Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies

Adenovirus is a widely used vector for cancer gene therapy because of its h igh infection efficiency and capacity for transgene expression in both divi ding and nondividing cells. However, neutralisation of adenovirus by pre-ex isting antibodies can lead to inefficient delivery, and the wide tissue dis tribution of the coxsackie and adenovirus receptor (CAR, the primary recept or for adenovirus type 5) precludes target selectivity. These limitations h ave largely restricted therapeutic use of adenovirus to local or direct adm inistration. A successful viral gene therapy vector would be protected from neutralising antibodies and exhibit a preferential tropism for target cell s. We report here the development of a covalent coating and retargeting str ategy using a multivalent hydrophilic polymer based on poly-[N-(2-hydroxypr opyl)methacrylamide] (pHPMA). Incorporation of targeting ligands such as ba sic fibroblast growth factor and vascular endothelial growth factor on to t he polymer-coated virus produces ligand-mediated, CAR-independent binding a nd uptake into cells bearing appropriate receptors. Retargeted virus is res istant to antibody neutralisation and can infect receptor-positive target c ells selectively in mixed culture, and also in xenografts in vivo. Multival ent polymeric modification of adenovirus is an effective way of changing if s tropism and interaction with the immune system. As a non-genetic onestep process, the technology is simple, versatile and should yield vectors with an improved safety profile.