Tuning TCR complex recruitment to the T cell antigen coupler (TAC) enhances TAC-T cell function

The T cell antigen coupler (TAC) receptor is a novel synthetic receptor designed to maximize the therapeutic potential of T cells in the absence of tonic signaling or receptor-related toxicities. Prior studies indicated that TACs provide safe and long-lasting anti-tumor immunity in multiple preclinical models of solid tumors supported by mounting clinical evidence. TAC receptors function by targeting a cancer associated surface antigen while recapitulating natural T cell receptor (TCR) signaling, which involves both TCR/CD3 recruitment and intracellular CD4 co-receptor activity. While other receptor designs exist that redirect TCR signaling towards cancer associated antigens, the TAC technology is unique in that antigen binding is distinctly separated from TCR/CD3 complex recruitment. In the present study, we show that single amino-acid changes in the TAC domain responsible for TCR recruitment of a Claudin 18.2-directed TAC receptor led to enhanced in vivo functionality. Analyzing biophysical properties of the receptor suggests that TAC receptors with high TCR affinities are suboptimal compared to receptor constructs that show lower TCR affinities with notably fast off-rates. This work demonstrates that balancing TCR recruitment is critical when designing effective TAC T cell receptors, a concept that may apply more broadly to other therapeutic approaches relying on TCR signaling.