6B3S

Crystal structure of the Fab fragment of necitumumab (Fab11F8) in complex with domain III from a cetuximab resistant variant of EGFR (sEGFRd3-S468R)

Summary for 6B3S

• Entry DOI: 10.2210/pdb6b3s/pdb
• Descriptor: Epidermal growth factor receptor, Necitumumab Fab Heavy chain, Necitumumab Fab Light chain, ... (8 entities in total)
• Functional Keywords: therapeutic antibody, cetuximab resistance, somatic mutation, colorectal cancer, transferase, transferase-immune system complex, transferase/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 287582.73

Authors

Ferguson, K.M.,Bagchi, A. (deposition date: 2017-09-23, release date: 2017-12-06, Last modification date: 2024-10-16)

Primary citation

Bagchi, A.,Haidar, J.N.,Eastman, S.W.,Vieth, M.,Topper, M.,Iacolina, M.D.,Walker, J.M.,Forest, A.,Shen, Y.,Novosiadly, R.D.,Ferguson, K.M.
Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance.
Mol. Cancer Ther., 17:521-531, 2018

PubMed Abstract: Acquired resistance to cetuximab, an antibody that targets the EGFR, impacts clinical benefit in head and neck, and colorectal cancers. One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA-approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab-resistant substitution, S468R (or S492R, depending on the amino acid numbering system). We determined an X-ray crystal structure to 2.8 Å resolution of the necitumumab Fab bound to an S468R variant of EGFR domain III. The arginine is accommodated in a large, preexisting cavity in the necitumumab paratope. We predict that this paratope shape will be permissive to other epitope substitutions, and show that necitumumab binds to most cetuximab- and panitumumab-resistant EGFR variants. We find that a simple computational approach can predict with high success which EGFR epitope substitutions abrogate antibody binding. This computational method will be valuable to determine whether necitumumab will bind to EGFR as new epitope resistance variants are identified. This method could also be useful for rapid evaluation of the effect on binding of alterations in other antibody/antigen interfaces. Together, these data suggest that necitumumab may be active in patients who are resistant to cetuximab or panitumumab through EGFR epitope mutation. Furthermore, our analysis leads us to speculate that antibodies with large paratope cavities may be less susceptible to resistance due to mutations mapping to the antigen epitope. .

PubMed: 29158469
DOI: 10.1158/1535-7163.MCT-17-0575

Experimental method

X-RAY DIFFRACTION (2.8 Å)