Scientific research on development of anti-fibrotic agent targeting multi-organ profibrotic factor IL-26 in GVHD

• Project/Area Number: 18H02782
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Juntendo University
• Principal Investigator: Kei Ohnuma 順天堂大学, 医学(系)研究科(研究院), 准教授 (10396872)
• Co-Investigator(Kenkyū-buntansha): 森本 幾夫 順天堂大学, 医学(系)研究科(研究院), 特任教授 (30119028) ; 岩田 哲史 順天堂大学, 医学(系)研究科(研究院), 非常勤講師 (00396871) ; 岩尾 憲明 順天堂大学, 医学部, 准教授 (00309139)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: IL-26 / 慢性GVHD / 線維化 / 造血幹細胞移植 / 肺線維症 / GVHD / 臓器線維症

Outline of Final Research Achievements

There are increasing more and more numbers of patients with chronic inflammation-related organ fibrosis disorders including diabetic nephropathy, arteriolosclerosis, age-related nephrosclerosis, and chronic obstructive pulmonary diseases. Control of systemic fibrosis is also indispensable in realization of regenerative medicine. Moreover, treatment of organ fibrosis is an important target for extension of healthy life expectancy of the people by preventing deterioration of lifestyle-related diseases and rare intractable immune disorders. In this study, we identified the key mechanisms of organ fibrosis by means of IL-26, a unique cytokine in human, which have been overlooked in murine models. We obtained the promising results in developing a novel antifibrotic agent against intractable organ fibrosis. Our results on a new antifibrotic treatment also possibley provide a proper condition for organ regeneration such as iPS cell-based regenerative therapy.

Academic Significance and Societal Importance of the Research Achievements

臓器の線維化は、慢性炎症や加齢による組織の老化と密接な関連があり、臓器線維症は今後益々増加する疾患である。現在、特発性肺線維症に対する抗線維化薬としてピルフェニドンとニンテダニブが薬事承認を受けている。しかし、消化管・皮膚障害、血栓症等の重篤な副作用が出現する。一方、本研究の標的分子IL-26は、線維化カスケードループの最上流に位置するエフェクタ分子という点で画期的な抗線維化薬の創薬シーズであり、われわれは、治療困難であった臓器線維症の独創的な創薬に繋がる成果を得た。国民の健康寿命の延伸と健康格差の縮小に貢献し、またiPS細胞等の再生医療に対しても適切な臓器再生の場を提供することができる。

