Target-dependent T-cell Activation by Coligation With a PSMA×CD3 Diabody Induces Lysis of Prostate Cancer Cells
- 1 July 2009
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of Immunotherapy
- Vol. 32 (6), 565-573
- https://doi.org/10.1097/cji.0b013e3181a697eb
Abstract
Recently, we have described a bispecific PSMA×CD3 diabody with one binding site for the T-cell antigen receptor (TCR-CD3) and another for the Prostate Specific Membrane Antigen (PSMA). It effectively eliminates human prostate cancer cells by redirecting T-lymphocytes in vitro and in vivo. Here, we show that activation of the T-cells and killing of the tumor cells, only occurred when the T-cells were coincubated with PSMA-positive tumor cells and the PSMA×CD3 diabody. Both CD4+ and CD8+ human T-lymphocytes were activated. Surprisingly, they were equally potent in their cytotoxic activity, proliferation, and up-regulation of activation markers. Both, CD4+, and CD8+ T-cells mainly used the perforin-granzyme– based pathway and to a somewhat lesser extent the FasL pathway to lyse tumor cells. When Jurkat T-cells were stimulated with the diabody alone, the TCR-CD3 was not triggered. In contrast, when the diabody was clustered with a secondary antibody the TCR-CD3 was stimulated as detected by Ca2+-influx and Erk, IκB, and linker of activated T-cell phosphorylation. Clustering of the diabody could also be achieved by the dimeric PSMA antigen expressed on tumor cells. Thus, although the diabody binds to all T-cells, only those in contact with PSMA-expressing cancer cells are activated. In conclusion, the PSMA×CD3 diabody is suitable for a controlled polyclonal T-cell therapy of prostate cancer.Keywords
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