DS-3939a: A TA-MUC1-directed Antibody-Drug Conjugate with Broad Anti-Tumor Activity.

Tumor-associated mucin-1 (TA-MUC1) is a glycoform of the MUC1 protein that is aberrantly glycosylated and is primarily observed in cancer cells. TA-MUC1 is highly expressed in various human epithelial cancers, making it an attractive target for cancer therapies. Here, we describe the development of DS-3939a, a novel TA-MUC1-targeting antibody-drug conjugate (ADC) that utilizes the potent DNA topoisomerase I inhibitor, DXd, and evaluation of its pharmacological activity in preclinical in vitro and in vivo models. Immunohistochemistry of clinical tumor tissue microarrays of various cancer types exhibited positive staining for TA-MUC1 in a number of samples, with a particularly high positive rate in bladder, lung, and breast cancers. In vitro profiling of DS-3939a confirmed that it could specifically bind to TA-MUC1 and inhibit growth of TA-MUC1-positive cancer cells by inducing DNA damage and apoptosis. DS-3939a also exhibited significant anti-tumor effects in multiple TA-MUC1-positive cell line-derived and patient-derived xenograft models. Moreover, DS-3939a elicited strong tumor regression in several xenograft models even following treatment with other cytotoxic ADCs, likely through its efficient payload delivery. Overall, these data provide evidence for the potential utility of DS-3939a for the treatment of TA-MUC1-expressing tumors and support the rationale for the ongoing phase I/II clinical study (NCT05875168).