Tumor Necrosis Factor receptor-Fc Research Articles

Cost-Effectiveness of Tofacitinib for Patients with Moderate-to-Severe Rheumatoid Arthritis in China.

Patients with moderate-to-severe rheumatoid arthritis have a heavy financial burden. The cost-effectiveness of introducing tofacitinib to the current treatment sequence for patients with moderate-to-severe rheumatoid arthritis who have inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs-IR) in China remains unknown. The objective of this study was to assess the cost-effectiveness of introducing tofacitinib into the current treatment sequence in China for patients with moderate-to-severe rheumatoid arthritis who have csDMARDs-IR. A Markov model was constructed from the perspective of the Chinese healthcare system to compare treatment sequences with and without first-line tofacitinib for patients with rheumatoid arthritis with csDMARDs-IR. The treatment sequence without tofacitinib included adalimumab, etanercept, recombinant human tumor necrosis factor receptor-Fc fusion protein, infliximab, and tocilizumab. Costs were derived from publicly available sources. Clinical trials, network meta-analysis, and real-world data were used to generate quality-adjusted life-years (QALYs), transition probabilities, and the incidence of adverse events. Mortality probabilities were estimated from rheumatoid arthritis-based, Chinese all-cause mortality data. One-way and probabilistic sensitivity analyses were conducted to verify the robustness of the model. In addition, the cost-effectiveness of adding tofacitinib as second- and third-line treatment options was evaluated in our analyses.Costs and effects were discounted at 5% per anum. Compared to the current treatment sequence, adding tofacitinib as first-line treatment led to a cost-saving of $US880.11 (2018 values)and incremental QALYs of 1.34. Sensitivity analyses showed the results to be robust. Adding tofacitinib at second-line therapy was also a cost-saving option with a cost saving of $US653.65 and incremental QALYs of 1.34, while the incremental cost-effectiveness ratio of adding tofacitinib at third-line therapy was $US5588.14 per QALY gained. Using the WHO-recommended ICER acceptability threshold of ≤ 1-time per capita Gross Domestic Product (GDP), our analysis suggests that the introduction of tofacitinib into the current treatment sequence for moderate-to-severe RA patients with csDMARDs-IR in China was a cost saving option as first- and second-line treatment, and cost-effective as a third-line treatment option. Of note, use of tofacitinib as first- and second-line treatment post-csDMARDs-IR appeared to be cost saving.

Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice.

In the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-α (TNF-α) transgenic (hTNF-Tg) mice. Single-drug treatments with etanercept and tacrolimus attenuated the clinical signs but not the radiographic changes associated with the development of arthritis in mice. On the contrary, combined treatment significantly suppressed the radiographic progression and also improved the clinical signs. The combined treatment exhibited synergistic effects of the two drugs in reducing the serum matrix metalloproteinase-3 level and the number of peripheral CD11bhigh osteoclast precursor cells. Moreover, tacrolimus inhibited the cytokine-induced osteoclast differentiation in synergy with etanercept in an in vitro assay. Interestingly, tacrolimus did not inhibit the production of antidrug antibodies (ADAs) against etanercept in the hTNF-Tg mice. This result implies that the synergistic effects of etanercept and tacrolimus are not due to secondary effects derived from the suppression of ADA production by tacrolimus but are due to their primary effects. These findings suggest that concomitant treatment with etanercept and tacrolimus may be one of preferable treatment options to control disease activities for patients with rheumatoid arthritis, especially for those with bone resorption.

Single Copy Transgene Integration in a Transcriptionally Active Site for Recombinant Protein Synthesis.

For the biomanufacturing of protein biologics, establishing stable cell lines with high transgene transcription is critical for high productivity. Modern genome engineering tools can direct transgene insertion to a specified genomic locus and can potentially become a valuable tool for cell line generation. In this study, the authors survey transgene integration sites and their transcriptional activity to identify characteristics of desirable regions. A lentivirus containing destabilized Green Fluorescent Protein (dGFP) is used to infect Chinese hamster ovary cells at a low multiplicity of infection, and cells with high or low GFP fluorescence are isolated. RNA sequencing and Assay for Transposase Accessible Chromatin using sequencing data shows integration sites with high GFP expression are in larger regions of high transcriptional activity and accessibility, but not necessarily within highly transcribed genes. This method is used to obtain high Immunoglobulin G (IgG) expressing cell lines with a single copy of the transgene integrated into transcriptionally active and accessible genomic regions. Dual recombinase-mediated cassette exchange is then employed to swap the IgG transgene for erythropoietin or tumor necrosis factor receptor-Fc. This work thus highlights a strategy to identify desirable sites for transgene integration and to streamline the development of new product producing cell lines.

