2021 Fiscal Year Final Research Report

Novel anti-cancer therapy against super-enhancer using humanized monoclonal antibody with transportation activity into nucleus

Research Project

PDF

Project/Area Number	19H03519
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 50020:Tumor diagnostics and therapeutics-related
Research Institution	Saitama Medical University
Principal Investigator	YAMADA TAKETO 埼玉医科大学, 医学部, 教授 (60230463)
Co-Investigator(Kenkyū-buntansha)	林睦慶應義塾大学, 医学部(信濃町), 特任助教 (60327575) 西田浩子慶應義塾大学, 医学部(信濃町), 助教 (80317130) 山田幸司東京慈恵会医科大学, 医学部, 講師 (90570979)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	CD26 / がん / スーパーエンハンサー / 抗体 / 核移行 / 分子標的療法
Outline of Final Research Achievements	CD26 is highly expressed in malignancies. We developed humanized anti-CD26 monoclonal antibody YS110 with both ADCC/CDC and direct anti-tumor effects via nuclear transport of CD26 and repression of transcription of POLR2A gene, a subunit of RNA polymerase II (Pol II). We developed an antibody-drug conjugate(ADC) with YS110 (Y) and an Pol II inhibitor(PI). Y-PI was transported into nucleus and then suppressed mRNA synthesis, subsequently causing cell death. Y-PI showed cytotoxicity against CD26 positive cancer cells in dose dependent manner via inhibition of Pol II and impaired super-enhancer formation. CD26 positive cells were more susceptible to Y-PI than CD26 negative cells. Xenografted tumors treated with Y-PI were smaller than that of mice treated with YS110 without toxicity. Induced internalization of Y-PI into nucleus may inhibit Pol II and super-enhancer, resulting in growth suppression of cancer cells.
Free Research Field	病理学
Academic Significance and Societal Importance of the Research Achievements	がん特異的スパーエンハンサー(SE)による遺伝子制御機構が発見され、SEを標的とした治療法の開発が難治性がんにおいて期待されている。本研究では、SE形成におけるPOL IIの分子病理学的解析を通じて、POL II抑制がそのリン酸化を阻害し、がん特異的SEの形成と機能を低下させること、さらにがん細胞特異的に核移行する抗体とPOL II阻害剤を結合させた抗体-薬剤複合体を開発し、SE抑制を通じた抗がん効果を見出した。本抗体-薬剤複合体は、多くのがんに高発現しているCD26を細胞表面での第一の標的、核内POL IIを第二の標的、がん特異的SEを第三の標的とする、強力で安全性の高い治療法となりうる。