Cryo-EM Structure of HER2-trastuzumab-pertuzumab complex
Cryo-EM Structure of HER2-trastuzumab-pertuzumab complex
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DOI：
10.1371/journal.pone.0216095
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发表时间：
2019-05-01
期刊：
影响因子：
3.7
通讯作者：
Huang, Xin
中科院分区：
文献类型：
--
作者：
Hao, Yue;Yu, Xinchao;Huang, Xin
曲妥珠单抗和帕妥珠单抗是结合人表皮生长因子受体2 （HER2）细胞外结构域不同亚域的单克隆抗体。将这些单克隆抗体添加到her2阳性乳腺癌的治疗方案中已经改变了这种癌症的治疗模式。这两种抗体的协同作用已经被观察到，这导致了关于机制的假设，并导致了双特异性抗体的发展，以进一步最大化临床效果。尽管her2 -曲妥珠单抗和her2 -帕妥珠单抗的单独晶体结构揭示了不同的结合位点，并为其抗肿瘤活性提供了结构基础，但关于her2 -曲妥珠单抗-帕妥珠单抗复合物的详细结构信息一直难以捉摸。在这里，我们展示了her2 -曲妥珠单抗-帕妥珠单抗在4.36 A分辨率下的低温电镜结构。与二元复合物的比较显示曲妥珠单抗和帕妥珠单抗之间没有合作相互作用，并为设计具有潜在更大临床疗效的新型高亲和力双特异性分子提供了关键见解。
Trastuzumab and pertuzumab are monoclonal antibodies that bind to distinct subdomains of the extracellular domain of human epidermal growth factor receptor 2 (HER2). Adding these monoclonal antibodies to the treatment regimen of HER2-positive breast cancer has changed the paradigm for treatment in that form of cancer. Synergistic activity has been observed with the combination of these two antibodies leading to hypotheses regarding the mechanism(s) and to the development of bispecific antibodies to maximize the clinical effect further. Although the individual crystal structures of HER2-trastuzumab and HER2-pertuzumab revealed the distinct binding sites and provided the structural basis for their anti-tumor activities, detailed structural information on the HER2-trastuzumab-pertuzumab complex has been elusive. Here we present the cryo-EM structure of HER2-trastuzumab-pertuzumab at 4.36 A resolution. Comparison with the binary complexes reveals no cooperative interaction between trastuzumab and pertuzumab, and provides key insights into the design of novel, high-avidity bispecific molecules with potentially greater clinical efficacy.