Establishment of the first WHO International Standard for etanercept, a TNF receptor II Fc fusion protein: Report of an international collaborative study

Etanercept, a recombinant human tumor necrosis factor (TNF) receptor Fc fusion protein is an effective treatment option in adults with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or plaque psoriasis and paediatrics with juvenile idiotypic arthritis and plaque psoriasis.Patent expiration in Europe and intense development of various etanercept products worldwide triggered a need for an international reference standard to facilitate determination of biological activity. Therefore, three candidate preparations of etanercept were lyophilized and evaluated in a multi-centre collaborative study comprising twenty eight laboratories from 15 countries for their suitability to serve as an international standard for the bioactivity of TNF receptor II Fc fusion proteins (international nonproprietary name, Etanercept). The preparations were tested for neutralization activity against the third TNF-α international standard (IS) in different in vitro cell-based assays, e.g., cytotoxicity, apoptosis and reporter gene methods. Regardless of the assay and the amount of TNF-α IS used, potency estimates for the different preparations were very similar. An indication of the inhibitory activity of etanercept in terms of the biological activity of the TNF-α IS based on ED50 data derived from a limited number of laboratories using a cytotoxicity assay was also derived. Results indicated that the candidate preparation coded 13/204 was stable and suitable to serve as an international standard for the biological activity of etanercept. Therefore, the preparation coded 13/204 was established by the WHO Expert Committee on Biological Standardization (ECBS) in 2015 as the WHO first International Standard for TNF receptor II Fc fusion protein (INN, etanercept) with an assigned in vitro bioactivity of 10,000IU per ampoule.It should be noted that this first-in-class international standard for a Fc fusion protein, available from the National Institute for Biological Standards and Control and also as a biological reference preparation (BRP) from the European Directorate for the Quality of Medicines and Healthcare, is intended for controlling the performance of biological assays for etanercept and to support the establishment of in-house bioassay standards. This standard is not intended for describing the labelling or dosage of etanercept therapeutic products or for use as a comparator (reference product) for biosimilarity determination.

Comparison of three transposons for the generation of highly productive recombinant CHO cell pools and cell lines

Several naturally occurring vertebrate transposable elements have been genetically modified to enable the transposition of recombinant genes in mammalian cells. We compared three transposons-piggyBac, Tol2, and Sleeping Beauty-for their ability to generate cell pools (polyclonal cultures of recombinant cells) and clonal cell lines for the large-scale production of recombinant proteins using Chinese hamster ovary cells (CHO-DG44) as the host. Transfection with each of the dual-vector transposon systems resulted in cell pools with volumetric yields of tumor necrosis factor receptor-Fc fusion protein (TNFR:Fc) that were about ninefold higher than those from cell pools generated by conventional plasmid transfection. On average, the cell pools had 10-12 integrated copies of the transgene per cell. In the absence of selection, the volumetric productivity of the cell pools decreased by 50% over a 2-month cultivation period and then remained constant. The average volumetric TNFR:Fc productivity of clonal cell lines recovered from cell pools was about 25 times higher than that of cell lines generated by conventional transfection. In 14-day fed-batch cultures, TNFR:Fc levels up to 900 mg/L were obtained from polyclonal cell pools and up to 1.5 g/L from clonal cell lines using any of the three transposons. Biotechnol. Bioeng. 2016;113: 1234-1243. © 2015 Wiley Periodicals, Inc.

