Glucagon Receptor Blockade With a Human Antibody Normalizes Blood Glucose in Diabetic Mice and Monkeys

• Published in: Endocrinology (Philadelphia) Vol. 156; no. 8; pp. 2781 - 2794
• Main Authors: Okamoto, Haruka, Kim, Jinrang, Aglione, JohnPaul, Lee, Joseph, Cavino, Katie, Na, Erqian, Rafique, Ashique, Kim, Jee Hae, Harp, Joyce, Valenzuela, David M, Yancopoulos, George D, Murphy, Andrew J, Gromada, Jesper
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-08-2015; Oxford University Press
• Subjects: Adipose tissue; Amino acids; Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Blocking antibodies; Blood; Blood circulation; Blood glucose; Blood Glucose - drug effects; Blood Glucose - metabolism; Blood levels; Body weight; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diet; Female; Fibroblast Growth Factors - genetics; Food intake; Glucagon; Glucagon-like peptide 1; Glucose; Glucose tolerance; Growth factors; Humans; Hyperglycemia; Hyperplasia; Hypoglycemia; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Immunological tolerance; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Monkeys; Monoclonal antibodies; Nutrient deficiency; Obesity - complications; Obesity - drug therapy; Obesity - pathology; Pancreas; Receptors; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - genetics; Receptors, Glucagon - immunology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2015-1011

Antagonizing glucagon action represents an attractive therapeutic option for reducing hepatic glucose production in settings of hyperglycemia where glucagon excess plays a key pathophysiological role. We therefore generated REGN1193, a fully human monoclonal antibody that binds and inhibits glucagon receptor (GCGR) signaling in vitro. REGN1193 administration to diabetic ob/ob and diet-induced obese mice lowered blood glucose to levels observed in GCGR-deficient mice. In diet-induced obese mice, REGN1193 reduced food intake, adipose tissue mass, and body weight. REGN1193 increased circulating levels of glucagon and glucagon-like peptide 1 and was associated with reversible expansion of pancreatic α-cell area. Hyperglucagonemia and α-cell hyperplasia was observed in fibroblast growth factor 21-deficient mice treated with REGN1193. Single administration of REGN1193 to diabetic cynomolgus monkeys normalized fasting blood glucose and glucose tolerance and increased circulating levels of glucagon and amino acids. Finally, administration of REGN1193 for 8 weeks to normoglycemic cynomolgus monkeys did not cause hypoglycemia or increase pancreatic α-cell area. In summary, the GCGR-blocking antibody REGN1193 normalizes blood glucose in diabetic mice and monkeys but does not produce hypoglycemia in normoglycemic monkeys. Thus, REGN1193 provides a potential therapeutic modality for diabetes mellitus and acute hyperglycemic conditions.