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Published on: January 19, 2018
In vivo solid tumor targeting with recombinant VEGF-diphtheria immunotoxin
Mohammad Hosseininejad-Chafi1, Ehsan Alirahimi1, Behzad Ramezani1
1Biotechnology Research Center, Venom & Biotherapeutics Molecules Lab, Pasteur Institute of Iran, Tehran, Iran.
Objectives:
A variety of signaling molecules have been identified that play a role in angiogenesis, of prime importance, vascular endothelial growth factor (VEGF) and its resceptor (VEGFR), which is highly expressed in most human solid tumors. Targeting VEGF or/and VEGFR with immunotoxin may be a promising approach to directly affect cancer cells. Immunotoxins are for targeted treatment comprising two functional moieties, an antibody that binds to target cells along with toxin that kills molecules.
Materials And Methods:
In this study, an immunotoxin comprising domain of diphtheria toxin subunit A (DT386) genetically fused to mouse VEGF (mVEGF-DT) was developed. The second construct, which contains the DT386 domain, was made to investigate the action of the DT386 domain on tumor cells. Both gene constructs were cloned, expressed, and were further purified. The biological activity of mVEGF-DT and DT386 proteins was assessed on the TC1 cell line bearing mouse model. Proteins were injected intra-tumoral in mice, in separate groups.
Results:
Tumors in the mVEGF-DT group started to dwindle after six injections, but tumor size in both control groups (DT386 and PBS), continued to grow.
Conclusion:
Successful targeting of solid tumor cells by mVEGF-DT immunotoxin demonstrates the therapeutic potential utility of these conjugates for tumor targeting.
Insights
A novel immunotoxin targeting vascular endothelial growth factor (VEGF) showed significant tumor reduction in a mouse model. This conjugate, mVEGF-DT, demonstrates potential for targeted cancer therapy by selectively affecting tumor cells.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Angiogenesis is crucial for tumor growth, with vascular endothelial growth factor (VEGF) and its receptor (VEGFR) being key players.
- VEGF is highly expressed in many human solid tumors, making it a potential therapeutic target.
- Immunotoxins, combining tumor-specific antibodies with cell-killing toxins, offer a targeted cancer treatment strategy.
Purpose of the Study:
- To develop and evaluate an immunotoxin (mVEGF-DT) targeting VEGF for cancer therapy.
- To assess the therapeutic efficacy of the mVEGF-DT immunotoxin in a preclinical tumor model.
- To investigate the anti-tumor activity of a diphtheria toxin subunit A (DT386) construct.
Main Methods:
- Genetically engineered a fusion protein (mVEGF-DT) linking mouse VEGF to diphtheria toxin subunit A (DT386).
- Constructed and purified mVEGF-DT and DT386 proteins.
- Assessed biological activity and anti-tumor efficacy by intra-tumoral injection in a TC1 cell line mouse model.
Main Results:
- The mVEGF-DT immunotoxin demonstrated significant tumor regression after six injections.
- Tumor growth continued in control groups treated with DT386 or phosphate-buffered saline (PBS).
Conclusions:
- The mVEGF-DT immunotoxin successfully targeted solid tumor cells, indicating its therapeutic potential.
- These VEGF-targeting immunoconjugates show promise for effective tumor targeting in cancer therapy.
