Presentation: Y-320, a New Class of Immunomodulator, Inhibits IL-17 Production II. Y-320 Ameliorates Type II Collagen-Induced Arthritis in Mice and Monkeys (2007)

136 Y-320, a New Class of Immunomodulator, Inhibits IL-17 Production II. Y-320 Ameliorates Type II Collagen-Induced Arthritis in Mice and Monkeys

BACKGROUND: We have found that a new pyrazole-anilide derivative, Y-320, inhibits IL-17 production from mouse and human T cells including Th17 cells. Because high levels of IL-17 and IL-15 are detected in the synovial fluid of active rheumatoid arthritis (RA) patients, overproductions of these cytokines play an important role for the development and progression of RA. Moreover, it has been reported that IL-17 knockout mice develop only a weak magnitude of arthritis in type II collagen-induced arthritis (CIA). Thus, it is highly likely that IL-17 plays an important role in mouse CIA as well as in RA.
PURPOSE: In this study, we evaluated the effect of Y-320 on CIA in mice and monkeys. Furthermore, we analyzed the mRNA expression levels of inflammatory cytokines including IL-17 in arthritic joints of mouse CIA.
METHODS: Mouse CIA was induced by immunization with bovine type II collagen (CII) and Freund's complete adjuvant (FCA) to DBA/1J mice, followed by boost immunization after 21 days. The mRNA expression of cytokines including IL-17 in arthritis joints of mouse CIA was analyzed by real-time RT-PCR. Monkey CIA was induced by immunization with bovine CII and FCA to cynomolgus monkeys, followed by boost immunization after three and six weeks and CIA-established monkeys were selected and used for the experiment.
RESULTS: In mouse CIA, prophylactic treatment of Y-320 at an oral dose of 0.3 mg/kg or higher significantly inhibited elevation of arthritis score, increase in total paw thickness, joint destruction, and production of anti-CII antibodies in a dose-dependent manner. When Y-320 at doses of 0.3 to 3 mg/kg was administered therapeutically, the progression of arthritis and joint destruction was inhibited significantly and dose-dependently. Y-320 at 0.3 mg/kg in combination with anti-mouse TNF-α mAb 50 μg/mouse intravenously resulted in a synergistic effect on mouse CIA. The elevated mRNA expression of IL-17 in arthritic joints of CIA mice was significantly lower by treatment with Y-320, suggesting inhibition of IL-17 production by Y-320 in vivo. In monkey CIA, therapeutic treatment with Y-320 at oral doses of 0.3 and 1 mg/kg resulted in a significant decreased in the areas of the swelled joint in a dose-dependent manner. Particularly, treatment with Y-320 at 1 mg/kg showed a marked improvement on CIA and the improving effect was maintained for more than 4 weeks, even after withdrawal of Y-320, suggesting no exacerbation of CIA.
CONCLUSION: Treatment with an orally active compound, Y-320 resulted in an ameliorating effect on mouse and monkey CIA and its therapeutic effect appeared to be mediated by inhibiting IL-17 production in vivo. From these results, it is expected that a new pyrazole-anilide derivative, Y-320, become a useful anti-rheumatic drug with new mechanisms of actions.

 N. Sato, None; K. Oshita, None; H. Kataoka, None; N. Seki, None; K. Shimano, None; K. Sugahara, None; K. Chiba, None.