CD14 receptor occupancy in severe sepsis: results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14).
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.
Reinhart
Konrad
K
Department of Anesthesia and Critical Care, University Medical Center, University of Jena, Germany.
Glück
Thomas
T
Ligtenberg
Jack
J
Tschaikowsky
Klaus
K
Bruining
Albert
A
Bakker
Jan
J
Opal
Steven
S
Moldawer
Lyle L
LL
Axtelle
Tim
T
Turner
Terence
T
Souza
Sonia
S
Pribble
John
J
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
D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; D016207:Cytokines; D019040:E-Selectin; D018950:Lipopolysaccharide Receptors; D011993:Recombinant Fusion Proteins