Rheumatoid arthritis Enbrel treatment

TNF)-a - a highly effective approach to the treatment of chronic inflammatory illnesses. Originally approved for rheumatoid arthritis (approximately 5 million people globally suffer from rheumatoid arthritis), Enbrel has now gained approval for additional indications, including psoriatic arthritis, juvenile rheumatoid arthritis and ankylosing spondylitis. 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

Enbrel Enbrel is used for the treatment of rheumatoid arthritis. It is supplied as a sterile, preservative-free, lyophilized powder. The powder is reconstituted with 1 mL sterile bacteriostatic water-for-injection (containing 0.9% benzyl alcohol) prior to parenteral injection. 

Two recently introduced biological therapies were designed to interfere with the inflammatory cascade initiate by TNF-a. Etanercept (Enbrel) is indicated for the treatment of moderate to severe rheumatoid arthritis in individuals over age 4. Infliximab in conjunction with methotrexate (Remicade) is approved for use by adults in the treatment of rheumatoid arthritis. It is also indicated for therapy of Crohn s disease. Over the short term, the efficacy of these drugs in the treatment of rheumatoid arthritis appears to be superior to that of methotrexate alone however, their ability to prevent bone erosion for longer than 24 months must be further studied. The cost of both drugs is significantly higher than that of the other DMARDs. 

Understanding the role of Fc and FcRN has allowed engineering of hybrid molecules that take advantage of Fc-dependent plasma half-life extension in designing fusion proteins intended for therapeutic use. An example is the construct of the TNF receptor-Fc fusion protein, which results in a significant increase in the half-life of the TNF receptor [20-22]. Enbrel, a recombinant TNF-a-receptor-Fc fusion protein, has provided effective treatment for rheumatoid arthritis patients. 

H. Other considerations Enbrel has been designated an orphan product for use in the treatment of juvenile rheumatoid arthritis and Wegener s granulomatosis. 

A small-molecule inhibitor of tumor necrosis factor a, a protein involved in inflammatory diseases such as rheumatoid arthritis, has been identified <2005SCI1022>. Direct inhibition by the commercial biological agents Enbrel and Remicade has produced major advances in rheumatoid arthritis treatment and validated extracellular inhibition of this proinflammatory cytokine as an effective therapy. The new inhibitor 35 is composed of trifluoromethylphenyl indole and dimethylchromone moieties linked by a dimethylethylenediamine spacer. 

Antibody development radics can be learned by reviewing the product labeling for some agents mentioned. Antitumor necrosis factor alpha (infliximab Enbrel Amgen, Inc., Wyeth, Inc.) has revolutionized the treatment of rheumatoid arthritis, even if its labeling, in small font, occupies both sides of a small poster. 

Exhibit 10.12 presents the production of etanercept (Enbrel, Immunex), a new generation drug for the treatment of rheumatoid arthritis. 

Etanercept (Enbrel) is FDA approved for the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis. Etanercept is a soluble, recombinant, fully human tumor necrosis factor (TNF) receptor fusion protein consisting of two molecules of the hgand-binding portion of the TNF receptor fused to the Fc portion of IgGl. As a dimeric molecule, it can bind two molecules of TNF. Etanercept binds soluble and membrane-bound TNF, thereby inhibiting the action of TNF. 

Etanercept (Enbrel ) is used in the treatment of rheumatoid and psoriatic arthritis. It is produced using CHO cells. The protein acts as a soluble version of the tumour necrosis factor (TNF-a) receptor, TNF is involved in the pathology of rheumatoid arthritis (RA) and psoriasis. The soluble receptor binds to TNF before it can bind to TNF receptors on the inflammatory cells within the body, thus interrupting the inflammatory cascade. 

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