Design of a split-superantigen for a safer cancer immunotherapy
The global cancer immunotherapy market is growing due to an increasing incidence of cancer. One of the potential therapies involves superantigens (SAg) – proteins produced by bacteria or viruses that are among the most potent activators of the immune system. Strong T cell activation is one of the main weaknesses of this strategy as it may lead to systemic T cell activation. We thus designed a split SAg, where SAg is split into two individually inactive fragments. The fragments come in close proximity by binding to cell surface antigens, dimerize, and reconstitute into a biologically active form capable of activating T cell response.
Our SAg of choice was a highly potent and well characterized staphylococcal enterotoxin A (SEA) from S. aureus. Proof-of-concept fusion proteins were designed, where individually inactive split SAg fragments were genetically fused to a single chain variable fragment against B cell antigen CD20 (scFv–CD20). The binding of scFv fused with split SAg fragments to target tumor antigens brings the inactive split SAg fragments into close proximity, so they can reassemble into a biologically active form to trigger a T cell response. This strategy opens the possibility of linking split SAg fragments with two different antibodies, each specific for a different tumor antigen, which could increase the selectivity for tumor cells.
Our technology makes it possible to target tumor cells without affecting healthy cells, overcoming systemic immune activation and dose-limiting toxicity. Additional benefits include high specificity by linking split SAg fragments with antibodies – possibly ones that are widely used in clinical practice for cancer treatment – and a screening technique for detecting SAg with a favorable splitting site to retain its efficacy.
Developed by: Department of Synthetic Biology and Immunology.
Technology readiness level: TRL3.
Status of intellectual property:Patent granted.
Cooperation opportunities: Intellectual property licensing.
Scientific and academic papers
Golob-Urbanc, A., Rajčević, U., Strmšek, Ž., Jerala, R. Design of split superantigen fusion proteins for cancer immunotherapy. J Biol Chem. 2019 Apr 19;294(16):6294-6305. https://doi.org/10.1074/jbc.RA118.006742.
Golob-Urbanc, Anja, 2019, Načrtovanje cepljenega superantigena za imunoterapijo raka [na spletu]. Doctoral dissertation (in the Slovenian language). Available at: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=slv&id=108009.