Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus

PLoS One. 2018 Apr 2;13(4):e0193236. doi: 10.1371/journal.pone.0193236. eCollection 2018.

Abstract

Ozanimod (RPC1063) is a specific and potent small molecule modulator of the sphingosine 1-phosphate receptor 1 (S1PR1) and receptor 5 (S1PR5), which has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. Ozanimod and its active metabolite, RP-101075, exhibit a similar specificity profile at the S1P receptor family in vitro and pharmacodynamic profile in vivo. The NZBWF1 mouse model was used in therapeutic dosing mode to assess the potential benefit of ozanimod and RP-101075 in an established animal model of systemic lupus erythematosus. Compared with vehicle-treated animals, ozanimod and RP-101075 reduced proteinuria over the duration of the study and serum blood urea nitrogen at termination. Additionally, ozanimod and RP-101075 reduced kidney disease in a dose-dependent manner, as measured by histological assessment of mesangial expansion, endo- and exo-capillary proliferation, interstitial infiltrates and fibrosis, glomerular deposits, and tubular atrophy. Further exploration into gene expression changes in the kidney demonstrate that RP-101075 also significantly reduced expression of fibrotic and immune-related genes in the kidneys. Of note, RP-101075 lowered the number of plasmacytoid dendritic cells, a major source of interferon alpha in lupus patients, and reduced all B and T cell subsets in the spleen. Given the efficacy demonstrated by ozanimod and its metabolite RP-101075 in the NZBWF1 preclinical animal model, ozanimod may warrant clinical evaluation as a potential treatment for systemic lupus erythematosus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA / immunology
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / drug effects
  • Immunoglobulin G / metabolism
  • Indans / pharmacology*
  • Inflammation / drug therapy*
  • Inflammation / pathology
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / pathology
  • Kidney Function Tests
  • Lupus Erythematosus, Systemic / drug therapy
  • Lupus Erythematosus, Systemic / pathology*
  • Mice
  • Oxadiazoles / pharmacology*
  • Receptor, Interferon alpha-beta / metabolism
  • Receptors, Lysosphingolipid / metabolism*
  • Sphingosine-1-Phosphate Receptors
  • Spleen / drug effects
  • Spleen / pathology

Substances

  • Ifnar1 protein, mouse
  • Immunoglobulin G
  • Indans
  • Oxadiazoles
  • Receptors, Lysosphingolipid
  • S1pr1 protein, mouse
  • Sphingosine-1-Phosphate Receptors
  • Receptor, Interferon alpha-beta
  • DNA
  • ozanimod

Grant support

Celgene Corporation (http://www.celgene.com/) funded this study. The funder provided support in the form of salaries and research materials for authors KRTM, MWS, BC, MES, GJO, RP and FLS. KRTM, MWS, BC, MES, GJO, RP and FLS had additional roles in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The specific roles of these authors are articulated in the "author contributions" section.