| Project/Area Number |
16H04714
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | Saitama Medical University |
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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), 助教 (60327575)
西田 浩子 慶應義塾大学, 医学部(信濃町), 助教 (80317130)
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| Research Collaborator |
YAMADA koji
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥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)
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| 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 |
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| 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.
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| 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。
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