Identifying Agonist MAbs against GPCRs

摘要 针对G蛋白偶联受体(GPCRs)的单抗很难 分离，以及激动剂单抗(激活GPCRs)更难发现。隔离 抗GPCRs的功能性单抗要求目标蛋白以其天然的形式呈现 构象和定位是困难的，因为GPCRs是疏水的，形成复合体 跨膜结构，难以提纯。此外，识别激动剂单抗 需要产生大量不同的单抗来全面覆盖表位 靶标GPCR的表面。一个可以通过数百万个单独的B细胞进行筛选的平台 识别稀有的激活单抗将使一种全新的治疗方法被引入 市场，激动剂单抗对抗GPCRs。

ABSTRACT Monoclonal antibodies (MAbs) that target G protein-coupled receptors (GPCRs) are difficult to isolate, and agonist MAbs (that activate GPCRs) are even more difficult to discover. Isolating functional MAbs against GPCRs requires that the target protein be presented in its native conformation and orientation, which is difficult because GPCRs are hydrophobic, form complex transmembrane structures, and are difficult to purify. Moreover, identifying agonist MAbs requires generating a large number of diverse MAbs that comprehensively cover the epitope surface of the target GPCR. A platform that could screen through millions of individual B cells to identify rare activating MAbs would enable an entirely new class of therapeutics to be brought to market, agonist MAbs against GPCRs.