A Two-in-One Antibody against HER3 and EGFR Has Superior Inhibitory Activity Compared with Monospecific Antibodies
A Two-in-One Antibody against HER3 and EGFR Has Superior Inhibitory Activity Compared with Monospecific Antibodies
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DOI：
10.1016/j.ccr.2011.09.003
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发表时间：
2011-10-18
期刊：
影响因子：
50.3
通讯作者：
Eigenbrot, Charles
中科院分区：
文献类型：
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作者：
Schaefer, Gabriele;Haber, Lauric;Eigenbrot, Charles
ErbB/HER受体之间广泛的串扰表明，阻断来自多个家族成员的信号传导可能对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具有HER3/EGFR双特异性的传统IgG分子MEHD7945A，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IgG1， MEHD7945A在体外和体内表现出双重作用，既能抑制EGFR-和her3介导的信号传导，又能参与免疫效应功能。与单特异性抗her抗体相比，MEHD7945A在多种肿瘤模型中更广泛地有效，表明单抗体联合抑制EGFR和HER3是有益的。
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.