Novel therapy against human cancers using intra-nuclear transportable humanized monoclonal antibody against CD26.

• Project/Area Number: 16H04714
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Saitama Medical University
• Principal Investigator: YAMADA TAKETO 埼玉医科大学, 医学部, 教授 (60230463)
• Co-Investigator(Kenkyū-buntansha): 林 睦 慶應義塾大学, 医学部(信濃町), 助教 (60327575) ; 西田 浩子 慶應義塾大学, 医学部(信濃町), 助教 (80317130)
• Research Collaborator: YAMADA koji
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2016: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 抗体療法 / Antibody-Drug Conjugate / CD26 / 核移行 / RNAポリメラーゼII / 抗体薬物複合体 / RNAポリメラーゼⅡ

Outline of Final Research Achievements

We developed a novel Antibody-Drug Conjugate (ADC), Y-TR-1, with the humanized anti-CD26 monoclonal antibody YS110 and triptolide (TR-1), an inhibitor for TFIIH (a general transcription factors for RNA polymerase II (Pol II)). YS110 has an inhibitory activity against CD26-positive tumor growth via immunological and direct pathway, such as an induction of intra-nuclear transportation of CD26 and YS110, and a suppressed transcription of Pol II subunit POLR2A by nuclear CD26. Y-TR1 showed significant cytotoxicity against CD26-positive cell lines but not CD26-negative cell lines in a dose-dependent manner via significant suppression of mRNA synthesis caused by impairment of RNA polymerase II activity. The tumors in xenografted mice administered Y-TR1 was smaller than that of mice treated with unconjugated YS110 without severe toxicity. In conclusion, the novel compound Y-TR1 showed antitumor properties against CD26-positive cancer cell lines both in vitro and in vivo without toxicity.

Academic Significance and Societal Importance of the Research Achievements

がんの分子標的療法では、少ない副作用で高い抗がん効果を発揮することが期待される。本研究では、がん細胞核内へ移行可能なヒト化抗体に、これまで毒性が強く使用不可であった抗がん剤を結合させた抗体-薬剤複合体の合成に成功した。がんには多様性があり薬剤耐性や治療抵抗性の原因と考えられているが、本分子は、複数の抗がん分子機構を介して効果を発揮するため、薬剤耐性や治療抵抗性を乗り越える抗腫瘍効果が期待できる。

