Development of a novel therapy for refractory inflammatory diseases targeting an inflammatory cytokine IL-26

• Project/Area Number: 17K10008
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Juntendo University
• Principal Investigator: Hatano Ryo 順天堂大学, 医学(系)研究科(研究院), 特任助教 (30638789)
• Co-Investigator(Kenkyū-buntansha): 岩田 哲史 順天堂大学, 医学(系)研究科(研究院), 非常勤講師 (00396871)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: IL-26 / 中和抗体 / 乾癬 / 血管新生 / 慢性炎症疾患 / 分子標的療法 / 炎症性サイトカイン / 炎症性腸疾患 / 自己免疫疾患 / 慢性GVHD / CD26共刺激 / 慢性炎症 / Th17 / CD26

Outline of Final Research Achievements

Due to the deficiency of the gene encoding IL-26 in mice, the precise functions and identification of target cells of IL-26 in inflammatory disorders remain to be elucidated. From these reasons, our group has developed human IL-26 transgenic (hIL-26Tg) mice. In the present study, we found that vascularization and immune cell infiltration were dramatically enhanced in hIL-26Tg mice in the imiquimod-induced psoriasis-like murine model. Moreover, we have shown that IL-26 directly acts on vascular endothelial cells to promote proliferation and tube formation at a similar level as VEGF.In addition, we have succeeded in developing novel neutralizing anti-human IL-26 monoclonal antibodies (mAbs) which can inhibit the biological functions of IL-26.
Our newly developed anti-human IL-26 mAb is a potential therapeutic agent for the treatment of diverse chronic inflammatory diseases including psoriasis, inflammatory bowel diseases, chronic graft-versus-host disease, lung fibrosis and so on.

Academic Significance and Societal Importance of the Research Achievements

申請者らはCD26分子を介したヒトT細胞の活性化が、炎症性サイトカインIL-26の産生に極めて重要であることを明らかにした。IL-26は多様な機能が報告されているが、マウスやラットに欠損した遺伝子であることもあり、炎症病態における役割について解明されていない点が多い。申請者グループは、炎症環境下でヒトIL-26の発現が誘導されるヒトIL-26トランスジェニックマウスを開発し、炎症病態におけるIL-26の新たな機能の解明に取り組むとともに、IL-26の中和モノクローナル抗体の樹立にも成功した。これらのツールを用いて、難治性の慢性炎症疾患に対する革新的なIL-26分子標的療法の確立を進めていく。

