Mechanisms of Neutralization of a Human Anti-Alpha Toxin Antibody [Protein Structure and Folding]

September 10th, 2014 by Oganesyan, V., Peng, L., Damschroder, M. M., Cheng, L., Sadowska, A., Tkaczyk, C., Sellman, B. R., Wu, H., Dall'Acqua, W. F.

MEDI4893 is a neutralizing human monoclonal antibody that targets alpha 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 A, and further characterized its epitope using various engineered AT variants. We have found that MEDI4893 recognizes a novel epitope in AT so-called rim domain, and exerts its neutralizing effect through a dual mechanism. More particularly, MEDI4893 not only sterically blocks binding of AT to its cell receptor, but also prevents it from adopting a lytic heptameric trans-membrane conformation.