Abstract LB021: TJ102: A promising bispecific dual-payload ADC targeting CDH6 and folate receptor alpha (FRα) for the treatment of ovarian and kidney cancers

Abstract Antibody-drug conjugates (ADCs) represent a promising class of targeted therapies; however, their development has been hindered by challenges such as off-tumor toxicity and drug resistance. Bispecific ADCs, which target two distinct antigens or different epitopes on the same antigen, offer enhanced tumor specificity and reduced off-tumor toxicity compared to monoclonal ADCs. CDH6 is a calcium-dependent adhesion protein that mediates cell-cell binding. It is overexpressed in various solid tumors including ovarian and kidney cancers, while its expression in normal tissues is limited. Folate receptor alpha (FRα), encoded by the FOLR1 gene, facilitates folic acid uptake, supporting cell survival and proliferation. FRα is frequently overexpressed in epithelium-derived cancers, such as ovarian, endometrial, kidney, pancreatic, breast and lung cancers, with minimal expression in normal tissues. Importantly, CDH6 and FRα are co-expressed in most human ovarian and kidney cancers (TCGA dataset), making them attractive targets for bispecific ADCs. TJ102 is a bispecific dual linker-payload ADC engineered to target human CDH6 and FRα. A natural IgG1 format bispecific antibody, heterodimerized through knobs-into-holes (KIHs) technology, was conjugated with a novel topoisomerase I inhibitor payload, PY-4CAR2, and a microtubule inhibitor payload, PE-E2K, via a branched cleavable linker in a single step. The dual-payload ADC with PY-4CAR2 and PE-E2K exhibited greater in vivo efficacy than single payload ADCs with either PY-4CAR2 or PE-E2K in topoisomerase inhibitor-sensitive and resistant CDX models. In preclinical studies, TJ102 exhibited robust and selective cytotoxicity in multiple cancer cell lines. It demonstrated superior internalization and cytotoxicity compared to anti-CDH6 or anti-FRα monoclonal ADCs, particularly in cell lines with low CDH6 and FRα expression. In vivo, a single dose of TJ102 produced potent and durable anti-tumor activity in ovarian and kidney cancer CDX models, outperforming anti-CDH6 or anti-FRα monoclonal ADCs even in tumor models with low antigen expression. Notably, TJ102 induced complete tumor regressions in multiple ovarian cancer PDX models with low levels of CDH6 and FRα expression. A non-GLP toxicity study in cynomolgus monkeys showed that TJ102 was well-tolerated, with the highest non-severely toxic dose (HNSTD) exceeding 60 mg/kg. Observed toxicities, including reductions in white blood cells, neutrophils, and reticulocytes, were transient and manageable. Altogether, these findings highlight TJ102 as a promising bispecific dual-payload ADC with highly potent anti-tumor efficacy and a favorable safety profile in ovarian and kidney cancers. Its dual-targeting approach not only increases the therapeutic index but also mitigates potential tumor resistance that may arise during future clinical applications. Citation Format: Yangxin Zhang, Shugaku Takeda, Li Qi, Mao Huang, Lianjun Zhang, Wenchao Liu, Yanli Mao, Zhaoyuan Chen, Siyi Hu. TJ102: A promising bispecific dual-payload ADC targeting CDH6 and folate receptor alpha (FRα) for the treatment of ovarian and kidney cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB021.