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

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.

Circulating Fatty Acid-Binding Protein 4 Concentration Predicts the Progression of Carotid Atherosclerosis in a General Population Without Medication

“…9 Furthermore, a recent study demonstrated the possibility of a new strategy to treat metabolic disease by targeting serum FABP4 with a monoclonal antibody. 10 Circulating FABP4 may directly promote the progression of atherosclerosis in humans.…”

“…Furthermore, a recent study demonstrated the possibility of a new strategy to treat metabolic disease by targeting serum FABP4 with a monoclonal antibody to FABP4. 10 Elevated circulating FABP4 levels are associated with obesity, IR, T2DM, hypertension, dyslipidemia, cardiac dysfunction, renal dysfunction, atherosclerosis and cardiovascular events. 6,11-18 Notably, an increased plasma level of FABP4 was shown to be independently associated with the presence of coronary artery disease.…”

Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment

“…Mechanistically, secreted FABP4 has been demonstrated to increase liver glucose production and insulin secretion and decrease cardiomyocyte contractility (59,200,201), and hence, may explain some of the detrimental effects of uncontrolled lipolysis. These effects of circulating FABP4 support the possibility of using neutralizing antibodies to treat metabolic disease, and this approach has proven successful in preclinical models (59,202,203).…”

Plasma Levels of Fatty Acid–Binding Protein 4, Retinol-Binding Protein 4, High-Molecular-Weight Adiponectin, and Cardiovascular Mortality Among Men With Type 2 Diabetes

“…14–17 Moreover, animal experiments have shown that FABP4, when expressed in macrophages, contributes particularly to the etiology of atherosclerosis. 18,19 In addition, epidemiological data supported a positive association between circulating FABP4 levels and the risk of T2D, heart failure, and stroke in the general population.…”