Etanercept

The extracellular domain of cell membrane receptors can be produced recombi-nantly and used as a therapeutic product. The soluble receptor can be used to bind and neutralize the receptor s endogenous ligands (e.g., etanercept), or it can be used for stimulation of a co-receptor (e.g., abatacept). Soluble receptors are typically produced as IgG Fc fusion proteins to extend the half-life of the receptor in circulation. 

Etanercept is dimeric fusion protein that consists of the extracellular ligandbinding protein of the human 75-kDa tumor necrosis factor (TNF) receptor linked to the Fc portion of human IgC, immunoglobulin. Etanercept has a short half-life (3-6 days) and is administered at doses of 25 mg SC twice weekly [62]. The population PK/PD of etanercept were described recently [63]. Following SC administration of the protein at 25 mg and 50 mg twice weekly doses in rheumatoid arthritis (RA) patients, linear pharmacokinetic behavior was ob- 

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Recombinant soluble TNF-RI-IgGl fusion protein Etanercept, Enbrel is a chimeric molecule consisting of the extracellular domain of the TNF receptor I (TNF-RI) and the Fc portion of human IgGl. Two Fc domains are bound to each other via disulfide bonds, thereby yielding dimers with two binding sites for the TNF trimer. Etanercept binds with high affinity to extracellular TNF and reduces TNF activity. Etanercept is not effective in Crohn s disease, possibly because it does not lead to destiuction of membrane TNF-a expressing cells. Indications and side effects are similar to those of Infliximab and Adalimumab. 

Soluble receptor constructs Etanercept This genetically engineered drug consists of the extracellular-part of the TNF-receptor type I and the Fc portion of human IgG. Its application in rheumatoid arthritis mirrors that of infliximab. 

Commercially available dtugs used for therapeutic therapy comprise up to date mainly injectable monoclonal antibodies like Infliximab (Remicade ) and Adalimumab (Humira ) or TNF-receptor derivatives like Etanercept (Enbrel ) (Fig. 3). One possible way of action of these reagents is the neutralization of TNF, thereby blocking its inflammatory effects and dampening (auto)immune responses [3, 4]. 

More data on etanercept, infliximab, and pentoxifylline are needed before any recommendations can be made... 

Etanercept (Enbrel) 25 mg twice weekly or 50 mg once weekly SC injection 1 -4 weeks ISR Monitor for infection ISR—topical corticosteroids, antipruritics, analgesics, rotate injection sites Screen for tuberculosis... 

Etanercept is a recombinant form of human tumor necrosis factor receptor.24 Etanercept provides a therapeutic effect by binding to soluble TNF and preventing its binding with TNF receptors. It is administered subcutaneously once or twice weekly noticeable symptomatic improvement is seen in 1 to... 

Systemic therapies are seldom used for mild to moderate psoriasis, and are generally reserved for patients with moderate to severe psoriasis.17 29 Oral agents include sulfasalazine, acitretin, methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, and hydroxyurea. Parenteral agents include the biologic response modifiers alefacept, efalizumab, etanercept, infliximab, and many others, currently at various stages of research or approval for psoriasis. 

The combination of cyclosporine with calcipotriol may be more efficacious than either agent used alone.21,37 Cyclosporine and SCAT may also be effective.21,38 However, cyclosporine should not be used concurrently with PIJVA there is a well-documented increased risk of squamous cell cancer and the combination may have a negative effect on lesion clearance.21 The combination of cyclosporine with methotrexate is extremely effective and minimizes toxicity from either agent as discussed. Cyclosporine has also been used successfully with mycophenolate mofetil38 and etanercept.29... 

Etanercept is a fully human dimeric fusion protein composed of human TNF-a p75 receptor fused to the Fc portion of human IgG 1.41 It acts as a tumor necrosis factor-a (TNF-a) inhibitor by binding to and inactivating TNF-a, thus preventing interactions with its cell surface receptors.41 This agent is useful for chronic moderate to severe plaque psoriasis and for psoriatic... 

Enbrel Etanercept Immunex Corporation Rheumatoid arthritis... 

Etanercept 50 mg SC once weekly Tuberculin skin test None... 

Etanercept adali- Local injection-site reactions, Symptoms of infection... 

Kang, C. P. et al., The influence of a polymorphism at position -857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis, Rheumatology (Oxford), 44, 547, 2005. 

Several pro-inflammatory cytokines, such as TNFa, IL-1, IL-6, are important in the initiation and maintenance of various autoimmune diseases, such as RA, CD, and psoriasis. Thus, targeted therapies, which have been developed to inhibit their activity, have resulted in clinical improvement of these patients. Currently, there are three TNFa inhibitors (etanercept, infliximab, and adalimumab) and one IL-1 receptor antagonist (anakinra) that have been approved for the treatment of at least one of these diseases. In addition, a number of other anti-cytokine therapies are in clinical development. The TNFa antagonists will be reviewed here. 

Wyeth-Ayerst Laboratories and Immunex Inc. Etanercept (Enbrel ) Product Insert, 2006. 

Moreland, L.W. et al., Etanercept treatment in adults with established rheumatoid arthritis 7 years of clinical experience, J. Rhematol., 33, 854, 2006. 

Brion, P.H., Mittal-Henkle, A., and Kalunian, K.C., Autoimmune skin rashes associated with etanercept for rheumatoid arthritis [letter], Awn. Intern. Med., 131, 634, 1999. 

Mohan, N. et al., Demyelination diagnosed during etanercept (TNF receptor fusion protein) therapy [abstract], Arthritis Rheum., 43 Suppl. 9, S228, 2000. 

Etanercept (Enbrel, Immunex) is a dimerized protein molecule that consists of a portion of the tumor necrosis factor receptor coupled to the Fc portion of human IgGl (see Section 4.3). It has 934 amino acids and a molecular weight of approximately 150 kDa. 

Etanercept is produced by recombinant technology in a Chinese hamster ovary mammalian cell expression system. The WCB is grown in a proprietary media system. The cells are cultured initially in flasks and then inoculated into the bioreactor vessel. The product is purified in a number of chromatographic steps, followed by viral inactivation and viral filtration steps. 

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