Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization.
An increasing number of therapeutic antibodies targeting tumors that express the epidermal growth factor receptor (EGFR) are in clinical use or late stages of clinical development. Here we investigate the molecular basis for inhibition of EGFR activation by the therapeutic antibody matuzumab (EMD72000). We describe the X-ray crystal structure of the Fab fragment of matuzumab (Fab72000) in complex with isolated domain III from the extracellular region of EGFR. Fab72000 interacts with an epitope on EGFR that is distinct from the ligand-binding region on domain III and from the cetuximab/Erbitux epitope. Matuzumab blocks ligand-induced receptor activation indirectly by sterically preventing the domain rearrangement and local conformational changes that must occur for high-affinity ligand binding and receptor dimerization.
Schmiedel
Judith
J
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Blaukat
Andree
A
Li
Shiqing
S
Knöchel
Thorsten
T
Ferguson
Kathryn M
KM
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D000068818:Cetuximab; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D000939:Epitopes / Q000737:chemistry; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D012995:Solubility
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D066246:ErbB Receptors; C520777:matuzumab; D000068818:Cetuximab