TY - JOUR T1 - Fully Human Monoclonal Antibodies Antagonizing the Glucagon Receptor Improve Glucose Homeostasis in Mice and Monkeys JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 102 LP - 111 DO - 10.1124/jpet.108.147009 VL - 329 IS - 1 AU - Hai Yan AU - Wei Gu AU - Jie Yang AU - Vivian Bi AU - Yuqing Shen AU - Eunkyung Lee AU - Katherine A. Winters AU - Renée Komorowski AU - Cheng Zhang AU - Jennifer J. Patel AU - Dorothy Caughey AU - Gary S. Elliott AU - Yvonne Y. Lau AU - Jin Wang AU - Yue-Sheng Li AU - Tom Boone AU - Richard A. Lindberg AU - Sylvia Hu AU - Murielle M. Véniant Y1 - 2009/04/01 UR - http://jpet.aspetjournals.org/content/329/1/102.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -