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Research ArticleENDOCRINE AND DIABETES

Fully Human Monoclonal Antibodies Antagonizing the Glucagon Receptor Improve Glucose Homeostasis in Mice and Monkeys

Hai Yan, Wei Gu, Jie Yang, Vivian Bi, Yuqing Shen, Eunkyung Lee, Katherine A. Winters, Renée Komorowski, Cheng Zhang, Jennifer J. Patel, Dorothy Caughey, Gary S. Elliott, Yvonne Y. Lau, Jin Wang, Yue-Sheng Li, Tom Boone, Richard A. Lindberg, Sylvia Hu and Murielle M. Véniant
Journal of Pharmacology and Experimental Therapeutics April 2009, 329 (1) 102-111; DOI: https://doi.org/10.1124/jpet.108.147009
Hai Yan
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Wei Gu
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Jie Yang
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Vivian Bi
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Yuqing Shen
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Eunkyung Lee
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Katherine A. Winters
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Renée Komorowski
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Cheng Zhang
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Jennifer J. Patel
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Dorothy Caughey
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Gary S. Elliott
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Yvonne Y. Lau
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Jin Wang
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Yue-Sheng Li
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Tom Boone
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Richard A. Lindberg
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Sylvia Hu
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Murielle M. Véniant
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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.

Footnotes

  • H.Y. and W.G. contributed equally to this work.

  • doi:10.1124/jpet.108.147009.

  • ABBREVIATIONS: GCGR, glucagon receptor; GPCR, G protein-coupled receptor; ASO, antisense oligonucleotide; HGO, hepatic glucose output; mAb, monoclonal antibody; GLP-1R, glucagon-like peptide-1 receptor; h, human; GFP, green fluorescent protein; FACS, fluorescence-activated cell sorting; IBMX, 3-isobutyl-1-methylxanthine; HTRF, homogeneous time-resolved fluorescence; GTT, glucose tolerance test; OGTT, oral glucose tolerance test; GLP-1, glucagon-like peptide 1; DPP-IV, dipeptidyl peptidase-4; AUC, area under the curve.

    • Received October 3, 2008.
    • Accepted January 6, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 329 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 329, Issue 1
1 Apr 2009
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Research ArticleENDOCRINE AND DIABETES

Fully Human Monoclonal Antibodies Antagonizing the Glucagon Receptor Improve Glucose Homeostasis in Mice and Monkeys

Hai Yan, Wei Gu, Jie Yang, Vivian Bi, Yuqing Shen, Eunkyung Lee, Katherine A. Winters, Renée Komorowski, Cheng Zhang, Jennifer J. Patel, Dorothy Caughey, Gary S. Elliott, Yvonne Y. Lau, Jin Wang, Yue-Sheng Li, Tom Boone, Richard A. Lindberg, Sylvia Hu and Murielle M. Véniant
Journal of Pharmacology and Experimental Therapeutics April 1, 2009, 329 (1) 102-111; DOI: https://doi.org/10.1124/jpet.108.147009

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Research ArticleENDOCRINE AND DIABETES

Fully Human Monoclonal Antibodies Antagonizing the Glucagon Receptor Improve Glucose Homeostasis in Mice and Monkeys

Hai Yan, Wei Gu, Jie Yang, Vivian Bi, Yuqing Shen, Eunkyung Lee, Katherine A. Winters, Renée Komorowski, Cheng Zhang, Jennifer J. Patel, Dorothy Caughey, Gary S. Elliott, Yvonne Y. Lau, Jin Wang, Yue-Sheng Li, Tom Boone, Richard A. Lindberg, Sylvia Hu and Murielle M. Véniant
Journal of Pharmacology and Experimental Therapeutics April 1, 2009, 329 (1) 102-111; DOI: https://doi.org/10.1124/jpet.108.147009
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