Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies.
Adenovirus is a widely used vector for cancer gene therapy because of its high infection efficiency and capacity for transgene expression in both dividing and nondividing cells. However, neutralisation of adenovirus by pre-existing antibodies can lead to inefficient delivery, and the wide tissue distribution of the coxsackie and adenovirus receptor (CAR, the primary receptor for adenovirus type 5) precludes target selectivity. These limitations have largely restricted therapeutic use of adenovirus to local or direct administration. A successful viral gene therapy vector would be protected from neutralising antibodies and exhibit a preferential tropism for target cells. We report here the development of a covalent coating and retargeting strategy using a multivalent hydrophilic polymer based on poly-[N-(2-hydroxypropyl)methacrylamide] (pHPMA). Incorporation of targeting ligands such as basic fibroblast growth factor and vascular endothelial growth factor on to the polymer-coated virus produces ligand-mediated, CAR-independent binding and uptake into cells bearing appropriate receptors. Retargeted virus is resistant to antibody neutralisation and can infect receptor-positive target cells selectively in mixed culture, and also in xenografts in vivo. Multivalent polymeric modification of adenovirus is an effective way of changing its tropism and interaction with the immune system. As a non-genetic one-step process, the technology is simple, versatile and should yield vectors with an improved safety profile.
Fisher
K D
KD
CRC Institute for Cancer Studies, The University of Birmingham, Edgbaston, Birmingham, UK.
Stallwood
Y
Y
Green
N K
NK
Ulbrich
K
K
Mautner
V
V
Seymour
L W
LW
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000821:virology; D008689:Methacrylates; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000821:virology; D011108:Polymers; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000914:Antibodies, Viral; D008024:Ligands; D008689:Methacrylates; D011108:Polymers; C032802:hydroxypropyl methacrylate