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Tumor Penetrating Peptide-Functionalized Tenascin-C Antibody for Glioblastoma Targeting

[ Vol. 21 , Issue. 1 ]

Author(s):

Prakash Lingasamy, Anett-Hildegard Laarmann and Tambet Teesalu *Pages 70-79 (10)

Abstract:


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.

Keywords:

Tenascin-C, extracellular matrix, iRGD, single-chain antibody, tumor penetrating peptide, glioblastoma.

Affiliation:

Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411, Tartu, Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411, Tartu, Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411, Tartu

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