Interleukin-12, interleukin-23, and psoriasis: Current prospects

Interleukin-12, interleukin-23, and psoriasis: Current prospects Dorothea C. Torti, MD,a,b and Steven R. Feldman, MD, PhDb,c,d Lebanon, New Hampshire, and Winston-Salem, North Carolina The clinical phenotype of psoriasis results from infiltration of T cells in the skin and elaboration of inflammatory cytokines. Interleukin (IL)-12 and, more recently, IL-23 have been implicated in the pathogenesis of psoriatic lesions. New therapies, including a monoclonal antibody against a subunit shared by IL-12 and IL-23, have been developed to treat psoriasis. Our purpose was to review the literature on IL-12 and IL-23 as a basis for understanding the use of anti-IL-12/IL-23 therapy for psoriasis. A review of English-language articles was performed using PubMed to identify articles pertaining to IL-12, IL-23, and psoriasis. IL-12 and IL-23 share a common subunit (p40) and have a distinct subunit (p35 and p19, respectively). Transgenic mice that overexpress IL-12 p40 develop inflammatory skin lesions. Both IL-12 knockout mice, which are deficient in IL-12, and human beings with a genetic IL-12 deficiency show increased susceptibility to intracellular pathogens and defective delayed-type hypersensitivity responses. These genetic deficiency states suggest the potential for adverse side effects from clinical administration of anti IL-12 p40 therapy. IL-12 p40 antibody was well tolerated in a phase I clinical trial with few adverse events and substantial improvements in psoriasis in most individuals. There was dose-dependent efficacy and substantial improvement in a larger cohort of patients in a phase II clinical trial. Larger and longer trials of anti IL-12/IL-23 therapies are needed to assess their clinical use and potential for infection and other adverse events. ( J Am Acad Dermatol 2007;57:1059-68.)

T

he pathophysiology of psoriasis is immunologically mediated: the clinical phenotype results from infiltration of T cells in the skin and elaboration of inflammatory cytokines by immune cells, endothelial cells, and keratinocytes. Interleukin (IL)-12 and, more recently, IL-23 have been implicated in the pathogenesis of psoriatic lesions. New therapies, including monoclonal antibodies against a subunit shared by IL-12 and IL-23, have recently been developed that target this arm of the psoriatic immune response. IL-12, which was first discovered in 1989, plays an important role in the cell-mediated immune response, which is responsible for defense against

From Dartmouth Medical School, Lebanona; and Center for Dermatology Research, Departments of Dermatology,b Pathology,c and Public Health Sciences,d Wake Forest University School of Medicine, Winston-Salem. Funding sources: The Center for Dermatology Research is funded by a grant from Galderma Laboratories LP. Conflicts of interest: None declared. Reprints not available from the authors. Correspondence to: Steven R. Feldman, MD, PhD, Department of Dermatology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1071. E-mail: [email protected]. Published online August 16, 2007. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.07.016

Abbreviations used: IFN: IL: mRNA: Th1:

interferon interleukin messenger RNA T-helper 1

certain intracellular bacterial and parasitic infections. IL-12 is a heterodimeric cytokine composed of a covalently linked heavy chain (IL-12p40) and light chain (IL-12p35) (Fig 1). The receptor comprises two transmembrane subunits, IL-12Rß1 and IL-12Rß2.1 IL-12 is produced by dendritic cells and macrophages (Fig 2). It induces differentiation of CD4 naı¨ve T cells to T-helper 1 (Th1) cell and activates natural killer cells.2 These Th1 cells and activated natural killer cells produce interferon (IFN)-g, and other type1 cytokines, such as IL-2 and tumor necrosis factor-ß. IFN-g plays a critical role in the pathogenesis of psoriasis by facilitating T-cell infiltration into epidermis and inducing keratinocyte proliferation.3 IL-23 is a more recently described cytokine that is closely related to IL-12 in structure. Both cytokines are heterodimers that share the common subunit IL-12p40 (IL-12p40 1 IL-23p19 = IL-23; IL-12p40 1 IL-12p35 = IL-12) (Fig 1). Further, the receptor for IL23 shares the common subunit, IL-12Rß1, to which the common IL-12p40 subunit binds. IL-23 was 1059

1060 Torti and Feldman

J AM ACAD DERMATOL DECEMBER 2007

Fig 1. Interleukin (IL)-12 and IL-23 cytokines and their receptors: economy of structures. Heterodimeric cytokines IL-12 and IL-23 contain nonshared subunits, p35 (IL-12) and p19 (IL-23), as well as a shared common subunit, p40. Receptors also share common subunit, IL-12Rb1, and contain nonshared subunits (IL-12Rb2 and IL-23R).

originally thought to function similarly to IL-12. However, recent studies have revealed that the dominant role of IL-23 involves the stimulation of a subset of CD41 T-cells (sometimes called IL-17 T cells) to produce IL-174 (Fig 2). IL-17 is a critical component in the establishment and perpetuation of autoimmune inflammation.1 IL-17 induces the production of proinflammatory cytokines, predominately by endothelial cells and macrophages. It is believed that IL-17 and IFN-g synergize to increase production of proinflammatory cytokines by keratinocytes, which is likely important for the development of inflammation in the skin seen in psoriasis.5 The purpose of this study was to review the literature on IL-12 and IL-23 as a basis for understanding the use of anti-IL-12/IL-23 therapy for psoriasis.

