针对HPK1降解的口服PROTAC可以增强抗固体瘤免疫力
Yuejun Yao1,2,3, Mingfei Wu1,4, Yanfang Wang1,2,3
1National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Advanced materials (Deerfield Beach, Fla.)
|November 21, 2024
概括
开发一种口服蛋白质溶解向奇默体 (PROTAC) 降解血造原体激酶1 (HPK1) 增强了抗瘤免疫力. 这种口服的PROTAC改善了CAR-T细胞的疗效,并在临床前癌症模型中增强了抗PD-L1疗法.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 造血原体激酶1 (HPK1) 是免疫反应的关键调节者.
- 抑制HPK1可以增强抗瘤免疫力,但需要有效的治疗策略.
研究的目的:
- 开发和评估一种口服可用的针对蛋白质分解的嵌合体 (PROTAC),用于选择性HPK1降解.
- 评估针对HPK1的PROTAC在增强抗瘤免疫疗法的疗效.
主要方法:
- 开发一种针对HPK1.1的口服PROTAC.
- 在接受CAR-T细胞治疗的NSG小鼠中对术后人类子宫癌模型的评估.
- 在BALB/c小鼠的CT26实体瘤中对抗PD-L1抗体的联合治疗的评估.
主要成果:
- 口服的PROTAC达到瘤并降低了CAR-T细胞中的HPK1水平.
- 在宫癌模型中,PROTAC治疗导致50%的部分响应和50%的完全响应.
- 组合疗法在CT26瘤中增加了免疫细胞透 (CD45+和CD3+T细胞).
结论:
- 口服针对HPK1的PROTAC是一种可行的策略,可以增强抗瘤免疫疗法.
- 这种方法可以改善CAR-T细胞功能,并加强检查点抑制剂治疗.
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