TY - JOUR
T1 - Targeting IL-5 pathway against airway hyperresponsiveness
T2 - A comparison between benralizumab and mepolizumab
AU - Calzetta, Luigino
AU - Ritondo, Beatrice Ludovica
AU - Matera, Maria Gabriella
AU - Facciolo, Francesco
AU - Rogliani, Paola
N1 - Funding Information:
L.C. reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, non‐financial support from AstraZeneca, grants from Chiesi Farmaceutici, grants from Almirall, personal fees from ABC Farmaceutici, personal fees from Edmond Pharma, grants and personal fees from Zambon, personal fees from Verona Pharma and personal fees from Ockham Biotech. B.L.R. reports no conflict of interest. MGM reports personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, personal fees from AstraZeneca, personal fees from Chiesi Farmaceutici, personal fees from Almirall, personal fees from ABC Farmaceutici and personal fees from GlaxoSmithKline. F.F. reports no conflict of interest. P.R. reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, personal fees from AstraZeneca, grants and personal fees from Chiesi Farmaceutici, grants and personal fees from Almirall, grants from Zambon, personal fees from Biofutura, personal fees from GlaxoSmithKline, personal fees from Menarini and personal fees from Mundipharma.
Publisher Copyright:
© 2020 The British Pharmacological Society
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Background and Purpose: Airway hyperresponsiveness (AHR) is a central abnormality in asthma. IL-5 may modulate AHR in animal models of asthma, but the available data is inconsistent on the impact of targeting IL-5 pathway against AHR. The difference between targeting IL-5 or the IL-5 receptor, α subunit (IL-5Rα) in modulating AHR remains to be investigated 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 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 inhibited 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 more potent than mepolizumab. Benralizumab and mepolizumab significantly inhibited the AHR to transmural stimulation and mechanical stress. Benralizumab was 0.45 ± 0.16 logarithm significantly more potent than mepolizumab against AHR to parasympathetic activation. The effect of these agents was significantly correlated with increased levels of cAMP. Conclusion and Implications: Targeting the IL-5/IL-5Rα axis is an effective strategy to prevent the AHR. Benralizumab was more potent than the mepolizumab and the concentration-dependent beneficial effects of both these monoclonal antibodies were related to improved levels of cAMP in hyperresponsive airways.
AB - Background and Purpose: Airway hyperresponsiveness (AHR) is a central abnormality in asthma. IL-5 may modulate AHR in animal models of asthma, but the available data is inconsistent on the impact of targeting IL-5 pathway against AHR. The difference between targeting IL-5 or the IL-5 receptor, α subunit (IL-5Rα) in modulating AHR remains to be investigated 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 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 inhibited 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 more potent than mepolizumab. Benralizumab and mepolizumab significantly inhibited the AHR to transmural stimulation and mechanical stress. Benralizumab was 0.45 ± 0.16 logarithm significantly more potent than mepolizumab against AHR to parasympathetic activation. The effect of these agents was significantly correlated with increased levels of cAMP. Conclusion and Implications: Targeting the IL-5/IL-5Rα axis is an effective strategy to prevent the AHR. Benralizumab was more potent than the mepolizumab and the concentration-dependent beneficial effects of both these monoclonal antibodies were related to improved levels of cAMP in hyperresponsive airways.
KW - airway hyperresponsiveness
KW - airway smooth muscle
KW - benralizumab
KW - head to head
KW - IL-5
KW - mepolizumab
KW - severe asthma
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U2 - 10.1111/bph.15240
DO - 10.1111/bph.15240
M3 - Article
C2 - 32857420
AN - SCOPUS:85091018874
VL - 177
SP - 4750
EP - 4765
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 20
ER -