METHODS A PubMed search was performed to identify articles with the key words ‘‘IL-12’’ or ‘‘IL-23’’ and ‘‘psoriasis.’’ Relevant articles were selected. In addition, broader searches for IL-12, IL-23, IL-17, and deficiencies were performed to identify other conditions involved and basic mechanisms. A Google search was performed to identify updates on clinical trials involving IL-12 and IL-23 targets. Reference lists from recent articles were used as a secondary method to trace the completeness of the literature reviewed.

IL-12 and IL-23 in the pathogenesis of psoriasis: Evidence from mouse models Murine models have helped elucidate the role of IL-12 and IL-23 in psoriasis (Table I). One model involves transfer of CD41CD45Rbhigh T cells into scid/scid mice.3 In this model, IL-12 induced pathogenic T cells resulting in psoriasiform lesions. Further, when anti-IL-12 p40 antibody was administered to murine psoriasis models, psoriatic lesions resolved.3 More indirect evidence for the involvement of IL-12 and IL-23 in inflammatory diseases of the skin has come from transgenic mice that overexpress IL-12p40.6,7 Transgenic mice that overexpress IL-12p40 develop an eczematous skin disease, characterized by hyperkeratosis, focal epidermal spongiosis, and an inflammatory infiltrate in keratinocytes.6 Because IL-12p40 is a shared subunit of IL-12 and IL-23, either or both cytokines could potentially be involved in the skin lesions that develop in these mice. However, p40 transgenic mice constitutively produce IL-23, but not IL-12 in basal keratinocytes; further, injections of recombinant IL-23 in nontransgenic littermates resulted in an inflammatory skin disease similar to that of p40 transgenic mice.7 Collectively, these studies on transgenic p40 mice indicate that IL-23 may be particularly important for the involvement of keratinocytes in inflammation, and led to the suggestion that IL-23 may be an important target in psoriasis.7

J AM ACAD DERMATOL

Torti and Feldman 1061

VOLUME 57, NUMBER 6

Fig 2. Pathways engaged by interleukin (IL)-12 and IL-23. NK, Natural killer; TH1, T-helper 1.

IL-12 and IL-23 in the pathogenesis of psoriasis: Evidence from human psoriatic lesions Studies of human psoriatic lesions also support a role for IL-12 and IL-23 in psoriasis (Table I). Several human studies have demonstrated increased levels of IL12p40 and IFN-g messenger RNA (mRNA) in psoriatic lesions.8-11 Lesional and nonlesional skin was taken from 30 patients with different clinical types of psoriasis including psoriasis vulgaris, erythrodermic psoriasis, generalized pustular psoriasis, guttate psoriasis, palmoplantar psoriasis, and localized palmoplantar pustular psoriasis, in addition to 10 healthy control subjects. The mean levels of IL-12p40 and IFN-g mRNA were significantly higher in lesional skin than nonlesional and control skin.10 No significant differences in levels were observed among different clinical types of psoriasis. Based on the lack of correlation between Psoriasis Area and Severity Index score or plaque thickness and IL12p40 levels in skin, it was suggested that IL-12p40 is implicated in the development rather than the severity of psoriasis.10

The relationship between IL-12 and the development but not severity of psoriasis is further supported by a study of levels of a number of type-1 proinflammatory cytokine genes, including IFN-g and IL12p40, in 16 patients with large plaque and small plaque psoriasis and healthy control subjects.9 Increased gene expression of the majority of these type-1 proinflammatory cytokines was similar in both small and large plaque psoriasis in this study of 16 patients. Because small and large plaque psoriasis may represent opposite ends of the spectrum of clinical severity of plaque psoriasis, similarities between genetic ‘‘fingerprints’’ of large and small plaque psoriasis, including IL-12p40, demonstrate that disease severity/extent must be regulated by other factors.9 Increased levels of IL-12p40 protein are present in psoriatic lesions. IL-12 subunit mRNA and protein was assessed in lesional, nonlesional, and normalappearing skin. An 11-fold increase of IL-12p40 mRNA was found in lesional skin of 12 patients with psoriasis compared with nonlesional and normal-appearing skin. On the other hand, IL-12p35

1062 Torti and Feldman

J AM ACAD DERMATOL DECEMBER 2007

Table I. Evidence for a role of interleukin12/interleukin-23 in psoriasis Species

Evidence

Mouse Experimentally induced psoriatic lesions abolished by anti-IL-12 antibody Overexpression of IL-12 p40 results in inflammatory skin disease Injection of IL-23 results in inflammatory skin disease Human IL-12 p40 mRNA and protein is increased in psoriatic lesions IL-23 p19 mRNA and protein is increased in psoriatic lesions IL-12 and IL-23 decrease after psoriasis therapy A genetic polymorphism in IL-12 p40 is linked to increased susceptibility to psoriasis

Reference

3

6 7 8-12 12,13 14,16-19, 65 25

IL, Interleukin; mRNA, messenger RNA.

