2015
DOI: 10.1158/1535-7163.mct-14-0772
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Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

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 highaffinity 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 th… Show more

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Cited by 51 publications
(31 citation statements)
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“…In addition, antibody constructs with greater size or flexibility to their binding components could strongly impact the ability of the construct to bind multivalently. There is literature evidence that this occurs and that antibodies can be categorized by their propensity to efficiently bind bivalently (36). Although the bispecific antibody constructs used in these experiments are primarily tetravalent and not bivalent as depicted in our mathematical model, we reason that our simplified framework and mathematical model is still a useful approximation of multivalent binding in general.…”
Section: Discussionmentioning
confidence: 99%
“…In addition, antibody constructs with greater size or flexibility to their binding components could strongly impact the ability of the construct to bind multivalently. There is literature evidence that this occurs and that antibodies can be categorized by their propensity to efficiently bind bivalently (36). Although the bispecific antibody constructs used in these experiments are primarily tetravalent and not bivalent as depicted in our mathematical model, we reason that our simplified framework and mathematical model is still a useful approximation of multivalent binding in general.…”
Section: Discussionmentioning
confidence: 99%
“…MM-151 is a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, non-overlapping epitopes on the EGFR [64,65]. MM-151 was designed using a systems biology approach to substantially improve on the mechanisms that enable potent EGFR antagonism, EGFR downregulation, and immune effector function.…”
Section: Resistance Mechanism To Anti-egfr Therapiesmentioning
confidence: 99%
“…EGFR-targeted antibodies on the market or under development differ in their isotype, binding affinity, and mechanism of EGFR binding, and show different characteristics (23,24). Recently, mixtures of antibodies targeting nonoverlapping epitopes on EGFR (Sym004 and MM-151) were developed and reported to have enhanced inhibitory activity on EGFR signaling and tumor progression (25,26).…”
Section: Introductionmentioning
confidence: 99%