GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands
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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. Mol Cancer Ther; 15(2); 251–63. ©2015 AACR.
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GC1118 displays inhibitory effects against patient-derived xenografts from colorectal cancer tumours with a KRAS mutation, especially those with elevated expression of high-affinity ligands.
“In addition, GC1118 is a novel, fully humanized anti-EGFR IgG1 antibody that displays inhibitory effects against patient-derived xenografts from CRC tumours with a KRAS mutation [40], especially in those with elevated expression of high-affinity ligands [72].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [72]
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- Authors
- 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., Kim, D. G., Cho, H.-S., & Won, J.
- Affiliations
- 1MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
- Yonsei University (KR)
- Korea University (KR)
- Kangwon National University (KR)
- Pohang University of Science and Technology (KR)
- Samsung (South Korea) (KR)
- Samsung Medical Center (KR)
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2016-02-01
- Volume
- 15
- Issue
- 2
- Pages
- 251-263
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2172727255
- Cited by
- 38
- References
- 49
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 6 · 2017: 2 · 2016: 2
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- the Korea Healthcare technology R&D project, Ministry for Health & Welfare Affairs, Republic of Korea (HI14C3418, A080320)
- NRF (MEST; no. 2009-0073145, 2009-0084897, NRF-2012R1A2A2A01012830)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- anti-EGFR monoclonal antibody, binding epitope, EGF binding, EGFR signaling inhibition, cetuximab, panitumumab, metastatic colorectal cancer, tumor xenografts, treatment resistance, tumor microenvironment
- MeSH terms
- Animals, Epitopes, Antineoplastic Agents, Female, Humans, Ligands, Models, Molecular, Protein Binding, Colorectal Neoplasms, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, Antibodies, Monoclonal, Humanized, ErbB Receptors
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