Unlocking the IL22-IL22R Axis: Precision Strategies for Inflammation and Tissue Damage

In the field of autoimmune and inflammatory disease treatment, the focus is often on suppressing an overactive immune system, but this is frequently accompanied by the risk of systemic immunosuppression. IL22-IL22R offers an alternative approach; it does not act directly on immune cells but targets epithelial cells to promote barrier repair and tissue regeneration, providing a novel therapeutic concept that does not rely on immunosuppression. However, this pathway possesses a dual nature: overactivation can induce inflammation and promote cancer, while loss of signaling leads to barrier damage. Precisely regulating its signal activation and blockade is the core challenge in drug research and development. 

The IL-22/IL-22R Pathway Mediates Immune-Epithelial Cross-Boundary Dialogue

IL-22 (Interleukin-22) is a member of the IL-10 cytokine family and shares homology in sequence and secondary structure with IL-10. Its receptor is a heterodimer composed of IL-22R1 and IL-10R2. Among them, IL-22R1, also known as IL-22RA1, is the high-affinity subunit for IL-22 and exhibits strict tissue expression specificity. It is primarily highly expressed in epithelial and glandular cells of the intestine, skin, liver, and lungs, and is essentially absent on the surface of hematopoietic immune cells (such as T cells, B cells, and macrophages). IL-10R2, also known as IL-10RB, is the low-affinity co-receptor subunit that is widely expressed across various cell types. 

IL-22 also has a secreted receptor, IL-22BP (also known as IL-22RA2 or IL-22R2), which acts as an endogenous blocker by competitively binding to IL-22 in blood and tissues with strong affinity. 

During signal transduction, IL-22 first binds to IL-22R1, triggering a conformational change in IL-22. This promotes the secondary binding of the IL-22 & IL-22R1 complex with IL-10R2, thereby activating signaling pathways such as JAK-STAT3, which promote tissue repair, barrier maintenance, and antibacterial defense. 

IL22-IL22R Signaling Pathway^[1]

Abnormalities in the IL22-IL22R1 pathway are closely related to inflammation, barrier damage, and repair imbalances in multiple tissues such as the skin, intestine, liver, and pancreas. Its role has obvious two-sidedness: it can promote epithelial survival, regeneration, and repair in states of tissue injury and barrier disruption, whereas sustained or dysregulated IL-22 signaling may drive abnormal epithelial proliferation and chronic inflammation. 

IL-22 promotes repair in acute injury, but may exacerbate abnormal proliferation in chronic diseases^[2]

Accordingly, drug development is divided into two paths: antagonists primarily target inflammatory diseases such as atopic dermatitis and psoriasis, while agonists target emerging areas such as MASH, metabolic syndrome, and GVHD, utilizing its tissue repair and metabolic regulation functions to open up new therapeutic fields. This is also a distinct difference between IL-22 and many other cytokine targets.

IL22-IL22R Drug Development

Antagonist Route: Targeting Abnormal Skin Hyperplasia and Atopic Inflammation

Temtokibart is the world's first and currently the most clinically validated, highly selective monoclonal antibody targeting IL-22R1. This drug was initially developed by argenx and subsequently licensed to LEO Pharma, which focuses on dermatology, to advance further clinical research. Compared to antibodies that only block the IL-22 ligand, Temtokibart can "kill three birds with one stone" by simultaneously cutting off the downstream signaling of three inflammatory factors: IL-22, IL-20, and IL-24, achieving a broader pathway inhibition from the receptor end. At the same time, Temtokibart precisely selected atopic dermatitis, where the IL22-IL22R1 pathway is predominant, as its primary indication. Combined with its ultra-high affinity at the pM level, these factors collectively laid the foundation for its excellent clinical efficacy. 

