EpCAM- and EGFR-targeted selective gene therapy for biliary cancers using Z33-fiber-modified adenovirus

Area of Science:

• Oncology
• Gene Therapy
• Virology

Background:

• Adenovirus (Ad)-based cancer gene therapy requires improved specificity for enhanced efficacy and safety.
• Targeting human biliary cancers presents a significant challenge in Ad-based gene therapy.

Purpose of the Study:

• To develop a retargeting strategy for Ad vectors to achieve selective gene therapy in human biliary cancers.
• To evaluate the efficacy of Ad vectors modified with an IgG Fc-binding motif (Z33) and tumor-specific antibodies against EpCAM and EGFR.

Main Methods:

• Engineered Ad vectors (Ad-FZ33) incorporating the Z33 motif from Staphylococcus protein A.
• Combined Ad-FZ33 with antibodies targeting EpCAM or EGFR, highly expressed on biliary cancer cells.
• Assessed gene transduction efficiency using LacZ and β-gal assays.
• Evaluated enhanced 5-fluorouracil (5-FU) sensitivity using uracil phosphoribosyl transferase (UPRT)-expressing Ad-FZ33.
• Tested therapeutic efficacy in nude mouse xenograft models of biliary cancer.

Main Results:

• Flow cytometry confirmed high EpCAM and EGFR expression on human biliary cancer cells.
• Ad-FZ33 with anti-EpCAM or anti-EGFR antibodies demonstrated highly efficient gene transduction.
• UPRT-expressing Ad-FZ33 combined with antibodies significantly enhanced biliary cancer cell sensitivity to 5-FU.
• This enhanced sensitivity was not observed in cells lacking EpCAM/EGFR or in normal hepatocytes.
• Ad-FZ33/antibody/5-FU treatment significantly suppressed biliary cancer xenograft growth in vivo.

Conclusions:

• Z33-modified Ad vectors combined with tumor-specific antibodies offer a promising strategy for targeted gene delivery in biliary cancer.
• This approach enhances the efficacy of gene therapy and sensitizes cancer cells to chemotherapeutic agents like 5-FU.
• The retargeting strategy shows potential as an effective therapeutic modality for human biliary cancers.