Dataset Information

Effects of monoclonal antagonist antibodies on calcitonin gene-related peptide receptor function and trafficking.

ABSTRACT: BACKGROUND:Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor are efficacious for the prevention of migraine headaches. The downstream molecular mechanisms following ligand-receptor blockade by which these antibodies prevent CGRP signaling through CGRP receptors have not been demonstrated. METHODS:Here we produced tool monoclonal functional antagonist antibodies against CGRP and its canonical receptor and developed a novel cellular model using fluorogen-activated protein technology that allows detection of CGRP receptor internalization by flow cytometry and, for an extended time course, visualization by confocal microscopy. RESULTS:Using this cell model we showed that these antagonist antibodies block both CGRP-induced cAMP signaling and CGRP receptor internalization. At least 10-fold higher concentrations of either antibody are necessary to block CGRP receptor internalization compared with cAMP accumulation in our cell model. CONCLUSION:These data reinforce our understanding of how monoclonal functional antagonist antibodies interfere with CGRP signaling.

SUBMITTER: Manoukian R

PROVIDER: S-EPMC6734291 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Effects of monoclonal antagonist antibodies on calcitonin gene-related peptide receptor function and trafficking.

Manoukian Raffi R Sun Hong H Miller Silke S Shi Di D Chan Brian B Xu Cen C

The journal of headache and pain 20190430 1

<h4>Background</h4>Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor are efficacious for the prevention of migraine headaches. The downstream molecular mechanisms following ligand-receptor blockade by which these antibodies prevent CGRP signaling through CGRP receptors have not been demonstrated.<h4>Methods</h4>Here we produced tool monoclonal functional antagonist antibodies against CGRP and its canonical receptor and developed a novel cellular model using flu ...[more]

PMID: 31039731

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Project description:Objective Cranial autonomic symptoms (CAS), including conjunctival injection, tearing, nasal congestion or rhinorrhea, eyelid edema, miosis or ptosis, and forehead or facial sweating ipsilateral to headache, are often reported by patients with migraine during headache attacks. CAS is a consequence of the activation of the trigeminovascular system, which is the target of monoclonal antibodies acting on the CGRP pathway. Therefore, we hypothesized that patients with CAS might have higher trigeminovascular activation than those without CAS leading to a better response to anti-CGRP treatments. Methods We performed a prospective analysis including patients with episodic or chronic migraine treated with anti-CGRP monoclonal antibodies (i.e., erenumab, fremanezumab, and galcanezumab) between 2019 and 2021. The observation period included a 12-week baseline before treatment with anti-CGRP antibodies and a 12-week treatment follow-up. We evaluated the prevalence of CAS in our cohort and compared disease characteristics and treatment response (i.e., 12-week monthly headache days and 0–29, 30–49, 50–74, 75–99, and 100% monthly headache days reduction from baseline) among patients with and without CAS using the χ2 test, Kruskal–Wallis test, and Mann–Whitney U-test. Results Out of 136 patients, 88 (65%) had CAS. Both patients with and without CAS reported a significant decrease in monthly headache days from baseline. During the 12-week follow-up, the median difference in monthly headache days from baseline was higher in patients with CAS (-10, IQR−15 to−6) than in those without CAS (6, IQR 12 to 3; P = 0.009). However, the proportions of patients with 0 to 29, 30 to 49, 50 to 74, 75 to 99, and 100% response rates did not differ between the two groups. Conclusions In our cohort, the presence of CAS was associated with a greater response to monoclonal antibodies targeting the CGRP pathway. CAS could be a clinical marker of trigeminovascular activation and thus be related to a better response to CGRP treatments.

Dataset Information

Effects of monoclonal antagonist antibodies on calcitonin gene-related peptide receptor function and trafficking.

Publications

Effects of monoclonal antagonist antibodies on calcitonin gene-related peptide receptor function and trafficking.

Similar Datasets

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