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

Background: MEDI4893 is an anti--toxin (AT) antibody currently in clinical trial in the field of Staphylococcus aureus-mediated diseases. Results: Structure/function studies of MEDI4893 reveal its epitope and mechanisms of action. Conclusion: MEDI4893 recognizes a novel epitope and exhibits a possible dual neutralization mechanism. Significance: Understanding the molecular basis of AT/MEDI4893 interaction has important implications to design potent antibodies targeting Staphylococcus aureus. MEDI4893 is a neutralizing human monoclonal antibody that targets -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 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.