GC1118, an anti-EGFR antibody with a distinct binding epitope and superior inhibitory activity against high-affinity EGFR ligands

Yangmi Lim, Jiho Yoo, Min Soo Kim, Minkyu Hur, Eun Hee Lee, Hyung Suk Hur, Jae Chul Lee, Shi Nai Lee, Tae Wook Park, Kyuhyun Lee, Ki Hwan Chang, Kuglae Kim, Yingjin Kang, Kwang Won Hong, Se Ho Kim, Yeon Gil Kim, Yeup Yoon, Do Hyun Nam, Heekyoung Yang, Dong Geon KimHyun Soo Cho, Jonghwa Won

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11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)251-263
Number of pages13
JournalMolecular Cancer Therapeutics
Volume15
Issue number2
DOIs
Publication statusPublished - 2016 Feb

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lim, Y., Yoo, J., Kim, M. S., Hur, M., Lee, E. H., Hur, H. S., Lee, J. C., Lee, S. N., Park, T. W., Lee, K., Chang, K. H., Kim, K., Kang, Y., Hong, K. W., Kim, S. H., Kim, Y. G., Yoon, Y., Nam, D. H., Yang, H., ... Won, J. (2016). GC1118, an anti-EGFR antibody with a distinct binding epitope and superior inhibitory activity against high-affinity EGFR ligands. Molecular Cancer Therapeutics, 15(2), 251-263. https://doi.org/10.1158/1535-7163.MCT-15-0679