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

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

Author information

1
Department of Medicine Department of Microbiology and Immunology.
2
Pfizer Centers for Therapeutic Innovation, New York, New York.
3
Pfizer Global BioTechnologies, Cambridge, Massachusetts.
4
Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx.

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

PMID:
24803533
PMCID:
PMC4192055
DOI:
10.1093/infdis/jiu198
[Indexed for MEDLINE]
Free PMC Article

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