Recombinant human bactericidal/permeability-increasing protein (rBPI23) is a universal lipopolysaccharide-binding ligand.
A recombinant 23-kDa protein (rBPI23) derived from human bactericidal/permeability-increasing protein (BPI) possesses potent endotoxin-neutralizing abilities in vitro and in vivo. Binding of rBPI23 to those endotoxins (lipopolysaccharides [LPSs]) encountered clinically would be a prerequisite for efficacy in decreasing mortality among patients suffering from gram-negative sepsis and shock, a disease state in which an etiological role for LPS has been implicated. rBPI23 binds well to lipid A (n = 7), to rough-mutant O-chain-deficient LPS (n = 18, Re to Ra chemotypes), to lipid A-core covalently linked to the O chain, to LPSs from clinically relevant serotypes (n = 100), and to bacterial cells (n = 88) of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, the species most often implicated in clinical gram-negative sepsis and shock. Significant binding of rBPI23 to these antigens took place at rBPI23 concentrations of 1 to 500 ng/ml (median, 16 to 32 ng/ml). Binding did not involve 3-deoxy-D-manno-octulosonate of the inner core. Determining the exact epitope recognized by rBPI23 would require further studies with synthetic lipid A substructures. The demonstrated ability of rBPI23 to universally bind LPS provides a sound basis for further testing of its endotoxin-neutralizing abilities, including clinical trials.
Department of Medical Microbiology, Vrije Universiteit, Amsterdam, The Netherlands.
B J
BJ
Appelmelk
Y Q
YQ
An
B G
BG
Thijs
D M
DM
MacLaren
J
J
de Graaff
D000911:Antibodies, Monoclonal / Q000276:immunology; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008050:Lipid A / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008565:Membrane Proteins; D011994:Recombinant Proteins / Q000378:metabolism
D000911:Antibodies, Monoclonal; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D008024:Ligands; D008050:Lipid A; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011994:Recombinant Proteins; C021623:bactericidal permeability increasing protein