Design and development of a biparatopic antibody-drug conjugate against CDH17

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.