备治疗肝细胞癌药物中的应用。
背景技术
原发性肝癌位居癌症相关死亡数量最多的癌种前列，特别是肝细胞癌(Hepatocellular carcinoma,HCC)，几乎占据原发性肝癌全部病例的90％。肝癌治疗的选择有限、侵袭程度较高，早中期肝癌病人通常选择射频消融、肝切除、肝移植等局部治疗方式，对于晚期肝癌患者通常采用全身治疗，使用多激酶抑制剂索拉菲尼与仑伐替尼是当前主要的一线疗法。常规疗法虽然具有一定的抗肿瘤作用，但并不能显著改善其预后效果。
在过去的10余年中，多数药物并未表现出显著的生存获益。目前，肝细胞癌的治疗新方向包含分子靶向抑制剂联合治疗的策略，通过增强靶向药物的敏感性来达到更好的协同作用。因此，开发新的治疗策略为肝细胞癌的治疗提供了一定的参考价值。
磷酸肌醇-3-激酶-雷帕霉素靶点抑制剂Dactolisib(NVP-BEZ235)是一种双重ATP竞争性PI3K和mTOR抑制剂，目前正处于临床前Ⅰ/Ⅱ期试验阶段。药物毒性是小分子抑制剂面临的普遍挑战，许多接受PI3K抑制剂治疗的患者在之前的临床报道中，出现了肺炎、结肠炎、免疫相关毒性等不良反应。
在前期实验中显示单独给药能通过抑制肿瘤增殖发挥抗肿瘤效应，同时发现NVP-BEZ235用药后会引起促炎性细胞因子IL-6水平升高。炎症反应的发生与肿瘤的发展密切相关，细胞因子被认为是连接二者的关键介质。IL-6已被证明能够促进多种肿瘤细胞的发生发展，同时大量临床样本显示，肝癌患者血清中IL-6的含量与健康者相比显著升高，并伴随着较差的预后。针对这一发现，我们提出：靶向抑制IL-6同时联合使用NVP-BEZ235治疗HCC的方案。对于分子靶向药物联合治疗的研究，一定程度上弥补了单药使用的不足，规避了药物毒性，达到增强NVP-BEZ235抗肿瘤效果的目的。
发明内容
发明的目的是提供抗IL-6抗体组合物在制备治疗肝细胞癌药物中的应用，是抗IL-6抗体与NVP-BEZ235(磷酸肌醇-3-激酶-雷帕霉素靶点小分子抑制剂)组合物在制备治疗肝细胞癌药物中的应用，所述组合物由抗IL-6抗体与NVP-BEZ235组合，组合比例为10mg/kg：60mg/kg。所述药物由组合物与药用辅料制备。
本发明首先利用水动力转染法构建小鼠肝细胞癌模型，发现NVP-BEZ235用药后IL-6表达升高(图1)，根据肿瘤进程设计用药方案(图2)。实验证明，治疗后观察组合物治疗组小鼠的肝重/体重、最大肿瘤直径、肿瘤结节数明显下降(图3)，生存时间显著延长(图4)。组合物组治疗显著降低了肿瘤负荷(图5)。组合物组肝癌区域的Ki-67阳性率显著降低(图6)。本发明组合物在降低NVP-BEZ235用药产生副作用的同时，起到协同治疗肝细胞癌的目的。所述组合物制备的药物可提高NVP-BEZ235的治疗效果，并应用于肝细胞癌的治疗。
附图说明
图1为H&E检测不同处理组小鼠HCC组织中IL-6的蛋白表达。
图2为不同治疗组小鼠HCC的构建及药物治疗过程。
图3为肿瘤负荷小鼠肝重/体重、最大肿瘤直径、肿瘤结节数的结果示意图。
图4为小鼠肿瘤负荷生存时间统计图。
图5为不同治疗组小鼠肝脏标本大体观和H&E染色情况。
图6为免疫组化检测小鼠荷瘤Ki-67表达情况。
具体实施方式
本发明结合附图和实施例作进一步的说明。
实施例1
通过构建小鼠肝细胞癌模型，并检测抗IL-6抗体与NVP-BEZ235组合物及荷瘤指标对荷瘤生存时间的影响。
1.构建小鼠肝细胞癌模型
1.1实验动物及主要材料：雄性纯系C57小鼠，体重20-25g，购于上海斯莱科公司。
1.2方法：选取野生型C57小鼠，构建质粒诱导小鼠肝细胞癌(HCC)模型。按照C-myc质粒：N-ras质粒：SB质粒＝1:19:2的比例，将质粒加入到无菌的1×PBS中，配制成浓度为11μg/mL的质粒混合液；将8-10周龄的小鼠称重，按照小鼠体重(g)的10％抽取相应体积(mL)的混合质粒溶液；将小鼠固定在静脉可视小鼠尾注固定器内，按压小鼠尾部至尾静脉充分暴露，在5-9秒内用注射器将混合质粒注入小鼠体内；待小鼠状态恢复正常后归笼继续饲养。
2.实验结果。首先构建了小鼠肝细胞癌模型，与对照组小鼠相比，NVP-BEZ235用药后会引起促炎性细胞因子IL-6表达水平升高(图1)。不同药物治疗后(图2)，NVP-BEZ235治疗组和IL-6抗体治疗组能在一定程度上能够抑制HCC的肿瘤进程但十分有限。组合物治疗组小鼠与对照组小鼠相比，在肝重体重比、最大肿瘤直径和肿瘤结节数这些指标方面，组合物组显著降低(图3)。生存分析显示组合物组小鼠的荷瘤生存时间延长最显著(图4)。根据肝脏标本大体观和H&E染色情况显示，组合物治疗显著延缓了肿瘤进程(图5)。组合物组小鼠肿瘤区域Ki-67显著降低(图6)。
Claims (3)
1.抗IL-6抗体组合物在制备治疗肝细胞癌药物中的应用，其特征在于，所述组合物由抗IL-6抗体与磷酸肌醇-3-激酶-雷帕霉素靶点小分子抑制剂组成。
2.根据权利要求1所述的应用，其特征在于，所述组合物的组合比例为：抗IL-6抗体：磷酸肌醇-3-激酶-雷帕霉素靶点小分子抑制剂为10mg/kg：60mg/kg。
3.根据权利要求1所述的应用，其特征在于，所述药物由组合物与药用辅料制备。
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| CN115252774A (zh) * | 2022-07-15 | 2022-11-01 | 天津市肿瘤医院（天津医科大学肿瘤医院） | DZNep联合IL-6抗体在制备抑制肝细胞癌肿瘤药物中的应用 |
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| US20210213020A1 (en) * | 2018-05-30 | 2021-07-15 | Inserm (Institut National De La Santé Et De La Rechirche Médicale) | Methods and pharmaceutical compositions for treating cancer |
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| WO2018189403A1 (en) * | 2017-04-14 | 2018-10-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of cancer |
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| YAO WANG ET AL.: "The synergistic antitumor effect of IL-6 neutralization with NVPBEZ235 in hepatocellular carcinoma", 《CELL DEATH & DISEASE》 * |
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| CN115252774A (zh) * | 2022-07-15 | 2022-11-01 | 天津市肿瘤医院（天津医科大学肿瘤医院） | DZNep联合IL-6抗体在制备抑制肝细胞癌肿瘤药物中的应用 |
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