确定负责PD-1结合和启动PD-1信号的功能PD-L1接口区域
Rachel Carter1, Fatimah Alanazi1, Amanda Sharp2
1Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, Virginia, USA.
The Journal of biological chemistry
|October 20, 2023
概括
研究人员开发了MN1.4,这是一种稳定的,可以阻止编程细胞死亡蛋白1 (PD-1) 和编程死亡1 (PD-L1) 的相互作用. 这种调节T细胞的反应,可以治疗自身免疫性疾病.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- PD-1/PD-L1通路调节免疫反应,是免疫治疗的目标.
- 了解启动PD-1/PD-L1信号的精确蛋白质相互作用至关重要.
- 之前的工作设计了基于PD-L1.1的PD-1向.
研究的目的:
- 描述一种类 (MN1.1) 并设计一种针对PD-1/PD-L1相互作用的优化 (MN1.4).
- 为了确定PD-1结合中的关键残留物.
- 评估MN1.4在阻断PD-1/PD-L1信号传递和调节免疫反应方面的稳定性和有效性.
主要方法:
- 基于PD-L1接口的体设计和优化.
- 在血清中评估的稳定性.
- 在体外测试测量PD-1/PD-L1复合物的形成.
- 与卵巢癌细胞和外周血液单核细胞共同培养模型,以评估T细胞激活标记物和细胞因子分泌.
主要成果:
- 与MN1.1.1.4相比,优化MN1.4在血清中表现出明显增强的稳定性.
- MN1.4有效地阻止了PD-1/PD-L1复合体的形成.
- MN1.4治疗减少了细胞因子分泌和抑制了T细胞反应,模仿了复合PD-L1效应.
- PD-L1接口区域足以用于PD-1识别和信号启动.
结论:
- 设计的MN1.4是PD-1的稳定激动剂.
- MN1.4能够阻止PD-1/PD-L1相互作用并调节T细胞反应,这表明MN1.4具有治疗潜力.
- 这种可以用于治疗与PD-1缺乏或免疫治疗副作用相关的自身免疫疾病.
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