Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM (original) (raw)

Gene Therapy volume 6, pages 1469–1474 (1999)Cite this article

Abstract

The utility of adenoviral vectors for cancer therapy is limited due to their lack of specificity for tumor cells. In order to target adenovirus to tumor, the natural tropism of the adenovirus should be ablated and replaced by a tumor-specific binding domain. To this end, a neutralizing anti-fiber antibody conjugated to an anti-EpCAM antibody was created that targets the adenovirus to the EpCAM antigen present on tumor cells. The EpCAM antigen was chosen as the target because this antigen is highly expressed on a variety of adenocarcinomas of different origin such as breast, ovary, colon and lung, whereas EpCAM expression is limited in normal tissues. In these studies, the EpCAM-targeted adenovirus was shown to infect specifically cancer cell lines of different origin expressing EpCAM such as ovary, colon and head and neck. Gene transfer was blocked by excess anti-EpCAM antibody and dramatically reduced in EpCAM negative cell lines, thus showing the specificity of the EpCAM-targeted adenovirus. Importantly, infection with targeted adenovirus was independent of CAR, which is the natural receptor for adenovirus binding, since blocking of CAR with recombinant fiber knob did not affect infection with targeted adenovirus. Apart from the cancer cell lines, the efficacy of targeted viral infection was studied in freshly isolated primary human colon cancer cells. As colon cancer predominantly metastasizes to liver, and adenovirus has a high tropism for hepatocytes, we also sought to determine if the EpCAM-targeted adenovirus showed reduced infectivity of human liver cells. The bispecific antibody could successfully mediate gene transfer to primary human colon cancer cells, whereas it almost completely abolished infection of liver cells. This work thus demonstrates that EpCAM-targeted adenoviral vectors can be specifically directed to a wide variety of adenocarcinomas. This approach may prove to be useful for selective gene therapy of cancer.

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References

  1. Bergelson JM et al. Isolation of a common receptor for Coxsackie Bviruses and adenoviruses 2 and 5 Science 1997 275: 1320–1323
    Article CAS PubMed Google Scholar
  2. Douglas JT et al. Targeted gene delivery by tropism-modified adenoviral vectors Nature Biotechnol 1996 14: 1574–1578
    Article CAS Google Scholar
  3. Watkins SJ et al. The adenobody approach to viral targeting – specific and enhanced adenoviral gene delivery Gene Therapy 1997 4: 1004–1012
    Article CAS PubMed Google Scholar
  4. Rogers BE et al. Use of a novel cross-linking method to modify adenovirus tropism Gene Therapy 1997 4: 1387–1392
    Article CAS PubMed Google Scholar
  5. Wickham TJ et al. Targeted adenovirus gene transfer to endothelial and smooth muscle cells by using bispecific antibodies J Virol 1996 70: 6831–6838
    CAS PubMed PubMed Central Google Scholar
  6. Li W et al. Human colorectal cancer (CRC) antigen CO17-1A/GA733 encoded by adenovirus inhibits growth of established CRC cells in mice J Immunol 1997 159: 763–769
    CAS PubMed Google Scholar
  7. Edwards DP et al. Monoclonal antibody identification and characterization of a Mr 43,000 membrane glycoprotein associated with human breast cancer Cancer Res 1986 46: 1306–1317
    CAS PubMed Google Scholar
  8. Haisma HJ et al. Construction and characterization of a fusion protein of single-chain anti-carcinoma antibody 323/A3 and human beta-glucuronidase Cancer Immunol Immunother 1998 45: 266–272
    Article CAS PubMed Google Scholar
  9. Riethmuller G et al. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes’ C colorectal carcinoma. German Cancer Aid 17-1A Study Group (see comments) Lancet 1994 343: 1177–1183
    Article CAS PubMed Google Scholar
  10. Woo DV, Li D, Mattis JA, Steplewski Z . Selective chromosomal damage and cytotoxicity of 125l-labeled monoclonal antibody 17-1a in human cancer cells Cancer Res 1989 49: 2952–2958
    CAS PubMed Google Scholar
  11. Wickham TJ et al. Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types Nature Biotechnol 1996 14: 1570–1573
    Article CAS Google Scholar
  12. Krasnykh V et al. Characterization of an adenovirus vector containing heterologous peptide epitope in the Hi loop of the fiber knob J Virol 1998 72: 1844–1852
    CAS PubMed PubMed Central Google Scholar
  13. Yee D et al. Adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase in an ascites model of human breast cancer Hum Gene Ther 1996 7: 1251–1257
    Article CAS PubMed Google Scholar
  14. Sterman DH et al. Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy – results of a phase I clinical trial in malignant mesothelioma Hum Gene Ther 1998 9: 1083–1092
    Article CAS PubMed Google Scholar
  15. Peters LC, Hanna MG Jr . Active specific immunotherapyof established micrometastases: effect of cryopreservationprocedures on tumor cell immunogenicity in guinea pigs J NatlCancer Inst 1980 64: 1521–1525
    CAS Google Scholar
  16. Herz J, Gerard RD . Adenovirus-mediated transfer of low density lipoprotein receptor gene acute accelerates cholesterol clearance in normal mice Proc Nat Acad Sci USA 1993 90: 2812–2816
    Article CAS PubMed PubMed Central Google Scholar

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Acknowledgements

This work was supported in part by the American Lung Association (DTC), the American Heart Association (DTC), NIH grants CA74242 (DTC), CA68245 (DTC), and RO1 HL-50255 (DTC).

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Authors and Affiliations

  1. Department of Medical Oncology, Gene Therapy Program, University Hospital Vrije Universiteit, Amsterdam, The Netherlands
    H J Haisma, H M Pinedo, A van Rijswijk, I van der Meulen-Muileman, V W van Beusechem & W R Gerritsen
  2. Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA
    B W Tillman & D T Curiel
  3. Selective Genetics, San Diego, CA, USA
    B A Sosnowski & W Ying

Authors

  1. H J Haisma
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  2. H M Pinedo
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  3. A van Rijswijk
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  4. I van der Meulen-Muileman
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  5. B A Sosnowski
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  6. W Ying
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  7. V W van Beusechem
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  8. B W Tillman
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  9. W R Gerritsen
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  10. D T Curiel
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Haisma, H., Pinedo, H., van Rijswijk, A. et al. Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM.Gene Ther 6, 1469–1474 (1999). https://doi.org/10.1038/sj.gt.3300969

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