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The promise and challenges of functionally active GPCR antibody drugs

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Abalone Bio’s Functional Antibody Selection Technology (FAST), a high-throughput, yeast cell-based platform, directly identifies functional Ab candidates that modulate GPCR activity. The FAST platform overcomes these discovery challenges by individually testing ~100 million antibodies for functional activation of the GPCR target of interest in yeast cells, which serve as femtoliter-scale, living test tubes of GPCR agonism. Yeast cells have a cell membrane similar to human cells and can support the functional expression of multiple classes of human membrane proteins, including GPCRs. In Abalone Bio’s platform, non-essential GPCRs have been replaced by the human GPCR of interest to provide a yeast cell that only interrogates activation of the human GPCR without interference from yeast GPCRs. The cells have been further engineered to proliferate upon activation of the GPCR. Each yeast cell also expresses one of the hundred million antibodies in the antibody library, one antibody variant per yeast cell, and presents it to the extracellular face of the GPCR target. Antibodies that interact with and activate the GPCR will drive the proliferation of the yeast cells containing that antibody (Figure 1). These antibodies contained within the proliferating yeast are the rare, GPCR-activating agonist antibodies.