<p>New horizons for the treatment of severe, eosinophilic asthma: benralizumab, a novel precision biologic</p>

Abstract

In the last decades, the increasing evidence concerning inflammation mechanisms underlying severe eosinophilic asthma has highlighted new potential therapeutic targets and has paved the way to new selective biologic drugs. Understanding the mechanism of action and the clinical outcomes of a particular drug along with the clinical and biological characteristics of the patient population for which that drug was intended may ensure appropriate selection of patients that will respond to that drug. Under this perspective, the present review will focus on the mechanisms of action and clinical evidence of benralizumab as a treatment option for severe eosinophilic asthma, in order to provide a concise overview and a reference for clinical practice. Benralizumab is a fully humanized afucosylated IgG1κ mAb that binds to an epitope on IL-5 Rα, and inhibits IL-5 signaling. Benralizumab also sustains antibody-directed cell-mediated cytotoxicity (ADCC) of eosinophils and basophils and consequently depletes IL-5Rα-expressing cells. As a result, it is responsible for a substantial depletion of blood, tissue, and bone marrow eosinophilia. This unique mechanism of action may account for a more complete and rapid action profile. Randomized clinical trials have demonstrated that benralizumab provides an optimal safety profile, and is able to significantly reduce asthma exacerbations, oral steroid intake, and to improve lung function. Some clinical predictors of enhanced clinical response to benralizumab have also been identified, including: a level of blood eosinophils ≥300 μL −1 , oral steroids use, the presence of nasal polyposis, FVC <65% of predicted, and a history of three or more exacerbations per year at baseline. These results can be helpful in identifying the best responder patients to benralizumab. As a step forward, the definition of the responder profile for each of the available biological treatment options will potentially support even more the pathway to precision medicine and the critical matching of the right drug with the right patient.

ChAracterization of ItaliaN severe uncontrolled Asthmatic patieNts Key features when receiving Benralizumab in a real-life setting: the observational rEtrospective ANANKE study

“…The advent of monoclonal antibodies (mAbs) targeting the interleukin-5 (IL-5) pathway has provided a new phenotype-specific approach. Unlike the anti-IL-5 mAbs mepolizumab [ 15 ] and reslizumab [ 16 ], benralizumab [ 17 ] targets IL-5 receptor alpha (IL-5Rα), which is highly expressed by human eosinophils and eosinophil progenitors [ 6 ], and has the unique ability to induce rapid and complete depletion of blood and tissue eosinophils, and of other IL-5Rα + cells as well, via afucosylation-dependent Ab-dependent cell-mediated cytotoxicity (ADCC) [ 18 , 19 ]. In the pivotal phase 3 trials, benralizumab as add-on maintenance treatment in patients with uncontrolled SEA decreased the annual exacerbation rate (AER) by up to 70%, improved lung function and asthma symptoms, and allowed a 75% reduction in the median dose of OCS (discontinuation rate: 52%), with a good safety and tolerability profile [ 20 – 22 ].…”

Fasting impairs type 2 helper T cell infiltration in the lung of an eosinophilic asthma mouse model

“…In addition, eosinophils differentiate and mature in the bone marrow, for suppressing the lung infiltration of eosinophils. Mepolizumab and benralizumab are antibody preparations that target IL-5 and IL-5R and have been used in the treatment of asthma [30,31]. Therefore, we focused on the Th2 cytokine, IL-5, as a key player in fasting induced suppression of eosinophil infiltration.…”

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities

“…As a result, eosinophilia is reduced in blood, tissue and bone marrow due to the inhibition of eosinophil differentiation and maturation. In addition, benralizumab also depletes eosinophils in tissues and systemic circulation via antibody-dependent, cell-mediated cytotoxicity as it can bind to the RIIIa region of the Fc receptor on NK cells, neutrophils and macrophages through its afucosylated Fc domain (97,98). The dual-function of benralizumab allows for a more rapid and sustained reduction of eosinophilia than other IL-5-targeted monoclonal antibodies (97).…”

“…Thus, benralizumab is shown to J o u r n a l P r e -p r o o f selectively modulate blood proteins and eosinophil-or basophil-associated genes, with alterations occurring prominently in eosinophil-high patients rather than eosinophil-low patients (99). Randomized clinical trials have also provided evidence on the optimal safety profile of benralizumab, as well as its efficacy in reducing asthma exacerbations, steroidsparing and improvement of lung function (98). When compared to reslizumab, benralizumab was associated with a significantly improved lung function in asthma patients with severe eosinophilia (≥400 cells/μL) (95).…”