Antibody Dependent Enhancement of Acinetobacter baumannii Infection in a Mouse Pneumonia Model

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 368; no. 3; pp. 475 - 489
• Main Authors: Wang-Lin, Shun Xin, Olson, Ruth, Beanan, Janet M., MacDonald, Ulrike, Russo, Thomas A., Balthasar, Joseph P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019
• Subjects: Acinetobacter baumannii - drug effects; Acinetobacter baumannii - isolation & purification; Acinetobacter baumannii - metabolism; ADE; American Type Culture Collection; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - metabolism; antibody-dependent enhancement; Antibody-Dependent Enhancement - physiology; area under the concentration-time curve; ATCC; AUC; AUC for 0–24 hours; AUC0–24 h; capsule type in Acinetobacter baumannii; CFU; change of absorbance over time; colony-forming units; dA/dt; Disease Models, Animal; ELISA; endotoxin units; enzyme-linked immunosorbent assay; equilibrium dissociation constant; extensively drug resistant; Fc gamma receptor; FcγR; Female; FITC; fluorescein isothiocyanate; Humans; lactate dehydrogenase; LDH; LLOD; LLOQ; lower limit of detection; lower limit of quantification; lysogeny broth; mAb; Male; Mice; Mice, Inbred BALB C; mIgG3; MOI; monoclonal antibody; mouse IgG3; multiplicity of infection; PBS; phosphate-buffered saline; Pneumonia, Bacterial - drug therapy; Pneumonia, Bacterial - metabolism; Protein Binding - physiology; quality control sample; t1/2; TCA; terminal half-life; trichloroacetic acid; XDR; PBS; AB; LLOQ; ADE; MOI; XDR; ATCC; AUC; mAb; EU; LDH; FITC; QC; CFU; TCA; mIgG3; t1/2; LB; LLOD; Kd; AUC0–24 h; dA/dt; FcγR; ELISA
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.118.253617

Acinetobacter baumannii has become a pathogen of increasing medical importance because of the emergence of multidrug-resistant strains and the high rate of mortality of infected patients. Promising animal study results have been reported recently with active and passive immunization against A. baumannii virulence factors. In the present study, a monoclonal IgG3 antibody, 8E3, was developed with specificity for the K2 capsular polysaccharide of A. baumannii, and its therapeutic potential was assessed. 8E3 enhanced macrophage-mediated bactericidal activity against the A. baumannii clinical strain AB899. However, 8E3 treatment (passive immunization) of AB899-infected mice led to a substantial increase in mortality and to substantial increases in bacterial load in blood, lung, and in splenic samples. In vitro investigations showed a large binding capacity in the supernatant of bacterial cultures, suggesting that shed capsule components act as a binding sink for 8E3. Investigations of 8E3 pharmacokinetics in mice demonstrated that unbound concentrations of the antibody dropped below detection limits within 24 hours after a 200 mg/kg dose. However, total concentrations of antibody declined slowly, with an apparent terminal half-life (t1/2) of 6.7–8.0 days, suggesting that the vast majority of 8E3 in blood is bound (e.g., with soluble capsule components in blood). We hypothesize that high concentrations of 8E3-capsule immune complexes act to inhibit bacterial clearance in vivo. To the best of our knowledge, this is the first demonstration of antibody-dependent enhancement of A. baumannii infection, and these observations highlight the complexity of antibody-based therapy for A. baumannii infections.