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

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic ß-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the ß-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI 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, and increased plasma glucose levels 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. ARTICLE HIGHLIGHTS: Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.

Discovery and design of G protein-coupled receptor targeting antibodies.

INTRODUCTION: G protein-coupled receptors (GPCRs) are the target of one-third of all approved drugs; however, these drugs only target about one-eighth of the human repertoire of GPCRs. GPCRs regulate a diverse range of critical physiological processes including organ development, cardiovascular function, mood, cognition, multicellularity, cellular motility, immune responses and sensation of light, taste, and odor. However, many GPCRs are expressed poorly, and a significant proportion have unknown ligands and unclear signaling pathways. AREAS COVERED: GPCRs are better suited to be targeted by monoclonal antibodies (mAbs) because of the challenges encountered in small-molecule discoveries such as druggability, selectivity, and distribution. mAbs have better drug-like properties in these respects. Herein, the authors review previously discovered functional mAbs that target GPCRs that are in the clinic and/or in development. They also review the biophysical considerations that make GPCRs so challenging to work with but also provide opportunities for biologic druggability. EXPERT OPINION: GPCRs are proven targets of small molecules yet remain an under-represented target of biologics. We believe that antibody drugs that target GPCRs have the potential to unlock new therapeutic avenues and also uncover previously unappreciated receptor biology, particularly when harnessing next-generation biologic modalities.