Biologic Therapy for Psoriasis: Title and subTitle BreakThe New Therapeutic Frontier FREE

AS KNOWLEDGE of the immunopathogenesis of psoriasis has grown over the past decade, there has been a significant effort to find a more specific therapy for this disease with fewer adverse outcomes. The standard systemic therapy for psoriasis has consisted of relatively nonspecific treatment modalities with adverse effects that involve multiple organ systems. More recently, biotechnology, using genetic engineering techniques, has created a real possibility for efficacious and safe psoriasis therapy. Recombinant proteins, the outcome of recent biotechnology initiatives, function as agents that comprise biologic therapy.

Biologic agents are proteins that possess pharmacologic activity and can be extracted from animal tissue or, much more commonly, synthesized in large quantities through recombinant DNA techniques. Outside of dermatology, biologic therapies have been in use for decades. The most commonly used biologic therapy has been insulin, a protein first extracted from pigs and now made as recombinant human insulin. Other areas in which biologic therapy has been in common use include hematopoietic support (eg, erythropoietin, granulocyte, and platelet growth factors)¹ and in solid organ transplantation,² in which monoclonal antibodies designed to inhibit rejection have been used.³ More recently, immune-mediated diseases analogous to psoriasis, including Crohn disease and rheumatoid arthritis,^{4 - 5} have been treated with biologic agents designed to inhibit immune responses that are central to their pathological condition. As a consequence of successful biologic therapy for immune-mediated diseases, psoriasis has become a primary target for biologic therapy in dermatology.

Biologic molecules can be designed to either mimic the actions of normal human proteins or to interact with circulating proteins or cellular receptors. There are 3 distinct types of molecules that have been studied for use in psoriasis: (1) recombinant human cytokines or growth factors, (2) monoclonal antibodies, and (3) fusion proteins. All of these agents can be manufactured using recombinant DNA technology. After the molecule is made, complementary DNA encoding the protein is transfected into a prokaryotic or eukaryotic cell line that secretes the protein drug.⁶ The appropriate protein can then be isolated and purified for use as a therapeutic agent.

Recombinant human proteins are molecules that are either exact replicas of normal human proteins or fragments thereof that have specific physiological effects. These drugs function by interacting with normal cellular receptors to induce their effects.^{6 - 8} These effects are often limited to normal physiological function of the protein as is the case with recombinant insulin and type 1 diabetes mellitus. However, when these drugs are given in supraphysiological doses, they may have effects that are not readily predicted.

Monoclonal antibodies are proteins that specifically bind to proteins on cell surfaces in the circulation or tissue. This interaction alters activity of the target protein. Most often, the monoclonal antibody inhibits effects of the protein, thus altering the course of disease. Because the targets of monoclonal antibody therapy are human proteins, these molecules must originally be made in other species, usually in mice. Initial monoclonal antibody therapies were simply these murine antibodies. However, patients given these drugs frequently developed immune responses to the foreign protein, making them inappropriate therapy for nonlethal diseases. More recent monoclonal antibody therapies have been humanized.⁹ In other words, the specific binding site from a murine antibody is attached (through recombinant DNA technology) to the Fc portion of human immunoglobulin.^{10 - 12} This process results in a new protein drug similar to a normal human antibody, significantly reducing immune response to the agent and prolonging both its half-life and activity.

Abgenix Inc, Fremont, Calif, has developed a transgenic mouse that can produce fully human antibodies directed against human proteins.¹³ The mouse was designed by first knocking out the DNA that encodes mouse immunoglobulin. The human immunoglobulin locus was then substituted for the mouse DNA to create a mouse that produces only human antibodies. Since these mice are not developmentally exposed to human proteins, they will produce fully human antibodies when presented with a foreign, human protein. Because these antibodies have almost no foreign elements, this process could produce biologic proteins that are more completely accepted by the patient's immune system.

The final designs used in biologic therapy include fusion proteins. Fusion proteins are molecules that combine sections of different proteins. There are 2 distinct types of fusion proteins. The first combines a human protein with a toxin.¹⁴ Human protein binds to a cell and causes the entire complex to be internalized. Once inside the cell, toxin is released, thereby killing the cell.¹⁵ The other design is similar to humanized monoclonal antibodies. However, instead of using a mouse antibody binding site to confer specificity, these agents use human receptors for proteins.¹¹ Receptors are then bound to the Fc portion of human immunoglobulin in a similar manner as humanized monoclonal antibodies.

