2018 Fiscal Year Final Research Report

Discovery research of medium molecule drugs for cancer immunotherapy using in vitro molecular evolution technology

Research Project

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Project/Area Number	16K07182
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Tumor therapeutics
Research Institution	St. Luke's International University
Principal Investigator	HEIKE Yuji 聖路加国際大学, 専門職大学院公衆衛生学研究科(公衆衛生大学院), 教授 (90260322)
Co-Investigator(Kenkyū-buntansha)	久保泰国立研究開発法人産業技術総合研究所, 生命工学領域, 副研究センター長 (10178030) 五島直樹国立研究開発法人産業技術総合研究所, 生命工学領域, 研究チーム長 (70215482)
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	PD-1 / 3-finger protein / 小麦胚芽蛋白合成系 / 合成ペプチド / 試験管内進化技術
Outline of Final Research Achievements	We screened two of ‘three-finger protein’ specifically binding to PD-1 using ‘in vitro evolution system’ from three-finger protein library. Although we attempted to synthesize 3-finger protein in a wheat germ protein synthesis system based on the cDNA clone obtained, enough protein was not finally acquired. In parallel to that, we acquired each finger peptide down-sized from three-finger peptide and performed functional analysis. We obtained one-finger peptides with high purity by using reversed HPLC method and confirmed that each peptide showed moderate to high binding activity to the target PD-1. We also made an assessment for the peptides of agonist / antagonist activity using in vitro functional assay of human lymphocytes PD-1. However, none of the synthesized one-finger peptides had any effect on the biological function of PD-1 or was evidently less active than the existing anti-PD-1 / PD-L1 antibody. Furthermore, the peptide mixtures did not affect the function of PD-1.
Free Research Field	臨床がん免疫
Academic Significance and Societal Importance of the Research Achievements	本研究は、がん治療の分野で注目を集めている、抗PD-1抗体の問題点を解決するために、PD-1/PD-L1の相互作用を阻害する中分子特殊蛋白（3-finger protein）をスクリーニングした上で合成を行い、より効果が高く、かつ安価なPD－１阻害剤の開発を行うことを目標とした。免疫チエックポイント阻害によるがん治療は今後がん治療の主流となると期待されているが、薬剤の価格が高いため医療財源を圧迫しかねないとの懸念が生じている。本研究より、3-finger proteinによるチエックポイント阻害効果が確認できれば、より安価な治療薬剤の開発につながる可能性があり学術的・社会的意義は大きい。