title: Mechanisms of neutralization of a human anti-α-toxin antibody.
abstract: MEDI4893 is a neutralizing human monoclonal antibody that targets α-toxin (AT) and is currently undergoing evaluation in the field of Staphylococcus aureus-mediated diseases. We have solved the crystal structure of MEDI4893 Fab bound to monomeric AT at a resolution of 2.56 Å and further characterized its epitope using various engineered AT variants. We have found that MEDI4893 recognizes a novel epitope in the so-called "rim" domain of AT and exerts its neutralizing effect through a dual mechanism. In particular, MEDI4893 not only sterically blocks binding of AT to its cell receptor but also prevents it from adopting a lytic heptameric trans-membrane conformation.
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and oganesyanv@medimmune.com.
authors.forename: Vaheh
authors.initials: V
authors.lastname: Oganesyan
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and.
authors.forename: Li
authors.initials: L
authors.lastname: Peng
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Damschroder
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and.
authors.forename: Li
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Infectious Diseases, MedImmune, Gaithersburg, Maryland 20878.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sadowska
authors.affiliation: Infectious Diseases, MedImmune, Gaithersburg, Maryland 20878.
authors.forename: Christine
authors.initials: C
authors.lastname: Tkaczyk
authors.affiliation: Infectious Diseases, MedImmune, Gaithersburg, Maryland 20878.
authors.forename: Bret R
authors.initials: BR
authors.lastname: Sellman
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and.
authors.forename: Herren
authors.initials: H
authors.lastname: Wu
authors.affiliation: From the Departments of Antibody Discovery and Protein Engineering and dallacquaw@medimmune.com.
authors.forename: William F
authors.initials: WF
authors.lastname: Dall'Acqua
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D001427:Bacterial Toxins / Q000276:immunology*; D000080908:Broadly Neutralizing Antibodies; D002460:Cell Line; D018360:Crystallography, X-Ray; D018604:Epitope Mapping; D006460:Hemolysin Proteins / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D008958:Models, Molecular; D009500:Neutralization Tests; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D020349:Surface Plasmon Resonance
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; D000080908:Broadly Neutralizing Antibodies; D006460:Hemolysin Proteins; D007140:Immunoglobulin Fab Fragments; D011994:Recombinant Proteins; C021091:staphylococcal alpha-toxin; C000600718:suvratoxumab
keywords: Alpha Toxin; Antibody; Crystal Structure; Fab; Infectious Disease; Mutagenesis; Staphylococcus aureus (S. aureus)