期刊
MOLECULAR CANCER THERAPEUTICS
卷 15, 期 2, 页码 251-263出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-15-0679
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资金
- Ministry for Health & Welfare Affairs, Republic of Korea [HI14C3418, A080320]
- Green Cross Corp., Republic of Korea
- Mid-career Researcher Program through a NRF grant, Korea government (MEST) [2009-0073145, 2009-0084897, NRF-2012R1A2A2A01012830]
- Korea Healthcare technology RD project
- Korea Health Promotion Institute [A080320] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2009-0084897, 2009-0073145] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 micro-environment 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. (C) 2015 AACR.
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