Fully human monoclonal antibodies antagonizing the glucagon receptor improve glucose homeostasis in mice and monkeys.
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.
Yan
Hai
H
Department of Protein Sciences, Amgen Inc., Thousand Oaks, CA 91320, USA. hyan@amgen.com
Gu
Wei
W
Yang
Jie
J
Bi
Vivian
V
Shen
Yuqing
Y
Lee
Eunkyung
E
Winters
Katherine A
KA
Komorowski
Renée
R
Zhang
Cheng
C
Patel
Jennifer J
JJ
Caughey
Dorothy
D
Elliott
Gary S
GS
Lau
Yvonne Y
YY
Wang
Jin
J
Li
Yue-Sheng
YS
Boone
Tom
T
Lindberg
Richard A
RA
Hu
Sylvia
S
Véniant
Murielle M
MM
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
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D005947:Glucose