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- Title
Humanized Staphylococcal Enterotoxin B (SEB)–Specific Monoclonal Antibodies Protect From SEB Intoxication and Staphylococcus aureus Infections Alone or as Adjunctive Therapy With Vancomycin.
- Authors
Varshney, Avanish K.; Wang, Xiaobo; MacIntyre, Jennifer; Zollner, Richard S.; Kelleher, Kerry; Kovalenko, Oleg V.; Pechuan, Ximo; Byrne, Fergus R.; Fries, Bettina C.
- 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.
- Subjects
STAPHYLOCOCCAL diseases; ENTEROTOXINS; LABORATORY mice; MONOCLONAL antibodies; STAPHYLOCOCCUS aureus infections; VANCOMYCIN; ABSCESSES; PREVENTION
- Publication
Journal of Infectious Diseases, 2014, Vol 210, Issue 6, p973
- ISSN
0022-1899
- Publication type
Article
- DOI
10.1093/infdis/jiu198