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T Cell Activation by Antibody-Like Immunoreceptors: Increase in Affinity of the Single-Chain Fragment Domain above Threshold Does Not Increase T Cell Activation against Antigen-Positive Target Cells but Decreases Selectivity¹

Markus Chmielewski^*, Andreas Hombach^*, Claudia Heuser^*, Gregory P. Adams and Hinrich Abken^2,*

^* Klinik I für Innere Medizin, Tumorgenetik, Kliniken der Universität zu Köln, and Center for Molecular Medicine Cologne, Köln, Germany; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111

Chimeric TCRs with an Ab-derived binding domain confer predefined specificity and MHC-independent target binding to T cells for use in adoptive immunotherapy. We investigated the impact of receptor binding affinity on the activation of grafted T cells. A series of anti-ErbB2 single-chain fragment binding domains with a K_d ranging from 3.2 x 10^–7 to 1.5 x 10^–11 M was linked to CD3-derived immunoreceptors and expressed in human PBL. Solid phase bound ErbB2 protein triggered activation of receptor-grafted T cells in a dose-dependent manner. The activation threshold inversely correlated with the affinity of the receptor binding domain. The maximum level of cellular activation, however, was the same and independent of the binding affinity. Upon binding to ErbB2⁺ cells, T cells grafted with immunoreceptors carrying a single-chain fragment of K_d < 10^–8 M were activated in a similar fashion against cells with different amounts of ErbB2 on the surface. T cells with a low affinity receptor (K_d > 10^–8 M), however, were activated exclusively by cells with high amounts of ErbB2. In conclusion, recombinant immunoreceptors of higher affinity do not necessarily induce a more potent activation of T cells than low affinity immunoreceptors, but the higher affinity immunoreceptors exhibit less discrimination between target cells with high or low Ag expression levels.

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