Novel anti-cancer therapy against super-enhancer using humanized monoclonal antibody with transportation activity into nucleus
Project/Area Number |
19H03519
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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Research Institution | Saitama Medical University |
Principal Investigator |
YAMADA TAKETO 埼玉医科大学, 医学部, 教授 (60230463)
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Co-Investigator(Kenkyū-buntansha) |
林 睦 慶應義塾大学, 医学部(信濃町), 特任助教 (60327575)
西田 浩子 慶應義塾大学, 医学部(信濃町), 助教 (80317130)
山田 幸司 東京慈恵会医科大学, 医学部, 講師 (90570979)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
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Keywords | CD26 / がん / スーパーエンハンサー / 抗体 / 核移行 / 分子標的療法 / Antibody-Drug Conjugate / 抗体療法 / RNAポリメラーゼII / 抗体抗がん剤結合薬ADC |
Outline of Research at the Start |
ヒト化抗CD26モノクローナル抗体は、がん特異的にCD26を細胞膜から核内に移行させ、RNAポリメラーゼII(POL II)サブユニット(POLR2A)の転写抑制し増殖を阻害する。POL IIは、がん特異的スパーエンハンサー(SE)構成分子であるとともに、p53近傍のPOLR2A遺伝子がヘテロ欠失し、がん細胞がPOLR2A阻害剤に高感受性となる。本研究では、1)がん組織特異的SE形成へのPOL IIの関与の分子病理学的解析、2)がん組織検体におけるSE形成およびPOLR2A遺伝子欠失と相関するバイオマーカーの探索、3)本抗体とSE・POL II阻害分子結合による分子標的療法の開発、を行う。
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Outline of Final Research Achievements |
CD26 is highly expressed in malignancies. We developed humanized anti-CD26 monoclonal antibody YS110 with both ADCC/CDC and direct anti-tumor effects via nuclear transport of CD26 and repression of transcription of POLR2A gene, a subunit of RNA polymerase II (Pol II). We developed an antibody-drug conjugate(ADC) with YS110 (Y) and an Pol II inhibitor(PI). Y-PI was transported into nucleus and then suppressed mRNA synthesis, subsequently causing cell death. Y-PI showed cytotoxicity against CD26 positive cancer cells in dose dependent manner via inhibition of Pol II and impaired super-enhancer formation. CD26 positive cells were more susceptible to Y-PI than CD26 negative cells. Xenografted tumors treated with Y-PI were smaller than that of mice treated with YS110 without toxicity. Induced internalization of Y-PI into nucleus may inhibit Pol II and super-enhancer, resulting in growth suppression of cancer cells.
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Academic Significance and Societal Importance of the Research Achievements |
がん特異的スパーエンハンサー(SE)による遺伝子制御機構が発見され、SEを標的とした治療法の開発が難治性がんにおいて期待されている。本研究では、SE形成におけるPOL IIの分子病理学的解析を通じて、POL II抑制がそのリン酸化を阻害し、がん特異的SEの形成と機能を低下させること、さらにがん細胞特異的に核移行する抗体とPOL II阻害剤を結合させた抗体-薬剤複合体を開発し、SE抑制を通じた抗がん効果を見出した。本抗体-薬剤複合体は、多くのがんに高発現しているCD26を細胞表面での第一の標的、核内POL IIを第二の標的、がん特異的SEを第三の標的とする、強力で安全性の高い治療法となりうる。
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Report
(4 results)
Research Products
(16 results)
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[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.
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Journal Title
Biomark Res
Volume: 9
Issue: 1
Pages: 21-21
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Single-cell atlas of colonic CD8+ T-cells in ulcerative colitis.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.
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Journal Title
Nat Med
Volume: 26
Issue: 9
Pages: 1480-1490
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Development of novel monoclonal antibodies with specific binding affinity for denatured human CD26 in formalin-fixed paraffin-embedded and decalcified specimens2019
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
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Journal Title
PLoS ONE
Volume: 14
Issue: 6
Pages: e0218330-e0218330
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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