Superantigen-staphylococal-enterotoxin-A-dependent and antibody-targeted lysis of GD2-positive neuroblastoma cells |
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Authors: | Ursula Holzer Wolfgang Bethge Frauke Krull Johannes Ihle Rupert Handgretinger Ralph A Reisfeld Mikael Dohlsten Terje Kalland Dietrich Niethammer Günther E Dannecker |
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Institution: | 1. Department of Oncology/Haematology, Children's University Hospital, Rümelinstra?e 23, 72070, Tübingen, Germany 2. Department of Immunology, The Scripps Research Institute, 92037, La Jolla, CA, USA 3. Pharmacia, Department of Oncology/Immunology, Box 724, S-22007, Lund, Sweden 4. Department of Tumor Immunology, The Wallenberg Laboratory, University of Lund, Box 7031, S-22007, Lund, Sweden
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Abstract: | 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) Vβ 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.
Received: 15 March 1995 / Accepted: 22 May 1995 |
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Keywords: | Anti-GD2 antibody Cytotoxic T cells Immunoconjugate Neuroblastoma Superantigens |
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