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Complement activation by recombinant adenoviruses

Gene Therapy volume 8, pages 1794–1800 (2001)Cite this article

Abstract

Recombinant adenoviruses are currently the most important vector system in gene therapy. Adenoviruses frequently cause upper respiratory tract infections in humans and anti-adenoviral antibodies are found in 35–70% of the population. Therefore in the majority of potential patients receiving adenoviral gene therapy, the contact of virus particles and blood will lead to the formation of antigen–antibody complexes. These complexes have the ability to induce inflammatory reactions via an activation of the complement system. We have determined the level of C3a (the most reactive complement component) generated in isolated citrate plasma of healthy individuals after challenge with recombinant and wild-type adenoviruses in amounts corresponding to virus blood levels to be expected in patients during adenoviral gene therapy. All plasma samples containing anti-adenoviral antibodies showed a substantial, dose-dependent generation of C3a. A virus plasma level of about 7.5 × 109 particles/ml (which was calculated to be the highest blood level reached during clinical trials in the past) induced an average release of about 3000 ng/ml C3a (baseline levels <140 ng/ml). Analyzing the nature of anti-adenoviral antibodies showed, that not only antibodies with neutralizing properties (anti-Ad5), but also non-neutralizing anti-adenoviral antibodies are capable of complement activation. This study suggests that complement activation can be ignored in local low-dose applications of recombinant adenoviruses, but warrants attention after systemic application of large viral quantities. In clinical protocols aiming at systemic virus application, measures for monitoring and controlling the complement system should be included on a regular basis.

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Acknowledgements

This work was supported by the Bundesministerium für Forschung und Technologie (01KV9901/1). We are grateful for the technical assistance of Beate Goldbrich, Christel Uhse, Gudrun Kliem and Hannelore Scharfenorth. The authors would like to thank Friedrich Luft and Charles Coutelle for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Molecular Cell Biology, Institute for Biology, Humboldt-University Berlin at the Max Delbrueck-Center for Molecular Medicine, Berlin, Germany

    G Cichon & S Boeckh-Herwig

  2. Department of Gastroenterology, Charité, Berlin, Germany

    HH Schmidt

  3. Max Delbrueck-Center for Molecular Medicine, Berlin, Germany

    E Wehnes

  4. Department of Molecular and Clinical Cardiology, Franz-Vollhardt Clinic, Charité, Berlin, Germany

    T Müller

  5. Department of Virology, Medizinische Hochschule Hannover, Hannover, Germany

    P Pring-Akerblom

  6. Robert Koch-Institute, Berlin, Germany

    R Burger

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  1. G Cichon
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  3. HH Schmidt
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  7. R Burger
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Cichon, G., Boeckh-Herwig, S., Schmidt, H. et al. Complement activation by recombinant adenoviruses. Gene Ther 8, 1794–1800 (2001). https://doi.org/10.1038/sj.gt.3301611

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