Interleukin-31 (IL31) is a proinflammatory cytokine and a key member of the IL-6 family of cytokines. IL31 has been implicated in a variety of atopic diseases, such as atopic dermatitis (AD), allergic rhinitis, and airway hyperresponsiveness. In AD, IL31 has been identified as one of the primary drivers of pruritus, the primary symptom of AD.

Origin of IL31

IL31 is primarily secreted by CD4+ T cells, which are type II helper T cells, but it is also produced by dendritic cells, mast cells, type 2 innate lymphocytes, basophils, eosinophils, or M2 macrophages, and plays an important role in the induction and maintenance of itch.

(Data source: Datsi A, et al. Allergy. 2021)

Structure of IL31

IL31 is a secreted protein, a single-chain molecule composed of four α-helices. The IL31 gene is located at 12g24.31 and encodes a polypeptide chain consisting of 164 amino acid residues. The mature IL31 molecule contains 141 amino acids. The IL31 receptor is a heterodimer composed of the IL31 receptor A ( IL31 RA) and oncostatin receptor M ( OSMR ) subunits.

(Data source: Cornelissen C, et al. Eur J Cell Biol. 2012)

IL31 in itch signaling

IL31 is a major component of the immune system. In keratinocytes, IL31R is upregulated by the TLR2 ligand (Pam3Cys) , IFNγ , and LPS. Upon activation, keratinocytes release pruritic agents such as chemokine ligand 2 (CCL2) , initiating or maintaining inflammatory responses. In eosinophils, IL31 induces chemotaxis, calcium mobilization, and the release of numerous other proinflammatory cytokines. IL31 mediates the interaction between eosinophils and keratinocytes, which may be particularly important in patients with pruritic skin diseases accompanied by eosinophil infiltration. Stimulated basophils also release IL31, triggering chemotaxis and autostimulating the release of IL-4 and IL-13, key mediators of allergic inflammation.

(Data source: Roh YS, et al. Drugs. 2021)

IL31 signaling occurs through its cognate IL31RA/OSMRβ receptor heterodimer. IL31RA /OSMRβ is activated with similar affinity by OSM and IL31. IL31 binding leads to receptor dimerization, cytoplasmic phosphorylation, and subsequent activation of canonical kinase pathways, including the JAK/STAT, PI3K/Akt, and MAPK cascades.

Targeted therapy for IL31:

Nemolizumab is the first approved monoclonal antibody targeting IL31 RA. It blocks the IL31 signaling pathway by binding to IL31 receptor α. It is developed by Chugai Pharmaceutical for the treatment of prurigo nodularis, atopic dermatitis, systemic scleroderma. Nemolizumab received Breakthrough Therapy Designation ( BTD) from the U.S. FDA in 2019 and received priority review for the treatment of prurigo nodularis in February of this year.

Vixarelimab, is a monoclonal antibody developed by Roche that targets OSMRβ, blocks the IL31 signaling pathway by binding to OSMRβ. It is currently in Phase 2 clinical trials for the treatment of ulcerative colitis, idiopathic pulmonary fibrosis, and interstitial lung disease associated with systemic sclerosis. In two Phase 2 randomized controlled trials, it demonstrated a rapid reduction in itch intensity and significant improvement in skin lesions.

(Data source: Nilforoushzadeh MA, et al. Inflammopharmacology. 2024)

NM26-2198 (NM26) is a bispecific antibody targeting IL-4Rα and IL31, being developed by Numab Therapeutics for the treatment of atopic dermatitis (AD). NM26-2198 prevents IL-4/IL-13- and IL31 -induced keratinocyte immunopathology, immune cell activation, skin barrier impairment, and itch, all hallmarks of atopic dermatitis pathophysiology. Compared to the current standard of care for AD, NM26 combines IL31-mediated neuroinflammation blockade with IL-4/IL-13 blockade to suppress Th2-driven inflammation, resulting in a faster onset of action, improved efficacy, and the convenience of subcutaneous administration. On May 28, 2024, Johnson & Johnson announced that it had reached a definitive agreement with Numab Therapeutics to acquire Yellow Jersey Therapeutics, a wholly-owned subsidiary of Numab, from Numab's shareholders. The acquisition will grant Numab global rights to NM26, a first-in-class bispecific antibody currently in clinical trials, for approximately $1.25 billion. The transaction is expected to close in the second half of 2024.