Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Br J Pharmacol. 2024 Jan;181(1):142-161. doi: 10.1111/bph.16218. Epub 2023 Sep 14.
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 and receptor activity-modifying protein 1 (RAMP1); the AMY receptor comprises the calcitonin receptor 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 AMY receptor. However, it is difficult to estimate its selectivity 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.
Erenumab antagonism was quantified through IC and pK 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 AMY receptors.
Erenumab antagonised both the CGRP and AMY receptors with an ~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.
Despite being designed to target the CGRP receptor, erenumab can antagonise the AMY receptor. Its ability to antagonise CGRP activity at both receptors may be useful in better understanding the clinical profile of erenumab.
降钙素基因相关肽（CGRP）参与偏头痛的病理生理学。CGRP 可以通过两种受体传递信号。经典的 CGRP 受体由降钙素受体样受体和受体活性修饰蛋白 1（RAMP1）组成；AMY 受体由 RAMP1 与降钙素受体组成。减少 CGRP 活性的药物，如受体拮抗剂，已被批准用于偏头痛的治疗和预防。尽管这些药物旨在针对经典的 CGRP 受体，但新出现的证据表明，这些拮抗剂，包括依那西普（一种单克隆抗体拮抗剂），也可以拮抗 AMY 受体。然而，由于没有在匹配条件下对受体进行直接比较，因此很难估计其选择性。因此，我们使用多种配体（包括 αCGRP 和 βCGRP）对 CGRP 反应性受体（包括 CGRP 受体和 AMY 受体）进行了依那西普的特征描述。
通过 IC 和 pK 实验，测量 cAMP 产生，对依那西普的拮抗作用进行了量化。我们使用 SK-N-MC 细胞，该细胞内源性表达人类 CGRP 受体，以及瞬时转染表达人 CGRP 或 AMY 受体的 HEK293S 和 Cos7 细胞。
依那西普对 CGRP 和 AMY 受体均具有拮抗作用，对 CGRP 受体的选择性约为 20-120 倍，具体取决于细胞、激动剂、分析方法和/或测定形式。依那西普对两种形式的 CGRP 均具有同等拮抗作用，并且似乎在两种受体上均作为竞争性可逆拮抗剂发挥作用。
尽管旨在针对 CGRP 受体，但依那西普仍可以拮抗 AMY 受体。它在两种受体上拮抗 CGRP 活性的能力可能有助于更好地了解依那西普的临床特征。
