Abstract 5460: C6P, a claudin 6 (CLDN6) directed ADC containing pyrolobenzodiazepine (PBD) for the treatment of advanced solid tumors

Claudin 6 (CLDN6), a member of the claudin family of tight junction proteins, is highly expressed in multiple solid tumors such as ovarian and endometrial cancers with limited expression in normal tissues. Here we developed an anti-CLDN6 ADC C6P comprising a Fc-silenced anti-CLDN6 monoclonal antibody, a cleavable linker and a modified PBD (compound A). C6P selectively bound to CLDN6 without cross-reactivity to other claudin family members such as CLDN 3/4/5/8/9. Additionally, it also bound to I143V-mutated CLDN6, a major single nucleotide polymorphism (SNP) in human population. The antibody demonstrated strong binding affinity to several ovarian cancer cell lines with different CLDN6 expression levels and showed good endocytosis. Compound A was an optimized mono-imine PBD dimer with less cytotoxicity than conventional bis-imine PBD dimers. High systemic clearance of this payload was also designed to minimize toxicities. To achieve homogeneous ADC, a glycan mediated site-specific conjugation was used to generate C6P. C6P showed CLDN6-dependent growth inhibition against various cell lines, without effect on CLDN6 negative cells. In PA-1 and OVCAR3 xenograft mouse models, C6P showed a dose-dependent anti-tumor effect and led to robust and sustained tumor regression. C6P demonstrated good stability and safety profiles, likely due to site-specific conjugation and the higher systemic clearance of compound A. Less than 1% payload release was observed in human plasma after a 21-days incubation. C6P was well-tolerated at a single dose of 0.5 mg/kg in cynomolgus monkeys and did not show hematology-related toxicity. The intact ADC/total antibody AUC ratio was above 95%, and the payload was undetectable in the plasma of cynomolgus monkeys after injection with C6P. Overall, the highly specific CLDN6-targeting antibody, the optimized PBD payload, site-specific conjugation and well-controlled DAR value collectively contributed to the potent anti-tumor efficacy, and good safety profile of C6P, supporting its future clinical research. Citation Format: Xiaolan Yu, Shuting Wang, Lingfeng You, Zhibin Xu, Zhendong Xue, Yuchang Mao, Shuyu Cai, Jun Feng, Ting Zhang, Xin Ye, Min Hu, Feng He. C6P, a claudin 6 (CLDN6) directed ADC containing pyrolobenzodiazepine (PBD) for the treatment of advanced 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 5460.