Optimizing Clinical Translation of Bispecific T-cell Engagers through Context Unification with a Quantitative Systems Pharmacology Model.

Bispecific T-cell engagers (bsTCEs) have emerged as a promising class of cancer immunotherapy. BsTCEs enable physical connections between T cells and tumor cells to enhance T-cell activity against cancer. Despite several marketing approvals, the development of bsTCEs remains challenging, especially at early clinical translational stages. The intricate design of bsTCEs makes their pharmacologic effects and safety profiles highly dependent on patient's immunological and tumor conditions. Such context-dependent pharmacology introduces considerable uncertainty into translational efforts. In this study, we developed a Quantitative Systems Pharmacology (QSP) model, through context unification, that can facilitate the translation of bsTCEs preclinical data into clinical activity. Through characterizing the formation dynamics of immunological synapse (IS) induced by bsTCEs, this model unifies a broad range of contexts related to target affinity, tumor characteristics, and immunological conditions. After rigorous calibration using both experimental and clinical data, the model enables consistent translation of drug potency observed under diverse experimental conditions into predictable exposure-response relationships in patients. Moreover, the model can help identify optimal target-binding affinities and minimum efficacious concentrations across different clinical contexts. This QSP approach holds significant promise for the future development of bsTCEs.