Preclinical development of a potential first-in-class CDH17/CEACAM5 targeted bispecific antibody drug conjugate (ADC)

Colorectal carcinoma (CRC) remains one of the most prevalent and lethal malignancies worldwide. Cadherin‑17 (CDH17) and Carcinoembryonic antigen‑related cell adhesion molecule 5 (CEACAM5) are consistently co‑up‑regulated in CRC tissues, whereas their sub‑cellular distribution differs markedly in normal epithelia. This differential expression pattern presents an attractive opportunity for a bispecific antibody‑drug conjugate (ADC) that selectively targets tumor cells co‑expressing CEACAM5 and CDH17 while sparing normal tissues. We have engineered a novel ADC comprising a CDH17/CEACAM5 bispecific antibody linked via a cleavable linker to a topoisomerase I inhibitor (TOP1i) payload. The conjugate exhibits high stability in human plasma and mouse circulation. In vitro cytotoxicity assays demonstrate robust killing of cell lines harboring both antigens, whereas single‑positive or double‑negative lines show markedly reduced sensitivity, underscoring the synergistic advantage of the bispecific format. Moreover, a pronounced by‑stander effect was observed in mixed‑culture assays, indicating potential efficacy against heterogeneous tumors with variable CDH17/CEACAM5 expression. In vivo, the bispecific ADC achieved potent single‑agent activity in cell‑line‑derived xenograft (CDX) models. A comprehensive panel of patient‑derived organoids (PDOs) further confirmed superior antitumor efficacy across diverse CRC specimens. Comparative studies revealed that the bispecific ADC outperforms single‑target ADCs, likely due to enhanced avidity conferred by dual antigen engagement. In summary, we have generated a promising CDH17/CEACAM5 bispecific ADC that delivers potent antitumor activity both in vitro and in vivo. The observed efficacy advantage over monovalent ADCs supports continued preclinical development and positions this bispecific ADC as a compelling therapeutic candidate for CRC patients.