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  • Viral Transfer Technology
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Signaling antibodies complexed with adenovirus circumvent CAR and integrin interactions and improve gene delivery

Gene Therapy volume 7, pages 1593–1599 (2000)Cite this article

Abstract

Current adenoviral (Ad) vectors cannot be targeted to specific cell types due to the widespread distribution of the Ad receptor (CAR). Moreover, CAR and/or internalization receptors (αv integrins) are absent or present at low levels on some cell types, rendering them resistant to Ad-mediated gene delivery. To address these problems, we have developed a novel vector targeting approach that takes advantage of the common cell signaling pathways initiated by ligation of αv integrins and growth factor receptors. Recombinant growth factor/cytokines (TNF-α, IGF-1, EGF) which trigger phosphatidylinositol-3-OH kinase (PI3K) activation, a signaling molecule involved in adenovirus internalization, were fused to a monoclonal antibody specific for the viral penton base. Ad vectors complexed with these bifunctional mAbs increased gene delivery 10 to 50-fold to human melanoma cells lacking αv integrins. The bifunctional mAbs also enhanced gene delivery by fiberless adenovirus particles which cannot bind to CAR. Improved gene delivery correlated with increased virus internalization and attachment as well as PI3K activity. The use of bifunctional mAbs to trigger specific cell signaling pathways offers a widely applicable method for bypassing the normal Ad receptors in gene delivery and potentially increasing the selectivity of gene transfer.

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Acknowledgements

This research was supported by grants RO1 EY11431 and RO1 HL54352 from the National Institutes of Health and from SFP1089 from the Novartis Corporation. E Li was supported by NIH T32 AI07354. We would like to thank Catalina Hope and Joan Gausepohl for preparation of this manuscript. This is manuscript No. 12865 -IMM at The Scripps Research Institute.

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Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA

    E Li, S L Brown, D J Von Seggern & G R Nemerow

  2. Invitrogen, Carlsbad, CA, USA

    G B Brown

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  1. E Li
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  3. D J Von Seggern
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  4. G B Brown
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Li, E., Brown, S., Von Seggern, D. et al. Signaling antibodies complexed with adenovirus circumvent CAR and integrin interactions and improve gene delivery. Gene Ther 7, 1593–1599 (2000). https://doi.org/10.1038/sj.gt.3301271

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