Functional Analysis of TAS-115, a Second Generation Antifibrotic Tyrosine Kinase Inhibitor, and its Clinical Application

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17183
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: The University of Tokushima
• Principal Investigator: KOYAMA Kazuya 徳島大学, 病院, 特任助教 (90724089)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 肺線維症 / マクロファージ / TAS-115 / ニンテダニブ

Outline of Final Research Achievements

We evaluated the effect of new anti-fibrotic drug, TAS-115, in silica induced pulmonary fibrosis murine model, particularly focusing on its suppressive effect on profibrotic macrophages. Administration of TAS-115 decreased the number of CD11b+CD11c+ macrophages expressing profibrotic genes in silica induced pulmonary fibrosis murine model unlike nintedanib. However, TAS-115 treatment resulted in worsening of pulmonary fibrosis, although this was not statistically significant. These findings suggest that the mechanism of fibrosis differs in different fibrosis murine models and that inhibition of profibrotic macrophage function may lead to worsened fibrosis in some pathological conditions.

Free Research Field

呼吸器内科学

Academic Significance and Societal Importance of the Research Achievements

TAS-115は第Ⅱ相試験にてニンテダニブを含む既存の抗線維化薬治療下で肺線維化進行例において有効性を示した。そのため本検討はTAS-115のニンテダニブよりも強いc-FMSリン酸化抑制作用に着目しシリカ肺線維症モデルにおけるマクロファージ活性抑制からその抗線維化作用を検討した。TAS-115はシリカ誘発性肺線維症モデルにおいて線維化に関連すると考えられるマクロファージの増加を抑制したが、肺線維症を改善しなかった。このことから肺の線維化が病態により多彩な機序を有していること、必ずしも線維化に関わるマクロファージの抑制が病的な線維化につながるわけではないことが示唆された。