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Targeting IL-23/IL-17 Axis for Treatment of Psoriasis and Psoriatic Arthritis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Subhashis Banerjee, Philip Mease
Bimekizumab is a humanized IgG1 mAb that binds to both IL-17A and IL-17F, in contrast to the anti-IL-17A antibodies, secukinumab and ixekizumab [40]. IL-17A and IL-17F both bind to the IL-17 receptor, a dimer of IL-17RA and IL-17RC. Both cytokines are expressed during inflammation at similar sites at different levels, and share similar functions. Bimekizumab has the potential advantage of blocking both of these cytokines without the potential negative effect of IL-17RA blockade related to potential IL-25 antagonism seen with brodalumab.
IL-17 and Other New Agents
Published in John Y. M. Koo, Ethan C. Levin, Argentina Leon, Jashin J. Wu, Alice B. Gottlieb, Moderate to Severe Psoriasis, 2014
Ethan C. Levin, Argentina Leon, John Y. M. Koo
The receptor for IL-17C is expressed predominantly on epithelial cells and is a heterodimer composed of IL-17RE and IL-17RA (Figure 16.3) [46]. Recall that the receptor for IL-17A also contains the IL-17RA subunit, which is expressed widely on many cell types. Therefore, the target cell specificity for IL-17C is determined by the IL-17RE subunit of the receptor complex. Thus, because epithelial cells express both the cytokine (IL-17C) and its receptor (IL-17RE/A complex), the IL-17C pathway has an autocrine mechanism of function.
Biologic therapies for chronic obstructive pulmonary disease
Published in Expert Opinion on Biological Therapy, 2023
Maria Gabriella Matera, Luigino Calzetta, Mario Cazzola, Josuel Ora, Paola Rogliani
Many anti-IL-17A and anti-IL-17 receptor A (IL-17RA) mAbs are being developed to reduce neutrophil recruitment and airway inflammation [23]. Targeting the IL-17 pathway causes a slight improvement in lung function [24], but it may raise the risk of AECOPD by weakening host defense [23]. In patients with moderate-to-severe symptomatic COPD, CNTO 6785, a mAb that binds to human IL-17A, improved FEV1% predicted slightly, but failed to demonstrate any statistically or clinically significant difference in primary or secondary end points between the intervention and placebo arms [24]. Brodalumab, a human, anti-IL17RA IgG2 mAb, and secukinumab, a fully human anti-IL-17A of the IgG1κ isotype, have been tested in asthmatics [25,26] but not yet in COPD patients. Interestingly, secukinumab appeared to be effective in patients with severe asthma, increased nasal epithelial neutrophilic inflammation and decreased markers of IgE driven systemic inflammation who have not been able to control their symptoms despite taking high doses of ICS and LABA [26]. However, in healthy individuals with acute neutrophilic airway inflammation following ozone exposure, secukinumab did not diminish the overall quantity of sputum neutrophils [27].
Anti-interleukin-23 agents for the treatment of ulcerative colitis
Published in Expert Opinion on Biological Therapy, 2020
Jurij Hanžel, Geert R. D’Haens
This caveat is well illustrated by the failed clinical trials of secukinumab (anti-IL-17A) and brodalumab (anti-IL-17RA) in CD [23,24]. Although IL-17 is closely connected to the IL-23 pathway and would therefore represent a rational drug target in inflammatory bowel disease, both studies were terminated early because of disease worsening in the active treatment groups. The IL-17 family consists of six proteins (IL-17A to IL-17F), which have heterogeneous roles with most of them promoting inflammation, but IL-17E being involved in the Th2 response to parasites and the development of allergy [25]. Animal studies following the failed clinical trials have demonstrated an exacerbation of colitis with IL17-A and IL-17RA inhibition owing to a weakened intestinal epithelial barrier [26]. Clinically significant mucocutaneous candidiasis observed in the secukinumab trial also alludes to the potential role of disrupted interactions with the intestinal mycobiome mediated by IL-17.
Interleukin-17 inhibition: role in psoriasis and inflammatory bowel disease
Published in Journal of Dermatological Treatment, 2018
Megan Hohenberger, Leah A. Cardwell, Elias Oussedik, Steven R. Feldman
Various mouse model experiments have elaborated on the roles of IL-17 by demonstrating the consequences of IL-17 blockade. While limited research has illustrated that knocking out IL-17 A mitigates colitis in mouse models, (11) the vast majority of preclinical trials revealed results to the contrary. Anti-IL-17 antibody increased severity of dextran sulfate sodium (DSS)-induced colitis in treated mice, suggesting that IL-17 aids in preventing the development of DSS-colitis (12). IL-17 knockout mice developed severe colitis, while mice with IL-17 F deficiency had decreased DSS-induced colitis (13). Using the CD45RBhi transfer model of colitis, O’Connor et al. illustrated the protective function of IL-17 A (14). IL-17 A or IL-17RA inhibition led to exacerbation of colitis and p40 neutralization led to colitis inhibition (Figure 2) (15–17). They noted that IL-17RA inhibition amplified disease through reduction of intestinal neutrophil aggregation, increased IFN-y+IL-17+ double-positive effector cell generation, intestinal epithelial barrier breakdown and decreased antimicrobial peptide expression in the gut; these factors favored bacterial invasion, increased gut permeability and augmentation of gut inflammation. This lends some explanation to the dichotomy between inhibiting IL-17 A, IL-17RA and IL-23 in psoriasis patients versus IBD patients (Table 2).