Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic
Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic
复制标题
DOI：
10.1158/1535-7163.mct-14-0772
复制
发表时间：
2015-07-01
影响因子：
5.7
通讯作者：
Wolf, Beni B.
中科院分区：
文献类型：
--
作者：
Kearns, Jeffrey D.;Bukhalid, Raghida;Wolf, Beni B.
尽管EGFR是多种癌症适应症的经验证的治疗靶点，但对当前抗EGFR药物的临床应答通常不高，这表明需要改进治疗方法。在这里，我们证明了由高亲和力EGFR配体驱动的信号放大限制了单克隆抗EGFR抗体阻断通路信号传导和细胞增殖的能力，并且这些配体通常与上皮肿瘤中的低亲和力EGFR配体共表达。为了开发能够克服高亲和力配体介导的信号放大的改进的抗体治疗剂，我们使用了包括信号传导研究和受体-拮抗剂相互作用的计算建模的网络生物学方法。模型模拟表明，寡克隆抗体组合可以克服由所有EGFR配体驱动的EGFR：ERK通路内的信号放大。基于此，我们设计了MM-151，这是一种三种完全人源IgG 1单克隆抗体的组合，可以同时以亚纳摩尔亲和力结合EGFR上不同的非重叠表位。在信号传导研究中，MM-151拮抗高亲和力EGFR配体的效果比西妥昔单抗更好，导致ERK信号放大降低约65倍。在细胞活力研究中，MM-151表现出对高亲和力EGFR配体的抗增殖活性，无论是单独使用还是联合使用，而西妥昔单抗的活性在这些条件下基本上被消除。我们在体外和体内自分泌高亲和力配体表达的细胞系模型中证实了这一发现。总之，这些临床前研究为MM-151的临床研究提供了依据，并表明高亲和力EGFR配体表达可能是区分MM-151与其他抗EGFR治疗的预测性缓解标志物。(C)2015年AACR。
Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR: ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics. (C) 2015 AACR.