Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR:Fc) in rheumatoid arthritis

被引:71
作者
Murray, KM
Dahl, SL
机构
[1] UNIV WASHINGTON, DEPT PHARM, SEATTLE, WA 98195 USA
[2] UNIV MISSOURI, SCH MED, KANSAS CITY, MO 64108 USA
关键词
tumor necrosis factor; rheumatoid arthritis; recombinant human tumor necrosis factor receptor p75 Fc fusion protein;
D O I
10.1177/106002809703101111
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
BACKGROUND: Tumor necrosis factor (TNF) is the dominant mediator of the cytokine cascade that causes inflammation and joint destruction in rheumatoid arthritis. A new class of agents under investigation, the biologic TNF inhibitors, inhibits the activity of TNF. Recombinant human TNF receptor p75 Fc fusion protein (TNFR:Fc; Enbrel) blocks the activity of the cytokine TNF. The preclinical, Phase I, and Phase II data of TNFR:Fc in rheumatoid arthritis are reviewed in this article. METHODS: All available data on TNFR:Fc in rheumatoid arthritis were reviewed. These data included published literature and data on file at the manufacturer. RESULTS: TNFR:Fc has been effective in many models of inflammation, including animal models of rheumatoid arthritis and in clinical rheumatoid arthritis trials. Conclusions from a study with TNFR ''knockout'' mice (genetically altered mice incapable of producing TNFR proteins) demonstrated that p75 TNFR is a natural antagonist of TNF-mediated inflammation. A placebo-controlled, dose-escalation, Phase I trial evaluated the safety and efficacy of TNFR:Fc in patients with rheumatoid arthritis. There were no serious adverse effects reported. A Phase II, randomized, double blind, placebo-controlled trial evaluated 180 patients with active rheumatoid arthritis whose previous therapy had failed. A dose-response relationship was observed in the number of tender and swollen joints; patients who received the highest dose (16 mg/m(2)) of TNFR:Fc had the greatest improvement. Treatment was generally well tolerated. TNFR:Fc is nonimmunogenic; no antibodies to TNFR:Fc have been detected thus far in human studies. CONCLUSIONS: Preliminary data indicate that TNFR:Fc is an excellent candidate for future long-term studies in the treatment of rheumatoid arthritis.
引用
收藏
页码:1335 / 1338
页数:4
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