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

Research output: Contribution to journalArticle

10 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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Epitopes
Anti-Idiotypic Antibodies
Ligands
Colorectal Neoplasms
Therapeutics
Tumor Microenvironment
Antibodies
Epidermal Growth Factor
Heterografts
Neoplasms
Monoclonal Antibodies
Cetuximab

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. / GC1118, an anti-EGFR antibody with a distinct binding epitope and superior inhibitory activity against high-affinity EGFR ligands. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 2. pp. 251-263.
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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.",
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Lim, Y, Yoo, J, Kim, MS, Hur, M, Lee, EH, Hur, HS, Lee, JC, Lee, SN, Park, TW, Lee, K, Chang, KH, Kim, K, Kang, Y, Hong, KW, Kim, SH, Kim, YG, Yoon, Y, Nam, DH, Yang, H, Kim, DG, Cho, HS & 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, vol. 15, no. 2, pp. 251-263. https://doi.org/10.1158/1535-7163.MCT-15-0679

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

In: Molecular Cancer Therapeutics, Vol. 15, No. 2, 02.2016, p. 251-263.

Research output: Contribution to journalArticle

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T1 - GC1118, an anti-EGFR antibody with a distinct binding epitope and superior inhibitory activity against high-affinity EGFR ligands

AU - Lim, Yangmi

AU - Yoo, Jiho

AU - Kim, Min Soo

AU - Hur, Minkyu

AU - Lee, Eun Hee

AU - Hur, Hyung Suk

AU - Lee, Jae Chul

AU - Lee, Shi Nai

AU - Park, Tae Wook

AU - Lee, Kyuhyun

AU - Chang, Ki Hwan

AU - Kim, Kuglae

AU - Kang, Yingjin

AU - Hong, Kwang Won

AU - Kim, Se Ho

AU - Kim, Yeon Gil

AU - Yoon, Yeup

AU - Nam, Do Hyun

AU - Yang, Heekyoung

AU - Kim, Dong Geon

AU - Cho, Hyun Soo

AU - Won, Jonghwa

PY - 2016/2

Y1 - 2016/2

N2 - 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.

AB - 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.

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