Non-clinical characteristics of BH3120, a clinical stage bispecific antibody targeting PD-L1 and 4-1BB, in combination with CD3 T cell engagers

In the tumor microenvironment (TME), T cell activation often leads to upregulation of immune checkpoints such as PD-1 and PD-L1. This adaptive resistance mechanism, combined with insufficient co-stimulatory signals, creates an immunosuppressive milieu that compromises T cell cytotoxicity and contributes to resistance against T cell-targeted immunotherapies. Activation of T cells with CD3 stimulation alone is often associated with cytokine-related safety concerns and limited efficacy in solid tumors. To overcome the limitation with CD3 T cell engagers, different combination strategies have been discussed and co-stimulatory signals have been suggested as potential combination partner of T cell stimulators. BH3120 is a clinical-stage bispecific antibody designed to induce 4-1BB co-stimulation in a PD-L1-positive tumor tissue-localized manner, promoting immune activation within the TME while minimizing immune-related adverse events (irAEs), including liver toxicity. The therapeutic potential of BH3120 in combination with CD3 T cell engagers was evaluated, demonstrating enhanced T cell activation and specific lysis of tumor cells in vitro. Furthermore, this combination regimen exhibited synergistic tumor growth inhibition across different animal models without significant safety concerns. These findings support BH3120 as a rational combination partner for T cell-engaging therapies, offering a promising strategy to overcome adaptive immune resistance while minimizing systemic toxicities.