Ligand-Blocking and Agonist Antibodies Targeting TNFR2 Use Distinct Modes of Action to Induce Antitumor Immunity.

Although checkpoint inhibitors have revolutionized cancer treatment, responses are largely restricted to targeting CTLA-4 and PD-(L)1. TNFR2 has been identified as a promising target, but further therapeutic development requires a better understanding of whether agonists or blockers should be used and whether FcγR interactions promote efficacy. In this study, we engineered two distinct α-TNFR2 antibody types: ligand-blocking FcγR-engaging versus non-ligand-blocking agonist antibodies. Both showed potent antitumor efficacy across multiple syngeneic mouse tumor models and combined effectively with α-PD-1. The ligand-blocking antibody depleted intratumoral regulatory T cells (Treg) and reprogrammed the myeloid compartment, directing monocytes toward a proinflammatory macrophage and dendritic cell trajectory. Interestingly, this effect depended on both inhibitory and activating FcγRs, reflecting the simultaneous action on Tregs and myeloid cells. In contrast, the agonist directly costimulated T and NK cells, partially through FcγR-independent mechanisms. Both antibodies converged on activating tumor-specific CD8+ T cells mediating tumor rejection. Clinical assessment of both ligand-blocking (BI-1808) and agonist (BI-1910) α-TNFR2 antibodies is currently ongoing. SIGNIFICANCE: Identification and mechanistic characterization of two functionally distinct TNFR2 targeting antibodies highlights factors important for leveraging this target for successful cancer immunotherapy.