Locally Misfolded HER2 Expressed on Cancer Cells is a Promising Target for Development of Cancer-Specific Antibodies
40 Pages Posted: 11 Sep 2023 Publication Status: Under ReviewMore...
Overexpression of human epidermal growth factor receptor 2 (HER2) in breast and gastric cancers is known to be associated with poor prognosis, making it an attractive therapeutic target. Here, we established a novel cancer-specific anti-HER2 antibody, H2Mab-214. H2Mab-214 reacted with HER2 on cancer cells, but unlike the therapeutic antibody trastuzumab, did not react with HER2 on normal cells in flow cytometry. Using X-ray crystallography, we revealed that H2Mab-214 recognizes a structurally disrupted portion in the HER2 domain IV, which normally forms a β-sheet. This misfolding was shown to be inducible by site-directed mutagenesis mimicking the disulfide bond defects that may occur in cancer cells, indicating that the local misfolding in the Cys-rich domain IV governs the cancer-specificity of H2Mab-214. Furthermore, we showed that H2Mab-214 effectively suppresses tumor growth in xenograft mouse models. Our findings offer a potential strategy for developing cancer-specific therapeutic antibodies that target partially misfolded cell surface receptors.
Keywords: Cancer-specific monoclonal antibody, Human epidermal growth factor receptor 2, breast cancer, Misfolding, Crystal structure, Trastuzumab, Xenograft model, Anti-tumor effect, Fv-clasp
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