Monoclonal antibody-superantigen fusion proteins: tumor-specific agents for T-cell-based tumor therapy.
AUTOR(ES)
Dohlsten, M
RESUMO
The bacterial superantigen staphylococcal enterotoxin A (SEA) is an extremely potent activator of T lymphocytes when presented on major histocompatibility complex (MHC) class II molecules. To develop a tumor-specific superantigen for cancer therapy, we have made a recombinant fusion protein of SEA and the Fab region of the C215 monoclonal antibody specific for human colon carcinoma cells. SEA as part of a fusion protein showed a > 10-fold reduction in MHC class II binding compared to native SEA, and accordingly, the affinity of the FabC215-SEA fusion protein for the C215 tumor antigen was approximately 100-fold stronger than to MHC class II molecules. The FabC215-SEA fusion protein efficiently targeted T cells to lyse C215+ MHC class II- human colon carcinoma cells, which demonstrates functional substitution of the MHC class II-dependent presentation of SEA with tumor specificity. Treatment of mice carrying B16 melanoma cells expressing a transfected C215 antigen resulted in 85-99% inhibition of tumor growth and allowed long-term survival of animals. The therapeutic effect was dependent on antigen-specific targeting of the FabC215-SEA fusion protein, since native SEA and an antigen-irrelevant FabC242-SEA fusion protein did not influence tumor growth. The results suggest that Fab-SEA fusion proteins convey superantigenicity on tumor cells, which evokes T cells to suppress tumor growth.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=44723Documentos Relacionados
- Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors
- Myeloma Proteins as Tumor-Specific Transplantation Antigens
- Cellular requirements for tumor-specific immunity elicited by heat shock proteins: tumor rejection antigen gp96 primes CD8+ T cells in vivo.
- Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment
- Induction of type I IFN is required for overcoming tumor-specific T-cell tolerance after stem cell transplantation