肺線維症に対する抗線維化薬開発：がんと線維化肺の接点を捉えたトランスレーショナルリサーチ

Development of antifibrotic drugs against pulmonary fibrosis：translational research focusing on the interface between cancer and fibrotic lungs

抄録

　特発性肺線維症（idiopathic pulmonary fibrosis：IPF）は，特発性間質性肺炎の50～60％を占め，5年生存率が30～50％と予後不良の慢性進行性肺疾患である．標準的治療薬がなく，その開発が大きな課題となってきた．2000年代初頭からIPFの基本病態を「慢性炎症」ではなく「肺胞上皮傷害に続く異常修復」からの線維化と捉える新たな考え方を基盤に抗線維化薬の開発が進められてきた．我々は治療標的として増殖因子，特に血小板由来増殖因子（platelet-derived growth factor：PDGF）に着目し，ドラッグリポジショニングの観点からイマチニブをはじめとした複数のがん分子標的治療薬の肺線維症治療薬として可能性を見出した．さらに肺線維症治療薬として望ましいキナーゼ阻害プロファイルを確立し，産学連携の推進により高いPDGF受容体阻害作用を持つ新規抗線維化薬TAS-115を見出した．IPF患者を対象とした早期臨床試験において治療効果が示唆され，本邦発の抗線維化薬開発を目指し後期臨床試験を進めている．一方，新たな治療標的として骨髄由来のコラーゲン産生細胞と定義される線維細胞（fibrocyte）に着目し，その実態解明と機能解析を進めてきた．その結果，fibrocyteは高い増殖因子産生能や細胞外小胞の放出によるパラクリン作用により線維芽細胞を活性化し肺線維化促進作用を示すことを報告し，肺線維症に対する治療標的としての可能性を示した．Fibrocyte標的治療の開発を目的に，線維化肺と腫瘍組織を用いてCD45陽性細胞の1細胞遺伝子発現解析（single-cell RNA sequencing：scRNA-seq）を行い，fibrocyte特異的マーカーを探索した．その結果，腫瘍内CD45陽性細胞のscRNA-seq解析からfibrocyte clusterの同定に成功し，標的分子を見出した．現在これらの標的分子に対する抗体医薬としての抗線維化薬開発に向けて基礎研究を進めている．基礎および臨床両面からの研究の推進による新規抗線維化薬の開発が期待される．

Abstract

　Idiopathic pulmonary fibrosis（IPF）is a chronic and progressive lung fibrotic disease belonging to idiopathic interstitial pneumonias. The 5-year survival of IPF is poor to be 30 to 50％, and therefore novel therapy has been required. From the 2000s, the concept of basic pathogenesis of IPF changed from chronic inflammation to chronic injury of alveolar epithelial cells and the subsequent aberrant repair. Based on the concept, the development of antifibrotic, not anti-inflammatory, drugs has been expected. We aimed a drug repositioning with molecular-targeting agents for cancer to develop antifibrotic therapy. We firstly focused on growth factors including platelet-derived growth factor（PDGF）as a therapeutic target, and demonstrated that imatinib showing the inhibitory effects of PDGF receptor（PDGFR）inhibited pulmonary fibrosis in mice. By an industry-academia collaboration, we found TAS-115 showing the strong inhibitory effect on PDGFR as a novel antifibrotic agents. The exploratory phase Ⅱa trial with TAS-115 against IPF patients showed the promising antifibrotic effects to reduce the decline of a forced vital capacity. The phase Ⅱb trial of TAS-115 is ongoing in Japan. To find out the novel target, we focused on the fibrocytes, which are recognized to be bone marrow-derived collagen-producing cells. We analyzed the profibrotic function of fibrocytes and found that fibrocytes had the paracrine effects to activate lung fibroblasts by producing of growth factor and releasing extracellular vesicles. To identify the specific marker for fibrocytes, we performed a single-cell RNA sequencing（scRNA-seq）of CD45^＋ cells in both tumor and fibrotic lung tissues in mouse models. From scRNA-seq of tumor-infiltrating CD45^＋ cells, we successfully identified fibrocyte clusters and found the specific marker of fibrocytes. We are developing the novel antifibrotic therapy targeting to fibrocytes with specific antibodies. We hope that our basic and clinical research will lead to develop novel antifibrotic drugs for patients with IPF.