| ○種別 (必須): | □ | 学術論文 (審査論文)
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| ○言語 (必須): | □ | 英語
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| ○招待 (推奨): |
| ○審査 (推奨): |
| ○カテゴリ (推奨): |
| ○共著種別 (推奨): |
| ○学究種別 (推奨): |
| ○組織 (推奨): |
| ○著者 (必須): | 1. | (英) Asano Ryutaro (日) (読)
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| 2. | (英) Shimomura Ippei (日) (読)
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| 3. | (英) Konno Shota (日) (読)
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| 4. | (英) Ito Akiko (日) (読)
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| 5. | (英) Masakari Yosuke (日) (読)
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| 6. | (英) Orimo Ryota (日) (読)
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| 7. | (英) Taki Shintaro (日) (読)
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| 8. | (英) Arai Kyoko (日) (読)
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| 9. | (英) Ogata Hiromi (日) (読)
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| 10. | (英) Okada Mai (日) (読)
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| 11. | (英) Furumoto Shozo (日) (読)
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| 12. | 鬼塚 正義 ([徳島大学.大学院社会産業理工学研究部.生物資源産業学域.応用生命系.生体分子機能学分野]/[徳島大学.生物資源産業学部.生物資源産業学科.応用生命講座])
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| 13. | 大政 健史
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| 14. | (英) Hayashi Hiroki (日) (読)
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| 15. | (英) Katayose Yu (日) (読)
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| 16. | (英) Unno Michiaki (日) (読)
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| 17. | (英) Kudo Toshio (日) (読)
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| 18. | (英) Umetsu Mitsuo (日) (読)
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| 19. | (英) Kumagai Izumi (日) (読)
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| ○題名 (必須): | □ | (英) Rearranging the domain order of a diabody-based IgG-like bispecific antibody enhances its antitumor activity and improves its degradation resistance and pharmacokinetics. (日)
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| ○副題 (任意): |
| ○要約 (任意): | □ | (英) One approach to creating more beneficial therapeutic antibodies is to develop bispecific antibodies (bsAbs), particularly IgG-like formats with tetravalency, which may provide several advantages such as multivalent binding to each target antigen. Although the effects of configuration and antibody-fragment type on the function of IgG-like bsAbs have been studied, there have been only a few detailed studies of the influence of the variable fragment domain order. Here, we prepared four types of hEx3-scDb-Fc, IgG-like bsAbs, built from a single-chain hEx3-Db (humanized bispecific diabody [bsDb] that targets epidermal growth factor receptor and CD3), to investigate the influence of domain order and fusion manner on the function of a bsDb with an Fc fusion format. Higher cytotoxicities were observed with hEx3-scDb-Fcs with a variable light domain (VL)-variable heavy domain (VH) order (hEx3-scDb-Fc-LHs) compared with a VH-VL order, indicating that differences in the Fc fusion manner do not affect bsDb activity. In addition, flow cytometry suggested that the higher cytotoxicities of hEx3-scDb-Fc-LH may be attributable to structural superiority in cross-linking. Interestingly, enhanced degradation resistance and prolonged in vivo half-life were also observed with hEx3-scDb-Fc-LH. hEx3-scDb-Fc-LH and its IgG2 variant exhibited intense in vivo antitumor effects, suggesting that Fc-mediated effector functions are dispensable for effective anti-tumor activities, which may cause fewer side effects. Our results show that merely rearranging the domain order of IgG-like bsAbs can enhance not only their antitumor activity, but also their degradation resistance and in vivo half-life, and that hEx3-scDb-Fc-LHs are potent candidates for next-generation therapeutic antibodies. (日)
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| ○キーワード (推奨): | 1. | (英) Animals (日) (読)
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| 2. | (英) Antibodies, Bispecific (日) (読)
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| 3. | (英) Antigens, CD3 (日) (読)
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| 4. | (英) Antineoplastic Agents (日) (読)
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| 5. | (英) Area Under Curve (日) (読)
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| 6. | (英) Binding Sites (日) (読)
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| 7. | (英) Cell Line, Tumor (日) (読)
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| 8. | (英) Cell Proliferation (日) (読)
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| 9. | (英) Cell Survival (日) (読)
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| 10. | (英) Dose-Response Relationship, Drug (日) (読)
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| 11. | (英) Female (日) (読)
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| 12. | (英) Humans (日) (読)
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| 13. | (英) Immunoglobulin G (日) (読)
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| 14. | (英) Interferon-gamma (日) (読)
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| 15. | (英) MCF-7 Cells (日) (読)
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| 16. | (英) Mice, SCID (日) (読)
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| 17. | (英) Neoplasms (日) (読)
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| 18. | (英) Protein Binding (日) (読)
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| 19. | (英) Receptor, Epidermal Growth Factor (日) (読)
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| 20. | (英) Tumor Burden (日) (読)
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| 21. | (英) Xenograft Model Antitumor Assays (日) (読)
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| ○発行所 (推奨): |
| ○誌名 (必須): | □ | mAbs ([Taylor & Francis])
(pISSN: 1942-0862, eISSN: 1942-0870)
| ○ISSN (任意): | □ | 1942-0870
ISSN: 1942-0862
(pISSN: 1942-0862, eISSN: 1942-0870) Title: mAbsTitle(ISO): MAbsPublisher: Taylor & Francis (NLM Catalog)
(Scopus)
(CrossRef)
(Scopus information is found. [need login]) | [継承] |
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| ○巻 (必須): | □ | 6
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| ○号 (必須): | □ | 5
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| ○頁 (必須): | □ | 1243 1254
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| ○都市 (任意): |
| ○年月日 (必須): | □ | 西暦 2014年 10月 30日 (平成 26年 10月 30日)
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| ○URL (任意): |
| ○DOI (任意): | □ | 10.4161/mabs.29445 (→Scopusで検索)
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| ○PMID (任意): | □ | 25517309 (→Scopusで検索)
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| ○備考 (任意): | 1. | (英) PublicationType: Journal Article (日)
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| 2. | (英) PublicationType: Research Support, Non-U.S. Gov't (日)
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