Abstract CDH17 is overexpressed in various adenocarcinomas, including colorectal, gastric, and pancreatic cancers. High levels of CDH17 are associated with metastatic disease and poor prognosis in patients with these malignancies, In normal tissues, the expression of CDH17 is limited. Currently, various CDH17-based therapeutics, including bispecific antibodies, ADCs, and CAR-T, are under clinical investigation for treating CRC. Here, we describe the discovery and optimization of a novel biparatopic anti-CDH17 antibody. The biparatopic antibody exhibits efficient CDH17-directed cell binding and promotes rapid internalization at a much higher efficiency than the mono-epitope targeting ADCs. Next, we conjugated the biparatopic antibody to various cytotoxic payloads. The ADCs showed selective cytotoxicity towards multiple tumor cell lines with varying levels of CDH17 expression in vitro, and potently inhibited the growth of CDH17-expressing tumor xenografts in animal models. Together, these findings indicate that our lead biparatopic anti-CDH17 ADC is a promising candidate for the treatment of cancers that overexpress CDH17. Citation Format: Jinxiu Hou, Lisha Dong, Tingting Gu, Jiyuan Tian, Dandan Liu, Yongxin Shang, Rongmei Yan, Lifeng Pan, Liang Tian, Jian Peng, Zhenping Zhu. Design and development of a biparatopic antibody-drug conjugate against CDH17 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7096.
Hou et al. (2026) studied this question.