2. Academic Validation
  3. Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies

Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies

  • Front Immunol. 2014 May 22;5:233. doi: 10.3389/fimmu.2014.00233.
Philipp Haselmayer 1,  Montserrat Camps 2,  Mathilde Muzerelle 3,  Samer El Bawab 4,  Caroline Waltzinger 2,  Lisa Bruns 1,  Nada Abla 5,  Mark A Polokoff 6,  Carole Jond-Necand 2,  Marilène Gaudet 7,  Audrey Benoit 7,  Dominique Bertschy Meier 7,  Catherine Martin 7,  Denise Gretener 8,  Maria Stella Lombardi 2,  Roland Grenningloh 9,  Christoph Ladel 10,  Jørgen Søberg Petersen 11,  Pascale Gaillard 3,  Hong Ji 7
Affiliations

Affiliations

  • 1 Immunology, Department of Preclinical Pharmacology, Merck Serono , Darmstadt , Germany ; Biologics and Immunology Platform, Merck Serono , Darmstadt , Germany.
  • 2 Department of Cellular Immunology, Merck Serono SA , Geneva , Switzerland ; Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland.
  • 3 Department of Chemistry, Merck Serono SA , Geneva , Switzerland.
  • 4 Drug Metabolism and Pharmacokinetics (DMPK), Non-Clinical Development, Merck Serono , Darmstadt , Germany.
  • 5 Drug Metabolism and Pharmacokinetics (DMPK), Non-Clinical Development, Merck Serono SA , Geneva , Switzerland.
  • 6 BioSeek® Division, DiscoveRx Corporation , South San Francisco, CA , USA.
  • 7 Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland ; Department of Early PK/PD Biomarker, Merck Serono SA , Geneva , Switzerland.
  • 8 Department of Screening, Merck Serono SA , Geneva , Switzerland.
  • 9 Immunology, Department of Preclinical Pharmacology, EMD Serono Research and Development Institute , Billerica, MA , USA.
  • 10 Biologics and Immunology Platform, Merck Serono , Darmstadt , Germany.
  • 11 Biologics and Immunology Platform, Merck Serono SA , Geneva , Switzerland.
PMID: 24904582 DOI: 10.3389/fimmu.2014.00233
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.

Keywords

PI3Kδ inhibitor; SLE; drug development; immune response; lupus nephritis; pharmacodynamic biomarker; pharmacokinetic/pharmacodynamic modeling.

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