Identifying Agonist MAbs against GPCRs

ABSTRACT Monoclonal antibodiesMAbsthat target G protein coupled receptorsGPCRsare difficult to isolateand agonist MAbsthat activate GPCRsare even more difficult to discoverIsolating functional MAbs against GPCRs requires that the target protein be presented in its native conformation and orientationwhich is difficult because GPCRs are hydrophobicform complex transmembrane structuresand are difficult to purifyMoreoveridentifying agonist MAbs requires generating a large number of diverse MAbs that comprehensively cover the epitope surface of the target GPCRA 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 marketagonist MAbs against GPCRs PROJECT NARRATIVE The human health significance of the proposed work is the isolation of unique biologic therapeutics that target two validated GPCR targetsThe specific targets chosen for this project have been pursued bydifferent companiesbut nearly all of the existing drug candidatessmall moleculeshave failed due to off target specificity or entry into the CNSIn addition to these therapeutic MAb candidatesthis project will result in a platform supporting an entirely new class of therapeuticsagonist MAbsthat largely does not exist today