New ‘biologic’ treatments that offer a new direction for treating a diverse range of diseases are currently being researched and developed through the use of recombinant DNA technology. Each cell in our body contains DNA - a substance containing the blueprint (or genetic code) for the structure and function of each organism. The genetic code is made up of genes, unique sequences of DNA, each one coding for a different protein in the body. Using new DNA technology, researchers can identify elements that are important in a disease and use a copy of the relevant gene or genes to produce specific protein molecules that could be used as treatment. These treatments are made up from proteins that are naturally found in the body which is beneficial for the safety of the treatment. Although biologic treatments use copies of genes to produce the therapeutic molecule, they do not involve modifying the patient’s genes.

The term ‘biologics’ describes a diverse range of therapeutic products. These include proteins such as monoclonal antibodies, cytokines (interferon, interleukin), and tissue growth factors.¹ These cutting-edge therapies may be able to provide substantial improvements on the current "chemical" treatments available, offering improved levels of efficacy and safety.

In the mid-1970s Herbert Boyer at the University of California in San Francisco used knowledge of the sequence of amino acids in insulin to synthesise a copy of the gene which produces insulin. He inserted the gene into some E. coli bacteria. The E. coli then proceeded to produce the exact same insulin as would be produced normally in the human body. This was the first use of recombinant DNA technology to produce a therapeutic molecule. After becoming commercially available in the early 1980s recombinant human insulin revolutionised diabetes treatment. Since the 1980s, similar technologies have been used by companies to discover and mass produce exact copies of many other human proteins.

This technology has already been used to manufacture hormones for metabolic disorders, to treat conditions such as anaemia, as well as to produce numerous vaccines. Future applications of this technology include treatments aimed at tackling a variety of diseases, including skin conditions, such as psoriasis. Psoriasis involves a series of reactions associated with the immune system, this means that a biologic therapy could be developed which targets one of the reactions involved. Such a therapy would modify the series of reactions that cause the disease itself, rather than simply treating or reducing the symptoms and could therefore provide patients with long term disease-free and treatment-free periods.

The recent completion of the mapping of the human genome will enhance current research into the proteins that can cause or inhibit certain diseases, which indicates the vast potential of biologic treatments.

The developments being made in biologic therapies mean that new methods of treatment for psoriasis are now being researched. These new therapies could offer added benefits, such as effective treatment without the side effects of current treatment options. Of the people who have psoriasis, 25% have a moderate or severe form of the disease,² and it is for this subset of patients that current treatment options fall particularly short.

In patients with moderate to severe psoriasis, systemic therapies are used, such as phototherapy (ultraviolet A or B irradiation), cyclosporine, methotrexate and acitretine. These therapies are associated with side effects including immuno-suppression (putting a patient at risk of infections), renal and liver toxicity, skeletal abnormalities and hyperlipidemia, and, with phototherapy, increased risk of skin cancers. As these side effects can often be disabling and even life threatening some patients can be unwilling or unable to use the medication. A recent survey in the US suggested that as many as two-thirds of those suffering from psoriasis are not seeking the care of a physician because of dissatisfaction with treatment efficacy.³

Therefore a new immuno-selective biologic treatment which is targeted to the pathological changes in psoriasis promises to provide efficacy with minimal side effects. This would be very welcome for patients with moderate to severe psoriasis and could aid with compliance issues. Additionally, some new selective biologic therapies may be able to provide long-term relief, resulting in long-lasting clearance of disease. This would enable a patient to stop treatment for a certain time once their psoriasis had cleared, which would have a profound benefit on their quality of life. Importantly, for some biologics it seems possible to be able to stop treatment without worrying about rebound, a phenomenon experienced with some treatments whereby the psoriasis comes back even worse than before once the treatment is stopped.

Research has shown that there is a relationship between psoriasis and the humanimmune system, highlighting specifically the role which a type of white blood cell (the T lymphocyte or T cell) plays in the development of disease.

New biologic treatments are currently being developed that selectively act on a subset of the T cells that are thought to be responsible for forming and maintaining the psoriatic plaques. These biologic treatments aim to block the underlying mechanism of psoriasis. This selective action of the biologic treatment should help to overcome many of the problems associated with current psoriasis therapies.

Current research into biologic treatments means that in the near future there may be treatments for psoriasis which are both safe and effective. Additionally these new treatments may be able to modify the disease and provide patients with long term disease-free and treatment-free periods.

Alefacept (LFA-3/lgG1 human fusion protein) is a biologically engineered fusion protein (a type of biologic treatment). It is one of the first of a new class of biologic treatments (called selective immunomodulatory agents) developed for moderate to severe psoriasis designed to specifically target the underlying immunoinflammatory mechanism of the disease.

Alefacept inhibits a specific T cell reaction within the immune system that is thought play a major role for the production of lesions in chronic plaque psoriasis.

• Foreign proteins (known as antigens) bind to special cells in the immune system known as Antigen Presenting Cells (APCs), which act as sentinels of the skin

• The APCs migrate to the lymph nodes and, following a series of interactions involving surface molecules, present the captured antigen to the T cell

• One of the most important of these interactions is between the LFA-3 molecule on the surface of the APC and the CD2 molecule on the T cell

• In psoriasis, this interaction will abnormally activate the T cells causing them to divide and to produce inflammatory molecules, known as cytokines

• These inflammatory molecules will in turn induce the inflammation in the skin as well as the proliferation of skin cells (keratinocytes), leading to the development of psoriatic lesions

• Alefacept binds to the CD2 molecules on T cells and thus blocks the interaction between the APC and the T cell

• In this way, alefacept blocks the abnormal activation of T cells and the subsequent release of inflammatory cytokines

• Therefore alefacept prevents the immunoinflammatory reactions underlying psoriasis

1. Gottlieb et al Strand V: Use of the interleukin-2 fusion protein, DAB389IL-2, for the treatment of psoriasis. Dermatologic Therapy 5:48-63 (1998)

2. Gottlieb et al Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nature Medicine 1:442-447, (1995)