Critical Players and Therapeutic Targets in Chronic Itch
Abstract
:1. Introduction
2. Neuropeptide Targets in Itch Transmission
2.1. CGRP
2.2. SP
2.3. BNP
2.4. GRP
2.5. NMB
2.6. SST
2.7. Endothelin-1 (ET-1)
3. Itch Targets in G-Protein-Coupled Receptor Pathways
3.1. Histamine
3.2. Proteases, Tryptase, and Kallikreins (KLK) 5 and 14
3.3. Mas-Related G-Protein Coupled Receptors (Mrgprs)
3.4. 5-Hydroxytryptamine (5-HT, Serotonin)
3.5. Leukotrienes
4. Cytokine and Chemotactic Factor Induced Itch
4.1. IL-13
4.2. IL-31
4.3. IL-33
4.4. IL-6
4.5. IL-2
4.6. TSLP
4.7. Periostin
4.8. Lipocalin-2 (LCN2)
4.9. Serpin E1
4.10. Oncostatin M (OSM)
4.11. C-X-C Motif Chemokine Ligand 10 (CXCL10)
4.12. Chemokine C-C Motif Chemokine 2 (CCL2)
5. Research Progress on Itch Therapeutical Development
6. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug Category | Drug Names | Advantages | Disadvantages |
---|---|---|---|
Targeted monoclonal antibodies (mAb) | Dupilumab | Is a fully human mAb against IL-4Rα that inhibits both IL-4 and IL-13 signaling; is the first approved mAb for AD treatment; demonstrated efficacy and acceptable safety on patients with AD and some other chronic pruritic diseases [192,193]; currently, is ongoing second phase 3 trials on Prurigo Nodularis; is effective in Netherton syndrome, an itchy disease, in a case study [194]. | High cost and side effects that cause eye discomfort (especially conjunctivitis) [80,195,196]; administered subcutaneously twice weekly which is painful for children [197]; cannot treat sub-population of patients. |
Tralokinumab | Is a fully human mAb that potently and specifically neutralizes IL-13; in phase 3 for moderate-to-severe adult AD; subcutaneous tralokinumab has an acceptable safety and tolerability profile and appears to provide early improvements in disease symptoms including itch, in participants with moderate-to-severe AD [2]; less costly than dupilumab. | Less effective than Dupilumab [198]. | |
Lebrikizumab | Is a novel, high-affinity, monoclonal antibody targeting IL-13 that selectively inhibits IL-13 signaling [144,199]; in phase 2 for moderate-to-severe AD; significantly improves clinical manifestations of AD, pruritus, and quality of life in a rapid, dose-dependent manner; generally well tolerated [200,201]; might simultaneously target both inflammation and itch via blocking signals on both immune cells and neurons; less frequency in subcutaneous injection comparing to dupilumab [202]. | Might induce conjunctivitis in a few patients with AD [199,203]. | |
Nemolizumab (CIM331) | Is a humanized antibody against IL-31RA, in the treatment of AD [204]; significantly improves pruritus in patients with moderate-to-severe AD; in two phase 3 trials, nemolizumab plus topical agents improved atopic AD and moderate-to-severe pruritus for up to 68 weeks, without safety issue [205]. | Subcutaneous injection might be associated with higher incidence of injection-site reaction than placebo [204]. | |
Vixarelimab (KPL-716) | Is an OSMRβ antagonist and a fully-human antibody, inhibits the IL-31 signaling and OSM pathway by antagonizing the OSM beta receptor [206]; in phase 2a, subcutaneous injection improves Prurigo Nodularis signs and symptoms, with an average pruritus reduction of 70% by week 8 of treatment as well as significantly improved nodules as early as week 4; safe; currently, it just completed phase 2b in Prurigo Nodularis (ClinicalTrials.gov Identifier: NCT03816891). | No severe adverse effects [206]. | |
Tezepelumab (AMG-157/ MEDI9929) | Is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions; has high curative effect, good safety, and high tolerance level [207]; in phase 2a AD treatment (ClinicalTrials.gov Identifier: NCT02525094), tezepelumab achieved improvement on week 12 and 16 (post hoc), albeit not statistically significant over placebo and the itch relief is limited [177]. | The treatment cycle is longer and expensive, and a few (5.4%) patients developed injection-site erythema, which was not seen in placebo group [177]. | |
Brodalumab (AMG 827) | Is a human anti–IL-17 receptor A IgG2 mAb; in phase 3, it significantly and rapidly improves moderate-to-severe psoriasis, including itch, in patients [208,209,210]; approved by FDA to treat adult moderate-to-severe plaque psoriasis. | Subcutaneous injection might be associated with higher incidence of injection-site reaction than placebo [204]. | |
