Abstract 2881: QLS5133-a novel CDH6-targeting antibody-drug-conjugate for solid tumors

Abstract Background: Cell-cell adhesion molecule cadherin-6 (CDH6), a member of the CDH family, is expressed in the basolateral membrane of epithelial cells and mediates calcium-dependent cell-cell adhesion. Although the function of CDH6 has not been fully elucidated, it is believed to be associated with epithelial-mesenchymal transition (EMT) and metastasis during tumor development. CDH6 is upregulated in various cancers, including ovarian cancer, renal cell carcinoma, and thyroid carcinoma, while its expression in normal tissues is limited. The therapeutic potential of CDH6 as an ADC target was recently unraveled by DS-6000a, a Dxd-based ADC from Daiichi/MSD. In this study, we present the development of a novel CDH6 ADC that is in the IND enabling stage. The new ADC demonstrates a superior safety profile compared to DS-6000a and shows robust anti-tumor activities in preclinical studies. Method: QLS5133 is built on the QILU's proprietary novel topoisomerase-1(TOPO 1) inhibitor QLS6917 platform, with site-specific conjugation to yield a uniform DAR 8 product. The payload QLS6916 displayed nanomolar activity across various cancer cell lines and much faster systematic clearance than Dxd in vitro. Result: QLS5133 exhibited a higher affinity and internalization compared to DS-6000a. Treatment with QLS5133 induced significant tumor regressions in multiple CDH6-expressing human cancer cell line xenograft studies encompassing ovarian cancer and renal cell carcinoma. Notably, in one CDX model with ultralow and highly heterogeneous CDH6 expression, QLS5133 still demonstrated strong efficacy. Additionally, QLS5133 was able to achieve a durable response even after resistance to Mirvetuximab soravtansine (FRα ADC/ImmunoGen) in preclinical models. This suggests that QLS5133 could potentially serve as a late-line treatment following treatment failure with Mirvetuximab soravtansine. More importantly, QLS5133 showed much less severe hematotoxicity than DS-6000a particularly regarding changes in platelets, white blood cells, neutrophils, as well as having a lesser impact on body weight reduction when dosed up to 80 mg/kg (single dose administration) in cyno monkeys. Meanwhile, QLS5133 demonstrated a better PK profile than DS-6000a in cyno monkeys, with longer T1/2 and slower systematic clearance as intact ADC, and sustained DAR retention for a period of 21 days. Conclusion: The promising efficacy, superior tolerability, and favorable PK profile support the potential of QLS5133 as a novel therapeutic agent to address the high unmet needs in patients with variable CDH6-expressing cancers. QLS5133 will enter clinical trials. Citation Format: Ying Huang, Fanrui Meng, Liuqing Yang, Shuyong Zhao, Xinmei Wang, Ling Zhang, Yang Yang, Hua Ying, Weikang Tao. QLS5133-a novel CDH6-targeting antibody-drug-conjugate for solid tumors [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 2881.