Monoclonal antibody-superantigen fusion proteins: tumor-specific agents for T-cell-based tumor therapy.
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.
Dohlsten
M
M
Wallenberg Laboratory, Department of Tumor Immunology, University of Lund, Sweden.
Abrahmsén
L
L
Björk
P
P
Lando
P A
PA
Hedlund
G
G
Forsberg
G
G
Brodin
T
T
Gascoigne
N R
NR
Förberg
C
C
Lind
P
P
D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000951:Antigens, Neoplasm / Q000276:immunology; D001483:Base Sequence; D002277:Carcinoma / Q000628:therapy; D003001:Cloning, Molecular; D003110:Colonic Neoplasms / Q000628:therapy; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000737:chemistry; D004768:Enterotoxins / Q000008:administration & dosage; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D018089:Superantigens / Q000737:chemistry*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D017931:DNA Primers; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal