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Lim, Yangmi; Yoo, Jiho; Kim, Min-Soo; Hur, Minkyu; Lee, Eun Hee; Hur, Hyung-Suk; Lee, Jae-Chul; Lee, Shi-Nai; Park, Tae Wook; Lee, Kyuhyun; Chang, Ki Hwan; Kim, Kuglae; Kang, YingJin; Hong, Kwang-Won; Kim, Se-Ho; Kim, Yeon-Gil; Yoon, Yeup; Nam, Do-Hyun; Yang, Heekyoung; Kim, Dong Geon; Cho, Hyun-Soo; Won, Jonghwa
Molecular cancer therapeutics 15, Issue: 2Journal Article
The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR-GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251-63. ©2015 AACR.
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