Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys.
We generated three fully human monoclonal antibody antagonists against fibroblast growth factor receptor-1 (FGFR1) that potently block FGF signaling. We found that antibodies targeting the c-splice form of the receptor (FGFR1c) were anorexigenic when administered intraperitoneally three times weekly to mice, resulting in rapid, dose-dependent weight loss that plateaued (for doses>4 mg/kg) at 35-40% in 2 wk. Animals appeared healthy during treatment and regained their normal body weights and growth trajectories upon clearance of the antibodies from the bloodstream. Measurements of food consumption and energy expenditure indicated that the rapid weight loss was induced primarily by decreased energy intake and not by increased energy expenditure or cachexia and was accompanied by a greater reduction in fat than lean body mass. Hypophagia was not caused through malaise or illness, as indicated by absence of conditioned taste aversion, pica behavior, and decreased need-induced salt intake in rats. In support of a hypothalamic site of action, we found that, after intraperitoneal injections, anti-FGFR1c (IMC-A1), but not a control antibody, accumulated in the median eminence and adjacent mediobasal hypothalamus and that FGFR1c is enriched in the hypothalamus of mice. Furthermore, a single intracerebroventricular administration of 3 microg of IMC-A1 via the 3rd ventricle to mice caused an approximately 36% reduction in food intake and an approximately 6% weight loss within the ensuing 24 h. Our data suggest that FGF signaling through FGFR1c may play a physiological role in hypothalamic feeding circuit and that blocking it leads to hypophagia and weight loss.
Sun
Haijun D
HD
ImClone Systems Inc., 180 Varick St., New York, NY 10014, USA. haijun@imclone.com
Malabunga
Maria
M
Tonra
James R
JR
DiRenzo
Roberto
R
Carrick
Francine E
FE
Zheng
Huiyuan
H
Berthoud
Hans-Rudolf
HR
McGuinness
Owen P
OP
Shen
Juqun
J
Bohlen
Peter
P
Leibel
Rudolph L
RL
Kussie
Paul
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology*; D000918:Antibody Specificity; D001823:Body Composition / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects; D004435:Eating / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D015431:Weight Loss / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D020033:Protein Isoforms; D051496:Receptor, Fibroblast Growth Factor, Type 1