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Retargeting adenoviral vectors to improve gene transfer into tumors

Cancer Gene Therapy volume 18, pages 275–287 (2011)Cite this article

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Abstract

Gene targeting to tumors using adenoviral (Ad) vectors holds great potential for cancer imaging and therapy, but the limited efficacy of current methods used to improve delivery to target tissues and reduce unwanted interactions remain substantial barriers to further development. Progress in characterizing the set of molecular interactions used by Ad vectors to infect particular tissues has aided the development of novel strategies for retargeting vectors to tumor cells. One method is chemical retargeting of adenovirus using bispecific antibodies (bsAbs) against both viral capsid proteins and tumor-specific cell surface molecules. This approach can be combined either with competitive inhibitors designed to reduce viral tropism in undesired tissues, or with traditional therapeutics to increase the expression of surface molecules for improved tumor targeting. Ablating liver cell-specific interactions through mutation of capsid proteins or chemical means are promising strategies for reducing adenovirus-induced liver toxicity. The nature of tumor neovasculature also influences Ad delivery, and the use of vascular disrupting agents (VDAs) such as combretastatin can help elucidate these contributions. In this investigation, we evaluate a variety of these methods for retargeting Ad vectors to tumor cells in vitro and in vivo, and assess the contributions of specific molecular and tissue interactions that affect Ad transgene delivery.

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Acknowledgements

We wish to thank Julie Poirot and Jessica Mullens for technical help with recombinant virus construction and preparation, and Shuzhen Li for preparation of the bispecific antibodies and providing the purified β2GP1 protein. Paul Card helped to prepare the manuscript for publication. Bavituximab was generously provided by Peregrine Pharmaceuticals Inc., Tustin, CA, and Oxigene (Waltham, MA) generously provided the combretastatin 1 phosphate. Optical imaging was facilitated by the UT Southwestern Small Animal Imaging Research Program funded by NCI U24 CA126608. This work was supported by a Texas Higher Education Coordinating Board Advanced Technology Program grant and by NIH R01 CA115935 to RDG, and by the Gillson Longenbaugh Foundation to PT.

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  1. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    R T Hogg & R D Gerard

  2. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    P Thorpe

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  1. R T Hogg
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Correspondence to R D Gerard.

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Both Dr Thorpe and Dr Gerard hold equity interests in Peregrine Pharmaceuticals, a company that is commercially developing the anti-PS antibody bavituximab. Dr Thorpe is also on the advisory board of the company and receives research support. Mr Hogg declares no conflicts of interest.

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Hogg, R., Thorpe, P. & Gerard, R. Retargeting adenoviral vectors to improve gene transfer into tumors. Cancer Gene Ther 18, 275–287 (2011). https://doi.org/10.1038/cgt.2010.78

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