Affiliation:
1. Kenta Biotech AG, Rehhagstrasse 79, 3018 Bern, Switzerland
2. Department of Clinical Microbiology, Rigshospitalet, Juliane Maries Vej 22, 2100 Copenhagen, Denmark
Abstract
ABSTRACT
Pseudomonas aeruginosa
infection in ventilator-associated pneumonia is a serious and often life-threatening complication in intensive care unit patients, and new treatment options are needed. We used B-cell-enriched peripheral blood lymphocytes from a volunteer immunized with a
P. aeruginosa
O-polysaccharide-toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individual
P. aeruginosa
lipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/κ antibody that binds
P. aeruginosa
of International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 × 10
7
M
−1
± 2.8 × 10
7
M
−1
) without cross-reacting with other serotypes. KBPA101 specifically opsonized the
P. aeruginosa
of IATS O11 serotype and mediated complement-dependent phagocytosis
in vitro
by the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml).
In vivo
evaluation of KBPA101 demonstrated a dose-response relationship for protection against systemic infections in a murine burn wound sepsis model, where 70 to 100% of animals were protected against lethal challenges with
P. aeruginosa
at doses as low as 5 μg/animal. Furthermore, a high efficacy of KBPA101 in protection from local respiratory infections in an acute lung infection model in mice was demonstrated. Preclinical toxicology evaluation on human tissue, in rabbits, and in mice did not indicate any toxicity of KBPA101. Based on these preclinical findings, the first human clinical trials have been initiated.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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