ANGPTL8 blockade with a monoclonal antibody promotes triglyceride clearance, energy expenditure, and weight loss in mice

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

doi:10.1210/en.2016-1894

ANGPTL8 blockade with a monoclonal antibody promotes triglyceride clearance, energy expenditure, and weight loss in mice

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

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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.

Original language	English (US)
Pages (from-to)	1252-1259
Number of pages	8
Journal	Endocrinology
Volume	158
Issue number	5
DOIs	https://doi.org/10.1210/en.2016-1894
State	Published - May 1 2017

ASJC Scopus subject areas

Endocrinology

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Gusarova, V., Banfi, S., Alexa-Braun, C. A., Shihanian, L. M., Mintah, I. J., Lee, J. S., Xin, Y., Su, Q., Kamat, V., Cohen, J. C., Hobbs, H. H., Zambrowicz, B., Yancopoulos, G. D., Murphy, A. J., & Gromada, J. (2017). ANGPTL8 blockade with a monoclonal antibody promotes triglyceride clearance, energy expenditure, and weight loss in mice. Endocrinology, 158(5), 1252-1259. https://doi.org/10.1210/en.2016-1894

Gusarova, V, Banfi, S, Alexa-Braun, CA, Shihanian, LM, Mintah, IJ, Lee, JS, Xin, Y, Su, Q, Kamat, V, Cohen, JC , Hobbs, HH, Zambrowicz, B, Yancopoulos, GD, Murphy, AJ & Gromada, J 2017, 'ANGPTL8 blockade with a monoclonal antibody promotes triglyceride clearance, energy expenditure, and weight loss in mice', Endocrinology, vol. 158, no. 5, pp. 1252-1259. https://doi.org/10.1210/en.2016-1894

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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.",

author = "Viktoria Gusarova and Serena Banfi and Alexa-Braun, {Corey A.} and Shihanian, {Lisa M.} and Mintah, {Ivory J.} and Lee, {Joseph S.} and Yurong Xin and Qi Su and Vishal Kamat and Cohen, {Jonathan C.} and Hobbs, {Helen H.} and Brian Zambrowicz and Yancopoulos, {George D.} and Murphy, {Andrew J.} and Jesper Gromada",

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doi = "10.1210/en.2016-1894",

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AU - Banfi, Serena

AU - Alexa-Braun, Corey A.

AU - Shihanian, Lisa M.

AU - Mintah, Ivory J.

AU - Lee, Joseph S.

AU - Xin, Yurong

AU - Su, Qi

AU - Kamat, Vishal

AU - Cohen, Jonathan C.

AU - Hobbs, Helen H.

AU - Zambrowicz, Brian

AU - Yancopoulos, George D.

AU - Murphy, Andrew J.

AU - Gromada, Jesper

PY - 2017/5/1

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N2 - 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.

AB - 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.

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ANGPTL8 blockade with a monoclonal antibody promotes triglyceride clearance, energy expenditure, and weight loss in mice

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