Research Products

• [Int'l Joint Research] University of Florida/Vanderbilt University(米国)
• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] University of Florida/Vanderbilt University(米国)
• [Journal Article] CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions (2021)
  • Author(s): Pan Kelsey、Ohnuma Kei、Morimoto Chikao、Dang Nam H
  • Journal Title: Cureus Volume: 13
  • DOI: 10.7759/cureus.13495
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum soluble CD26/DPP4 titer variation is a potential prognostic biomarker in cancer therapy with a humanized anti-CD26 antibody. (2021)
  • Author(s): Kaneko Y, Hatano R, Hirota N, Isambert N, Trillet-Lenoir V, You B, Alexandre J, Zalcman G, Valleix F, Podoll T, Umezawa Y, Takao S, Iwata S, Hosono O, Taguchi T, Yamada T, Dang NH, Ohnuma K, Angevin E, Morimoto C.
  • Journal Title: Biomark Res Volume: 9 Issue: 1 Pages: 21-21
  • DOI: 10.1186/s40364-021-00273-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of novel monoclonal antibodies with specific binding affinity for denatured human CD26 in formalin-fixed paraffin-embedded and decalcified specimens (2019)
  • Author(s): Hatano R, Yamada T, Madokoro H, Otsuka H, Komiya E, Itoh T, Narita Y, Iwata S, Yamazaki H, Matsuoka S, Dang NH, Morimoto C
  • Journal Title: PLoS ONE Volume: 14 Issue: 6 Pages: e0218330-e0218330
  • DOI: 10.1371/journal.pone.0218330
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biological effects of IL-26 on T cell-mediated skin inflammation, including psoriasis. (2019)
  • Author(s): Itoh T, Hatano R, Komiya E, Otsuka H, Narita Y, Aune TM, Dang NH, Matsuoka S, Naito H, Tominaga M, Takamori K, Morimoto C, Ohnuma K.
  • Journal Title: J Invest Dermatol Volume: 139 Issue: 4 Pages: 878-889
  • DOI: 10.1016/j.jid.2018.09.037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rheumatic diseases associated with immune checkpoint inhibitors in cancer immunotherapy. (2019)
  • Author(s): Ohnuma K, Hatano R, Dang NH, Morimoto C.
  • Journal Title: Modern Rheumatology Volume: 29 Pages: 721-732
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of novel anti-IL-26 neutralizing monoclonal antibodies for the treatment of inflammatory diseases including psoriasis. (2019)
  • Author(s): Hatano R, Itoh T, Otsuka H, Okamoto S, Komiya E, Iwata S, Aune TM, Dang NH, Kuwahara-Arai K, Ohnuma K, Morimoto C.
  • Journal Title: MAbs Volume: 11 Pages: 1428-1442
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DPP8 is a novel therapeutic target for multiple myeloma. (2019)
  • Author(s): Sato T, Tatekoshi A, Takada K, Iyama S, Kamihara Y, Jawaid P, Rehman MU, Noguchi K, Kondo T, Kajikawa S, Arita K, Wada A, Murakami J, Arai M, Yasuda I, Dang NH, Hatano R, Iwao N, Ohnuma K, Morimoto C.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 18094-18094
  • DOI: 10.1038/s41598-019-54695-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Caveolin-1, a binding protein of CD26, is essential for the anti-inflammatory effects of dipeptidyl peptidase-4 inhibitors on human and mouse macrophages (2018)
  • Author(s): Hiromura Munenori、Nohtomi Kyoko、Mori Yusaku、Kataoka Hideo、Sugano Marika、Ohnuma Kei、Kuwata Hirotaka、Hirano Tsutomu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 1 Pages: 223-229
  • DOI: 10.1016/j.bbrc.2017.11.016
  • Peer Reviewed / Open Access
• [Journal Article] A novel role for CD26/dipeptidyl peptidase IV as a therapeutic target (2018)
  • Author(s): Ohnuma K, Hatano R, Komiya E, Otsuka H, Itoh T, Iwao N, Kaneko Y, Yamada T, Dang NH, Morimoto C.
  • Journal Title: Front Biosci Volume: 23 Issue: 9 Pages: 1754-1779
  • DOI: 10.2741/4671
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeting CD26 suppresses proliferation of malignant mesothelioma cell via downmodulation of ubiquitin-specific protease 22. (2018)
  • Author(s): Okamoto T, Yamazaki H, Hatano R, Yamada T, Kaneko Y, Xu CW, Dang NH, Ohnuma K, Morimoto C.
  • Journal Title: Biochem Biophys Res Commun Volume: 504 Issue: 2 Pages: 491-498
  • DOI: 10.1016/j.bbrc.2018.08.193
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 9.Endomorphin preferentially induces mechanical alloknesis under the control of DPPIV enzyme (2020)
  • Author(s): Eriko Komiya, Ryo Hatano, Takumi Itoh, Kotaro Honda, Yayoi Kamata, Sumika Toyama, Catharina Sagita Moniaga, Haruna Otsuka, Nobuaki Takahashi, Kei Ohnuma, Mitsutoshi Tominaga, Chikao Morimoto, Kenji Takamori
  • Organizer: The 45th Annual Meeting of the Japanese Society for Investigative Dermatology
• [Presentation] Interleukin-26-targeted therapy for the control of chronic GVHD (2018)
  • Author(s): Hating R, Otsuka H, Komiya E, Itoh T, Iwao I, Yamada T, Morimoto C, Ohnuma K.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 全身性エリテマトーデスのステロイド減量困難例における CD26陰性T細胞サブセットの増加について (2018)
  • Author(s): 波多野 良, 大沼 圭, 石井 智徳, 伊藤 匠, 岩田 哲史, 奥村 康, 関川 巖, 森本 幾夫
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] 難治性自己免疫疾患における新規炎症性サイトカインIL-26の役割と分子標的療法の開発 (2018)
  • Author(s): 伊藤 匠, 波多野 良, 大沼 圭, 岩田 哲史, 奥村 康, 森本 幾夫
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Book] Regulation of proliferation of malignant mesothelioma cells by CD26-cyclophilin A molecular complex. In: Advanced in Medicine and Biology. (2019)
  • Author(s): Okamoto T, Hatano R, Nakano K, Yamada T, Yamazaki H, Kaneko Y, Dang NH, Morimoto C, Ohnuma K.
  • Total Pages: 283
  • Publisher: Nova Science Publishers, Inc.
  • ISBN: 9781536166903
• [Book] THE USE OF THE HUMANIZED ANTI-CD26 MONOCLONAL ANTIBODY YS110 AS A NOVEL TARGETED THERAPY FOR REFRACTORY CANCERS AND IMMUNE DISORDERS (2018)
  • Author(s): Hating R, Ohnuma K, Yamada T, Okamoto T, Kaneko Y, Dang NH, Morimoto C.
  • Total Pages: 272
  • Publisher: Nova Scientific Publishers
  • ISBN: 9781536133486
• [Remarks] 順天堂大学大学院 免疫病・がん先端治療学講座
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/immunity_cancer/
• [Remarks] 順天堂大学大学院医学研究科 免疫病・がん先端治療学講座
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/immunity_cancer/
• [Patent(Industrial Property Rights)] 抗癌剤への抵抗性改善剤 (2020)
  • Inventor(s): 森本幾夫、大沼圭、伊藤匠、波多野良、金子有太郎
  • Industrial Property Rights Holder: ワイズ・エー・シー株式会社、学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-099449
  • Filing Date: 2020
  • Overseas
• [Patent(Industrial Property Rights)] 免疫チェックポイント阻害剤 (2019)
  • Inventor(s): 大沼圭、森本幾夫、波多野良
  • Industrial Property Rights Holder: 大沼圭、森本幾夫、波多野良
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-004480
  • Filing Date: 2019