title: GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands.
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.
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Yangmi
authors.initials: Y
authors.lastname: Lim
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Jiho
authors.initials: J
authors.lastname: Yoo
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea. Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Minkyu
authors.initials: M
authors.lastname: Hur
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Lee
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Hur
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Jae-Chul
authors.initials: JC
authors.lastname: Lee
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Shi-Nai
authors.initials: SN
authors.lastname: Lee
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Tae Wook
authors.initials: TW
authors.lastname: Park
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Kyuhyun
authors.initials: K
authors.lastname: Lee
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Kuglae
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: YingJin
authors.initials: Y
authors.lastname: Kang
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea.
authors.forename: Kwang-Won
authors.initials: KW
authors.lastname: Hong
authors.affiliation: University-Industry Cooperation Foundation, and Department of Systems Immunology, College of Biomedical Science, Kangwon National University, Chuncheon, Kangwon-Do, Republic of Korea.
authors.forename: Se-Ho
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Pohang Accelerator Laboratory, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Yeon-Gil
authors.initials: YG
authors.lastname: Kim
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: Yeup
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea. Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea. Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: Heekyoung
authors.initials: H
authors.lastname: Yang
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: Dong Geon
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. agnes@mogam.re.kr hscho8@yonsei.ac.kr.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Republic of Korea. agnes@mogam.re.kr hscho8@yonsei.ac.kr.
authors.forename: Jonghwa
authors.initials: J
authors.lastname: Won
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000939:Epitopes / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000939:Epitopes; C000611922:GC1118; D008024:Ligands; D066246:ErbB Receptors