Background
Trophoblast glycoprotein (5T4) is significantly overexpressed in a variety of cancers, including breast, lung, ovarian, endometrial, bladder, pancreatic, esophageal, and colorectal cancers, while demonstrating minimal expression in normal tissues. Its presence in cancer stem cells is correlated with poor prognoses, possibly contributing to metastasis, resistance, and recurrence. MUC1, a highly glycosylated member of the transmembrane mucin family, is also overexpressed across a range of solid cancers. Abnormalities in MUC1 expression and glycosylation in cancer activate multiple pathways that drive tumor migration, invasion, and accelerated growth. Importantly, 5T4 and MUC1 are frequently co-expressed in various solid tumors, such as lung, breast, ovarian, colorectal, and pancreatic cancers.
Results
In our study, we generated and evaluated antibodies targeting 5T4 and MUC1 using fully human common light chain RenLite mice. The 5T4 parental antibody demonstrated stronger and specific binding and greater efficacy than the benchmark in vivo. We previously generated the MUC1-C parental antibody, which was identified as targeting membrane-bound MUC1 on cancer cells. The anti-5T4×MUC1 bsAb demonstrated good binding to tumor cells with varying levels of 5T4 and MUC1 expression, with enhanced binding observed in cases of high expression of both 5T4 and MUC1. The bsAb demonstrated efficient internalization activity in the 5T4/MUC1 co-expression cell line, performing either as well as or better than benchmark antibodies. Notably, the anti-5T4×MUC1-vcMMAE demonstrated improved efficacy compared to parental ADCs, outperforming benchmark ADCs in patient-derived xenograft (PDX) models. BCG016, in combination with a TOP1 inhibitor linker-payload (BLD1102), exhibited enhanced efficacy in PDX models compared to parental ADCs, significantly outperforming benchmark ADCs targeting 5T4 and MUC1.
Conclusion
In summary, we have developed a novel bispecific ADC that targets both 5T4 and the membrane-bound MUC1-C. BCG016 showed superior anti-tumor efficacy in PDX models, underscoring its potential as a new therapeutic option for tumors that co-express 5T4 and MUC1.