A simple plasmid-based transient gene expression method using High Five cells

The High Five (H5) cell line, derived from the lepidopteran Trichoplusia ni, is one of the major insect cell hosts for the production of recombinant proteins using the baculovirus expression vector system (BEVS). Here, we describe a simple polyethylenimine (PEI)-based transient gene expression (TGE) process for the rapid production of recombinant proteins from suspension-adapted H5 cells. The method was optimized using two model proteins, enhanced green fluorescent protein (EGFP) and human tumor necrosis factor receptor-Fc fusion protein (TNFR-Fc). After screening several promoter and enhancer combinations for high levels of TNFR:Fc production, an expression vector containing the Autographa californica multicapsid nucleopolyhedrovirus immediate early 1 (ie1) promoter and homologous region 5 (hr5) enhancer was selected. Cells were transfected at a density of 2×106 cells/mL by direct addition of DNA and PEI. Under optimized conditions, a 90% transfection efficiency (percentage of EGFP-positive cells) was obtained. In addition, we observed volumetric TNFR-Fc yields over 150μg/mL within 4 days of transfection. The method was found to be reproducible and scalable to 300mL. This plasmid-based transient transfection process is a simple and efficient alternative to the BEVS for recombinant protein production in H5 cells.

Purification of TNFR-Fc produced in recombinant CHO cells: Characterization of product-related impurities

Because of its large size and structural complexity, preparations of the cysteine-rich tumor necrosis factor receptor-Fc (TNFR-Fc) that are produced using recombinant CHO cells contain many undesirable impurities. In this study, to purify TNFR-Fc, cell culture supernatant was first clarified using a pre-filter and sterilization filter and then subjected to a series of purification steps consisting of protein A affinity column chromatography, anion exchange chromatography, and hydrophobic interaction chromatography (HIC). To characterize the presence of TNFR-Fc-related impurities after the HIC step, the HIC eluates were further fractionated using analytical HIC and then separated by size exclusion chromatography (SEC). Several product-related impurities were detected during SEC, including low molecular weight (LMW) species, high molecular weight aggregates, and species with a size equivalent to authentic TNFR-Fc. N-terminal sequence analysis of the LMW species indicated that N-terminal amino acids had been partially deleted from the protein sequence at amino acid positions 1–185 or 1–223. Peptide mapping analysis followed by quadrupole time-of-flight mass spectrometry (Q-TOF-MS) and MS/MS indicated that the species that was equivalent in size to authentic TNFR-Fc contained scrambled disulfide bonds linked as Cys98-Cys115 or Cys104-Cys112. These product-related impurities, which led to a marked reduction in TNF-α neutralizing activity during cytotoxicity neutralization assays in L929 cells, should be removed from the final product during purification.

Study of the improved Sf9 transient gene expression process

Insect cells have been widely used for the production of recombinant proteins using recombinant baculovirus for gene delivery [1]. To simplify protein production in insect cells, we have previously described a method, based on transient gene expression (TGE) with cultures of suspension-adapted Sf9 cells using polyethylenimine (PEI) for DNA delivery [2]. Expression of GFP has been realized at high efficiency and a tumor necrosis factor receptor-Fc fusion protein (TNFR-Fc) was produced at a level of 40 mg/L. However, the efficiency of the insect cells TGE system has not been studied and further opti- mization may improve protein titers. Here, we studied the efficiency of PEI for plasmid delivery in Sf9 cells.

Efficacy and safety of recombinant human type Ⅱ tumor necrosis factor receptor-Fc fusion protein combined with methotrexate in the treatment of moderate to severe rheumatoid arthritis

Efficacy and safety of recombinant human type Ⅱ tumor necrosis factor receptor-Fc fusion protein combined with methotrexate in the treatment of moderate to severe rheumatoid arthritis

Clinical efficacy of etanercept for the treatment of psoriasis

Objective To evaluate the efficacy profile of etanercept,a recombinant human type Ⅱ tumor necrosis factor receptor-Fc fusion protein,in patients with moderate to severe psoriasis.Methods A retrospective study was performed.This study included 24 patients with moderate to severe psoriasis vulgaris resistant to conventional therapy.They were treated with subcutaneous injection of etanercept 25 mg twice weekly for three months during February 2008 and August 2011.Six months of follow up was carried out.Clinical efficacy was evaluated by psoriasis area and severity index (PASI) and physician global assessment (PGA).Results After 24-week treatment,12 (50％) patients achieved a 75％ reduction in PASI score,1 (4.2％) patient failed to respond.Adverse reaction,such as erythematous swelling at the injection site,was observed in 4 patients.Conclusion Anti-tumor necrosis factor may be effective for the treatment of moderate to severe psoriasis recalcitrant to traditional therapy.

