title: CD14 receptor occupancy in severe sepsis: results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14).
abstract: OBJECTIVE
  Binding of bacterial cell wall components to CD14 and co-receptors on myeloid cells results in cellular activation and production of proinflammatory mediators. A recombinant anti-CD14 monoclonal antibody (IC14) has been shown to decrease lipopolysaccharide-induced responses in animal and human models of endotoxemia. This study was performed to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical pharmacology of IC14 in patients with severe sepsis.
  
  
  METHODS
  Randomized, double-blind, placebo-controlled, dose-ranging, multiple-center trial.
  
  
  METHODS
  Six medical and surgical intensive care units located in Germany and The Netherlands.
  
  
  METHODS
  Forty patients with severe sepsis.
  
  
  METHODS
  IC14 was administered intravenously to eight patients/cohort as single (1 mg/kg or 4 mg/kg) or multiple doses (4 mg/kg daily for 4 days, or 4 mg/kg on day 1 followed by 2 mg/kg daily for 3 days). A placebo group (two patients/cohort) was also included.
  
  
  RESULTS
  The overall incidence and types of adverse events were similar among treatment groups. One patient in the group receiving multiple-dose IC14 4 mg/kg daily for 4 days experienced an anaphylactic reaction after receiving the first dose of study drug. IC14 did not induce antibody formation or increase the incidence of secondary bacterial infection. A mean IC14 serum concentration of approximately 1 microg/mL was required to achieve 50% of maximum membrane-bound CD14 receptor occupancy on peripheral blood monocytes. The pattern of proinflammatory and anti-inflammatory cytokines, chemokine, soluble receptor, soluble E-selectin, and acute phase proteins in response to treatment was highly variable by patient and IC14 treatment group.
  
  
  CONCLUSIONS
  Single and multiple doses of IC14 were generally well tolerated and did not induce antibody formation or increase the incidence of secondary bacterial infection. The results suggest that CD14 blockade with IC14 warrants further clinical investigation to determine its ability to attenuate the proinflammatory response due to infection.
authors.affiliation: Department of Anesthesia and Critical Care, University Medical Center, University of Jena, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Reinhart
authors.forename: Thomas
authors.initials: T
authors.lastname: Glück
authors.forename: Jack
authors.initials: J
authors.lastname: Ligtenberg
authors.forename: Klaus
authors.initials: K
authors.lastname: Tschaikowsky
authors.forename: Albert
authors.initials: A
authors.lastname: Bruining
authors.forename: Jan
authors.initials: J
authors.lastname: Bakker
authors.forename: Steven
authors.initials: S
authors.lastname: Opal
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: Tim
authors.initials: T
authors.lastname: Axtelle
authors.forename: Terence
authors.initials: T
authors.lastname: Turner
authors.forename: Sonia
authors.initials: S
authors.lastname: Souza
authors.forename: John
authors.initials: J
authors.lastname: Pribble
mesh_terms: D000209:Acute-Phase Proteins / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001424:Bacterial Infections / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D019040:E-Selectin / Q000097:blood / Q000187:drug effects; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007262:Infusions, Intravenous; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009426:Netherlands / Q000453:epidemiology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012449:Safety; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; D016207:Cytokines; D019040:E-Selectin; D018950:Lipopolysaccharide Receptors; D011993:Recombinant Fusion Proteins