In a Phase 2a study of 58 patients with moderate-to-severe AD, the EASI score at week 16 improved by 65.4% from baseline, significantly outperforming the 19.7% in the placebo group (P=0.003). The achievement rates for EASI-75, EASI-90, and EASI-100 reached 41.6%, 30.8%, and 20.9%, respectively, whereas the placebo group was only 13.7%, 3.5%, and 0%, and overall tolerability was good with no new safety signals observed. The subsequently announced Phase 2b study further met its primary endpoint, with the EASI score at week 16 improving from baseline by 64.3%, 57.1%, and 61.2% in the 300, 450, and 600 mg dose groups, respectively, all of which were significantly superior to the 41.7% in the placebo group, and the efficacy was sustained until week 32 after drug discontinuation. 

Clinical efficacy of Temtokibart in atopic dermatitis^[3]

Agonist Route: Targeting Mucosal Barrier Repair and Organ Damage Rescue

Promenakin (F-652) is an IL-22 fusion protein developed by Yifan/Evive Biotech. It is formed by the fusion of human IL-22 with human IgG2 Fc to create a homodimer, combining the biological activity of IL-22 with the long-acting characteristics mediated by the Fc region. In a Phase 2 clinical study, patients with alcoholic hepatitis (AH) who received treatment showed a significant decrease in MELD score and transaminases on days 28 and 42, and the proportion of patients with a Lille score ≤0.45 on day 7 reached 83%. Patients with gastrointestinal acute graft-versus-host disease (GIaGVHD) achieved an overall response rate of 70% after combined treatment with systemic corticosteroids, demonstrating clinical potential in the field of tissue damage repair in organs such as the liver and intestines. 

Changes in △MELD, bilirubin, and aminotransferases after Promenakin treatment in AH patients^[4]

Improvement in GVHD staging after Promenakin treatment in GIaGVHD patients^[5]

IL22-IL22R1 is not merely a pro-inflammatory or anti-inflammatory target; the direction of drug development depends on the core pathological features of the disease. When the disease is primarily driven by abnormal epithelial proliferation and inflammation, it should be blocked (e.g., atopic dermatitis); however, when it is dominated by tissue injury and inadequate barrier repair, it needs to be activated (e.g., alcoholic hepatitis, GVHD). Therefore, the key to developing indications for this target lies in whether the disease requires suppression or repair. Overview of IL22-IL22R1 related drugs:

KACTUS Recombinant IL22-IL22R Proteins Support Related Drug Development

Focusing on cutting-edge drug development for immune inflammation and tissue repair, KACTUS has launched a series of recombinant IL-22 and IL-22R products, covering multiple species and diverse tag proteins, with strictly controlled endotoxin levels and activity, providing support for the screening and evaluation of innovative drugs targeting the IL-22 pathway. 

Data Examples 

Immobilized Human IL-22, His Tag at 2 μg/ml (100 μl/Well) on the plate. Dose response curve for Human IL-22R alpha 1, hFc Tag with the EC50 of 10.6 ng/ml determined by ELISA (QC Test).

Loaded Human IL-22R alpha 1, hFc Tag on ProA-Biosensor can bind Human IL-22, His Tag with an affinity constant of 42.60 nM as determined in BLI assay (QC Test).

Immobilized Human IL-22R alpha 1, His Tag at 0.5 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-IL-22R alpha 1 Antibody, hFc Tag with the EC50 of 6.4 ng/ml determined by ELISA (QC Test).

Product List

References

[1] Harnessing IL-22 for metabolic health: promise and pitfalls. doi: 10.1016/j.molmed.2024.10.016.
[2] I don’t know about you, but I’m feeling IL-22. doi: 10.1016/j.cytogfr.2024.11.001.
[3] Targeting IL-22RA1 with temtokibart: A novel approach in atopic dermatitis: Phase 2a monotherapy
study results. doi: 10.1016/j.jaci.2025.08.034.
[4] AN OPEN LABEL, DOSE ESCALATION STUDY TO ASSESS THE SAFETY AND EFFICACY OF
IL-22 AGONIST F-652 IN PATIENTS WITH ALCOHOLIC HEPATITIS. doi: 10.1002/hep.31046.
[5] A phase 2 study of interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of
the lower GI tract. doi: 10.1182/blood.2021015111.