Enhanced antitumor immunity by fusion of CTLA-4 to a self tumor antigen

The idiotypic determinant (Id) of the immunoglobulin expressed by a B-cell malignancy can serve as an effective tumor-specific antigen but is only wea kly immunogenic. This study demonstrates that the immunogenicity of the tum or Id protein can be dramatically increased by directing it to antigen-pres enting cells (APCs). Cytotoxic T-lymphocyte antigen 4 (CTLA-4) present on a ctivated T cells has a strong binding affinity to both B7-1 and B7-2 molecu les, which are primarily expressed on APCs. After construction of a fusion protein consisting of Id and CTLA-4 (Id-CTLA4), mice immunized with the fus ion protein induced high titers of Id-specific antibody and T-cell prolifer ative responses without adjuvants and were protected from lethal tumor chal lenge. The Id-CTLA4 fusion protein was so potent that even low doses (down to 0.1 mug) of the immunogen were able to elicit strong antibody responses. By using an Id-CTLA4 mutant protein, the ability to bind 87 molecules on A PCs was shown to be required for the enhanced immunogenicity of Id-CTLA4. T hese findings demonstrate that fusing CTLA-4 to a potential tumor antigen r epresents an effective approach to prime antitumor immunities in vivo and m ay be applicable to the design of vaccines for a variety of other diseases. (C) 2000 by The American Society of Hematology.