Antivirulence Bispecific Monoclonal Antibody-Mediated Protection against Pseudomonas aeruginosa Ventilator-Associated Pneumonia in a Rabbit Model

Abstract

Ventilator-associated pneumonia is an important clinical manifestation of the nosocomial pathogen Pseudomonas aeruginosa . We characterized the correlates of protection of MEDI3902, a bispecific human IgG1 mAb that targets the P. aeruginosa type-3-secretion PcrV protein and the Psl exopolysaccharide, in a rabbit model of ventilator-associated pneumonia using lung-protective, low-tidal volume mechanical ventilation. Rabbits infused with MEDI3902 prophylactically were protected, whereas those pretreated with irrelevant isotype-control IgG (c-IgG) succumbed between 12 and 44 hours post infection [100% (8/8) vs. 0% (8/8) survival, P <0.01 by log-rank test]. Lungs from rabbits pretreated with c-IgG, but not those with MEDI3902, had bilateral, multifocal areas of marked necrosis, hemorrhage, neutrophilic inflammatory infiltrate, diffuse fibrinous edema in alveolar spaces. All rabbits pretreated with c-IgG developed worsening bacteremia that peaked at the time of death, whereas only 38% (3/8) rabbits pretreated with MEDI3902 developed such high-grade bacteremia (two-sided Fisher’s exact test, P =0.026). Biomarkers associated with acute respiratory distress syndrome were evaluated longitudinally in blood samples collected every 2-4 hours to assess systemic pathophysiological changes in rabbits pretreated with MEDI3902 or c-IgG. Biomarkers were sharply increased or decreased in rabbits pretreated with c-IgG, but not those pretreated with MEDI3902, including ratio of arterial oxygen partial pressure to fractional inspired oxygen PaO 2 /FiO 2 <300, hypercapnia or hypocapnia, severe lactic acidosis, leukopenia and neutropenia. Cytokines and chemokines associated with ARDS were significantly downregulated in lungs from rabbits pretreated with MEDI3902 compared with c-IgG. These results suggest that MEDI3902 prophylaxis could have potential clinical utility for decreasing severity of P. aeruginosa ventilator-associated pneumonia.

Vaccines and Monoclonal Antibodies as Alternative Strategies to Antibiotics to Fight Antimicrobial Resistance

“…Antibodies that are effective in vivo in animal models often show limited protection in clinical trials, highlighting a discrepancy that can be explained by the genetic and immunological differences between human and animal models. For instance, DiGiandomenico and co-workers reported the efficacy of a bispecific antibody against P. aeruginosa PcrV protein and PsI exopolysaccharide in mouse and rabbit models of infection [17,148]. Unfortunately, the candidate medication was not effective in preventing pneumonia when tested in P. aeruginosa-colonized mechanically ventilated subjects in a Phase 2 clinical trial [18].…”

Microbiota and Immunity during Respiratory Infections: Lung and Gut Affair

“…The mAb promotes bacterial clearance by neutrophils and prevents its attachment to airway epithelial cells [247]. Prophylactic as well as therapeutic administration of Gremubamab was highly protective in animal models of acute P. aeruginosa pneumonia and of VAP [248]. A clinical trial in P. aeruginosa-colonized ICU patients showed a risk reduction in patients with lower baseline inflammation.…”