Secukinumab | Is a fully human anti-interleukin-17A IgG1 monoclonal antibody [211]; is well-tolerated, safe, and effective in psoriasis and associated itch and pain; approved by the US FDA and European Medicines Agency for moderate-to-severe plaque psoriasis and psoriatic arthritis [212,213]; in phase 2 for AD treatment including intrinsic, Asian, and pediatric AD, secukinumab is not effective in reduction of epidermal thickness, epidermal hyperplasia, and immune cell infiltrates, or inflammatory markers in relation to TH17/IL-23 at week 16 [212]. | Observed adverse events, all in secukinumab-treated patients: orbital cellulitis, upper respiratory infection, and streptococcal pharyngitis [212]; treatment of AD is not effective, however, may be helpful in conjunction with TH-2 biological agents [212]. | |
Ixekizumab | Is an IgG4 monoclonal antibody that targets IL-17A; achieved outstanding performance in the itch and moderate-to-severe psoriasis treatment effect at 12 weeks [214]; can demonstrate persistent efficacy through 108 weeks (80 mg ixekizumab every 2 weeks up to week 12 and every 4 weeks thereafter); FDA approved for treatment of adult moderate to severe plaque psoriasis, active psoriatic arthritis [215,216]. | Mild or moderate adverse events included nasopharyngitis, upper respiratory tract infections, injection-site reactions, arthralgia, bronchitis, and headache [217]; some patients may be associated with eczematous eruptions in the face [218]. | |
Ustekinumab | Is an IL-12/IL-23p40 IgG1κ monoclonal antibody that suppresses Th1, Th17, and Th22 activation; approved for psoriasis patients [219]; beneficial clinical effects in moderate-to-severe AD patients [220]; has unique mechanistic effects in AD as early as 4 weeks of treatment; strongest anti-inflammatory effects already occur within 4–8 weeks following an ustekinumab dose, with waning efficacy thereafter [221]. | Individual patients were excluded from analyses after week 28 due to newly developed contact dermatitis and due to worsening skin infection (eczema herpeticum) [221]. | |
Risankizumab | Is a novel IL-23 mAb, with relatively high efficacy and low risk; had been approved by the FDA in April 2019 to treat AD [214], and in June 2022 to treat moderate-to-severe active Crohn’s disease in adults, an itchy disease. | The most relevant adverse events were nasopharyngitis, upper respiratory tract inflammation, and injection site reaction [214]. | |
Guselkumab | Is an IL-23 mAb; approved for moderate-to-severe plaque psoriasis. It has demonstrated safety and efficacy in phase III clinical trials [222,223,224,225]; combined treatment by dupilumab and guselkumab rapidly and sustainably improved itch, erythroderma, and eczema in severe AD associated with congenital ichthyosiform erythroderma (CIE), whereas treatment with dupilumab or guselkumab was less or not effective [226]. | There are scarce data regarding its drug survival in clinical practice [224]; serious adverse events included serious infections, nonmelanoma skin cancer, malignancies other than nonmelanoma skin cancer, and major adverse cardiovascular events [222]. | |
Tildrakizumab | Is a high-affinity, humanized, IgG1 κ antibody targeting p19 subunit of IL-23; demonstrated superior efficacy, safety, and long-term control of moderate-to-severe chronic plaque psoriasis; FDA-approved in 2018 for moderate-to-severe plaque psoriasis [214,227]. | Caused some minor adverse events, including body aches or pain, chills, cough, difficulty in breathing, ear congestion, fever, etc. [227]. | |
IgE antibody | Omizumab | Is a humanized IgG1 mAb. It binds to the Ce3 domain of IgE with higher affinity; is highly selective for human and non-human primate IgE, with higher efficacy, good safety and high tolerance level in vivo; effective in AD, bullous pemphigoid, and urticaria [228]; received FDA breakthrough therapy designation for patients with chronic spontaneous urticaria in patients that cannot be treated effectively by H1 antihistamine. | Reported serious adverse events, viral upper respiratory tract infection (20%), injection-site reaction [229]. |
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Yang, H.; Chen, W.; Zhu, R.; Wang, J.; Meng, J. Critical Players and Therapeutic Targets in Chronic Itch. Int. J. Mol. Sci. 2022, 23, 9935. https://doi.org/10.3390/ijms23179935
Yang H, Chen W, Zhu R, Wang J, Meng J. Critical Players and Therapeutic Targets in Chronic Itch. International Journal of Molecular Sciences. 2022; 23(17):9935. https://doi.org/10.3390/ijms23179935
Chicago/Turabian StyleYang, Hua, Weiwei Chen, Renkai Zhu, Jiafu Wang, and Jianghui Meng. 2022. "Critical Players and Therapeutic Targets in Chronic Itch" International Journal of Molecular Sciences 23, no. 17: 9935. https://doi.org/10.3390/ijms23179935