Research Products

• [Int'l Joint Research] University of Oxford(英国)
• [Journal Article] Single-cell atlas of colonic CD8+ T-cells in inflammatory bowel disease. (2020)
  • Author(s): Corridoni D, Antanaviciute A, Gupta T, Fawkner-Corbett D, Aulicino A, Jagielowicz M, Parikh K, Repapi E, Taylor S, Ishikawa D, Hatano R, Yamada T, Xin W, Slawinki H, Bowden R, Napolitani G, Brain O, Morimoto C, Koohy H, Simmons A.
  • Journal Title: Nat Med Volume: in press
  • 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] 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 Issue: 8 Pages: 1428-1442
  • DOI: 10.1080/19420862.2019.1654305
  • 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] GVHDの発症と慢性炎症. (2019)
  • Author(s): 岩尾憲明、大沼圭、波多野良、大塚春奈、古宮栄利子、伊藤匠、森本幾夫.
  • Journal Title: BIO Clinica Volume: 8 Pages: 128-133
  • Peer Reviewed
• [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: Mod Rheumatol Volume: 印刷中 Issue: 5 Pages: 721-732
  • DOI: 10.1080/14397595.2018.1532559
  • 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
• [Journal Article] 抗CD26抗体(anti-CD26 monoclonal antibody). (2018)
  • Author(s): 大沼圭、波多野良、森本幾夫.
  • Journal Title: 腫瘍内科 Volume: 22 Pages: 190-197
  • Peer Reviewed
• [Journal Article] Establishment of intestinal epithelial cell line derived from fetal mouse colon and its immune-related characteristics - Comparison with mouse small intestinal epithelial cell line -. (2018)
  • Author(s): Iwamoto T, Totsuka M, Yamada K, Emoto T, Hatano R, Shimizu M.
  • Journal Title: Cytotechnology Volume: in press
  • Peer Reviewed
• [Journal Article] A novel role for CD26/dipeptidyl peptidase IV as a therapeutic target in selected immune disorders and cancers. (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: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A possible role for CD26/DPPIV enzyme activity in the regulation of psoriatic pruritus (2017)
  • Author(s): Komiya, E. Hatano, R. Otsuka, H. Itoh, T. Yamazaki, H. Yamada, T. Dang, N. H. Tominaga, M. Suga, Y. Kimura, U. Takamori, K. Morimoto, C. Ohnuma, K.
  • Journal Title: J Dermatol Sci Volume: 印刷中 Issue: 3 Pages: 212-221
  • DOI: 10.1016/j.jdermsci.2017.03.005
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Possible regulation of mechanical itch by CD26/DPPIV. (2019)
  • Author(s): Komiya E, Hatano R, Itoh T, Otsuka H, Kamata Y, Honda K, Toyama S, Moniaga CS, Ohnuma K, Tominaga M, Morimoto C, Takamori K.
  • Organizer: 10th World Congress on Itch (WCI), Sydney, Australia
  • Int'l Joint Research
• [Presentation] Possible role for CD26/DPPIV in regulating mechanical itch (Alloknesis). (2019)
  • Author(s): Komiya E, Hatano R, Itoh T, Otsuka H, Kamata Y, Honda K, Toyama S, Moniaga CS, Ohnuma K, Tominaga M, Morimoto C, Takamori K.
  • Organizer: 28th European Academy of Dermatology and Venereology (EADV) Congress, Madrid, Spain
  • Int'l Joint Research
• [Presentation] CD26/dipeptidyl-peptidase IVは機械的かゆみの抑制因子である. (2019)
  • Author(s): 古宮栄利子, 波多野良, 冨永光俊, 伊藤匠, 鎌田弥生, 本田耕太郎, 外山扇雅, カタリナサギタモニアガ, 大沼圭, 森本幾夫, 高森建二.
  • Organizer: 第24回 日本病態プロテアーゼ学会, 岐阜
• [Presentation] CD26/DPPIV regulates mechanical itch by enzymatic degradation of mu-opioid receptor ligands. (2019)
  • Author(s): Komiya E, Hatano R, Itoh T, Otsuka H, Ohnuma K, Tominaga M, Morimoto C, Takamori K.
  • Organizer: 24th World Congress of Dermatology (WCD), Milan, Italy
  • Int'l Joint Research
• [Presentation] 加齢皮膚で誘発される機械的かゆみ調節機構の解明. (2019)
  • Author(s): 古宮栄利子、冨永光俊、波多野良、伊藤匠、大塚春奈、本田耕太郎、外山扇雅、鎌田弥生、大沼圭、森本幾夫、高森建二.
  • Organizer: 第15回加齢皮膚医学研究会、くまもと森都心プラザ(熊本県熊本市)
• [Presentation] 機械的かゆみの調節メカニズムの解明. (2018)
  • Author(s): 古宮栄利子、波多野良、大塚春奈、伊藤匠、松田浩則、須賀康、大沼圭、冨永光俊、森本幾夫、高森建二.
