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Optimization of a glucagon-like peptide 1 receptor antagonist antibody for treatment of hyperinsulinism

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posted on 2023-06-26, 00:10 authored by Sean M. Peterson, Christine A. Juliana, Cameron F. Hu, Jinghua Chai, Carson Holliday, Kara Y. Chan, Ana G. Lujan Hernandez, Zoe Challocombe, Linya Wang, Zhen Han, Nikhil Haas, Ryan Stafford, Fumiko Axelrod, Tom Z. Yuan, Diva D. De León, Aaron K. Sato

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic beta cell insulin secretion is excessive and results in hypoglycemia that can cause brain damage or death without treatment. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the beta cell ATP sensitive potassium channel (KATP), are unresponsive to diazoxide, the only FDA approved medical therapy, and require a pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent to inhibit insulin secretion in both congenital and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage-display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as Avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI as well as increased plasma glucose and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism.

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