RT Journal Article
SR Electronic
T1 Pharmacological Characterization of AMG 334, a Potent and Selective Human Monoclonal Antibody Against the Calcitonin Gene-Related Peptide (CGRP) Receptor
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.115.227793
DO 10.1124/jpet.115.227793
A1 Licheng Shi
A1 Sonya Lehto
A1 Dawn X-D. Zhu
A1 Hong Sun
A1 Jianhua Zhang
A1 Brian P. Smith
A1 David C. Immke
A1 Kenneth D. Wild
A1 Cen Xu
YR 2015
UL http://jpet.aspetjournals.org/content/early/2015/11/11/jpet.115.227793.abstract
AB Therapeutic agents that block the calcitonin gene-related peptide (CGRP) signaling pathway are a highly anticipated and promising new drug class for migraine, especially following reports that small-molecule CGRP-receptor antagonists are efficacious for both acute migraine treatment and migraine prevention. Using XenoMouse® technology, we successfully generated AMG 334, a fully human monoclonal antibody against the CGRP receptor. Here we show that AMG 334 competes with [125I]-CGRP binding to the human CGRP receptor, with a Ki of 0.02 nM. AMG 334 fully inhibited CGRP-stimulated cAMP production with an IC50 of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors. The potency of AMG 334 at the cynomolgus monkey (cyno) CGRP receptor was similar to that at the human receptor, with an IC50 of 5.7 nM, but its potency at the dog, rabbit, and rat receptors was significantly reduced (> 5000-fold). Therefore, in vivo target coverage of AMG 334 was assessed in cynos using the capsaicin-induced increase in dermal blood flow model. AMG 334 dose dependently prevented capsaicin-induced increases in dermal blood flow on days 2 and 4 post-dosing. These results indicate AMG 334 is a potent, selective, full antagonist of the CGRP receptor and show in vivo dose-dependent target coverage in cynos. AMG 334 is currently in clinical development for the prevention of migraine.