癌症
抗体
癌细胞
生物
癌症研究
细胞生物学
计算生物学
免疫学
遗传学
作者
Takao Arimori,Emiko Mihara,Hiroyuki Suzuki,Tomokazu Ohishi,Tomohiro Tanaka,Mika K. Kaneko,Junichi Takagi,Yukinari Kato
标识
DOI:10.1016/j.str.2024.02.007
摘要
Summary
Overexpression of human epidermal growth factor receptor 2 (HER2) in breast and gastric cancers is associated with a poor prognosis, making it an important therapeutic target. Here, we establish a novel cancer-specific anti-HER2 antibody, H2Mab-214. H2Mab-214 reacts with HER2 on cancer cells, but unlike the therapeutic antibody trastuzumab, it does not react with HER2 on normal cells in flow cytometry measurements. A crystal structure suggests that H2Mab-214 recognizes a structurally disrupted region in the HER2 domain IV, which normally forms a β-sheet. We show that this misfolding is inducible by site-directed mutagenesis mimicking the disulfide bond defects that also 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 show 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.
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