Discovery of the Migraine Prevention Therapeutic Aimovig (Erenumab), the First FDA-Approved Antibody against a G-Protein-Coupled Receptor

Abstract

In 2018, the United States Food and Drug Administration (FDA) approved Aimovig (erenumab) for the prevention of migraine. Erenumab is the first FDA approved antibody therapeutic against a G-protein-coupled receptor, the canonical receptor of calcitonin gene related peptide (CGRP-R). A novel, epitope-focused antigen was created to reconstruct the extracellular domains of the CGRP-R in a stable conformation. Successful inoculation of XenoMouse animals and careful screening yielded multiple candidate molecules for high potency and exquisite selectivity toward the CGRP-R over related receptors. These efforts led to the discovery of erenumab which has demonstrated the desired efficacy and safety profiles in multiple clinical studies for the prevention of migraine. The innovation developed in the discovery of erenumab furthers the ability to target G-coupled protein receptors using antibody approaches.

New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis

“…CALCB encodes the calcitonin-related polypeptide beta (CGRP), which has been shown to contribute to migraine [63][64][65] . Several monoclonal antibodies targeting CGRP or its receptor have been proven to be effective therapeutics for the preventive treatment of migraine 66,67 and have been recently approved by the U.S. Food and Drug Administration 68,69 . In parallel, common genetic polymorphisms at CALCB have been reported to contribute to diverticular disease that is a common of intestinal neuromuscular function 70 .…”

Molecular Insight into Recognition of the CGRPR Complex by Migraine Prevention Therapy Aimovig (Erenumab)

“…The immunization campaign was carried out on a transgenic XenoMouseâ platform using the following forms of CGRPR antigens: (i) AM-1 CHO transfectants expressing full-length human CRLR and RAMP1 at the cell surface, obtained by co-transfecting CHO cells with human full-length CRLR cDNA and RAMP1 cDNA (ii) membrane extract from the cells (iii) soluble CGRP receptor obtained by coexpressing and purifying the N-terminal ECD of CRLR and the extracellular domain (ECD) of RAMP1 (King et al, 2019). Briefly, XenoMouseâ animals, a transgenic mouse strain that has fully human immunoglobulin genes, were used to generate human anti-CGRPR antibodies.…”

“…The immunization campaign with XenoMouse, utilizing epitope-focused design of the antigen, generated a panel of antibodies with desired properties, and subsequent screening campaign of these lead molecules led to the discovery of erenumab (King et al, 2019). Erenumab binds to CGRPR with high affinity and superior selectivity, effectively inhibiting the receptor activation and downstream signaling (Shi et al, 2016).…”

Antigen Design for Successful Isolation of Highly Challenging Therapeutic Anti-GPCR Antibodies

“…Based on the finding that the CGRP binding site spans the extracellular regions of CLR and RAMP1 [35], a heterodimeric Fc (fragment crystallizable) fusion protein consisting of an ectodomain of RAMP and an N-terminal extracellular region of CLR was designed as an antigen to isolate CGRPR antagonistic antibodies (Figure 4a). In addition, the prepared heterodimeric Fc fusion was immunized into XenoMouse to generate erenumab, followed by hybridoma screening [36,37] (Figure 4b). Erenumab showed a high binding affinity to CGRPR (K D = 56 pM) and excellent inhibition of cAMP production (IC 50 = 2.3 nM) [38].…”