To view this page ensure that Adobe Flash Player version 11.1.0 or greater is installed.

Headache Editorial Therapeutic Monoclonal Antibodies for Migraine Stephen Silberstein, MD Professor of Neurology and Director, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, US Abstract Monoclonal antibody (mAb) treatment has revolutionized the approach to many diseases. They comprise immunoglobulin G (IgG) isotypes. Calcitonin gene-related peptide (CGRP) is important in migraine pathogenesis. Four mAbs that target either CGRP or the CGRP receptor are in development for prophylaxis of episodic migraine or chronic migraine. Preliminary data suggest that they are effective. Keywords Monoclonal antibodies, migraine treatment, calcitonin gene-related peptide (CGRP) Disclosures: Stephen Silberstein, MD, serves as a consultant and/or advisory panel member and receives honoraria from Alder Biopharmaceuticals, Allergan, Inc., Amgen, Avanir Pharmaceuticals, Inc., Dr. Reddy’s Laboratories, eNeura Inc., ElectroCore Medical, LLC, Medscape, LLC, Medtronic, Inc., Mitsubishi Tanabe Pharma America, Inc., NINDS, Supernus Pharmaceuticals, Inc., Trigemina, and Teva Pharmaceuticals. No funding was received for the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: February 2, 2015 Accepted: February 13, 2015 Citation: US Neurology, 2015;11(1):64–5 Correspondence: Stephen Silberstein, MD, Thomas Jefferson University, Jefferson Headache Center, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, US, E: stephen. silberstein@jefferson.edu Monoclonal antibody (mAb) treatment has revolutionized the approach to many diseases and represents a fast-growing area of drug development. 1,2 They are composed of immunoglobulin G (IgG) isotypes, divided into four subclasses. 3 In 1986, the US Food and Drug Administration (FDA) approved muromonab-CD3, the first mouse-derived therapeutic mAb indicated for transplant rejection. 4 Human or “fully human” mAbs were later developed in 2002 that contained human heavy and light chains. How are mAb named? The stem -mAb indicates an mAb, and the substem indicates the species: murine (-omAb), chimeric (-ximAb), humanized (-zumAb), and human (-umAb). 5 Antibodies can bind directly to the ligand or its receptor. 6 Binding to a cell-surface receptor prevents binding of the ligand and causes downstream processes (e.g. receptor dimerization, receptor breakdown, and signal transduction). 6 dermal blood flow. The CGRP receptor mAb prevented capsaicin-induced increase in dermal blood flow in cynomolgus monkeys for up to 7 days. 10 Monoclonal antibodies are delivered parenterally because of their large size and hydrophilicity. They are not filtered by the kidney or excreted into the urine intact. Their average serum half-life is weeks to months, allowing them to be administered monthly. 7, 8 Another approach is CGRP antibodies that would inhibit neurogenic vasodilation with a long duration of action. Incorporating two rat blood-flow models measuring electrically stimulated vasodilation in the skin or the middle meningeal artery, vasodilatatory responses were found largely dependent on the neurogenic release of CGRP from sensory afferents. Treatment with anti-CGRP antibodies inhibited skin vasodilation or the increase in middle meningeal artery diameter to a similar magnitude as treatment with CGRP receptor antagonists, but with a slower onset of action. The inhibition was evident 1 week after dosing. Chronic treatment with anti- CGRP antibodies had no detectable effects on heart rate or blood pressure. 12 Monoclonal Antibodies in Migraine Prophylaxis Calcitonin gene-related peptide (CGRP) is important in migraine pathogenesis. 9 Recently, multiple human monoclonal antibodies that specifically target the human CGRP receptor have been generated. The inhibition of capsaicin-induced increases in dermal blood flow has been used as an in vivo pharmacodynamic model in humans and nonhuman primates during their development. Topically applied capsaicin stimulates dermal neurons to release CGRP resulting in a localized increase in 64 The immunochemical distribution of CGRP receptor mAb has been tested. This recognizes the functional CLR/RAMP1 receptor complex, but not its individual components. CGRP receptor complexes are expressed on multiple levels in the trigeminal vascular system of the cynomolgus monkey: 1) in the meningeal vasculature innervated by CGRP-positive nerve fibers; 2) in neurons and satellite cells in the trigeminal ganglion; and 3) in neurons in the spinal trigeminal nucleus. The CGRP receptor localization is consistent with CGRP’s role in trigeminal sensitization and suggests that interfering with CGRP receptor transmission may be beneficial for the treatment of migraines. 11 Four mAbs that target either CGRP or the CGRP receptor are currently in development for prophylaxis of episodic migraine (four to 14 headache Touch ME d ica l ME d ia