| Autor: |
Nielsen TB; Stritch School of Medicine, Loyola University Chicagogrid.164971.c, Maywood, Illinois, USA.; Parkinson School of Health Sciences and Public Health, Loyola University Chicagogrid.164971.c, Maywood, Illinois, USA.; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Yan J; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Slarve M; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Lu P; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Li R; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Ruiz J; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Lee B; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Burk E; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Talyansky Y; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Oelschlaeger P; Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciencesgrid.268203.d, Pomona, California, USA., Hurth K; Department of Pathology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Win W; Department of Pathology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Luna BM; Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern Californiagrid.42505.36, Los Angeles, California, USA., Bonomo RA; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.; Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.; Departments of Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA., Spellberg B; Los Angeles County and University of Southern Californiagrid.42505.36 Medical Center, Los Angeles, California, USA. |
| Abstrakt: |
Extremely drug-resistant (XDR) Acinetobacter baumannii is a notorious and frequently encountered pathogen demanding novel therapeutic interventions. An initial monoclonal antibody (MAb), C8, raised against A. baumannii capsule, proved a highly effective treatment against a minority of clinical isolates. To overcome this limitation, we broadened coverage by developing a second antibody for use in a combination regimen. We sought to develop an additional anti-A. baumannii MAb through hybridoma technology by immunizing mice with sublethal inocula of virulent, XDR clinical isolates not bound by MAb C8. We identified a new antibacterial MAb, 65, which bound to strains in a pattern distinct from and complementary to that of MAb C8. MAb 65 enhanced macrophage opsonophagocytosis of targeted strains and markedly improved survival in lethal bacteremic sepsis and aspiration pneumonia murine models of A. baumannii infection. MAb 65 was also synergistic with colistin, substantially enhancing protection compared to monotherapy. Treatment with MAb 65 significantly reduced blood bacterial density, ameliorated cytokine production (interleukin-1β [IL-1β], IL-6, IL-10, and tumor necrosis factor), and sepsis biomarkers. We describe a novel MAb targeting A. baumannii that broadens immunotherapeutic strain coverage, is highly potent and effective, and synergistically improves outcomes in combination with antibiotics. |
