RESUMEN
Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence.
Asunto(s)
Fiebre Hemorrágica Ebola/tratamiento farmacológico , Enfermedad del Virus de Marburg/tratamiento farmacológico , Morfolinos/farmacocinética , Adulto , Animales , Área Bajo la Curva , Método Doble Ciego , Ebolavirus/efectos de los fármacos , Ebolavirus/genética , Femenino , Fiebre Hemorrágica Ebola/virología , Humanos , Infusiones Intravenosas , Masculino , Enfermedad del Virus de Marburg/virología , Marburgvirus/efectos de los fármacos , Marburgvirus/genética , Persona de Mediana Edad , Morfolinos/efectos adversos , Morfolinos/sangre , Placebos , Adulto JovenRESUMEN
An overview and discussion of clinical studies with IC14, a chimeric monoclonal antibody directed against human CD14 is presented. These studies include phase 1 trials in: (i) healthy subjects; (ii) healthy subjects challenged with lipopolysaccharide (LPS); and (iii) patients with severe sepsis. The results from clinical studies of IC14 demonstrate this chimeric monoclonal antibody diminishes the systemic inflammatory response directed against LPS and may have potential as a treatment to prevent organ dysfunction in patients with severe sepsis. Furthermore, IC14 treatment was generally well-tolerated in both healthy subjects and severe sepsis patients and did not increase the incidence of secondary infections. Analysis of pharmacology data indicate that higher doses of IC14 are required to saturate membrane-bound CD14 receptors effectively in patients with severe sepsis than in healthy subjects. Finally, the results of non-clinical studies indicate that IC14 should only be administered with concurrent antimicrobial therapy in patients with infection.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Ensayos Clínicos como Asunto , Receptores de Lipopolisacáridos/inmunología , Sepsis/fisiopatología , Sepsis/terapia , Humanos , Inflamación/terapia , Lipopolisacáridos/efectos adversos , Proteínas Recombinantes de Fusión/inmunología , Sepsis/inmunología , Sepsis/mortalidad , Resultado del TratamientoRESUMEN
To determine the role of CD14 in lipopolysaccharide (LPS)-induced release of chemokines, 16 humans were injected with LPS (4 ng/kg) preceded (-2 h) by intravenous IC14, an anti-human CD14 monoclonal antibody, or placebo. LPS elicited increases in interleukin (IL)-8 concentrations in plasma and in lysates of red blood cell (RBC), polymorphonuclear cell and mononuclear cell fractions, which were all reduced by IC14. LPS also induced rises in the plasma and RBC levels of monocyte chemoattractant protein (MCP)-1, which were diminished by IC14. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, chemokines that in contrast to IL-8 and MCP-1 can not bind to the Duffy antigen receptor for chemokines on RBCs, were only detected in plasma. IC14 attenuated the LPS-induced release of MIP-1beta, but not of MIP-1alpha. IL-8 and MCP-1, but not MIP-1alpha and MIP-1b, circulate in RBC-associated form during endotoxemia. LPS-induced chemokine release is, in part, mediated by an interaction with CD14.
Asunto(s)
Antígenos/administración & dosificación , Quimiocinas/sangre , Endotoxemia/sangre , Receptores de Lipopolisacáridos/inmunología , Adulto , Antígenos/inmunología , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Humanos , Lipopolisacáridos/administración & dosificación , Masculino , Placebos , Valores de ReferenciaRESUMEN
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 1 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 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.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Infecciones Bacterianas/terapia , Receptores de Lipopolisacáridos/inmunología , Proteínas Recombinantes de Fusión/uso terapéutico , Sepsis/terapia , Proteínas de Fase Aguda/efectos de los fármacos , Proteínas de Fase Aguda/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Área Bajo la Curva , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/mortalidad , Citocinas/sangre , Citocinas/efectos de los fármacos , Relación Dosis-Respuesta Inmunológica , Método Doble Ciego , Selectina E/sangre , Selectina E/efectos de los fármacos , Femenino , Alemania/epidemiología , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Monocitos/inmunología , Países Bajos/epidemiología , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/farmacocinética , Seguridad , Sepsis/inmunología , Sepsis/metabolismo , Sepsis/mortalidad , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
CD14 is a receptor important for activation of cells by lipopolysaccharide (LPS). Treatment with the CD14 antibody IC14 was previously found to attenuate the release of proinflammatory cytokines and some chemokines into the circulation of healthy humans intravenously injected with LPS. To determine the role of circulating leukocytes in CD14-dependent gene expression, 16 healthy volunteers received LPS preceded by either IC14 or placebo. At different time points, mRNA was isolated from whole blood and gene expression was determined by multiplex ligation-dependent probe amplification (MLPA). LPS induced MIP-1alpha, MIP-1beta, IL-8, IL-1beta, and IL-1Ra mRNA production, which was delayed by 1 hr and reduced twofold by IC14 treatment. TNFR1 was unresponsive, whereas other investigated cytokines remained undetectable. Further, LPS showed differential effects on NFkappaB gene expression. LPS induced IkappaBalpha production, whereas p50 was unresponsive and p65 and p49/p100 remained undetectable. LPS induced IkappaBalpha expression was delayed (1 hr) and reduced by IC14. Gene expression profiles in blood cells corresponded poorly with observed changes in plasma levels. These data suggest that peripheral blood cells are of negligible importance in LPS-induced production of inflammatory mediators in vivo and that LPS may activate genes via a CD14-independent pathway that is slower and less efficient.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Receptores de Lipopolisacáridos/fisiología , Adulto , Citocinas/genética , Perfilación de la Expresión Génica/métodos , Humanos , Leucocitos/fisiología , Receptores de Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , FN-kappa B/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , ARN Mensajero/análisisRESUMEN
To determine the role of CD14 in lipopolysaccharide (LPS)-induced effects on coagulation and fibrinolysis in humans, 16 healthy subjects received an intravenous injection of LPS preceded by intravenous IC14, a recombinant chimeric monoclonal antibody against human CD14, or placebo. LPS-induced coagulation activation (tissue-factor mRNA in whole blood cells and plasma concentrations of F1+2) was not influenced by IC14, whereas the antibody reduced the increase in thrombin-antithrombin complexes and soluble fibrin. LPS injection also was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator and plasmin-alpha(2)-antiplasmin complexes), followed by an inhibitory response (plasminogen activator inhibitor type 1), which were attenuated by IC14. Furthermore, LPS reduced thrombin-activatable fibrinolysis-inhibitor antigen levels and increased soluble thrombomodulin levels, which were not influenced by IC14. These results suggest that different hemostatic responses during endotoxemia may proceed via CD14-dependent and -independent pathways.