A Novel Anti-PcrV Antibody Providing Enhanced Protection against Pseudomonas aeruginosa in Multiple Animal Infection Models

• Published in: Antimicrobial agents and chemotherapy 2014-08, Vol.58 (8), p.4384-4391
• Main Authors: WARRENER, Paul, VARKEY, Reena, STOVER, C. Kendall, BONNELL, Jessica C, DIGIANDOMENICO, Antonio, CAMARA, Maria, COOK, Kimberly, LI PENG, JINGYING ZHA, CHOWDURY, Partha, SELLMAN, Bret
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antibodies, Bacterial; Antibodies, Bacterial - administration & dosage; Antibodies, Bacterial - biosynthesis; Antibodies, Monoclonal; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - biosynthesis; Antigens, Bacterial; Antigens, Bacterial - chemistry; Antigens, Bacterial - immunology; Bacterial Secretion Systems - immunology; Bacterial Toxins; Bacterial Toxins - chemistry; Bacterial Toxins - immunology; Biological and medical sciences; Cytotoxicity Tests, Immunologic; Disease Models, Animal; Dose-Response Relationship, Immunologic; Epitopes - chemistry; Epitopes - immunology; Experimental Therapeutics; Humans; Immunization, Passive; Immunoglobulin Fab Fragments - administration & dosage; Injections, Intraperitoneal; Injections, Intravenous; Medical sciences; Mice; Pharmacology. Drug treatments; Pore Forming Cytotoxic Proteins; Pore Forming Cytotoxic Proteins - chemistry; Pore Forming Cytotoxic Proteins - immunology; Pseudomonas aeruginosa; Pseudomonas aeruginosa - chemistry; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - immunology; Pseudomonas Infections; Pseudomonas Infections - immunology; Pseudomonas Infections - microbiology; Pseudomonas Infections - mortality; Pseudomonas Infections - prevention & control; Survival Analysis
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.02643-14

Pseudomonas aeruginosa is a major cause of hospital-acquired infections, particularly in mechanically ventilated patients, and it is the leading cause of death in cystic fibrosis patients. A key virulence factor associated with disease severity is the P. aeruginosa type III secretion system (T3SS), which injects bacterial toxins directly into the cytoplasm of host cells. The PcrV protein, located at the tip of the T3SS injectisome complex, is required for T3SS function and is a well-validated target in animal models of immunoprophylactic strategies targeting P. aeruginosa. In an effort to identify a highly potent and protective monoclonal antibody (MAb) that inhibits the T3SS, we generated and characterized a panel of novel anti-PcrV MAbs. Interestingly, some MAbs exhibiting potent inhibition of T3SS in vitro failed to provide protection in a mouse model of P. aeruginosa infection, suggesting that effective in vivo inhibition of T3SS with anti-PcrV MAbs is epitope dependent. V2L2MD, while not the most potent MAb as assessed by in vitro cytotoxicity inhibition assays, provided strong prophylactic protection in several murine infection models and a postinfection therapeutic model. V2L2MD mediated significantly (P < 0.0001) better in vivo protection than that provided by a comparator antibody, MAb166, a well-characterized anti-PcrV MAb and the progenitor of a clinical candidate, KB001-A. The results described here support further development of a V2L2MD-containing immunotherapeutic and may suggest even greater potential than was previously recognized for the prevention and treatment of P. aeruginosa infections in high-risk populations.