2022 Fiscal Year Final Research Report
Molecular basis of multimeric antibody fragments towards the construction of highly functional antibody-drug conjugates
| Project/Area Number |
20K05721
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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 37020:Chemistry and chemical methodology of biomolecules-related
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| Research Institution | Tokyo University of Science, Yamaguchi (2021-2022)
Hokkaido University (2020) |
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Principal Investigator |
Tadokoro Takashi 山陽小野田市立山口東京理科大学, 薬学部, 講師 (10762396)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 抗体 / 蛋白質工学 / 抗がん剤 / 相互作用解析 / 合理的分子設計 |
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| Outline of Final Research Achievements |
In this study, we aimed to investigate the molecular basis and physicochemical properties of antibody fragment by designing novel molecular format to replace conventional antibody drugs. Therefore, focusing on a single-chain Fv antibody fragment (scFv) in which the variable region (Fv) of an antibody is connected with a flexible peptide linker, multimeric antibody fragments with multivalent binding sites were generated as follows; the scFv which utilizes a mutation that reduces antigen-binding ability is fused with a multimerized peptide sequence. The interaction analysis showed that the apparent binding dissociation constant was improved by about two orders of magnitude by multimerization of the mutant with multiple mutations whose dissociation constant was deteriorated by about two orders of magnitude. We also found that this multivalent effect is affected by the linker sequence connecting the scFv and the multimerized peptide.
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| Free Research Field |
蛋白質工学
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| Academic Significance and Societal Importance of the Research Achievements |
全長抗体では、その強すぎる抗原結合能のため、不十分な細胞内取り込みや薬効あるいはOn-targetの副作用がしばしば問題となっている。アカデミアを中心に抗体の高機能化を目指した低分子抗体の研究が進められてきており、最近になり低分子抗体を基盤とした抗体医薬品が上市されるなど、ようやく実装されつつある。本研究の、scFv一価当たりの親和性を低下させ、結合価数により高親和性を達成する設計は独自である。抗原結合部位によらずリンカー配列により結合能が影響を受けるという知見は、今後の合理的設計に新しい視点を与える。従来とは異なる本研究の分子設計は、新たな選択肢を提供できるという意味でも非常に意義深い。
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