Development and Characterization of a Lysosome-Targeting SLC3A2/PD-L1 Bispecific Antibody–Drug Conjugate for Enhanced Antitumor Efficacy in Solid Tumors

Bispecific antibodies (BsAb) and antibody-drug conjugates (ADC) have shown significant promise in cancer treatment, enhancing drug selectivity and therapeutic efficacy as demonstrated in multiple clinical studies. Bispecific antibody-drug conjugates (BsADC), which combine the targeting capabilities of BsAbs with the cytotoxic potential of ADCs, offer a novel approach to overcoming several challenges associated with ADCs, including limited internalization, off-target toxicity, and drug resistance. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as a highly expressed protein in a variety of solid tumors, making it a promising therapeutic target. We developed a BsAb targeting SLC3A2 and PD-L1 and conjugated it to monomethyl auristatin E (MMAE) to create the SLC3A2/PD-L1 BsADC. The SLC3A2/PD-L1 BsAb effectively blocked PD-1 binding to PD-L1 and activated T cells while also facilitating lysosomal targeting and degradation of poorly internalized PD-L1 antibodies. The SLC3A2/PD-L1 BsADC demonstrated superior antitumor efficacy in PD-L1 low-expressing tumor cells compared with single-target ADCs in both in vitro studies and in multiple xenograft and immunocompetent mouse models. Overall, our engineered SLC3A2/PD-L1 BsADC exhibited enhanced internalization and improved tumor cell targeting, highlighting the potential of lysosome-targeting BsAbs in advancing ADC therapeutic strategies for solid tumors.