Superantigen-staphylococcal-enterotoxin-A-dependent and antibody-targeted lysis of GD2-positive neuroblastoma cells.
Superantigens such as the staphylococcal enterotoxin A (SEA) are among the most potent T cell activators known. They bind to major histocompatibility complex (MHC) class II molecules and interact with T cells depending on their T cell receptor (TCR) V beta expression. Superantigens also induce a variety of cytokines and trigger a direct cytotoxic effect against MHC-class-II-positive target cells. In order to extend superantigen-dependent cell-mediated cytotoxicity (SDCC) to MHC-class-II-negative neuroblastoma cells, SEA was linked to the anti-ganglioside GD2 human/mouse chimeric monoclonal antibody (mAb) ch14.18. Ganglioside GD2 is expressed on most tumours of neuroectodermal origin but is expressed to a lesser extent on normal tissues. The linkage of ch14.18 to SEA was achieved either with a protein-A-SEA fusion protein or by chemical coupling. Both constructs induced T-cell-mediated cytotoxicity towards GD2-positive neuroblastoma cells in an effector-to-target(E:T)-ratio- and dose-dependent manner in vitro. To reduce the MHC class II affinity of SEA, a point mutation was introduced in the SEA gene (SEAm9) that resulted in 1000-fold less T cell killing of MHC-class-II-expressing cells as compared to native SEA. However, a protein-A-SEAm9 fusion protein mediated cytotoxicity similar to that of protein-A-SEA on ch14.18-coated, MHC-class-II-negative neuroblastoma cells. Taken together, these findings suggest that superantigen-dependent and monoclonal-antibody-targeted lysis may be a potent novel approach for neuroblastoma therapy.
Holzer
U
U
Children's University Hospital, Department of Oncology/Haematology, Tübingen, Germany.
Bethge
W
W
Krull
F
F
Ihle
J
J
Handgretinger
R
R
Reisfeld
R A
RA
Dohlsten
M
M
Kalland
T
T
Niethammer
D
D
Dannecker
G E
GE
D000911:Antibodies, Monoclonal / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D005732:Gangliosides / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D013205:Staphylococcal Protein A / Q000276:immunology; D018089:Superantigens / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D004768:Enterotoxins; D005732:Gangliosides; D000949:Histocompatibility Antigens Class II; D013205:Staphylococcal Protein A; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal; C019403:ganglioside, GD2