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Complex mosaicism is a novel approach to infectivity enhancement of adenovirus type 5-based vectors

Cancer Gene Therapy volume 12, pages 475–486 (2005)Cite this article

Abstract

The use of adenovirus type 5 (Ad5) for cancer therapy is limited by deficiency of its primary cell attachment receptor, coxsackie and adenovirus receptor (CAR), on cancer cells. Ad5 retargeting to alternate receptors through fiber genetic modification can be used to circumvent CAR dependence of its tropism, and thereby achieve infectivity enhancement. Here we propose and test a novel “complex mosaicism” approach for fiber modification, which combines serotype chimerism with peptide ligand(s) incorporation in a single-fiber molecule. We incorporated integrin-binding peptide RGD-4C in the HI-loop, at the carboxy (C)-terminus, or both locales of the Ad3 knob, in the context of Ad5/3 chimera fiber in order to retarget simultaneously the Ad vector to integrins and Ad3 receptors. The infectivity enhancement of the fiber modifications was assessed in various cancer cell lines as cancer-targeting models. Replication-defective complex mosaic Ad-luc vectors bearing chimeric fiber (F.5/3), with or without C-terminal RGD-modification of Ad3 knob, demonstrated up to 55-fold gene transfer increase in bladder cancer cell lines. Although this augmentation was primarily due to Ad3 receptor targeting, some contribution of RGD-mediated integrin-targeting was also observed, suggesting that complex mosaic modification can function in a dual-receptor targeting via a single Ad3 fiber knob.

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Acknowledgements

We thank Dr Joshua J Short for providing purified recombinant Ad3 knob. We also thank Dr Joel Glasgow and Dr Nikolay Korokhov for critical comments on this manuscript.

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Author notes

  1. Anton V Borovjagin and Alexandre Krendelchtchikov: Both authors contributed equally.

Authors and Affiliations

  1. VectorLogics Inc., Birmingham, Alabama, USA

    Anton V Borovjagin, Alexandre Krendelchtchikov, Joanne T Douglas & David T Curiel

  2. Cell Genesys Inc., South San Francisco, California, USA

    Nagarajan Ramesh & De-Chao Yu

  3. Departments of Medicine, Pathology and Surgery, Division of Human Gene Therapy, University of Alabama at Birmingham, Alabama, USA

    Joanne T Douglas & David T Curiel

  4. Gene Therapy Center, University of Albama at Birmingham, Alabama, USA

    Joanne T Douglas & David T Curiel

Authors
  1. Anton V Borovjagin
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  2. Alexandre Krendelchtchikov
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  3. Nagarajan Ramesh
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  4. De-Chao Yu
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  5. Joanne T Douglas
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  6. David T Curiel
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Correspondence to Anton V Borovjagin.

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Supplementary information accompanies the paper on Cancer Gene Therapy website (http://www.nature.com/cgt).

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Borovjagin, A., Krendelchtchikov, A., Ramesh, N. et al. Complex mosaicism is a novel approach to infectivity enhancement of adenovirus type 5-based vectors. Cancer Gene Ther 12, 475–486 (2005). https://doi.org/10.1038/sj.cgt.7700806

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