Open AccessMonoclonal antibody-superantigen fusion proteins: tumor-specific agents for T-cell-based tumor therapy.
Author(s) -
Mikael Dohlsten,
Lars Abrahmsén,
Per Björk,
Peter A. Lando,
Gunnar Hedlund,
G. Forsberg,
Thomas Brodin,
Nicholas R. J. Gascoigne,
Cecilia Förberg,
Peter Lind
Publication year - 1994
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.91.19.8945
Subject(s) - fusion protein , major histocompatibility complex , superantigen , biology , antigen , mhc class i , monoclonal antibody , antigen presentation , tumor antigen , cancer research , microbiology and biotechnology , antibody , t cell , immunotherapy , immune system , immunology , recombinant dna , biochemistry , gene
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.