High Affinity Insulin Receptor Antibodies Sensitize the Insulin Receptor to Insulin and Restore Glycemic Control in Murine Models of Diabetes
Abstract Number: 1008-P
Authors: JOHN A. CORBIN, VINAY BHASKAR, IRA D. GOLDFINE, DANIEL H. BEDINGER, HUA F. KUAN, LISA GROSS, ANGELA LAU, MASAHISA HANDA, SUSAN R. WATSON, LYNN WEBSTER, RAPHAEL LEVY, BETTY A. MADDUX, SUJEEWA WIJESURIYA, NAICHI LIU, XIAORONG WU, DAVID CHEMLA-VOGEL, AJAY J. NARASIMHA, STEVE R. LEE, CATARINA TRAN, MARK L. WHITE
Institutions: Berkeley, CA, San Francisco, CA
Results: Dysregulation of the insulin receptor (INSR) plays a role in the insulin resistance that is associated with both type-2 diabetes mellitus (T2DM) and the metabolic syndrome. As a unique approach to diabetes treatment, we employed our phage display technology to produce a panel of fully human monoclonal antibodies with picomolar affinities that sensitized the INSR to insulin. Biophysical studies demonstrated that these antibodies were allosteric modulators that increased the binding affinity of insulin to the INSR up to 20-fold. Moreover they were active on both forms of the INSR.
These antibodies similarly enhanced insulin stimulation of INSR autophosphorylation, tyrosine phosphorylation of IRS-1, serine phosphorylation of AKT, and glucose transport. In contrast, they did not potentiate insulin stimulation of cell growth. Also these antibodies did not influence IGF-1 stimulated autophosphorylation of its receptor, and IGF-1 and IGF-2 dependent activation of mitogenesis. Studies performed in hyperinsulinemic and insulinopenic mouse models of diabetes, demonstrated the capacity of these antibodies to enhance insulin sensitivity in vivo, and improve several indices of T2DM. In the diet-induced obesity model of insulin resistance, the antibodies markedly improved fasting blood glucose levels and HOMA, and normalized glucose tolerance. Similar dramatic improvements in fasting blood glucose and glucose tolerance were also observed in the insulinopenic, low dose, streptozotocin-high fat diet mouse. Consistent with restoration of glycemic control, the antibodies improved several markers of dyslipidemia in these mouse models. In neither mouse model did the antibodies cause hypoglycemia. These data indicate therefore that monoclonal antibodies can act as insulin sensitizers both in vitro and in vivo. They also suggest that these monoclonal antibodies have the potential to be new therapeutic agents for the treatment of human T2DM and other related metabolic disorders.