Bispecific T-cell engagers: From receptor to systems’ level modeling to rationalize dose-effect relationships

Harnessing the power of T cells to enhance anti-tumor activities beyond checkpoint inhibition has become a promising strategy in clinical management of cancer. The development of bispecific antibodies (BsAbs) that can recruit T cells to tumors (also termed T cell engagers, BiTEs or TCEs) has led to successful approval for non-solid oncology indications and is also coming of age for solid tumors. The appearance of non-monotonous and non-linear dose effect relationships as well as potentially fatal immune related adverse events require a conservative FIH strategy and comprehensive model-based extrapolations. There exist several mathematical bispecific T-cell engager QSP models that describe three body complex formation of the antibody linking receptors with various levels of detail as well as downstream T-cell activation kinetics and tumor effects. In this contribution, we would like to center on T cell kinetics, and show mechanistic approaches that could help better understand where and how quickly T-cells migrate when engaged and how one can discriminate between binding and function. We elaborate these features by elaborating between different modeling approaches on the example of CD19xCD3 and HER2xCD3 targeting T-cell engagers and we outline potential contexts of use of such models in the development life cycle.