帕妥珠单抗
曲妥珠单抗
单克隆抗体
多西紫杉醇
抗体
人源化抗体
癌症研究
医学
生长抑制
转移性乳腺癌
癌症
药理学
乳腺癌
化学
细胞生长
内科学
免疫学
生物化学
作者
Xuesai Zhang,Jianhe Chen,Zhibing Weng,Qingrou Li,Le Zhao,Ning Yu,Lan Deng,Wei Xu,Yan Yang,Zhenping Zhu,Haomin Huang
标识
DOI:10.1016/j.molimm.2020.01.009
摘要
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.
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