Abstract 2869: DXC014, a novel bispecific ADC targeting B7-H3 and PSMA, demonstrates favorable antitumor efficacy and safety profiles in preclinical evaluations

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Abstract B7-H3 (also known as CD276), a member of the B7 ligand family, is overexpressed on differentiated malignant cells and cancer-initiating cells, with limited heterogeneity, and high frequency (60% of 25,000 tumor samples), such as the cells of prostate cancer, non-small cell lung cancer (NSCLC), melanoma, bladder cancer, breast cancer, clear cell renal carcinoma, and head and neck squamous cancer cell (HNSCC), but scarcely detected in normal tissues. PSMA is highly expressed in prostate cancer cells and the endothelial neovasculature of several solid human malignancies. High PSMA expression is an independent biomarker of poor prognosis throughout the course of prostate cancer and across anatomical sites. Normal human tissues, including prostate epithelium, small intestine, renal tubules, and salivary glands, demonstrate considerably lower levels of PSMA expression than prostate cancer. DXC014 is an innovative bispecific antibody-drug conjugate (ADC) targeting both B7H3 and PSMA, utilizing a topoisomerase I inhibitor as its payload. This dual-target design aims to enhance therapeutic efficacy across a wide range of solid tumors, in particular, for prostate cancers. In vitro studies demonstrated that DXC014 binds to B7H3 and PSMA with high specificity and affinity, enabling precise targeted cytotoxicity. DXC014 induces DNA damage in cancer cells while exhibiting a significant bystander effect, and thus kills both target-positive cells and surrounding target-negative cells. Furthermore, DXC014 exhibited broad cytotoxic activity across various cancer cell lines, including prostate cancer and small-cell lung cancer cells with different levels of target expression. Overlapping pharmacokinetic profiles of both ADC and total antibody indicated excellent linker stability. DXC014 was well-tolerated at doses up to 300 mg/kg in mice and 40 mg/kg in repeat-dose studies in cynomolgus monkeys. In xenograft models, including C4-2B, 22RV1, and SHP77 models, DXC014 showed superior or comparable antitumor efficacy to Dxd conjugate at equivalent doses. These findings underscore the therapeutic potential of DXC014 as a dual-targeting ADC for the treatment of various solid tumors. Its innovative design and excellent preclinical performance position DXC014 as a promising candidate for further clinical development. Citation Format: Huihui Guo, Zhicang Ye, Yuanyuan Huang, Weibin Li, Qingliang Yang, Hangbo Ye, Junxiang Jia, Jun Zheng, Yongxiang Chen, Xiafen Wu, Yunxia Zheng, Binbin Chen, Meng Dai, Naiyan Yang, Gaituo Chen, Li Chen Chen, Xiaolei Liu, Junpeng Wang, Yi Luo, Xiaoqiang Xie, Xia Zhou, Lu Bai, Miaomiao Chen, Wenjun Li, Xiang Cai, Wei Liu, Robert Y. Zhao. DXC014, a novel bispecific ADC targeting B7-H3 and PSMA, demonstrates favorable antitumor efficacy and safety profiles in preclinical evaluations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2869.

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