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Fremanezumab blocks CGRP induced dilatation in human cerebral, middle meningeal and abdominal arteries

Ohlsson, Lena LU ; Kronvall, Erik LU ; Stratton, Jennifer and Edvinsson, Lars LU (2018) In Journal of Headache and Pain 19(1).
Abstract

Background: Fremanezumab (TEV-48125) is a fully humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) that has shown positive results in the prevention of episodic migraine and chronic migraine. Previous preclinical studies have revealed CGRP antagonistic effects on intracranial arteries (ICA). The aim of the study was to evaluate the in vitro antagonistic effects of fremanezumab on human arteries. Methods: Arteries were removed in conjunction with neurosurgery (cerebral, CA, and middle meningeal artery, MMA, n = 7) or reconstructive abdominal surgery (abdominal artery, AA, n = 6). Ring segments of the vessels were mounted in a sensitive myograph, the functional responses of vasoactive intestinal peptide (VIP),... (More)

Background: Fremanezumab (TEV-48125) is a fully humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) that has shown positive results in the prevention of episodic migraine and chronic migraine. Previous preclinical studies have revealed CGRP antagonistic effects on intracranial arteries (ICA). The aim of the study was to evaluate the in vitro antagonistic effects of fremanezumab on human arteries. Methods: Arteries were removed in conjunction with neurosurgery (cerebral, CA, and middle meningeal artery, MMA, n = 7) or reconstructive abdominal surgery (abdominal artery, AA, n = 6). Ring segments of the vessels were mounted in a sensitive myograph, the functional responses of vasoactive intestinal peptide (VIP), substance P and CGRP in increasing concentrations (10- 10-10- 7 M) were studied using pre-contraction with 30 mM potassium chloride (KCl). The concentrations of fremanezumab or isotype control antibody (66.7 nM, 0.33 μM, 0.67 μM) were given 30 min prior to CGRP administration. Results: All included arteries responded with a strong stable contraction to the application of 30 mM KCl. During this pre-contraction, CGRP caused a concentration-dependent relaxation which differed slightly in maximum effect (Imax) between the types of arteries (ICA = 100%; AA 80%). Fremanezumab (66.7 nM) showed a shift in the IC50 value of CGRP, but no significant change in Imax. At higher doses there was also a reduction of Imax. For AA, the Imax decreased from 71% at 66.7 nM, to 4.5% with 0.33 μM of fremanezumab. Isotype control antibody did not modify the responses. There was no effect on concentration-dependent relaxation with VIP with 66.7 nM of fremanezumab or isotype control. Conclusion: CGRP relaxes pre-contracted human arteries by 80-100%, but with different IC50; the potency range was ICA < AA. The antagonistic effect and potency of fremanezumab was similar, suggesting that there are vasodilatory CGRP receptors present in all studied arteries and that the antibody may have effect in all studied vessels.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antibody, CGRP, CGRP receptor antagonist, Fremanezumab, Human vessels
in
Journal of Headache and Pain
volume
19
issue
1
article number
66
publisher
Springer
external identifiers
  • pmid:30109438
  • scopus:85051441164
ISSN
1129-2369
DOI
10.1186/s10194-018-0905-8
language
English
LU publication?
yes
id
dfd93922-13d5-40e3-aa8f-838fca394e3a
date added to LUP
2018-09-10 10:42:56
date last changed
2024-03-02 00:05:13
@article{dfd93922-13d5-40e3-aa8f-838fca394e3a,
  abstract     = {{<p>Background: Fremanezumab (TEV-48125) is a fully humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) that has shown positive results in the prevention of episodic migraine and chronic migraine. Previous preclinical studies have revealed CGRP antagonistic effects on intracranial arteries (ICA). The aim of the study was to evaluate the in vitro antagonistic effects of fremanezumab on human arteries. Methods: Arteries were removed in conjunction with neurosurgery (cerebral, CA, and middle meningeal artery, MMA, n = 7) or reconstructive abdominal surgery (abdominal artery, AA, n = 6). Ring segments of the vessels were mounted in a sensitive myograph, the functional responses of vasoactive intestinal peptide (VIP), substance P and CGRP in increasing concentrations (10<sup>- 10</sup>-10<sup>- 7</sup> M) were studied using pre-contraction with 30 mM potassium chloride (KCl). The concentrations of fremanezumab or isotype control antibody (66.7 nM, 0.33 μM, 0.67 μM) were given 30 min prior to CGRP administration. Results: All included arteries responded with a strong stable contraction to the application of 30 mM KCl. During this pre-contraction, CGRP caused a concentration-dependent relaxation which differed slightly in maximum effect (I<sub>max</sub>) between the types of arteries (ICA = 100%; AA 80%). Fremanezumab (66.7 nM) showed a shift in the IC<sub>50</sub> value of CGRP, but no significant change in I<sub>max</sub>. At higher doses there was also a reduction of I<sub>max</sub>. For AA, the I<sub>max</sub> decreased from 71% at 66.7 nM, to 4.5% with 0.33 μM of fremanezumab. Isotype control antibody did not modify the responses. There was no effect on concentration-dependent relaxation with VIP with 66.7 nM of fremanezumab or isotype control. Conclusion: CGRP relaxes pre-contracted human arteries by 80-100%, but with different IC<sub>50</sub>; the potency range was ICA &lt; AA. The antagonistic effect and potency of fremanezumab was similar, suggesting that there are vasodilatory CGRP receptors present in all studied arteries and that the antibody may have effect in all studied vessels.</p>}},
  author       = {{Ohlsson, Lena and Kronvall, Erik and Stratton, Jennifer and Edvinsson, Lars}},
  issn         = {{1129-2369}},
  keywords     = {{Antibody; CGRP; CGRP receptor antagonist; Fremanezumab; Human vessels}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{1}},
  publisher    = {{Springer}},
  series       = {{Journal of Headache and Pain}},
  title        = {{Fremanezumab blocks CGRP induced dilatation in human cerebral, middle meningeal and abdominal arteries}},
  url          = {{http://dx.doi.org/10.1186/s10194-018-0905-8}},
  doi          = {{10.1186/s10194-018-0905-8}},
  volume       = {{19}},
  year         = {{2018}},
}