Anti-IL-17 Receptor Antibody AMG 827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial

Papp, Kim; Reid, Cathy; Foley, Peter; Sinclair, Rodney; Salinger, David H.; Williams, Gary W.; Dong, Hua; Krueger, James G.; Russell, Chris B.; Martin, David

doi:10.1038/jid.2012.163

Cited by 128 publications

(99 citation statements)

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“…Similar circuitry may exist in humans that would help explain the great efficacy of anti-IL-17 signaling therapies. Indeed, initial limited studies on skin biopsies have shown that anti-IL-17/IL-17RA treatment rapidly reverses disease-associated keratinocyte proliferation and cellular infiltration and, remarkably, also rapidly diminishes the production of IL-17 itself (39). Thus, the 5-d IMQ model analyzed here may phenocopy the human disease in fundamentally important ways.…”

Section: Discussionmentioning

confidence: 99%

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

Wang

Pisitkun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

136

121

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Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory cells. The mechanisms underlying psoriasis in humans and in mouse models are poorly understood, although evidence strongly points to crucial contributions of IL-17 cytokines, which signal via the obligatory adaptor CIKS/Act1. Here we identify critical roles of CIKS/Act1-mediated signaling in imiquimod-induced psoriatic inflammation, a mouse model that shares features with the human disease. We found that IL-17 cytokines/CIKS-mediated signaling into keratinocytes is essential for neutrophilic microabscess formation and contributes to hyperproliferation and markedly attenuated differentiation of keratinocytes, at least in part via direct effects. In contrast, IL-17 cytokines/CIKS-mediated signaling into nonkeratinocytes, particularly into dermal fibroblasts, promotes cellular infiltration and, importantly, leads to enhanced the accumulation of IL-17-producing γδT cells in skin, comprising a positive feed-forward mechanism. Thus, CIKS-mediated signaling is central in the development of both dermal and epidermal hallmarks of psoriasis, inducing distinct pathologies via target cell-specific effects. CIKS-mediated signaling represents a potential therapeutic target in psoriasis.

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Section: Discussionmentioning

confidence: 99%

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

Wang

Pisitkun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

136

121

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“…In the form of homogenous or heterogeneous dimers, IL-17 binds to its IL-17 receptor (IL-17R) and subsequently activates the signaling pathways of phosphoinositide 3-kinase (PI3K), nuclear factor (NF)-κB and mitogen-activated protein kinase in order to regulate cell proliferation (14,15). A previous study, based on the upregulation of IL-17R in the keratinocytes of psoriatic lesions, has demonstrated that the administration of IL-17R receptor antagonists may rapidly control the symptoms of psoriasis, and reduce the psoriasis area and severity index (16). This suggests that IL-17 may mediate this immune disorder, resulting in the excessive proliferation and differentiation of keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

IL-17 promotes keratinocyte proliferation via the downregulation of C/EBPα

Jia

Zhang

2015

Experimental and Therapeutic Medicine

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Abstract. Psoriasis vulgaris is a common chronic inflammatory skin disease characterized by the hyperproliferation and abnormal differentiation of keratinocytes. CCATT/enhancer binding protein α (C/EBPα) is abundant in the epidermis and is associated with the proliferation of keratinocytes. However, the role of C/EBPα in the proliferation of keratinocytes and the pathogenesis of psoriasis vulgaris are yet to be elucidated. In the present study, using two-step immunohistochemistry, the expression levels of C/EBPα and Ki-67 were examined in skin biopsies harvested from 30 patients with psoriasis vulgaris and 30 healthy control subjects. The proliferation index (PI) was calculated and the correlation between C/EBPα expression levels and the PI was assessed using Pearson's correlation coefficient. In addition, the effect on HaCaT immortalized human keratinocytic cells of treatment with various concentrations of interleukin (IL)-17 was investigated. Subsequently, cell proliferation rates were examined using a Cell Counting kit-8 assay and the mRNA and protein expression levels of C/EBPα were analyzed using semiquantitative reverse transcription-polymerase chain reaction and western blotting, respectively, in order to analyze the effects of IL-17 stimulation on C/EBPα expression levels. C/EBPα expression was predominantly detected in the cytoplasm of the keratinocytes and C/EBPα expression levels were significantly lower in the psoriatic lesions (P<0.05), as compared with the control group. An inverse correlation was detected between the expression levels of C/EBPα and the PI in the psoriatic lesions. Furthermore, a significant increase in the cell proliferation rate and significant reductions in the mRNA and protein expression levels of C/EBPα were detected in HaCaT cells following treatment with IL-17. These results demonstrated that C/EBPα may act as a downstream target of IL-17 and may be associated with the pathogenesis of psoriasis.

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“…The pathogenesis of psoriasis is not fully understood; however, critical T-cell subsets and effector cytokines that mediate chronic inflammation observed in psoriasis have been identified [2]. More specifically, mechanistic studies have demonstrated that therapeutic blockade of the cytokine interleukin (IL)-17A or its receptor can reverse the clinical, histologic, and molecular features of psoriasis [4][5][6]. These initial studies led to the development and approval of new psoriasis drugs that selectively targeted IL-17A, including secukinumab (Cosentyx ® , Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) and ixekizumab (Taltz ® , Eli Lilly and Company, Indianapolis, IN, USA) [2].…”

Section: Introductionmentioning

confidence: 99%

Safety of secukinumab in the treatment of psoriasis

Blauvelt

2016

Expert Opinion on Drug Safety

109

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Introduction: Secukinumab is a human monoclonal antibody that selectively targets and neutralizes interleukin (IL)-17A, a cytokine that is normally involved in mucocutaneous defense against extracellular organisms and is abnormally expressed in psoriasis. In 2015, secukinumab was the first IL-17A inhibitor approved for the treatment of moderate-to-severe psoriasis. Areas covered: This review evaluates the safety profile of secukinumab for the treatment of moderateto-severe psoriasis and its role in the clinical landscape. A literature search was performed for articles published through February 2016; additional data from a pooled safety analysis of 10 Phase II and III secukinumab studies were reviewed. Expert opinion: Collectively, these studies show that secukinumab demonstrates a highly favorable safety profile, especially compared with commonly used psoriasis treatments such as methotrexate and TNF-α blockers. More specifically, secukinumab carries no increased risks for end-organ toxicities, serious infection, multiple sclerosis, reactivation of latent tuberculosis or hepatitis B, leukemia/lymphoma, and nonmelanoma skin cancer. Mucocutaneous candidiasis is a common side effect and occurs at a rate of 3.55/100 subject-years with secukinumab 300 mg, yet these infections usually do not interfere with maintenance of secukinumab therapy. The combination of proven efficacy and safety make secukinumab an excellent new treatment choice for individuals with moderate-to-severe psoriasis.ARTICLE HISTORY

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Anti-IL-17 Receptor Antibody AMG 827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial

Cited by 128 publications

References 10 publications

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

IL-17 promotes keratinocyte proliferation via the downregulation of C/EBPα

Safety of secukinumab in the treatment of psoriasis

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