Multiple myeloma cells are killed by syndecan-1-directed superantigen-activated T cells.
Multiple myeloma (MM) is an incurable plasma cell/plasmablast malignancy with a great need for innovative treatment strategies. Since experimental immunotherapy with targeted superantigens (SAg) proved to be effective in other haematopoietic tumours, we investigated whether this would also hold true for MM. We used the bacterial SAg Staphylococcus enterotoxin A (SEA), a potent activator of T cell cytotoxicity by means of its binding to particular T cell receptor Vbeta sequences on effector cells and MHC class II molecules on target cells. To eliminate potentially unspecific binding via MHC class II, SEA was point mutated (SEAm). In a second step SEAm was genetically fused to protein A (PA), resulting in a fusion protein (PA-SEAm). This fusion protein was used together with four different plasma-cell-specific/associated mAbs to direct T cells towards 10 MM target cell lines. Three of these mAbs were directed against syndecan-1/CD138, known to be highly expressed on MM and plasma cells, but absent on other haematopoietic cells. All MM cell lines proved to be sensitive to SAg-activated T cell killing (15-50% lysis), as measured in a 51Cr-release assay. This effect was clearly mediated via the plasma-cell-reactive antibodies, as control antibodies only conferred a low background lysis. MM therapy based on targeted SAgs could in theory be hampered by dysfunctional T cells in MM patients. However, we show that T cells from MM patients and healthy controls responded equally well to activation by SAg.
Ragnarsson
L
L
Clinical Immunology Division, Rudbeck Laboratory, Uppsala University, Sweden.
Strömberg
T
T
Wijdenes
J
J
Tötterman
T H
TH
Weigelt
C
C
D000911:Antibodies, Monoclonal / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000032:analysis / Q000276:immunology*; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D011509:Proteoglycans / Q000032:analysis / Q000276:immunology*; D018089:Superantigens / Q000276:immunology*; D053668:Syndecan-1; D053667:Syndecans; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D004768:Enterotoxins; D008562:Membrane Glycoproteins; D011509:Proteoglycans; C508241:SDC1 protein, human; D018089:Superantigens; D053668:Syndecan-1; D053667:Syndecans; C026066:enterotoxin A, Staphylococcal