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On March 25, 2023, China has achieved a significant milestone by successfully launching the first developed monoclonal antibody drug targeting IL-17A (Xeligekimab, GR1501). GR1501 is a human IL-17A-neutralizing IgG4 monoclonal antibody, which was applied for the treatment in skin and rheumatic diseases like psoriasis, spondylitis, even inflammation-associated cancers. In recent years, IL-17A’s exceptional clinical efficacy made it a highly sought-after inflammation target globally.
With the advent of a new series of IL-17A monoclonal antibodies, it is anticipated that the market size for IL-17A drugs will sky-rocket. In parallel, as an indispensable member of the Interleukin-17 (IL-17) family, IL-17A has been identified as a key driver in the interleukin inhibitors market which is projected to surge over $57.87 billion by 2026!
1. What are Members of Interleukin-17 Family?
3. How’s the Mechanism of Action of IL-17A in Inflammation?
The interleukin-17 (IL-17) cytokines are emerging as critical players in host defence responses and inflammatory diseases [1]. The IL-17 family comprises at least six members (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, andIL-17F), which is mainly produced by activated CD4+ T helper type 17 (Th17) subset [2]. IL-17 ligands exert their biological effects by binding to the corresponding heterodimeric receptors (IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE) (Figure 1) [3]. Among all the members, IL-17A is best understood, but the other members have been far less extensively studied. Accumulating research suggested that IL-17A plays a central role in inflammatory processes and participates in cancer progression.
Figure 1. IL-17 binds to the specific receptor to exert biological functions [3]
Interleukin-17A (IL17A, commonly referred to as IL-17), is a cytokine that belongs to the interleukin 17 family. IL17A is initially identified as CTLA-8, mainly produced by Th17 cells, while other diverse immune cells including CD8+ T cells, γδ T cells, NK cells also express IL-17A [5]. IL17A is a key proinflammatory cytokine that links T cell activation to neutrophil mobilization and activation. As such, IL-17A can mediate protective innate immunity to pathogens or contribute to the pathogenesis of inflammatory diseases.
At present, a variety of IL-17A monoclonal antibodies and inhibitors are presently in development to tackle an array of inflammatory conditions like psoriasis, atopic dermatitis (AD), vitiligo, rheumatoid arthritis, spondylitis, and even malignant melanoma [6]. Besides, IL-17A also functions as a multifaceted cytokine in cancers, which has predominantly been identified as a protumorigenic factor, while some investigations have indicated its potential as an antitumorigenic cytokine [7].
IL-17A mainly mediates its immune regulatory function by promoting the generation of pro-inflammatory cytokines and chemokines. IL-17-driven inflammation is normally controlled by regulatory T cells and the anti-inflammatory cytokines IL-10, TGF-β, and IL-35. Plus, its aberrant expression has also been linked to various malignancies, but it exhibits oncogenic or proto-oncogenic behavior in diverse cancers.
In psoriasis, the IL-23/Th17/IL-17A axis plays a key role. IL-17A engages with its receptor IL-17R, facilitating aberrant keratinocyte differentiation and proliferation, activating chemokine expression (CXCL1, CXCL2, and CCL20), promoting recruitment of Th17 and dendritic cells to the skin, ultimately leading to disruption of skin barrier function (Figure 2) [8-9]. Similarly, in atopic dermatitis, the elevated expression of IL-17A, IL-17E, IL-17F, and IL-23 has been observed in children with AD, which is correlated with the disease severity [11].
Figure 2. IL-17A regulates cytokines or chemokines in psoriasis [9]
In Ankylosing spondylitis, elevated disease activity is positively correlated with enhanced IL-17A expression levels. Furthermore, IL-17A and IL-35 function as a pair of pro-/anti-inflammatory cytokines that are closely interrelated, and thereby sustain a relative equilibrium in their expression levels under normal physiological circumstances; however, once this homeostasis is disrupted, a cascade of autoimmune disorders may ensue [12]. Notably, excessive IL-17 expression can inflict damage on skin cells and tissues, thereby impairing melanocyte function and causing depigmentation, ultimately culminating in vitiligo [13].
In the case of melanoma, IL-17A has been implicated in driving the secretion of PGE2 and VEGF, leading to increased expression of intercellular adhesion molecules. This process ultimately facilitates tumor angiogenesis through IL-17-VEGF pathway (Figure 3) [16]. In addition, colorectal cancer is characterized by up-regulated IL-17A expression, which triggers the expression of TGF-β, CXCR3, CCR6, IL-6, and other immunosuppressive mediators [17]. Moreover, in ovarian cancer, IL-17A knockdown can effectively curtail VEGF-A expression by inhibiting the IL-17-STAT3 signaling pathway. As a result, this approach could suppress tumor cell proliferation [18].
