Relationship between association rate constant and characteristics of antibody-drug conjugate

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16021
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Tsumura Ryo 国立研究開発法人国立がん研究センター, 先端医療開発センター・新薬開発分野, 研究員 (90785586)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 抗体抗がん剤複合体 / 抗体改変技術 / 結合カイネティクス / 性状評価

Outline of Final Research Achievements

In the present study, we aimed to improve a potency of antibody-drug conjugates (ADCs) by increasing the association rate constants (ka) of the antibody. The monoclonal antibody against tissue factor (TF) was modified some specific amino acids, and we confirmed that the ka of the engineered antibody was more than 20 times higher than that of the wild-type antibody. The engineered antibody was more efficiently internalized into TF-positive cancer cell line, PSN-1 cells than the wild-type antibody. Also, the engineered ADC showed greater cytotoxicity against PSN-1 cells in vitro than the wild-type ADC. However, we could not observe the changes in the degree of tumor accumulation and the anti-tumor effect against PSN-1 tumor.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

近年複数の抗体抗がん剤複合体（antibody-drug conjugate, ADC)が承認され、ADCが有望ながん治療戦略である事が認知されている。今後の更なる追加検討が必須であるが、本研究において、抗体改変によりADCの薬効増強の可能性が示唆され、また結合速度定数がADC開発の抗体クローン選択に重要な指標になりえることが示唆された。これらの検討は、今後の高機能なADC医薬品創出に寄与すると考える。