Clinical Efficacy and Safety of Anti-IL-17 Agents for the Treatment of Patients with Psoriasis

Chen, Yan; Qian, Tian; Zhang, Dongmei; Yan, Hong‐Bin; Fei, Hao

doi:10.2217/imt.15.50

Cited by 19 publications

(14 citation statements)

References 29 publications

(75 reference statements)

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“…Pathogenic Th17 cells, recently characterized as dual IFN-γ and IL-17 expressing cells, have been implicated in psoriasis, type 1 diabetes, MS, and other autoimmune diseases [19, 20]. In recent clinical trials, antibodies targeting IL-17A and IL-17Ra have demonstrated remarkable efficacy in psoriasis patients [21–25]. Also, the pathogenic potential of Th17 cells has been identified in MS [19, 26].…”

Section: Introductionmentioning

confidence: 99%

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

et al. 2017

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CD6 is associated with T-cell modulation and is implicated in several autoimmune diseases. We previously demonstrated that Itolizumab, a CD6 domain 1 (CD6D1) specific humanized monoclonal antibody, inhibited the proliferation and cytokine production by T lymphocytes stimulated with anti-CD3 antibody or when co-stimulated with ALCAM. Aberrant IL-17 producing CD4+ helper T-cells (Th17) have been identified as pivotal for the pathogenesis of certain inflammatory autoimmune disorders, including psoriasis. Itolizumab has demonstrated efficacy in human diseases known to have an IL-17 driven pathogenesis. Here, in in vitro experiments we show that by day 3 of human PBMC activation using anti-CD3 and anti-CD28 co-stimulation in a Th17 polarizing milieu, 15–35% of CD4+ T-cells overexpress CD6 and there is an establishment of differentiated Th17 cells. Addition of Itolizumab reduces the activation and differentiation of T cells to Th17 cells and decreases production of IL-17. These effects are associated with the reduction of key transcription factors pSTAT3 and RORγT. Further, transcription analysis studies in these conditions indicate that Itolizumab suppressed T cell activation by primarily reducing cell cycle, DNA transcription and translation associated genes. To understand the mechanism of this inhibition, we evaluated the effect of this anti-human CD6D1 mAb on ALCAM-CD6 as well as TCR-mediated T cell activation. We show that Itolizumab but not its F(ab’)2 fragment directly inhibits CD6 receptor hyper-phosphorylation and leads to subsequent decrease in associated ZAP70 kinase and docking protein SLP76. Since Itolizumab binds to CD6 expressed only on human and chimpanzee, we developed an antibody binding specifically to mouse CD6D1. This antibody successfully ameliorated the incidence of experimental autoimmune encephalitis in the mice model. These results position CD6 as a key molecule in sustaining the activation and differentiation of T cells and an important target for modulating autoimmune diseases.

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Section: Introductionmentioning

confidence: 99%

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

et al. 2017

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“…While IL-17 has a role in the normal host immune response to Gram-negative bacterial infections (8,44), it has been associated with a wide spectrum of diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease, in which there is a dysregulated inflammatory response typically in the absence of a coexisting bacterial infection (17,(45)(46)(47)(48). Further, the IL-17 receptor appears to be ubiquitously expressed throughout the body, implicating IL-17 as an important regulator of the host response during chronic inflammation (49,50).…”

