Humanized staphylococcal enterotoxin B (SEB)-specific monoclonal antibodies protect from SEB intoxication and Staphylococcus aureus infections alone or as adjunctive therapy with vancomycin

J Infect Dis. 2014 Sep 15;210(6):973-81. doi: 10.1093/infdis/jiu198. Epub 2014 May 5.

Abstract

Background: Staphylococcal enterotoxin B (SEB), a potential biological warfare agent, is a potent superantigen that contributes to the virulence of methicillin-resistant Staphylococcus aureus (MRSA), which is a major health threat in the United States. Efforts to develop toxin-neutralizing antibodies as adjunctive therapies are justified, given the high mortality and frequent failure of therapy despite available antibiotics.

Methods: Murine SEB-specific mAb 20B1 was humanized, and treatment benefits of Hu-1.6/1.1 and Hu-1.4/1.1 variants were investigated in mice in an SEB intoxication model, as well as in sepsis and deep-tissue infection models.

Results: Hu-1.6/1.1 and Hu-1.4/1.1 protected mice against SEB-induced lethal shock. Hu-1.6/1.1 also enhanced survival of mice that developed fatal sepsis after challenge with a SEB-producing MRSA strain. Combined treatment of Hu-1.6/1.1 with vancomycin further increased survival and altered cytokine responses, compared with monotherapy with either monoclonal antibody or vancomycin alone. Efficacy was also demonstrated in the deep-tissue infection model, where Hu-1.4/1.1 bound to SEB in vivo and decreased abscess formation, as well as proinflammatory cytokine levels.

Conclusions: SEB-neutralizing mAb 20B1 was successfully humanized. The mAb affects outcome by modulating the proinflammatory host response in both the sepsis and the intoxication models, which justifies further development.

Keywords: Staphylococcus aureus; adjuvant therapy; monoclonal antibody; superantigen; virulence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abscess / immunology
  • Abscess / prevention & control
  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / therapeutic use*
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Binding Sites, Antibody / immunology
  • Cytokines / blood
  • Enterotoxins / genetics
  • Enterotoxins / immunology*
  • Methicillin-Resistant Staphylococcus aureus* / immunology
  • Mice
  • Mice, Inbred BALB C
  • Staphylococcal Infections / immunology
  • Staphylococcal Infections / prevention & control*
  • Vancomycin / administration & dosage
  • Vancomycin / therapeutic use*

Substances

  • Anti-Bacterial Agents
  • Antibodies, Monoclonal, Humanized
  • Cytokines
  • Enterotoxins
  • enterotoxin B, staphylococcal
  • Vancomycin