Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic.
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.
Merrimack Pharmaceuticals, Cambridge, Massachusetts. jkearns@merrimackpharma.com.
Jeffrey D
JD
Kearns
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Raghida
R
Bukhalid
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Mark
M
Sevecka
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Gege
G
Tan
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Nastaran
N
Gerami-Moayed
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Shannon L
SL
Werner
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Neeraj
N
Kohli
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Olga
O
Burenkova
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Callum M
CM
Sloss
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Anne M
AM
King
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Jonathan B
JB
Fitzgerald
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Ulrik B
UB
Nielsen
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Beni B
BB
Wolf
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016513:Mice, SCID; D018613:Microscopy, Confocal; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000939:Epitopes; D008024:Ligands; C000607291:MM-151; D066246:ErbB Receptors