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.
The human health significance of the proposed work is the isolation of unique biologic therapeutics that target two validated GPCR targets. The specific targets chosen for this project have been pursued by 13 different companies, but nearly all of the existing drug candidates (small molecules) have failed due to off-target specificity or entry into the CNS. In addition to these therapeutic MAb candidates, this project will result in a platform supporting an entirely new class of therapeutics (agonist MAbs) that largely does not exist today.