| Autor: |
Per Antonsson, Jesper Olsson, Mikael Dohlsten, Robert Persson, Per-Olov Gunnarsson, Lennart Ohlsson, Terje Kalland, Thomas Brodin, Morten Soegaard, Anna Molander, Roland d'Argy |
| Rok vydání: |
1998 |
| Předmět: |
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| Zdroj: |
Advanced Drug Delivery Reviews. 31:131-142 |
| ISSN: |
0169-409X |
| Popis: |
Superantigens (SAgs) are a collection of bacterial and viral proteins with potent immunostimulatory properties. SAgs bind to Major Histocompatibility Complex Class II (MHC II) molecules of antigen presenting cells (APCs) and activate a high frequency of T lymphocytes. To target a T-cell attack against tumor cells we genetically linked tumor-specific antibody Fab fragments to the SAg Staphylococcal enterotoxin A (SEA). Fab-SEA fusion protein efficiently targeted to solid tumors and induced a T-cell-mediated eradication of established metastases in animal models. Successful therapy was T-cell-dependent and required tumor specificity of the Fab moiety of the Fab-SEA fusion protein. Due to the high affinity of SAg for MHC II, a limitation of this approach was retention of Fab-SEA proteins in normal tissues expressing MHC II, which caused systemic immune activation and dose limiting toxicity. We recently solved the structure of SEA and applied structure-based drug design to develop a novel generation of `man-made' SAg with improved pharmacological 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 tumor sites was retained. The Fab-SEA mutants display a 10 000-fold higher affinity for tumor tissue compared to normal tissue and the therapeutic window was improved >100-fold compared to native Fab-SEA protein. Thus protein engineering can be applied to convert harmful bacterial toxins into tolerable tumor-specific agents. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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