Wang Zeng, Zheng Meijun, Li Mengyao, Lu Huaqing, Liu Nanxi, Chen Yongdong, Yang Nian, Zeng Wanqin, Dong Yijun, Li Jia, Zhu Zhixiong, Yang Chen, Zhang Zongliang, Lu Qizhong, Li Hexian, Zhou Liangxue, Yang Hui, Tong Aiping
State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China.
Department of Otolaryngology, Head and Neck Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, P. R. China.
Mol Cancer Ther. 2025 Feb 4;24(2):261-274. doi: 10.1158/1535-7163.MCT-24-0319.
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.
双特异性抗体（BsAb）和抗体药物偶联物（ADC）在癌症治疗中已显示出巨大前景，多项临床研究表明它们可提高药物选择性和治疗效果。双特异性抗体药物偶联物（BsADC）将BsAb的靶向能力与ADC的细胞毒性潜力相结合，为克服与ADC相关的若干挑战提供了一种新方法，这些挑战包括内化受限、脱靶毒性和耐药性。在本研究中，我们确定溶质载体家族3成员2（SLC3A2）为多种实体瘤中高表达的蛋白，使其成为一个有前景的治疗靶点。我们开发了一种靶向SLC3A2和PD-L1的BsAb，并将其与单甲基奥瑞他汀E（MMAE）偶联，以创建SLC3A2/PD-L1 BsADC。SLC3A2/PD-L1 BsAb有效阻断PD-1与PD-L1的结合并激活T细胞，同时还促进溶酶体靶向和内化不良的PD-L1抗体的降解。在体外研究以及多个异种移植和免疫健全小鼠模型中，与单靶点ADC相比，SLC3A2/PD-L1 BsADC在PD-L1低表达肿瘤细胞中表现出卓越的抗肿瘤疗效。总体而言，我们构建的SLC3A2/PD-L1 BsADC表现出增强的内化作用和改善的肿瘤细胞靶向性，突出了溶酶体靶向BsAb在推进实体瘤ADC治疗策略方面的潜力。
