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Single-chain antibody-based gene therapy: inhibition of tumor growth by in situ production of phage-derived human antibody fragments blocking functionally active sites of cell-associated matrices

Gene Therapy volume 9, pages 1049–1053 (2002)Cite this article

Abstract

Experimental evidence suggests that blocking the interactions between endothelial cells and extracellular matrix (ECM) components may provide a potent and general strategy to inhibit tumor neovascularization. Based on these considerations, we have focused our efforts on laminin, component of the vascular basement membrane of every tumor-associated vessel, which serves an essential role in tube formation. We screened anti-laminin single-chain antibody fragments (scFv) derived from a human phage-display library and identified one that blocks the formation of capillary-like structures in vitro. This scFv inhibits angiogenesis in vivo in the chick embryo chorioallantoic membrane assay and prevents the establishment and growth of subcutaneous tumors in mice, either when administered as bolus protein therapy or when produced locally by gene-modified tumor cells. Our work represents the first demonstration of a direct in vivo therapeutic effect of a single-chain antibody secreted by gene-modified mammalian cells. These results open the way for a new antibody-based gene therapy strategy of cancer.

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Acknowledgements

This study was supported by the Fondo de Investigación Sanitaria (grants 99/0496 and 99/6047 to LA-V), the Helen C Levitt Endowed Visiting Professorship in Molecular Medicine at Mayo Foundation (to LA-V), the Danish Research Council (to PK) and the Carlsberg Foundation (to PK). LS was supported by the European Commission. BB is a recipient of a Comunidad Autónoma de Madrid training grant (01/0369/2000). We gratefully acknowledge JR Ramirez, C Corbacho and V Sánchez for immunohistochemical studies; E de la Rosa for chick CAM assays; M Santos and M Fuente for animal care; I Millán for statistical analysis; and MJ de Pablos for expert secretarial assistance.

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Authors and Affiliations

  1. Department of Immunology, Hospital Universitario Clínica Puerta de Hierro, Madrid, Spain

    L Sanz, B Blanco & L Álvarez-Vallina

  2. Department of Molecular and Structural Biology, University of Aarhus, Denmark

    P Kristensen

  3. Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota, USA

    S Facteau & SJ Russell

  4. Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

    G Winter

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  1. L Sanz
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Sanz, L., Kristensen, P., Blanco, B. et al. Single-chain antibody-based gene therapy: inhibition of tumor growth by in situ production of phage-derived human antibody fragments blocking functionally active sites of cell-associated matrices. Gene Ther 9, 1049–1053 (2002). https://doi.org/10.1038/sj.gt.3301725

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