Novel mechanisms of action contributing to Benralizumab's potent anti-eosinophilic activity

Author:

Dagher RaniaORCID,Kumar Varsha,Copenhaver Alan M.,Gallagher Sandra,Ghaedi Mahboobe,Boyd Jonathan,Newbold Paul,Humbles Alison A.,Kolbeck Roland

Abstract

Benralizumab is a humanised, anti-IL-5Rα monoclonal antibody with anti-eosinophilic activity. Lack of fucose (afucosylation) increases its affinity to CD16a and significantly enhances antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells. Although benralizumab proved clinically efficacious in clinical trials for patients with severe asthma and hypereosinophilic syndrome, in-depth characterisation of its anti-eosinophilic mechanisms of action remain elusive. Here, we further investigated the mechanisms involved in benralizumab's anti-eosinophilic activities. In the presence of NK cells benralizumab induced potent eosinophil apoptosis as demonstrated by the upstream induction of caspase 3/7 and upregulation of cytochrome C. In addition, we uncovered a previously unrecognised mechanism whereby benralizumab can induce eosinophil phagocytosis/efferocytosis by macrophages, a process called antibody-dependent cell phagocytosis (ADCP). Using live cell imaging we unravel the stepwise processes leading to eosinophil apoptosis and uptake by activated macrophages. Through careful observations of cellular co-culture assays we identified a novel role for macrophage derived TNF to further enhance benralizumab-mediated eosinophil apoptosis through activation of TNF-receptor 1 on eosinophils. TNF-induced eosinophil apoptosis was associated with Cytochrome C upregulation, mitochondrial membrane depolarisation, and increased caspase 3/7 activity. Moreover, activated NK cells were found to amplify this axis through the secretion of IFNγ, subsequently driving TNF expression by macrophages. Our data provide insights into the timely appearance of events leading to benralizumab-induced eosinophil apoptosis and suggest that additional mechanisms may contribute to the potent anti-eosinophilic activity of benralizumab in vivo. Importantly, afucosylation of benralizumab strongly enhanced its potency for all mechanisms investigated.

Publisher

European Respiratory Society (ERS)

Subject

Pulmonary and Respiratory Medicine

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