Glycemic Control Improved In Vivo By Allosteric Insulin Receptor-Activating Antibody

XOMA Corporation (Nasdaq: XOMA) announced that its study of XMetA, the company's fully-human allosteric monoclonal antibody to the insulin receptor, is available online and will be published in the May issue of the American Diabetes Association's journal Diabetes. XMetA is the first antibody specific for the insulin receptor shown to correct hyperglycemia in a mouse model ofdiabetes. Results of a study conducted by XOMA and confirmed by investigators at the University of California, San Francisco, demonstrate that XMetA has the potential to be a novel, long-acting agent for the control of blood glucose levels in patients with diabetes.
The study by Bhaskar, et al. demonstrated that XMetA markedly reduced elevated fasting blood glucose levels and normalized glucose tolerance in mice experimentally rendered diabetic. After six weeks of treatment, there was a statistically significant reduction in hemoglobin A1c levels in animals treated with XMetA compared to controls (p < 0.05). In addition, elevated non-HDL cholesterol levels were improved relative to control mice (p < 0.05).Hypoglycemia and weight gain were not observed during this study, nor was proliferation of cell growth.
"In the treatment of diabetes, novel and improved therapeutic modalities for patients with impaired insulin secretory function are needed," said Ira D. Goldfine, M.D., Professor Emeritus, Department of Medicine and the Diabetes Center, University of California, San Francisco. Dr. Goldfine is currently a XOMA Distinguished Scientific Fellow. "XMetA has shown potential to deliver a long-acting, glucose-regulating effect without generating hypoglycemia. The characteristics of this molecule may result in an opportunity to leverage this potential therapeutic option earlier in the treatment of diabetes."
"Through insights into the regulation of signaling pathways gained using XOMA's ModulX™ technology, we have discovered three distinct classes of allosteric antibodies that act differentially on the insulin receptor. XMetA, an antibody from one such class, selectively activates pathways leading to glucose lowering while avoiding pathways leading to cellular proliferation. We believe this profile is unique and offers a new approach to treatment of diabetes," said Patrick J. Scannon, M.D., Ph.D., Executive Vice President and Chief Scientific Officer, XOMA.
Conventional monoclonal antibodies bind at the ligand-receptor binding site to provide either complete activation or inhibition akin to an on/off switch. However, many receptors also have sites, termed allosteric sites, which function as a dimmer switch to modulate the ligand-receptor interaction. XOMA's XMet antibodies bind to these allosteric sites, offering expanded potential for the targeted treatment of diabetes.
XOMA has developed proprietary methods for identifying allosteric modulating monoclonal antibodies using its ModulX™ technology platform and is focusing its research efforts towards the discovery of these types of antibodies. Its first allosteric antibody, gevokizumab, is an allosteric inhibitor of the ligand interleukin-1beta (IL-1β), currently in clinical development. XOMA is pursuing development partnerships to maximize the value of XMetA and other antibodies from its technology platforms.