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 histocompatibi lity complex (MHC) class II molecules activate a high frequency of T c ells 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 cre ated a tumor-reactive SAg by engineering a fusion protein composed of a tumor-reactive mAb (C215Fab) and the bacterial SAg staphylococcal en terotoxin A (SEA), A point mutation D227A was introduced at the major MHC class II binding site in SEA to reduce systemic toxicity. Treatmen t of tumor bearing mice with the Fab-SEA D227A fusion protein resulted in profound antitumor effects with a markedly reduced toxicity as com pared with the wild type Fab-SEA fusion protein, The reduced toxicity was probably due to a weak distribution of the SEA D227A fusion protei n in tissues with a high MHC class II expression and low systemic cyto kine levels as exhibited in mice and rabbits. The data presented demon strate the efficacy of immunoconjugates containing a mutated SAg in di recting a T cell attack against tumor cells with minimal systemic immu ne activation.