Design of a Humanized Immunotoxin Based on Pertuzumab-Derived scFv and Shiga-Like Toxin 2 Subunit A Against Breast Cancer: An In Silico Study
Background and purpose: Breast cancer is the second cause of mortality among women. HER2, a member of the epidermal growth factor receptor family, is overexpressed in approximately 25% of breast cancer cases. This receptor represents a valuable therapeutic target in the management of breast cancer....
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Mazandaran University of Medical Sciences
2025-05-01
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| Series: | Journal of Mazandaran University of Medical Sciences |
| Subjects: | |
| Online Access: | http://jmums.mazums.ac.ir/article-1-21452-en.pdf |
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| Summary: | Background and purpose: Breast cancer is the second cause of mortality among women. HER2, a member of the epidermal growth factor receptor family, is overexpressed in approximately 25% of breast cancer cases. This receptor represents a valuable therapeutic target in the management of breast cancer. For the treatment of HER2-positive breast cancer, several agents, including trastuzumab (Herceptin), have been approved. Herceptin is a monoclonal antibody capable of binding to the HER2 receptor. A single-chain variable fragment (scFv) derived from Herceptin can also be utilized in the development of immunotoxins targeting HER2-positive cancer cells. Shiga toxins are bacterial exotoxins commonly produced by Shigella dysenteriae and certain strains of Escherichia coli. The A subunit of Shiga-like toxin 2 (Stx2A) is a potent cytotoxic agent with the potential to kill cancer cells.
Materials and methods: In this insilico study, we employed bioinformatics tools to design an immunotoxin composed of a HER2-specific single-chain variable fragment (scFv) and the A subunit of Shiga-like toxin 2. To construct the immunotoxin, the amino acid sequences of the scFv and Shiga-like toxin 2 subunit A were joined via a peptide linker. The secondary structure, physicochemical properties, solubility, and potential allergenicity of the construct were predicted. The tertiary structure of the immunotoxin was modeled, refined, and evaluated. Protein-protein docking was performed to assess immunotoxin-receptor binding, and molecular dynamics simulations were used to evaluate immunotoxin stability.
Results: According to the findings, the designed construct appears to be a stable protein with adequate solubility, non-allergenic properties, and a structurally favorable configuration for binding to HER2.
Conclusion: In conclusion, the designed construct demonstrates potential for the production of a HER2-targeted immunotoxin. However, further validation through comprehensive in vitro and in vivo immunological assays is necessary to confirm the efficacy and therapeutic potential of the construct. |
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| ISSN: | 1735-9260 1735-9279 |