Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis

Sci Rep. 2016 Dec 1;6:37977. doi: 10.1038/srep37977.

Abstract

The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases.

MeSH terms

  • Administration, Oral
  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / metabolism
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Interleukin-17 / metabolism
  • Interleukins / metabolism
  • Mice
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Peptides, Cyclic / administration & dosage*
  • Peptides, Cyclic / pharmacology
  • Psoriasis / drug therapy*
  • Psoriasis / genetics
  • Psoriasis / metabolism
  • Th17 Cells / cytology
  • Th17 Cells / drug effects*
  • Th17 Cells / metabolism
  • Transcription, Genetic

Substances

  • IL17A protein, human
  • Interleukin-17
  • Interleukins
  • JNJ-54452840
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Peptides, Cyclic
  • RORC protein, human
  • interleukin-22