Pharmacological effects of TAK-828F: an orally available RORγt inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease

Keiko Igaki, Yoshiki Nakamura, Masayuki Tanaka, Shinta Mizuno, Yusuke Yoshimatsu, Yusaku Komoike, Keiko Uga, Akira Shibata, Hisashi Imaichi, Satou Takayuki, Yoshimasa Ishimura, Masashi Yamasaki, Takanori Kanai, Yasuhiro Tsukimi, Noboru Tsuchimori

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Objective and design: To evaluate the potency of RORγt blockade for treatment of Inflammatory Bowel Disease (IBD), the efficacy of TAK-828F, a novel RORγt inverse agonist, in anti-TNF-α mAb non-responsive mouse colitis model and effect of TAK-828F on IL-17 production in peripheral mononuclear blood cells (PBMCs) of anti-TNF-α naive and treatment-failure patients of IBD was investigated. Methods and results: The colitis model showed Th17-dependent pathogenicity and response to anti-IL-12/23p40 monoclonal antibody (mAb), but no response to anti-TNF-α mAb. In the model, TAK-828F, at oral dosages of 1 and 3 mg/kg, inhibited progression of colitis and reduced the immune reaction that characterize Th17 cells. Anti-IL-17A mAb showed neither efficacy nor change in the T cell population and colonic gene expression in the model. In the normal mouse, a 4-week treatment of TAK-828F at 30 mg/kg did not severely reduce lymphocyte cell counts in peripheral and intestinal mucosa, which was observed in RORγ −/− mice. TAK-828F strongly inhibited IL-17 gene expression with IC 50 values from 21.4 to 34.4 nmol/L in PBMCs from anti-TNF mAb naive and treatment-failure patients of IBD. Conclusions: These results indicate that RORγt blockade would provide an effective approach for treating refractory patients with IBD by blocking IL-23/Th17 pathway.

Original languageEnglish
Pages (from-to)493-509
Number of pages17
JournalInflammation Research
Volume68
Issue number6
DOIs
Publication statusPublished - 2019 Jun 1

Keywords

  • IL-23/Th17 pathway
  • Inflammatory bowel disease
  • Mouse colitis model
  • RORγt inverse agonist
  • TAK-828F

ASJC Scopus subject areas

  • Immunology
  • Pharmacology

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    Igaki, K., Nakamura, Y., Tanaka, M., Mizuno, S., Yoshimatsu, Y., Komoike, Y., Uga, K., Shibata, A., Imaichi, H., Takayuki, S., Ishimura, Y., Yamasaki, M., Kanai, T., Tsukimi, Y., & Tsuchimori, N. (2019). Pharmacological effects of TAK-828F: an orally available RORγt inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease. Inflammation Research, 68(6), 493-509. https://doi.org/10.1007/s00011-019-01234-y