Anti-human CD14 monoclonal antibody improves survival following sepsis induced by endotoxin, but not following polymicrobial infection.
Cluster of differentiation 14 (CD14), a pattern recognition receptor expressed on myeloid cells and a critical component of the innate immune system, mediates local and systemic host responses to gram-negative bacterial products, including lipopolysaccharide (LPS). Therefore, CD14 is an attractive target for development of sepsis therapies, and several monoclonal anti-CD14 antibodies have been reported. In this study, we prepared an anti-human CD14 monoclonal antibody, F1024-1-3, which suppressed LPS-induced upregulation of pro-inflammatory cytokines and an adhesion molecule in human peripheral mononuclear cells and human vascular endothelial cells. Half-maximal inhibitory concentrations in these assays ranged from 0.1 to 1μg/ml. In rabbits, intravenous administration (3mg/kg) as well as in vitro exposure of F1024-1-3 suppressed LPS-induced cytokine production in whole blood. In endotoxemia models generated by three sequential injections of LPS, intravenous administration of F1024-1-3 at 0.3-3mg/kg sharply reduced pro-inflammatory responses in a dose-dependent manner and moderately attenuated pro-coagulant responses; at 1mg/kg, the protein protected rabbits from lethality even when administered 2h after the initial LPS injection. However, F1024-1-3 (10mg/kg) given 2h post-surgery did not prevent death of rabbits in a cecal ligation and puncture model. Thus, suppression of CD14-mediated activation of leukocytes and endothelial cells alone may not be clinically efficacious for the treatment of severe sepsis and septic shock.
Discovery Research, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan. Electronic address: mnakamur@mochida.co.jp.
Masaki
M
Nakamura
Discovery Research, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
Takashi
T
Takeuchi
Discovery Research, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
Kamon
K
Shirakawa
Discovery Research, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
Shoji
S
Furusako
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001777:Blood Coagulation / Q000187:drug effects; D060085:Coinfection / Q000188:drug therapy / Q000382:microbiology; D004731:Endotoxins / Q000633:toxicity*; D000939:Epitopes / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008297:Male; D011817:Rabbits; D051381:Rats; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D016019:Survival Analysis
D000911:Antibodies, Monoclonal; D004731:Endotoxins; D000939:Epitopes; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors
Coagulation; Hemostasis; Inflammation; Lipopolysaccharide; Lipopolysaccharide (PubChem CID: 11970143); Mortality