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Use of synthetic vectors for neutralising antibody resistant delivery of replicating adenovirus DNA

Gene Therapy volume 13, pages 1579–1586 (2006)Cite this article

Abstract

Use of synthetic vectors to deliver genomes of conditionally replicating lytic viruses combines the strengths of viral and non-viral approaches by enabling neutralising antibody resistant deployment of cancer virotherapy. Adenovirus is particularly suitable for this application since all proteins essential for replication can be expressed from the input DNA, although the presence of terminal protein (TP) covalently linked to the 5′ termini of the input virus genomes both improves expression of transgenes encoded in the input DNA and also enhances replication. These roles of TP were distinguished in experiments where E1-deleted AdGFPDNA bearing TP (AdGFPDNA-TP), delivered with DOTAP, gave a two-fold greater frequency of transduction than AdGFPDNA(without TP) in non-complementing A549 cells, while in 293 cells (which support replication of E1-deleted viruses) the presence of TP mediated a much greater differential transgene expression, commensurate with its ability to promote replication. Subsequent studies using AdDNA for virotherapy, therefore, included covalently linked TP. AdDNA-TP delivered to A549 cells using a synthetic polyplex vector was shown to be resistant to levels of neutralising antisera that completely ablated infection by wild-type adenovirus, enabling polyplex/Adwild typeDNA-TP to mediate a powerful cytopathic effect. Similarly in vivo, direct injection of a polyplex/Adwild typeDNA-TP into A549 tumours was neutralising antibody-resistant and enabled virus replication, whereas intact virus was neutralised by the antibody and failed to infect. The delivery of adenovirus genomes–TP using synthetic vectors should provide a strategy to bypass neutralising antibodies and facilitate clinical application of replicating adenovirus for cancer virotherapy.

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Acknowledgements

We are grateful to Professor Ron Hay and Dr Huanting Liu for generous advice and the kind provision of autographa californica polyhedrosis virus expressing preterminal protein. This work was supported by the Cystic Fibrosis Trust, Medical Research Council, Cancer Research UK, National Translational Cancer Research Network (NTRAC), SBRI award from the BBSRC and European Union (LSHB-CT-2004–512087).

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Oxford University, Radcliffe Infirmary, Oxford, UK

    R C Carlisle, S S Briggs, A B Hale, K D Fisher & L W Seymour

  2. Hybrid Systems Ltd, Cherwell Innovation Centre, Heyford Park, Oxfordshire, UK

    N K Green

  3. Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, The Czech Republic

    T Etrych & K Ulbrich

  4. Cancer Research UK Institute for Cancer Studies, Birmingham University, Edgbaston, Birmingham, UK

    V Mautner

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  1. R C Carlisle
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Correspondence to L W Seymour.

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Carlisle, R., Briggs, S., Hale, A. et al. Use of synthetic vectors for neutralising antibody resistant delivery of replicating adenovirus DNA. Gene Ther 13, 1579–1586 (2006). https://doi.org/10.1038/sj.gt.3302814

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