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Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality
W Lesslauer1, H Tabuchi, R Gentz
1F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Abstract:
The in vivo efficacy of human recombinant soluble tumor necrosis factor (TNF) receptor protein to prevent and to treat lipopolysaccharide (LPS)-induced lethal toxicity in D-galactosamine-treated mice was investigated. Chimeric proteins of the receptor extracellular domains fused to the hinge region of human IgG3 were expressed in myeloma cells (rsTNFR-h gamma 3). The fusion proteins had a disulfide-bonded dimeric structure. Upon intravenous injection, their serum concentration decreased relatively slowly after an initial phase of rapid elimination. D-galactosamine-sensitized mice were fully protected from the toxic effects of LPS, if the animal were pretreated with rsTNFR-h gamma 3 at 20 micrograms/animal. Partial protection was seen at significantly lower doses and when rsTNFR-h gamma 3 was given up to 3 h after LPS.
Insights
Human recombinant soluble tumor necrosis factor (TNF) receptor protein effectively prevented and treated lipopolysaccharide (LPS)-induced lethal toxicity in mice. Pretreatment offered full protection, while later administration provided partial protection.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Lipopolysaccharide (LPS) induces lethal toxicity, particularly in D-galactosamine-sensitized hosts.
- Tumor necrosis factor (TNF) plays a critical role in mediating LPS-induced shock.
- Soluble TNF receptor fusion proteins are potential therapeutic agents against TNF-mediated inflammation.
Purpose of the Study:
- To investigate the in vivo efficacy of a human recombinant soluble TNF receptor protein (rsTNFR-h gamma 3) in preventing and treating LPS-induced lethal toxicity.
- To evaluate the protective effects of rsTNFR-h gamma 3 in a D-galactosamine-sensitized mouse model.
Main Methods:
- Expression of chimeric receptor extracellular domains fused to human IgG3 hinge region (rsTNFR-h gamma 3) in myeloma cells.
- Administration of rsTNFR-h gamma 3 intravenously to D-galactosamine-sensitized mice challenged with LPS.
- Assessment of survival rates and toxic effects at various doses and time points relative to LPS challenge.
Main Results:
- rsTNFR-h gamma 3 exhibited a disulfide-bonded dimeric structure and slow serum elimination after rapid initial clearance.
- Pretreatment with 20 micrograms/animal of rsTNFR-h gamma 3 conferred complete protection against LPS-induced lethality.
- Partial protection was observed with lower doses and when rsTNFR-h gamma 3 was administered up to 3 hours post-LPS.
Conclusions:
- Human recombinant soluble TNF receptor protein (rsTNFR-h gamma 3) demonstrates significant therapeutic potential.
- rsTNFR-h gamma 3 can both prevent and treat LPS-induced lethal toxicity, offering a therapeutic window.
- This study supports the development of TNF receptor fusion proteins as treatments for sepsis and inflammatory conditions.