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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., (©2024 American Association for Cancer Research.)

Background: Antibody-drug conjugates (ADCs) offer a promising approach, combining monoclonal antibodies with chemotherapeutic drugs to target cancer cells effectively while minimizing toxicity., Methods: This study examined the therapeutic efficacy and potential mechanisms of a bispecific ADC (BsADC) in laryngeal squamous cell carcinoma. This BsADC selectively targets the immune checkpoints programmed cell death ligand-1 (PD-L1) and B7-H3, and the precise delivery of the small-molecule toxin monomethyl auristatin E., Results: Our findings demonstrated that the BsADC outperformed its bispecific antibody and PD-L1 or B7-H3 ADC counterparts, particularly in terms of in vitro/in vivo tumor cytotoxicity, demonstrating remarkable immune cytotoxicity. Additionally, we observed potent activation of tumor-specific immunity and significant induction of markers of immunogenic cell death (ICD) and potential endoplasmic reticulum stress., Conclusion: In conclusion, this novel BsADC, through immune checkpoint inhibition and promotion of ICD, amplified durable tumor immune cytotoxicity, providing novel insights and potential avenues for future cancer treatments and overcoming resistance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The survival prognosis of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) is largely different, and little is known about the anti-tumor mechanism of tumor-infiltrated exhausted CD8 + T cells (Tex) in HNSCC. We performed cell-level multi-omics sequencing on human HNSCC samples to decipher the multi-dimensional characteristics of Tex cells. A proliferative exhausted CD8 + T cell cluster (P-Tex) which was beneficial to survival outcomes of patients with HPV-positive HNSCC was identified. Interestingly, P-Tex cells expressed CDK4 genes as high as cancer cells, which could be simultaneously inhibited by CDK4 inhibitors and might be a potential reason for the ineffectiveness of CDK4 inhibitors in treating HPV-positive HNSCC. P-Tex cells could aggregate in the antigen-presenting cell niches and activate certain signaling pathways. Together, our findings suggest a promising role for P-Tex cells in the prognosis of patients with HPV-positive HNSCC by providing modest but persistent anti-tumor effects., Competing Interests: DC, KQ, YR, MM, LL, YW, YS, JC, XY, XS, SH, YZ, XC, SW, SY, JL, HW, XP, DL, LY, LC, ZY, YZ, MZ, BY, XZ, WZ, WX, GL, FC, HY, YZ, JR No competing interests declared, (© 2023, Cheng, Qiu, Rao et al.)