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Mechanisms of neutralization of a human anti-?-toxin antibody.

ABSTRACT: 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 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.

SUBMITTER: Oganesyan V

PROVIDER: S-EPMC4207998 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Mechanisms of neutralization of a human anti-α-toxin antibody.

Oganesyan Vaheh V Peng Li L Damschroder Melissa M MM Cheng Li L Sadowska Agnieszka A Tkaczyk Christine C Sellman Bret R BR Wu Herren H Dall'Acqua William F WF

The Journal of biological chemistry 20140910 43

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 mechani ...[more]

PMID: 25210036

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