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Peptide Scanning-assisted Identification of a Monoclonal Antibody-recognized Linear B-cell Epitope
Published on: March 24, 2017
B-cell epitope peptide vaccination targeting dimer interface of epidermal growth factor receptor (EGFR)
1Guangdong Provincial Key Laboratory of Biotechnology Candidate Drug Research, College of Life Science and Biopharmaceutical, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Abstract:
Epidermal growth factor receptor (EGFR) was the first receptor to be proposed as the target for cancer therapy, however, the anti-EGFR therapy showed a low response rate clinically. Dimerization plays a key role in the activation of EGFR, so targeting the conservative dimer interface probably improve the responses of anti-EGFR clinically. To evoke a high titers of antibodies (Abs) targeting the dimer interface of EGFR in patients, a chimeric peptide, comprising a linear B-cell epitope peptide from the highly conservative β-hairpin loop of dimer interface of human EGFR (EGFR237-267) and a 'promiscuous' Th-cell epitope MVF from the measles virus fusion protein, was constructed. The construct was immunogenic and able to elicit high titers of peptide-specific Abs in both mice and rabbits, while both animals' EGFRs contain a sequence 100% homologous to EGFR237-267. The peptide-specific Abs could recognize and inhibit EGFR over-expressing epithelial cancer cells, such as epidermoid carcinoma A431 and Lewis lung cancer (LLC), furthermore, the binding of the Abs to the native EGFR on the surface of cells was ligand-dependent, which meant that these Abs did target the dimer interface of EGFR as designed, because the exposure of the interface needs ligand binding. The chimeric peptide immunization was able to significantly inhibit the growth of subcutaneously transplanted LLC cells in C57BL6 mice. Therefore, the MVF-EGFR237-267 construct represents a promising candidate for active anti-EGFR immunotherapy and provides a novel targeting strategy for the anti-EGFR therapy.
Insights
A novel chimeric peptide targeting the epidermal growth factor receptor (EGFR) dimer interface successfully elicited high-titer antibodies. These antibodies inhibited EGFR-overexpressing cancer cells and suppressed tumor growth, offering a promising strategy for active anti-EGFR immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) is a key target in cancer therapy, but current anti-EGFR treatments have limited clinical efficacy.
- EGFR activation relies on dimerization, suggesting that targeting the dimer interface could enhance therapeutic responses.
- Developing strategies to target the EGFR dimer interface is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To design and evaluate a chimeric peptide vaccine targeting the EGFR dimer interface for active immunotherapy.
- To assess the immunogenicity and efficacy of the peptide in generating antibodies against the EGFR dimer interface.
- To investigate the potential of this novel approach for enhancing anti-EGFR cancer therapy.
Main Methods:
- A chimeric peptide (MVF-EGFR237-267) was constructed, combining a human EGFR β-hairpin loop epitope with a T-cell epitope from the measles virus.
- The immunogenicity of the peptide was tested in mice and rabbits, measuring peptide-specific antibody titers.
- The ability of elicited antibodies to recognize and inhibit EGFR-overexpressing cancer cells (A431, LLC) and their binding to native EGFR in a ligand-dependent manner was assessed.
- In vivo efficacy was evaluated by challenging C57BL6 mice with subcutaneously transplanted LLC cells after immunization.
Main Results:
- The MVF-EGFR237-267 construct was immunogenic, inducing high titers of peptide-specific antibodies in both mice and rabbits.
- The generated antibodies recognized and inhibited EGFR-overexpressing cancer cells, including epidermoid carcinoma A431 and Lewis lung cancer (LLC).
- Antibody binding to native EGFR on cells was ligand-dependent, confirming targeting of the dimer interface.
- Immunization with the chimeric peptide significantly inhibited the growth of LLC tumors in mice.
Conclusions:
- The MVF-EGFR237-267 chimeric peptide is a promising candidate for active anti-EGFR immunotherapy.
- This approach provides a novel strategy for targeting the EGFR dimer interface, potentially improving clinical responses in anti-EGFR therapy.
- The study demonstrates the feasibility of using peptide-based vaccines to elicit antibodies against critical protein-protein interaction sites in cancer therapy.
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