MAN-MADE SUPERANTIGENS - TUMOR-SELECTIVE AGENTS FOR T-CELL-BASED THERAPY

Superantigens (SAgs) are a collection of bacterial and viral proteins with potent immunostimulatory properties. SAgs bind to Major Histocomp atibility Complex Class II (MHC II) molecules of antigen presenting ce lls (APCs) and activate a high frequency of T lymphocytes. To target a T-cell attack against tumor cells we genetically linked tumor-specifi c antibody Fas fragments to the SAg Staphylococcal enterotoxin A (SEA) . Fab-SEA fusion protein efficiently targeted to solid tumors and indu ced a T-cell-mediated eradication of established metastases in animal models. Successful therapy was T-cell-dependent and required tumor spe cificity of the Fas moiety of the Fab-SEA fusion protein. Due to the h igh affinity of SAg for MHC II, a limitation of this approach was rete ntion of Fab-SEA proteins in normal tissues expressing MHC II, which c aused systemic immune activation and dose limiting toxicity. We recent ly solved the structure of SEA and applied structure-based drug design to develop a novel generation of 'man-made' SAg with improved pharmac ological and pharmacokinetic properties, Mutation of the major MHC II binding site of SEA substantially reduced retention in MHC II; tissues and systemic toxicity, while local immune activation at targeted tumo r sites was retained. The FLU-SEA mutants display a 10 000-fold higher affinity for tumor tissue compared to normal tissue and the therapeut ic window was improved > 100-fold compared to native Fab-SEA protein, Thus protein engineering can be applied to convert harmful bacterial t oxins into tolerable tumor-specific agents. (C) 1998 Elsevier Science B.V.