Section: Rag1mentioning

confidence: 99%

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

et al. 2016

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c Cystic fibrosis (CF) is characterized by an excessive neutrophilic inflammatory response within the airway as a result of defective cystic fibrosis transmembrane receptor (CFTR) expression and function. Interleukin-17A induces airway neutrophilia and mucin production associated with Pseudomonas aeruginosa colonization, which is associated with the pathophysiology of cystic fibrosis. The objectives of this study were to use the preclinical murine model of cystic fibrosis lung infection and inflammation to investigate the role of IL-17 in CF lung pathophysiology and explore therapeutic intervention with a focus on IL-17. Cftr-deficient mice (CF mice) and wild-type mice (WT mice) infected with P. aeruginosa had robust IL-17 production early in the infection associated with a persistent elevated inflammatory response. Intratracheal administration of IL-17 provoked a neutrophilic response in the airways of WT and CF animals which was similar to that observed with P. aeruginosa infection. The neutralization of IL-17 prior to infection significantly improved the outcomes in the CF mice, suggesting that IL-17 may be a therapeutic target. We demonstrate in this report that the pathophysiological contribution of IL-17 may be due to the induction of chemokines from the epithelium which is augmented by a deficiency of Cftr and ongoing inflammation. These studies demonstrate the in vivo contribution of IL-17 in cystic fibrosis lung disease and the therapeutic validity of attenuating IL-17 activity in cystic fibrosis. Cystic fibrosis (CF) lung disease is characterized by an exaggerated inflammatory response associated with the robust infiltration of neutrophils within the airways (1, 2). The etiology of this excessive inflammation remains to be elucidated. Many cytokines and small molecules have been shown to recruit neutrophils into the airway of individuals with CF, including interleukin-8 (IL-8) and leukotriene (LT) B4 (3-7). IL-17 has traditionally been identified to be a product of activated T lymphocytes and is critically important in the host lung response to infections caused by Gram-negative bacteria, including Pseudomonas aeruginosa (8,9). Experiments with IL-17 receptor knockout (KO) mice have demonstrated an increased susceptibility to Gram-negative bacterial pneumonia due to excessive neutrophil recruitment into the airways (10-13) and the upregulation of airway mucins, potentially contributing to inefficient mucociliary clearance (5,14).Increased concentrations of IL-17 have been associated with a wide range of inflammatory diseases, including rheumatoid arthritis (15, 16), inflammatory bowel disease (17), diabetes (18,19), cancer (20), and allergic asthma (21, 22). The utilization of neutralizing IL-17A antibodies in a mouse model of allergic asthma (23, 24) and lipopolysaccharide-induced inflammation (9, 25) demonstrated decreased airway neutrophilia, implicating IL-17 as a potential therapeutic target in asthma. IL-17 has also been associated with P. aeruginosa infections, linking it to not just the patholo...

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“…Indeed, IL-6, IL-1 and IL-23 are critical drivers of Th17 differentiation and elevated IL-6 levels in GCA patients are promptly responsive to corticosteroids (21). Recent data have emphasized the explicit role of Th17 cells in psoriasis, with prompt and complete resolution of skin lesions when patients are treated with anti-IL-17 reagents (22, 23). In mice, IL-17 cells are critical amplifiers of gut inflammation, but in humans anti-IL-17 therapy is contraindicated in patients with inflammatory bowel disease (24, 25).…”

Section: Introductionmentioning

confidence: 99%

Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis

et al. 2017

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Giant cell arteritis is an autoimmune disease defined by explicit tissue tropism to the walls of medium and large arteries. Pathognomic inflammatory lesions are granulomatous in nature, emphasizing the functional role of CD4 T cells and macrophages. Evidence for a pathogenic role of antibodies and immune complexes is missing. Analysis of T cell populations in giant cell arteritis, both in the tissue lesions and in the circulation, has supported a model of broad, polyclonal T cell activation, involving an array of functional T cell lineages. The signature of T cell cytokines produced by vasculitic lesions is typically multifunctional, including IL-2, IFN-γ, IL-17, IL-21, and GM-CSF, supportive for a general defect in T cell regulation. Recent data describing the lack of a lymph node-based population of anti-inflammatory T cells in giant cell arteritis patients offers a fresh look at the immunopathology of this vasculitis. Due to defective CD8+NOX2+ regulatory T cells, giant cell arteritis patients appear unable to curtail clonal expansion within the CD4 T cell compartment, resulting in wide-spread CD4 T cell hyperimmunity. Why unopposed expansion of committed CD4 effector T cells would lead to invasion of the walls of medium and large arteries needs to be explored in further investigations.

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Clinical Efficacy and Safety of Anti-IL-17 Agents for the Treatment of Patients with Psoriasis

Cited by 19 publications

References 29 publications

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation

Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis

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