Department of Research Oncology, Genentech, Inc, South San Francisco, CA 94080, USA.
Cancer Cell. 2011 Oct 18;20(4):472-86. doi: 10.1016/j.ccr.2011.09.003.
Extensive crosstalk among ErbB/HER receptors suggests that blocking signaling from more than one family member may be essential to effectively treat cancer and limit drug resistance. We generated a conventional IgG molecule MEHD7945A with dual HER3/EGFR specificity by phage display engineering and used structural and mutational studies to understand how a single antigen recognition surface binds two epitopes with high affinity. As a human IgG1, MEHD7945A exhibited dual action by inhibiting EGFR- and HER3-mediated signaling in vitro and in vivo and the ability to engage immune effector functions. Compared with monospecific anti-HER antibodies, MEHD7945A was more broadly efficacious in multiple tumor models, showing that combined inhibition of EGFR and HER3 with a single antibody is beneficial.
ErbB/HER 受体之间的广泛串扰表明，阻断来自不止一个家族成员的信号可能对于有效治疗癌症和限制耐药性至关重要。我们通过噬菌体展示工程生成了一种常规的 IgG 分子 MEHD7945A，具有双重 HER3/EGFR 特异性，并利用结构和突变研究来了解单个抗原识别表面如何以高亲和力结合两个表位。作为一种人源 IgG1，MEHD7945A 通过抑制 EGFR 和 HER3 介导的信号转导在体外和体内发挥双重作用，并具有结合免疫效应功能的能力。与单特异性抗 HER 抗体相比，MEHD7945A 在多种肿瘤模型中更广泛有效，表明用单克隆抗体联合抑制 EGFR 和 HER3 是有益的。
