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Cancer Gene Therapy (2006) 13, 10721081
r 2006 Nature Publishing Group All rights reserved 0929-1903/06 $30.00
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S Ni1,4, A Gaggar1,4, N Di Paolo1,4, ZY Li1, Y Liu1, R Strauss1, P Sova2, J Morihara2, Q Feng2, N Kiviat2, P Tour3, PS Sow3 and A Lieber1,2
1Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA;
2Department of Pathology, University of Washington, Seattle, WA, USA and 3Department of Infectious Diseases, University of Dakar, Senegal, West Africa
There is growing evidence from in vitro studies that subgroup B adenoviruses (Ad) can overcome the limitations in safety and tumor transduction efficiency seen with commonly used subgroup C serotype 5-based vectors. In this study, we confirm that the expression level of the B-group Ad receptor, CD46, correlates with the grade of malignancy of cervical cancer in situ. We also demonstrate the in vivo properties of Ad5-based vectors that contain the B-group Ad serotype 35 fiber (Ad5/35) in transgenic mice that express CD46 in a pattern and at a level similar to humans. Upon intravenous and intraperitoneal injection, an Ad5/35 vector did not efficiently transduce normal tissue, but was able to target metastatic or intraperitoneal tumors that express CD46 at levels comparable to human tumors. When an oncolytic Ad5/35-based vector was employed, in both tumor models antitumor effects were observed. Furthermore, injection of Ad5/35 vectors into CD46 transgenic mice caused less innate toxicity than Ad5 vectors. Our data demonstrate that Ad vectors that target CD46 offer advantages over Ad5-based vectors for treatment of cancer. Cancer Gene Therapy (2006) 13, 10721081. doi:10.1038/sj.cgt.7700981; published online 28 July 2006
Keywords: CD46; adenovirus; serotype 35; tumor targeting; transgenic mice; CAR
Introduction
There are more than 50 serotypes of human adenoviruses (Ad); many of them differ in their tissue tropism.1 Ad
serotype 5 (Ad5) has been intensively studied over the past 20 years and has been modified as a gene transfer vector. Key features that make Ad vectors an attractive vehicle for gene transfer in vitro and in vivo include the ability to easily prepare high-titer stocks of purified virus and the remarkable efficiency of each step in the Ad cell/ nucleus entry process leading to high-level gene expression. Attachment of Ad5 to the primary cell surface receptor, the coxsackievirus-adenovirus receptor (CAR),...