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

Guanjie Li, Hiroyuki Suzuki, Tomokazu Ohishi, Teizo Asano, Tomohiro Tanaka, Miyuki Yanaka, Takuro Nakamura, Takeo Yoshikawa, Manabu Kawada, Mika K. Kaneko, Yukinari Kato

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10 Citations (Scopus)

Abstract

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 adhe- sion, 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 IgG1, kappa) was previously devel- oped by the authors, using the cell-based immunization and screening method. In the present study, a defucosylated version of anti-EpcAM mAb (EpMab-37-mG2a-f) was generated to evaluate the antitumor activity against EpcAM-positive cells. EpMab-37-mG2a-f recognized EpcAM-overexpressing cHO-K1(cHO/EpCAM)cellswithamoderatebinding-affinity [dissociation constant (Kd)=2.2x10-8 M] using flow cytometry. EpMab-37-mG2a-fexhibitedpotentantibody-dependentcellular cytotoxicity (Adcc) and complement-dependent cytotoxicity (cdc) for cHO/EpcAM cells by murine splenocytes and complements, respectively. Furthermore, the administration of EpMab-37-mG2a-f significantly suppressed CHO/EpcAM xenograft tumor development compared with the control mouse IgG. EpMab-37-mG2a-f also exhibited a moderate binding-affinity (Kd=1.5x10-8 M) and high Adcc and cdc activities for a colorectal cancer cell line (caco-2 cells). The administration of EpMab-37-mG2a-f to caco-2 tumor-bearing mice significantly suppressed tumor development compared with the control. By contrast, EpMab-37-mG2a-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-mG2a-f may exert antitumor activities against EpcAM-positive cancers and may thus be a promising therapeutic regimen for colorectal cancer.

Original languageEnglish
Article number18
JournalInternational Journal of Molecular Medicine
Volume51
Issue number2
DOIs
Publication statusPublished - 2023 Feb

Keywords

  • Adcc
  • EpcAM monoclonal antibody
  • cdc
  • colorectal cancer

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