Abstract 4338: SYS6042, a novel anti-TROP2 pH-sensitive antibody-drug conjugate (ADC) with improved therapeutic window

TROP2 is a ubiquitously expressed tumor-associated antigen. Its expression in normal tissues such as skin, oral mucosa, esophagus, liver, and cornea severely limits the development of anti-TROP2 ADCs. It is difficult to balance the efficacy and toxicity to obtain a larger therapeutic window. In clinical, Dato-DXd, Trodelvy and SKB264 showed obvious on-target toxicity or off-target toxicity, which affect clinical development and patient benefit. To address the unmet needs, we developed the SYS6042, an ADC composed of an anti-TROP2 pH-sensitive antibody, a tetrapeptide-based stable linker, and a topoisomerase I inhibitor payload, with a drug-to-antibody ratio (DAR) of 8. It binds TROP2 with nanomolar affinity at pH 6.0 but hardly binds the target at pH 7.4, thereby reducing on-target toxicity. In several cell line-derived xenografts (CDX) models, a single dose of SYS6042 at 0.4 - 4.0 mg/kg exhibited remarkable tumor growth inhibition. Notably, the antitumor activity of SYS6042 was superior to homemade Dato-DXd and SKB264. In exploratory toxicology study, SYS6042 showed favorable PK and good safety profiles with toxic findings unrelated to on-target toxicity(hematotoxicity) despite high levels of TROP2 expression in normal tissues of cynomolgus monkey. The highest non-severely toxic dose (HNSTD) for monkeys was defined as 30 mg/kg for repeating dosing. Based on these results, it demonstrates that the novel design of SYS6042 leads to an improved therapeutic window, which would help address unmet needs in the treatments of TROP2-positive tumors. Citation Format: Yancui Wang, Xiao Gao, Mo Dan, Xiwu Hui, Bing Yao, Yang Zhang, Congcong Niu, Can Yuan, Xiaoque Zhu, Zhaopeng Sun, Bin Kang, Miaomiao Wei. SYS6042, a novel anti-TROP2 pH-sensitive antibody-drug conjugate (ADC) with improved therapeutic window [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 4338.