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, HMab-214. HMab-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 HMab-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 HMab-214. Furthermore, we show that HMab-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.

中文翻译：

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癌细胞上表达的局部错误折叠的 HER2 是开发癌症特异性抗体的有希望的目标

人表皮生长因子受体 2 (HER2) 在乳腺癌和胃癌中的过度表达与不良预后相关，使其成为重要的治疗靶点。在这里，我们建立了一种新型癌症特异性抗 HER2 抗体 HMab-214。 HMab-214 与癌细胞上的 HER2 发生反应，但与治疗性抗体曲妥珠单抗不同，在流式细胞术测量中，它不与正常细胞上的 HER2 发生反应。晶体结构表明 HMab-214 识别 HER2 结构域 IV 中的结构破坏区域，该区域通常形成 β-折叠。我们表明，这种错误折叠是通过模仿癌细胞中也可能发生的二硫键缺陷的定点诱变来诱导的，表明富含Cys的结构域IV中的局部错误折叠控制着HMab-214的癌症特异性。此外，我们表明 HMab-214 可以有效抑制异种移植小鼠模型中的肿瘤生长。我们的研究结果为开发针对部分错误折叠的细胞表面受体的癌症特异性治疗抗体提供了潜在的策略。