Benito-Villalvilla, Cristina, de la Rocha-Munoz, Andres, Lopez-Abente, Jacobo, Eggel, Alexander, Bottoli, Ivan, Severin, Thomas, Woisetschlaeger, Maximilian and Palomares, Oscar (2022) Ligelizumab impairs IgE-binding to plasmacytoid dendritic cells more potently than omalizumab and restores IFN-α production and FOXP3+ Treg generation. Allergy. ISSN 1398-9995

Abstract

Ligelizumab is an anti-IgE monoclonal antibody binding IgE with higher affinity than omalizumab that is under clinical investigation for several IgE-mediated diseases. We previously showed that omalizumab removes IgE bound to FcεRI on plasmacytoid dendritic cells (pDCs) and restores their ability to produce IFN-α and regulatory T cells (Tregs). The aim of this work is to investigate the capacity of ligelizumab to regulate functional properties of pDCs in comparison with omalizumab.pDCs were isolated from atopic donors and IgE was detached from FcεRI on pDCs with designed ankyrin repeat protein (DARPin) bi53-79. pDCs were resensitized with IgE alone or in the presence of ligelizumab or omalizumab prior to IgE-FcεRI crosslinking and Toll-like receptor 9 (TLR9) stimulation. Flow cytometry, ELISA, coculture experiments and intranuclear staining were performed to determine cytokine production and Treg generation. An antigen-specific model of resensitization and IgE-crosslinking was also performed.The levels of serum total free IgE show a non-linear positive correlation with the frequency of IgE+ pDCs displaying IgE bound to FcεRI within the 43 individual donors included in the study. Ligelizumab displays stronger capacity than omalizumab to block the binding of free IgE to FcεRI on human pDCs, resulting in a greater restoration of TLR9-L-induced IFN-α production. Ligelizumab also restores the ability of pDCs to generate FOXP3+ Tregs as previously reported for omalizumab.The uncovered novel molecular mechanisms of ligelizumab to regulate functional properties of pDCs from atopic donors might have important clinical implications for anti-IgE treatments in different IgE-mediated diseases.

Item Type:	Article
Date Deposited:	01 Mar 2023 00:45
Last Modified:	01 Mar 2023 00:45
URI:	https://oak.novartis.com/id/eprint/47891