The majority of patients with metastatic breast cancer who are treated with the anti-HER2 monoclonal antibody, trastuzumab, generally develop resistance to the drug within a year after initiation of the treatment. Here we describe a new anti-HER2 humanized monoclonal antibody, 19H6-Hu, which binds to HER2 extracellular domain (ECD) with high affinity and inhibits proliferation of multiple HER2-overexpressing cancer cell lines as a single agent or in combination with trastuzumab. 19H6-Hu binds to the domain III in proximity to the domain IV of HER2 ECD, which differs from trastuzumab and pertuzumab. 19H6-Hu in combination with trastuzumab was more effective at blocking phosphorylation of ERK1/2, AKT(S473)and HER2 (Y1248) in HER2-positive cancer cells compared to trastuzumab alone or in combination with pertuzumab. Combination of three antibodies, 19H6-Hu, inetetamab (a trastuzumab analog) and pertuzumab exhibited much stronger inhibition of large NCI-N87 tumor xenografts (>400mm3) than the current standard of care, inetetamab (trastuzumab) plus Docetaxel (DTX), as well as the combination of 19H6-Hu, inetetamab and DTX. Our results highlight the functional variability of HER2 domains and provide a new insight into the design of HER2-targeting agents.

中文翻译：

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一种新型抗HER2抗体，具有独特的作用机制，可增强曲妥珠单抗和帕妥珠单抗的抗肿瘤功效。

用抗HER2单克隆抗体曲妥珠单抗治疗的大多数转移性乳腺癌患者通常在治疗开始后一年内对药物产生耐药性。在这里，我们描述了一种新的抗HER2人源化单克隆抗体19H6-Hu，它以高亲和力与HER2细胞外域（ECD）结合，并作为单一药物或与曲妥珠单抗组合抑制多种过表达HER2的癌细胞系的增殖。19H6-Hu在与HER2 ECD的结构域IV邻近的区域III上结合，这不同于曲妥珠单抗和帕妥珠单抗。与单独使用曲妥珠单抗或与曲妥珠单抗联用相比，与曲妥珠单抗合用的19H6-Hu与曲妥珠单抗相比，在阻断HER2阳性癌细胞中ERK1 / 2，AKT（S473）和HER2（Y1248）的磷酸化方面更有效。三种抗体的组合，19H6-Hu，inetetamab（曲妥珠单抗类似物）和pertuzumab对大型NCI-N87肿瘤异种移植物（> 400mm3）的抑制作用要强于目前的治疗标准，inetetamab（trastuzumab）和Docetaxel（DTX）以及以下药物的组合19H6-Hu，inetetamab和DTX。我们的结果突出了HER2域的功能变异性，并为HER2靶向剂的设计提供了新的见识。