As with any new therapy, the adverse effect profile of biologic therapy will be established after years of experience. However, the current prevailing attitude is that the greatest advantage of biologic therapy may be its potentially greater safety profile. Because biologic agents are specific to which cell types they bind, multiorgan adverse effect profiles (as seen with traditional antipsoriatic drugs, such as retinoids, methotrexate, and macrolides) should not present as an issue. In the published literature on solid organ transplants, along with early studies with biologic agents in psoriasis, the liver and kidneys seem not to be adversely affected.^{3 ,16 - 17} Likewise, because these agents are metabolized as endogenous proteins and antibodies, clinically significant drug interactions are unlikely.

There are 2 areas of concern with biologic therapy that should be addressed. Cytokine release syndrome has been a long-time concern since early immunotherapy for organ transplants with OKT3, which is a nonhumanized monoclonal antibody that binds to CD3, the initial signaling step in the T-cell receptor. After a transient activation by binding CD3, OKT3 nonselectively depletes all T cells.¹⁸ This often causes fever, hypotension, headache, skin rash, and abdominal symptoms.¹⁹ Immunologically, cytokine release syndrome is characterized by the rapid release of cytokine tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ).^{20 - 21} At times, cytokine release syndrome due to OKT3 may be life threatening. Importantly, cytokine release syndrome seems to be a specific manifestation of agents that bind CD3 and should not be a concern for biologic drugs directed against other proteins.

Immunosuppression is an additional significant concern for any drug used to treat immune-mediated diseases such as psoriasis. Systemic therapies for psoriasis including cyclosporine, methotrexate, and psoralen –UV-A, as well as other drugs commonly used in dermatology (eg, corticosteroids), are all potent immunosuppressive agents. While there is no doubt that the efficacy of biologic therapies is related to their ability to inhibit specific functions within the immune system, early studies have suggested that the risk of infection with several biologic agents may not be significantly greater than placebo.¹⁶ Current evidence indicates that the risk of immunosuppression from biologic agents used in psoriasis is unlikely to be worse than commonly used dermatological drugs and may more likely be a significant improvement in immunosuppression risk.

It is currently understood that psoriasis is driven by activated memory T cells.^{22 - 23} There are 2 populations of these T cells: dermal cells (which are primarily CD4⁺ cells) and epidermal T cells (which are predominantly CD8⁺ cells). CD4⁺ T cells as well as many CD8⁺ cells migrate preferentially to the skin from the circulation via cutaneous lymphocyte antigen. Some CD8⁺ cells in the epidermis may be resident to the skin. For these T cells to induce psoriatic plaques, they must be activated by antigen-presenting cells (APCs). This process of activation requires 2 signals between the T cell and the APC (Figure 1). Signal 1 requires recognition of a specific antigen processed and presented by the APC and recognized by the T-cell receptor of the interacting T cell. At present, however, no specific antigens have been recognized in psoriasis. If this recognition is accomplished, the T cell must receive a second, costimulatory signal from the APC. There are a number of interactions that participate in this costimulatory apparatus, some of which are listed in Table 1. This activation process has been a target for many biologic drugs.

T cells in psoriatic plaques are mainly effector T cells that have been previously activated, which is demonstrated by their expression of the memory T-cell marker CD45RO. The effector function of many of the T cells is the secretion of cytokines. The specific cytokine pattern produced in psoriasis is the T1 type,²⁴ primarily with interleukin (IL) 2 and IFN-γ.²⁵ CD4⁺ cells may activate or provide help to the epidermal T cells through their cytokine secretion and are necessary for the development and maintenance of psoriasis. Likewise, the epidermal changes in psoriasis are likely a function of the cytokines produced by epidermal T cells or cell-cell interactions that have not been fully elucidated. These factors produce keratinocyte and vascular changes, including increased proliferation and decreased cellular maturation that is clinically recognized as psoriasis. Keratinocytes and other local cells including dendritic cells and monocytes produce other cytokines that magnify these effects, including TNF-α^{26 - 27} and IL-8.^{28 - 29} Many therapies have sought to alter these cytokine responses to treat psoriatic plaques.

The immunopathological features of psoriasis provide the basis for a conceptual model that incorporates the mechanism of action and target for rationally designed biologic therapy. There are 4 strategies within this model that clarify the mechanism of action for the various biologic agents (Figure 2). These strategies include (1) reduction of the pathogenic T cells, (2) inhibition of T-cell activation, (3) immune deviation, and (4) blocking the activity of inflammatory cytokines. Some biologic agents may have multiple mechanisms of action.