mRNA was expressed equally in lesional, nonlesional, and normal-appearing skin.11 Similarly, a study of 18 individuals revealed IL-12p40 mRNA expression in psoriatic lesions but not in normal-appearing skin, whereas IL-12 p35 mRNA was expressed similarly in both psoriatic lesions and normal-appearing skin.8 The antibodies used in a number of studies did not distinguish between IL-12 and IL-23 because they were raised to the shared subunit of IL-12 and IL-23. However, the lack of increase in IL-12p35 mRNA (the subunit distinctive of IL-12) suggested a role for IL-23 in the pathogenesis of psoriasis. More recent studies have used specific antibodies or evaluation of mRNA to discriminate between IL-12 and IL-23. For example, in 22 patients, an 11.6-fold increase in IL-12p40 mRNA was found in psoriatic plaques without an increase in IL-12p35 mRNA (mRNA for the subunit distinctive of IL-12), but was associated with a 22.3fold increase in IL-23p19 mRNA (mRNA for the subunit distinctive of IL-23). Further, mRNA for p19 and p40 (the IL-23 subunits) was up-regulated in monocytes and monocyte-derived dendritic cells; this response was sustained for longer periods than for IL-12p35. Positive immunohistochemical staining for p40 (in light of lack of p35 up-regulation in lesions) suggested that IL-23 is likely actively synthesized in psoriatic lesions and infiltrating mononuclear leukocytes are a likely source of this IL-23. In aggregate, these data suggest a dominant role for IL-23 rather than IL-12 in psoriasis.12 A recent study further expands on the importance of IL-23 in the pathogenesis of psoriasis.13 In this study, immunohistochemistry showed increased

IL-23p19 in lesional skin compared with nonlesional and normal-appearing skin. There was diffuse and very strong staining for p19 in the epidermis that was significantly higher than in nonlesional and normalappearing skin. This suggests that keratinocytes are also capable of synthesizing and secreting IL-23 in sufficient quantities to amplify IFN-g production by memory T cells. Keratinocytes may contribute to cutaneous inflammation and have a role in the enhancement of type-1 immune responses in the skin via IL-23 production.13 Although reports consistently demonstrate striking evidence that IL-12p40 is up-regulated in psoriatic skin lesions, whether IL-12 levels are increased in serum is controversial. For example, in a study of 27 patients and 30 healthy control subjects serum levels of IL-12 in patients with psoriasis and healthy control subjects were similar.14 However, in a serologic study of 17 individuals using an enzyme-linked immunosorbent assay technique to evaluate serum cytokine profile and correlation with disease, it was reported that serum IL-12 is decreased in patients with psoriasis.15 However, serum IFN-g was significantly elevated and correlated with disease severity.15 Further evidence for a role for IL-12 and IL-23 in psoriasis is based on an examination of these cytokines before and after psoriasis treatment. Narrowband ultraviolet therapy,16 cyclosporine,14,17 etanercept,18 and alefacept19 all decrease IL-12 and IL-23 expression. Genetic support for the role of IL-12 and IL-23 in psoriasis Early work on polymorphic markers in psoriasis has identified variants in genes coding for cytokines that might confer susceptibility to psoriasis. For example, polymorphisms in the gene for the antiinflammatory cytokine IL-10 are associated with familial psoriasis.20 Genetic variants that alter the balance of cytokine production in favor of proinflammatory cytokines such as IL-10 and tumor necrosis factor-a have also been associated with psoriasis: tumor necrosis factor-a and IL-10 proinflammatory genes were associated with early and late-onset psoriasis, respectively.21 Psoriasis susceptibility is also associated with variant loci on chromosome 1922 and chromosome 17.23 Few studies have scrutinized the IL-12 or IL-23 gene for genetic rearrangement or polymorphic variants that might explain susceptibility to psoriasis and other inflammatory diseases. For psoriasis, genetic changes that would be expected to induce IL-12 (or other type-1 cytokines such as IFN-g or IL-2 that are secreted by activated Th1 helper cells) might identify individuals at high risk of psoriasis

J AM ACAD DERMATOL

Torti and Feldman 1063

VOLUME 57, NUMBER 6

development or progression. Promoter mutations that induce higher or constitutive gene expression, or rearrangements of chromosomes that might juxtapose the IL-12 coding region with a strong promoter, are the theoretic scenarios that might be anticipated to affect genetic susceptibility. The constitutively expressed IL-12p35 subunit and the inducible p40 subunit are the products of different genes. The p35 subunit is located on chromosome 3p and the p40 subunit on 5q. In asthma, an IL-12 promoter polymorphism was associated with IL-12 production and IL-12B (the gene encoding IL-12p40) mRNA expression. This polymorphic region was, therefore, examined in patients with psoriasis. However, Litjens et al24 were unable to show any differences between the promoter region implicated in asthma and the presence or type (early vs late onset) of psoriasis. However, a polymorphism in the 3’ untranslated region of the IL-12p40 subunit gene was associated with susceptibility to psoriasis: the A allele of the 3’-UTR SNP was increased in psoriasis (and decreased in atopic dermatitis).25 No reports of investigations of IL-23 genetic variants have been reported, although the p40 subunit is shared between IL-12 and IL-23 proteins. Insights from IL-12/IL-23 deficiency states in murine models IL-12 knockout mice and human genetic deficiency states of IL-12 and IL-23 may provide insight into potential adverse side effects that could result from clinical administration of therapies aimed at reducing IL-12 and IL-23. In particular, reports of heightened susceptibility to bacterial, parasitic, fungal, viral, and inflammatory insults in IL-12 and/or IL-23 knockout mice suggest that blockade of IL-12/IL-23 function through administration of antibodies to IL-12p40 may have the potential to lower patient resistance to infection (Table II). Several independent studies have shown that mice with deletions of IL-12/IL-23 demonstrate reduced resistance to mycobacteria and other intracellular bacteria, and Salmonella. These results are of particular interest, because human beings with genetic deficiencies in p40 show overlapping sensitivities to these infectious agents (see below).

