2018 Fiscal Year Final Research Report
Construction of structure/function relationship analysis system of CAR contributing to optimization of CAR-T cell therapy
| Project/Area Number |
16K15160
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Medical pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
OKADA NAOKI 大阪大学, 薬学研究科, 教授 (90312123)
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| Research Collaborator |
Fujiwara Kento
Tsunei Ayaka
Kitaura Masaki
Shigematsu Kazuki
Imaeda Keisuke
Masutani Mitsuki
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | キメラ抗原受容体 / 構造/活性相関 / 細胞療法 |
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| Outline of Final Research Achievements |
The structure of the chimeric antigen receptor (CAR) is divided into following four parts: antigen recognition domain (ARD), hinge domain (HD), transmembrane domain (TMD), and signal transduction domain (STD). The CAR structure-activity relationship was analyzed in mouse T cells in which each CAR construct in which 4 regions were variously modified. CDR-grafting in ARD could significantly improve membrane expression efficiency of CAR. By post-translational modification, HD affected not only the mode and stability of membrane expression of CAR but also the antigen-stimulation responsiveness. Moreover, the function addition of CAR by the insertion of a 2nd STD required optimizing the combination of each STD and HD/TMD, or the near-membrane charge of STD.
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| Free Research Field |
腫瘍免疫学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究が目指すCARの構造活性相関に関する体系的な基礎情報の集積によって、これまでは経験則に基づきつつも半ば闇雲に構築されてきたCARの設計思想に有効性増強や副作用低減のための構造情報を導入することが可能となる。すなわち、本研究成果はCAR機能のチューニング (構造改変によるCARシグナル強度の調節) をも考慮した最適なCAR-T細胞の創製に活かされるとともに、科学的・理論的根拠に基づいたCAR設計・創製技術の開発へとつながることが期待される。
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