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

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.

• Authors: Xiaohua Xue, Pejman Soroosh, Aimee De Leon-Tabaldo, Rosa Luna-Roman, Marciano Sablad, Natasha Rozenkrants, Jingxue Yu, Glenda Castro, Homayon Banie, Wai-Ping Fung-Leung, Luis Santamaria-Babi, Thomas Schlueter, Michael Albers, Kristi Leonard, Alison L Budelsky, Anne M Fourie
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 37977 (12 01 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27905482 (Publication Type: Journal Article)

Chemical References

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

Topics

• Administration, Oral
• Animals
• Arthritis, Rheumatoid (drug therapy, genetics, 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, metabolism)
• Peptides, Cyclic (administration & dosage, pharmacology)
• Psoriasis (drug therapy, genetics, metabolism)
• Th17 Cells (cytology, drug effects, metabolism)
• Transcription, Genetic
• Interleukin-22