| Autor: |
Horn, Michael P., Zuercher, Adrian W., Imboden, Martin A., Rudolf, Michael P., Lazar, Hedvika, Wu, Hong, Hoiby, Niels, Fas, Stefanie C., Lang, Alois B. |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; June 2010, Vol. 54 Issue: 6 p2338-2344, 7p |
| Abstrakt: |
ABSTRACTPseudomonas aeruginosainfection 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. aeruginosaO-polysaccharide-toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individual P. aeruginosalipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/κ antibody that binds P. aeruginosaof International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 × 107M−1± 2.8 × 107M−1) without cross-reacting with other serotypes. KBPA101 specifically opsonized the P. aeruginosaof IATS O11 serotype and mediated complement-dependent phagocytosis in vitroby the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml). In vivoevaluation 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. aeruginosaat 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. |
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