Science Immunology:彭华/傅阳心合作开发新一代高效低毒肿瘤特异性IL-12前体药物

2022-01-09 “生物世界”公众号 “生物世界”公众号

白细胞介素12(IL-12)是由P35和P40亚基组成的异源二聚体,是诱导细胞免疫的主要细胞因子之一。在肿瘤微环境中,IL-12刺激活化的T细胞和自然杀伤细胞(NK)释放毒杀性的酶类或分泌效应细胞因子

白细胞介素12(IL-12)是由P35和P40亚基组成的异源二聚体,是诱导细胞免疫的主要细胞因子之一。在肿瘤微环境中,IL-12刺激活化的T细胞和自然杀伤细胞(NK)释放毒杀性的酶类或分泌效应细胞因子如IFNγ,这些效应分子对于肿瘤的清除至关重要。

伴随IL-12强大的抗肿瘤活性,上世纪90年代掀起了IL-12临床研究的热潮。因为IL-12在体内的半衰期短,为了达到足够的血药浓度,IL-12在临床治疗时多采用静脉多次给药,导致IL-12在到达肿瘤部位前会刺激活化血循环中的免疫细胞,同时也会产生与剂量相关的细胞因子风暴或肝脏或其他器官组织损伤等严重的副作用。这些因素严重限制了IL-12的临床应用及推广。

2022年1月7日,中科院生物物理研究所彭华团队与德克萨斯大学西南医学中心傅阳心团队合作在 Science Immunology 期刊发表了题为:A tumor-specific pro-IL-12 activates preexisting cytotoxic T cells to control established tumors 的研究论文。

研究团队首次设计了一种能在肿瘤微环境中特异性释放活性的IL-12前体药物(pro-IL-12),并进一步探究了这种新一代、低毒的肿瘤特异性白介素12前体药物分子的抗肿瘤机制,该设计策略同样可以应用于其它细胞因子药物的修饰或改造

为了延长IL-12的半衰期,研究团队首先构建了重组IL-12-Fc融合蛋白。在此基础上进一步设计了pro-IL-12:用IL-12天然细胞受体的胞外结合域封闭IL-12的活性,受体与IL-12之间是由可切割的基质金属蛋白酶底物多肽连接。该药物在外周保持无活性状态,当药物到达肿瘤,肿瘤中特异性高表达的基质金属蛋白酶(MMP14)切割pro-IL-12释放IL-12的生物活性,发挥抗肿瘤效果。在多种小鼠以及人源化小鼠肿瘤模型中均验证了pro-IL-12在降低毒性的同时提高了抗肿瘤效果。

进一步机制研究发现,pro-IL-12可直接作用于肿瘤中的杀伤性T细胞(CTL),促进其分泌IFNγ发挥抗肿瘤作用。临床中由原癌基因驱动的肿瘤往往对免疫治疗没有响应,靶向药物治疗虽然有效但后期很容易复发。研究人员观察到pro-IL-12 可以与 TKI 靶向治疗产生协同作用,提高了肿瘤的治愈率。

如何克服免疫检查点阻断药物(ICB)的耐药性是临床免疫治疗面临的挑战。研究团队提出并证明了通过pro-IL-12提供T细胞活化的第三信号,在解除T 细胞免疫抑制的同时增强其活性,最终克服anti-PDL1耐药性

中国科学院生物物理研究所的薛娣媛博士和德克萨斯大学西南医学中心的Benjamin Moon博士是本论文的共同第一作者;中国科学院生物物理研究所彭华研究员,德克萨斯大学西南医学中心傅阳心教授是本论文共同通讯作者。该研究得到国家科技重大专项的资助。

原始出处:

DIYUAN XUE, et al. A tumor-specific pro-IL-12 activates preexisting cytotoxic T cells to control established tumors. SCIENCE IMMUNOLOGY ? 7 Jan 2022 ? Vol 7, Issue 67.

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    2022-01-11 jichang
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    2022-01-11 jjjiang0202
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    2022-01-10 ms8000000945331327

    学习学习学习

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