IL-22 Drug Screening Cell Model

Interleukin 22 (IL-22) is a member of the IL-10 cytokine superfamily. Unlike most interleukins, it does not directly regulate the function of immune cells, but acts on cells on the tissue barrier, inducing them to produce antibacterial proteins and specific Chemokines are important proteins in anti-infection immunity. It shares IL-10R2 with other members of this family, IL-10, IL-19, IL-20, IL-24 and IL-26, in cell signaling, but functions differently. IL-22 protein, consisting of 146 amino acids, is a key cytokine that regulates tissue responses and is upregulated in patients with many chronic inflammatory diseases, including psoriasis, rheumatoid arthritis and inflammatory bowel disease (IBD), becoming a potential targets for the treatment of these diseases.

The receptor of IL-22 is a heterodimer composed of IL-22R1 and IL-10R2. IL-22R1 is also the receptor subunit of another IL-10 family cytokine (IL-24). In addition to the receptors routinely expressed on the cell membrane, IL-22 also has a single-chain secretory receptor IL-22BP, which has a very high affinity with IL-22 ligands and can block IL-22 binding to extracellular IL-22. Signal. IL-22 binds to its receptor complex in two steps. First, on the surface of the cell membrane, IL-22 binds to IL-22RA1, causing a change in the conformation of IL-22 protein, allowing it to bind to IL-10RB2. The combination of IL-10RB can make IL The combination of -22 and IL-22RA1 is more stable. The formation of IL-22/IL-22RA1/IL-10RB complex can phosphorylate downstream JAK1 and TYK2, and the activated JAK1 phosphorylates STAT3, and STAT3 is transported to the nucleus, binds to response elements, and regulates the expression of its target genes. At the same time, it can also activate STAT1 and STAT5, and can also activate MAPK and Akt-mTOR signaling pathways. IL-22-mediated signaling pathway can enhance cell anti-infection, anti-inflammation, strengthen the expression of mitosis, proliferation and anti-apoptosis genes, promote local tissue regeneration and host defense, and accelerate the proliferation, remodeling and repair of various tissues and organs , to maintain the inherent host defense mechanisms that control pathogen invasion.

IL-22 function

IL-22 can inhibit the production of cytokines in lung epithelial cells, play an anti-inflammatory role, and inhibit allergic airway inflammation.

In epithelial cells, IL-22 can enhance the expression of antibacterial binding proteins and cell chemokines, inhibit the differentiation of epithelial cells, play a host defense role, and have antibacterial effects.

IL-22 acts on skin epithelial cells to promote their regeneration, inhibit their apoptosis and promote the expression of tight junction proteins to maintain the integrity of the epithelial barrier.

In gastrointestinal epithelial cells, IL-22 can enhance the production of mucus-associated proteins and regulate the composition of gut microbiota, thus playing a host defense role in the gastrointestinal mucosal defense mechanism.

In hepatocytes, IL-22 can increase the expression of anti-apoptotic proteins, mitotic proteins, regenerative and antibacterial proteins, induce the production of acute phase proteins, and protect the liver.

IL-22 and disease

In patients with atopic dermatitis (AD), the level of IL-22 will be significantly increased. Its role has two sides, mainly reflected in the effect on keratinocytes: IL-22 promotes the proliferation of keratinocytes, inhibits differentiation, and can be used in Plays a role in wound healing remodeling and innate defense mechanisms. But more importantly, overexpression of IL-22 can induce significant skin hyperplasia and inflammation, inhibit epithelial cell differentiation and promote keratinocyte migration, playing an important role in the immune pathogenesis of AD.

In psoriasis, the level of IL-22 is significantly increased, leading to changes in cytokines and inflammatory mediators, playing a role in chemoattracting inflammatory cells, promoting keratinocyte proliferation, and inhibiting keratinocyte differentiation. It is an important factor in the pathogenesis of psoriasis. of cytokines.

IL-22 is associated with IBD (inflammatory bowel disease, inflammatory bowel disease). Although IL-22 levels are higher in IBD patients, intestinal barrier dysfunction and inflammation persist, IL-22BP expression is upregulated and IL-22 receptor The lack of IL-22 may be the reason, and IL-22 may be required to overcome IL-22BP-mediated inhibition and induce mucosal healing, leading to the exacerbation of enteritis.

GVHD (graft-versus-host disease, graft-versus-host disease) is the main cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. Before transplantation, patients need to use radiotherapy or chemotherapy drugs to eliminate host immune cells, resulting in the destruction of the epithelial barrier. Subsequent leakage of microbial products into the systemic circulation is thought to activate recipient antigen-presenting cells and increase the subsequent expansion of donor T cells, leading to T-cell-dependent inflammation. IL-22 can act on barrier repair and anti-inflammation.

The most common cause of alcoholic hepatitis is alcohol consumption. Existing studies have shown that IL-22 has a strong protective effect on liver cell damage. The mechanism of IL-22 action may include inducing the expression of anti-apoptotic, mitotic, anti-inflammatory, antibacterial, regenerative acute phase proteins and antioxidant proteins in damaged hepatocytes and hepatic stem cells, acting on hepatocytes and hepatic stem cells, Protects the liver from damage and promotes its regeneration, promotes cell proliferation and prevents apoptosis, protects liver cells from oxidative stress.

Current status of research and development of IL-22-targeted drugs

At present, IL-22-targeted drugs mainly include IL-22 recombinant or fusion protein, IL-22RA1/IL-22 antibody, etc., all of which are in the clinical research stage, and no drug has yet been marketed. At present, the following 5 drugs are in the clinical research stage, among which the leading ones are EVIVE's F-652 and LEO Pharma's 138559:

(1) LEO 138559 is an IL-21RA1 monoclonal antibody for the treatment of moderate to severe atopic dermatitis. It has completed Phase IIa study and reached the primary endpoint. It can block the interaction between IL-22RA1 receptor subunit and IL -22 binding, thereby inhibiting the role of IL-22.

(2) F-652 is a recombinant human interleukin 22-Fc (IgG2) fusion protein expressed by CHO cells. The Fc fragment can prolong the half-life of IL-22 and improve the efficacy of the drug. It has completed two indications for AH and GVHD The phase IIa clinical trial in the United States initially verified the safety and effectiveness, and was granted orphan drug qualification by the FDA for the treatment of acute graft-versus-host disease;

(3) Fezakinumab is a drug developed by IIT for the treatment of atopic dermatitis. It is a humanized IL-22 monoclonal antibody. It has completed the phase IIa clinical trial, and the results show that there is no observation in the entire research population. There was a significant difference in SCORAD decline, but in the subgroup of patients with severe atopic dermatitis, SCORAD decline (primary endpoint) was significantly higher in fezakinumab-treated patients than placebo.

In response to the needs of IL-22 drug development and research, we have developed the IL22 Effector Reporter Cell drug screening cell model, welcome to inquire. Part of the data is shown below:

IL22 Effector Reporter Cell RQP74175

Figure 4. Recombinant IL22 Effector Reporter Cell constitutively expressing IL22R.

Figure 5. Recombinant IL22 Effector Reporter Cell constitutively expressing IL10RB.

Figure 6.Dose Response of Recombinant Human IL-22 in Human IL-22 Effector Reporter Cells(C8).

Figure 7.Inhibition of IL-22-induced Reporter Activity By IL-22 Neutralization Ab in IL-22 Effector Reporter Cells(C8).