Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Treatment of cancer with tumor targeted superantigens

G Forsberg PhD, K Behm BSc, T Brodin MD PhD, M Celander BSc, T Nederman PhD, L Nielsen PhD, L Ohlsson PhD, A Sjöberg PhD, M Wallén-Öhman PhD

Active Biotech Research, Box 724, 220 07 Lund, Sweden,

AIM: We want to overcome limitations in the use of monoclonal antibodies, mAbs, for treatment of solid tumours, such as limited ability to penetrate the tumor, heterogeneity in expression of the antigens and modest potency. Therefore, fusion proteins between Fab moieties of tumour selective mAbs and the superantigen Staphylococcal enterotoxin A, SEA, an extremely potent activator of T lymphocytes, were made. METHODS: Fab-SEA fusion proteins were produced in Escherichia coli and investigated for therapy using a transfected B16 melanoma lung metastasis model. RESULTS: Fab-SEA localises to experimental tumours and activates T cells to eradicate tumour cells. However, repeated injections of SEA induce a state of T cell unresponsiveness, which we are trying to circumvent. Here we show that combining Fab-SEA with interleukin 2, IL-2, leads to sustained T cell activation. Also, the levels of both CD4 and CD8 positive T cells, as well as tumouricidal cytokines such as TNF-alpha and IFN-gamma, are increased in the tumour tissue after repeated injections of the combination therapy. These levels were not affected by antibody targeting of IL-2. When animals receive Fab-SEA intravenously and IL-2 either via an osmotic pump or subcutanously, significant improvement in the therapy is observed compared to Fab-SEA alone. Fab-SEA constructs have been investigated in clinical phase I studies with encouraging results, especially for therapy of nonsmall cell lung cancer. The results obtained from preclinical studies with combination therapy with IL-2 are used to design clinical trials. CONCLUSIONS: Fab-SEA therapy is an interesting approach for cancer treatment. This concept can be further potentiated with IL-2.

KEY WORDS: Antibody, Fusion protein, Superantigen, Targeting, Immunotherapy, Cytokine.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on synergistic therapies.