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J Infect Dis. 2017 Aug 15;216(4):489-501. doi: 10.1093/infdis/jix315.

Monoclonal Antibody Protects Against Acinetobacter baumannii Infection by Enhancing Bacterial Clearance and Evading Sepsis.

Author information

1
Department of Medicine and Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles.
2
National Research Council Canada, Ottowa, Ontario.
3
Louis Stokes Cleveland Veterans Affairs Medical Center.
4
Department of Medicine.
5
Departments of Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio.
6
Veterans Administration Western New York Healthcare System, and the Departments of Medicine and Microbiology and Immunology, and Witebsky Center for Microbial Pathogenesis, University at Buffalo-State University of New York, Buffalo, New York.
7
STC Biologics, Inc, Cambridge, Massachusetts.

Abstract

Background:

Extremely drug-resistant (XDR) Acinetobacter baumannii is one of the most commonly encountered, highly resistant pathogens requiring novel therapeutic interventions.

Methods:

We developed C8, a monoclonal antibody (mAb), by immunizing mice with sublethal inocula of a hypervirulent XDR clinical isolate.

Results:

C8 targets capsular carbohydrate on the bacterial surface, enhancing opsonophagocytosis. Treating with a single dose of C8 as low as 0.5 μg/mouse (0.0167 mg/kg) markedly improved survival in lethal bacteremic sepsis and aspiration pneumonia models of XDR A. baumannii infection. C8 was also synergistic with colistin, substantially improving survival compared to monotherapy. Treatment with C8 significantly reduced blood bacterial density, cytokine production (tumor necrosis factor α, interleukin [IL] 6, IL-1β, and IL-10), and sepsis biomarkers. Serial in vitro passaging of A. baumannii in the presence of C8 did not cause loss of mAb binding to the bacteria, but did result in emergence of less-virulent mutants that were more susceptible to macrophage uptake. Finally, we developed a highly humanized variant of C8 that retains opsonophagocytic activity in murine and human macrophages and rescued mice from lethal infection.

Conclusions:

We describe a promising and novel mAb as therapy for lethal, XDR A. baumannii infections, and demonstrate that it synergistically improves outcomes in combination with antibiotics.

KEYWORDS:

Acinetobacter baumannii; XDR; carbapenem-resistant; immunotherapy; monoclonal antibody

PMID:
28931235
PMCID:
PMC5853763
DOI:
10.1093/infdis/jix315
[Indexed for MEDLINE]
Free PMC Article

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