Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena

Abstract

BackgroundIn clinical trials, the two anti-IL-5 monoclonal antibodies (mAbs, mepolizumab and reslizumab) that are approved to treat severe eosinophilic asthma, reduce exacerbations by approximately 50–60%.ObjectiveTo observe response to anti-IL-5 mAbs in real-life clinical setting, and to evaluate predictors of sub-optimal response.MethodsIn four Canadian academic centres, pre-defined clinical end-points in 250 carefully characterised moderate-to-severe asthmatics were collected prospectively to assess response to the two anti-IL-5 mAbs. Sub-optimal responses was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (ACQ) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders were assessed based on reduced lung function by 25% or any increase in MCS/ACQ. A representative sub-set of 39 patients were evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs.ResultsSub-optimal responses were observed in 42.8% (107/250) patients treated with either mepolizumab/reslizumab. Daily prednisone requirement, sinus disease, and late-onset asthma diagnoses were the strongest predictors of sub-optimal response. Asthma worsened in 13% (34/250) of these patients. Majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of sub-optimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology.ConclusionA significant number of patients who meet currently approved indications for anti-IL5 mAbs show sub-optimal response to them in real-life clinical practice. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement-activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.

Exacerbations of Severe Asthma While on Anti–IL-5 Biologics

“…In fact, sputum and blood eosinophils were completely suppressed in all other patients, irrespective of whether they were responders or suboptimal responders. This finding is in direct contrast with those reported for the other anti-IL-5 biologics, where the main cause of treatment failure can be attributed to suboptimal eosinophil suppression-as witnessed in this study-and with data from other mechanistic studies of anti-IL-5 biologic failures [25,52]. While infective exacerbations can occur while being treated with all anti-IL5 biologics, they seem to be more common in a subset of patients with benralizumab for reasons that we do not currently understand.…”

“…Moreover, a review of 250 patients prescribed anti-IL-5 mAbs (mepolizumab and reslizumab) found that 68.8% had persistent sputum eosinophils (>3%) despite normalization of blood eosinophils. This was associated with elevated sputum anti-EPX IgG, a marker of localized autoimmune response associated with increased eosinophil activity and suboptimal response to biologics [25]. Benralizumab, which is an afucosylated mAb, enhances binding to FcγRIIIa expressed on immune cells such as natural killer (NK) cells and facilitates antibody-dependent cell-mediated cytotoxicity (ADCC).…”

Predictors of response to anti‐IL‐5 biologics

“…7 Recent observations suggest that galectin-10, coded by the CLC gene, may also regulate airway eosinophilia and this is independent of IL-5. 8 In our cohort study of over 250 severe asthmatic patients treated with mepolizumab or reslizumab, 6 the majority of suboptimal responders (with persistent sputum eosinophils but normal blood eosinophils) had elevated IL-5 in their sputum and not the other potential target proteins, suggesting that sub-optimal response was indeed due to inadequate neutralization of IL-5 in the airway.…”

“…Underdosing with an anti-IL-5 Mab not only may lead to suboptimal response, but may also potentially worsen both airflow and eosinophilia in 10-15% of patients in whom the treatment is indicated. 6 This tends to happen in patients who already have endogenous immunoglobulin G (IgG)-type antibodies in their sputum to various cell products such as eosinophil peroxidase. Anti-IL-5 forms heterocomplexes with IL-5 and the endogenous IgG autoantibodies, and could potentially activate complement as well.…”

“…Anti-IL-5 forms heterocomplexes with IL-5 and the endogenous IgG autoantibodies, and could potentially activate complement as well. 6 These immune complexes could trigger the release of tumor necrosis factor-like cytokine-1 (TL-1) from monocytes and macrophages, which would act as 'danger signals' and stimulate ILC2 cells (through death receptor 3) to produce more IL-5, 9 thus perpetuating sputum eosinophilia. The patients most likely to have this phenomenon tend to be those on high doses of oral prednisone (usually >10-12.5 mg/ day), eosinophils and granules in sputum, history of recurrent respiratory bacterial infections (leading to airway lymphoid follicle formation) and lymphopenia (associated with loss of immune tolerance).…”