Abstract 6741: AT65474, a highly selective anti-CLDN6 ADC with a proprietary payload

Abstract CLDN6 is a membrane-bound oncofetal protein and a promising target for cancers such as ovarian and testicular cancer. AT65474 is an antibody drug conjugate (ADC) candidate composed of a highly selective humanized anti-CLDN6 antibody conjugated to a proprietary payload, namely TCS132, with a drug-to-antibody (DAR) ratio of 4. The antibody is engineered to incorporate AxcynCYSTM technology for site-specific conjugation which can reproducibly achieve high DAR4 ratios of greater than 97% by HIC analysis. The payload, TCS132, is derived from an FDA approved drug and when compared to the parent drug, demonstrates increased potency with broad sub-nanomolar activities across a wide range of cancer cell lines including those resistant to paclitaxel, DM1, MMAE and DXd. Additionally, TCS132 was chemically optimized for better PK properties and demonstrates a much-improved safety profile despite its increased potency over the parent drug. In vitro, AT65474 specifically binds to CLDN6 presenting tumor cells and upon internalization into lysosomes, releases the payload effectively inhibiting tumor cell proliferation. AT65474 displays a bystander killing effect that enables it to kill surrounding CLDN6-negative tumor cells, further enhancing its anti-proliferative effects. In vivo, AT65474 shows strong anti-tumor activity in CLDN6-positive CDX and PDX models at low doses and long intervals, which reflects the elevated payload levels in the tumors. Furthermore, safety assessment of AT65474 including GLP-compliant toxicology studies in Cynomolgus monkeys and SD rats reveals a good safety profile of AT65474. Taken together, the results of the nonclinical studies support the intended clinical trial, dose selection, and regimen in humans. Citation Format: Chen Zhong, Yin Wen Cheng, You Xue Wu, Xi Yun Zhang, Rui Yang Zhao, Qian Wang, Ping Du, Shao Jun Liu, Bin Zou. AT65474, a highly selective anti-CLDN6 ADC with a proprietary payload [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 6741.