title: Assessment of an anti-alpha-toxin monoclonal antibody for prevention and treatment of Staphylococcus aureus-induced pneumonia.
abstract: Alpha-toxin (AT) is a major virulence factor in the disease pathogenesis of Staphylococcus aureus. We previously identified a monoclonal antibody (MAb) against AT that reduced disease severity in a mouse dermonecrosis model. Here, we evaluate the activity of an affinity-optimized variant, LC10, in a mouse model of S. aureus pneumonia. Passive immunization with LC10 increased survival and reduced bacterial numbers in the lungs and kidneys of infected mice and showed protection against diverse S. aureus clinical isolates. The lungs of S. aureus-infected mice exhibited bacterial pneumonia, including widespread inflammation, whereas the lungs of mice that received LC10 exhibited minimal inflammation and retained healthy architecture. Consistent with reduced immune cell infiltration, LC10-treated animals had significantly lower (P < 0.05) proinflammatory cytokine and chemokine levels in the bronchoalveolar lavage fluid than did those of the control animals. This reduction in inflammation and damage to the LC10-treated animals resulted in reduced vascular protein leakage and CO2 levels in the blood. LC10 was also assessed for its therapeutic activity in combination with vancomycin or linezolid. Treatment with a combination of LC10 and vancomycin or linezolid resulted in a significant increase (P < 0.05) in survival relative to the monotherapies and was deemed additive to synergistic by isobologram analysis. Consistent with improved survival, the lungs of animals treated with antibiotic plus LC10 exhibited less inflammatory tissue damage than those that received monotherapy. These data provide insight into the mechanisms of protection provided by AT inhibition and support AT as a promising target for immunoprophylaxis or adjunctive therapy against S. aureus pneumonia.
authors.affiliation: Department of Infectious Disease, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: L
authors.initials: L
authors.lastname: Hua
authors.forename: J J
authors.initials: JJ
authors.lastname: Hilliard
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: C
authors.initials: C
authors.lastname: Tkaczyk
authors.forename: L I
authors.initials: LI
authors.lastname: Cheng
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.forename: V
authors.initials: V
authors.lastname: Datta
authors.forename: S
authors.initials: S
authors.lastname: Ren
authors.forename: H
authors.initials: H
authors.lastname: Feng
authors.forename: R
authors.initials: R
authors.lastname: Zinsou
authors.forename: A
authors.initials: A
authors.lastname: Keller
authors.forename: T
authors.initials: T
authors.lastname: O'Day
authors.forename: Q
authors.initials: Q
authors.lastname: Du
authors.forename: L
authors.initials: L
authors.lastname: Cheng
authors.forename: M
authors.initials: M
authors.lastname: Damschroder
authors.forename: G
authors.initials: G
authors.lastname: Robbie
authors.forename: J
authors.initials: J
authors.lastname: Suzich
authors.forename: C K
authors.initials: CK
authors.lastname: Stover
authors.forename: B R
authors.initials: BR
authors.lastname: Sellman
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D007116:Immunization, Passive; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D000069349:Linezolid; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D023303:Oxazolidinones / Q000494:pharmacology; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D016019:Survival Analysis; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D018925:Chemokines; D006460:Hemolysin Proteins; D023303:Oxazolidinones; C021091:staphylococcal alpha-toxin; D014640:Vancomycin; D000069349:Linezolid