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

被引：76

作者：

Gusarova, Viktoria ^{[1
]}

Banfi, Serena ^{[2
]}

Alexa-Braun, Corey A. ^{[1
]}

Shihanian, Lisa M. ^{[1
]}

Mintah, Ivory J. ^{[1
]}

Lee, Joseph S. ^{[1
]}

Xin, Yurong ^{[1
]}

Su, Qi ^{[1
]}

Kamat, Vishal ^{[1
]}

Cohen, Jonathan C. ^{[2
]}

Hobbs, Helen H. ^{[3
,4
]}

Zambrowicz, Brian ^{[1
]}

Yancopoulos, George D. ^{[1
]}

Murphy, Andrew J. ^{[1
]}

Gromada, Jesper ^{[1
]}

机构：

[1] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[3] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA

[4] Howard Hughes Med Inst, Dallas, TX 75390 USA

来源：

ENDOCRINOLOGY | 2017年 / 158卷 / 05期

基金：

美国国家卫生研究院;

关键词：

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

D O I：

10.1210/en.2016-1894

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：1252 / 1259

页数：8

共 17 条

[1]

Some mathematical and technical issues in the measurement and interpretation of open-circuit indirect calorimetry in small animals [J].

Arch, J. R. S. ;

Hislop, D. ;

Wang, S. J. Y. ;

Speakman, J. R. .

INTERNATIONAL JOURNAL OF OBESITY, 2006, 30 (09) :1322-1331

[2]

Determination of lipoprotein lipase activity using a novel fluorescent lipase assay [J].

Basu, Debapriya ;

Manjur, Jahan ;

Jin, Weijun .

JOURNAL OF LIPID RESEARCH, 2011, 52 (04) :826-832

[3]

A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase [J].

Fu, Zhiyao ;

Abou-Samra, Abdul B. ;

Zhang, Ren .

SCIENTIFIC REPORTS, 2015, 5

[4]

Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways [J].

Goldberg, Ira J. ;

Eckel, Robert H. ;

Abumrad, Nada A. .

JOURNAL OF LIPID RESEARCH, 2009, 50 :S86-S90

[5]

ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys [J].

Gusarova, Viktoria ;

Alexa, Corey A. ;

Wang, Yan ;

Rafique, Ashique ;

Kim, Jee Hae ;

Buckler, David ;

Mintah, Ivory J. ;

Shihanian, Lisa M. ;

Cohen, Jonathan C. ;

Hobbs, Helen H. ;

Xin, Yurong ;

Valenzuela, David M. ;

Murphy, Andrew J. ;

Yancopoulos, George D. ;

Gromada, Jesper .

JOURNAL OF LIPID RESEARCH, 2015, 56 (07) :1308-1317

[6]

ANGPTL8/Betatrophin Does Not Control Pancreatic Beta Cell Expansion [J].

Gusarova, Viktoria ;

Alexa, Corey A. ;

Na, Erqian ;

Stevis, Panayiotis E. ;

Xin, Yurong ;

Bonner-Weir, Susan ;

Cohen, Jonathan C. ;

Hobbs, Helen H. ;

Murphy, Andrew J. ;

Yancopoulos, George D. ;

Gromada, Jesper .

CELL, 2014, 159 (03) :691-696

[7]

Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo [J].

Labrijn, Aran F. ;

Buijsse, Antonio Ortiz ;

van den Bremer, Ewald T. J. ;

Verwilligen, Annemiek Y. W. ;

Bleeker, Wim K. ;

Thorpe, Susan J. ;

Killestein, Joep ;

Polman, Chris H. ;

Aalberse, Rob C. ;

Schuurman, Janine ;

van de Winkel, Jan G. J. ;

Parren, Paul W. H. I. .

NATURE BIOTECHNOLOGY, 2009, 27 (08) :767-U122

[8]

Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes [J].

Macdonald, Lynn E. ;

Karow, Margaret ;

Stevens, Sean ;

Auerbach, Wojtek ;

Poueymirou, William T. ;

Yasenchak, Jason ;

Frendewey, David ;

Valenzuela, David M. ;

Giallourakis, Cosmas C. ;

Alt, Frederick W. ;

Yancopoulos, George D. ;

Murphy, Andrew J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (14) :5147-5152

[9]

GPR17 gene disruption does not alter food intake or glucose homeostasis in mice [J].

Mastaitis, Jason ;

Min, Soo ;

Elvert, Ralf ;

Kannt, Aimo ;

Xin, Yurong ;

Ochoa, Francisca ;

Gale, Nicholas W. ;

Valenzuela, David M. ;

Murphy, Andrew J. ;

Yancopoulos, George D. ;

Gromada, Jesper .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (06) :1845-1849

[10]

Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice [J].

Murphy, Andrew J. ;

Macdonald, Lynn E. ;

Stevens, Sean ;

Karow, Margaret ;

Dore, Anthony T. ;

Pobursky, Kevin ;

Huang, Tammy T. ;

Poueymirou, William T. ;

Esau, Lakeisha ;

Meola, Melissa ;

Mikulka, Warren ;

Krueger, Pamela ;

Fairhurst, Jeanette ;

Valenzuela, David M. ;

Papadopoulos, Nicholas ;

Yancopoulos, George D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (14) :5153-5158

← 1 2 →