2. Academic Validation
  3. Pharmacological characterisation of erenumab, Aimovig, at two CGRP responsive receptors

Pharmacological characterisation of erenumab, Aimovig, at two CGRP responsive receptors

  • Br J Pharmacol. 2023 Aug 14. doi: 10.1111/bph.16218.
Michael L Garelja 1 2,  Tyla I Alexander 1 2,  Amy Bennie 1,  Mhairi Nimick 1,  Jakeb Petersen 3,  Christopher S Walker 2 3,  Debbie L Hay 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, University of Otago, Dunedin, 9016, New Zealand.
  • 2 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, 1010, New Zealand.
  • 3 School of Biological Sciences, University of Auckland, Auckland, 1010, New Zealand.
PMID: 37580864 DOI: 10.1111/bph.16218
Abstract

Background and purpose: Calcitonin 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 approach: Erenumab 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 results: Erenumab 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 implications: Despite 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.

Keywords

Amylin; calcitonin gene-related peptide; calcitonin receptor; calcitonin receptor-like receptor; erenumab; migraine; receptor activity-modifying protein.

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