Population pharmacokinetics of rhTNFR-Fc in healthy Chinese volunteers and in Chinese patients with Ankylosing spondylitis

To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS). Thirty-two healthy volunteers were randomly assigned to receive a single SC injection of 12.5, 25, 37.5, or 50 mg of rhTNFR-Fc. Twenty male patients with moderate AS were randomly assigned to receive seven consecutive SC injections of rhTNFR-Fc at either 25 mg twice a week (BIW) or 50 mg once a week (QW). Population pharmacokinetic (PK) analysis was applied to obtain PK parameters of rhTNFR-Fc by the NONMEM method. The data were best described by a one-compartment model with lag time. We found that gender had a significant effect on the apparent clearance (CL/F), with the male CL/F ratio being only 0.665 times the female ratio; the absorption coefficient (F) of multiple dosages of rhTNFR-Fc was only 0.674 times that of a single dosage. The outcome parameters were CL/F (female: 0.168 L/h, male: 0.110 L/h), the apparent volume of distribution (Vd/F: 15.5 L), the absorption rate constant (Ka) (single dosage: 0.0605 h⁻¹, multiple dosage: 0.0408 h⁻¹), and the lag time (T(lag): 1.03 h). The inter-individual variability in the CL/F, Vd/F, Ka, and T(lag) were 33.3%, 42.7%, 55.6%, and 81.8%, respectively. Chinese females have a higher CL/F than Chinese males, and multiple dosings can significantly decrease the absorption of rhTNFR-Fc (SC). The population PK parameters of rhTNFR-Fc in healthy Chinese volunteers and patients with AS were similar to those reported for subjects in published American studies.

Calnexin overexpression sensitizes recombinant CHO cells to apoptosis induced by sodium butyrate treatment

Sodium butyrate (NaBu) can enhance the expression of foreign genes in recombinant Chinese hamster ovary (rCHO) cells, but it can also inhibit cell growth and induce cellular apoptosis. In this study, the potential role of calnexin (Cnx) expression in rCHO cells treated with 5 mM NaBu was investigated for rCHO cells producing tumor necrosis factor receptor FC. To regulate the Cnx expression level, a tetracycline-inducible system was used. Clones with different Cnx expression levels were selected and investigated. With regard to productivity per cell (q (p)), NaBu enhanced the q (p) by over twofold. Under NaBu treatment, Cnx overexpression further enhanced the q (p) by about 1.7-fold. However, under NaBu stress, the cells overexpressing Cnx showed a poorer viability profile with a consistent difference of over 25% in the viability when compared to the Cnx-repressed condition. This drop in the viability was attributed to increased apoptosis seen in these cells as evidenced by enhanced poly (ADP-ribose) polymerase cleavage and cytochrome C release. Ca(2+) localization staining and subsequent confocal imaging revealed elevated cytosolic Ca(2+) ([Ca(2+)](c)) in the Cnx-overexpressing cells when compared to the Cnx-repressed condition, thus endorsing the increased apoptosis observed in these cells. Taken together, Cnx overexpression not only improved the q (p) of cells treated with NaBu, but it also sensitized cells to apoptosis.

Clinical evaluation and radiological observation of recombinant human tumor necrosis factor receptor-Fc fusion protein in treatment of active ankylosing spondylitis

To evaluate the efficacy of recombinant human tumor necrosis factor receptor-Fc fusion protein (rh TNFR:Fc) in the treatment of active ankylosing spondylitis (AS). 68 patients with active AS underwent subcutaneous injection of rh TNFR: Fc 25 mg twice a week for 24 weeks. The following indexes were observed: improvement of at least 20% of reported symptoms, based on the multicomponent Assessments in AS (ASAS) response criteria (ASAS 20) at weeks 2, 6, 12 and 24, ASAS 50 and ASAS 70 responses, and improved scores on individual components of ASAS, including Bath AS disease activity index (BASDAI), acute phase reactants, and Bath AS metrology index (BASMI). And the X-ray images of patient's pelvis at weeks 0, 12, and 24 were graded based on BASRI. After treatment of rh TNFR:Fc the primary and secondary efficacy end points of the 68 patients were all improved compared with the baseline values. During the process of treatment, the number of patients with the efficacy achieving ASAS20 was gradually rising: 44 cases (64.7%) at week 12 and 58 (85.0%) at week 24. The efficacy of 41 cases (60.3% ) reached ASAS50 and that of 34 cases reached ASAS70 at week 24. Other efficacy end points also reflected the similar effect and were improved significantly compared with the baseline values at different time points ( all P < 0.01). BASRI showed that the radiological improvement of sacroiliac joint was not significant (P > 0.05) and that the radiological improvement of hip was not obvious at week 12 (P > 0.05) but significant at week 24 (P < 0.05). rh TNFR:Fc rapidly improves the signs and symptoms of active AS.

