title: 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.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xue
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Pejman
authors.initials: P
authors.lastname: Soroosh
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Aimee
authors.initials: A
authors.lastname: De Leon-Tabaldo
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Rosa
authors.initials: R
authors.lastname: Luna-Roman
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Marciano
authors.initials: M
authors.lastname: Sablad
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Natasha
authors.initials: N
authors.lastname: Rozenkrants
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Jingxue
authors.initials: J
authors.lastname: Yu
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Glenda
authors.initials: G
authors.lastname: Castro
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Homayon
authors.initials: H
authors.lastname: Banie
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Wai-Ping
authors.initials: WP
authors.lastname: Fung-Leung
authors.affiliation: Translational Immunology (PCB/UB), Department of Physiology and Immunology, Universitat de Barcelona Barcelona, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Santamaria-Babi
authors.affiliation: Department of Research, Phenex Pharmaceuticals AG, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schlueter
authors.affiliation: Department of Research, Phenex Pharmaceuticals AG, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Albers
authors.affiliation: Janssen Research &Development, Spring House, Pennsylvania, United States.
authors.forename: Kristi
authors.initials: K
authors.lastname: Leonard
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Budelsky
authors.affiliation: Janssen Research &Development, La Jolla, California, United States.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fourie
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000494:pharmacology; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic; D000097043:Interleukin-22
chemical_list: D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010456:Peptides, Cyclic; D000097043:Interleukin-22; C508717:IL17A protein, human; C000611983:JNJ-54452840; C539900:RORC protein, human