assessed. Wildtype mice survived the infection. In contrast, all p35e/e mice had succumbed by 20 weeks postinfection, and no p35e/ep40e/e mice survived beyond 10 weeks. Sensitivity in the p35e/ep40e/e mice was linked to impaired responses by antigenspecific Th1 cells and cytotoxic T cells, and by impaired delayed-type hypersensitivity responses. These responses could be partially restored by administration of recombinant IL-12 p40 protein, implying an important protective role of IL-12 p40 in mycobacterial infection. Another study similarly concluded that IL-12 was required to control growth of M tuberculosis, although in the absence of IL-12, IL-23 provided a moderate level of protection.27 These finds are congruent with earlier results demonstrating that administration of IL-12 enhances resistance of mice to M tuberculosis.28 Both p35e/e and p40e/e knockout mice are more susceptible to infection with S enteritidis than wildtype mice.29 The p40e/e knockout mice were particularly affected, with increased bacterial burden, decreased mature mononuclear granulomas, and increased liver necrosis. Sensitivity was correlated with decreased production of IFN-g.29 These results are concordant with experiments demonstrating that neutralization of IL-12 impairs the response to S typhimurium,30 and that exogenous administration of IL-12 enhances resistance of mice to S dublin.31 Infection with Francisella tularensis was used to assess the role of IL-12/IL-23 in the response to intracellular bacteria.32 Although mice lacking the p40 subunit survived infection, bacteria were never cleared, and a chronic infection ensued. In contrast, mice lacking the p35 protein survived large infectious doses of F tularensis. These results were interpreted to indicate a predominant role for the IL-12 p40 protein, likely as a component of IL-23, in the clearance of this intracellular bacterium. Other reports have documented enhanced sensitivity to several other bacteria in knockout mice, including Klebsiella pneumoniae33 and Citrobacter rodentium.34 In addition, neutralization of IL-12 decreases resistance to Listeria,35 and administration of IL-12 enhances resistance of mice to Listeria.36 IL-12 antibody also enhances sensitivity to group B streptococci.37

IL-12/IL-23 deficiency and bacterial infections in mice To evaluate a role for IL-12/IL-23 p40 subunit in protection from mycobacterial infection, the natural route of infection in human beings was modeled.26 Both single (p35e/e) and double (p35e/ep40e/e) knockout mice were infected by the pulmonary route with Mycobacterium tuberculosis and mortality

IL-12/IL-23 deficiency and parasitic infections in mice Toxoplasma gondii is an opportunistic pathogen in patients with T-cell deficiencies. Infection of mice with T gondii stimulates expression of IL-23 in peritoneal exudate cells. Mice lacking p35 or p40 were infected with T gondii (p40 knockout mice lack both IL-23 and IL-12, whereas p35 knockouts lack

1064 Torti and Feldman

J AM ACAD DERMATOL DECEMBER 2007

Table II. Interleukin-12/interleukin-23 deficiency enhances susceptibility to infectious agents in mice and human beings Agent class

Viral Bacterial

Mice

Human

Murine cytomegalovirus Murine AIDS caused by BM5def Mycobacterium bovis; M tuberculosis

Mycobacterium

Francisella tularensis Klebsiella pneumoniae Listeria monocytogenes Salmonella typhimurium; S dublin; S enteritidis

Salmonella

Group B streptococci Cryptococcus neoformans

Parasitic

Citrobacter rodentium Toxoplasma gondii Leishmania major

Fungal

Trypanosoma cruzi Cryptococcus neoformans

IL, Interleukin. *Knockout mice: p35

/

, p40

/

, p35

/

p40

/

, or p19

/

Experimental evidence

Reference

Enhanced sensitivity in knockout mice* IL-12 is protective Enhanced sensitivity in knockout mice; exogenous IL-12 transiently increases resistance to the infection Enhanced sensitivity in knockout mice Enhanced sensitivity in knockout mice IL-12 antibodies increase sensitivity; rIL-12 enhances resistance Enhanced sensitivity in knockout mice; IL-12 antibodies increase sensitivity; exogenous IL-12 is protective IL-12 antibodies increase sensitivity; exogenous IL-12 is protective Enhanced sensitivity in knockout mice; IL-12 antibodies increase sensitivity Enhanced sensitivity in knockout mice Enhanced sensitivity in knockout mice; IL-12 antibodies increase sensitivity Enhanced sensitivity in knockout mice; IL-12 antibodies increase sensitivity Enhanced sensitivity in knockout mice Enhanced sensitivity in knockout mice

53 48 26,28,30,66

32 33 35,36 28-31,66

37 54,55 34 38-40,67 41-44,46,68 69 55

demonstrate increased sensitivity to indicated agent.

only IL-12) and their response to infection compared with wildtype. Under the conditions of these experiments, there was 100% survival of wildtype mice after infection. In contrast, in p40e/e mice, 100% of the mice had succumbed by 20 days postinfection, indicating that in combination, IL12 and IL23 play a critical role in the response to T gondii. The p35e/e mice exhibited a sensitivity to T gondii that was intermediate between wildtype and p40e/e mice38; however, p19e/e mice were as resistant to T gondii as wildtype. The p35e/e p40e/e mice exhibited higher parasite burden than wildtype mice.39 Thus, IL-12 plays a primary role in resistance to T gondii, but IL23 can also contribute to resistance in the absence of IL-12.38 Neutralization of IL-12 accelerates mortality in mice infected with T gondii.40 IL-12 also plays a role in resistance to Leishmania major, an intracellular protozoan parasite. IL-12 antibody enhances sensitivity to Leishmania donovani.41-43 Although wildtype mice were resistant to infection, demonstrating small lesions that resolved spontaneously, both p35e/e and p40e/e mice exhibited large, progressing lesions.44 The p40e/e mice could be rescued by treatment with IL-12 during the first weeks of infection, although the response was not preserved after rechallenge.45,46 IL-12 (and/or

