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PMID: 10577978 Published · ppublish English Journal Article Review

PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases.

Annals of the rheumatic diseases ·Vol. 58 Suppl 1 ·1999-11-00 ·Pages I73-81

Edwards CK

Abstract

The proinflammatory cytokine, tumour necrosis factor alpha (TNFalpha) has been shown to play a pivotal part in mediating acute and chronic inflammation. The activities of TNFalpha are modulated by the proteolytic shedding of the soluble extracellular domains of the two TNF receptors, p55 sTNF-RI and p75 sTNF-RII. Amgen Inc has cloned and expressed a recombinant form of a natural inhibitor of TNFalpha, referred to as recombinant human soluble TNF receptor type I (r-Hu-sTNF-RI, sTNF-RI). sTNF-RI is an E coli recombinant, monomeric form of the soluble TNF-type I receptor. A high molecular weight polyethylene glycol (PEG) molecule is attached at the N-terminus position to form the molecule intended for clinical evaluations (PEG sTNF-RI). Preclinical studies to date demonstrate that PEG sTNF-RI is efficacious in rodent models of chronic inflammatory disease including rheumatoid arthritis and Crohn's disease at doses as low as 0.3 mg/kg given every other day. This dose results in plasma concentrations of 0.3 to 0.5 microg/ml. Higher doses with correspondingly higher plasma concentrations yield higher efficacy. It has also demonstrated efficacy in E coli lipopolysaccharide, and Staphylococcus enterotoxin B mediated models of acute inflammation in rodents and primates. Pharmacokinetic studies in mice, rats, cynomolgus monkeys, baboons, and chimpanzees have been conducted with PEG sTNF-RI. Absorption from a subcutaneous dose was slow, with the time to reach maximal plasma concentrations of 24-48 hours in rats, and in monkeys, and 3-29 hours in chimpanzees. The initial volume of distribution of PEG sTNF-RI was essentially equivalent to that of plasma (40 ml/kg). This suggests the protein does not appear to extensively distribute from the systemic circulation with a volume of distribution at steady state (Vss) less than 200 ml/kg in all species studied. These results are consistent with previous experience with PEGylated proteins in which PEGylation decreases both the rate of absorption and the plasma clearance of human recombinant proteins in animals and humans. The use of a PEG molecule will probably provide a more advantageous dosing schedule (that is, less frequent dosing) for the patient compared with a non-PEG sTNF-RI.

MeSH Terms
Animals Antirheumatic Agents/therapeutic use Arthritis, Rheumatoid/immunology,therapy Disease Models, Animal Drug Design Humans Receptors, Tumor Necrosis Factor/therapeutic use Receptors, Tumor Necrosis Factor, Type I Tumor Necrosis Factor Decoy Receptors Tumor Necrosis Factor-alpha/antagonists & inhibitors,immunology
Chemicals
Antirheumatic Agents Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Tumor Necrosis Factor Decoy Receptors Tumor Necrosis Factor-alpha recombinant human tumor necrosis factor-binding protein-1
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Edwards C K
Department of Product Development, Amgen Inc, One Amgen Center Drive, MS: 27-5-A, Thousand Oaks, CA 91320-1789, USA.
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Article Info
Journal
Annals of the rheumatic diseases
Abbr.
Ann Rheum Dis
ISSN
0003-4967
DOI
10.1136/ard.58.2008.i73
Published
1999-11-00
Pages
I73-81
Language
English
Region
England
NLM ID
0372355
PMCID
PMC1766570
Subset
IM
External Links
PubMed source DOI: 10.1136/ard.58.2008.i73 PMC Full Text View journal details
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