A Fully Human, Allosteric Monoclonal Antibody That Activates the Insulin Receptor and Improves Glycemic Control
Vinay Bhaskar1 , Ira D. Goldfine2, Daniel H. Bedinger1, Angela Lau1, Hua F. Kuan1, Lisa M. Gross1, Masahisa Handa1, Betty A. Maddux2, Susan R. Watson1, Shirley Zhu1, Ajay J. Narasimha1, Raphael Levy1, Lynn Webster1, Sujeewa D. Wijesuriya1, Naichi Liu1, Xiaorong Wu1, David Chemla-Vogel1, Catarina Tran1, Steve R. Lee1, Steve Wong1, Diane Wilcock1, Mark L. White1 and John A. Corbin1 +Author Affiliations
1Preclinical Research Department, XOMA (US) LLC, Berkeley, California2Department of Medicine, University of California, San Francisco, CaliforniaCorresponding author: Vinay Bhaskar,
Abstract
Many patients with diabetes mellitus (both type 1 and type 2) require therapy to maintain normal fasting glucose levels. To develop a novel treatment for these individuals, we used phage display technology to target the insulin receptor (INSR) complexed with insulin and identified a high affinity, allosteric, human monoclonal antibody, XMetA, which mimicked the glucoregulatory, but not the mitogenic, actions of insulin. Biophysical studies with cultured cells expressing human INSR demonstrated that XMetA acted allosterically and did not compete with insulin for binding to its receptor. XMetA was found to function as a specific partial agonist of INSR, eliciting tyrosine phosphorylation of INSR but not the IGF-IR. Although this antibody activated metabolic signaling, leading to enhanced glucose uptake, it neither activated Erk nor induced proliferation of cancer cells. In an insulin resistant, insulinopenic model of diabetes, XMetA markedly reduced elevated fasting blood glucose and normalized glucose tolerance. After 6 weeks, significant improvements in HbA1c, dyslipidemia, and other manifestations of diabetes were observed. It is noteworthy that hypoglycemia and weight gain were not observed during these studies. These studies indicate, therefore, that allosteric monoclonal antibodies have the potential to be novel, ultra-long acting, agents for the regulation of hyperglycemia in diabetes.
Received November 11, 2011.Accepted January 13, 2012.© 2012 by the American Diabetes Association. |