Figure 3. IL-17A regulates angiogenic factors in tumors [16]
IL-17A, a recently discovered cytokine, possesses potent pro-inflammatory properties that facilitate the initiation and persistence of the inflammatory response. Inflammatory cells and their associated factors play vital roles within the tumor microenvironment. Although the involvement of IL-17A in inflammatory and autoimmune skin diseases is well documented, its precise contribution to tumorigenesis needs to be further elucidated.
Psoriasis is a chronic inflammatory skin disease mediated by a variety of genetic, environmental, and immune factors. A variety of inflammatory cell-secreted cytokines known to be involved in psoriasis include IL-17A, IL-8, IL-21, IL-6, IL-25, IL-19, IL-36, and TNF-α etc. IL-17A plays an important role in the immunological pathogenesis of psoriasis. There are corresponding monoclonal antibody drugs targeting IL-17A that can rapidly and effectively treat moderate to severe psoriasis, including Ixekizumab, Secukizumab, Bimekizumab, Netakimab [19].
Ankylosing Spondylitis (AS) is a persistent inflammatory autoimmune ailment that leads to joint ankylosis and spinal deformity. The primary genetic risk factors associated with AS include TBX21, IL-27, PTGER4, NKX2-1, IL-12B, IL-7R, IL-6R, IL-1R2, IL-1R1, which are predominantly linked with a key effector cytokine IL-17A. Presently, the role of IL-17A in AS has garnered widespread attention since it is highly expressed in joints, synovial fluid, and serum with CD4+ T lymphocytes in AS patients [20].
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disorder that results from aberrant immune activation, leading to tissue damage. The pathogenesis of SLE involves the dysregulation of various immune cells, among which Th17 cells have been found to play a pivotal role in orchestrating inflammatory responses and promoting organ damage. Notably, SLE patients present with elevated expression of various cytokines including IL-17A, IL-23, and HMGB1, which are closely linked to disease activity. These observations underscore the potential involvement of IL-17A in modulating the SLE development [21].
The intricate involvement of IL-17A and Th17 in melanoma has been identified by various studies. Notably, Th17 cells have been shown to activate CD8+ T cells in mouse tumor models, which leads to the eradication of melanoma in mice [22]. In addition, it has been reported that Th17 cells play a pivotal role in mediating the destruction of advanced B16 melanoma, with the therapeutic effect being highly contingent on interferon (IFN) production [23]. On the other hand, the pro-tumor impact of IL-17A is facilitated via the IL-6-STAT3 signaling pathway in tumor cells [24]. Emerging evidence suggests that elevated expression of IL-17A and IL-23 in cutaneous melanoma may be linked to its aggressiveness when compared to benign naevi [25].
In colon cancer, CT26 cells stably transfected with pc DNA3.1-IL-17, researchers found that the tumor growth in pc DNA3.1-IL-17 was inhibited than that of the pc DNA3.1 cell group. Besides, higher levels of IFN-γ, IL-4, GATA-3, ROR-γt, and IL-10 have been observed in pc DNA3.1 cell group. These findings implied that IL-17 has significant anti-tumor effects. However, IL-17A has been shown to promote the migration and invasiveness of colorectal cancer cells through NF-κB-mediated MMP expression [26-27]. Therefore, what is worth highlighting is IL-17A's dual character in cancer development-it could be pro- as well as anti-tumorigenic.
In a xenograft model of human epithelial ovarian cancer, mice were randomly assigned to either control or IL-17A-siRNA groups. The study found that as IL-17A knockdown, the expression of JAK and p-STAT3 was significantly reduced, while Caspase-3, Caspase-8, and Caspase-9 expression were markedly increased. Another study also suggested that IL-17 induces MTA1 expression to enhancing epithelial-to-mesenchymal transition (EMT) and tumor cell invasion. Collectively, it can be concluded that inhibiting IL-17A expression induces apoptosis in tumor tissues and constrains the progression of ovarian cancer [28-29].