An obvious approach to treating psoriasis would be to reduce the numbers of T cells that are inducing the disease. Ideally, this strategy would work best when the cells most responsible for psoriasis (CD45RO⁺ T cells³⁰ in the skin producing T_H1 cytokines) could be targeted without altering other immunological processes. This strategy would have the potential advantage of inducing longer lasting remissions because it is likely that some of the T cells, particularly the epidermal cells, may take time to repopulate the skin. This mechanism may explain why psoralen–UV-A therapy induces relatively long remissions by inducing apoptosis in epidermal T cells.³¹

Because pathogenic cells in psoriasis are activated T cells, it is reasonable to believe that if T cells are not able to become activated, they cannot induce psoriasis. T-cell activation requires interactions between an APC and T cell.²² These are currently referred to as signal 1 and signal 2. Signal 1 is the well-known interaction in which the APC presents a specific antigen to the T cell in the context of the major histocompatibility complex and an association with CD4 or CD8 on the T cell. The T cell recognizes this antigen through the T-cell receptor and signals through CD3. Signal 2 is termed costimulation and is accomplished through the multiple APC–T-cell interactions listed in Table 1.^{32 - 33} Biologic agents are therefore designed to interact with either signal 1 or signal 2 and may block the ability of the T cell to become activated and, thus, propagate psoriasis. Activation and migration are coupled in this model because many of the cell-cell interactions are mediated via the same receptors.

As mentioned above, the activated T cells in psoriatic plaques produce cytokines of the T_H1 phenotype. These cytokines include IL-2 and IFN-γ and are vital to the expression of psoriasis. It is well known that cytokines produced by T_H2 T cells, including IL-4, IL-10, and IL-11,³⁴ tend to reduce the activity of T_H1 cells.^{35 - 36} Immune deviation is induced by the "deviation" of a T_H1 immune response toward a greater T_H2-type response through the involvement of these T_H2-type cytokines.³⁷ Therefore, it may be possible to decrease the activity of psoriasis by the administration of T_H2 cytokines in an effort to inhibit the appropriate T_H1 cytokine production.

Many of the phenotypic and pathological changes in psoriasis are related to the effects of cytokines secreted by T cells, dendritic cells and monocytes, and local keratinocytes. These cytokines likely induce keratinocyte changes, induce angiogenesis, and increase the already active immune response. This strategy relies on the ability of biologic agents to bind to secreted cytokines and block their ability to contribute to psoriasis.³⁸ Therefore, a biologic medication that can bind to TNF-α or IL-8³⁹ might be able to decrease the severity of psoriasis by eliminating the activity of these cytokines and all of their effects on the various cell types involved in psoriasis.

Some of the biologic agents being considered for the treatment of psoriasis are listed in the following tabulation (drugs are listed in the order of the phase of development).

*Drug was approved by the Food and Drug Association (FDA) for an indication other than psoriasis.

Considerably more biologic molecules will likely be developed for use in psoriasis as biotechnology progresses. Selected biologic agents, classified by the strategy they represent and in the context of available published data, are described to illustrate the concepts of biologic therapy for psoriasis. All of the agents discussed in these strategic mechanisms are in various stages of clinical development as potential agents in the treatment of psoriasis.

Alefacept (LFA-3TIP) (Amevive; Biogen Pharmaceuticals, Cambridge, Mass) is a fusion protein combining the binding site of lymphocyte function–associated antigen-3 (LFA-3) with the Fc portion of human IgG. This medication binds specifically to T cells expressing CD2, the natural ligand of LFA-3. CD2 is expressed maximally in T cells that have been activated and express CD45RO, a sign of a memory T-cell phenotype. These are the specific group of cells that are most important in the propagation of psoriasis. When this drug is given therapeutically, the number of these cells circulating in the blood is reduced.³⁰

Published results with this medication have shown efficacy with an excellent safety profile. Results of phase 2 trials showed a statistically significant reduction in psoriasis from baseline measured by the Psoriasis Activity and Severity Index (PASI).⁴⁰ Of the patients, 60% showed more than 50% improvement, and in one dose range, one third of the patients had at least 75% improvement. It was also noted that of the patients who "cleared," the mean duration of the remission was 8 months. This likely reflects slow repopulation of the skin with native T cells. There was also no increased incidence of infection and no incidence of cytokine release syndrome. In a retreatment study, the response was similar, with one half of the patients achieving more than 50% improvement, and one fifth improving by at least 75%.⁴¹

