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Impact of chimeric immune receptor extracellular protein domains on T cell function

Gene Therapy volumeΒ 6,Β pages 412–419 (1999)Cite this article

Abstract

Chimeric immune receptors (CIR) encompass tumor- or virus-specific ligands or antibodies fused to the signaling domains of either the T cell receptor or Fc receptor. T cells expressing these receptors recapitulate the cytopathic effects mediated by the T cell receptor and allow the targeting of tumor or virus infected cells in an MHC-independent manner. With this technology, large numbers of T cells with redirected target specificity can be generated. To define the structural features of recombinant CIRs required for optimal function, a panel of five closely related CIRs with identical target specificity were generated. These receptors recognized HIVenv through the single chain Fv (scFv) of an anti-gp120 antibody. These scFv-ΞΆ receptors were constructed to include alternative extracellular spacer and transmembrane protein domains derived from members of the immunoglobulin supergene family. The effect of these alternative extracellular protein domains on receptor stability, antigen affinity and T cell activity was assessed. We demonstrate that modifying the extracellular protein domains of the anti-HIVenv CIRs significantly impacted receptor stability and substrate binding affinity and that these effects, and not simply the level of cell surface expression, correlated most strongly with changes in CIR-mediated killing. These studies will aid in the rationale design of recombinant CIRs for the immunotherapy of viral infections, cancer and other diseases.

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Authors and Affiliations

  1. Department of Preclinical Biology and Immunology, Cell Genesys Inc., 344 Lakeside Drive, Foster City, 94404, CA, USA

    S D Patel,Β M Moskalenko,Β D Smith,Β B Maske,Β M H FinerΒ &Β J G McArthur

  2. Virologic Inc., 270 E Grand Avenue, South San Francisco, 94080, CA, USA

    D Smith

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  1. S D Patel
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  2. M Moskalenko
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  3. D Smith
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  4. B Maske
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  5. M H Finer
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  6. J G McArthur
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Patel, S., Moskalenko, M., Smith, D. et al. Impact of chimeric immune receptor extracellular protein domains on T cell function. Gene Ther 6, 412–419 (1999). https://doi.org/10.1038/sj.gt.3300831

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