GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands.

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

doi:10.1158/1535-7163.mct-15-0679

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.

Highlights

EGFR, a member of the ErbB or HER family of receptors, regulates various cellular processes including proliferation, differentiation, migration, and invasion [1]
B, the indicated colon cancer cell lines were preincubated with 0.1 mg/mL of cetuximab or GC1118 for 2 hours prior to the addition of EGFR ligands for 10 minutes (EGF, heparin-binding EGF-like growth factor (HB-EGF), BTC, and TGFa, 500 ng/mL; AREG and EREG, 1 mg/mL)
The gray and black bars indicate the relative percentage of cetuximab and GC1118, respectively, bound to EGFR in the presence of competing ligands compared with bound antibodies in the absence of blocking ligands

Summary

Introduction

EGFR, a member of the ErbB or HER family of receptors, regulates various cellular processes including proliferation, differentiation, migration, and invasion [1]. Enhanced EGFR ligand expression and an autocrine or paracrine EGFR circuit are the main mechanisms in cancer development and progression [5]. The EGFR ligand family is comprised of seven transmembrane precursor proteins whose expression and processing is tightly regulated. These ligands can be classified on the basis of their affinity for EGFR. An increased expression of high-affinity ligands, such as TGFa and HB-EGF, was observed in a mouse colorectal cancer model with acquired resistance to cetuximab [14]. The superior inhibitory activity of GC1118 on high-affinity EGFR ligands, to which current clinical antibodies show restricted inhibitory activity, reflects the potential therapeutic advantage of GC1118 in treating cancer patients where high-affinity EGFR ligands are implicated in tumor progression, metastasis, and resistance to current cancer therapeutics

Materials and Methods

Results

Discussion

Disclosure of Potential Conflicts of Interest