Enhanced targeting of the EGFR network with MM-151, an oligoclonal anti-EGFR antibody therapeutic
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé MM-151 qui associe 3 anticorps monoclonaux ciblant des épitopes différents du récepteur EGFR
While epidermal growth factor receptor (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 co-expressed 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, non-overlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to a ~65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated anti-proliferative 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.
http://mct.aacrjournals.org/content/early/2015/04/24/1535-7163.MCT-14-0772.abstract 2015