IL-17A has emerged as an important target for the treatment of inflammatory, autoimmune, and neoplastic skin diseases. Four IL-17-targeting drugs have been approved worldwide for the treatment of psoriasis and ankylosing spondylitis. Data from Pharmsanp show that more biologics targeting IL-17A are in clinical research stage, mainly for the treatment of inflammation-induced immune system diseases such as psoriasis, systemic lupus erythematosus and malignant melanoma. Currently, more IL-17A monoclonal antibodies have been developed by global pharmaceutical companies such as Eli Lilly & Co., Novartis Pharma AG, Affibody AB, and Immunic AG etc (Table 1)
| Drug Name | Target | Drug Type | Institutes | Global R&D Status | China R&D Status |
|---|---|---|---|---|---|
| Ixekizumab | IL17A | Humanized monoclonal antibodies | Eli Lilly and Company | Approval for listing | Approval for listing |
| Secukinumab | IL17A | Fully human monoclonal antibody | Novartis Pharmaceuticals | Approval for listing | Approval for listing |
| Bimekizumab | IL17 | Humanized monoclonal antibodies | UCB | Approval for listing | Clinical Phase III |
| Netakimab | IL17 |
Chimeric monoclonal antibodies; Humanized monoclonal antibodies |
Biocad | Approval for listing | Clinical Phase III |
| Xeligekimab | IL17A | Fully human monoclonal antibody | Ji Xiang Jintai | Application for listing | Application for listing |
| Gumokimab | IL17A | Monoclonal antibodies | Zhongshan Kangfang | Clinical Phase III | Clinical Phase III |
| SSGJ-608 | IL17A | Humanized monoclonal antibodies | Sansheng Guojian | Clinical Phase III | Clinical Phase III |
| Secukinumab biosimilar | IL17A |
Fully human monoclonal antibodies; Biosimilars |
BIOTEK | Clinical Phase III | Clinical Phase III |
| Vunakizumab | IL17A | Humanized monoclonal antibodies | Hengrui Pharmaceutical | Clinical Phase III | Clinical Phase III |
| Recombinant anti-lL 17A humanized monoclonal antibody | IL17A | Humanized monoclonal antibodies | Junshi Bio | Clinical Phase II | Clinical Phase II |
| Recombinant human IL-17A/F humanized antibody | IL-17F, IL17A | Humanized monoclonal antibodies | Lizhu Pharmaceutical Xinkanghe | Clinical Phase II | Clinical Phase II |
| Sonelokimab | IL-17F, IL17A | Nanobodies | Ablynx Nv | Clinical Phase II | No declaration |
| QX002N | IL17A | Biologics | Tsuenxin Bio | Clinical Phase II | Clinical Phase II |
| HB-0017 | IL17 | Biologics | Huabo Bio/Huaotai | Clinical Phase II | Clinical Phase II |
| JNJ-63823539 | IL17A, TNFα | Bispecific antibodies | Yang Sen | Clinical Phase I | No declaration |
| ZL-1102 | IL17A | Fragment Antibodies | Crescendo Pharmaceuticals/Crescendo | Clinical Phase I | Clinical Phase I |
| CMAB-015 | IL17A | Biosimilars | Meibertec | Clinical Phase I | Clinical Phase I |
| UCB-0159 | IL17A, TNF | Bispecific antibodies | UCB | Clinical Phase I | No declaration |
| JNJ-61178104 | TNFα, IL17A | Bispecific antibodies | Yang Sen | Clinical Phase I | No declaration |
| SCH-900117 | IL17A | Humanized monoclonal antibodies | Merck Sharp & Dohme | No progress (clinical phase I) | No declaration |
| Perakizumab | IL17 | Humanized monoclonal antibodies | Roche | No progress (clinical phase I) | No declaration |
| Tibulizumab | BAFF/BLy, IL17A | Bispecific antibodies | Eli Lilly and Company | No progress (clinical phase I) | No declaration |
| RO-7040547 | IL13, IL17A | Bispecific antibodies | Genentech | No progress (clinical phase I) | No declaration |
| Afasevikumab | IL17 | Fully human monoclonal antibody | Novimmune Sa | No progress (clinical phase I) | No declaration |
| ABBV-257 | IL17, TNFα | Immunoglobulins, Bispecific antibodies | Abbott Abbott Laboratories | No progress (clinical phase I) | No declaration |
| BCD-121 | IL17, TNFα | Fully human monoclonal antibody | Biocad | No progress (clinical phase I) | No declaration |
| LQ-025 | IL17A | Nanobodies | Loqi Bio | Preclinical | Preclinical |
| Ori-Ab-004 | IL17A | Monoclonal antibodies | Hara-Ki Bio | Preclinical | Preclinical |
