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Changing the adenovirus fiber for retaining gene delivery efficacy in the presence of neutralizing antibodies

Gene Therapy volume 15, pages 921–929 (2008)Cite this article

Abstract

Prior infection has primed most adult humans for a rapid neutralizing antibody (NAb) response when re-exposed to adenovirus. NAb induction can severely limit the efficacy of systemic re-administration of adenoviral gene therapy. We hypothesized that changing the fiber knob could overcome NAb. Immune-competent mice were exposed to serotype 5 adenovirus (Ad5)(GL), Ad5/3luc1, Ad5lucRGD or Ad5pK7(GL). Mice immunized with Ad5(GL) featured reduced intravenous Ad5(GL) gene transfer to most organs, including the liver, lung and spleen. Ad5(GL) gene transfer was affected much less by exposure to capsid-modified viruses. Anti-Ad5(GL) NAb blocked intravenous Ad5(GL) gene transfer to orthotopic lung cancer xenografts, whereas capsid-modified viruses were not affected. When gene transfer to fresh cancer and normal lung explants was analyzed, we found that capsid-modified viruses allowed effective gene delivery to tumors in the presence of anti-Ad5(GL) NAb, whereas Ad5(GL) was blocked. In contrast, crossblocking by NAbs induced by different viruses affected gene delivery to normal human lung explants, suggesting the importance of non-fiber-knob-mediated infection mechanisms. We conclude that changing the adenovirus fiber knob is sufficient to allow a relative degree of escape from preexisting NAb. If confirmed in trials, this approach might improve the efficacy of re-administration of adenoviral gene therapy to humans.

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Acknowledgements

This study was supported by EU FP6 THERADPOX and APOTHERAPY, HUCH Research Funds (EVO), Sigrid Juselius Foundation, Academy of Finland, Emil Aaltonen Foundation, Finnish Cancer Society, University of Helsinki, Schering Research Foundation (unrestricted), Finnish Cultural Foundation, Biomedicum Helsinki Foundation and Foundation of Jalmari and Rauha Ahokas. Akseli Hemminki is K Albin Johansson Research Professor of the Foundation for the Finnish Cancer Institute.

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Authors and Affiliations

  1. Molecular Cancer Biology Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland

    M Särkioja, S Pesonen, M Raki, T Hakkarainen, J Salo, M T Ahonen, A Kanerva & A Hemminki

  2. Helsinki University Central Hospital Laboratory, Helsinki University Central Hospital, Helsinki, Finland

    M Särkioja, S Pesonen, M Raki, T Hakkarainen, M T Ahonen & A Hemminki

  3. Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland

    J Salo

  4. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

    A Kanerva

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  1. M Särkioja
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Correspondence to A Hemminki.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Särkioja, M., Pesonen, S., Raki, M. et al. Changing the adenovirus fiber for retaining gene delivery efficacy in the presence of neutralizing antibodies. Gene Ther 15, 921–929 (2008). https://doi.org/10.1038/gt.2008.56

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