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Published on: September 14, 2018
HER2-specific immunotoxins constructed based on single-domain antibodies and the improved toxin PE24X7
1State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, PR China.
Abstract:
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.
Insights
New anti-HER2 immunotoxins using single-domain antibodies and PE24X7 toxin show high efficacy and selectivity against HER2-positive tumors. These promising therapeutics offer improved safety and a broader therapeutic window for cancer treatment.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Human epidermal growth factor receptor 2 (HER2) is a key cancer target, but resistance to therapies remains a challenge.
- Immunotoxins offer a potent solution by combining targeted antibodies with cytotoxic agents.
- Existing immunotoxins can face challenges in preparation and off-target toxicity.
Purpose of the Study:
- To develop novel anti-HER2 immunotoxins with simplified preparation and reduced toxicity.
- To utilize single-domain antibody (sdAb) fragments for enhanced targeting and effector function.
- To evaluate the efficacy and safety of new immunotoxins against HER2-positive cancers.
Main Methods:
- Construction of three novel anti-HER2 immunotoxins using sdAbs and an engineered PE24X7 toxin.
- Assessment of immunotoxin expression, solubility, and stability.
- In vitro cytotoxicity assays against HER2-positive and HER2-negative tumor cells.
- In vivo efficacy and maximum tolerated dose (MTD) studies in tumor models.
Main Results:
- Immunotoxins were efficiently expressed in soluble, stable forms, simplifying production.
- Demonstrated high cytotoxicity against HER2-positive tumor cells with >1000-fold selectivity over HER2-negative cells.
- One immunotoxin halted tumor growth at low doses (<0.75 mg/kg) with an MTD >8.0 mg/kg, indicating an improved therapeutic window.
Conclusions:
- The novel sdAb-based immunotoxins are effective and selective against HER2-positive cancers.
- These agents exhibit improved MTD and a broadened therapeutic window compared to previous immunotoxins.
- The developed immunotoxins represent promising candidates for future anti-HER2 cancer therapeutic strategies.
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