Treatment of experimental gram-negative bacterial sepsis with murine monoclonal antibodies directed against lipopolysaccharide.
Monoclonal antibodies (MAbs) directed against gram-negative bacterial lipopolysaccharide (endotoxin, LPS) are currently being evaluated as an adjunctive form of therapy for lethal gram-negative bacterial sepsis and shock. The exact binding site within the LPS molecule against which antibody should be directed in order to maximize both cross-reactivity among bacterial strains and protective capacity has not been established. By developing a panel of MAbs that bound to various regions of the LPS molecule (O saccharide; outer, intermediate, and inner core; lipid A), we were able to determine that some epitopes in the inner core/lipid A region of LPS were broadly shared among different genera of gram-negative microorganisms, on the basis of immunoblot analysis of MAb binding to LPS. Pretreatment with lower doses of O saccharide-specific MAbs (2 micrograms per animal) provided protection against a lethal intraperitoneal challenge of viable Salmonella minnesota bacteria, compared with core LPS-specific MAbs, which required at least 1.0 mg of MAb per mouse to provide a similar degree of immunoprotection. Although inner core LPS-specific MAbs are less protective than O saccharide-specific MAbs, these MAbs will probably be more useful in the treatment of gram-negative sepsis because of their ability to bind to many types of LPS and enhance survival during infection, which is caused by a wide variety of gram-negative bacteria.
Priest
B P
BP
Department of Surgery, University of Minnesota, Minneapolis 55455.
Brinson
D N
DN
Schroeder
D A
DA
Dunn
D L
DL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D001424:Bacterial Infections / Q000628:therapy*; D006090:Gram-Negative Bacteria / Q000378:metabolism; D006825:Hybridomas / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010538:Peritonitis / Q000209:etiology; D012475:Salmonella / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000628:therapy
D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides