期刊
ANTICANCER RESEARCH
卷 42, 期 7, 页码 3453-3461出版社
INT INST ANTICANCER RESEARCH
DOI: 10.21873/anticanres.15832
关键词
c-Kit; antibody-drug conjugate; FcBP; immunotoxin; cancer
类别
In this study, the authors developed 2G4 immunotoxins as an alternative therapeutic strategy for microtubule inhibitor-resistant cancer cells. The immunotoxins efficiently induced cytotoxicity in c-Kit-positive cells by inhibiting protein synthesis, leading to a significant inhibition of tumor growth in vivo.
Background/Aim: Cytotoxic payload conjugation to antibodies efficiently suppresses tumors and contributes to the improvement of cancer survival. In our previous study, c-Kit targeting antibody-drug conjugate (2G4-DM1) with DM1, a microtubule inhibitor, efficiently suppressed tumor growth. However, slow-growing c-Kit-positive tumors, such as GIST-48, did not efficiently respond to DM1. In this study, we aimed to treat tumors using 2G4 immunotoxin with Pseudomonas exotoxin A (PE) as a payload. Materials and Methods: Modified FcBP-PE24 containing p-benzoyl-L-phenylalanine, unnatural amino acid, was expressed in E. coli and purified. Then, photoconjugation of 2G4 antibody and FcBP-PE24 at 365 nm was carried out and 2G4 immunotoxin was purified using anion exchange chromatography. In vitro cytotoxicity of 2G4 immunotoxins was assessed in HMC-1.2, GIST-48, and MDA-MB-453 cells. Then, in vivo efficacy analysis was performed using C.B-17 SCID mice. Results: 2G4 immunotoxin efficiently induced cytotoxicity in 2G4-DM1-resistant HMC-1.2 and GIST-48 cells by inhibiting protein synthesis but not in c-Kit-negative MDA-MB-453 cells. The results showed similar to 200-fold or more increase in cytotoxicity against c-Kit-positive cells compared to IC50 of 2G4-DM1. In addition, 2G4 immunotoxin suppressed tumor growth in the in vivo xenograft mouse model. Conclusion: 2G4 immunotoxins could be an alternative therapeutic strategy for microtubule inhibitor-resistant cancer cells.
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