T cell–mediated depletion of intratumoral regulatory T cells using a CCR8xCD3 T cell–engaging bispecific antibody (TCB) promotes antitumor immunity in preclinical mouse models

T cell–engaging bispecific antibodies (TCBs) have seen notable successes in hematologic malignancies, and emerging data demonstrate their potential for the treatment of solid tumors. Most oncology applications of TCBs have focused on targeting tumor cells via tumor-specific antigens; however, TCBs have been underutilized for strategic depletion of immunosuppressive cells in the TME. Regulatory T cells (T reg cells) play a crucial role in suppressing antitumor immune responses, making them an attractive target for immune-based therapies. T reg cells express several surface markers that can serve as potential targets for antibody-mediated depletion, including C-C chemokine receptor type 8 (CCR8), which is highly enriched on tumor-infiltrating T reg cells. Monoclonal antibody (mAb)–mediated T reg cell depletion relies on natural killer (NK) cells, which can be scarce in some solid tumors, whereas TCBs can broadly engage the T cell compartment by overwriting antigen specificity and redirecting potent T cell cytotoxicity against target cells. Here, we have developed a CCR8xCD3 TCB and show that it effectively depletes CCR8-expressing T reg cells in a T cell–mediated manner. CCR8xCD3 TCB led to the selective depletion of intratumoral T reg cells from human solid tumor samples in vitro and mediated inhibition of tumor growth in multiple syngeneic tumor models with variable levels of T cell infiltration alone or in combination with anti–PD-L1. In cynomolgus monkeys, CCR8xCD3 TCB was well tolerated without evidence of acute phase inflammation or cytokine release syndrome and led to effective and durable depletion of the CCR8-expressing subset of T reg cells.