title: Glucagon Receptor Blockade With a Human Antibody Normalizes Blood Glucose in Diabetic Mice and Monkeys.
abstract: 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.
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Haruka
authors.initials: H
authors.lastname: Okamoto
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Jinrang
authors.initials: J
authors.lastname: Kim
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: JohnPaul
authors.initials: J
authors.lastname: Aglione
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lee
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Katie
authors.initials: K
authors.lastname: Cavino
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Erqian
authors.initials: E
authors.lastname: Na
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Ashique
authors.initials: A
authors.lastname: Rafique
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Jee Hae
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Joyce
authors.initials: J
authors.lastname: Harp
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, New York 10591.
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; C414620:fibroblast growth factor 21; C000601829:crotedumab; D005346:Fibroblast Growth Factors