HER2-specific immunotoxins constructed based on single-domain antibodies and the improved toxin PE24X7
| Autor: | Wenjing Li, Jianhua Zhao, Yutong Xing, Keyuan Xu, Liqing Zhao, Li Cao, Jessica Yijia Wang, Zhangyong Hong, Qiyu Li, Zhen Tong |
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| Rok vydání: | 2019 |
| Předmět: |
Receptor
ErbB-2 Pharmaceutical Science Mice Nude Antineoplastic Agents 02 engineering and technology 030226 pharmacology & pharmacy 03 medical and health sciences Mice 0302 clinical medicine In vivo Immunotoxin Cell Line Tumor medicine Cytotoxic T cell Animals Humans Cytotoxicity Mice Inbred BALB C biology Chemistry Effector Immunotoxins Cancer Antibodies Monoclonal Single-Domain Antibodies 021001 nanoscience & nanotechnology medicine.disease Xenograft Model Antitumor Assays Single-domain antibody biology.protein Cancer research Antibody 0210 nano-technology |
| Zdroj: | International journal of pharmaceutics. 574 |
| ISSN: | 1873-3476 |
| Popis: | Human epidermal growth factor receptor 2 (HER2) is an attractive target for cancer therapy, although a large fraction of tumors that express HER2 may still resist first-line therapies. Immunotoxins with antibodies that are armed with extremely potent cytotoxic toxin molecules may provide an important solution to this problem. In this work, we constructed three new anti-HER2 immunotoxins by using single-domain antibody (sdAb) molecules as the targeting moiety and the improved toxin PE24X7 as the effector with the aim of simplifying the preparation and reducing the off-target toxicity of the immunotoxins. Due to the beneficial outcomes of sdAb molecules, the synthesized immunotoxins were efficiently expressed in soluble form, avoiding the refolding process required by the common immunotoxin design and having high solubility and stability. Cell toxicity experiments showed that they have high cytotoxicity against various HER2-positive tumor cells and good selectivity (more than 1000-fold) towards HER2-positive rather than HER2-negative cells. Importantly, in vivo treatment experiments showed that one of the new immunotoxins could efficiently halt tumor growth at doses lower than 0.75 mg/kg, and it had a maximum tolerated dose (MTD) higher than 8.0 mg/kg, showing a substantially improved MTD and a broadened therapeutic window than the previously reported anti-HER2 immunotoxins. Given that PE toxin-based immunotoxins have been approved for clinical cancer therapy, the unique characteristics of the immunotoxins presented here make them promising for use in the development of anti-HER2 cancer therapeutics. |
| Databáze: | OpenAIRE |
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