title: 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.
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: M Furkan
authors.initials: MF
authors.lastname: Burak
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Inouye
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: White
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Gurol
authors.initials: G
authors.lastname: Tuncman
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Ediz S
authors.initials: ES
authors.lastname: Calay
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Tirosh
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Kosei
authors.initials: K
authors.lastname: Eguchi
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birrane
authors.affiliation: UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lightwood
authors.affiliation: UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Howells
authors.affiliation: UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
authors.forename: Geofrey
authors.initials: G
authors.lastname: Odede
authors.affiliation: UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
authors.forename: Hanna
authors.initials: H
authors.lastname: Hailu
authors.affiliation: UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
authors.forename: Shauna
authors.initials: S
authors.lastname: West
authors.affiliation: UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Garlish
authors.affiliation: UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Neale
authors.affiliation: UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
authors.forename: Carl
authors.initials: C
authors.lastname: Doyle
authors.affiliation: UCB (Union Chimique Belge), 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Moore
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker 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.
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001823:Body Composition / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D059305:Diet, High-Fat; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry / Q000276:immunology*; D005234:Fatty Liver / Q000150:complications / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D055442:Metabolome / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008820:Mice, Obese
chemical_list: D000911:Antibodies, Monoclonal; C493410:FABP4 protein, human; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; D005947:Glucose