Panobacumab is a monoclonal antibody (mAb) directed against the lipopolysaccharide (LPS) O-polysaccharide moiety of Pseudomonas aeruginosa (P. aeruginosa) serotype IATS O11. It is a fully human pentameric IgM antibody with a mouse J chain. The efficacy of Panobacumab in a clinically relevant murine model of neutropenia induced by cyclophosphamide and in combination with meropenem in susceptible and meropenem resistant P. aeruginosa induced pneumonia was investigated. It was observed that P. aeruginosa induced pneumonia was dramatically increased in neutropenic mice compared to immunocompetent mice. First, Panobacumab significantly reduced lung inflammation and enhanced bacterial clearance from the lung of neutropenic host. Secondly, combination of Panobacumab and meropenem had an additive effect. Third, Panobacumab retained activity on a meropenem resistant P. aeruginosa strain. In conclusion, the present data established that Panobacumab contributes to the clearance of P. aeruginosa in neutropenic hosts as well as in combination with antibiotics in immunocompetent hosts.
P. aeruginosa is a common encapsulated, Gram-negative, rod-shaped bacterium that can cause a broad range of acute and chronic infections in plants and animals, including humans. In particular, nosocomial lung infections are associated with high morbidity and mortality in immunocompromised patients, e.g. after organ transplantation, severe burn, cancer, HIV infection and neutropenic patients. LPS, also known as lipoglycan and endotoxin, is the major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria, and protecting the membrane from certain kinds of chemical attack. LPS also increases the negative charge of the cell membrane and helps stabilize the overall membrane structure. It is of crucial importance to many Gram-negative bacteria, which die if it is mutated or removed; however, it appears that LPS is nonessential in at least some Gram-negative bacteria, such as Neisseria meningitidis, Moraxella catarrhalis, and Acinetobacter baumannii. LPS induces a strong response from normal animal immune systems. It has also been implicated in non-pathogenic aspects of bacterial ecology, including surface adhesion, bacteriophage sensitivity, and interactions with predators such as amoebae. LPS is required for the proper conformation of omptin activity; however, smooth LPS will sterically hinder omptins. A repetitive glycan polymer contained within an LPS is referred to as the O antigen, O polysaccharide, or O side-chain of the bacteria. The O antigen is attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. The presence or absence of O chains determines whether the LPS is considered rough or smooth. Full-length O-chains would render the LPS smooth, whereas the absence or reduction of O-chains would make the LPS rough. Bacteria with rough LPS usually have more penetrable cell membranes to hydrophobic antibiotics, since a rough LPS is more hydrophobic. O antigen is exposed on the very outer surface of the bacterial cell, and, as a consequence, is a target for recognition by host antibodies. Panobacumab targets the LPS O-polysaccharide moiety of P. aeruginosa to inhibit P. aeruginosa infection and reduce the inflammatory response caused by the LPS.
Fig.1 Mechanism of Action of Panobacumab