Mechanisms of Neutralization of a Human Anti-α-toxin Antibody

• Published in: The Journal of biological chemistry Vol. 289; no. 43; pp. 29874 - 29880
• Main Authors: Oganesyan, Vaheh, Peng, Li, Damschroder, Melissa M., Cheng, Li, Sadowska, Agnieszka, Tkaczyk, Christine, Sellman, Bret R., Wu, Herren, Dall'Acqua, William F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.10.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Bacterial Toxins - immunology; Broadly Neutralizing Antibodies; Cell Line; Crystallography, X-Ray; Epitope Mapping; Hemolysin Proteins - immunology; Humans; Immunoglobulin Fab Fragments - chemistry; Models, Molecular; Neutralization Tests; Protein Binding; Protein Structure and Folding; Recombinant Proteins - chemistry; Staphylococcus aureus; Surface Plasmon Resonance; Crystal Structure; Alpha Toxin; Mutagenesis; Antibody; Fab; Staphylococcus aureus (S. aureus); Infectious Disease
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.601328

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.