Current medicinal chemistry · 2026
In Silico Design and Structural Characterization of 4D5mocB-PE24: A Novel Immunotoxin for EpCAM-Targeted Cancer Therapy.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Heidari Fatemeh, Farajnia Safar, Salahlou Reza, Babaei Hossein, Rahbarnia Leila
Аннотация
INTRODUCTION: Antibody-based immunotoxins are a promising novel therapeutic approach aimed at targeted cancer therapy, utilizing the target specificity of antibody fragments attached to a potent cytotoxic molecule. Oportuzumab monatox, an EpCAM-specific immunotoxin, has shown clinical activity in Non-Muscle-Invasive Bladder Cancer (NMIBC) but is limited by its high immunogenicity. To address this limitation, we developed a novel construct comprising the 4D5mocB antibody fragment fused to a truncated, deimmunized Pseudomonas aeruginosa exotoxin A.
METHODS: Various bioinformatics methods were employed to assess physicochemical characteristics and analyze structural stability using Molecular Dynamics (MD) simulations. The predicted epitope content for B cells and T cells, as well as the binding affinity for the EpCAM receptor, were also evaluated and compared with that of the parental immunotoxin.
RESULTS: Molecular dynamics analysis showed that the 4D5mocB-PE24 immunotoxin rapidly stabilized within 10 ns, maintaining RMSD values of 0.5-0.7 nm, whereas the PE40-based complex exceeded 2.0 nm after 22 ns. Moreover, computational modeling of the truncation and deimmunization process reduced the predicted number of B- and T-cell epitopes by 56% and 43%, respectively, and markedly decreased MHC class II binding.
DISCUSSION: These findings demonstrate that epitope deletion and rational mutagenesis substantially reduce predicted immunogenicity while preserving high target-binding affinity; however, these findings will require experimental validation.
CONCLUSION: This study identifies 4D5mocB-PE24 as a promising anti-EpCAM immunotoxin candidate with reduced immunogenicity, supporting further preclinical and clinical evaluation for EpCAM-positive cancers.
METHODS: Various bioinformatics methods were employed to assess physicochemical characteristics and analyze structural stability using Molecular Dynamics (MD) simulations. The predicted epitope content for B cells and T cells, as well as the binding affinity for the EpCAM receptor, were also evaluated and compared with that of the parental immunotoxin.
RESULTS: Molecular dynamics analysis showed that the 4D5mocB-PE24 immunotoxin rapidly stabilized within 10 ns, maintaining RMSD values of 0.5-0.7 nm, whereas the PE40-based complex exceeded 2.0 nm after 22 ns. Moreover, computational modeling of the truncation and deimmunization process reduced the predicted number of B- and T-cell epitopes by 56% and 43%, respectively, and markedly decreased MHC class II binding.
DISCUSSION: These findings demonstrate that epitope deletion and rational mutagenesis substantially reduce predicted immunogenicity while preserving high target-binding affinity; however, these findings will require experimental validation.
CONCLUSION: This study identifies 4D5mocB-PE24 as a promising anti-EpCAM immunotoxin candidate with reduced immunogenicity, supporting further preclinical and clinical evaluation for EpCAM-positive cancers.