IL-23) is required not only to initiate Th1 cell development, but to maintain resistance to Leishmania major. IL-12/IL-23 deficiency and viral infections in mice IL-12 promotes immunity to several viruses in animal models, including herpes simplex virus, encephalomyelitis virus, vesicular stomatitis virus, and murine AIDS.47-52 These observations led to the examination of the responsive of IL-12-deficient mice to infection with murine cytomegalovirus.53 The p40e/e and p35e/e mice exhibited a sustained elevation in viral titer, and p35e/e mice showed reduced survival compared with wildtype mice after infection with murine cytomegalovirus (32% vs 97%, P \.02). IL-12/IL-23 deficiency and fungal infections in mice Cryptococcus neoformans is an opportunistic pathogen in immunocompromised patients. Longterm administration of IL-12 prevented death of mice chronically infected with Cryptococcus neoformans. Conversely, anti-IL-12 antibody enhanced sensitivity to Cryptococcus neoformans.54 Mice with deficiencies

J AM ACAD DERMATOL

Torti and Feldman 1065

VOLUME 57, NUMBER 6

in either the p35 (p35e/e) or p40 (p40e/e) subunits of IL-12 died significantly earlier than infected wildtype mice. The p40e/e mice were more severely affected than p35e/e, suggesting that IL-23 and IL-12 may play a role in Cryptococcus neoformans resistance.55 Insights from IL-12/IL-23 genetic alterations in human beings Linkages between the IL-12 axis and susceptibility to infection in human beings have also been reported. Although it is induction of IL-12 that would be expected to be associated with increased susceptibility to psoriasis, heritable mutations that functionally disrupt IL-12 production have a clinical phenotype, arguing for the importance of the balance between Th1 and T-helper 2 cytokines in health and disease. For example, familial susceptibility to mycobacterial disease (termed ‘‘mendelian susceptibility to mycobacterial disease’’) is associated with IL-12 (and other cytokine) mutations, and results in infection with low virulence nontuberculous mycobacterium.56 Deficiency of the receptor for IL12/IL-23 is associated exclusively with Salmonella infections,57 whereas mutations in IL-12 itself are associated with both Salmonella and mycobacterial infections, presumably because of the lack of IFN-g induction in these patients with IL-12 deficiency.56 Susceptibility to mycobacteria has also been documented in patients with germline mutations that lead to impaired IL-12 production.58 Clinical trials targeting IL-12 and IL-23 Immunologic components of psoriasis have been known for some time. However, it was not until the identification of T cellseand subsequently the seminal role of the Th1 helper T-cell subsetein the pathogenesis of psoriasis that therapeutic interventions that interfere with the cytokine signaling or T-cell function have been considered. Nonspecific immunologic agents that target T cells are effective in psoriasis. These include cyclosporin A and methotrexate. These agents target T cells broadly, resulting in generalized immunosuppression and systemic toxicities that limit their use. Recently, however, a monoclonal antibody that more specifically targets cytokine signaling in psoriasis has been developed. This antibody targets IL-12 and IL-23 signaling pathways and does so by targeting the p40 subunit that is shared by both the IL-12 and IL-23 receptors (see discussion above for details of the IL-12 and IL-23 receptors). Eighteen patients were enrolled on a dose escalation phase I study of this anti-IL-12p40 antibody (Centocor).59 Eligibility criteria required that the

patients have at least 3% body surface area involved with psoriasis. Four dose groups were evaluated: 0.1, 0.3, 1.0, and 5.0 mg/kg. Four patients were evaluated on each of the lower doses, and 5 patients at the higher doses. The antibody was administered intravenously. Pharmacokinetics were linear, with a long terminal half-life of 24 days. Only a single dose was administered to each of the 18 patients. Toxicities were mild, and none was dose limiting in this trial. CD41 cells (a marker that identifies T-helper cells) were transiently decreased in a number of the patients, although no dose-response effect on CD41 cells could be identified. In two subjects CD41 counts decreased below 400 for 5 days. CD161/CD561 (natural killer cells) also decreased transiently in a number of patients, although no adverse events occurred as a result of these transient low CD4 and CD16 cell counts. Although the primary end point was to determine tolerability and pharmacokinetics, 12 of the 18 patients responded to treatment, using the standard Psoriasis Area and Severity Index and Physicians Global Assessment to quantify response. Of the patients, 83% achieved at least a 50% improvement in the psoriatic lesions and 67% achieved a 75% improvement. Although some improvement of the plaques was seen at 2 weeks, the maximum response occurred at 12 weeks for most patients. Investigators have recently reported results of a double-blind, placebo-controlled phase II study of subcutaneously administered Centocor compound (CNTO 1275).60 Patients were randomized to placebo or one of 4 doses of CNTO 1275: one 45-mg dose, one 90-mg dose, 4 weekly 45-mg doses, and 4 weekly 90-mg doses. In all, 320 patients were enrolled, 64 to each group. At week 16, patients receiving CNTO 1275 with a Physicians Global Assessment score of less than excellent received one additional injection of their originally assigned dose. Patients initially receiving placebo were crossed over to receive one 90-mg dose of CNTO 1275 at week 20. No additional or maintenance therapy was administered. Response was assessed at 12 and 24 weeks. At week 12, there was at least a 75% improvement in Psoriasis Area and Severity Index score (the primary end point) in 52%, 59%, 67%, and 81% of the patients treated with 45 mg 3 1, 90 mg 3 1, 45 mg 3 4, and 90 mg 3 4, compared with 2% of control subjects (P \ .001 for each comparison), suggesting a dose and/or schedule dependency of the therapeutic effect. Dermatology Quality of Life Index also showed significant improvement in all treatment groups. Responses were maintained through week 24, then deteriorated. Serious adverse events were uncommon, and were not statistically different from control (P = .69). In particular, rates of

