TY - JOUR T1 - A pharmacologically active monoclonal antibody against the human melanocortin-4 receptor : Effectiveness after peripheral and central administration JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.109.163279 SP - jpet.109.163279 AU - Jean-Christophe PETER AU - Anne-Catherine Lecourt AU - Marjorie Weckering AU - Geraldine Zipfel AU - Michael L Niehoff AU - William A Banks AU - Karl G Hofbauer Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/early/2010/01/29/jpet.109.163279.abstract N2 - The hypothalamic melanocortin-4 receptor (MC4R) is a constituent of an important pathway regulating food intake and energy expenditure. We produced a monoclonal antibody (mAb) directed against the N-terminal domain of the MC4R and evaluated its potential as a possible therapeutic agent. This mAb (1E8a) showed specific binding to the MC4R in HEK-293 cells expressing the human MC4R and blocked the activity of the MC4R under basal conditions and after stimulation with α-melanocyte stimulating hormone (α-MSH). The inverse agonist action of agouti-related protein (AgRP) was significantly enhanced in the presence of mAb 1E8a. After a single intracerebroventricular (i.c.v.) injection into the third ventricle mAb 1E8a (1µg) increased 24h-food intake in rats. After 7 days of continuous i.c.v. administration mAb 1E8a increased food intake, body weight and fat pad weights and induced hyperglycemia. Because the complete mAb was ineffective after intravenous (i.v.) injection, we produced single chain variable fragments (scFv) derived from mAb 1E8a. In pharmacokinetic studies it was demonstrated that these scFv crossed the blood-brain barrier and reached the hypothalamus. Consequently, the scFv 1E8a increased significantly food intake and body weight in rats after i.v. administration (300µg/kg). The pharmacological profile of mAb 1E8a and the fact that its scFv fragment was active after peripheral administration suggest that derivatives of anti-MC4R mAbs may be useful in the treatment of patients with anorexia or cachexia.The American Society for Pharmacology and Experimental Therapeutics ER -