The CSF-1-receptor inhibitor, JNJ-40346527 (PRV-6527), reduced inflammatory macrophage recruitment to the intestinal mucosa and suppressed murine T cell mediated colitis.

Autor: Manthey CL; Janssen Research & Development, LLC, Pennsylvania, United States of America., Moore BA; Janssen Research & Development, LLC, Pennsylvania, United States of America., Chen Y; Janssen Research & Development, LLC, Pennsylvania, United States of America., Loza MJ; Janssen Research & Development, LLC, Pennsylvania, United States of America., Yao X; Janssen Research & Development, LLC, Pennsylvania, United States of America., Liu H; Janssen Research & Development, LLC, Pennsylvania, United States of America., Belkowski SM; Janssen Research & Development, LLC, Pennsylvania, United States of America., Raymond-Parks H; Janssen Research & Development, LLC, Pennsylvania, United States of America., Dunford PJ; Janssen Research & Development, LLC, Pennsylvania, United States of America., Leon F; Janssen Research & Development, LLC, Pennsylvania, United States of America., Towne JE; Janssen Research & Development, LLC, Pennsylvania, United States of America., Plevy SE; Janssen Research & Development, LLC, Pennsylvania, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2019 Nov 11; Vol. 14 (11), pp. e0223918. Date of Electronic Publication: 2019 Nov 11 (Print Publication: 2019).
DOI: 10.1371/journal.pone.0223918
Abstrakt: Background & Aims: Originally believed to be primarily a disorder of T-cell signaling, evidence shows that macrophage-lineage cells also contribute to the pathogenesis of Crohn's disease (CD). Colony stimulating factor-1 (CSF-1) is a key regulator of the macrophage lineage, but its role in CD has not been well established. We examined transcriptional data from CD mucosa for evidence of CSF-1 pathway activation and tested JNJ-40346527 (PRV-6527), a small molecule inhibitor of CSF-1 receptor kinase (CSF-1R), for its ability to inhibit disease indices in murine colitis.
Methods: A CSF-1 pathway gene set was created from microarray data of human whole blood cultured ex vivo with CSF-1 and compared to a TNFα-induced gene set generated from epithelial-lineage cells. Gene set variation analysis was performed using existing Crohn's mucosa microarray data comparing patients who either responded or failed to respond to anti-TNFα therapy. Commencing day 14 or day 21, mice with T-cell transfer colitis were treated with vehicle or JNJ-40346527 until study termination (day 42). Endpoints included colon weight/length ratios and histopathology scores, and macrophage and T cells were assessed by immunohistochemistry. Mucosal gene expression was investigated using RNAseq.
Results: Both the CSF-1 and the TNFα gene sets were enriched in the colonic mucosal transcriptomes of Crohn's disease and in mouse colitis, and expression of both gene sets was highest in patients who did not respond to anti-TNFα therapy. In these patients neither set was reduced by therapy. In the mouse model, JNJ-40346527 inhibited the increase in colon weight/length ratio by ∼50%, reduced histological disease scores by ∼60%, and reduced F4/80+ mononuclear cell and CD3+ lymphocyte numbers. RNAseq analysis confirmed the CSF-1 gene set was sharply reduced in treated mice, as were gene sets enriched in "M1" inflammatory and "M0" resident macrophages and in activated T cells.
Conclusions: CSF-1 biology is activated in Crohn's disease and in murine T cell transfer colitis. Inhibition of CSF-1R by JNJ-40346527 was associated with attenuated clinical disease scores and reduced inflammatory gene expression in mice. These data provide rationale for testing JNJ-40346527 (PRV-6527) in human inflammatory bowel disease.
Competing Interests: At the time of study conduct, all authors were salaried employees of Janssen R&D. Financial support for the study was solely provided by Janssen. All authors retain stock options with Janssen R&D. In addition, PJD and FL retain stock options with Provention Bio Inc. The authors would like to declare the following patents/patent applications associated with this research: CLM is listed as a co-inventor on Patent #’s 7,662,837 and 7,645,755 pertaining to JNJ40346527, however, all patents rights associated with this compound are solely owned by Janssen R&D and inventors do not receive financial remuneration. BAM is a part-time paid consultant for Provention Bio, but receives no remuneration associated with the development of the JNJ-40346527/PRV-6527. BAM receives additional salary support from BA Moore Pharmaceutical Consulting, HL from Incyte Corporation, PJD and FL from Provention Bio, and SEP from Synlogic Therapeutics. This does not alter our adherence to PLOS ONE policies on data integrity, data sharing and materials.
Databáze: MEDLINE
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