Identification of broadly protective human antibodies to Pseudomonas aeruginosa exopolysaccharide Psl by phenotypic screening
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Published on: July 16, 2020
Antonio DiGiandomenico1, Paul Warrener, Melissa Hamilton
1Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, MD 20878, USA.
Insights
New monoclonal antibodies targeting the Psl exopolysaccharide show promise for preventing Pseudomonas aeruginosa infections. These antibodies effectively combat bacterial attachment and biofilm formation, offering a novel strategy against antibiotic-resistant strains.
Area of Science:
- Microbiology
- Immunology
- Infectious Diseases
Background:
- Pseudomonas aeruginosa is a significant cause of hospital-associated infections and chronic lung infections in cystic fibrosis patients.
- Antibiotic resistance in P. aeruginosa, due to efflux systems and acquired resistance, necessitates novel therapeutic strategies.
- The Psl exopolysaccharide is crucial for P. aeruginosa adherence and biofilm formation, making it a potential therapeutic target.
Purpose of the Study:
- To develop a novel strategy for identifying monoclonal antibodies (mAbs) against Pseudomonas aeruginosa.
- To investigate the potential of targeting the Psl exopolysaccharide as a protective antigen.
- To evaluate the efficacy of identified mAbs in combating P. aeruginosa infections.
Main Methods:
- Utilized single-chain variable fragment phage libraries derived from healthy individuals and convalescent patients for mAb selection against whole P. aeruginosa cells.
- Identified mAbs binding to three distinct epitopes on the Psl exopolysaccharide.
- Performed functional assays including opsonophagocytic killing, cell attachment assays, and animal model protection studies.
Main Results:
- Successfully identified mAbs targeting three distinct epitopes on the Psl exopolysaccharide.
- mAbs targeting one specific epitope demonstrated superior activity in opsonophagocytic killing and cell attachment assays.
- These mAbs conferred significant protection in multiple animal models of P. aeruginosa infection.
Conclusions:
- Psl is a promising, accessible, and serotype-independent surface antigen for developing vaccines and therapeutics against P. aeruginosa.
- The mAb discovery strategy employed is effective and holds potential for application against other bacterial pathogens.
- Targeting Psl with monoclonal antibodies represents a novel and effective approach to prevent and treat Pseudomonas aeruginosa infections.
Abstract:
Pseudomonas aeruginosa is a leading cause of hospital-associated infections in the seriously ill, and the primary agent of chronic lung infections in cystic fibrosis patients. A major obstacle to effective control of P. aeruginosa infections is its intrinsic resistance to most antibiotic classes, which results from chromosomally encoded drug-efflux systems and multiple acquired resistance mechanisms selected by years of aggressive antibiotic therapy. These factors demand new strategies and drugs to prevent and treat P. aeruginosa infections. Herein, we describe a monoclonal antibody (mAb) selection strategy on whole P. aeruginosa cells using single-chain variable fragment phage libraries derived from healthy individuals and patients convalescing from P. aeruginosa infections. This approach enabled identification of mAbs that bind three distinct epitopes on the product of the Psl. This exopolysaccharide is important for P. aeruginosa attachment to mammalian cells, and for the formation and maintenance of biofilms produced by nonmucoid and mucoid P. aeruginosa isolates. Functional screens revealed that mAbs to one epitope exhibit superior activity in opsonophagocytic killing and cell attachment assays, and confer significant protection in multiple animal models. Our results indicate that Psl is an accessible serotype-independent surface feature and promising novel protective antigen for preventing P. aeruginosa infections. Furthermore, our mAb discovery strategy holds promise for application to other bacterial pathogens.
