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Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys

Gene Therapy volume 11, pages 241–252 (2004)Cite this article

Abstract

Immunogenicity of recombinant adenoviral (Ad) vectors severely hampers the clinical development of gene therapy protocols using repeated vector administrations. Inhibition of costimulation by APCs was explored as a strategy to circumvent the immune response against Ad particles. This strategy was tested in rhesus monkeys, treated transiently with chimeric anti-human CD40 and anti-human CD86 antagonist monoclonal antibodies (MAbs) at the time of systemic administration of a recombinant Ad vector. After Ad vector administration in the absence of immunosuppressive treatment, transgene expression in the serum lasted about 3–4 weeks. All control animals developed a strong neutralizing antibody (NAb) response to the Ad particles, which totally prevented efficient administration of a second vector, as shown by the lack of transgene expression. Treatment with anti-CD40 and anti-CD86 chimeric MAbs delayed or blocked the development of a humoral response against Ad and the infiltration of CD8+ lymphocytes into the liver. This resulted in (i) increased persistence of Ad-transduced cells after injection of a first vector encoding a nonimmunogenic transgene, and (ii) the possibility of readministering a second Ad vector with significant efficacy. In both respects, the combined blockade of CD40 and CD86 was more efficient than treatment with anti-CD40 alone. This study shows for the first time in non-human primates that blocking CD40 and CD86 costimulatory molecules represents a promising strategy to inhibit immune responses against an Ad vector injected systemically.

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Acknowledgements

We thank Marielle Christ for her role at the initiation of this project, and Bruce Acres for critical reading of the manuscript.

Author information

Author notes

  1. M Mehtali

    Present address: Deltagen Europe, rue Geiler de Kaysersberg, Illkirch-Graffenstaden, 67400, France

  2. Louis Boon

    Present address: BioCeros, Tafelbergweg 51, Amsterdam, 1105 BD, The Netherlands

Authors and Affiliations

  1. Transgene, 11 rue de Molsheim, Strasbourg, Cedex, France

    H Haegel-Kronenberger, C Ziller-Remy, F Stoeckel & M Mehtali

  2. Department of Immunobiology, Biomedical Primate Research Center (BPRC), Rijswijk, The Netherlands

    K Haanstra & M Jonker

  3. Pangenetics B.V., Amsterdam, The Netherlands

    AP OrtizBuijsse, M deBoer & Louis Boon

  4. Division of Experimental Immunology, Catholic University of Leuven, Belgium

    J Vermeiren, SW vanGool & JL Ceuppens

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  1. H Haegel-Kronenberger
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Additional information

This study was supported by research funding from the European Community (EUREKA project Σ!1925GISTCO)

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Haegel-Kronenberger, H., Haanstra, K., Ziller-Remy, C. et al. Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys. Gene Ther 11, 241–252 (2004). https://doi.org/10.1038/sj.gt.3302152

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  • DOI: https://doi.org/10.1038/sj.gt.3302152

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