Publications by authors named "Emiko Desvaux"

4 Publications

  • Page 1 of 1

Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19.

PLoS One 2021 22;16(7):e0254374. Epub 2021 Jul 22.

Servier, Research and Development, Suresnes Cedex, France.

While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1β, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254374PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297899PMC
August 2021

A new molecular classification to drive precision treatment strategies in primary Sjögren's syndrome.

Nat Commun 2021 06 10;12(1):3523. Epub 2021 Jun 10.

Institut de Recherches Internationales Servier, Departments of Translational Medicine and Immuno-Inflammatory Diseases Research and Development, Suresnes, France.

There is currently no approved treatment for primary Sjögren's syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren's syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials.
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http://dx.doi.org/10.1038/s41467-021-23472-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192578PMC
June 2021

S95021, a novel selective and pan-neutralizing anti interferon alpha (IFN-α) monoclonal antibody as a candidate treatment for selected autoimmune rheumatic diseases.

J Transl Autoimmun 2021 1;4:100093. Epub 2021 Mar 1.

Center for Therapeutic Innovation, Immuno-inflammatory Disease, Institut de Recherches Servier, 125 Chemin de Ronde, 78290, Croissy sur Seine, France.

Increased interferon-α (IFN-α) production is a critical component in the pathophysiology of systemic lupus erythematosus (SLE) and other rheumatic autoimmune diseases. Herein, we report the characterization of S95021, a fully human IgG1 anti-IFN-α monoclonal antibody (mAb) as a novel therapeutic candidate for targeted patient populations. S95021 was expressed in CHOZN GS-/- cells, purified by chromatography and characterized by using electrophoresis, size exclusion chromatography and liquid chromatography-mass spectrometry. High purity S95021 was obtained as a monomeric entity comprising different charge variants mainly due to -glycosylation. Surface plasmon resonance kinetics experiments showed strong association rates with all IFN-α subtypes and estimated KDs below picomolar values. Pan-IFN-α-binding properties were confirmed by immunoprecipitation assays and neutralization capacity with reporter HEK-Blue IFN-α/β cells. S95021 was IFN-α-selective and exhibited superior potency and broader neutralization profile when compared with the benchmark anti-IFN-α mAbs rontalizumab and sifalimumab. STAT-1 phosphorylation and the type I IFN gene signature induced in human peripheral blood mononuclear cells by recombinant IFN-α subtypes or plasmas from selected autoimmune patients were efficiently reduced by S95021 in a dose-dependent manner. Together, our results show that S95021 is a new potent, selective and pan IFN-α-neutralizing mAb. It is currently further evaluated as a valid therapeutic candidate in selected autoimmune diseases in which the IFN-α pro-inflammatory pathway is dysregulated.
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http://dx.doi.org/10.1016/j.jtauto.2021.100093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972961PMC
March 2021

Cherenkov luminescence imaging is a fast and relevant preclinical tool to assess tumour hypoxia in vivo.

EJNMMI Res 2018 Dec 20;8(1):111. Epub 2018 Dec 20.

Institut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB), 9 Avenue Alain Savary, 21078, Dijon, France.

Purpose: Molecular imaging techniques visualise biomarkers for both drug development and personalised medicine. In this field, Cherenkov luminescence imaging (CLI) seems to be very attractive by allowing imaging with clinical PET radiotracers with high-throughput capabilities. In this context, we developed a fast CLI method to detect tumour hypoxia with F-fluoromisonidazole (FMISO) for drug development purposes.

Methods: Colon cancer model was induced in mice by subcutaneous injection of 1 × 10 CT-26 cells. FMISO was injected, and simultaneous PET-blood oxygen level dependent (BOLD)-MRI followed by CLI were performed along with immunohistochemistry staining with pimonidazole.

Results: There was a significant correlation between FMISO PET and CLI tumour uptakes, consistent with the BOLD-MRI mapping. Tumour-to-background ratio was significantly higher for CLI compared with PET and MRI. Immunohistochemistry confirmed tumour hypoxia. The imaging workflow with CLI was about eight times faster than the PET-MRI procedure.

Conclusion: CLI is a fast and relevant tool to assess tumour hypoxia. This approach could be particularly interesting for hypoxia-targeting drug development.
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http://dx.doi.org/10.1186/s13550-018-0464-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301908PMC
December 2018
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