CD14 receptor occupancy in severe sepsis: Results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14)*
| Autor: | Lyle L. Moldawer, Sonia Souza, Steven M. Opal, Jan Bakker, John Pribble, Albert Bruining, Klaus Tschaikowsky, Tim Axtelle, Thomas Glück, Terence Turner, Konrad Reinhart, Jack J. M. Ligtenberg |
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| Přispěvatelé: | Radiology & Nuclear Medicine, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE) |
| Rok vydání: | 2004 |
| Předmět: |
Male
Lipopolysaccharide Receptors Phases of clinical research Critical Care and Intensive Care Medicine Severity of Illness Index Gastroenterology Monocytes INNATE RECOGNITION Germany Infusions Intravenous Netherlands Acute-phase protein Antibodies Monoclonal Bacterial Infections Middle Aged CIRCULATING SOLUBLE CD14 Treatment Outcome Area Under Curve Cytokines Female Safety CD14 E-Selectin Adult medicine.medical_specialty Recombinant Fusion Proteins Dose-Response Relationship Immunologic multiple organ dysfunction UNITED-STATES Proinflammatory cytokine Sepsis HOST-DEFENSE Double-Blind Method Pharmacokinetics Internal medicine Intensive care medicine Humans GRAM-NEGATIVE BACTERIA Aged TUMOR NECROSIS FACTOR Septic shock business.industry pattern recognition SEPTIC SHOCK medicine.disease Survival Analysis severe sepsis MICE monoclonal antibody Pharmacodynamics Immunology ENDOTOXIN business RESPONSES Acute-Phase Proteins |
| Zdroj: | Critical Care Medicine, 32(5), 1100-1108. Lippincott Williams & Wilkins Critical Care Medicine, 32(5), 1100-1108. LIPPINCOTT WILLIAMS & WILKINS |
| ISSN: | 0090-3493 |
| DOI: | 10.1097/01.ccm.0000124870.42312.c4 |
| Popis: | 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.Design: Randomized, double-blind, placebo-controlled, dose-ranging, multiple-center trial.Setting: Six medical and surgical intensive care units located in Germany and the Netherlands.Patients: Forty patients with severe sepsis.Interventions: 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 I followed by 2 mg/kg daily for 3 days). A placebo group (two patients/cohort) was also included.Measurements and Main 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 mug/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. |
| Databáze: | OpenAIRE |
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