Etanercept is a tumor necrosis factor-a (TNF-a) antagonist used in the treatment of adult and juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis. It is a recombinant, fully human, soluble, dimeric fusion protein that consists of two copies of the extracellular ligand-binding domain of the human 75-kDa TNF-a receptor linked to the Fc portion of human immunoglobulin (Ig) G1 (European Medicines Agency 2005). It is produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell expression system (European Medicines Agency 2005; Enbrel: US Full Prescribing Information 2006). A simplified structure of etanercept is provided in Fig. 4.1. The CH2 and CH3 domains and the hinge region of the Fc portion of IgG1 are included but not the CH1 domain. It consists of 934 amino acids (fully human amino acid sequences) with an apparent molecular weight of 150 kDa (European Medicines Agency 2005; Enbrel: US Full Prescribing Information 2006).
The structure of etanercept makes it a 50- to 100fold more potent binder of TNF-a than the endogenous unconjugated soluble TNF-a receptor (Goffe and Cather 2003; Strober 2005). Given its dimeric structure, each etanercept molecule can bind up to two TNF-a molecules (Goffe and Cather 2003), compared with the monomeric endogenous TNF- receptor, which can only bind one TNF-a molecule. Linkage of the receptor to the Fc portion of IgG1 also substantially prolongs the half-life of etanercept relative to the endogenous soluble forms (Strober 2005).
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