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<p>Epithelial cell adhesion molecule (EpCAM, CD326) is a transmembrane glycoprotein that plays important roles in both normal epithelial tissues and epithelial malignancies. Its frequent overexpression in several cancers, including pancreatic, colorectal, and prostate carcinomas, has made it an attractive therapeutic target. In this study, we designed and evaluated a novel EpCAM-binding diphtheria toxin fusion construct, DT-SNFYMPL, in which the EpCAM-binding peptide SNFYMPL was fused to a truncated diphtheria toxin. The recombinant construct was cloned, expressed in <i>Escherichia coli</i> BL21 cells, purified, refolded, and characterized in vitro. Structural modeling and validation predicted a stable three-dimensional structure for the designed protein. Binding analysis demonstrated interaction of DT-SNFYMPL with recombinant EpCAM in an ELISA-based assay. Cytotoxicity studies revealed dose- and time-dependent inhibition of MCF-7 and TC-1 cell proliferation, whereas no significant effect was observed in HUVEC cells under the conditions tested. DT-SNFYMPL also reduced the migration of cancer cells in Transwell assays; however, this effect is likely attributable, at least in part, to toxin-mediated cytotoxicity rather than direct inhibition of migratory pathways. Although the findings demonstrate biological activity of the DT-SNFYMPL construct and support its potential as an EpCAM-binding therapeutic candidate, the present study does not establish EpCAM-dependent internalization, receptor-mediated cytotoxicity, or therapeutic selectivity. Further mechanistic and preclinical studies are required to evaluate its mode of action, safety, and therapeutic potential in EpCAM-expressing malignancies.</p>

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Design and evaluation of an EpCAM-specific peptide–diphtheria toxin fusion (DT-SNFYMPL) for targeted epithelial cancer treatment

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Sara Rafia,
  • Pegah Tabanmehr,
  • Mahdi Habibi-Anbouhi,
  • Zohre Eftekhari,
  • Alireza Erfani,
  • Fatemeh Kazemi-Lomedasht

摘要

Epithelial cell adhesion molecule (EpCAM, CD326) is a transmembrane glycoprotein that plays important roles in both normal epithelial tissues and epithelial malignancies. Its frequent overexpression in several cancers, including pancreatic, colorectal, and prostate carcinomas, has made it an attractive therapeutic target. In this study, we designed and evaluated a novel EpCAM-binding diphtheria toxin fusion construct, DT-SNFYMPL, in which the EpCAM-binding peptide SNFYMPL was fused to a truncated diphtheria toxin. The recombinant construct was cloned, expressed in Escherichia coli BL21 cells, purified, refolded, and characterized in vitro. Structural modeling and validation predicted a stable three-dimensional structure for the designed protein. Binding analysis demonstrated interaction of DT-SNFYMPL with recombinant EpCAM in an ELISA-based assay. Cytotoxicity studies revealed dose- and time-dependent inhibition of MCF-7 and TC-1 cell proliferation, whereas no significant effect was observed in HUVEC cells under the conditions tested. DT-SNFYMPL also reduced the migration of cancer cells in Transwell assays; however, this effect is likely attributable, at least in part, to toxin-mediated cytotoxicity rather than direct inhibition of migratory pathways. Although the findings demonstrate biological activity of the DT-SNFYMPL construct and support its potential as an EpCAM-binding therapeutic candidate, the present study does not establish EpCAM-dependent internalization, receptor-mediated cytotoxicity, or therapeutic selectivity. Further mechanistic and preclinical studies are required to evaluate its mode of action, safety, and therapeutic potential in EpCAM-expressing malignancies.