| Project/Area Number |
16K07180
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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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| Research Field |
Tumor therapeutics
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| Research Institution | Keio University |
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Principal Investigator |
NISHIDA Hiroko 慶應義塾大学, 医学部(信濃町), 助教 (80317130)
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| Co-Investigator(Kenkyū-buntansha) |
山田 健人 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (60230463)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | CD26 / 破骨細胞 / ヒト化抗CD26モノクローナル抗体 / 多発性骨髄腫 / ADCC / 新規薬剤 / SP細胞 / 骨髄微小環境 / モノクローナル抗体 / 骨髄腫細胞 / SP分画 / 骨髄間質細胞 / 直接的効果 / 骨髄腫モデルマウス / 分子標的療法 / 間質細胞 / 血管内皮細胞 / 新規分子標的療法 |
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| Outline of Final Research Achievements |
Recently, we identified CD26 expression on human osteoclasts (OCs) and demonstrated that humanized anti-CD26 monoclonal antibody (huCD26mAb) inhibits human OC differentiation. We showed that CD26 expression was present on plasma cells in the bone marrow tissues of multiple myeloma (MM) patients. In vitro immunostaining studies revealed that although CD26 expression was low or absent on MM cell lines cultured alone, it was intensely and uniformly expressed on myeloma cell lines co-cultured with OCs. The augmented CD26 expression in MM cells was exploited to enhance anti-MM efficacy of huCD26mAb via a substantial increase in antibody-dependent cytotoxicity (ADCC). Moreover, huCD26mAb in combination with novel agents synergistically enhanced huCD26mAb induced ADCC activity against CD26+ MM cells, compared with each agent alone. huCD26mAb significantly reduced the MM tumor burden and OC formation in vivo. These results suggest that huCD26mAb could act as a therapeutic agent in MM.
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| Academic Significance and Societal Importance of the Research Achievements |
多発性骨髄腫は、主に骨髄において形質細胞が単クローン性に増殖する疾患で、骨髄微小環境に依存した進展を示し、骨髄腫細胞と破骨細胞は、密接な相互作用を営み、骨を破壊しつつ、腫瘍が進展するという悪循環を形成する。よって、骨髄腫の治療戦略においては、腫瘍進展と共に、破骨細胞活性化による溶骨性骨破壊を制御する治療法の確立が重要である。ヒト化抗CD26抗体は、骨髄腫において、骨髄腫細胞と破骨細胞の双方に発現するCD26を標的とし、免疫調整薬と抗体の併用で、腫瘍進展のみならず骨髄腫の治療抵抗性の獲得を抑制することが期待され、又、抗癌剤結合ヒト化抗CD26抗体の創薬など治療の臨床応用に繋がる点で意義がある。
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