A dual-targeting antibody against EGFR-VEGF for lung and head and neck cancer treatment
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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Hongzheng Zhang1, Sujin Yun, Thil D Batuwangala
1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Abstract:
An antibody simultaneously targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), two major tumor growth-driving machineries, may provide a novel effective strategy for optimizing tumor targeting and maximizing potential clinical benefits. Human domain antibodies selected against VEGF and EGFR were formatted into a fully human dual-targeting IgG (DT-IgG) to directly target both antigens in a single molecule. We evaluated the efficacy of DT-IgG in comparison with bevacizumab and cetuximab alone and in combination in the lung cancer cell line A549 (low EGFR expression and KRAS mutant) and the head and neck squamous cell carcinoma (HNSCC) cell line Tu212 (high EGFR expression and KRAS wild type) in vitro and in vivo. DT-IgG suppressed Tu212 and A549 cell growth, inhibited EGFR activation and induced apoptosis as effectively as cetuximab, and neutralized VEGF as effectively as bevacizumab. DT-IgG induced EGFR-dependent VEGF internalization, constituting a novel antiangiogenesis mechanism. In xenograft models with lung and head and neck cancer cell lines, DT-IgG displayed efficacy equivalent to bevacizumab in diminishing tumor growth despite its short serum half-life (36 hr in rats) and both agents may constitute preferable alternatives to cetuximab in KRAS-mutant tumors. Immunofluorescence staining revealed that localization of DT-IgG was similar to that of cetuximab, largely associated with EGFR+tumor cells. Our proof of principle study suggests a DT-IgG against EGFR and VEGF as an alternative therapeutic strategy with potentially enhanced clinical benefit.
Insights
A novel dual-targeting antibody (DT-IgG) effectively inhibits tumor growth by targeting both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). This approach shows promise as an alternative cancer therapy, particularly for KRAS-mutant tumors.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are key drivers of tumor growth.
- Targeting these pathways individually with antibodies like bevacizumab and cetuximab has shown clinical benefits.
- A single antibody targeting both EGFR and VEGF could offer a more optimized therapeutic strategy.
Purpose of the Study:
- To develop and evaluate a fully human dual-targeting IgG (DT-IgG) antibody capable of simultaneously targeting both EGFR and VEGF.
- To compare the efficacy of DT-IgG with existing therapies (bevacizumab and cetuximab) in lung and head and neck cancer models.
- To investigate the novel antiangiogenesis mechanism induced by DT-IgG.
Main Methods:
- Human domain antibodies against VEGF and EGFR were engineered into a dual-targeting IgG (DT-IgG).
- In vitro and in vivo studies were conducted using lung (A549) and head and neck (Tu212) cancer cell lines.
- Efficacy was assessed by measuring tumor cell growth, EGFR activation, apoptosis, and tumor growth in xenograft models. VEGF neutralization and antibody localization were also evaluated.
Main Results:
- DT-IgG effectively suppressed tumor cell growth and inhibited EGFR activation in both cell lines, comparable to cetuximab.
- DT-IgG neutralized VEGF activity as effectively as bevacizumab.
- DT-IgG induced EGFR-dependent VEGF internalization, a novel antiangiogenesis mechanism, and showed efficacy in xenograft models comparable to bevacizumab.
- DT-IgG localized to EGFR+ tumor cells, similar to cetuximab.
Conclusions:
- DT-IgG represents a promising novel therapeutic strategy for cancer treatment by simultaneously targeting EGFR and VEGF.
- The dual-targeting approach demonstrates potential for enhanced clinical benefits, especially in KRAS-mutant tumors where single-agent therapies may be less effective.
- DT-IgG offers a potentially preferable alternative to current treatments like cetuximab for specific cancer types.
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