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Structural Basis for Eculizumab-Mediated Inhibition of the Complement Terminal Pathway

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  • Janus Asbjørn Schatz-Jakobsen
  • ,
  • yuchun zhang, Alexion Pharmaceuticals, Inc., New Haven,
  • Krista Johnson, Alexion Pharmaceuticals, Inc., New Haven,
  • Alyssa Neill, Alexion Pharmaceuticals, Inc., New Haven,
  • Douglas Sheridan, Alexion Pharmaceuticals, Inc., New Haven,
  • Gregers Rom Andersen
Eculizumab is a humanized monoclonal antibody approved for treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uraemic syndrome. Eculizumab binds complement component C5 and prevents its cleavage by C5 convertases, inhibiting release of both the proinflammatory metabolite C5a and formation of the membrane attack complex via C5b. Here we present the crystal structure of the complex between C5 and a Fab fragment with the same sequence as eculizumab at a resolution of 4.2 Å. Five complementarity determining regions (CDRs) contact the C5 MG7 domain, which contains the entire epitope. A complete mutational scan of the sixty-six CDR residues identified twenty-eight residues as important for the C5-eculizumab interaction, and the structure of the complex offered an explanation for the reduced C5-binding observed for these mutant antibodies. Furthermore the structural observations of the interaction are supported by the reduced ability of a subset of these mutated antibodies to inhibit MAC formation as tested in a hemolysis assay. Our results suggest that eculizumab functions by sterically preventing C5 from binding to convertases and explain the exquisite selectivity of eculizumab for human C5 and how polymorphisms in C5 cause eculizumab-resistance in a small number of PNH patients
Original languageEnglish
JournalJournal of Immunology
Pages (from-to)337-344
Number of pages8
Publication statusPublished - 18 May 2016

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