1066 Torti and Feldman

J AM ACAD DERMATOL DECEMBER 2007

infection were not statistically different between treatment and control groups (P = .51), although the study was not powered to detect small differences. Thus, although there have been demonstrations of increased sensitivity to infection after depletion of IL-12/IL-23 in animal models and human genetic diseases, it is not clear that susceptibility to infection will be a major consideration in the treatment of dermal lesions such as psoriasis. Two other inhibitors of the IL-12/IL-23 pathway are in clinical trials. Synta Pharmaceuticals (Lexington, Mass) has a small molecule inhibitor of transcription of IL-12/IL-23, STA 5326.61 Recently, the results of phase IIa biomarker study and a phase IIb, placebo-controlled clinical study of STA 5326 in chronic plaque psoriasis were reported at the Fourth Psoriasis Gene to Clinic International Conference.62 Although the levels of proinflammatory cytokines such as IL-23 decreased, and there was evidence of skin clearing relative to placebo, the primary end point of the study was not met, and the company has decided not to further pursue a psoriasis indication for this compound. The third compound that is undergoing testing in psoriasis is ABT-874 (Abbott Laboratories, Abbott Park, Ill). ABT-874 is a human monoclonal antibody that targets IL-12. A randomized, double-blind phase II trial of subcutaneous ABT-874 administered for 7 weeks in Crohn’s disease showed substantial improvement in symptom score.63 No serious adverse events were attributable to the drug. A trial in psoriasis is planned.64 Conclusions IL-12 and IL-23 are potent cytokines with complex biological activities. These cytokines both have two polypeptide subunits, one of which is shared. Although their effects are mediated though intracellular signaling by different membrane-bound receptors, the receptors also share a common subunit. IL-12 and IL-23 are important in the pathogenesis of psoriasis. Targeting IL-12p40 subunit, which decreases the expression of both IL-12 and IL-23, may have clinical use in the treatment of psoriasis. However, IL-12 and IL-23 deficiency states in human beings and mouse knockout models both suggest a potential risk for increased susceptibility to infection, particularly with Mycobacterium and Salmonella species, in patients treated with IL-12p40 targeting agents. REFERENCES 1. Hunter CA. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 2005;5: 521-31.

2. Robertson MJ, Ritz J. Interleukin 12: basic biology and potential applications in cancer treatment. Oncologist 1996;1:88-97. 3. Hong K, Chu A, Ludviksson BR, Berg EL, Ehrhardt RO. IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J Immunol 1999;162:7480-91. 4. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003;278:1910-4. 5. Teunissen MB, Koomen CW, de Waal Malefyt R, Wierenga EA, Bos JD. Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 1998;111:645-9. 6. Kopp T, Kieffer JD, Rot A, Strommer S, Stingl G, Kupper TS. Inflammatory skin disease in K14/p40 transgenic mice: evidence for interleukin-12-like activities of p40. J Invest Dermatol 2001;117:618-26. 7. Kopp T, Lenz P, Bello-Fernandez C, Kastelein RA, Kupper TS, Stingl G. IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous immunity. J Immunol 2003;170:5438-44. 8. Cheng J, Tu Y, Li J, Huang C, Liu Z, Liu D. A study on the expression of interleukin (IL)-10 and IL-12 P35, P40 mRNA in the psoriatic lesions. J Tongji Med Univ 2001;21:86-8. 9. Lew W, Lee E, Krueger JG. Psoriasis genomics: analysis of proinflammatory (type 1) gene expression in large plaque (Western) and small plaque (Asian) psoriasis vulgaris. Br J Dermatol 2004;150:668-76. 10. Shaker OG, Moustafa W, Essmat S, Abdel-Halim M, El-Komy M. The role of interleukin-12 in the pathogenesis of psoriasis. Clin Biochem 2006;39:119-25. 11. Yawalkar N, Karlen S, Hunger R, Brand CU, Braathen LR. Expression of interleukin-12 is increased in psoriatic skin. J Invest Dermatol 1998;111:1053-7. 12. Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004;199:125-30. 13. Piskin G, Sylva-Steenland RM, Bos JD, Teunissen MB. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 2006;176:1908-15. 14. Economidou J, Barkis J, Demetriou Z, Avgerinou G, Psarra K, Degiannis D, et al. Effects of cyclosporin A on immune activation markers in patients with active psoriasis. Dermatology 1999;199:144-8. 15. Jacob SE, Nassiri M, Kerdel FA, Vincek V. Simultaneous measurement of multiple Th1 and Th2 serum cytokines in psoriasis and correlation with disease severity. Mediators Inflamm 2003;12:309-13. 16. Piskin G, Tursen U, Sylva-Steenland RM, Bos JD, Teunissen MB. Clinical improvement in chronic plaque-type psoriasis lesions after narrow-band UVB therapy is accompanied by a decrease in the expression of IFN-gamma inducerseIL-12, IL-18 and IL-23. Exp Dermatol 2004;13:764-72. 17. Tada Y, Asahina A, Takekoshi T, Kishimoto E, Mitsui H, Saeki H, et al. Interleukin 12 production by monocytes from patients with psoriasis and its inhibition by cyclosporin A. Br J Dermatol 2006;154:1180-3. 18. Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol 2005;175:2721-9. 19. Chamian F, Lowes MA, Lin SL, Lee E, Kikuchi T, Gilleaudeau P, et al. Alefacept reduces infiltrating T cells, activated dendritic

