stitution of Adenovirus Serotype 3 Hexon onto a Serotype ncolytic Adenovirus Reduces Factor X Binding, Decreases Ther r Tropism, and Improves Antitumor Efficacy

Download owing intravascular delivery, an important route of administration for many clinical applications, the s the predominant site of adenovirus serotype 5 (Ad5) sequestration, thereby posing a risk of toxicity. regard, it has recently been shown that the Ad5 capsid binds to the blood coagulation factor X (FX) e Ad5 hexon protein. This interaction mediates the majority of Ad5 liver transduction. Patient FX can be diminished by the administration of warfarin, a vitamin K inhibitor in the liver that decreases oduction; however, warfarin is a potent anticoagulant and can have a number of undesired side efTherefore, genetic modification of the virus to ablate FX binding is the preferred approach. Modificaof the hexon protein, specifically within the hypervariable 5 (HVR5) and 7 (HVR7) regions, have ced Ad5 vectors that show minimal liver sequestration. Our laboratory has pioneered adenovirus modifications, including insertion of peptide ligands into the hypervariable regions and substitution adenovirus hexon with hexon proteins from alternate serotypes. Substitution of the adenovirus se3 (Ad3) hexon protein onto the Ad5 capsid has been further characterized with regard to its interwith FX and incorporated into an infectivity-enhanced conditionally replicative adenovirus (CRAd). o evaluation of these hexon-modified vectors showed decreased binding to FX and decreased cell uction via FX-mediated pathways. Furthermore, in vivo biodistribution studies in mice exhibited a transd decrease in liver sequestration. With the use of xenograft tumor models, the antitumor efficacy of the hexon-modified CRAds was enhanced over nonmodified controls. Mol Cancer Ther; 9(9); OF1–9. ©2010 AACR.