Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes

Author: Burak, M.F.; Inouye, K.E.; White, A.; Lee, A.; Tuncman, G.; Calay, E.S.; Sekiya, M.; Tirosh, A.; Eguchi, K.; Birrane, G.; Lightwood, D.; Howells, L.; Odede, G.; Hailu, H.; West, S.; Garlish, R.; Neale, H.; Doyle, C.; Moore, A.; Hotamisligil, G.S.

Description: The lipid chaperone aP2/FABP4 has been implicated in the pathology of many immunometabolic diseases, including diabetes in humans, but aP2 has not yet been targeted for therapeutic applications. aP2 is not only an intracellular protein but also an active adipokine that contributes to hyperglycemia by promoting hepatic gluconeogenesis and interfering with peripheral insulin action. Serum aP2 levels are markedly elevated in mouse and human obesity and strongly correlate with metabolic complications. These observations raise the possibility of a new strategy to treat metabolic disease by targeting serum aP2 with a monoclonal antibody (mAb) to aP2. We evaluated mAbs to aP2 and identified one, CA33, that lowered fasting blood glucose, improved systemic glucose metabolism, increased systemic insulin sensitivity, and reduced fat mass and liver steatosis in obese mouse models. We examined the structure of the aP2-CA33 complex and resolved the target epitope by crystallographic studies in comparison to another mAb that lacked efficacy in vivo. In hyperinsulinemic-euglycemic clamp studies, we found that the antidiabetic effect of CA33 was predominantly linked to the regulation of hepatic glucose output and peripheral glucose utilization. The antibody had no effect in aP2-deficient mice, demonstrating its target specificity. We conclude that an aP2 mAb-mediated therapeutic constitutes a feasible approach for the treatment of diabetes.

Subject headings: Adipose Tissue/drug effects; Amino Acid Sequence; Animals; Antibodies, Monoclonal/therapeutic use; Body Composition/drug effects; Diabetes Mellitus, Type 2/complications/drug therapy; Diet, High-Fat; Fatty Acid-Binding Proteins/chemistry/immunology; Fatty Liver/complications/pathology; Glucose/metabolism; Humans; Insulin/pharmacology; Male; Metabolome/drug effects; Mice, Inbred C57BL; Mice, Obese

Publication year: 2015

Journal or book title: Science Translational Medicine

Volume: 7

Issue: 319

Pages: 319ra205

Find the full text :

Find more like this one (cited by):,16&hl=en

Type: Journal Article

Serial number: 2042