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Sci Transl Med. 2015 Dec 23;7(319):319ra205. doi: 10.1126/scitranslmed.aac6336. Epub 2015 Dec 23.

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

Author information

1
Department of Genetics and Complex Diseases and Sabri √úlker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
2
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
3
UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
4
Department of Genetics and Complex Diseases and Sabri √úlker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. ghotamis@hsph.harvard.edu.

Abstract

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.

PMID:
26702093
DOI:
10.1126/scitranslmed.aac6336
[Indexed for MEDLINE]

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