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Supplementary Tables S5, S6, S7, S8 from Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

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posted on 2023-04-03, 14:22 authored by Jeffrey D. Kearns, Raghida Bukhalid, Mark Sevecka, Gege Tan, Nastaran Gerami-Moayed, Shannon L. Werner, Neeraj Kohli, Olga Burenkova, Callum M. Sloss, Anne M. King, Jonathan B. Fitzgerald, Ulrik B. Nielsen, Beni B. Wolf

Supplementary Tables S5, S6, S7, S8. mRNA expression data for EGFR ligands as measured by RNAseq from The Cancer Genome Atlas (TCGA) across 14 cancer indications or by RT-qPCR of colorectal cancer FFPE samples. Table S5: Summary of TCGA datasets included in the analysis. Table S6: Raw and normalized expression data from TCGA. Table S7: EGFR ligand expression measured by RT-qPCR on commercially-obtained colorectal cancer FFPE samples. Table S8: Pairwise correlations of EGFR ligands across four TCGA indications.

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ARTICLE ABSTRACT

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. Mol Cancer Ther; 14(7); 1625–36. ©2015 AACR.