J AM ACAD DERMATOL

Torti and Feldman 1067

VOLUME 57, NUMBER 6

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci U S A 2005;102:2075-80. Hensen P, Asadullah K, Windemuth C, Ruschendorf F, Huffmeier U, Stander M, et al. Interleukin-10 promoter polymorphism IL10.G and familial early onset psoriasis. Br J Dermatol 2003;149:381-5. Reich K, Westphal G, Schulz T, Muller M, Zipprich S, Fuchs T, et al. Combined analysis of polymorphisms of the tumor necrosis factor-alpha and interleukin-10 promoter regions and polymorphic xenobiotic metabolizing enzymes in psoriasis. J Invest Dermatol 1999;113:214-20. Hensen P, Windemuth C, Huffmeier U, Ruschendorf F, Stadelmann A, Hoppe V, et al. Association scan of the novel psoriasis susceptibility region on chromosome 19: evidence for both susceptible and protective loci. Exp Dermatol 2003;12:490-6. Speckman RA, Wright Daw JA, Helms C, Duan S, Cao L, TaillonMiller P, et al. Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Hum Genet 2003;112:34-41. Litjens NH, van der Plas MJ, Ravensbergen B, Numan-Ruberg SC, van Assen Y, Thio HB, et al. Psoriasis is not associated with IL-12p70/IL-12p40 production and IL12B promoter polymorphism. J Invest Dermatol 2004;122:923-6. Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Fujita H, et al. Interleukin-12 p40 gene (IL12B) 3’-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci 2002;30:161-6. Holscher C, Atkinson RA, Arendse B, Brown N, Myburgh E, Alber G, et al. A protective and agonistic function of IL-12p40 in mycobacterial infection. J Immunol 2001;167:6957-66. Khader SA, Pearl JE, Sakamoto K, Gilmartin L, Bell GK, JelleyGibbs DM, et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigenspecific IFN-gamma responses if IL-12p70 is available. J Immunol 2005;175:788-95. Cooper AM, Roberts AD, Rhoades ER, Callahan JE, Getzy DM, Orme IM. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology 1995;84: 423-32. Lehmann J, Bellmann S, Werner C, Schroder R, Schutze N, Alber G. IL-12p40-dependent agonistic effects on the development of protective innate and adaptive immunity against Salmonella enteritidis. J Immunol 2001;167:5304-15. Mastroeni P, Harrison JA, Chabalgoity JA, Hormaeche CE. Effect of interleukin 12 neutralization on host resistance and gamma interferon production in mouse typhoid. Infect Immun 1996;64:189-96. Kincy-Cain T, Clements JD, Bost KL. Endogenous and exogenous interleukin-12 augment the protective immune response in mice orally challenged with Salmonella dublin. Infect Immun 1996;64:1437-40. Elkins KL, Cooper A, Colombini SM, Cowley SC, Kieffer TL. In vivo clearance of an intracellular bacterium, Francisella tularensis LVS, is dependent on the p40 subunit of interleukin-12 (IL-12) but not on IL-12 p70. Infect Immun 2002;70: 1936-48. Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ, et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med 2005;202:761-9. Simmons CP, Goncalves NS, Ghaem-Maghami M, Bajaj-Elliott M, Clare S, Neves B, et al. Impaired resistance and enhanced pathology during infection with a noninvasive, attachingeffacing enteric bacterial pathogen, Citrobacter rodentium, in mice lacking IL-12 or IFN-gamma. J Immunol 2002;168:1804-12.

35. Tripp CS, Gately MK, Hakimi J, Ling P, Unanue ER. Neutralization of IL-12 decreases resistance to Listeria in SCID and C.B-17 mice: reversal by IFN-gamma. J Immunol 1994;152: 1883-7. 36. Wagner RD, Steinberg H, Brown JF, Czuprynski CJ. Recombinant interleukin-12 enhances resistance of mice to Listeria monocytogenes infection. Microb Pathog 1994;17:175-86. 37. Mancuso G, Cusumano V, Genovese F, Gambuzza M, Beninati C, Teti G. Role of interleukin 12 in experimental neonatal sepsis caused by group B streptococci. Infect Immun 1997; 65:3731-5. 38. Lieberman LA, Cardillo F, Owyang AM, Rennick DM, Cua DJ, Kastelein RA, et al. IL-23 provides a limited mechanism of resistance to acute toxoplasmosis in the absence of IL-12. J Immunol 2004;173:1887-93. 39. Vossenkamper A, Struck D, Alvarado-Esquivel C, Went T, Takeda K, Akira S, et al. Both IL-12 and IL-18 contribute to small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii, but IL-12 is dominant over IL-18 in parasite control. Eur J Immunol 2004;34:3197-207. 40. Hunter CA, Subauste CS, Van Cleave VH, Remington JS. Production of gamma interferon by natural killer cells from Toxoplasma gondiieinfected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor alpha. Infect Immun 1994;62:2818-24. 41. Murray HW. Endogenous interleukin-12 regulates acquired resistance in experimental visceral leishmaniasis. J Infect Dis 1997;175:1477-9. 42. Engwerda CR, Murphy ML, Cotterell SE, Smelt SC, Kaye PM. Neutralization of IL-12 demonstrates the existence of discrete organ-specific phases in the control of Leishmania donovani. Eur J Immunol 1998;28:669-80. 43. Constantinescu CS, Hondowicz BD, Elloso MM, Wysocka M, Trinchieri G, Scott P. The role of IL-12 in the maintenance of an established Th1 immune response in experimental leishmaniasis. Eur J Immunol 1998;28:2227-33. 44. Mattner F, Magram J, Ferrante J, Launois P, Di Padova K, Behin R, et al. Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response. Eur J Immunol 1996;26:1553-9. 45. Hondowicz BD, Park AY, Elloso MM, Scott P. Maintenance of IL-12-responsive CD41 T cells during a Th2 response in Leishmania majoreinfected mice. Eur J Immunol 2000;30: 2007-14. 46. Park AY, Hondowicz BD, Scott P. IL-12 is required to maintain a Th1 response during Leishmania major infection. J Immunol 2000;165:896-902. 47. Carr JA, Rogerson J, Mulqueen MJ, Roberts NA, Booth RF. Interleukin-12 exhibits potent antiviral activity in experimental herpesvirus infections. J Virol 1997;71:7799-803. 48. Gazzinelli RT, Giese NA, Morse HC III. In vivo treatment with interleukin 12 protects mice from immune abnormalities observed during murine acquired immunodeficiency syndrome (MAIDS). J Exp Med 1994;180:2199-208. 49. Ozmen L, Aguet M, Trinchieri G, Garotta G. The in vivo antiviral activity of interleukin-12 is mediated by gamma interferon. J Virol 1995;69:8147-50. 50. Milich DR, Wolf SF, Hughes JL, Jones JE. Interleukin 12 suppresses autoantibody production by reversing helper T-cell phenotype in hepatitis B e antigen transgenic mice. Proc Natl Acad Sci U S A 1995;92:6847-51. 51. Bi Z, Quandt P, Komatsu T, Barna M, Reiss CS. IL-12 promotes enhanced recovery from vesicular stomatitis virus infection of the central nervous system. J Immunol 1995;155:5684-9. 52. Monteiro JM, Harvey C, Trinchieri G. Role of interleukin-12 in primary influenza virus infection. J Virol 1998;72:4825-31.

