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Targeting IL-5 pathway against airway hyperresponsiveness: a challenge between benralizumab and mepolizumab
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  • Luigino Calzetta,
  • Beatrice Ludovica Ritondo,
  • maria Gabriella Matera,
  • Francesco Facciolo,
  • Paola Rogliani
Luigino Calzetta
University of Rome Tor Vergata
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Beatrice Ludovica Ritondo
University of Rome Tor Vergata
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maria Gabriella Matera
University
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Francesco Facciolo
IFO
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Paola Rogliani
University of Rome Tor Vergata
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Abstract

Background and Purpose Airway hyperresponsiveness (AHR) is a central abnormality in asthma. Interleukin-5 (IL-5) may modulate AHR in animal models of asthma, but inconsistent data are available on the impact of targeting IL-5 pathway against AHR. The difference between targeting IL-5 or IL-5Rα in modulating AHR remains to be understood in human airways. The aim of this study was to compare the role of the anti-IL-5Rα benralizumab and the anti-IL-5 mepolizumab against AHR, and to assess whether these agents influence the levels of cyclic adenosine monophosphate (cAMP). Experimental Approach Passively sensitized human airways were treated with benralizumab and mepolizumab. The primary endpoint was the inhibition of AHR to histamine; the secondary endpoints were the protective effect against AHR to parasympathetic activation and mechanical stress, and the tissue modulation of cAMP. Key Results Benralizumab and mepolizumab significantly (P<0.001 vs. positive control) prevented the AHR to histamine (maximal effect -134.14±14.93% and -108.29±32.16%, respectively), with benralizumab being 0.73±0.10 logarithm significantly (P<0.05) more potent than mepolizumab. Benralizumab and mepolizumab significantly (P<0.001 vs. positive control) inhibited the AHR to transmural stimulation and mechanical stress. Benralizumab was 0.45±0.16 logarithm significantly (P<0.05) more potent than mepolizumab against AHR to parasympathetic activation. The effect of these agents was significantly correlated (P<0.001) with increased levels of cAMP. Conclusion Targeting the IL-5/IL-5Rα axis is an effective strategy to prevent the AHR. Benralizumab resulted more potent than the mepolizumab and the concentration dependent beneficial effects of both these agents were related with improved levels of cAMP in hyperresponsive airways.

Peer review status:ACCEPTED

28 Apr 2020Submitted to British Journal of Pharmacology
29 Apr 2020Submission Checks Completed
29 Apr 2020Assigned to Editor
30 Apr 2020Reviewer(s) Assigned
02 Jun 2020Editorial Decision: Revise Minor
14 Jul 20201st Revision Received
16 Jul 2020Submission Checks Completed
16 Jul 2020Assigned to Editor
18 Jul 2020Reviewer(s) Assigned
03 Aug 2020Review(s) Completed, Editorial Evaluation Pending
10 Aug 2020Editorial Decision: Accept