Targeting IL-25: A New Exploration in the Treatment of Type 2 Inflammation

The Signaling Pathway and Functions of IL-25

IL-25 (Interleukin-25), also designated as IL-17E, is secreted by a variety of immune cells, including T cells, dendritic cells, and type 2 innate lymphoid cells (ILC2s). However, the primary source of IL-25 is epithelial cells. It is a member of the IL-17 cytokine family, and functions structurally as a homodimer.

The receptor for IL-25 is a heterodimer consisting of IL-17RA and IL-17RB, the latter of which is the core receptor. IL-25 binds to IL-17RB with high affinity, subsequently recruiting IL-17RA through induced conformational changes to form a signaling-competent IL-17RB & IL-17RA heteroreceptor complex. In CD4+ T cells, this dimer can form a complex with CD3 and CD28. Upon formation, the receptor complex recruits the adapter protein Act1, triggering the upregulation of NF-κB activity and the activation of TRAF4 and TRAF6. This initiates signal transduction through multiple pathways, including p38 MAPK, GATA3, and STAT5 pathways, ultimately causing effector cells to produce and release various cytokines or chemokines including IL-6, Th2-related cytokines, and CXCL10, etc. Consequently, IL-25 plays a pivotal role in bridging innate and adaptive immunity.

IL-25 mediated signaling pathway[1]

IL-25 is a unique member of the IL-17 family. Although it shares limited sequence homology with other IL-17 members, it preserves the characteristic dimeric structure and several conserved cysteine residues of the family. Unlike other members that tend to drive Th17-type inflammation, IL-25 is the sole member that induces Type 2 (Th2) immune responses. By stimulating the production of cytokines such as IL-4, IL-5, and IL-13, it promotes eosinophil activation and mucosal inflammation. These mechanisms are vital for parasite defense but also underpin the pathogenesis of allergies and asthma. As such, IL-25 serves as an independent immune regulatory target, functionally distinct from classic targets like IL-17A.

The role of IL-25 in the pathogenesis of Type 2 Inflammation and autoimmune diseases[2]

The biological role of IL-25 is remarkably context-dependent, characterized by a capacity for dual regulation. On one hand, it drives pathogenesis of asthma and food allergies by enhancing Type 2 inflammation. On the other hand, in models of Type 1 diabetes, experimental autoimmune encephalomyelitis (EAE), and atherosclerosis, IL-25 suppresses Th1/Th17 responses, thereby exerting potent anti-inflammatory and protective effects. In the context of infectious diseases and inflammatory bowel diseases (IBD), the effects of IL-25 are more fluid and dynamically shift between pro-inflammatory and anti-inflammatory states based on the specific tissue microenvironment and disease stage.

Targeted Drug Development for IL-25 Related Diseases

Acting as an epithelial barrier "alarmin," IL-25 offers a strategic advantage by intercepting the early initiation of Th2 inflammation. This makes it an ideal target for specific Th2-driven disease phenotypes, including IL-25-high asthma, inflammatory bowel disease (IBD), allergic rhinitis, nasal polyposis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).

Current representative IL-25 drugs include XKH001 (developed by Kanova Biopharma) and PTH-0300 (from Protheragen). Notably, XKH001 is the first anti-IL-25 monoclonal antibody inhibitor. Currently, the proof-of-concept for Phase 1c clinical trials in China for moderate-to-severe asthma has been completed; Phase 2 clinical trials for moderate-to-severe atopic dermatitis (AD) are progressing both domestically and internationally, with the first dose already administered. In early 2025, regulatory approval was granted to expand Phase 2 clinical studies into COPD and IPF, significantly broadening the drug's therapeutic indications.

PD (Pharmacodynamic) time curves for various treatment groups during the SAD and MAD phases of XKH001 in healthy subjects[3]

The leading candidate for IL-25 receptor-targeted therapy is SM17, a monoclonal antibody (mAb) targeting IL-17RB developed by SinoMab BioScience.

SM17 represents the world's first humanized IgG4 monoclonal antibody targeting IL-17RB. By disrupting IL-25 signaling, it inhibits Th2 inflammatory cascades, primarily targeting allergic diseases such as atopic dermatitis. Following successful preclinical research, the drug has entered clinical development, where Phase 1 trials established a robust safety and tolerability profile. In a recent Phase 1b study involving patients with moderate-to-severe AD, SM17 demonstrated significant clinical efficacy, including marked improvement in skin lesions and substantial reduction in pruritus (itch). With no new safety signals observed, SM17 shows high potential as an innovative targeted therapy for the IL-25 signaling pathway[4].

Clinical trials for SM17 have been conducted in both China and the United States[5]

IL-25 is one of the "master switches" that initiates the Type 2 immune response.  Because its position in the signaling hierarchy is significantly further upstream than effector cytokines like IL-4 and IL-5, IL-25 can theoretically be neutralized prior to the amplification of the inflammatory cascade. This early-stage intervention offers the potential for broader, more comprehensive, and more thorough inhibitory effects compared to targeting downstream mediators.

Furthermore, compared to other upstream targets such as TSLP or IL-33, IL-25 exhibits significantly higher specificity for allergic inflammation by selectively targeting ILC2s and memory Th2 cells. At the same time, its receptor IL-17RB, has a more restricted expression profile. These characteristics suggest that IL-25-targeted therapies may be particularly effective in maintenance therapy and the prevention of disease recurrence by neutralizing the "memory" of the allergic response. . Theoretically, this high specificity reduces the risk of off-target effects, thereby preserving broader immune homeostasis. However, the complex, context-dependent mechanisms and potential dual regulatory effects of IL-25 requires further investigation. Future large-scale clinical trials are essential to validate these findings and define the optimal therapeutic utility of IL-25 inhibition across various disease states.

KACTUS Recombinant IL-25 and Its Receptor Protein Products

KACTUS supplies high-quality IL-25 and related recombinant proteins, covering other IL-17 subtypes and IL-17 receptors. These products can be applied to different usage scenarios in the development of IL-25 related drugs.

Product Data

The purity of Human IL-25 is greater than 95% and the molecular weight of this protein is around 40-60 kDa as determined by SEC-MALS (QC test).

Immobilized Human IL-25, His Tag at 0.5 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-IL-25 Antibody, hFc Tag with the EC50 of 2.1 ng/ml determined by ELISA.

Immobilized Mouse IL-25, His Tag at 0.5 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-IL-25 Antibody, hFc Tag with the EC50 of 2.7 ng/ml determined by ELISA (QC test).

Immobilized Human IL-17RB, His Tag at 0.2 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-IL-17RB Antibody, hFc Tag with the EC50 of 5.4 ng/ml determined by ELISA (QC test).

Human IL-17RB, His Tag immobilized on CM5 Chip can bind Human IL-25, His Tag with an affinity constant of 0.81 nM as determined in SPR assay (QC test).

Product List

References

[1] IL-25 (IL-17E) in epithelial immunology and pathophysiology. doi: 10.1016/j.jaci.2020.12.628.

[2] Roles of IL-25 in Type 2 Inflammation and Autoimmune Pathogenesis. doi: 10.3389/fimmu.2021.691559

[3] First-in-human study on tolerability, pharmacokinetics and pharmacodynamics of single and multiple escalating doses of XKH001, a recombinant humanized monoclonal antibody against IL-25 in healthy Chinese volunteers. doi: 10.1080/13543784.2025.2453162

[4] SM17, a new IL-17RB-targeting antibody, ameliorates disease progression in a mouse model of atopic dermatitis. doi: 10.1111/all.16120

[5] https://sinomab.com/en/clinical-trials.aspx