ANGPTL8 Blockade With a Monoclonal Antibody Promotes Triglyceride Clearance, Energy Expenditure, and Weight Loss in Mice

作者：Gusarova, Viktoria^*; Banfi, Serena; Alexa-Braun, Corey A.; Shihanian, Lisa M.; Mintah, Ivory J.; Lee, Joseph S.; Xin, Yurong; Su, Qi; Kamat, Vishal; Cohen, Jonathan C.; Hobbs, Helen H.; Zambrowicz, Brian; Yancopoulos, George D.; Murphy, Andrew J.; Gromada, Jesper

来源：Endocrinology, 2017, 158(5): 1252-1259.

DOI：10.1210/en.2016-1894

• IMMUNOGLOBULIN GENES
• GLUCOSE-HOMEOSTASIS
• HUMANIZATION
• METABOLISM
• LIPIDS

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.

• 出版日期2017-5