A pharmacologically active monoclonal antibody against the human melanocortin-4 receptor: effectiveness after peripheral and central administration.

The Journal of Pharmacology and Experimental Therapeutics
Jean-Christophe PeterKarl G Hofbauer

Abstract

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 human embryonic kidney 293 cells expressing the human MC4R and blocked the activity of the MC4R under basal conditions and after stimulation with alpha-melanocyte-stimulating hormone (alpha-MSH). The inverse agonist action of Agouti-related protein was significantly enhanced in the presence of mAb 1E8a. After a single intracerebroventricular injection into the third ventricle, mAb 1E8a (1 microg) increased 24-h food intake in rats. After 7 days of continuous intracerebroventricular administration, mAb 1E8a increased food intake, body weight, and fat pad weight and induced hyperglycemia. Because the complete mAb was ineffective after intravenous injection, we produced single-chain variable fragments (scFvs) derived from mAb 1E8a. In pharmacokinetic studies it was demonstrated that these scFvs crossed the blood-brain barrier and reached the hypothalamus. Consequently, the scFv 1E8a increased s...Continue Reading

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Citations

Aug 25, 2010·Current Opinion in Supportive and Palliative Care·Stephanie M Krasnow, Daniel L Marks
Jan 12, 2013·Journal of Molecular Endocrinology·Emma I KayKathleen G Mountjoy
Jan 23, 2016·Nature Reviews. Drug Discovery·William A Banks
Aug 23, 2012·Journal of Cachexia, Sarcopenia and Muscle·Jean-Christophe PeterKarl G Hofbauer
Aug 28, 2014·Biochemical and Biophysical Research Communications·Peter MolekTomaž Bratkovič
Aug 10, 2010·Current Opinion in Supportive and Palliative Care·Alessio MolfinoFilippo Rossi Fanelli
May 7, 2015·Journal of Neuro-oncology·Shilpa S PatilPaturu Kondaiah
Nov 5, 2010·Current Opinion in Supportive and Palliative Care

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