Protective efficacy of CAP18106-138-immunoglobulin G in sepsis.
Naturally present antibacterial proteins play an important role in innate host defense. A synthetic peptide mimicking the C-terminal lipopolysaccharide (LPS)-binding domain of rabbit cathelicidin CAP18 was coupled to immunoglobulin (Ig) G to create CAP18(106-138)-IgG, a construct that, in concentrations equimolar to those of peptide alone, binds and neutralizes LPS and kills multiple gram-negative bacterial strains. The protective efficacy of CAP18(106-138)-IgG was evaluated in a model of cecal ligation and puncture in mice. A single intravenous administration of 20 mg/kg CAP18(106-138)-IgG protected against mortality, compared with sham-coupled IgG (P<.03). There was no protection offered by administration of equimolar peptide alone (P=.96). There was a trend toward protection in C3H/HeJ mice that are minimally sensitive to LPS (P=.06), suggesting that direct detoxification of LPS was not the only mechanism of protection. Chemical or genetic coupling of antimicrobial peptides to IgG may be a means of using these peptides to treat infections.
Department of Pediatrics and Medicine, Massachusetts General Hospital, Boston, Massachusetts 02129, USA. swarren1@partners.org.
H Shaw
HS
Warren
Robina
R
Matyal
Jennifer E
JE
Allaire
David
D
Yarmush
Paul
P
Loiselle
Judith
J
Hellman
Barbara G
BG
Paton
Mitchell P
MP
Fink
D000818:Animals; D000900:Anti-Bacterial Agents / Q000276:immunology* / Q000494:pharmacology; D000907:Antibodies, Bacterial / Q000097:blood; D023181:Antimicrobial Cationic Peptides / Q000276:immunology* / Q000494:pharmacology / Q000592:standards; D001667:Binding, Competitive; D015153:Blotting, Western; D054804:Cathelicidins; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006090:Gram-Negative Bacteria / Q000254:growth & development* / Q000276:immunology; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000276:immunology*; D018796:Immunoconjugates / Q000276:immunology* / Q000494:pharmacology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008826:Microbial Sensitivity Tests; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology*
D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008070:Lipopolysaccharides