title: Fully human monoclonal antibodies antagonizing the glucagon receptor improve glucose homeostasis in mice and monkeys.
abstract: Antagonizing the glucagon signaling pathway represents an attractive therapeutic approach for reducing excess hepatic glucose production in patients with type 2 diabetes. Despite extensive efforts, there is currently no human therapeutic that directly inhibits the glucagon/glucagon receptor pathway. We undertook a novel approach by generating high-affinity human monoclonal antibodies (mAbs) to the human glucagon receptor (GCGR) that display potent antagonistic activity in vitro and in vivo. A single injection of a lead antibody, mAb B, at 3 mg/kg, normalized blood glucose levels in ob/ob mice for 8 days. In addition, a single injection of mAb B dose-dependently lowered fasting blood glucose levels without inducing hypoglycemia and improved glucose tolerance in normal C57BL/6 mice. In normal cynomolgus monkeys, a single injection improved glucose tolerance while increasing glucagon and active glucagon-like peptide-1 levels. Thus, the anti-GCGR mAb could represent an effective new therapeutic for the treatment of type 2 diabetes.
authors.affiliation: Department of Protein Sciences, Amgen Inc., Thousand Oaks, CA 91320, USA. hyan@amgen.com
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Vivian
authors.initials: V
authors.lastname: Bi
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Shen
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Lee
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Winters
authors.forename: Renée
authors.initials: R
authors.lastname: Komorowski
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Patel
authors.forename: Dorothy
authors.initials: D
authors.lastname: Caughey
authors.forename: Gary S
authors.initials: GS
authors.lastname: Elliott
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Lau
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Yue-Sheng
authors.initials: YS
authors.lastname: Li
authors.forename: Tom
authors.initials: T
authors.lastname: Boone
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lindberg
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hu
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D005947:Glucose