This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Beusechem, V. W. Articles by Gerritsen, W. R. Search for Related Content PubMed PubMed Citation Articles by van Beusechem, V. W. Articles by Gerritsen, W. R.

 Previous Article  |  Next Article 

Journal of Virology, March 2002, p. 2753-2762, Vol. 76, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.6.2753-2762.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Efficient and Selective Gene Transfer into Primary Human Brain Tumors by Using Single-Chain Antibody-Targeted Adenoviral Vectors with Native Tropism Abolished

Victor W. van Beusechem,^1* Jacques Grill,^1,2 D. C. Jeroen Mastenbroek,¹ Thomas J. Wickham,³ Peter W. Roelvink,³ Hidde J. Haisma,^1, Martine L. M. Lamfers,^1,4 Clemens M. F. Dirven,^1,4 Herbert M. Pinedo,¹ and Winald R. Gerritsen¹

Division of Gene Therapy, Department of Medical Oncology,¹ Department of Neurosurgery, Vrije Universiteit Medical Center, Amsterdam, The Netherlands,⁴ Department of Pediatric Oncology, Institut Gustave Roussy, Villejuif, France,² GenVec Inc., Gaithersburg, Maryland³

Received 16 August 2001/ Accepted 7 December 2001

The application of adenoviral vectors in cancer gene therapy is hampered by low receptor expression on tumor cells and high receptor expression on normal epithelial cells. Targeting adenoviral vectors toward tumor cells may improve cancer gene therapy procedures by providing augmented tumor transduction and decreased toxicity to normal tissues. Targeting requires both the complete abolition of native tropism and the addition of a new specific binding ligand onto the viral capsid. Here we accomplished this by using doubly ablated adenoviral vectors, lacking coxsackievirus-adenovirus receptor and _v integrin binding capacities, together with bispecific single-chain antibodies targeted toward human epidermal growth factor receptor (EGFR) or the epithelial cell adhesion molecule. These vectors efficiently and selectively targeted both alternative receptors on the surface of human cancer cells. Targeted doubly ablated adenoviral vectors were also very efficient and specific with primary human tumor specimens. With primary glioma cell cultures, EGFR targeting augmented the median gene transfer efficiency of doubly ablated adenoviral vectors 123-fold. Moreover, EGFR-targeted doubly ablated vectors were selective for human brain tumors versus the surrounding normal brain tissue. They transduced organotypic glioma and meningioma spheroids with efficiencies similar to those of native adenoviral vectors, while exhibiting greater-than-10-fold-reduced background levels on normal brain explants from the same patients. As a result, EGFR-targeted doubly ablated adenoviral vectors had a 5- to 38-fold-improved tumor-to-normal brain targeting index compared to native vectors. Hence, single-chain targeted doubly ablated adenoviral vectors are promising tools for cancer gene therapy. They should provide an improved therapeutic index with efficient tumor transduction and effective protection of normal tissue.

Present address: Department of Therapeutic Gene Modulation, University Center for Pharmacy, Groningen, The Netherlands.

This article has been cited by other articles:

• Kolodkin-Gal, D., Zamir, G., Edden, Y., Pikarsky, E., Pikarsky, A., Haim, H., Haviv, Y. S., Panet, A. (2008). Herpes Simplex Virus Type 1 Preferentially Targets Human Colon Carcinoma: Role of Extracellular Matrix. J. Virol. 82: 999-1010 [Abstract] [Full Text]  
• Lupold, S. E., Kudrolli, T. A., Chowdhury, W. H., Wu, P., Rodriguez, R. (2007). A novel method for generating and screening peptides and libraries displayed on adenovirus fiber. Nucleic Acids Res 35: e138-e138 [Abstract] [Full Text]  
• Peng, K.-W., Donovan, K. A., Schneider, U., Cattaneo, R., Lust, J. A., Russell, S. J. (2003). Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker. Blood 101: 2557-2562 [Abstract] [Full Text]