Research Products

• [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] A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress. (2018)
  • Author(s): 1.Okayama M, Kitabatake S, Sato M, Fujimori K, Ichikawa D, Matsushita M, Suto Y, Iwasaki G, Yamada T, Kiuchi F, Hirao M, Kunieda H, Osada M, Okamoto S, Hattori Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 505 Issue: 3 Pages: 787-793
  • DOI: 10.1016/j.bbrc.2018.09.177
  • Peer Reviewed / Open Access
• [Journal Article] A NOVEL ROLE OF CD26/DIPEPTIDYL PEPTIDASE IV IN THERAPEUTIC TARGET ON IMMUNE DISORDERS AND CANCERS. (2018)
  • Author(s): Ohnuma K, Hatano R, Komiya E, Ito T, Iwao N, Kaneko Y, Yamada T, Dang NH, Morimoto C.
  • Journal Title: Frontiers in Bioscience Volume: 23 Pages: 1754-1779
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CD26 is a potential therapeutic target by humanized monoclonal antibody for the treatment of multiple myeloma (2018)
  • Author(s): Hiroko Nishida, Mutsumi Hayashi, Chikao Morimoto, Michiie Sakamoto, Taketo Yamada
  • Journal Title: Blood Cancer Journal Volume: 8(99) Issue: 11 Pages: 1-17
  • DOI: 10.1038/s41408-018-0127-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Necrotizing enterocolitis caused by Clostridium butyricum in a Japanese man. (2018)
  • Author(s): Sato Y, Kujirai D, Emoto K, Yagami T, Yamada T, Izumi M, Ano M, Kase K, Kobayashi K.
  • Journal Title: Acute Medical Surgery Volume: 5 Issue: 2 Pages: 194-198
  • DOI: 10.1002/ams2.329
  • Peer Reviewed / Open Access
• [Journal Article] Signaling between pancreatic beta-cells and macrophages via S100 calcium-binding protein A8 exacerbates beta-cell apoptosis and islet inflammation. (2018)
  • Author(s): Inoue H, Shirakawa J, Togashi Y, Tajima K, Okuyama T, Kyohara M, Tanaka Y, Saisho Y, Yamada T, Shibue K, Kulkarni RN, Terauchi Y
  • Journal Title: The Journal of Biological Chemistry Volume: 293 Issue: 16 Pages: 5934-5946
  • DOI: 10.1074/jbc.m117.809228
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest. (2017)
  • Author(s): Aida S, Hozumi M, Ichikawa D, Iida K, Yonemura Y, Tabata N, Yamada T, Matsushita M, Sugai T, Yanagawa H, Hattori Y
  • Journal Title: Biochem. Biophysic. Res. Commun. Volume: 493 Issue: 1 Pages: 514-520
  • DOI: 10.1016/j.bbrc.2017.08.159
  • Peer Reviewed / Open Access
• [Journal Article] Pancreas fat and beta cell mass in humans with and without diabetes: An analysis in the Japanese population. (2017)
  • Author(s): Murakami R, Saisho Y, Watanabe Y, Inaishi J, Tsuchiya T, Kou K, Sato S, Kitago M, Kitagawa Y, Yamada T, Itoh H.
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 102 Issue: 9 Pages: 3251-3260
  • DOI: 10.1210/jc.2017-00828
  • Peer Reviewed
• [Journal Article] First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers (2017)
  • Author(s): Angevin, E. Isambert, N. Trillet-Lenoir, V. You, B. Alexandre, J. Zalcman, G. Vielh, P. Farace, F. Valleix, F. Podoll, T. Kuramochi, Y. Miyashita, I. Hosono, O. Dang, N. H. Ohnuma, K. Yamada, T. Kaneko, Y. Morimoto, C.
  • Journal Title: Br J Cancer Volume: 印刷中 Issue: 9 Pages: 1-9
  • DOI: 10.1038/bjc.2017.62
  • Peer Reviewed / Open Access / 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
• [Journal Article] A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition. (2016)
  • Author(s): Hayashi M, Madokoro H, Yamada K, Nishida H, Morimoto C, Sakamoto M, Yamada T.
  • Journal Title: Cancer Cell International Volume: 30 Issue: 1 Pages: 35-35
  • DOI: 10.1186/s12935-016-0310-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A novel komaroviquinone derivative, GTN024, induced apoptosis of high-risk myeloma cells in vivo via ROS production and ER stress (2018)
  • Author(s): Okayama M, Shotaro Kitabatake S, Sato M, Fujimori K, Samata K, Ichikawa D, Matsushita M, Suto Y, Iwasaki G, Yamada T, Kiuchi F, Hirao M, Kunieda H, Osada M, Okamoto S, Hattori Y
  • Organizer: 2018 American Society of Hematology Annual Meeting in San Diego
  • Int'l Joint Research
