A protective human monoclonal antibody directed to the outer core region of Pseudomonas aeruginosa lipopolysaccharide

Abstract

The protective activity against experimental Pseudomonas aeruginosa infection of a human monoclonal antibody, MH-4H7, which is thought to recognize L-rhamnose and its neighboring residues in the outer core region of P. aeruginosa lipopolysaccharide and which binds to strains of Homma serotypes A, F, G, H, K, and M, was studied in normal, burned, and leukopenic mice. MH-4H7 at doses of 0.1 to 1.0 micrograms per mouse (5 to 50 micrograms/kg) was effective against serotype A, F, G, H, and K clinical isolates of P. aeruginosa tested in normal mice but not against strains of serotype M, B, E, or I. The 50% protective doses were calculated to be 0.01 and 0.1 micrograms per mouse against challenge with serotype G strains and 3 to 8 micrograms per mouse against challenge with serotype A strains. MH-4H7 promoted macrophage-mediated opsonophagocytosis of serotype A, F, G, H, and K strains but not of serotype M strains. The opsonophagocytic activity, expressed as the reduction rate of viable bacteria in the presence of MH-4H7, macrophages, and complement, was higher against serotype G strains (more than 90%) than against serotype A strains (60 to 80%) and serotype F, H, and K strains (50 to 86%). It was correlated with the protective activity but not with the binding intensity of MH-4H7 to the organisms. In addition, burned and leukopenic mice as well as normal mice infected with serotype G strains recovered from a very low dosage of MH-4H7. Thus, a monoclonal antibody directed to the outer core region of P. aeruginosa lipopolysaccharide was effective against infection with a wide range of O-serotype strains of P. aeruginosa.

Mucosal and systemic immunizations with killed Pseudomonas aeruginosa protect against acute respiratory infection in rats

“…Similarly, immunization with lipopolysaccharide (LPS) protected against burn wound infection (4). Furthermore, protection by monoclonal antibodies directed against LPS (32,40) and flagella (31) has been demonstrated in murine burn wound sepsis models, and monoclonal antibodies to lipoprotein I have been shown to be protective against subcutaneous (s.c.) infection (12). Antibodies to conjugate vaccines of 0 polysaccharide and exotoxin A were protective in a burned-mouse model (5).…”

Pseudomonas aeruginosa antigens as potential vaccines

“…If the LPS chemotype protects mice against a strain with heterologous LPS but not vice versa (unidirectionally), it indicates that there could be some similarities of conformational protective determinants between the di¡erent LPS chemotypes ( Table 6) [126]. The view of the existence of a conformational epitope of O-antigen was supported by the immunochemical data whereby LPS-speci¢c monoclonal antibodies were produced and some of these antibodies showed cross-reactivity among di¡erent P. aeruginosa serotypes [116]. The structure of core oligosaccharide and/or lipid A plays an important role in the stimulation of cross-protection and probably also in conformation of LPS molecule.…”

Pseudomonas aeruginosaantigens as potential vaccines

“…The view of the existence of a conformational epitope of O‐antigen was supported by the immunochemical data whereby LPS‐specific monoclonal antibodies were produced and some of these antibodies showed cross‐reactivity among different P. aeruginosa serotypes [116]. The structure of core oligosaccharide and/or lipid A plays an important role in the stimulation of cross‐protection and probably also in conformation of LPS molecule.…”

“…Monoclonal antibody 177 is specific for a lipid A epitope of P. aeruginosa LPS and is broadly cross‐reactive to all Gram‐negative bacteria examined [114]. Others have reported the production of human monoclonal antibodies to the outer core region of serotype A and G respectively (Homma serogroups) also reacted in vitro with P. aeruginosa of several O‐serogroups and protected mice against P. aeruginosa clinical isolates of different O‐serogroups [115–117]. The protective activity of the human monoclonal antibody was apparently related to opsonophagocytic activity [118].…”