Fully human monoclonal antibodies antagonizing the glucagon receptor improve glucose homeostasis in mice and monkeys

H Yan, W Gu, J Yang, V Bi, Y Shen, E Lee… - … of Pharmacology and …, 2009 - ASPET
H Yan, W Gu, J Yang, V Bi, Y Shen, E Lee, KA Winters, R Komorowski, C Zhang, JJ Patel…
Journal of Pharmacology and Experimental Therapeutics, 2009ASPET
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 …
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.
ASPET