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T Cell Retargeting with MHC Class I-Restricted Antibodies: The CD28 Costimulatory Domain Enhances Antigen-Specific Cytotoxicity and Cytokine Production¹

Ralph A. Willemsen^2,*, Cees Ronteltap^*, Patrick Chames, Reno Debets^* and Reinder L. H. Bolhuis^*

^* Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus Medisch Centrum Daniel den hoed, Rotterdam, The Netherlands; and Cellectis, Romainville, France

T cells require both primary and costimulatory signals for optimal activation. The primary Ag-specific signal is delivered by engagement of the TCR. The second Ag-independent costimulatory signal is mediated by engagement of the T cell surface costimulatory molecule CD28 with its target cell ligand B7. However, many tumor cells do not express these costimulatory molecules. We previously constructed phage display derived F_AB, G8, and Hyb3, Ab-based receptors with identical specificity but distinct affinities for HLA-A1/MAGE-A1, i.e., "TCR-like" specificity. These chimeric receptors comprised the FcRI- signaling element. We analyzed whether linking the CD28 costimulation structure to it ( + CD28) could affect the levels of MHC-restricted cytolysis and/or cytokine production. Human scFv-G8^POS T lymphocytes comprising the + CD28 vs the signaling element alone produced substantially more IL-2, TNF-, and IFN- in response to HLA-A1/MAGE-A1^POS melanoma cells. Also a drastic increase in cytolytic capacity of scFv-G8^POS T cells, equipped with + CD28 vs the -chain alone was observed.

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