Denileukin diftitox (DAB₃₈₆IL2) (Ontak; Ligand Pharmaceuticals, San Diego, Calif) is one of the first biologic agents used for the treatment of psoriasis.¹⁴ This medication is a fusion protein that combines IL-2 with a subunit of diphtheria toxin. Because IL-2 is internalized exclusively in activated T cells, the toxin will only eliminate cells that are active when the drug is given. Thus, denileukin diftitox should selectively eliminate activated T cells and reduce the activity of psoriasis.¹⁵ This drug is approved by the FDA for the treatment of cutaneous T-cell lymphoma.^{42 - 44}

Published trials with denileukin diftitox for psoriasis are limited. One trial of low doses of this medication demonstrated clinical responses in 8 of 10 patients.¹⁴ More importantly, there was a marked reduction in the inflammatory infiltrate in patients treated with denileukin diftitox, along with correction of many of the immunohistochemical changes associated with psoriasis. In an early phase 2 clinical trial, all 6 patients achieved greater than 30% response, and 2 patients improved more than 50% from baseline PASI.⁴⁵

Efalizumab (anti-CD11a) (Genentech and XOMA; South San Francisco, Calif) is a humanized monoclonal antibody aimed at binding CD11a on T cells. CD11a is a component of LFA-1, that, when bound to intracellular adhesion molecule-1 (ICAM-1) on APCs, provides an important costimulatory signal. Moreover, the LFA-1–ICAM-1 interaction is also vital to T-cell adhesion to endothelial cells and is necessary for T-cell migration into inflamed tissues, including skin. Thus, efalizumab may block both T-cell activation and cellular migration, potential areas of therapeutic benefit in psoriasis.¹⁶

Clinical studies with efalizumab have shown efficacy with few adverse effects. In the optimal dose group in phase 2 trials, 62% of patients showed at least a 50% decrease in the PASI, while 30% had a 75% improvement.⁴⁶ Adverse effects consisted of mild headache, fever, and chills that generally subsided with continued use of the drug. Importantly, none of these effects was serious enough for a patient to choose to stop using the medication. In these phase 2 trials, there were no significant infectious complications that might suggest an immunosuppressive effect.⁴⁷

Among the most important interactions for T-cell stimulation is the costimulatory signal between the APCs CD80 (B7-1) and CD28 on the T cell. The anti-CD80 molecule (IDEC-114) blocks this interaction through a humanized monoclonal antibody directed against CD80. Not only should this block T-cell stimulation, but without binding of CD28 through B7, a T cell may become energized and not be able to respond to stimuli for some time.⁴⁸ Clinical data for this drug are just beginning to emerge. In a phase 1 trial with a single-dose regimen of IDEC-114, there was clinical efficacy with mild adverse effects such as headache, fever, chills, and upper respiratory tract infections.⁴⁹ Of the patients, 40% achieved at least 50% reduction in PASI after receiving 4 biweekly doses.⁵⁰

Daclizumab (anti-CD25) (Zenapax; Protein Design Labs, Fremont, Calif) is a humanized monoclonal antibody that has been FDA approved for the prevention of acute renal transplant rejection.⁵¹ Daclizumab binds to the CD25 subunit of the IL-2 receptor on T cells, thus blocking T-cell proliferation and responses to an important T-cell growth factor, IL-2. Because CD25 is expressed in high levels in lesions of psoriasis, the inhibition of IL-2 binding could play a role in suppressing psoriasis. One phase 2 trial of daclizumab in psoriasis has been published and demonstrates a mean reduction in PASI of 30% and a 44.8% decrease in IL-2 expression. Improvement was also noted to continue up to 4 weeks after the last dose.⁵²

Siplizumab (Medi-507; Medimmune, Gaithersburg, Md) is a humanized monoclonal antibody directed against CD2 expressed in high concentrations on activated T cells. It is designed to block costimulation by inhibiting the CD2–LFA-3 interaction. However, similar to alefacept, peripheral lymphocyte counts are diminished in patients treated in early phase 1/2 studies with siplizumab, suggesting that this drug may work through strategy 1.⁵³ Though only early phase 1/2 studies have been completed, some patients treated with siplizumab have achieved significant responses to therapy.⁵³

Instead of trying to block the immunological process, drugs that use strategy 3 push the immune response in a direction that will help control the disease pathological course. In psoriasis, immune deviation suggests that inhibiting T_H1-type T cells that drive the disease by the addition of T_H2-type cytokines will improve psoriasis.⁵⁴ Oprelvekin (rhIL-11) (Neumega; Genetics Institute, Cambridge, Mass), a recombinant form of human IL-11, is an FDA-approved therapy for the treatment of chemotherapy-induced thrombocytopenia. It has been determined that IL-11 may also act to induce immune deviation in T_H1-mediated immune diseases such as psoriasis.⁵⁵ In early trials with subcutaneously injected oprelvekin, there has been some histological evidence of decreased T_H1 gene expression and cytokine release. At present, clinical efficacy has not been reported.

