Tnf Receptor Fusion Biology Essay

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Etanercept, trade name Enbrel, is a biopharmaceutical produced jointly by Amgen and Wyeth now Pfizer. This drug is used to treat a number of inflammatory conditions including rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis (AS), plaque psoriasis in adults, and juvenile idiopathic arthritis (JIA). These conditions are suspected to be caused by excessive production of tumour necrosis factors-α in the patient's immune system and thus classified as autoimmune diseases.

Etanercept is a recombinant human protein used to treat inflammatory conditions as noted above. Enbrel was approved for the treatment of rheumatoid arthritis by the FDA in 1998.

This product was then approved by the FDA in 2002 for the treatment of psoriatic arthritis, following this it was later approved for the treatment of plaque psoriasis in both Europe and the United States, soon followed by approval for treating RA, JIA and AS.

Other methods of treating these conditions include monoclonal antibody treatments including infliximab and adalimumab.

1.2 Tumour Necrosis Factor-Alpha (TNF-α)

Tumour necrosis factor-alpha is a pleiotropic inflammatory cytokine which acts within the body to induce inflammation and programmed cell death or apoptosis. This mechanism is specifically catered to act once an infection has occurred or when a pathogen has been introduced into the body. This is carried out via binding of TNF-α to cell surface receptors, in the case of inducing apoptosis tumour necrosis factor receptor 1 (TNFR-1) specifically.

Inflammation in the body involves a number of characteristic changes, including increased local blood flow caused by increased vascular diameter, extravasation (endothelial cells activated to express adhesive molecules to allow leukocytes to bind and move into tissue from circulatory system) and an increase in vascular permeability. The function of TNF-α in the inflammatory response mechanism is to activate the endothelial cells to express the adhesion factors to allow leukocytes to bind.

1.3 Autoimmune Disease

Autoimmune diseases are characterized by an over active immune system which cannot differentiate between healthy cells and pathogens attacking the body and thus immune responses occur against host cells as well as invading cells.

The conditions noted above (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and juvenile idiopathic arthritis) come under the heading of autoimmune diseases as they are suspected to be caused by excessive secretion of TNF-α.

The precise cause of these diseases is unknown, however, close study has revealed that sufferers have been found to have an excess of TNF-α in the affected areas and thus TNF-α has been targeted as the suspected cause. In the case of plaque psoriasis the TNF-α causes skin cells to grow at an increased rate, resulting in plaques forming on the surface of the skin. Similarly with psoriatic arthritis plaque lesions can be seen to be present on the skin surrounding an inflamed joint.

The methods behind treating these conditions involves the use of TNF-α blockers, a commonly used blocker includes Etanercept which goes by the trade name of Enbrel.

2. Enbrel

2.1 Mechanism of Action

Enbrel acts to treat the conditions previously discussed by inhibiting the action of TNF-α in the patient's immune system. This involves specific binding of the protein to the TNF-α within the body and preventing it from acting on cell surface receptors such as TNFR-1. This action causes a reduction in the activity of TNF-α thus preventing inflammation from occurring.

2.2 Dosage Forms & General Guidelines

There are currently four methods of administration of Enbrel; these involve subcutaneous injection of the drug. Subcutaneous injections are those which are administered to the area just below the dermis and epidermis. This delivery method is highly effective at ensuring quick uptake into the blood stream due to the highly vascularized nature of the subcutaneous tissue. Due to this fact it is an ideal area for administration.

The four methods available include; the Enbrel SureClick Autoinjector, Enbrel prefilled syringes, Enbrel multiple-use vials, and the Enbrel 25mg vial adaptors. The SureClick autoinjector administers a once off injection of 50mg/ml of Enbrel. The prefilled syringes are also single use only with concentrations of 25mg/0.5 ml or 50mg/ml. As the name suggests the multiple-use vials can be used for multiple dosages containing 25mg of Enbrel. The vial adapters available can be used for mixing Enbrel powder with liquid and withdrawing the solution for injection containing 25mg of Enbrel.Dosage forms can differ depending on which condition the patient is suffering from.

2.2.1 Ankylosing Spondylitis (AS), Rheumatoid Arthritis (RA) & Psoriatic Arthritis

In the case of ankylosing spondylitis patients are recommended a dosage of 50mg of Enbrel per week. This can be administered via the use of the SureClick autoinjector or prefilled syringes. Similarly to AS, rheumatoid and psoriatic arthritis patients are recommended a dosage of 50mg of Enbrel weekly. With the same administration methods used.

2.2.2 Plaque Psoriasis

Dosing for patients suffering from plaque psoriasis differs slightly to those suffering from the above conditions. In this case patients are recommended a dosage of 50mg of Enbrel twice weekly for 12 weeks, after this period the dosage is reduced down to 50mg once weekly.

2.2.3 Juvenile Idiopathic Arthritis (JIA)

Patients suffering from JIA between the ages of 2 and 17 years are recommended a dosage of 0.8mg/kg of Enbrel per week with a maximum dose of 50mg. The way in which Enbrel is administered to these patients is very important due to their age and weight. Patients weighing up to and over 63kg are administered with a once weekly 50mg/ml concentration of Enbrel via the SureClick or prefilled syringe methods. Patients weighing between 31 and 62kg are administered with 25mg of Enbrel twice weekly to ensure overdosing does not occur. This is administered via the 25mg/0.5ml prefilled syringe. Any patients weighing less than 31kg are recommended a single injection of the correct dosage via free-hand vials.

2.3 Adverse Effects

The main negative side effects of Enbrel found during trials was injection site reactions in approximately 37% of patients, which involved swelling, pain and erythema (rash) with itching. These effects were seen to occur within the first month of administering the drug, lasting about three to five days, and were observed to subside following this period.

Other common adverse effects following administration of Enbrel to patients can include headaches and infections. Tuberculosis was observed in a number of patients administered with Enbrel, and lymphoma was seen to occur in an increased number of patients receiving the drug as opposed to those in the control group receiving the placebo. However, the reason behind why patients developed lymphoma while receiving TNF blockers such as Enbrel is unknown.

2.4 Clinical Trial Patient Responses to Enbrel

The clinical trials carried out on Enbrel for each of the conditions it treats were shown to be successful with a high response in each case. In the case of rheumatoid arthritis, over six months of treatment with Enbrel the condition was seen to alleviate in the majority of patients. This is outlined in figure 1 below. As seen in figure 1 from Enbrel's prescribing information, the response of patients administered with Enbrel was much better than those who were administered the placebo, as would be expected. The findings gave a maximum of 80% of patients responding to the treatment in the fourth month of administration.

Figure : Response of RA patients administered Enbrel or placebo

3. Conclusion

To conclude, the use of Enbrel to treat patients suffering from inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, and plaque psoriasis has shown to be safe and effective. The proof that TNF-α could be the cause of these diseases is yet to be seen, however, the extensive trials carried out on Enbrel show that TNF-α inhibitors, specifically Enbrel, can alleviate the signs and symptoms of these diseases with limited adverse effects. Perhaps this is the evidence needed to show that TNF-α is a contributor to the cause of these diseases.

Thus, the use of Enbrel for the treatment of these conditions is recommended by doctors around the world to patients who have not responded to other treatment methods. With up to an 80% response in RA patients in month 4 it is clear that Enbrel is the product of choice for patients suffering from inflammatory diseases.