Targeting IL-5 pathway against airway hyperresponsiveness: a challenge
between benralizumab and mepolizumab
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.