IC14, a CD14 specific monoclonal antibody, is a potential treatment for patients with severe sepsis.
CD14 is a pattern recognition receptor for the bacterial cell wall components from Gram-positive and Gram-negative bacteria as well as mycobacteria. Binding of lipopolysaccharide (LPS) or other cell wall constituents to CD14 initiates signal transduction through the Toll-like receptors resulting in the release of pro-inflammatory cytokines and the initiation of the systemic inflammatory response. In rabbits and non-human primates, CD14 specific antibodies were shown to attenuate responses to LPS or Escherichia coli challenge including pro-inflammatory cytokine release, acute lung injury, hypotension and changes in lung, liver, spleen and adrenal gland morphology. In healthy human subjects, single doses of a chimeric CD14 antibody (IC14) have been shown to be well tolerated and result in a dose-related degree of saturation of CD14 receptors on monocytes and granulocytes. Pretreatment of healthy subjects with IC14 2 h prior to LPS resulted in an attenuation of the LPS-induced fever, clinical symptoms, and leukocyte activation and degranulation. IC14 inhibited the release of TNF-alpha, IL-6, and IL-10 and delayed the release of sTNFR(I) and IL-1ra. Further studies are in progress to characterize the safety and clinical pharmacology of IC14 in patients with severe sepsis.
Axtelle
T
T
ICOS Corporation, Bothell, Washington 98021, USA. taxtelle@icos.com
Pribble
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D018805:Sepsis / Q000276:immunology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D018950:Lipopolysaccharide Receptors