Identifying Agonist MAbs against GPCRs

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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.