通过抗体结合到膜-近端纤维蛋白3型域的PTPRS蛋白质糖开关的调节
Thales Hein Da Rosa1, Sterling H Ramsey2, Judy J Lee1
1Department of Medicine, Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
The Journal of biological chemistry
|July 12, 2025
概括
针对受体蛋白氨酸酸酶西格玛 (PTPRS) 的纤维素第III类类似9 (Fn9) 域,激活了它的功能. 这种使用抗体或诱蛋白的方法,通过减轻小鼠的疾病来治疗类风湿性关节炎 (RA) 是有前途的.
科学领域:
- 生物化学 生物化学
- 免疫学 免疫学 免疫学
- 类风湿病学 类风湿病学
背景情况:
- 受体蛋白氨酸酸酶 (PTPs) 是通过在肝酸硫酸蛋白质甘油 (HSPGs) 上与糖氨酸甘油 (GAGs) 结合的细胞外域来调节的.
- 在类风湿性关节炎 (RA) 中,HSPGs对受体PTP sigma (PTPRS) 的不激活驱动了具有攻击性的纤维细胞样同胞细胞 (FLS) 行为.
- 以前的策略集中在阻断N端域,但其他ectodomain区域的治疗潜力仍然未被探索.
研究的目的:
- 为了研究治疗激活的新型PTPRS外域区域.
- 探索纤维内素III型类似9 (Fn9) 域作为PTPRS调制的目标.
- 评估针对Fn9治疗RA的抗体和诱蛋白的疗效.
主要方法:
- 在 PTPRS Fn9 域上映抗体结合部位.
- 描述抗体 (13G5,22H8,49F2) 及其碎片对PTPRS活性,寡合化和细胞迁移的影响.
- 使用重组Fn9蛋白作为诱来破坏PTPRS-SDC4相互作用.
- 在使用13G5衍生抗体的RA小鼠模型中评估疾病缓解.
主要成果:
- 确定了PTPRS Fn9域作为抗体的结合部位,为PTPRS激活提供了一个新的途径.
- 抗体13G5有效地降低了依赖PTPRS的FLS迁移,与syndecan-4 (SDC4) 的同定位和寡合化.
- 单链可变片段抗体和同型工程抗体显示了增强的PTPRS激活.
- 重组Fn9蛋白通过破坏PTPRS-SDC4相互作用和抑制FLS迁移来模仿抗体效应.
- 在小鼠模型中,来自13G5的抗体显著减轻了疾病的发生.
结论:
- 针对 PTPRS Fn9 域提供了一个用于激活 PTPRS.的新策略.
- 针对Fn9的抗体和诱蛋白可以逆转与RA相关的致病性FLS表型.
- 来自13G5的抗体代表了RA治疗的有希望的治疗候选者.
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