  • Organizer: 第82回日本皮膚科学会東京支部、ザ・プリンスパークタワー東京(東京都港区)
• [Presentation] Interleukin-26-targeted therapy for the control of chronic GVHD. (2018)
  • Author(s): Ryo Hatano, Haruna Otsuka, Eriko Komiya, Takumi Itoh, Noriaki Iwao, Taketo Yamada, Chikao Morimoto, Kei Ohnuma.
  • Organizer: 第80回日本血液学会、大阪国際会議場(大阪府大阪市)
• [Presentation] CD26/DPPIVはエンドモルフィンによる機械的かゆみを制御する. (2018)
  • Author(s): 古宮栄利子、波多野良、伊藤匠、松田浩則、大沼圭、森本幾夫、冨永光俊、高森建二.
  • Organizer: 第28回国際痒みシンポジウム、経団連会館カンファレンス(東京都千代田区)
  • Invited
• [Presentation] CD26分子はDPPIV酵素活性によって乾癬のかゆみを調節する. (2018)
  • Author(s): 古宮栄利子、波多野良、大塚春奈、伊藤匠、大沼圭、森本幾夫、冨永光俊、高森建二.
  • Organizer: 第33回日本乾癬学会、松山全日空ホテル(愛媛県松山市)
• [Presentation] 乾癬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、古宮栄利子、大塚春奈、冨永光俊、高森建二、森本幾夫、大沼圭.
  • Organizer: 第33回日本乾癬学会、松山全日空ホテル(愛媛県松山市)
• [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、岩田哲史、大沼圭、森本幾夫.
  • Organizer: 第62回日本リウマチ学会、東京国際フォーラム(東京都千代田区)
• [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、東京国際フォーラム(東京都千代田区)
• [Presentation] 急性GVHDマウスモデルにおけるHMGB1の動態に関する検討. (2018)
  • Author(s): 岩尾憲明、大沼圭、大塚春奈、波多野良、古宮栄利子、伊藤匠、森本幾夫.
  • Organizer: 第40回日本造血細胞移植学会、札幌市教育文化会館(北海道札幌市)
• [Presentation] CD26/DPPIV regulates mechanical itch in a mechanistically distinct manner from chemical itch. (2017)
  • Author(s): Eriko Komiya, Ryo Hatano, Haruna Otsuka, Takumi Itoh, Hiroto Yamazaki, Mitsutoshi Tominaga, Kenji Takamori, Kei Ohnuma, Chikao Morimoto.
  • Organizer: 第42回日本研究皮膚科学会、高知市文化プラザかるぽーと(高知県高知市)
• [Presentation] IL-26 facilitates angiogenesis and skin inflammation via inducing FGF2 production in a murine model of imiquimod-induced psoriasis. (2017)
  • Author(s): Takumi Itoh, Ryo Hatano, Haruna Otsuka, Noriaki Iwao, Satoshi Iwata, Taketo Yamada, Chikao Morimoto.
  • Organizer: 第46回日本免疫学会、仙台国際センター(宮城県仙台市)
• [Presentation] The regulation of pruritus in psoriasis and atopic dermatitis -a possible role for CD26/DPPIV. (2017)
  • Author(s): Eriko Komiya, Ryo Hatano, Haruna Otsuka, Takumi Itoh, Hiroto Yamazaki, Taketo Yamada, Yasushi Suga, Utako Kimura, Mitsutoshi Tominaga, Kenji Takamori, Kei Ohnuma, Chikao Morimoto.
  • Organizer: 9th World Congress on Itch, Novotel Centrum, Wroclaw, Poland
  • Int'l Joint Research
• [Presentation] 全身性エリテマトーデスのステロイド治療抵抗性とCD26陰性T細胞サブセットとの関係性について. (2017)
  • Author(s): 波多野良、大沼圭、石井智徳、岩田哲史、奥村康、関川巖、森本幾夫.
  • Organizer: 第61回日本リウマチ学会、福岡国際会議場(福岡県福岡市)
• [Book] Advances 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: 21
  • Publisher: Nova Science Publishers, Inc., Hauppauge, NY
• [Book] Advances in Medicine and Biology (2018)
  • Author(s): Hatano R, Ohnuma K, Yamada T, Okamoto T, Komiya E, Otsuka H, Itoh T, Yamazaki H, Iwao N, Kaneko Y, Dang NH, Morimoto C.
  • Total Pages: 44
  • Publisher: Nova Science Publishers, Inc., Hauppauge, NY
• [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ホームページ
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/immunity_cancer/
• [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: 学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-004480
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] 抗ヒトCD26モノクローナル抗体. (2018)
  • Inventor(s): 森本幾夫、波多野良、山田健人、大沼圭.
  • Industrial Property Rights Holder: 学校法人順天堂、学校法人埼玉医科大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-049308
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] 抗ヒトIL-26抗体. (2017)
  • Inventor(s): 森本幾夫、波多野良、大沼圭、伊藤匠.
  • Industrial Property Rights Holder: 学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-231439
  • Filing Date: 2017
• [Patent(Industrial Property Rights)] 抗CD10抗体. (2017)
  • Inventor(s): 水谷奈津子、阿部雅明、松岡周二、樋野興夫、大辻奈穂美、波多野良.
  • Industrial Property Rights Holder: 学校法人順天堂、日本抗体医薬株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017