Structural Insights into the Neutralization Properties of the Fully Human, Anti-interferon Monoclonal Antibody Sifalimumab.
We report the three-dimensional structure of human interferon α-2A (IFN-α2A) bound to the Fab fragment of a therapeutic monoclonal antibody (sifalimumab; IgG1/κ). The structure of the corresponding complex was solved at a resolution of 3.0 Å using molecular replacement and constitutes the first reported structure of a human type I IFN bound to a therapeutic antibody. This study revealed the major contribution made by the first complementarity-determining region in each of sifalimumab light and heavy chains. These data also provided the molecular basis for sifalimumab mechanism of action. We propose that its interferon-neutralizing properties are the result of direct competition for IFN-α2A binding to the IFN receptor subunit 1 (IFNAR1) and do not involve inhibiting IFN-α2A binding to the IFN receptor subunit 2 (IFNAR2).
From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878 oganesyanv@medimmune.com.
Vaheh
V
Oganesyan
From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878.
Li
L
Peng
From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878.
Robert M
RM
Woods
From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878.
Herren
H
Wu
From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878 dallacquaw@medimmune.com.
William F
WF
Dall'Acqua
D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D018360:Crystallography, X-Ray; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000187:drug effects* / Q000276:immunology; D008958:Models, Molecular; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; C568334:sifalimumab
autoimmune disease, epitope mapping, interferon, monoclonal antibody, nuclear magnetic resonance (NMR), protein expression, sifalimumab, structural biology, systemic lupus erythematosus, x-ray crystallography