LAUSR

Claudin-6 (CLDN6), a member of the claudin family, is localized in the tight junctions of epithelial cells to regulate permeability, barrier function and polarity of epithelial layers. CLDN6 is notably upregulated in multiple solid tumor types, including ovarian cancer, testicular cancer, endometrial cancer and non-small cell lung cancer, while exhibiting minimal or no expression in healthy adult tissues. Therapeutic potential of CLDN6 as a target for ADC was unraveled by TORL-1-23, a clinical stage ADC drug with MMAE as the payload from TORL BioTherapeutics, LLC, while QLS5132, a novel CLDN6-targeting ADC in IND-enabling stage, demonstrates superior efficacy and tolerability to TORL-1-23. QLS5132 is composed of a humanized anti-CLDN6 hIgG1 antibody with no cross-reactivity to CLDN9 conjugated to Qilu’s proprietary topoisomerase-1 inhibitor, QLS6916, via a hydrophilic cleavable linker. The payload QLS6916 showed nanomolar activity across a wide range of cancer cell lines in vitro and rapid systematic clearance in rodent models. QLS5132 showed sub-nanomolar activity in CLDN6-positive cancer cell lines, with faster internalization efficacy and stronger bystander killing activity than TORL-1-23. In in vivo pharmacology studies, QLS5132 demonstrated superior antitumor efficacy to TORL-1-23 across a panel of ovarian cancer cell line-derived xenograft (CDX) models with varying levels of CLDN6 expression. Furthermore, QLS5132 displayed synergistic activity when combined with PARP inhibitors in CLDN6-expressing ovarian CDX models, indicating its potential for possible combination with PAPR inhibitors in ovarian cancers. QLS5132 was well tolerated in cyno monkeys, with HNSTD up to 60 mpk Q3W x 4 in non-GLP toxicity study, which is 5 folds higher to TORL-1-23. QLS5132 showed an expanded therapeutic window with superior efficacy and tolerability to TORL-1-23 in preclinical models. QLS5132 also demonstrated great potential to combine with PARPi in CLDN6 positive ovarian cancers. QLS5132 is expected to offer a novel and promising treatment option either as a single agent or combo with PARPi or other SoCs for patients with CLDN6 expressing tumors. QLS5132 will enter clinical trials. Ying Huang, Zhongcui Sun, Shuyong Zhao, Xinmei Wang, Ling Zhang, Yang Yang, Hua Ying, Weikang Tao. QLS5132, a highly selective anti-CLDN6 ADC with broader 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 6750.