Genetically engineered superantigens as tolerable antitumor agents.
Superantigens (SAg) are a family of bacterial and viral proteins with strong immunostimulatory properties. SAg bound to major histocompatibility complex (MHC) class II molecules activate a high frequency of T cells and represent the most potent known activators of T cells to date. To explore the use of SAg for T cell-based tumor therapy we have created a tumor-reactive SAg by engineering a fusion protein composed of a tumor-reactive mAb (C215Fab) and the bacterial SAg staphylococcal enterotoxin A (SEA). A point mutation D227A was introduced at the major MHC class II binding site in SEA to reduce systemic toxicity. Treatment of tumor bearing mice with the Fab-SEA D227A fusion protein resulted in profound antitumor effects with a markedly reduced toxicity as compared with the wild-type Fab-SEA fusion protein. The reduced toxicity was probably due to a weak distribution of the SEA D227A fusion protein in tissues with a high MHC class II expression and low systemic cytokine levels as exhibited in mice and rabbits. The data presented demonstrate the efficacy of immunoconjugates containing a mutated SAg in directing a T cell attack against tumor cells with minimal systemic immune activation.
Hansson
J
J
Lund Research Center, Pharmacia & Upjohn, Sweden.
Ohlsson
L
L
Persson
R
R
Andersson
G
G
Ilbäck
N G
NG
Litton
M J
MJ
Kalland
T
T
Dohlsten
M
M
D000818:Animals; D000911:Antibodies, Monoclonal; D001665:Binding Sites; D003001:Cloning, Molecular; D016207:Cytokines / Q000097:blood; D004768:Enterotoxins / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D005818:Genetic Engineering / Q000379:methods; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity*; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation; D011817:Rabbits; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D011994:Recombinant Proteins / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013211:Staphylococcus aureus; D018089:Superantigens / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal