In vitro and in vivo properties of a fully human IgG1 monoclonal antibody that combats multidrug resistant Pseudomonas aeruginosa

• Published in: International journal of molecular medicine Vol. 30; no. 3; pp. 455 - 464
• Main Authors: ADAWI, AZMI, BISIGNANO, CARLO, GENOVESE, TIZIANA, FILOCAMO, ANGELA, KHOURI-ASSI, CAMELLIA, NEVILLE, ANAT, FEUERSTEIN, GIORA Z, CUZZOCREA, SALVATORE, NEVILLE, LEWIS F
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.09.2012; Spandidos Publications UK Ltd
• Subjects: Amino acids; Animals; Antibiotics; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Bronchoalveolar Lavage Fluid - immunology; CHO Cells; Cricetinae; Critical care; Cystic fibrosis; Drug Resistance, Multiple, Bacterial; flagellin; Flagellin - immunology; Humans; Immunoglobulin G - administration & dosage; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Immunoglobulin G - pharmacology; Immunoglobulins; Mice; Monoclonal antibodies; monoclonal antibody; Mortality; Motility; multidrug resistance; Multidrug resistant organisms; passive immunization; Pathogens; Patients; Pneumonia; Pneumonia - diet therapy; Pneumonia - immunology; Pneumonia - mortality; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - immunology; Pseudomonas Infections - drug therapy; Pseudomonas Infections - immunology; Pseudomonas Infections - mortality; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Recombinant Proteins - pharmacology; Studies; Urinary tract diseases; Urinary tract infections; Urogenital system; Ventilators; United States > US
• ISSN: 1107-3756; 1791-244X
• DOI: 10.3892/ijmm.2012.1040

The development of an anti-bacterial drug in the form of a monoclonal antibody (mAb) targeting an exposed virulence factor, represents an innovative therapeutic strategy. Consequently, a fully human IgG1 mAb (LST-007) targeting Pseudomonas aeruginosa (PA) flagellin type b was recombinantly expressed and characterized in vitro and in an infection model driven by a multidrug resistant (MDR) PA strain. LST-007 demonstrated a highly specific binding towards whole PA bacteria harboring flagellin type b and its recombinant counterpart, with a KD of 7.4×10−10 M. In bioactivity assays, LST-007 or titers of Cmax sera derived from pharmacokinetic studies, markedly attenuated PA motility in an equipotent manner. In vivo, parenteral LST-007 (20 mg/kg) given as a single or double-dosing paradigm post-infection, afforded survival (up to 75% at Day 7) in a lethal model of pneumonia driven by the intratracheal (i.t.) instillation of an LD80 of the MDR PA isolate. This protective effect was markedly superior to that of imipenem (30% survival at Day 7) and totally devoid with an irrelevant, human isotype mAb. These data lay credence that LST-007 may be a valuable adjunct to the limited list of anti-bacterials that can tackle MDR PA strains, thereby warranting its continued development for eventual clinical evaluation.