Identification of CD66c as a potential target in gastroesophageal junction cancer for antibody-drug conjugate development.

BACKGROUND: Gastroesophageal junction (GEJ) cancer exhibits unique biological characteristics and currently lacks specific targeted therapies. Given the clinical efficacy of antibody-drug conjugates (ADCs) in solid tumor treatment, we aimed to identify a novel ADC target and suitable payload for GEJ-targeted therapy. METHODS: In this study, we conducted bioinformatic analyses of multi-omics data, including transcriptomics, proteomics, and phosphoproteomics, to identify CD66c as a promising ADC target for GEJ cancer. We then engineered a CD66c-directed antibody-drug conjugate (CD66c-DXd) incorporating a GGFG linker. The preclinical efficacy of CD66c-DXd was determined in multi GEJ xenograft models. RESULTS: Proteomic analyses of 103 cases of GEJ cancer revealed that CD66c expression was significantly higher in tumoral tissues compared to normal tissues. Proteomic and phosphoproteomic analyses identified deruxtecan (DXd) as a potentially potent payload for ADCs targeting GEJ cancer. Furthermore, high CD66c expression in GEJ was associated with a significantly lower proportion of plasma cells. The drug-to-antibody ratio (DAR) of CD66c-DXd was determined to be 3.6. CD66c-DXd effectively and selectively ablated multiple human GEJ cell lines (OE-19, OE33 and SK-GT-4) without affecting non-malignant cells (GES-1) in vitro. Eventually, CD66c-DXd mediated potent and durable tumor regression in vivo with excellent safety profiles. CONCLUSIONS: This preclinical study provides a strong rationale for the further development of CD66c-DXd as promising therapeutic candidates to treat advanced GEJ cancer. Additionally, the study demonstrates the robustness of the multi-omics data in identifying novel potential ADC targets and payloads.