| Secukinumab biosimilar | IL17A | Monoclonal antibodies | Boan Bio | Preclinical | No declaration |
| LQ-026 | IL17A., TNFα | Bispecific antibodies | Loqi Bio | Preclinical | Preclinical |
| LNR-653.1 | PGF, VEGF, IL17A | Bispecific antibodies | Biophtha lnc | Preclinical | No declaration |
| ABM-125 | IL17 | Monoclonal antibodies | Abeome Corp | Preclinical | No declaration |
| SCT-650A | IL17 | Monoclonal antibodies | Shenzhou Cell | Preclinical | Preclinical |
| BH-1657 | IL17, TNFα | Bispecific antibodies | Hanmi Pharmaceutical Co. | Preclinical | No declaration |
| ND-016 | IL17, TNFα, IL5RA, CD3 | Trispecific antibodies | Numab Therapeutics Ag | Preclinical | No declaration |
| anti-IL-17A humanized monoclonal antibody | IL17A | Humanized monoclonal antibodies | Fontainez | Clinical Applications | Clinical Applications |
| CNTO-6785 | IL17A | Fully human monoclonal antibody | Morphosys Ag/Janssen | Clinical Applications | Clinical Applications |
| CJM-112 | IL17A | Fully human monoclonal antibody | Novartis Pharmaceuticals | Clinical Applications | Clinical Applications |
Table 1: IL-17A Clinical Trials for Drug Development
To fully support researchers and pharmaceutical companies in their research on IL-17A in psoriasis, autoimmune diseases, or cancers, CUSABIO presents a series of IL-17A active proteins to support your research on the mechanism of IL-17A or its potential clinical value. (click for the full list of IL-17A products: IL-17A Proteins; IL-17A antibodies; IL-17A ELISAs)
IL-17A protein:
Recombinant Human Interleukin-17A(IL17A)(T26A) (Active)
-SDS.jpg)
The high specifity was validated by western blot. (Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
-AC1.jpg)
Immobilized Human IL17A at 2 μg/ml can bind Anti-IL17A recombinant antibody (CSB-RA624104MA1HU), the EC50 is 1.818-2.170 ng/mL.
| Product Name | Code | Size |
|---|---|---|
| Recombinant Human Interleukin-17A(IL17A)(T26A) (Active) | CSB-BP624104HU(M) | 100ug/20ug |
| Recombinant Human Interleukin-17A (IL17A) (Active) | CSB-AP004331HU | 1mg/500ug/50ug/10ug |
| Recombinant Human Interleukin-17A (IL17A) (Active) | CSB-AP004341HU | 1mg/500ug/50ug/10ug |
| Recombinant Human Interleukin-17A & Interleukin-17F (IL17A & IL17F) (Active) | CSB-AP004701HU | 1mg/500ug/50ug/10ug |
| Recombinant Mouse Interleukin-17A(Il17a),partial (Active) | CSB-AP004781MO | 1mg/500ug/50ug/10ug |
| Recombinant Rat Interleukin-17A(Il17a) | CSB-EP717213RA | 1mg/100ug/20ug |
| Recombinant Human Interleukin-17A protein(IL17A) | CSB-AP001851HU | 500ug/100ug/5ug |
References
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[2] Baker, Kevin James, Elizabeth Brint, and Aileen Houston. "Transcriptomic and functional analyses reveal a tumour-promoting role for the IL-36 receptor in colon cancer and crosstalk between IL-36 signalling and the IL-17/IL-23 axis." British Journal of Cancer 128.5 (2023): 735-747.
[3] McGeachy, Mandy J., Daniel J. Cua, and Sarah L. Gaffen. "The IL-17 family of cytokines in health and disease. "Immunity 50.4 (2019): 892-906.
[4] Brevi, Arianna, et al. "Much more than IL-17A: cytokines of the IL-17 family between microbiota and cancer." Frontiers in immunology 11 (2020): 565470.
[5] Watad, Abdulla, et al. "Normal human enthesis harbours conventional CD4+ and CD8+ T cells with regulatory features and inducible IL-17A and TNF expression." Annals of the rheumatic diseases 79.8 (2020): 1044-1054.
[6] Le, Thai Van Thanh, et al. "Increased circulatory interleukin-17A levels in patients with progressive and leukotrichial vitiligo. "Dermatology research and practice 2021 (2021).
[7] Brevi, Arianna, et al. "Much more than IL-17A: cytokines of the IL-17 family between microbiota and cancer." Frontiers in immunology 11 (2020): 565470.
[8] Di Padova, Franco, and Jose Carballido. "IL-17A as a Therapeutic Target for Autoimmune Diseases. "IL-17, IL-22 and Their Producing Cells: Role in Inflammation and Autoimmunity (2013): 333-347.
