Basic Considerations for the Use of Monoclonal Antibodies in Migraine

Abstract

Background: Migraine impacts more than 36 million people in the United States and 1 billion people worldwide. Despite the increasing availability of acute and preventive therapies, there is still tremendous unmet need. Potential treatments in development include monoclonal antibodies (mAbs). Appropriate use of these “biologic” treatments will necessitate an understanding of the aspects that distinguish them from traditional medications.

Aim: Many drug classes are prescribed for migraine treatment, but all have limitations. Recently, calcitonin gene-related peptide (CGRP) activity has shown a significant promise as a target for preventive therapy. In this review, we provide an overview of the potential role of CGRP mAbs in migraine, with a focus on their design, pharmacokinetics, safety, and immunogenicity.

Conclusions: The CGRP mAbs are an innovative new therapy for migraine and address the need for effective and tolerable preventive options. MAbs, including those that target CGRP or its receptor, bind to a target with high specificity and affinity and lead to few off-target adverse effects, although mechanism-based adverse reactions may occur. Unlike other therapeutic antibodies used to treat neurologic disease, CGRP mAbs do not have a target within the immune system and have been designed to avoid altering the immune system. The safety and efficacy of mAbs against CGRP or its receptors are being investigated in clinical development programs, and the first of these therapies has received regulatory approval in the United States.

Keywords: CGRP; anti-CGRP mAbs for migraine; migraine; therapeutic antibodies.

Figure 1

Calcitonin gene‐related peptide (CGRP) in migraine. CGRP may contribute to migraine by affecting: (A) Neurogenic inflammation; (B) blood flow in cerebral vessels; and (C) pain transmission. [Color figure can be viewed at https://wileyonlinelibrary.com] [Correction added after first online publication on November 26, 2018: Figure swapped with Figure 2.]

Figure 2

Structure of Ig. Antibodies are composed of 2 identical heavy and light chains that join to form the characteristic “Y” shape. The light chain contains 1 variable domain and 1 constant domain. The heavy chain contains 1 variable domain and 3 constant domains. Each antibody has an Fc region – the stem of the “Y,” which determines the effector function – and a Fab domain, the arms of the “Y.” The variable domains of each chain include a framework region and 3 CDRs, also referred to as hypervariable regions. The set of CDRs constitutes the paratope, the antigen‐binding site that recognizes the epitope of a specific antigen. IgG (~150,000 Da) is shown next to aspirin (~180 Da) for a comparison between antibodies and small molecules. CH = heavy chain constant; CL = light chain constant; FV = variable fragment; VH = heavy chain variable; VL = light chain variable. [Color figure can be viewed at https://wileyonlinelibrary.com] [Correction added after first online publication on November 26, 2018: Figure swapped with Figure 1.]