Development of technology to search for novel antibody targets by proteomics specialized on the surface of circulating tumor cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02004
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 34020:Analytical chemistry-related
• Research Institution: Osaka University
• Principal Investigator: Inoue Tsuyoshi 大阪大学, 薬学研究科, 教授 (20263204)
• Co-Investigator(Kenkyū-buntansha): 鎌田 春彦 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 創薬デザイン研究センター, プロジェクトリーダー (00324509)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 癌 / 抗体医薬 / 標的探索 / ストレプトアビジン

Outline of Final Research Achievements

Antibodies cannot penetrate directly into cells due to their molecular weight, and it is essential to develop a technology for the accurate analysis of membrane proteins that exist on the cell surface of diseased tissues. In this project, we established a technology to label membrane proteins with iminobiotinylated reagents and purify them using a modified streptavidin that shows specificity only for the labeled proteins.
By applying this labeling proteomics technology to a mouse model of cancer, we found that membrane protein transporter X was significantly upregulated in the vascular endothelium of metastatic cancer by comparison with wild-type mice, and that administration of the inhibitor had an antitumor effect on malignant lymphoma. This method was found to be an excellent technique for the discovery of new targets for the development of antibody drugs.

Free Research Field

構造生物化学

Academic Significance and Societal Importance of the Research Achievements

抗体は高い特異性と親和性を有し副作用が低いが、アンメットメディカルニーズを満たすほど標的分子はなく、新規標的探索技術の開発が望まれていた。特に抗体は分子量の問題から細胞内部には直接侵入できず、疾患部位の膜表在性蛋白質を高精度に分析できる技術の開発が必須となる。そこで非天然型ビオチンにのみ特異性を示す改変型ストレプトアビジンを用い、血液循環細胞表面をはじめラベル化された膜表在性蛋白質に特化したプロテオミクスにより新規標的蛋白質を効率よく発見して、アンメットメディカルニーズに応えた新規抗体医薬品を開発できる可能性が高く、非天然型ビオチン化試薬による新規探索技術の開発の意義は大きい。