Monoclonal Antibody Protects Against Acinetobacter baumannii Infection by Enhancing Bacterial Clearance and Evading Sepsis. (5th July 2017)

• Record Type: Journal Article
• Authors: Nielsen, Travis B; Pantapalangkoor, Paul; Luna, Brian M; Bruhn, Kevin W; Yan, Jun; Dekitani, Ken; Hsieh, Sarah; Yeshoua, Brandon; Pascual, Bryan; Vinogradov, Evgeny; Hujer, Kristine M; Domitrovic, T Nicholas; Bonomo, Robert A; Russo, Thomas A; Lesczcyniecka, Magda; Schneider, Thomas; Spellberg, Brad
• Is Part Of: Journal of infectious diseases. Volume 216:Number 4(2017:Aug. 15)
• Page Start: 489
• Page End: 501
• Publication Date: 2017-07-05
• Subjects: Acinetobacter baumannii -- XDR -- carbapenem-resistant -- monoclonal antibody -- immunotherapy; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jix315
• Languages: English
• ISSNs: 0022-1899

Abstract

Summary: Acinetobacter baumannii is one of the most antibiotic-resistant pathogens encountered in medicine and causes high mortality rates. We developed a monoclonal antibody targeting A. baumannii that resulted in complete protection for infections of the blood and lung. 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.