Tumor Necrosis Factor Blockade: Mechanism of Action

Modulation of the immune response with tumor necrosis factor (TNF) blockers is not a new treatment strategy for many inflammatory disorders; however, relatively little is known about their specific mechanism of action. Understanding the mode of action, pharmacology, and pharmacokinetics of the monoclonal TNF antibodies, infliximab and adalimumab, and the soluble TNF receptor, etanercept, may therefore enable us to account for their differing clinical profiles. The aim of this supplement is to explore the roles and mechanisms of TNF and TNF blockade using in vitro pharmacological and in vivo animal modeling experiments, and in vivo studies of the effects of etanercept on the inflammatory cascade in patients with psoriasis.

Binding Characteristics of Tumor Necrosis Factor Receptor-Fc Fusion Proteins vs Anti-Tumor Necrosis Factor mAbs

Tumor necrosis factor (TNF) antagonists are efficacious in the treatment of various autoimmune diseases. Two classes of TNF antagonists are currently commercially available: soluble TNF receptor-Fc fusion proteins (etanercept) and anti-TNF mAbs (adalimumab and infliximab). The classes differ in molecular structures and mechanisms of action. The interactions between TNF antagonists with TNF molecules were characterized. The anti-TNF mAbs, but not the soluble TNF receptor, formed visible lines of precipitation in Ouchterlony assays. The molecular weights of complexes formed by TNF (52 kDa) with either etanercept (130 kDa), adalimumab (150 kDa), or infliximab (average 165 kDa) were determined by size exclusion chromatography-light-scattering assays. Etanercept and TNF formed complexes of 180 and 300 kDa, representing one and two etanercept monomers bound to a TNF trimer, respectively. Adalimumab and infliximab formed a variety of complexes with TNF with molecular weights as high as 4,000 and 14,000 kDa, respectively, suggesting the presence of complexes with a wide range of sizes and stoichiometries. The absence of large complex formation with the binding of soluble receptor-fusion proteins to TNF may account for the different clinical efficacy and safety profiles of the two classes of TNF antagonists.

Electro-gene therapy of collagen-induced arthritis by using an expression plasmid for the soluble p75 tumor necrosis factor receptor-Fc fusion protein.

Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. Among a number of techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive, and safe. In this study, we attempted to treat collagen-induced arthritis (CIA) with anti-TNF gene therapy by transferring the plasmid encoding soluble p75 TNF receptor linked to the Fc portion of human IgG1 (sTNFR:Fc) using in vivo electroporation. DBA/1 mice were immunized with bovine type II collagen and boosted with the same antigen. At 2 days after boosting, the plasmid vector containing cDNA for the sTNFR:Fc was injected into one selected site in the gastrocnemius muscle followed by electroporation. Serum levels of sTNFR:Fc reached 2.3 ng/ml on day 5 when gene expression reached its peak. Macroscopic analysis of paws for redness, swelling and deformities showed that the onset of moderate-to-severe CIA in mice treated with sTNFR:Fc was prevented on a significant level compared with the control mice (P<0.05). The beneficial effect of sTNFR:Fc DNA transfer lasted for at least 18 days following treatment. In addition, both the synovitis and the erosion of cartilage in the knee joints were dramatically reduced in mice treated with sTNFR:Fc (P<0.05). The expression of IL-1beta and IL-12 in the paw was also decreased by sTNFR:Fc treatment (P<0.01) while there was little change in the levels of IL-17 and vWF. These data showed that sTNFR:Fc expression plasmid was effective in the prevention of CIA, and in vivo electroporation-mediated gene transfer may provide a new approach to cytokine therapy in autoimmune arthritis.

