Pharmacological characterisation of erenumab, Aimovig, at two calcitonin gene‐related peptide responsive receptors

Abstract

Background and PurposeCalcitonin gene‐related peptide (CGRP) is involved in migraine pathophysiology. CGRP can signal through two receptors. The canonical CGRP receptor comprises the calcitonin receptor‐like receptor (CLR) and receptor activity‐modifying protein 1 (RAMP1); the AMY1 receptor comprises the calcitonin receptor (CTR) with RAMP1. Drugs that reduce CGRP activity, such as receptor antagonists, are approved for the treatment and prevention of migraine. Despite being designed to target the canonical CGRP receptor, emerging evidence suggests that these antagonists, including erenumab (a monoclonal antibody antagonist) can also antagonise the AMY1 receptor. However, it is difficult to estimate its selectivity between receptors because direct comparisons between receptors under matched conditions have not been made. We therefore characterised erenumab at both CGRP‐responsive receptors with multiple ligands, including αCGRP and βCGRP.Experimental ApproachErenumab antagonism was quantified through IC50 and pKB experiments, measuring cAMP production. We used SK‐N‐MC cells which endogenously express the human CGRP receptor, and HEK293S and Cos7 cells transiently transfected to express either human CGRP or AMY1 receptors.Key ResultsErenumab antagonised both the CGRP and AMY1 receptors with a ~20‐120‐fold preference for the CGRP receptor, depending on the cells, agonist, analytical approach and/or assay format. Erenumab antagonised both forms of CGRP equally, and appeared to act as a competitive reversible antagonist at both receptors.Conclusion and ImplicationsDespite being designed to target the CGRP receptor, erenumab can antagonise the AMY1 receptor. Its ability to antagonise CGRP activity at both receptors may be useful in better understanding the clinical profile of erenumab.

Cryo-EM Structure of the Human Amylin 1 Receptor in Complex with CGRP and Gs Protein

“…Our recent structural work revealed that activation of AMYRs by the 32-amino-acid CTs is distinct from that by the 37-amino-acid rAmy and that the orientation of the AMY 1 R ECD when bound to sCT differs to that when bound to rAmy, or CGRP as observed in the current study. More recent studies revealed that erenumab could bind competitively with longer peptide agonists, such as rAmy or CGRP, at AMY 1 R. − Overlay of the CGRP–AMY 1 R complex and the erenumab-bound CGRP ectodomain structure (PDB: 6UMG) revealed that the binding of erenumab is likely to be influenced by the orientation of the ECD of the receptors, in addition to residue-specific interactions (Figure C). This provides a rationale for the ability of erenumab to inhibit Amy and CGRP, but not CT binding to AMY 1 R, as well as providing an additional mechanism for its lack of AMR antagonism, as both AM 1 R and AM 2 R have distinct ECD orientations to the CGRPR …”