title: Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies.
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.
authors.affiliation: Immunology, Department of Preclinical Pharmacology, Merck Serono , Darmstadt , Germany ; Biologics and Immunology Platform, Merck Serono , Darmstadt , Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Haselmayer
authors.affiliation: Department of Cellular Immunology, Merck Serono SA , Geneva , Switzerland ; Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Camps
authors.affiliation: Department of Chemistry, Merck Serono SA , Geneva , Switzerland.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Muzerelle
authors.affiliation: Drug Metabolism and Pharmacokinetics (DMPK), Non-Clinical Development, Merck Serono , Darmstadt , Germany.
authors.forename: Samer
authors.initials: S
authors.lastname: El Bawab
authors.affiliation: Department of Cellular Immunology, Merck Serono SA , Geneva , Switzerland ; Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Waltzinger
authors.affiliation: Immunology, Department of Preclinical Pharmacology, Merck Serono , Darmstadt , Germany ; Biologics and Immunology Platform, Merck Serono , Darmstadt , Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bruns
authors.affiliation: Drug Metabolism and Pharmacokinetics (DMPK), Non-Clinical Development, Merck Serono SA , Geneva , Switzerland.
authors.forename: Nada
authors.initials: N
authors.lastname: Abla
authors.affiliation: BioSeek® Division, DiscoveRx Corporation , South San Francisco, CA , USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Polokoff
authors.affiliation: Department of Cellular Immunology, Merck Serono SA , Geneva , Switzerland ; Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Jond-Necand
authors.affiliation: Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland ; Department of Early PK/PD Biomarker, Merck Serono SA , Geneva , Switzerland.
authors.forename: Marilène
authors.initials: M
authors.lastname: Gaudet
authors.affiliation: Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland ; Department of Early PK/PD Biomarker, Merck Serono SA , Geneva , Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Benoit
authors.affiliation: Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland ; Department of Early PK/PD Biomarker, Merck Serono SA , Geneva , Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bertschy Meier
authors.affiliation: Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland ; Department of Early PK/PD Biomarker, Merck Serono SA , Geneva , Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Martin
authors.affiliation: Department of Screening, Merck Serono SA , Geneva , Switzerland.
authors.forename: Denise
authors.initials: D
authors.lastname: Gretener
authors.affiliation: Department of Cellular Immunology, Merck Serono SA , Geneva , Switzerland ; Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland.
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Lombardi
authors.affiliation: Immunology, Department of Preclinical Pharmacology, EMD Serono Research and Development Institute , Billerica, MA , USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Grenningloh
authors.affiliation: Biologics and Immunology Platform, Merck Serono , Darmstadt , Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ladel
authors.affiliation: Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland.
authors.forename: Jørgen Søberg
authors.initials: JS
authors.lastname: Petersen
authors.affiliation: Department of Chemistry, Merck Serono SA , Geneva , Switzerland.
authors.forename: Pascale
authors.initials: P
authors.lastname: Gaillard
authors.affiliation: Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland ; Department of Early PK/PD Biomarker, Merck Serono SA , Geneva , Switzerland.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
keywords: PI3Kδ inhibitor; SLE; drug development; immune response; lupus nephritis; pharmacodynamic biomarker; pharmacokinetic/pharmacodynamic modeling