A novel bispecific antibody-drug conjugate targeting CEACAM5 and CDH17 exhibits potent anti-tumor activity and enhanced tumor-selectivity

CEACAM5 and CDH17 are preferentially expressed in gastrointestinal tumors, including more than 95% of colorectal cancers, 80% of gastric and pancreatic cancers, and 70% of cholangiocarcinomas. Moreover, these two molecules are frequently co-expressed in gastrointestinal cancers. Recent advancements in CEACAM5 and CDH17 research have unveiled their potential as the promising targets for developing novel cancer therapeutics. Here we engineered a bispecific antibody (bsAb) capable of simultaneously binding to both CEACAM5 and CDH17. The cell binding and internalization activities of the bsAb were compared to a panel of monoclonal antibodies, including M9140 analog (an anti-CEACAM5 monoclonal antibody) and TORL-3-600 analog (an anti-CDH17 monoclonal antibody), using multiple colorectal and pancreatic cancer cell lines, The bsAb was conjugated to various topoisomerase I inhibitor payloads to generate several bispecific ADC molecules (bsADCs). The activity of these bsADC was studied in vitro in tumor cell-killing assay, and in vivo in multiple CDX models of GI malignancies. We further investigated the bsADC stability in human and cynomolgus monkey plasma over a three-week period, its pharmacokinetic profile and tolerability in both SD rats and cynomolgus monkeys. The results demonstrated that the bsAb exhibits excellent developability, and the resulting bsADCs maintained high purity after conjugation with different linker-payloads. The lead bsADC candidate showed superior bystander killing activity. In GI cancer CDX models with varying CEACAM5/CDH17 expression levels, it showed tumor inhibition comparable or superior to M9140a and TORL-3-600a, suggesting a broad application in GI cancer patients. Furthermore, the candidate exhibited favorable stability in human/cynomolgus plasma and good pharmacokinetic profile and tolerability in SD rats and cynomolgus monkeys. Taken together, these data support further development and broad utility of this bsADC for GI cancer treatment.