Targeting IL‐5 pathway against airway hyperresponsiveness: A comparison between benralizumab and mepolizumab

Abstract

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.

The Impact of Monoclonal Antibodies on Airway Smooth Muscle Contractility in Asthma: A Systematic Review

“…Of the 81 potentially relevant records identified in the initial search, 16 studies were deemed eligible for qualitative analysis ( Table 1 ). Overall, this systematic review included data obtained from ten randomized controlled trials (RCTs) involving patients with different levels of asthma severity [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ], five pre-clinical studies [ 18 , 25 , 43 , 44 , 45 ], and one observational study on patients with severe refractory asthma [ 46 ]. Among the pre-clinical studies, two were conducted ex vivo on passively sensitized human bronchi [ 25 , 45 ], one was carried out in vitro on human ASM cells (ASMCs) [ 44 ], one was performed both ex vivo on human isolated bronchial tissue and in vitro on ASMCs [ 18 ], and one was an in vivo murine model of chronic asthma [ 43 ].…”

“…Overall, this systematic review included data obtained from ten randomized controlled trials (RCTs) involving patients with different levels of asthma severity [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ], five pre-clinical studies [ 18 , 25 , 43 , 44 , 45 ], and one observational study on patients with severe refractory asthma [ 46 ]. Among the pre-clinical studies, two were conducted ex vivo on passively sensitized human bronchi [ 25 , 45 ], one was carried out in vitro on human ASM cells (ASMCs) [ 44 ], one was performed both ex vivo on human isolated bronchial tissue and in vitro on ASMCs [ 18 ], and one was an in vivo murine model of chronic asthma [ 43 ]. The investigated mAbs were omalizumab [ 35 , 36 , 38 , 40 , 41 , 43 , 44 , 45 , 46 ], mepolizumab [ 25 , 34 , 37 , 39 ], benralizumab [ 25 ], tezepelumab [ 33 , 42 ], and dupilumab [ 18 ].…”

“…The approved humanized monoclonal antibodies (mAbs) for the treatment of asthma are targeted against IgE (omalizumab), IL-5 (mepolizumab and reslizumab), IL-5 receptor α (IL-5Rα; benralizumab), and IL-4/IL-13 (dupilumab) [ 24 , 25 , 26 , 27 ]. Recently, the Biologics License Application (BLA) for the anti-thymic stromal lymphopoietin (TSLP) tezepelumab has been accepted and granted priority review for the treatment of asthma from the US Food and Drug Administration (FDA) [ 28 ].…”

An Overview of the Safety and Efficacy of Monoclonal Antibodies for the Chronic Obstructive Pulmonary Disease

“…There is no doubt that in the future it will be necessary to study in detail the impact of mAbs on other key outcomes such as pulmonary function, as important differences may also be detected. For example, an experimental study showed that benralizumab was more potent than mepolizumab in increasing levels of cAMP in the airways, 86 which may mean a different impact on lung function. Another experimental study documented that activation of the IL-4/IL-13 pathway can promote profound airway smooth muscle hyperreactivity, while neither IL-5 nor IL-17A enhanced airway contractile responses.…”

Oral Corticosteroids Dependence and Biologic Drugs in Severe Asthma: Myths or Facts? A Systematic Review of Real-World Evidence

“…Fortunately, in the last two decades, a new class of biological treatments has been introduced to treat severe asthmatic patients. These biological agents are humanized monoclonal antibodies (mAbs) anti-IgE (omalizumab), anti-IL-5 (mepolizumab and reslizumab), anti-IL-5Rα (benralizumab), and anti-IL-4/IL-13 (dupilumab) [18][19][20][21]. All these mAbs have been extensively proved to induce a significant OCS-sparing effect in randomized controlled trials (RCTs), and thus overcome the problem related to OCS dependence in severe asthma [22][23][24][25][26].…”