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

Authors :
Dagher R
Kumar V
Copenhaver AM
Gallagher S
Ghaedi M
Boyd J
Newbold P
Humbles AA
Kolbeck R
Source :
The European respiratory journal [Eur Respir J] 2022 Mar 03; Vol. 59 (3). Date of Electronic Publication: 2022 Mar 03 (Print Publication: 2022).
Publication Year :
2022

Abstract

Background: Benralizumab is a humanised, anti-interleukin-5 receptor α monoclonal antibody with anti-eosinophilic activity. Lack of fucose (afucosylation) increases its affinity to CD16a and significantly enhances antibody-dependent cell-mediated cytotoxicity by natural killer (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 remains elusive.<br />Methods: Here, we further investigated the mechanisms involved in benralizumab's anti-eosinophilic activities by employing relevant primary human autologous cell co-cultures and real-time-lapse imaging combined with flow cytometry.<br />Results: 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 cellular phagocytosis. Using live cell imaging, we unravelled 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 tumour necrosis factor (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 interferon-γ, subsequently driving TNF expression by macrophages.<br />Conclusions: Our data provide deeper 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.<br />Competing Interests: Conflict of interest: R. Dagher is employed by and shareholder of AstraZeneca. Conflict of interest: V. Kumar is employed by and shareholder of AstraZeneca. Conflict of interest: A.M. Copenhaver is a former employee and shareholder of AstraZeneca, and is employed by and shareholder of Takeda Pharmaceuticals. Conflict of interest: S. Gallagher is a former employee of AstraZeneca. Conflict of interest: M. Ghaedi is employed by and shareholder of AstraZeneca. Conflict of interest: J. Boyd is employed by and shareholder of AstraZeneca. Conflict of interest: P. Newbold is employed by and shareholder of AstraZeneca. Conflict of interest: A.A. Humbles is an owner of AstraZeneca shares. Conflict of interest: R. Kolbeck is an owner of AstraZeneca shares.<br /> (Copyright ©The authors 2022.)

Details

Language :
English
ISSN :
1399-3003
Volume :
59
Issue :
3
Database :
MEDLINE
Journal :
The European respiratory journal
Publication Type :
Academic Journal
Accession number :
34289975
Full Text :
https://doi.org/10.1183/13993003.04306-2020