Glucagon plays an important role in glucose metabolism. Upon hypoglycemia, pancreatic alpha cells can secrete glucagon which stimulates hepatic glucose production. However increased glucagon concentrations contribute to diabetic hyperglycemia. In addition to regulating glucose metabolism, glucagon also seems important for the minute-to-minute regulation of amino acid metabolism. Specifically, Amino acids stimulate glucagon secretion and glucagon in turn stimulates hepatic amino acid uptake and metabolism.

Glucagon receptor (GCGR) is a member of the class B G-protein coupled family of receptors and mediates the actions of glucagon. Glucagon receptors regulate adenylate cyclase (AC) and phospholipase C activities when activated. The glucagon receptor primarily exists in the liver, but it also exists in varying amounts in the central nervous system, kidneys, gastrointestinal tract, heart, and pancreas. Moreover, antagonists of the glucagon receptor are the glucose-lowering therapy in type 2 diabetes patients.

Crotedumab (REGN1193) is a fully human IgG4 monoclonal antibody that binds and inhibits glucagon receptor.

From: Jia Y, et al. Front Endocrinol (Lausanne). 2022;13:928016.

Crotedumab binds to GCGR from multiple species (mice, rats, monkeys, and humans) with high affinity (K_D=0.03 nM-0.39 nM). Thus, Crotedumab inhibits Glucagon-induced signaling through GCGR in HEK293 cells transfected with GCGR from humans, monkeys, mice, and rats, with IC₅₀s of 0.65, 3.2, 0.94 and 1.0 nM, respectively. In diabetic ob/ob mice, Crotedumab (10 mg/kg, a single s.c.) markedly decreases blood glucose for 18 days. What’s more, in diet-induced obese mice, Crotedumab reduces blood glucose and body weight and induces reversible hyperglucagonemia and α-cell hyperplasia. Plus, this inhibitor (20 mg/kg, a single i.v.) produces a robust reduction in overnight-fasted blood glucose in both the conscious and anesthetized state of diabetic cynomolgus monkeys as well as in blood glucose measured 1 hour after feeding.

All in all, Crotedumab is a fully human IgG4 monoclonal antibody that binds and inhibits glucagon receptors. And it has the potential for research on diabetes.

References:

[1]. Galsgaard KD, et, al. Front Physiol. 2019 Apr 24;10:413.

[2]. Okamoto H, et, al. Endocrinology. 2015 Aug;156(8):2781-94.