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

Abstract Bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) have shown significant promise in cancer treatment, enhancing drug selectivity and therapeutic efficacy as demonstrated in multiple clinical studies. Bispecific antibody-drug conjugates (BsADCs), 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 bispecific antibody 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 anti-tumor efficacy in PD-L1 low-expressing tumor cells compared to 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.