• [Presentation] Anti-CD26 Humanized Monoclonal Antibody Conjugated To Triptolide Inhibits Mesothelioma Cell Growth Via Transportation Into Nucleus And Impaired RNA Polymerase II. (2018)
  • Author(s): Yamada T, Madokoro H, Yamada K, Nishida H, Morimoto C, Sakamoto M, Hayashi M.
  • Organizer: The 6th JCA-AACR Special Joint Conference, The Latest Advances in Lung Cancer Research: From Basic Science to Therapeutics
  • Int'l Joint Research
• [Presentation] Anti-CD26 humanized antibody-triptolide conjugate moves into nucleus and impairs RNA polymerase II. (2018)
  • Author(s): Yamada T, Madokoro H, Yamada K, Nishida H, Morimoto C, Sakamoto M, Hayashi M.
  • Organizer: 第107回日本病理学会総会
• [Presentation] Interleukin-26-targeted therapy for the control of chronic GVHD IL-26を分子標的とした慢性GVHDの治療 (2018)
  • Author(s): Hatano R, Komiya E, Ito T, Iwao N, Kaneko Y, Yamada T, Dang NH, Morimoto C, Oinuma K
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] PEG(E)-TC11, a novel polyethylene glycol-linked phthalimide derivative, inhibited high-risk MM cell growth in vivo and in vitro via cell cycle G2/M arrest in a CRBN-independent manner. (2017)
  • Author(s): Aida S, Ichikawa D, Iida K, Hozumi M, Nakamura M, Uozaki R, Hashimoto N, Okayama M, Yonemura Y, Tabata N, Yamada T, Matsushita M, Sugai T, Yanagawa H, Hattori Y
  • Organizer: American Association for Cancer Research (AACR) Annual Meeting (Washington D.C., USA)
  • Int'l Joint Research
• [Presentation] Anti-tumor effects of humanized anti-CD26 monoclonal antibody against hepatocellular carcinoma. (2017)
  • Author(s): Yamada T, Madokoro H, Yamada K, Nishida H, Morimoto C, Sakamoto M, Hayashi M.
  • Organizer: 第106回日本病理学会総会（東京）
• [Presentation] Humanized anti-CD26 monoclonal antibody has a therapeutic potentiality against multiple myeloma. (2017)
  • Author(s): Nishida H, Hayashi M, Morimoto C, Sakamoto M, Yamada T.
  • Organizer: 第79回日本血液学会総会（東京）
• [Presentation] The regulation of pruritus in psoriasis and atopic dermatitis-a possible role for CD26/DPPIV (2017)
  • Author(s): Komiya-Suyama E, Hatano R, Ostuka H, Itoh T, Yamazaki H, Suga Y, Kimura U, Yamada T, Tominaga M, Takamori K, Ohnuma K, Morimoto C
  • Organizer: 9th World Congress on Itch (Wroclaw, Poland)
  • Int'l Joint Research
• [Presentation] Anti-CD26 humanized monoclonal antibody conjugated to triptolide is transported into nucleus and impairs RNA polymerase II. (2017)
  • Author(s): Yamada T, Madokoro H, Nishida H,Morimoto C,Sakamoto M, Hayashi M.
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）（神戸）
• [Presentation] IL-26 facilitates angiogenesis and skin inammation via inducing FGF2 production in a murine model of imiquimod-induced psoriasis. (2017)
  • Author(s): Itoh T, Hatano R, Otsuka H, Iwao N, Iwata S, Yamada T , Morimoto C.
  • Organizer: The 46th Japanese Society for Immunology（仙台）
• [Presentation] Humanized anti-CD26 monoclonal antibody, YS110, has anti-myeloma efficacy for the treatment of high-risk multiple myeloma (2017)
  • Author(s): Nishida H, Hayashi M, Morimoto C, Sakamoto M, Yamada T.
  • Organizer: the 59th American Society of Hematology Annual Meeting and Exposition. (Atlanta, USA)
  • Int'l Joint Research
• [Presentation] CD26/DPPIV-mediated regulation of pruritus in psoriasis. (2016)
  • Author(s): Eriko Komiya, Ryo Hatano, Haruna Otsuka, Takumi Itoh, Taketo Yamada, Mitsutoshi Tominaga, Lenji Takamori, Kei Okumura, Chikao Morimoto
  • Organizer: the 41st Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-12-09
• [Presentation] 乾癬においてCD26/DPPIVはsubstance Pの切断を促進してかゆみを調節する (2016)
  • Author(s): 古宮栄利子、波多野良、大塚春奈、伊藤匠、山田健人、富永光俊、高森建二、大沼圭、森本幾夫
  • Organizer: 第31回日本乾癬学会学術大会
  • Place of Presentation: ホテル東日本宇都宮
  • Year and Date: 2016-09-02
• [Presentation] Humanized anti-CD26 antibody conjugated with RNA polymerase II inhibitor Triptolide suppresses tumor (2016)
  • Author(s): 林 睦、間所裕子、山田幸司、西田浩子、坂元亨宇、森本幾夫、山田健人
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-05-12
• [Book] 抗体薬物複合体(ADC)の設計開発 ファインケミカルシリーズ 監修： 松村保広 (2016)
  • Author(s): 山田健人
  • Total Pages: 194
  • Publisher: シーエムシー出版