Abstract 7005: Discovery and characterization of DAC-1522, a novel Trop2-targeting degrader-antibody conjugate for precision oncology

Abstract Antibody-drug conjugates (ADCs) have revolutionized cancer therapies by enabling the targeted delivery of cytotoxic payloads to tumor cells. However, their efficacy and safety heavily rely on the toxins as their payloads, and the rare availability of toxin types often limits their efficacy and broader expansion of indications. Combining the precision targeting feature of ADCs and diverse options of protein degraders, degrader-antibody conjugates (DACs) have emerged as a next-generation therapeutic modality and offer a promising strategy to overcome these challenges. The human trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein widely expressed in various types of tumors. It has been clinically proven as a well-suited antigen for ADCs with its widespread overexpression in cancer cells and much lower expression in normal cells. Despite the clinical success of Trop2-targeting ADCs like IMMU-132 (sacituzumab govitecan-hziy), their dependence on topoisomerase inhibitors as payloads has exposed significant limitations, particularly in addressing both intrinsic and acquired drug resistance. This has created an urgent need for innovative therapeutic solutions. Here we introduce DAC-1522, a novel Trop2-directed DAC, that can potentially overcome the limitations of ADCs. In vitro studies have shown that DAC-1522 efficiently degrades the target protein in a dose-dependent manner and exhibits potent antiproliferative activity against multiple human cancer cell lines. Its efficacy is strongly correlated with the level of Trop2, ensuring selective cytotoxicity in Trop2-positive cells and sparing Trop2-negative cells, resulting in a favorable therapeutic window. Notably, DAC-1522 retains uncompromised antiproliferative activity in an ADC-induced acquired drug resistance model, underscoring its potential to overcome the drug resistance after ADC treatments. In vivo, DAC-1522 achieves complete tumor regression with a single intravenous injection in mice (human pancreatic cancer BXPC-3 xenograft model), significantly outperforming IMMU-132 in terms of efficacy. No obvious safety concerns were observed. These findings support further preclinical and clinical development of DAC-1522 as a highly promising therapeutic candidate for the Trop2-expressing cancers. Citation Format: Chuanjie Chen, Qianqian Shen, Xinhui Cai, Yaqi Ding, Xiaoyu Yang, Yanfen Fang, Jiangnan Luo, Jian Ding, Yi Chen, Xuan Zhang. Discovery and characterization of DAC-1522, a novel Trop2-targeting degrader-antibody conjugate for precision oncology [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 7005.