Antitumor activities of a defucosylated anti-EpCAM monoclonal antibody in colorectal carcinoma xenograft models

Epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein, which is highly expressed on tumor cells. As EpCAM plays a crucial role in cell adhesion, survival, proliferation, stemness, and tumorigenesis, it has been considered as a promising target for tumor diagnosis and therapy. Anti-EpCAM monoclonal antibodies (mAbs) have been developed and have previously demonstrated promising outcomes in several clinical trials. An anti-EpCAM mAb, EpMab-37 (mouse IgG(1), kappa) was previously developed by the authors, using the cell-based immunization and screening method. In the present study, a defucosylated version of anti-EpCAM mAb (EpMab-37-mG(2a)-f) was generated to evaluate the antitumor activity against EpCAM-positive cells. EpMab-37-mG(2a)-f recognized EpCAM-overexpressing CHO-K1 (CHO/EpCAM) cells with a moderate binding-affinity [dissociation constant (K-D)=2.2x10(-8) M] using flow cytometry. EpMab-37-mG(2a)-f exhibited potent antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) for CHO/EpCAM cells by murine splenocytes and complements, respectively. Furthermore, the administration of EpMab-37-mG(2a)-f significantly suppressed CHO/EpCAM xenograft tumor development compared with the control mouse IgG. EpMab-37-mG(2a)-f also exhibited a moderate binding-affinity (K-D) =1.5x10(-8) M] and high ADCC and CDC activities for a colorectal cancer cell line (Caco-2 cells). The administration of EpMab-37-mG(2a)-f to Caco-2 tumor-bearing mice significantly suppressed tumor development compared with the control. By contrast, EpMab-37-mG(2a)-f never suppressed the xenograft tumor growth of Caco-2 cells in which EpCAM was knocked out. On the whole, these results indicate that EpMab-37-mG(2a)-f may exert antitumor activities against EpCAM-positive cancers and may thus be a promising therapeutic regimen for colorectal cancer.

Automated summary

EpCAM is a type I transmembrane glycoprotein highly expressed on tumor cells, and it has been considered as a promising target for tumor diagnosis and therapy. In this study, a defucosylated version of an anti-EpCAM monoclonal antibody was generated and evaluated for its antitumor activity against EpCAM-positive cells. The results showed that the antibody exhibited potent cytotoxicity for EpCAM-overexpressing cells and suppressed tumor development in xenograft mouse models.