Heavy chain-only antibodies and tetravalent bispecific antibody neutralizing Staphylococcus aureus leukotoxins

BJ Laventie, Rik Rademaker, M Saleh, E Boer, Roel Janssens, T Bourcier, A Subilia, L Marcellin, Rien van Haperen, Joyce Lebbink, Tao Chen, G Prevost, Frank Grosveld, D. Drabek

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Abstract

Panton-Valentine leukocidin (PVL) is a pore-forming toxin associated with current outbreaks of community-associated methicillin-resistant strains and implicated directly in the pathophysiology of Staphylococcus aureus-related diseases. Humanized heavy chain-only antibodies (HCAb) were generated against S. aureus PVL from immunized transgenic mice to neutralize toxin activity. The active form of PVL consists of the two components, LukS-PV and LukF-PV, which induce osmotic lysis following pore formation in host defense cells. One anti-LukS-PV HCAb, three anti-LukF-PV HCAbs with affinities in the nanomolar range, and one engineered tetravalent bispecific HCAb were tested in vitro and in vivo, and all prevented toxin binding and pore formation. Anti-LukS-PV HCAb also binds to gamma-hemolysin C (HlgC) and inhibits HlgC/HlgB pore formation. Experiments in vivo in a toxin-induced rabbit endophthalmitis model showed that these HCAbs inhibit inflammatory reactions and tissue destruction, with the tetravalent bispecific HCAb performing best. Our findings show the therapeutic potential of HCAbs, and in particular, bispecific antibodies.
Original languageUndefined/Unknown
Pages (from-to)16404-16409
Number of pages6
JournalProceedings of the National Academy of Sciences of the U.S.A.
Volume108
Issue number39
DOIs
Publication statusPublished - 2011

Research programs

  • EMC MGC-01-12-03
  • EMC MGC-02-13-02
  • EMC MM-03-32-04

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