Immunotherapeutic strategies to recruit T cells against tumor cells, i.e. checkpoint inhibitors (CPIs), bispecific antibodies (bsAbs) as well as the functionally closely related CART cells have become a cornerstone of oncological treatment. However, so far durable therapeutic success is limited to a minority of patients in case of CPIs, and. in case of bsAbs and CART cells, almost exclusivel to hematopoietic malignancies (rather than solid tumors). These shortcomings are due to three major limitations:

1. insufficient accessibility of tumor site for immune effector cells in case of solid tumors (in contrast to hematopoietic neoplasias)
2. dose - and thus efficacy - limiting side effects due to toxicity, due to lack of truly tumor-specific target antigens (TAAs)
3. particularly in case of bsAbs, lacking costimulation resulting in not sufficiently sustained T cell activation

In general, bsAbs appear conceptually ideal, among the three T cell-based therapeutic approaches clinically available to date, as they allow to specifically direct T cells against tumor cells (in contrast to CPIs) and are ready to use “off the shelf reagents” not requiring time-consuming and costly preparative work (in contrast to CART cells). However, almost all bsAbs presently in development comprise anti-CD3 as effector part (bsAbCD3) and thus do not provide for costimulation, resulting in suboptimal T cell activation resulting in exhaustion.