IL23A

Official Full Name

interleukin 23 subunit alpha

Organism

Homo sapiens

GeneID

51561

Background

This gene encodes a subunit of the heterodimeric cytokine interleukin 23 (IL23). IL23 is composed of this protein and the p40 subunit of interleukin 12 (IL12B). The receptor of IL23 is formed by the beta 1 subunit of IL12 (IL12RB1) and an IL23 specific subunit, IL23R. Both IL23 and IL12 can activate the transcription activator STAT4, and stimulate the production of interferon-gamma (IFNG). In contrast to IL12, which acts mainly on naive CD4(+) T cells, IL23 preferentially acts on memory CD4(+) T cells. [provided by RefSeq, Jul 2008]

Synonyms

P19; SGRF; IL-23; IL-23A; IL23P19;

Bio Chemical Class

Cytokine: interleukin

Protein Sequence

MLGSRAVMLLLLLPWTAQGRAVPGGSSPAWTQCQQLSQKLCTLAWSAHPLVGHMDLREEGDEETTNDVPHIQCGDGCDPQGLRDNSQFCLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSPVGQLHASLLGLSQLLQPEGHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVFAHGAATLSP

Open

Disease

Asthma, Crohn disease, Indeterminate colitis, Inflammatory spondyloarthritis, Malaria, Mature B-cell leukaemia, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Solid tumour/cancer, Ulcerative colitis

Approved Drug

4 +

Clinical Trial Drug

7 +

Discontinued Drug

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Detailed Information

IL23A is the interleukin-23 alpha subunit, also known as IL-23p19, which combines with IL12B to form the pro-inflammatory cytokine IL-23. IL-23 plays distinct roles in innate and adaptive immunity and is released by antigen-presenting cells such as dendritic cells or macrophages. It binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R. The IL-23 signaling pathway is crucial in driving human chronic diseases and is essential for the pathogenesis of many autoimmune diseases, including ulcerative colitis (UC), Crohn's disease (CD), and inflammatory bowel disease (IBD). IL23A is primarily expressed in macrophages, dendritic cells, and Langerhans cells, with expression also found in glandular epithelial cells and specialized epithelial cells.

Structure of IL23A

IL23A is a secreted protein consisting of 189 amino acids, composed of 4 alpha helices. It forms a dimer with the IL-12p40 subunit through disulfide bonds to constitute IL-23. The IL-23 receptor complex includes IL-23R and IL-12Rβ1, where the IL-12p40 subunit binds to IL-12Rβ1, while the IL-23p19 subunit binds to IL-23R, initiating intracellular signal transduction.

IL-23 Signaling Pathway and Regulation

When IL-23 binds to its receptor complex, it activates JAK2 and TYK2, followed by phosphorylation of the receptor to form docking sites, leading to the phosphorylation of STAT3 and STAT4. The IL-23 signaling pathway promotes the proliferation and differentiation of T helper 17 (Th17) cells, which produce IL-17A, IL-17F, IL-22, tumor necrosis factor (TNF)-α, IFNγ, and IL-26. These cells are participants in autoimmunity and play important roles in the development of autoimmune diseases.

Figure 1.IL-23 Signaling Pathway. (Jairath V, et al., 2024)

Targeted Therapy of IL23A

By blocking IL-23A, the activation and proliferation of Th17 cells, which play a key role in autoimmune responses, can be reduced. Currently, four monoclonal antibody drugs targeting IL23A (IL23p19) have been approved for marketing: Mirikizumab, ABBV 066 (Risankizumab-RZAA), Tildrakizumab-ASMN, and Guselkumab. There are also numerous IL23p19 inhibitors in clinical development.

Guselkumab (TREMFYA), developed by Johnson & Johnson, was first approved in the United States in July 2017 for the treatment of adults with moderate to severe plaque psoriasis, and in July 2020 for the treatment of adults with active psoriatic arthritis. TREMFYA is the first and only approved fully human dual-action monoclonal antibody that blocks IL-23 while binding to the CD64 receptor on cells that produce IL-23.

Mirikizumab (Omvoh) is a humanized IgG4 anti-human IL-23p19 monoclonal antibody approved in 2023. It selectively targets the p19 subunit of IL-23 and inhibits the IL-23 pathway for the treatment of ulcerative colitis.

Picankibart (IBI112) is a monoclonal antibody targeting IL-23p19 developed by Innovent Biologics. Its New Drug Application (NDA)/Biologics License Application (BLA) has been accepted for review by the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) for the treatment of moderate to severe plaque psoriasis. The study successfully achieved its primary endpoint and all key secondary endpoints in May 2024, showing that a significantly higher proportion of subjects in the Picankibart monotherapy group achieved skin lesion clearance and quality of life improvement compared to the placebo group. During the treatment period, Picankibart monotherapy showed a good overall safety profile with no new safety signals identified. IBI112 has the potential to provide more effective treatment with longer dosing intervals for patients with psoriasis, ulcerative colitis, and other autoimmune diseases.

JNJ 4804 is a combination therapy of the TNF antibody Glolimumab and the IL-23 antibody Guselkumab for the treatment of ulcerative colitis and Crohn's disease, currently in phase 2 clinical studies.

References

Jairath V, Acosta Felquer ML, et al. IL-23 inhibition for chronic inflammatory disease. Lancet. 2024;404(10463):1679-1692.
Schinocca C, Rizzo C, Fasano S, et al. Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview. Front Immunol. 2021 Feb 22;12:637829.

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