Interleukin-23 (IL-23), a member of the IL-12 cytokine family, is a heterodimeric cytokine composed of the IL-12p40 subunit, and with a novel p19 subunit. Interleukin-23 is mainly secreted by activated macrophages and dendritic cells (DCs) located in peripheral tissues (skin, intestinal mucosa and lung) as a disulphide-linked complex with the polypeptide p19 binding protein p40. Interleukin-23 has been implicated in several autoimmune inflammatory disorders such as colitis, gastritis, psoriasis and arthritis, and as a novel pro-inflammatory cytokine, with close resemblance to IL-12.
Interleukin-23 is a major cytokine bridging the innate and adaptive arms of the immune response. It is essential for driving early local immune responses. Interleukin-23 was also initially shown to induce the production of IFN-c, which is important in Th1 responses and cell-mediated immunity against intracellular pathogens. Additionally, IL-23 plays a leading role in the activation of NK cells, enhancement of T-cell proliferation and regulation of antibody production.
Copious evidence supports the theory that increased amounts of IL-23 are associated with several autoimmune diseases including psoriasis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and multiple sclerosis (MS). Meanwhile IL-23 was sufficiently indicated acting as a maturation factor for Th17 cells, which had just been discovered and identified as a main player in autoimmunity. It is remarkable that the effect of antihuman IL-23 monoclonal antibody (mAb) was as efficacious as anti-TNF mAb, which is currently the standard therapy for psoriasis. Studies in mice and humans highlight IL-23 as a drug target for the development of novel therapies for Inflammatory bowel diseases. Serum and synovial fluid levels of IL-23 are correlated positively not only with the IL-17 concentration, but also with the IL-1b and TNF-a, implying that IL-23 is closely linked to the production of other pro-inflammatory and anti-inflammatory cytokines in the course of Rheumatoid arthritis. Hence, the IL-23p19/IL-17 axis is an essential inflammatory mediator for the offensive and destructive phases of autoimmune arthritis. Many findings highlight the importance of regulating the IL-23/IL-17 axis and emphasize the crucial role of IL-23 in the development and maintenance of chronic inflammatory autoimmune diseases.
The level of interest in this target can be seen from the fact that many IL-23 receptor antagonists are now reported to be in clinical or pre-clinical development:
Ustekinumab is an injectable (subcutaneous) mAb against the IL-12/IL-23p40 subunit. The mAb is a high-affinity IgG1j HumAb, which was originally isolated using Medarex Inc.'s HumAb transgenic mouse technology. Ustekinumab prevents the interaction of IL-12/IL-23 with their receptor, thereby blocking subsequent signalling, differentiation and cytokine production central to autoimmune inflammatory diseases.
Briakinumab ia a recombinant, fully human, IgG1 mAb designed to target the shared p40 subunit of IL-12 and IL-23, for the potential subcutaneous treatment of psoriasis.
The inhibition of IL-23 might be a novel and promising therapeutic strategy, especially in the therapy of autoimmune inflammatory diseases like psoriasis, for which therapeutic effectiveness and safety data from ustekinumab are positive. Interleukin-23 can be targeted by using an antibody against IL-12/IL-23; nevertheless, it would be much more useful to design drugs that target the IL-23p19 or IL-23 receptor, so inhibiting IL-23 without modifying the effects of IL-12.
Tang C, et al. Interleukin‐23: as a drug target for autoimmune inflammatory diseases[J]. Immunology, 2012, 135(2): 112-124.