title: ANGPTL8 Blockade With a Monoclonal Antibody Promotes Triglyceride Clearance, Energy Expenditure, and Weight Loss in Mice.
abstract: Angiopoietin-like protein (ANGPTL)8 is a negative regulator of lipoprotein lipase-mediated plasma triglyceride (TG) clearance. In this study, we describe a fully human monoclonal antibody (REGN3776) that binds monkey and human ANGPTL8 with high affinity. Inhibition of ANGPTL8 with REGN3776 in humanized ANGPTL8 mice decreased plasma TGs and increased lipoprotein lipase activity. Additionally, REGN3776 reduced body weight and fat content. The reduction in body weight was secondary to increased energy expenditure. Finally, single administration of REGN3776 normalized plasma TGs in dyslipidemic cynomolgus monkeys. In conclusion, we show that blockade of ANGPTL8 with monoclonal antibody strongly reduced plasma TGs in mice and monkeys. These data suggest that inhibition of ANGPTL8 may provide a new therapeutic avenue for the treatment of dyslipidemia with beneficial effects on body weight.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gusarova
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Serena
authors.initials: S
authors.lastname: Banfi
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Alexa-Braun
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shihanian
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Ivory J
authors.initials: IJ
authors.lastname: Mintah
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Qi
authors.initials: Q
authors.lastname: Su
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Vishal
authors.initials: V
authors.lastname: Kamat
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390.|Howard Hughes Medical Institute, Dallas, Texas 75390.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York, 10591.
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
mesh_terms: D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D050171:Dyslipidemias / Q000628:therapy; D004734:Energy Metabolism; D006801:Humans; D007700:Kinetics; D008071:Lipoprotein Lipase / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D014280:Triglycerides / Q000097:blood*; D015431:Weight Loss
chemical_list: C000595899:ANGPTL8 protein, mouse; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000911:Antibodies, Monoclonal; D014280:Triglycerides; D008071:Lipoprotein Lipase