通过强制酸酶招募抑制免疫受体
Ricardo A Fernandes1,2, Leon Su1,2, Yoko Nishiga3,4
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Nature
|October 22, 2020
概括
一种称为通过酸酶招募抑制 (RIPR) 的新策略直接去化细胞表面受体. 这种方法通过抑制增强和连接体激活的信号通路来增强癌症等疾病的治疗效果.
科学领域:
- 免疫学
- 分子生物学
- 治疗发展
背景情况:
- 目前针对细胞表面受体的抗体疗法抑制了细胞外联体相互作用,但不能抑制细胞内信号传递.
- 性信号,特别是来自像编程细胞死亡-1 (PD-1) 这样的受体,有助于疾病状态,并且无法完全被现有的抗体治疗阻断.
- 需要直接减弱细胞表面受体的细胞内信号传递的策略.
研究的目的:
- 通过酸酶招募 (RIPR) 引入和验证一种新方法,用于减弱细胞表面受体信号.
- 为了证明RIPR在抑制强化和配体激活信号通路方面的有效性.
- 在临床前模型中探索RIPR的治疗潜力.
主要方法:
- 设计了一种修改后的PD-1受体 (RIPR-PD1) 来将CD45酸酶引入受体.
- 评估了RIPR-PD1诱导PD-1的结和脱的能力.
- 评估了RIPR-PD1在抑制T细胞信号和小鼠瘤模型中的有效性,并将其与抗PD-1抗体进行比较.
- 将RIPR策略扩展到其他免疫受体,如SIRPα,以评估其一般适用性.
主要成果:
- RIPR-PD1成功诱导了PD-1与CD45的交叉链接,导致了直接的细胞内脱.
- 与抗PD-1抗体相比,RIPR- PD1在小鼠瘤模型中显示出更强的检查点阻断和更强的治疗效果.
- 针对SIRPα的RIPR分子 (SIRPα- CD45 RIPR) 比单独SIRPα阻断更有效地增强了抗体依赖的细胞细胞.
结论:
- 通过酸酶招募抑制受体 (RIPR) 是直接减弱激酶激活细胞表面受体信号的可行策略.
- 通过向细胞内信号事件,RIPR比传统抗体疗法具有显著的优势.
- RIPR策略在涉及细胞表面受体信号的各种疾病中具有广泛的治疗应用潜力.
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