1068 Torti and Feldman

J AM ACAD DERMATOL DECEMBER 2007

53. Carr JA, Rogerson JA, Mulqueen MJ, Roberts NA, Nash AA. The role of endogenous interleukin-12 in resistance to murine cytomegalovirus (MCMV) infection and a novel action for endogenous IL-12 p40. J Interferon Cytokine Res 1999;19: 1145-52. 54. Hoag KA, Lipscomb MF, Izzo AA, Street NE. IL-12 and IFNgamma are required for initiating the protective Th1 response to pulmonary cryptococcosis in resistant C.B-17 mice. Am J Respir Cell Mol Biol 1997;17:733-9. 55. Decken K, Kohler G, Palmer-Lehmann K, Wunderlin A, Mattner F, Magram J, et al. Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans. Infect Immun 1998;66:4994-5000. 56. Doffinger R, Dupuis S, Picard C, Fieschi C, Feinberg J, BarcenasMorales G, et al. Inherited disorders of IL-12- and IFNgammamediated immunity: a molecular genetics update. Mol Immunol 2002;38:903-9. 57. Sanal O, Turul T, De Boer T, Van de Vosse E, Yalcin I, Tezcan I, et al. Presentation of interleukin-12/-23 receptor beta1 deficiency with various clinical symptoms of Salmonella infections. J Clin Immunol 2006;26:1-6. 58. Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, et al. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med 2006;203:1745-59. 59. Kauffman CL, Aria N, Toichi E, McCormick TS, Cooper KD, Gottlieb AB, et al. A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J Invest Dermatol 2004;123:1037-44. 60. Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007; 356:580-92. 61. Burakoff R, Barish CF, Riff D, Pruitt R, Chey WY, Farraye FA, et al. A phase 1/2A trial of STA 5326, an oral interleukin-12/23

62.

63.

64. 65.

66.

67.

68.

69.

inhibitor, in patients with active moderate to severe Crohn’s disease. Inflamm Bowel Dis 2006;12:558-65. Gordon K, Tschen E, Korman N, Cather J, Gold M, Hampel F, et al. A phase II study of STA-5326, an oral IL-12 and IL-23 inhibitor, in patients with moderate to severe chronic plaque psoriasis. Paper presented at: 4th International Congress The Royal College of Physicians; December 1-3, 2005; London, United Kingdom. Sandborn WJ. How future tumor necrosis factor antagonists and other compounds will meet the remaining challenges in Crohn’s disease. Rev Gastroenterol Disord 2004;4(Suppl): S25-33. ABT-874. Available from: URL:http://www.cambridgeantibody. com. Accessed May 16, 2006. Toichi E, Torres G, McCormick TS, Chang T, Mascelli MA, Kauffman CL, et al. An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J Immunol 2006;177:4917-26. Cooper AM, Kipnis A, Turner J, Magram J, Ferrante J, Orme IM. Mice lacking bioactive IL-12 can generate protective, antigenspecific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J Immunol 2002;168: 1322-7. Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, et al. Parasite-induced IL-12 stimulates early IFNgamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol 1994;153:2533-43. Belkaid Y, Mendez S, Lira R, Kadambi N, Milon G, Sacks D. A natural model of Leishmania major infection reveals a prolonged ‘‘silent’’ phase of parasite amplification in the skin before the onset of lesion formation and immunity. J Immunol 2000;165:969-77. Muller U, Kohler G, Mossmann H, Schaub GA, Alber G, Di Santo JP, et al. IL-12-independent IFN-gamma production by T cells in experimental Chagas’ disease is mediated by IL-18. J Immunol 2001;167:3346-53.