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• W1978217578 abstract "Abstract Epidermal growth factor receptor (EGFR) is a key regulator of cancer cell proliferation, apoptosis, invasion, and metastasis. However, the clinical benefits of EGFR targeted agents such as erlotinib and cetuximab have been modest. Using Merrimack's Network Biology platform, a computational systems analysis was performed to identify how best to inhibit signaling through the EGFR-ERK network. These simulations predicted that enhanced inhibition is required to overcome the robust signal amplification inherent to this network and is best achieved through treatment with a combination of at least two noncompetitive ligand antagonists. The MM-151 therapeutic was developed to achieve the simulated design criteria and consists of a mixture of three fully human monoclonal antibodies directed against distinct non-overlapping epitopes in EGFR. Detailed in vitro and on-cell binding experiments, supported by computational simulations, with single component antibodies and their monovalent Fab variants, display a rich complexity of antibody affinity and avidity. All three antibodies are shown to have subnanomolar monovalent affinity to EGFR but to vary in the degree to which they functionally crosslink receptor (two antibodies display high avidity while the third has weak avidity). Ligand competition experiments with saturating antibody concentrations (EC90 of on-cell binding) demonstrate that two of the antibodies are each complete ligand antagonists while the third antibody is a partial (approx. 25%) antagonist. When combined into the MM-151 mixture, these antibodies simultaneously engage and robustly crosslink receptor to form a highly antagonistic therapeutic. Treatment of human tumor-derived cell lines with MM-151 elicits complete inhibition of ligand-mediated ERK signaling over a wide range of both EGF receptor density (as high as 2×10∘6 receptors per cell in the A431 cell line) and ligand burden (8 and 80nM EGF). In contrast, monoclonal EGFR targeted therapeutics, such as cetuximab and panitumumab, as well as oligoclonal inhibitors similar to MM-151, show weaker or even no effect on ERK signaling under similar conditions. Furthermore, the potency of monovalent MM-151 (Fab variants) is diminished in EGF mediated EGFR and ERK signaling, highlighting the importance of receptor crosslinking through antibody avidity as a determinant of efficacy. Together, these data demonstrate that MM-151 is a potent inhibitor of the EGFR-ERK signaling axis with the potential of improved efficacy over current EGFR targeted therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A210." @default.
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• W1978217578 date "2011-11-01" @default.
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• W1978217578 title "Abstract A210: Mechanism of action of MM-151, a potent mixture of three human antibody antagonists targeting EGFR." @default.
• W1978217578 doi "https://doi.org/10.1158/1535-7163.targ-11-a210" @default.
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