Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

• Published in: Molecular cancer therapeutics Vol. 14; no. 7; pp. 1625 - 1636
• Main Authors: Kearns, Jeffrey D, Bukhalid, Raghida, Sevecka, Mark, Tan, Gege, Gerami-Moayed, Nastaran, Werner, Shannon L, Kohli, Neeraj, Burenkova, Olga, Sloss, Callum M, King, Anne M, Fitzgerald, Jonathan B, Nielsen, Ulrik B, Wolf, Beni B
• Format: Journal Article
• Language: English
• Published: United States 01.07.2015
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Apoptosis - drug effects; Blotting, Western; Cell Line, Tumor; Cell Proliferation - drug effects; Epitopes - immunology; Epitopes - metabolism; Female; Humans; Ligands; MAP Kinase Signaling System - drug effects; Mice, SCID; Microscopy, Confocal; Molecular Targeted Therapy; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - immunology; Receptor, Epidermal Growth Factor - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-14-0772

Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics.