Design of a Humanized Immunotoxin Based on Pertuzumab-Derived scFv and Shiga-Like Toxin 2 Subunit A Against Breast Cancer: An In Silico Study
Year: 2025
Type: article
Abstract: 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.
Authors: Zeinab Ghesmati, Khadijeh Ahmadi, Navid Nezafat, Farzaneh Vahedi, Mortaza Taheri-Anganeh, Seyyed Hossein Khatami, Hasan Ghasemi, Rahmatollah Soltani, Vahid Zarezade, Ahmad Movahedpour, Ahmad Movahedpour
Institutions: Tabriz University of Medical Sciences, Hormozgan University of Medical Sciences, Shiraz University of Medical Sciences, Babol University of Medical Sciences, Urmia University of Medical Sciences, Shahid Beheshti University, Shahid Beheshti University of Medical Sciences, Abadan University of Medical Sciences, Yasouj University, Yasuj University of Medical Sciences
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6981030299
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