Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism

Abstract

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.

Dorothy Hodgkin lecture 2023: The enteroendocrine system—Sensors in your guts

“…Exendin‐9, under the name avexitide is currently under development for the treatment of post‐bariatric post‐prandial hypoglycaemia, 18 and linkage of fatty acids to exendin‐9, similar to the modifications improving receptor agonists pharmacokinetics might be possible, with GLP‐1R antagonising antibodies presenting a potential alternative approach. 19 , 20 Questions about the importance of GLP‐1 and PYY for the metabolic benefits of bariatric surgery have, however, been raised in rodent models, as animals with knockout or pharmacological blockade of GLP1R or PYY receptors (NPY2R) still exhibited weight loss and improved intraperitoneal glucose tolerance after gastric bypass surgery. 21 , 22 PYY action through other NPY receptors in pancreatic islets has been linked to increases in beta cell mass 23 and improved glucose homeostasis after bariatric surgery, 24 , 25 but it is difficult to establish the relative contribution of these mechanisms in the context of improved insulin sensitivity after weight loss.…”