Mechanisms of Neutralization of a Human Anti-Alpha Toxin Antibody

MEDI4893 is a neutralizing human monoclonal antibody that targets alpha toxin (AT), and is currently undergoing evaluation in the field of Staphylococcus aureusmediated 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 AT’s 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.