TNFR2/CCR8 bispecific antibody enhances antitumor activity through depleting Ti-Tregs and boosting effector CD8(+) T cell function.

Modulation or depletion of tumor-infiltrating Tregs (Ti-Tregs) is a promising strategy in the field of antitumor immunotherapy. However, this approach poses challenges due to the diversity within the Treg population and the lack of precision in targeting Ti-Tregs. To selectively and efficiently eliminate Ti-Tregs while sparing other immune cells, we developed a bispecific antibody, FT10-Fab, targeting TNFR2 and CCR8, which are highly expressed on Ti-Tregs. Our results showed that FT10-Fab outperformed the monotherapies in several tumor models by significantly reducing the proportion of Ti-Tregs while increasing the proportion of CD8(+) T cells. FT10-Fab was able to target and eliminate Ti-Tregs expressing TNFR2 or CCR8 (TNFR2(+)or CCR8(+) Tregs), particularly TNFR2(+) CCR8(+) Tregs, which are the most important proliferative and protumorigenic Tregs. In addition, FT10-Fab relies on CD8(+) T cells for its antitumor function and induces robust immune memory. Furthermore, the combination of FT10-Fab with PD-1 blockade showed synergistic therapeutic efficacy against tumors by significantly suppressing Tregs and enhancing effector CD8(+) T cell function. Taken together, our findings suggest that precision depletion of Ti-Tregs via the bispecific TNFR2/CCR8 antibody is a potential therapeutic for cancer immunotherapy, while combination with anti-PD1 amplifies the antitumor effect.