Erenumab (AMG 334), a monoclonal antagonist antibody against the canonical CGRP receptor, does not impair vasodilatory or contractile responses to other vasoactive agents in human isolated cranial arteries
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Background: Calcitonin gene-related peptide (CGRP) is a neuronal transmitter present in intracranial sensory nerves, where it is involved in migraine pathophysiology as well as other biological functions. Recently, the fully human monoclonal antibody erenumab (AMG 334), which targets the canonical calcitonin gene-related peptide receptor, showed significant prophylactic efficacy and favourable safety in phase II and III clinical trials for episodic and chronic migraine and is now approved for migraine prevention in several countries. Objective: Given that calcitonin gene-related peptide can mediate vasodilation, we investigated the effect of erenumab on vasoactive responses in the presence or absence of various vasodilatory and vasocontractile mediators in a model using isolated human cerebral and meningeal arteries. Methods: Ring segments of human isolated cerebral and meningeal arteries were mounted in a sensitive myograph. On arterial segments pre-contracted with 30 mM potassium chloride, vasoactive responses to calcitonin gene-related peptide were studied in the presence of different concentrations of erenumab. At the maximal tested inhibitory concentration of erenumab (100 nM), functional arterial relaxation in response to nicardipine or substance P, and the contractile responses to sumatriptan and dihydroergotamine were examined. Results: 30 mM potassium chloride produced a stable contraction of the vessel segments and calcitonin gene-related peptide induced a concentration-dependent relaxation. We observed that (i) erenumab had no direct contractile or relaxant effects per se (by itself), (ii) pre-treatment with erenumab antagonized the calcitonin gene-related peptide-induced relaxation in a competitive manner, (iii) the relaxant responses to nicardipine or substance P were unaffected in the presence of erenumab and (iv) the contraction induced by sumatriptan or dihydroergotamine was not modified by erenumab. Conclusion: Our findings demonstrate that erenumab, while not associated with vasoactive properties per se, specifically inhibits calcitonin gene-related peptide-induced relaxation of cranial arteries without impacting vasodilatory responses or contractile responses of endogenous or pharmacological vasoactive compounds.
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Subject classification (UKÄ) – MANDATORY
|Publication status||E-pub ahead of print - 2019 Jul 31|