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Published on: December 20, 2017
Tumor Penetrating Peptide-Functionalized Tenascin-C Antibody for Glioblastoma Targeting
Prakash Lingasamy1, Anett-Hildegard Laarmann1, Tambet Teesalu1
1Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411, Tartu, Estonia.
Background:
Conjugation to clinical-grade tumor penetrating iRGD peptide is a widely used strategy to improve tumor homing, extravasation, and penetration of cancer drugs and tumor imaging agents. The C domain of the extracellular matrix molecule Tenascin-C (TNC-C) is upregulated in solid tumors and represents an attractive target for clinical-grade single-chain antibody- based vehicles for tumor delivery drugs and imaging agents.
Objective:
To study the effect of C-terminal genetic fusion of the iRGD peptide to recombinant anti- TNC-C single-chain antibody clone G11 on systemic tumor homing and extravasation.
Methods:
Enzyme-linked immunosorbent assay was used to study the interaction of parental and iRGD-fused anti-TNC-C single-chain antibodies with C domain of tenascin-C and αVβ3 integrins. For systemic homing studies, fluorescein-labeled ScFV G11-iRGD and ScFV G11 antibodies were administered in U87-MG glioblastoma xenograft mice, and their biodistribution was studied by confocal imaging of tissue sections stained with markers of blood vessels and Tenascin C immunoreactivity.
Results:
In a cell-free system, iRGD fusion to ScFV G11 conferred the antibody has a robust ability to bind αVβ3 integrins. The fluorescein labeling of ScFV G11-iRGD did not affect its target binding activity. In U87-MG mice, iRGD fusion to ScFV G11 antibodies improved their homing to tumor blood vessels, extravasation, and penetration of tumor parenchyma.
Conclusion:
The genetic fusion of iRGD tumor penetrating peptide to non-internalizing affinity targeting ligands may improve their tumor tropism and parenchymal penetration for more efficient delivery of imaging and therapeutic agents into solid tumor lesions.
Insights
Genetic fusion of iRGD peptide to anti-TNC-C antibodies enhances tumor penetration and delivery of cancer agents. This strategy improves antibody homing to tumor blood vessels and parenchyma, aiding drug and imaging agent delivery.
Area of Science:
- Oncology
- Biotechnology
- Molecular Biology
Background:
- Conjugating tumor-penetrating iRGD peptide to agents improves tumor homing and drug delivery.
- Tenascin-C C-domain (TNC-C) is upregulated in tumors, making it a target for antibody-based delivery vehicles.
Purpose of the Study:
- To investigate the impact of C-terminal genetic fusion of iRGD peptide to anti-TNC-C single-chain antibody (ScFV G11) on tumor homing and extravasation.
- To evaluate the efficacy of ScFV G11-iRGD in enhancing systemic tumor targeting.
Main Methods:
- Enzyme-linked immunosorbent assay (ELISA) assessed antibody interactions with TNC-C and αVβ3 integrins.
- Fluorescein-labeled ScFV G11-iRGD and ScFV G11 were administered to U87-MG glioblastoma xenograft mice.
- Biodistribution was analyzed via confocal imaging of tumor tissue.
Main Results:
- iRGD fusion enhanced ScFV G11 binding to αVβ3 integrins in a cell-free system.
- Fluorescein labeling did not impede the binding activity of ScFV G11-iRGD.
- In vivo studies showed improved tumor blood vessel homing, extravasation, and parenchymal penetration for ScFV G11-iRGD.
Conclusions:
- Genetic fusion of iRGD peptide to non-internalizing ligands like anti-TNC-C antibodies can enhance tumor tropism and penetration.
- This approach holds promise for improving the delivery of imaging and therapeutic agents to solid tumors.
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