Migraine therapeutics differentially modulate the CGRP pathway.
Migraine therapeutics differentially modulate the CGRP pathway.
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DOI：
10.1177/0333102420983282
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Mackenzie KD
中科院分区：
文献类型：
--
作者：
Bhakta M;Vuong T;Taura T;Wilson DS;Stratton JR;Mackenzie KD
针对降钙素基因相关肽（CGRP）通路的偏头痛治疗剂的临床疗效证实了该轴在偏头痛发病中的关键作用。抗CGRP的三种抗体——fremanezumab、galcanezumab和eptinezumab，以及抗CGRP受体的一种抗体——erenumab，是临床批准的治疗偏头痛的药物。此外，两种小分子CGRP受体拮抗剂ubrogepant和rimegepant被批准用于急性偏头痛治疗。靶向CGRP配体或受体对偏头痛治疗有效；然而，文献中缺乏对这些治疗剂的作用机制的比较。为了深入了解这些CGRP途径疗法之间的潜在差异，我们通过结合、功能和成像分析，比较了CGRP配体抗体（fremanezumab）、CGRP受体抗体（erenumab）和CGRP受体小分子拮抗剂（telcagepant）的效果。Erenumab和telcagepant拮抗CGRP、肾上腺髓质素和介导人CGRP受体的cAMP信号传导。相比之下，fremanezumab仅在人CGRP受体上拮抗CGRP诱导的cAMP信号。此外，erenumab，而不是fremanezumab，结合并内化标准的人CGRP受体。有趣的是，erenumab也结合并内化了人类AMY1受体，这是CGRP受体家族的成员。erenumab和telcagepant均能拮抗AMY1受体诱导的cAMP信号传导，而fremanezumab不影响amyin反应。针对CGRP配体与受体的药物在偏头痛预防（抗体）或急性治疗（妊娠）中的治疗效果可能涉及不同的作用机制。这些发现表明，不同的机制可能会影响偏头痛患者的疗效、安全性和/或耐受性。
The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP – fremanezumab, galcanezumab and eptinezumab – and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature. To gain insights into the potential differences between these CGRP pathway therapeutics, we compared the effect of a CGRP ligand antibody (fremanezumab), a CGRP receptor antibody (erenumab) and a CGRP receptor small molecule antagonist (telcagepant) using a combination of binding, functional and imaging assays. Erenumab and telcagepant antagonized CGRP, adrenomedullin and intermedin cAMP signaling at the canonical human CGRP receptor. In contrast, fremanezumab only antagonized CGRP-induced cAMP signaling at the human CGRP receptor. In addition, erenumab, but not fremanezumab, bound and internalized at the canonical human CGRP receptor. Interestingly, erenumab also bound and internalized at the human AMY1 receptor, a CGRP receptor family member. Both erenumab and telcagepant antagonized amylin-induced cAMP signaling at the AMY1 receptor while fremanezumab did not affect amylin responses. The therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients.
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影响因子：
3.4
作者：
Bussiere, Jeanine L.;Davies, Rhian;Monticello, Thomas M.
通讯作者：
Monticello, Thomas M.
DOI：
10.1124/jpet.115.227793
发表时间：
2016-01-01
影响因子：
3.5
作者：
Shi, Licheng;Lehto, Sonya G.;Xu, Cen
通讯作者：
Xu, Cen
影响因子：
4.8
作者：
Kuwasako, K;Shimekake, Y;Sakata, T
通讯作者：
Sakata, T
影响因子：
1.6
作者：
Wong HK;Cheung TT;Cheung BM
通讯作者：
Cheung BM
DOI：
10.1007/164_2018_130
发表时间：
2019-01-01
期刊：
CALCITONIN GENE-RELATED PEPTIDE (CGRP) MECHANISMS: FOCUS ON MIGRAINE
影响因子：
--
作者：
Cottrell, Graeme S.
通讯作者：
Cottrell, Graeme S.