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Superantigen-staphylococal-enterotoxin-A-dependent and antibody-targeted lysis of GD2-positive neuroblastoma cells

  • Original Article
  • Anti-GD2 Antibody, Cytotoxic T Cells, Immunoconjugate, Neuroblastoma, Superantigens
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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 ch 14.18 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.

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Authors and Affiliations

  1. Department of Oncology/Haematology, Children's University Hospital, Rümelinstraße 23, 72070, Tübingen, Germany

    Ursula Holzer (recipient of a scholarship of the Kind-Philipp-Stiftung für Leukämieforschung grant T020/02.003/93), Wolfgang Bethge, Frauke Krull, Johannes Ihle, Rupert Handgretinger, Dietrich Niethammer & Günther E. Dannecker

  2. Pharmacia, Department of Oncology/Immunology, Box 724, S-22007, Lund, Sweden

    Mikael Dohlsten & Terje Kalland

  3. Department of Tumor Immunology, The Wallenberg Laboratory, University of Lund, Box 7031, S-22007, Lund, Sweden

    Mikael Dohlsten & Terje Kalland

  4. Department of Immunology, The Scripps Research Institute, 92037, La Jolla, CA, USA

    Ralph A. Reisfeld

Authors
  1. Ursula Holzer
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  2. Wolfgang Bethge
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  3. Frauke Krull
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  4. Johannes Ihle
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  5. Rupert Handgretinger
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  6. Ralph A. Reisfeld
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  7. Mikael Dohlsten
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  8. Terje Kalland
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  9. Dietrich Niethammer
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  10. Günther E. Dannecker
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Additional information

This work was supported by Deutsche Krebshilfe Grant W23/92/Da2 (Mildred Scheel Stiftung).

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Holzer, U., Bethge, W., Krull, F. et al. Superantigen-staphylococal-enterotoxin-A-dependent and antibody-targeted lysis of GD2-positive neuroblastoma cells. Cancer Immunol Immunother 41, 129–136 (1995). https://doi.org/10.1007/BF01527409

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  • DOI: https://doi.org/10.1007/BF01527409

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