Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis
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 proce...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41117-9 |
| _version_ | 1797558606440169472 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Céline Ortega-Ferreira |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:33:52Z |
| format | Article |
| id | doaj.art-b4ac4a8d08c9436badd6ef4d718b8e03 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:33:52Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-b4ac4a8d08c9436badd6ef4d718b8e032023-11-20T09:55:48ZengNature PortfolioNature Communications2041-17232023-08-0114112010.1038/s41467-023-41117-9Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosisCéline Ortega-Ferreira0Perrine Soret1Gautier Robin2Silvia Speca3Sandra Hubert4Marianne Le Gall5Emiko Desvaux6Manel Jendoubi7Julie Saint-Paul8Loubna Chadli9Agnès Chomel10Sylvie Berger11Emmanuel Nony12Béatrice Neau13Benjamin Fould14Anne Licznar15Franck Levasseur16Thomas Guerrier17Sahar Elouej18Sophie Courtade-Gaïani19Nicolas Provost20The Quyen Nguyen21Julien Verdier22David Launay23Frédéric De Ceuninck24Servier R&D Center, Biomarker Assay Development, Translational MedicineServier R&D Center, Biomarker BiostatisticsMabqi SASU1286 INFINITE, Institute for Translational Research in Inflammation, Lille UniversityServier R&D Center, Neurosciences and Immuno-inflammation Therapeutic AreaMabqi SASServier R&D Center, Neurosciences and Immuno-inflammation Therapeutic AreaU1286 INFINITE, Institute for Translational Research in Inflammation, Lille UniversityMabqi SASServier R&D Center, Clinical Biomarker Development, Translational MedicineServier R&D Center, Protein SciencesServier R&D Center, Structural SciencesServier R&D Center, Protein SciencesServier R&D Center, Preclinical Biostatistics, Quantitative PharmacologyServier R&D Center, Protein SciencesServier R&D Center, DMPK Department, Translational MedicineServier R&D Center, DMPK Department, Translational MedicineU1286 INFINITE, Institute for Translational Research in Inflammation, Lille UniversityServier R&D Center, Computational MedicineServier R&D Center, Computational MedicineServier R&D Center, Molecular GenomicsServier R&D Center, Structural SciencesServier R&D Center, Neurosciences and Immuno-inflammation Therapeutic AreaU1286 INFINITE, Institute for Translational Research in Inflammation, Lille UniversityServier R&D Center, Neurosciences and Immuno-inflammation Therapeutic AreaAbstract 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.https://doi.org/10.1038/s41467-023-41117-9 |
| spellingShingle | 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 Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis Nature Communications |
| title | Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis |
| title_full | Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis |
| title_fullStr | Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis |
| title_full_unstemmed | Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis |
| title_short | Antibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis |
| title_sort | antibody mediated neutralization of galectin 3 as a strategy for the treatment of systemic sclerosis |
| url | https://doi.org/10.1038/s41467-023-41117-9 |
| work_keys_str_mv | AT celineortegaferreira antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT perrinesoret antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT gautierrobin antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT silviaspeca antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT sandrahubert antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT mariannelegall antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT emikodesvaux antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT maneljendoubi antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT juliesaintpaul antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT loubnachadli antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT agneschomel antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT sylvieberger antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT emmanuelnony antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT beatriceneau antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT benjaminfould antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT annelicznar antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT francklevasseur antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT thomasguerrier antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT saharelouej antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT sophiecourtadegaiani antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT nicolasprovost antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT thequyennguyen antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT julienverdier antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT davidlaunay antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis AT fredericdeceuninck antibodymediatedneutralizationofgalectin3asastrategyforthetreatmentofsystemicsclerosis |