Development and clinical application of cancer-specific single-chain antibody using new technology of antibody modification

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02839
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Ehime Prefectural University of Health Science (2020); Ehime University (2018-2019)
• Principal Investigator: YASUKAWA MASAKI 愛媛県立医療技術大学, 保健科学部, 教授 (60127917)
• Co-Investigator(Kenkyū-buntansha): 越智 俊元 愛媛大学, 医学系研究科, 講師 (10571086)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: がん免疫療法 / CAR-T細胞 / 一本鎖抗体

Outline of Final Research Achievements

In this study, we have generated a single-chain antibody generation system in which CAR-library T cells have been screened based on their antitumor functions. A variable region library obtained from the human immunoglobulin was fused with that of an existing antitumor antibody to generate an scFv library. CAR-library T cells which express the scFv library were stimulated with tumor cells to enrich antigen-specific population. As the results, target-specific recognition of newly generated scFv-expressing CAR-T cells could be finely tuned by changing a new variable region. Moreover, scFv-optimized CAR-T cells showed sufficient antitumor cytotoxicity and better proliferation capacity with long-lived T-cell phenotype, resulting in enhanced antitumor effects in humanized mouse in vivo system. Collectively, this system can be applied to generate a new scFv optimal for each CAR-T cell targeting a variety of surface tumor antigens, resulting in further advancement of CAR-T-cell therapy.

Free Research Field

内科学、血液学、免疫学、腫瘍学

Academic Significance and Societal Importance of the Research Achievements

今回我々が確立した新規一本鎖抗体 (scFv)作製技術を用いれば、CAR-T細胞が発現するscFvの標的認識様式を繊細に調律しながら、CAR-T細胞の機能と抗腫瘍効果を最大限に誘導できるscFvを迅速かつ安定して作製することが可能となる。本研究は、これまでと異なる視点から、CAR-T細胞が標的抗原を認識するために重要な働きを担うscFvに着目した。本技術は、これまでに開発されてきた様々な改良型CAR-T細胞の機能をさらに高めることにも応用が可能であることから、難治性がんを標的とした次世代CAR-T細胞療法開発領域におけるインパクトは特に大きく、社会的意義も高いと考えられる。