Ligand-Blocking and Agonist Antibodies Targeting TNFR2 Employ 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. Here, we engineered two distinct α-TNFR2 antibody types: ligand-blocking FcγR-engaging versus non-ligand-blocking agonist antibodies. Both showed potent anti-tumor efficacy across multiple syngeneic mouse tumor models and combined effectively with α-PD-1. The ligand-blocking antibody depleted intratumoral Tregs and reprogrammed the myeloid compartment, directing monocytes towards a pro-inflammatory 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 co-stimulated 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.