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Background B7-H7 is a unique immunomodulatory receptor that can suppress T and NK cell activation through KIR3DL3 and stimulate T and NK cells through TMIGD2. NextPoint has developed T cell engagers that bind CD3 and B7-H7 with differential ability to allow for TMIGD2 interaction. T cell engagers that spared TMIGD2 binding to B7-H7 demonstrated enhanced T cell activation and potency against B7-H7+ tumors compared to those that blocked this interaction. Additional in vitro assays demonstrated the specific role of TMIGD2 co-stimulation as the source of increased T cell engager activity. As a follow-on, NextPoint Therapeutics has generated trispecific constructs with separate domains targeting the tumor antigen B7-H7, CD3, and TMIGD2 for potent anti-tumor T cell activity. The TMIGD2 binding arm co-stimulates T cells independent of the natural B7-H7-TMIGD2 interaction, expanding the potential applicability of the antibody beyond B7-H7 expressing tumor cells to other tumor targets.Methods Bispecific CD3/B7-H7 T cell engagers were generated with and without TMIGD2 binding capabilities. T cell engagers were evaluated for T cell anti-tumor activity in vitro and in vivo. Upon confirmation of the specific role of TMIGD2, CD3/TMIGD2/B7-H7 trispecific antibodies were generated and compared to the parental CD3/B7-H7 bispecific antibody for binding and anti-tumor T cell activation using a Jurkat reporter system with or without overexpression of TMIGD2. The role of TMIGD2 co-stimulation in primary T cell activation studies was further explored.Results CD3/B7-H7 T cell engagers with TMIGD2 co-stimulation induced substantial T cell activation in vitro and had potent anti-tumor activity in B7-H7+ tumor models in vivo. Antibody blockade of TMIGD2 co-stimulation confirmed the specific role of TMIGD2 in the observed potency. CD3/TMIGD2/B7-H7 trispecific antibodies demonstrated even stronger tumor-specific immune cell activation as compared to the parental bispecific in Jurkat reporter cells lines and primary cell in vitro assays.Conclusions Co-stimulation via TMIGD2 in a T cell engager demonstrated significant target dependent activation in vitro and in vivo. Trispecific antibodies targeting CD3, TMIGD2, and B7-H7 demonstrated potent anti-tumor immune activation. A trispecific T cell engager with a TMIGD2 co-stimulatory domain has the potential to induce particularly potent anti-tumor activity and potentially improve the potency of bispecific T cell engagers. As such, NextPoint has begun characterizing T cell engagers for additional tumor targets, confirming the broad utility of TMIGD2 co-stimulation.