Hyperinsulinism is commonly caused by genetic mutations and as a consequence of hypobaric surgery. Hyperinsulinism can lead to hypoglycemia, psychiatric disorders and insulin resistance, a cause of type two diabetes. An effective avenue for therapeutic treatment of hyperinsulinism is antagonism of the Glucagon-Like Peptide 1 Receptor (GLP1R). Previously, we identified a highly potent antagonist antibody, called TB-001-003, which was from our synthetic antibody libraries designed to target G protein-coupled receptors (GPCRs). Here, we designed a library to optimize the activity of TB-001-003 against GLP1R and performed phage-display on cells overexpressing GLP1R. We found many optimized antagonists, including partial agonists. One antagonist, called TB-222-023, is a β-arrestin biased inverse agonist. In vivo, TB-222-023 effectively decreased insulin secretion in mouse pancreatic islets and increased plasma glucose in a mouse model of hyperinsulinism. We show that targeting GLP1R with an antibody antagonist is an effective strategy for treatment of hyperinsulinism.  

Tyler Starr, PhD, Assistant Professor in the Department of Biochemistry at the University of Utah, presents the dynamics of SARS-CoV-2 Variant Evolution and its Implications. Since 2020, Dr. Starr and his colleagues have been using high-throughput “deep mutational scanning” assays to study the ongoing evolution of COVID-19.