Benralizumab's anti-eosinophil efficacy may be decreased by impaired NK cell activity

Abstract

We read with interest the report by DAGHER et al.[1] of a novel anti-eosinophil action of benralizumab. Benralizumab was shown to induce eosinophil apoptosis by a macrophage-derived tumour necrosis factor (TNF)-induced caspase 3/7 activation, and this was amplified by interferon-γ (IFN-γ) secreted from natural killer (NK) cells. Indeed, in patients with severe asthma, including those who are dependent on daily systemic glucocorticosteroids for asthma control, benralizumab effectively depletes sputum eosinophils [2]. Although no direct head-to-head comparisons have been made, eosinophil suppression is likely to be greater than with the currently approved dose of mepolizumab [3], leading to greater clinical efficacy [4]. However, there may be instances when the anti-eosinophil activity of benralizumab may be impaired due to decreased NK cell numbers or activity that are described in patients with severe asthma on high doses of glucocorticosteroids [5].A 34-year-old female with severe airway hyperresponsiveness and mild sinus and asthma symptoms was seen in 2012, shortly after she had a baby, with dyspnoea, diffuse alveolar haemorrhage, left ventricular ejection fraction of 25%, skin vasculitis and peak blood eosinophils of 13.9 cells•µL −1 . Antineutrophil cytoplasmic antibodies (ANCA) were not detected in serum. However, it was detected in sputum in low titres, along with other autoantibodies such as anti-MARCO. She was treated with high doses of systemic corticosteroids and intravenous cyclophosphamide (10 doses), and later switched to oral prednisone and azathioprine. She participated in a clinical trial of subcutaneous mepolizumab 300 mg monthly for eosinophilic granulomatosis with polyangiitis (EGPA) [6], received the active drug, and successfully tapered her daily prednisone from 35 mg to 5 mg, and her asthma remained well controlled on additional high doses of inhaled corticosteroids and long-acting beta-agonists. Her sputum and blood eosinophil levels were 0 after 4 years of follow-up. Mepolizumab had to be discontinued in 2018 when she finished participating in the open-label extension of the clinical trial, and the drug was not re-imbursed by the provincial insurance plan. Her vasculitis did not flare but her asthma exacerbated, with a 1-L decrease in forced expiratory volume in 1 s (FEV 1 ), and her blood eosinophils rose to 0.5 cells•µL −1 . Prednisone dose had to be increased to 15 mg daily, which suppressed eosinophils to 0.1 cells•µL −1 . Given her significant adverse reactions to prednisone, including suicidal psychosis, she was then switched to benralizumab to attempt steroid weaning. She received 30 mg subcutaneously monthly for 3 months, and her prednisone was reduced by 2.5 mg daily after each injection. She noticed increasing shortness of breath with prednisone reduction and, at 7.5 mg daily prednisone, had an exacerbation with a reduction in FEV 1 to 2.24 L (77% predicted) and increase in sputum eosinophils to 78% and blood eosinophils to 0.4 cells•µL −1 . She did not have a relapse of any oth...

Airway autoimmunity, asthma exacerbations, and response to biologics

“…Second, endogenous IgG autoantibodies in the airways (as exemplified in clinical histories 1 and 2) or the development of other immune dysfunctions (i.e. inadequate ADCC and NK cell dysfunction in patients with eosinophilic exacerbations on benralizumab) 24,93 may contribute to an eosinophilic exacerbation. Third, development of neutralizing anti‐drug antibodies needs to be considered.…”

Perspectives on the Efficacy of Benralizumab for Treatment of Eosinophilic Granulomatosis With Polyangiitis

“…Impaired NK cell activity may have been the cause, suggesting a lack of NK cell-releasing IFN-γ in macrophage-mediated eosinophil apoptosis in benralizumab-refractory cases. Lack of response to benralizumab therapy may be partly because of the lack of NK activity, in addition to the development of anti-drug neutralizing antibodies ( Poznanski et al, 2021 ).…”