Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis

Céline Ortega-Ferreira, Perrine Soret, Gautier Robin, Silvia Speca, Sandra Hubert, Marianne Le Gall, Emiko Desvaux, Manel Jendoubi, Julie Saint-Paul, Loubna Chadli, Agnès Chomel, Sylvie Berger, Emmanuel Nony, Béatrice Neau, Benjamin Fould, Anne Licznar, Franck Levasseur, Thomas Guerrier, Sahar Elouej, Sophie Courtade-Gaïani, Nicolas Provost, The Quyen Nguyen, Julien Verdier, David Launay and Frédéric De Ceuninck ()
Additional contact information
Céline Ortega-Ferreira: Translational Medicine
Perrine Soret: Biomarker Biostatistics
Gautier Robin: Mabqi SAS
Silvia Speca: Lille University
Sandra Hubert: Neurosciences and Immuno-inflammation Therapeutic Area
Marianne Le Gall: Mabqi SAS
Emiko Desvaux: Neurosciences and Immuno-inflammation Therapeutic Area
Manel Jendoubi: Lille University
Julie Saint-Paul: Mabqi SAS
Loubna Chadli: Translational Medicine
Agnès Chomel: Protein Sciences
Sylvie Berger: Structural Sciences
Emmanuel Nony: Protein Sciences
Béatrice Neau: Preclinical Biostatistics, Quantitative Pharmacology
Benjamin Fould: Protein Sciences
Anne Licznar: Translational Medicine
Franck Levasseur: Translational Medicine
Thomas Guerrier: Lille University
Sahar Elouej: Computational Medicine
Sophie Courtade-Gaïani: Computational Medicine
Nicolas Provost: Molecular Genomics
The Quyen Nguyen: Structural Sciences
Julien Verdier: Neurosciences and Immuno-inflammation Therapeutic Area
David Launay: Lille University
Frédéric De Ceuninck: Neurosciences and Immuno-inflammation Therapeutic Area

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Systemic sclerosis (SSc) is an autoimmune, inflammatory and fibrotic disease with limited treatment options. Developing new therapies is therefore crucial to address patient needs. To this end, we focused on galectin-3 (Gal-3), a lectin known to be associated with several pathological processes seen in SSc. Using RNA sequencing of whole-blood samples in a cross-sectional cohort of 249 patients with SSc, Gal-3 and its interactants defined a strong transcriptomic fingerprint associated with disease severity, pulmonary and cardiac malfunctions, neutrophilia and lymphopenia. We developed new Gal-3 neutralizing monoclonal antibodies (mAb), which were then evaluated in a mouse model of hypochlorous acid (HOCl)-induced SSc. We show that two of these antibodies, D11 and E07, reduced pathological skin thickening, lung and skin collagen deposition, pulmonary macrophage content, and plasma interleukin-5 and -6 levels. Moreover, E07 changed the transcriptional profiles of HOCl-treated mice, resulting in a gene expression pattern that resembled that of control mice. Similarly, pathological pathways engaged in patients with SSc were counteracted by E07 in mice. Collectively, these findings demonstrate the translational potential of Gal-3 blockade as a therapeutic option for SSc.

Date: 2023
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DOI: 10.1038/s41467-023-41117-9

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