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Anti-EGFR antibody-drug conjugate for triple-negative breast cancer therapy
Yingnan Si1, Yuanxin Xu1, JiaShiung Guan2
1Department of Biomedical Engineering University of Alabama at Birmingham (UAB) Birmingham AL USA.
Abstract:
Triple-negative breast cancers (TNBCs) are highly aggressive, metastatic and recurrent. Cytotoxic chemotherapies with limited clinical benefits and severe side effects are the standard therapeutic strategies, but, to date, there is no efficacious targeted therapy. Literature and our data showed that epidermal growth factor receptor (EGFR) is overexpressed on TNBC cell surface and is a promising oncological target. The objective of this study was to develop an antibody-drug conjugate (ADC) to target EGFR+ TNBC and deliver high-potency drug. First, we constructed an ADC by conjugating anti-EGFR monoclonal antibody with mertansine which inhibits microtubule assembly via linker Sulfo-SMCC. Second, we confirmed the TNBC-targeting specificity of anti-EGFR ADC by evaluating its surface binding and internalization in MDA-MB-468 cells and targeting to TNBC xenograft in subcutaneous mouse mode. The live-cell and live-animal imaging with confocal laser scanning microscopy and In Vivo Imaging System (IVIS) confirmed the TNBC-targeting. Finally, both in vitro toxicity assay and in vivo anti-cancer efficacy study in TNBC xenograft models showed that the constructed ADC significantly inhibited TNBC growth, and the pharmacokinetics study indicated its high circulation stability. This study indicated that the anti-EGFR ADC has a great potential to against TNBC.
Insights
A novel antibody-drug conjugate (ADC) targeting epidermal growth factor receptor (EGFR) shows promise for treating aggressive triple-negative breast cancer (TNBC). This targeted therapy effectively inhibited tumor growth in preclinical models with high stability.
Area of Science:
- Oncology
- Pharmacology
- Immunology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with limited treatment options.
- Cytotoxic chemotherapies offer minimal benefit and severe side effects.
- Epidermal growth factor receptor (EGFR) is overexpressed on TNBC cells, presenting a viable therapeutic target.
Purpose of the Study:
- To develop an antibody-drug conjugate (ADC) for targeted delivery of potent drugs to EGFR-positive TNBC.
- To evaluate the efficacy and specificity of the anti-EGFR ADC in preclinical TNBC models.
Main Methods:
- Constructed an ADC by linking an anti-EGFR monoclonal antibody to mertansine via a Sulfo-SMCC linker.
- Confirmed TNBC targeting specificity through in vitro cell binding/internalization assays and in vivo imaging in mouse xenograft models.
- Assessed in vitro cytotoxicity and in vivo anti-cancer efficacy, alongside pharmacokinetic profiling.
Main Results:
- The anti-EGFR ADC demonstrated specific binding and internalization in EGFR-positive TNBC cells (MDA-MB-468).
- Live-cell and live-animal imaging confirmed TNBC targeting.
- In vitro and in vivo studies showed significant inhibition of TNBC growth with favorable pharmacokinetics and circulation stability.
Conclusions:
- The developed anti-EGFR ADC is a promising targeted therapeutic strategy for triple-negative breast cancer.
- This targeted approach offers potential for improved efficacy and reduced side effects compared to conventional chemotherapy.
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