1032. Electro-Gene Therapy of Collagen-Induced Arthritis by Using an Expression Plasmid for the Soluble p75 Tumor Necrosis Factor Receptor-Fc Fusion Protein

1032. Electro-Gene Therapy of Collagen-Induced Arthritis by Using an Expression Plasmid for the Soluble p75 Tumor Necrosis Factor Receptor-Fc Fusion Protein

Treatment of experimental autoimmune myasthenia gravis with recombinant human tumor necrosis factor receptor Fc protein

Lymphotoxin-α (TNF-β) and TNF receptor p55 gene knockout mice are resistant to the development of antibody and complement mediated experimental autoimmune myasthenia gravis (EAMG), suggesting a possible role of TNF in mediating EAMG. Therefore, we tested the hypothesis that blocking the functional interaction of TNF with their receptors by soluble recombinant human TNFR:Fc would suppress the ongoing clinical EAMG. Recombinant human TNFR:Fc administered daily for 2 weeks to C57BL6 mice with ongoing clinical EAMG significantly improved clinical EAMG when compared with placebo-treated mice. A clinical trial of selected myasthenia gravis patients with recombinant human TNFR:Fc could be attempted.

Treatment with the interleukin-I receptor antagonist and soluble tumor necrosis factor receptor Fc fusion protein does not prevent endotoxin-induced preterm parturition in mice.

To determine whether the administration of anticytokine agents, the interleukin-1 receptor antagonist (IL-1ra) and a soluble tumor necrosis factor receptor Fc fusion protein (sTNFR-Fc), prevents endotoxin-induced preterm delivery in mice. C3H/HeN pregnant mice at 15 days of gestation (70% gestation) were randomized to receive phosphate-buffered saline (PBS) or lipopolysaccharide (LPS) (50 micrograms/mouse) intraperitoneally (i.p.). Randomly selected PBS- or LPS-treated mice were additionally treated intravenously (i.v.), i.p., or subcutaneously (s.c.) every 3 hours with IL-1ra (1-50 mg) or every 12 hours with sTNFR-Fc (200-400 micrograms) beginning 1 hour before LPS injection. Animals were observed for vaginal bleeding and preterm delivery. Mice treated i.p. with 50 micrograms LPS (n = 13) had a shorter injection-to-delivery interval than mice treated similarly with PBS (n = 19) (median 13.5 hours, range 10-105 versus median 86.8 hours, range 53-120, respectively; P < .001). Saline-treated mice given 10 mg IL-1ra every 3 hours i.p. (n = 3) or 200 micrograms sTNFR-Fc every 12 hours i.v. (n = 4) had similar injection-to-delivery intervals as PBS-treated control mice (median 70 hours, range 70-76 versus median 58 hours, range 50-120, respectively). Similarly, LPS-treated mice given PBS every 3 hours (n = 20) had injection-to-delivery intervals comparable to LPS-treated mice (n = 13) (median 15.5 hours, range 9.8-92 versus median 13.5 hours, range 10-105, respectively). Lipopolysaccharide-treated mice given i.p. injections of 1 (n = 4), 10 (n = 31), or 50 (n = 15) mg of IL-1ra every 3 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 13) (medians 11.6, 15, 14.5 and 13.5 hours; ranges 10.8-12, 8-95, 11-92, and 10-105, respectively). Lipopolysaccharide-treated mice given i.v. injections of 200 (n = 4) or 400 (n = 9) micrograms sTNFR-Fc every 12 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 8) (medians 23.3, 22.5, and 21.9 hours; ranges 14.8-33, 15-95.5, and 15.5-44, respectively). The median injection-to-delivery interval of LPS-treated mice given both IL-1ra (10 mg) every 3 hours i.p. and sTNFR-Fc (200 micrograms) every 12 hours i.v. (n = 5) was not different from that of LPS-treated mice (median 26 hours, range 24.5-72 versus median 13.5 hours, range 10-105, respectively; P > .05). The anticytokine agents IL-1ra and sTNFR-Fc did not prevent preterm delivery or prolong pregnancy in endotoxin-induced preterm labor in mice.

Treatment with the interleukin-I receptor antagonist and soluble tumor necrosis factor receptor fc fusion protein does not prevent endotoxin-induced preterm parturition in mice

Treatment with the interleukin-I receptor antagonist and soluble tumor necrosis factor receptor fc fusion protein does not prevent endotoxin-induced preterm parturition in mice