[9] Martin, David A., et al. "The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings." Journal of Investigative Dermatology 133.1 (2013): 17-26.
[10] Nakajima, Saeko, et al. "IL-17A as an inducer for Th2 immune responses in murine atopic dermatitis models." journal of Investigative Dermatology 134.8 ( 2014): 2122-2130.
[11] Brembilla, Nicolo Costantino, Luisa Senra, and Wolf-Henning Boehncke. "The IL-17 family of cytokines in psoriasis: IL-17A and beyond. "Frontiers in immunology 9 (2018): 1682.
[12] Tan, Haitao, Shan Huang, and Tingrui Wang. "Clinical significance of peripheral blood Th1 and Th17 cell content and serum il-35 and il-17 expression in patients with ankylosing spondylitis." Evidence-Based Complementary and Alternative Medicine 2022 (2022).
[13] Bhardwaj, Supriya, et al. "Role of IL-17A receptor blocking in melanocyte survival: a strategic intervention against vitiligo." Experimental Dermatology 28.6 (2019): 682-689.
[14] Sirikanjanapong, Sasis, et al. "Collision tumor of primary laryngeal mucosal melanoma and invasive squamous cell carcinoma with IL-17A and CD70 gene over-expression." Head and neck pathology 4 (2010): 295-299.
[15] Chen, Chen, and Feng-Hou Gao. "Th17 cells paradoxical roles in melanoma and potential application in immunotherapy. "Frontiers in Immunology 10 (2019) : 187.
[16] Ganzetti, Giulia, et al. "IL-17, IL-23, and p73 expression in cutaneous melanoma: a pilot study." Melanoma Research 25.3 (2015): 232-238.
[17] Liu, Chao, et al. "Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer." journal for immunotherapy of cancer 9.1 (2021).
[18] Yu, Chunyan, et al. "IL-17A promotes fatty acid uptake through the IL-17A/IL-17RA/p-STAT3/FABP4 axis to fuel ovarian cancer growth in an adipocyte- rich microenvironment." Cancer Immunology, Immunotherapy 69 (2020): 115-126.
[19] von Stebut, Esther, et al. "IL-17A in psoriasis and beyond: cardiovascular and metabolic implications." Frontiers in immunology 10 (2020): 3096.
[20] Dubash, Sayam, et al. "The advent of IL-17A blockade in ankylosing spondylitis: secukinumab, ixekizumab and beyond." expert review of clinical immunology 15.2 (2019): 123-134.
[21] Montúfar-Robles, Isela, et al. "IL-17A haplotype confers susceptibility to systemic lupus erythematosus but not to rheumatoid arthritis in Mexican patients." International Journal of Rheumatic Diseases 22.3 (2019): 473-479.
[22] Chen, Chen, and Feng-Hou Gao. "Th17 cells paradoxical roles in melanoma and potential application in immunotherapy. "Frontiers in Immunology 10 (2019) : 187.
[23] Wei, Calvin, et al. "Primary mucosal melanoma arising from the eustachian tube with CTLA-4, IL-17A, IL-17C, and IL-17E upregulation. "Ear, Nose & Throat Journal 92.1 (2013): 36-40.
[24] Ghahartars, Mehdi, et al. "Investigation of IL-17A serum levels in patients with nonmelanoma skin cancer." Dermatology Research and Practice 2021 ( 2021): 1-5.
[25] Ganzetti, Giulia, et al. "IL-17, IL-23, and p73 expression in cutaneous melanoma: a pilot study." Melanoma Research 25.3 (2015): 232-238.
[26] Li Yanshuang, et al. "In vivo anti-tumor mechanism of mouse colon cancer cells transfected with IL-17 gene." Chinese Journal of Immunology 31.5 (2015). 643-649.
[27] Wang, Dan, et al. "Serum CCL20 combined with IL-17A as early diagnostic and prognostic biomarkers for human colorectal cancer." journal of translational medicine 17 (2019): 1-11.
[28] Yu, Chunyan, et al. "IL-17A promotes fatty acid uptake through the IL-17A/IL-17RA/p-STAT3/FABP4 axis to fuel ovarian cancer growth in an adipocyte- rich microenvironment." Cancer Immunology, Immunotherapy 69 (2020): 115-126.
[29] Li, Xiaojing, et al. "Celastrol strongly inhibits proliferation, migration and cancer stem cell properties through suppression of Pin1 in ovarian cancer cells." European Journal of Pharmacology 842 (2019): 146-156.
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