A novel peptide-IgG conjugate, CAP18(106-138)-IgG, that binds and neutralizes endotoxin and kills gram-negative bacteria.
Although type-specific IgG directed to the O-polysaccharide antigen of bacterial lipopolysaccharide (LPS) is protective in most models of LPS or bacterial challenge, no currently available IgG binds to LPS from all gram-negative bacteria. The ability of a peptide-IgG conjugate, CAP18(106-138)-IgG, to bind and neutralize LPS, to kill gram-negative bacteria, and to protect in a sensitized mouse model of LPS toxicity was studied. CAP18(106-138)-IgG bound LPS from multiple gram-negative bacteria in four different binding assays. In a fluid-phase RIA, half-maximal binding of 5 microg/mL 3H-labeled LPS occurred at 5-10 microg/mL CAP18(106-138)-IgG, similar to binding with monoclonal type-specific IgG. CAP18(106-138)-IgG neutralized LPS, as assessed by LPS-induced coagulation of limulus amebocyte lysate and production of tumor necrosis factor in vitro, was bactericidal for a wide range of gram-negative bacteria, and decreased LPS-induced lethality in sensitized mice. Antibacterial peptide-IgG conjugates merit further study as a novel adjunctive therapy for gram-negative sepsis.
Fletcher
M A
MA
Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston 02129, USA.
Kloczewiak
M A
MA
Loiselle
P M
PM
Ogata
M
M
Vermeulen
M W
MW
Zanzot
E M
EM
Warren
H S
HS
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000737:chemistry*; D054804:Cathelicidins; D002478:Cells, Cultured; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D007074:Immunoglobulin G / Q000737:chemistry; D008033:Limulus Test; D008070:Lipopolysaccharides / Q000737:chemistry*; D051379:Mice; D011485:Protein Binding; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D002352:Carrier Proteins; D054804:Cathelicidins; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha