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EpCAM- and EGFR-Specific Antibody Drug Conjugates for Triple-Negative Breast Cancer Treatment
Chaoyu Zhang1, Wenjie Sheng1, Marwah Al-Rawe1
1Department of Gynecology and Obstetrics, Medical Faculty, Justus-Liebig-University Giessen, Klinikstr. 33, 35392 Giessen, Germany.
Abstract:
Triple-negative breast cancer (TNBC) is a group of heterogeneous and refractory breast cancers with the absence of estrogen receptor (ER), progesterone receptor (PgR) and epidermal growth factor receptor 2 (HER2). Over the past decade, antibody drug conjugates (ADCs) have ushered in a new era of targeting therapy. Since the epidermal growth factor receptor (EGFR) and epithelial cell adhesion molecule (EpCAM) are over expressed on triple-negative breast cancer, we developed novel ADCs by conjugating benzylguanine (BG)-modified monomethyl auristatin E (MMAE) to EpCAM- and EGFR-specific SNAP-tagged single chain antibody fragments (scFvs). Rapid and efficient conjugation was achieved by SNAP-tag technology. The binding and internalization properties of scFv-SNAP fusion proteins were confirmed by flow cytometry and fluorescence microscopy. The dose-dependent cytotoxicity was evaluated in cell lines expressing different levels of EGFR and EpCAM. Both ADCs showed specific cytotoxicity to EGFR or EpCAM positive cell lines via inducing apoptosis at a nanomolar concentration. Our study demonstrated that EGFR specific scFv-425-SNAP-BG-MMAE and EpCAM-specific scFv-EpCAM-SNAP-BG-MMAE could be promising ADCs for the treatment of TNBC.
Insights
Novel antibody drug conjugates (ADCs) targeting EGFR and EpCAM show promise for treating triple-negative breast cancer (TNBC). These ADCs demonstrate specific cytotoxicity in preclinical models, offering a new therapeutic avenue for this aggressive cancer. Keywords: antibody drug conjugates, triple-negative breast cancer, EGFR, EpCAM, targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies.
- Antibody drug conjugates (ADCs) represent a promising targeted therapy approach.
- EGFR and EpCAM are overexpressed in TNBC, making them potential therapeutic targets.
Purpose of the Study:
- To develop novel ADCs targeting EGFR and EpCAM for TNBC treatment.
- To evaluate the efficacy and specificity of these novel ADCs.
Main Methods:
- Developed ADCs by conjugating MMAE to scFvs targeting EGFR and EpCAM using SNAP-tag technology.
- Confirmed binding and internalization of scFv-SNAP fusion proteins via flow cytometry and fluorescence microscopy.
- Assessed dose-dependent cytotoxicity in cell lines with varying EGFR and EpCAM expression levels.
Main Results:
- Successfully developed EGFR- and EpCAM-specific ADCs with rapid conjugation via SNAP-tag technology.
- Demonstrated specific binding and internalization of the scFv-SNAP fusion proteins.
- Showed dose-dependent cytotoxicity in EGFR- or EpCAM-positive cell lines, inducing apoptosis at nanomolar concentrations.
Conclusions:
- EGFR-specific scFv-425-SNAP-BG-MMAE and EpCAM-specific scFv-EpCAM-SNAP-BG-MMAE are promising ADCs for TNBC treatment.
- These ADCs exhibit specific cytotoxicity against TNBC cells expressing target antigens.
- Further investigation is warranted to explore their therapeutic potential in TNBC.
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