| Project/Area Number |
21K06540
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | Kobe Gakuin University |
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Principal Investigator |
Inoue Masaki 神戸学院大学, 薬学部, 助教 (80757097)
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| Co-Investigator(Kenkyū-buntansha) |
角田 慎一 神戸学院大学, 薬学部, 教授 (90357533)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
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| Keywords | 腫瘍壊死因子 / TNF阻害薬 / 1型TNF受容体 / TNF / 自己免疫疾患 / TNFR1アンタゴニスト |
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| Outline of Research at the Start |
これまで独自に開発してきたTNFR1選択的アンタゴニスト「T2」の抗炎症作用や生体内安定性の向上を目指して、“3量体構造の一本鎖化”及び“IgG-Fc融合”による構造最適化を図ったT2誘導体「scT2-Fc」の創製を試みる。免疫疾患治療に資する新規モダリティ分子としての有用性を検証するとともに、サイトカインを医薬品として活用するための創薬基盤技術の確立を図る。
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| Outline of Final Research Achievements |
Excessive activation of the proinflammatory cytokine tumor necrosis factor-α (TNFα) is a major cause of autoimmune diseases, including rheumatoid arthritis. TNFα induces immune responses via TNF receptor 1 (TNFR1) and TNFR2. Signaling via TNFR1 induces proinflammatory responses, whereas TNFR2 signaling is suggested to suppress the pathophysiology of inflammatory diseases. Here, we developed a TNFR1-selective, antagonistic TNFα mutant (T2) derivative, scT2-Fc, which represents a single-chain form of trimeric T2 with a human IgG-Fc domain. scT2-Fc had properties similar to those of T2, including TNFR1-selective binding avidity, TNFR1 antagonistic activity, and thermal stability, and had a significantly extended plasma t1/2 in vivo. In a murine rheumatoid arthritis model, scT2-Fc delayed the onset of collagen-induced arthritis, suppressed arthritis progression in mice, and required a reduced frequency of administration.
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| Academic Significance and Societal Importance of the Research Achievements |
scT2-Fcは、(1)2価アンタゴニストによるTNFR1シグナル阻害活性の向上、(2)IgG-Fc融合の分子量増大による血中半減期の延長、(3)TNFR2シグナル温存による制御性T細胞の免疫抑制効果の維持、などの分子特性を有することで、TNF阻害薬よりも高い治療効果を発揮したと示唆された。生体内で長期間、炎症の抑制や免疫抑制活性の維持ができ、抗TNF抗体など他の免疫疾患治療薬に優位性を示すと考えられた。
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