A bispecific ADC against CCR8 and TNFR2 elicits potent antitumor efficacy

Abstract

Tumor-infiltrating regulatory T (Ti-Treg) cells play a pivotal role in suppressing antitumor immune responses within tumor microenvironment. Targeted depletion of Treg cells has emerged as a promising strategy to enhance antitumor immunity. However, current approaches such as antibody-drug conjugates (ADCs) that target a single Treg-associated antigen often suffer from limited specificity and efficacy. Here, we developed four formats of bispecific antibodies (BsAbs) targeting mouse C–C motif chemokine receptor 8 (CCR8) and tumor necrosis factor receptor 2 (TNFR2), two surface markers predominantly expressed on Treg cells. These BsAbs were efficiently expressed with retained high-affinity binding to both antigens. By conjugation with pyrrolobenzodiazepine (PBD) dimer payload using a cleavable linker, the resulting bispecific ADCs (BsADCs) exhibited potent cytotoxic activity in vivo. In murine syngeneic tumor models, BsADCs significantly suppressed tumor growth and exhibited superior therapeutic efficacy over monospecific ADCs, achieving complete tumor regression in 4 out of 5 mice (80%). Collectively, our findings have established a BsADC-based strategy for selective Treg depletion, providing a novel immunotherapeutic approach for solid tumors.