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Single-chain antibody and its derivatives directed against vascular endothelial growth factor: application for antiangiogenic gene therapy

Gene Therapy volume 10, pages 1850–1859 (2003)Cite this article

Abstract

Single-chain antibodies (scFv) have an enormous potential for clinical application. However, rapid blood clearance and difficulties in large-scale production of active scFvs have limited the practical use of these antibody fragments. Recently, an anti-vascular endothelial growth factor (VEGF) scFv (scFv V65) was selected in our laboratory from a human antibody phage-display library. This antibody was able to reduce tumor growth in mice by approximately 50%. Here, we employ a gene therapy strategy for sustained in vivo expression of scFv V65 and its derivatives. scFv fusion proteins containing parts of the constant IgG1 region were generated (minibody and scFv V65–Fc) to increase the serum half-life of the scFv V65. Systemic administration of recombinant adenovirus encoding scFv V65 resulted in substantial tumor inhibition. This effect could be improved by multiple virus injections. We found that the efficacy of different scFv V65 formats was dependent on the mode of administration: whereas scFv V65–Fc was the most efficient when expressed locally, scFv V65 was superior when delivered systemically. Our results show that therapeutic levels of scFv V65 can be obtained by systemic injection of recombinant adenoviruses. Therefore, therapeutic gene delivery of scFv is a feasible strategy that overcomes several limitations of conventional antibody therapy.

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Acknowledgements

This work was supported by Swiss National Foundation NFP37, Grant 40-44820.95 (to RK) and by the donation of an anonymous client of the United Bank of Switzerland.

We are very grateful to Professor Ph. U Heitz for support of this project. We thank Alain Lamarre for a helpful discussion and Cornelia Halin for providing us with the anti-ED-B scFv L19–VEGF164 fusion protein used in a BIAcore assay.

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Authors and Affiliations

  1. Division of Cancer Research, Department of Pathology, University Hospital, Zürich, Switzerland

    T A Afanasieva, M Wittmer, A Vitaliti, M Ajmo & R Klemenz

  2. Department of Applied Biosciences, ETH Zürich, Zürich, CH-8092, Switzerland

    D Neri

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  1. T A Afanasieva
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  2. M Wittmer
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  3. A Vitaliti
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Afanasieva, T., Wittmer, M., Vitaliti, A. et al. Single-chain antibody and its derivatives directed against vascular endothelial growth factor: application for antiangiogenic gene therapy. Gene Ther 10, 1850–1859 (2003). https://doi.org/10.1038/sj.gt.3302085

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