Nature Communications (Aug 2023)

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,
  • Frédéric De Ceuninck

DOI
https://doi.org/10.1038/s41467-023-41117-9
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 20

Abstract

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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.