Interleukin 10 is an important T_H2-type cytokine that is extremely important in the down-regulation of ongoing T_H1 immune responses.⁵⁶ Recombinant human IL-10 (Tenovil; Schering, Berlin, Germany) is a recombinant cytokine that can be given in subcutaneous injections. Early phase 1/2 trials have shown that subcutaneous injections of recombinant human IL-10 three times a week decreased the level of T_H1 cytokines and subsequently improved psoriasis. There was a mean reduction of 55% in the PASI to patients receiving the molecule, with the immunological changes persisting for several months after the last dose. In general, the research subjects tolerated the medication with few and nonserious adverse effects.^{57 - 58}

Tumor necrosis factor α is central cytokine to both the persistence of the immune response that drives psoriasis and the aberrant keratinocyte response.²⁶ The anti–TNF-α agents etanercept (Embrel; Immunex Corporation, Seattle, Wash) and infliximab (Remicade, Centocor, Malvern, Pa) bind and inhibit the activity of TNF-α through slightly different mechanisms. Etanercept is a fusion protein using the extracellular domain of the TNF-α receptor given twice a week as a subcutaneous injection.⁵⁹ Infliximab is a monoclonal antibody derived from mouse directed against human TNF-α and is given as an intravenous infusion at intervals dependent on the state of the disease.⁶⁰ Both of these molecules are FDA approved for the treatment of rheumatoid arthritis, while etanercept is approved for psoriatic arthritis and infliximab is approved for Crohn disease.⁵ There is very early evidence that both these agents will have efficacy in psoriasis. In the psoriatic arthritis trials with etanercept, there was a noticeable response in several patients' cutaneous psoriasis. Mean improvement in PASI was 46%, with 12 of 30 patients achieving at least a 50% improvement. Likewise, a number of case reports support a response of cutaneous psoriasis to infliximab.⁶¹ One recent, small, randomized, controlled study demonstrated a greater than 80% response rate (more than a 75% improvement in PASI) with minimal adverse effects.⁶²

ABX-IL8 (Abgenix Inc, Fremont, Calif) is a fully human monoclonal antibody designed to bind free IL-8 and deactivate it in the skin. A chemokine that is secreted in large amounts by keratinocytes and immune cells in psoriatic plaques, IL-8 is important for the attraction of lymphocytes and neutrophils into the skin and may play a key role in the vascular responses found in psoriasis.^{28 - 29} In early trials, there has been some demonstrated clinical response to this molecule, with a phase 1 dose escalation approach showing increased benefit with larger doses. In a phase 2 trial, about 1 in 5 patients in the group receiving 3 mg/kg every 3 weeks had a 75% improvement in their PASI. Additionally, there were histological responses suggesting improvement in psoriasis.⁶³ Importantly, as would be expected from a fully human molecule, the drug has been well tolerated, and doses may be escalated to demonstrate increased efficacy.¹³

Because IFN-γ is central to both the T_H1 cytokine profile in psoriasis and keratinocyte hyperproliferation in this disease, it should be a prime target for anticytokine therapy. SMART anti–IFN-γ (Huzaf; Protein Design Labs, Fremont, Calif), a humanized monoclonal antibody, binds and inactivates IFN-γ and could be an excellent targeted molecule for this strategy. Early phase 1/2 studies are being performed at this time.

Systemic treatment of psoriasis has been limited by the safety of many of the drugs that are effective in clearing this disease. Recent advances in biotechnology have led to a proliferation of new strategies for treating this disease with agents that can be designed to specifically act on the immune system, which may prove to be much safer than traditional therapies. These therapies hold promise for revolutionizing the therapy for psoriasis for those patients whose quality of life is reduced by this chronic, debilitating disease.

Accepted for publication December 12, 2001.

Corresponding author and reprints: Kenneth B. Gordon, MD, Department of Dermatology, Feinberg School of Medicine, 675 N St Clair St, Suite 19-150, Chicago, IL 60611 (e-mail: kbg704@northwestern.edu).