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Objectives: To investigate the in vivo efficacy in a murine pulmonary infection model of panobacumab (KBPA101), a human IgM monoclonal antibody directed against the O-polysaccharide moiety of Pseudomonas aeruginosa serotype O11, and to describe the anti-inflammatory effects in the lung as a consequence of the treatment., Methods: We established an experimental murine model of acute pneumonia by intranasal administration of P. aeruginosa serotype O11. Mice were treated, after infection, with a single intravenous injection of panobacumab and panobacumab lung bioavailability was assessed. Inflammatory parameters such as pro-inflammatory cytokine production and neutrophil recruitment in broncho-alveolar lavage fluid (BALF) were measured and bacterial load in the lung was analysed., Results: Panobacumab plays a significant role in addition to the host innate immune response, leading to improved control of pulmonary infection. The IgM antibody is able to reach the broncho-alveolar space and reduce the pulmonary bacterial load as well as lung inflammation in a dose-dependent manner. Furthermore, panobacumab treatment leads to enhanced neutrophil recruitment in BALF while reducing the host-derived production of pro-inflammatory mediators and lung injury., Conclusions: These data provide evidence that panobacumab, an IgM-based immunotherapeutic, is highly efficacious in controlling acute lung infection by enhancing the natural innate immune response.

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/kappa antibody that binds P. aeruginosa of International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 x 10(7) M(-1) +/- 2.8 x 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 microg/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.