title: Humanized staphylococcal enterotoxin B (SEB)-specific monoclonal antibodies protect from SEB intoxication and Staphylococcus aureus infections alone or as adjunctive therapy with vancomycin.
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.
authors.affiliation: Department of Medicine Department of Microbiology and Immunology.
authors.forename: Avanish K
authors.initials: AK
authors.lastname: Varshney
authors.affiliation: Department of Medicine Department of Microbiology and Immunology.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Pfizer Centers for Therapeutic Innovation, New York, New York.
authors.forename: Jennifer
authors.initials: J
authors.lastname: MacIntyre
authors.affiliation: Pfizer Global BioTechnologies, Cambridge, Massachusetts.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Zollner
authors.affiliation: Pfizer Global BioTechnologies, Cambridge, Massachusetts.
authors.forename: Kerry
authors.initials: K
authors.lastname: Kelleher
authors.affiliation: Pfizer Global BioTechnologies, Cambridge, Massachusetts.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Kovalenko
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx.
authors.forename: Ximo
authors.initials: X
authors.lastname: Pechuan
authors.affiliation: Pfizer Centers for Therapeutic Innovation, New York, New York.
authors.forename: Fergus R
authors.initials: FR
authors.lastname: Byrne
authors.affiliation: Department of Medicine Department of Microbiology and Immunology.
authors.forename: Bettina C
authors.initials: BC
authors.lastname: Fries
mesh_terms: D000038:Abscess / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D001666:Binding Sites, Antibody / Q000276:immunology; D016207:Cytokines / Q000097:blood; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D013203:Staphylococcal Infections / Q000276:immunology / Q000517:prevention & control*; D014640:Vancomycin / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D004768:Enterotoxins; C031818:enterotoxin B, staphylococcal; D014640:Vancomycin
keywords: Staphylococcus aureus; adjuvant therapy; monoclonal antibody; superantigen; virulence