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针对细胞表面免疫检查点蛋白PD-L1降解的基于抗体的PROTAC的开发

Adam D Cotton¹, Duy P Nguyen¹, Josef A Gramespacher¹

¹Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United States.

Journal of the American Chemical Society

|January 4, 2021

概括

基于抗体的PROTACs (AbTACs) 是一种新型的双功能抗体,可降解细胞表面蛋白质. 这项研究表明AbTACs可以通过溶解体途径消除编程死亡配体1.

科学领域:

分子生物学
免疫学
药物发现

背景情况:

有针对性的蛋白质降解是控制细胞蛋白质稳定的一个关键策略.
化向化学分子 (PROTACs) 是诱导蛋白质降解的双功能分子.
现有的PROTAC主要向细胞内蛋白质.

研究的目的:

开发针对细胞表面蛋白质的基于抗体的PROTAC (AbTAC).
通过膜结合E3链酶诱导蛋白质降解的AbTAC的有效性.
建立AbTAC作为一种针对蛋白质清除的新生物药物.

主要方法:

开发完全重组双特异性抗体 (AbTACs).
招募与膜结合的E3链酶以向细胞表面蛋白质.
通过溶酶体途径评估蛋白质无化和随后的降解.

主要成果:

通过AbTAC证明了E3连接酶RNF43的成功招募.
展示了 AbTAC 诱导的被编程死亡配体 1 (PD-L1) 的溶酶体降解.
证实了AbTACs有效向细胞表面蛋白的潜力.

结论:

AbTACs代表了针对细胞表面蛋白质的向降解的新疗法.
这种方法利用重组生物来精确控制蛋白质平衡.
AbTAC扩展了PROTAC技术的范围到细胞外的目标.

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