Cell Chemical Biology:上科大仓勇团队发现分子胶可增强PD-1抗体肿瘤免疫疗效

2022-07-01 “生物世界”公众号 “生物世界”公众号

该研究发现分子胶药物来那度胺可以恢复 PD-1 抗体的肿瘤免疫治疗效果,并抑制缺乏 T 细胞共刺激信号的小鼠的肿瘤生长。这表明来那度胺可以增强 PD-1 抗体治疗癌症的潜力。

近日,上海科技大学生命科学与技术学院仓勇教授团队在 Cell 子刊 Cell Chemical Biology 上发表了题为:Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling 的研究论文。

该研究发现分子胶药物来那度胺可以恢复 PD-1 抗体的肿瘤免疫治疗效果,并抑制缺乏 T 细胞共刺激信号的小鼠的肿瘤生长。这表明来那度胺可以增强 PD-1 抗体治疗癌症的潜力。

仓勇教授是达歌生物(Degron Therapeutics)的联合创始人兼首席科学官,达歌生物是一家具有独特分子胶(Molecular Glue)靶向蛋白降解技术平台的新药研发公司,该公司于今年6月9日完成2200万美元A轮融资。

在这项最新研究中,研究团队构建了一个对来那度胺敏感的 CRBN 人源化小鼠模型,并证明来那度胺可以在没有 CD28 受体的情况下共刺激 CD8+ T细胞。研究他的利用 CD28-KO 的 CRBN 人源化小鼠模型和结直肠癌患者的肿瘤样本,证明来那度胺可以恢复 CD28- CD8+ T 细胞对 PD-1 抗体的反应,从而使 CD28 缺失导致的 PD-1 抗体治疗无效得到恢复。

这项研究证明,来那度胺可以通过上调免疫系统信号分子白细胞介素2(IL-2)的分泌来共同刺激 T 细胞。通过转录组测序,研究团队发现来那度胺还能上调 Notch 靶点。同时阻断 IL-2 和 Notch 信号通路,会限制来那度胺对 T 细胞的共刺激作用,使来那度胺和 PD-1 抗体的联合治疗失效。

来那度胺作为抗骨髓瘤药物于 2005 年获批上市,它能直接杀死骨髓瘤细胞,同时增强 T 细胞抗肿瘤活性以抑制肿瘤生长。来那度胺被批准用于治疗多发性骨髓瘤(MM)、5q 缺失型骨髓增生异常综合征(MDS)、套细胞淋巴瘤和其他血液肿瘤。此外,来那度胺的迭代产品泊马度胺,第三代免疫调节剂,作为分子胶在治疗复发难治性多发性骨髓瘤(MM)方面也取得了巨大成功。

达歌生物联合创始人兼首席执行官邹丽晖博士表示,基于科学的创新是达歌探索分子胶药物和癌症免疫机制研究的核心战略。仓教授实验室所做的这项工作揭示了 IKZF1 和 IKZF3的降解剂可以通过调节免疫调节网络重新激活 T 细胞来攻击癌症。这一发现也为达歌提供了新的思路,可以将这种机制引入公司的分子胶项目。

仓勇教授表示,达歌管线中针对新型肿瘤靶点的分子胶降解剂可以通过化学修饰,选择性地保留降解 IKZF1 和 IKZF3 的能力。因此,此类药物可以通过两种不同的机制杀死癌细胞,即直接失活癌基因和诱导T细胞激活免疫反应来控制癌症。

 

原始出处:

Chen-Lu Geng, et al. Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling. Cell Chemical Biology, 2022.

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    2023-05-09 sunylz
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    2023-03-12 stfoxst
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    2023-03-09 维他命
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