Targeting Strategy for Gene Delivery to Carcinoembryonic Antigen-Producing Cancer Cells by Retrovirus Displaying a Single-Chain Variable Fragment Antibody

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Abstract
Cancer-specific antigens are promising targets for the specific delivery of certain drugs or genes to cancer cells in cancer therapy. Carcinoembryonic antigen (CEA) is one of the cancer-associated antigens predominantly detected in the gastrointestinal cancer of the colon and stomach. Targeting strategies for CEA-producing cancer cells have been thoroughly developed mainly by the production of monoclonal antibodies to CEA and further single-chain variable fragment (scFv) antibodies. Here, we have generated Moloney murine leukemia virus-derived retroviral vectors co-displaying an anti-CEA scFv-envelope chimeric protein and an unmodified envelope protein to deliver a gene for hepres simplex virus thymidine kinase (HSV-tk) or Escherichia coli β-galactosidase. The harvested viruses successfully incorporated the chimeric envelope protein as well as the unmodified envelope into the viral particles, and specifically bound to and infected human CEA-producing cancer cells via recognition of CEA, depending on the CEA-producing phenotype of the target cells. These results may have significant implications for the use of scFv directed against tumor-specific antigens for targeting specific antigen-producing cancer cells, a potential step toward in vivo cancer therapy. Targeting to tumor-specific antigens is a powerful approach to obtain safe and efficient therapeutic effects in cancer gene therapy. The present study showed that a murine leukemia virus-derived virus co-displaying an anti-CEA scFv-envelope protein and an unmodified envelope could infect human CEA-producing cancer cells and deliver a suicide gene to human CEA-producing cancer cells specifically through the recognition of CEA, depending on the CEA-producing phenotype of the target cells. This strategy may possibly lead to a specific killing of the antigen-producing cancer cells by specific suicide gene delivery, and may also be applied to other tumor-specific cell-surface antigens or receptors expressed solely on cancer cells. However, further improvement is required to achieve more efficient and specific retroviral gene transfer. For this purpose, the following issues should be addressed: Appropriate target antigens or receptors on target cells should be selected to facilitate more efficient viral infection of the target cells; high-affinity scFv antibodies should then be selected; and appropriate scFv insertion sites in the envelope protein, an appropriate linker size between the scFv and the envelope, and an appropriate expression ratio of the chimeric envelope to the unmodified envelope should be determined.