title: ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys.
abstract: Angiopoietin-like protein 3 (ANGPTL3) is a circulating protein synthesized exclusively in the liver that inhibits LPL and endothelial lipase (EL), enzymes that hydrolyze TGs and phospholipids in plasma lipoproteins. Here we describe the development and testing of a fully human monoclonal antibody (REGN1500) that binds ANGPTL3 with high affinity. REGN1500 reversed ANGPTL3-induced inhibition of LPL activity in vitro. Intravenous administration of REGN1500 to normolipidemic C57Bl/6 mice increased LPL activity and decreased plasma TG levels by ≥50%. Chronic administration of REGN1500 to dyslipidemic C57Bl/6 mice for 8 weeks reduced circulating plasma levels of TG, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) without any changes in liver, adipose, or heart TG contents. Studies in EL knockout mice revealed that REGN1500 reduced serum HDL-C through an EL-dependent mechanism. Finally, administration of a single dose of REGN1500 to dyslipidemic cynomolgus monkeys caused a rapid and pronounced decrease in plasma TG, nonHDL-C, and HDL-C. REGN1500 normalized plasma TG levels even in monkeys with a baseline plasma TG greater than 400 mg/dl. Collectively, these data demonstrate that neutralization of ANGPTL3 using REGN1500 reduces plasma lipids in dyslipidemic mice and monkeys, and thus provides a potential therapeutic agent for treatment of patients with hyperlipidemia.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gusarova
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Alexa
authors.affiliation: Howard Hughes Medical Institute and Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Ashique
authors.initials: A
authors.lastname: Rafique
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Jee Hae
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: David
authors.initials: D
authors.lastname: Buckler
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Ivory J
authors.initials: IJ
authors.lastname: Mintah
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shihanian
authors.affiliation: Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cohen
authors.affiliation: Howard Hughes Medical Institute and Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
mesh_terms: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D050171:Dyslipidemias / Q000097:blood*; D006801:Humans; D008049:Lipase / Q000097:blood; D008055:Lipids / Q000097:blood*; D008071:Lipoprotein Lipase / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D051381:Rats; D014280:Triglycerides / Q000097:blood
chemical_list: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; D000911:Antibodies, Monoclonal; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids; D014280:Triglycerides; D008049:Lipase; C498741:Lipg protein, mouse; D008071:Lipoprotein Lipase
keywords: angiopoietin-like protein 3; cholesterol; dyslipidemia; endothelial lipase; hyperlipidemia; lipoprotein lipase; triglycerides