Ligelizumab impairs IgE‐binding to plasmacytoid dendritic cells more potently than omalizumab and restores IFN‐α production and FOXP3⁺ Treg generation

Abstract

Background: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 IFNα 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. Methods: 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 IgEcrosslinking was also performed. Results: 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 IFNα production. Ligelizumab also restores the ability of pDCs to generate FOXP3 + Tregs as previously reported for omalizumab. Conclusions: 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.

Autoreactive IgE: Pathogenic role and therapeutic target in autoimmune diseases

“…shown to remove IgE from pDC surface and to restore TLR9 and T regulatory cells homeostasis. 173,174 The IgE-dependent basophilmediated AAb production amplification in SLE also supports targeting IgE in this disease. 32 Hence, it will be of primary interest to confirm the therapeutic value of the anti-IgE approach for SLE in clinical trials with larger patient populations.…”

“…Importantly, IgE AAb in SLE facilitate TLR9‐mediated pDC activation and IFNα production 23 . OMZ and LGZ have both been shown to remove IgE from pDC surface and to restore TLR9 and T regulatory cells homeostasis 173,174 . The IgE‐dependent basophil‐mediated AAb production amplification in SLE also supports targeting IgE in this disease 32 .…”

The Role of Regulatory T Cells in Allergic Diseases: Collegium Internationale Allergologicum (CIA) Update 2024

“…Omalizumab restores in vitro the ability of pDCs from atopic donors to produce IFN-α and Tregs by blocking the signaling induced by the crosslinking of the IgE high affinity receptor (FcεRI) and IgE [130]. Interestingly, ligelizumab, a humanized anti-IgE mAb with higher affinity for IgE than omalizumab, demonstrated stronger capacity than omalizumab to block the binding of free IgE to FcεRI on pDCs, retaining also the capacity to restore the ability of pDCs to generate FOXP3 + Tregs [131].…”

Autoreactive IgE: pathogenic role and therapeutic target in autoimmune diseases

“…Importantly, IgE AAb in SLE facilitate TLR9-mediated pDC activation and IFNα production 23 . OMZ and LGZ have both been shown to remove IgE from pDC surface and to restore TLR9 and T regulatory cells homeostasis 171,172 . The IgE-dependent basophil-mediated AAb production amplification in SLE also supports targeting IgE in this disease 32 .…”