Abstract
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. Here, we showed the overexpression of CEACAM6 in colorectal, lung, and breast cancers (CRC, LC, BC) and the broad-spectrum efficacy of 84-EBET in mouse models of these cancers. In vitro assays using cancer organoids and cell lines of CRC, LC, and BC revealed that 84-EBET was more potent than ADCs with known approved payloads-DXd, SN38, and monomethyl auristatin E (MMAE)-or standard chemotherapies. In mouse studies, a single injection of 84-EBET induced marked regression of CRC-, LC-, and BC-patient-derived xenograft tumors and cell-line-derived xenograft tumors. Moreover, in mouse syngeneic CRC, LC, and BC 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 BRD4 protein 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.
Published Version
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