W110 - Local Delivery of IL-35 mRNA Therapeutic Using Lipid Based Nanoparticles Vector Demonstrates High Efficacy to Suppress Autoimmune Hepatitis

Damien Habrant – phD,R&D Project Manager - RNA Therapeutics, OseImmunotherapeutics; Emmanuelle Wilhelm – phD,Senior Engineer, Ex vivo Platform Manager, OseImmunotherapeutics; Sabrina Pengam – Engineer, OseImmunotherapeutics; Ariane Desselle – phD,Engineer, OseImmunotherapeutics; Amandine Georges – Antibody Discovery Scientist, OseImmunotherapeutics; Géraldine Teppaz – Engineer, OseImmunotherapeutics; Caroline Mary – Head of Lab, Ab Engineering Leader, OseImmunotherapeutics; Aurore Morello – phD,Head of Research, Director of R&D program, OseImmunotherapeutics; Nicolas Poirier – phD,CEO,CSO, OseImmunotherapeutics

Abstract Text: IL-35 is a pleiotropic immunosuppressive cytokine suppressing T and B lymphocytes proliferation and functions, inducing regulatory T and B cells and activating Myeloid-suppressor-cells limiting inflammatory responses. The clinical use of cytokine is limited by their short half-live (less than 1 hour) and peripheral large immunosuppressive action caused by a non-specific biodistribution. We have evaluated the therapeutic potential of IL-35-encoded mRNA vectorized with Lipid-based nanoparticles (LNP) for a local delivery and expression of IL-35 into the inflammatory microenvironment.
Efficacy of mRNA IL-35/LNP therapy was assessed in acute autoimmune hepatitis mouse model induced by Concavalin A characterized by T and B cell activation, increased of pro-inflammatory cytokines (IL-2/IL-6/IFNγ/IL-12p40) and hepatotoxicity (ASAT/ALAT). IL35 mRNA/LNP treatment reverses inflammation and liver-induced damage associated with a significant decrease of pro-inflammatory cytokines and transaminase levels even at low dose of mRNA injected (dose 0,5μg to 4ug) (*p < 0,05, n=3 experiments, n=10-13 mouse) as compared to untreated or empty LNP control groups. Further phenotypic analysis showed that IL-35 mRNA therapy decreases T cell activation (CD25) and favors expression of the inhibitory receptor PD-1 on B and T cells in vivo.
Altogether, our results illustrate that localized IL-35 expression, through the use of mRNA/LNP therapy, has the potential to reverse acute autoimmune hepatitis inflammation and open potential new perspectives to use this novel RNA Therapeutic strategy for treatment of multiple auto-immune or inflammatory diseases.