Broad-Spectrum Efficacy of CEACAM6-Targeted Antibody-Drug Conjugate with BET Protein Degrader in Colorectal, Lung, and Breast Cancer Mouse Models.

Despite remarkable advances in cancer treatment, most solid cancers remain difficult to cure. We recently developed an antibody-drug conjugate (ADC; 84-EBET) for pancreatic cancer by using the carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) antibody #84.7 and the bromodomain and extra-terminal (BET) protein degrader EBET. In this study, we showed the overexpression of CEACAM6 in colorectal, lung, and breast cancers and the broad-spectrum efficacy of 84-EBET in mouse models of these cancers. In vitro assays using cancer organoids and cell lines of colorectal, lung, and breast cancers revealed that 84-EBET was more potent than ADCs with known approved payloads-DXd, SN38, and monomethyl auristatin E-or standard chemotherapies. In mouse studies, a single injection of 84-EBET induced marked regression of colorectal-, lung-, and breast cancer patient-derived xenograft tumors and cell line-derived xenograft tumors. Moreover, in mouse syngeneic colorectal cancer, lung cancer, and breast cancer models resistant to PD-1 antibody, the combination of 84-EBET and PD-1 antibody induced complete regression of most tumors. Mechanistically, 84-EBET degraded bromodomain-containing protein 4 in both cancer and stromal cells via bystander efficacy. It decreased stromal inflammatory phenotypes and increased activated T-cell numbers in tumors. These results demonstrate that delivering BET protein degraders to tumors and their microenvironments via a CEACAM6-targeted ADC may be effective against a wide range of solid cancers.