AUTHOR=Haselmayer Philipp , Camps Montserrat , Muzerelle Mathilde , El Bawab Samer , Waltzinger Caroline , Bruns Lisa , Abla Nada , Polokoff Mark A. , Jond-Necand Carole , Gaudet Marilène , Benoit Audrey , Bertschy Meier Dominique , Martin Catherine , Gretener Denise , Lombardi Maria Stella , Grenningloh Roland , Ladel Christoph , Petersen Jørgen Søberg , Gaillard Pascale , Ji Hong TITLE=Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies JOURNAL=Frontiers in Immunology VOLUME=5 YEAR=2014 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00233 DOI=10.3389/fimmu.2014.00233 ISSN=1664-3224 ABSTRACT=

SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T–B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP®) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.