2. Academic Validation
  3. Mechanisms of neutralization of a human anti-α-toxin antibody

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

  • J Biol Chem. 2014 Oct 24;289(43):29874-80. doi: 10.1074/jbc.M114.601328.
Vaheh Oganesyan 1,  Li Peng 2,  Melissa M Damschroder 2,  Li Cheng 2,  Agnieszka Sadowska 3,  Christine Tkaczyk 3,  Bret R Sellman 3,  Herren Wu 2,  William F Dall'Acqua 4
Affiliations

Affiliations

  • 1 From the Departments of Antibody Discovery and Protein Engineering and [email protected].
  • 2 From the Departments of Antibody Discovery and Protein Engineering and.
  • 3 Infectious Diseases, MedImmune, Gaithersburg, Maryland 20878.
  • 4 From the Departments of Antibody Discovery and Protein Engineering and [email protected].
PMID: 25210036 DOI: 10.1074/jbc.M114.601328
Abstract

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.

Keywords

Alpha Toxin; Antibody; Crystal Structure; Fab; Infectious Disease; Mutagenesis; Staphylococcus aureus (S. aureus).

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