Pharmacologic Characterization of AMG 334, a Potent and Selective Human Monoclonal Antibody against the Calcitonin Gene-Related Peptide Receptor
Autor: | David C. Immke, Brian Smith, Jianhua Zhang, Hong Sun, Sonya G. Lehto, Licheng Shi, Kenneth D. Wild, Cen Xu, Dawn Zhu |
---|---|
Rok vydání: | 2015 |
Předmět: |
medicine.medical_specialty
Calcitonin Gene-Related Peptide Migraine Disorders Calcitonin gene-related peptide Pharmacology Antibodies Monoclonal Humanized Binding Competitive chemistry.chemical_compound Mice Calcitonin gene-related peptide receptor antagonist Dogs In vivo Calcitonin Gene-Related Peptide Receptor Antagonists Internal medicine medicine Cyclic AMP Animals Humans Receptor Skin integumentary system Dose-Response Relationship Drug Antibodies Monoclonal Receptors Calcitonin Rats Adrenomedullin Macaca fascicularis Endocrinology chemistry Capsaicin Calcitonin Regional Blood Flow Molecular Medicine Rabbits Signal transduction |
Zdroj: | The Journal of pharmacology and experimental therapeutics. 356(1) |
ISSN: | 1521-0103 |
Popis: | Therapeutic agents that block the calcitonin gene-related peptide (CGRP) signaling pathway are a highly anticipated and promising new drug class for migraine therapy, especially after 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 [(125)I]-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 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 postdosing. 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. |
Databáze: | OpenAIRE |
Externí odkaz: |