IL-33

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Ligands
IL-33 (Human)

GtoPdb Ligand ID: 5880

Synonyms: IL-1F11

Compound class: Endogenous peptide in human, mouse or rat

Comment: IL-33 is a pleiotropic IL-1 family cytokine that can both promote type 2 inflammation and also drive immunoregulation through expansion of Foxp3⁺T_reg cells. The outcomes of IL-33 activity appear to depend on the cells that produce it, either myeloid dendritic cells (DC) or epithelial cells [6]. DC-derived IL-33 supports T_reg cells. The main cellular targets of IL-33 are innate lymphoid cells type 2 (ILC2), involved in the initiation of the type 2 immune response (secretion of IL-5 and IL-13) during parasitic infection and allergic diseases such as asthma. Full length IL-33 is cleaved by mast cell chymase (chymase 1; CMA1) to produce its significantly more active form [7].

The ST2/IL-33 axis is recognised as playing an important role in the development/exacerbation of IgE-dependent inflammations such as asthma and atopic dermatitis [1,5], and received much interest from the pharmaceutical industry. Blockade of IL-33 activity (and/or its receptor ST2) represent potential novel mechanisms for pharmaceutical intervention to suppress allergy and mast cell-eosinophil interplay. Indeed, astegolimab (RG6149/AMG 282) is an example of a fully human anti-IL-33 monoclonal antibody, that was developed as a potential therapy for mild atopic asthma and chronic rhinosinusitis. Unfortunalely, in common with other anti-IL-33 leads, RG6149 failed to deliver clinical efficacy in these indications.

Species: Human

Immunopharmacology Comments
The IL-33 precursor can bind and activate its receptor. IL-33 is pro-inflammatory and involved in Th2 responses. The dominant function of IL-33 is as an alarmin cytokine [2]. IL-33 as an inflammation therapeutic target: A number of anti-IL-33 mAbs that antagonise binding of IL-33 to the interleukin 1 receptor-like 1 (IL1RL1; a.k.a. ST2 receptor) are in development pipelines, including astegolimab (Amgen; for mild atopic asthma and chronic rhinosinusitis), REGN3500 (a.k.a. SAR-440340, Regeneron/Sanofi; allergic asthma), ANB020 (etokimab, AnaptysBio; allergic asthma [8], eosinophilic esophagitis and atopic dermatitis [3]), MEDI 3506 (MedImmune/AstraZeneca; for atopic dermatitis, chronic obstructive pulmonary disease and diabetic kidney disease) and GSK3772847 (GSK/Johnson & Johnson; asthma). By late 2020 it was becoming evident that several of these candidates were delivering less than convincing clinical efficacy data (although published data was unavailable at this time), casting doubt on the outcome for this class of agents. In particular, REGN3500 has reportedly failed in a proof-of-concept asthma trial and a Phase 2b atopic dermatitis study, and development of GSK3772847 was terminated, based both on results from their asthma trial, and in light of the evidence coming from the rival candidates for this target. SARS-CoV-2 and COVID-19: In response to the SARS-CoV-2 pandemic, astegolimab/RG6149 was investigated in patients with COVID-19 pneumonia, as part of the UK's Accelerating COVID-19 Research and Development (ACCORD) initiative (June 2020). ACCORD aims to fast-track potential treatments for COVID-19 through early-stage clinical trials [10], However, Roche discontinued the phase 2 study due to an unlikelihood of delivering clinical efficacy.

Immunopharmacology Comments

The IL-33 precursor can bind and activate its receptor. IL-33 is pro-inflammatory and involved in Th2 responses. The dominant function of IL-33 is as an alarmin cytokine [2].

IL-33 as an inflammation therapeutic target: A number of anti-IL-33 mAbs that antagonise binding of IL-33 to the interleukin 1 receptor-like 1 (IL1RL1; a.k.a. ST2 receptor) are in development pipelines, including astegolimab (Amgen; for mild atopic asthma and chronic rhinosinusitis), REGN3500 (a.k.a. SAR-440340, Regeneron/Sanofi; allergic asthma), ANB020 (etokimab, AnaptysBio; allergic asthma [8], eosinophilic esophagitis and atopic dermatitis [3]), MEDI 3506 (MedImmune/AstraZeneca; for atopic dermatitis, chronic obstructive pulmonary disease and diabetic kidney disease) and GSK3772847 (GSK/Johnson & Johnson; asthma). By late 2020 it was becoming evident that several of these candidates were delivering less than convincing clinical efficacy data (although published data was unavailable at this time), casting doubt on the outcome for this class of agents. In particular, REGN3500 has reportedly failed in a proof-of-concept asthma trial and a Phase 2b atopic dermatitis study, and development of GSK3772847 was terminated, based both on results from their asthma trial, and in light of the evidence coming from the rival candidates for this target.

SARS-CoV-2 and COVID-19: In response to the SARS-CoV-2 pandemic, astegolimab/RG6149 was investigated in patients with COVID-19 pneumonia, as part of the UK's Accelerating COVID-19 Research and Development (ACCORD) initiative (June 2020). ACCORD aims to fast-track potential treatments for COVID-19 through early-stage clinical trials [10], However, Roche discontinued the phase 2 study due to an unlikelihood of delivering clinical efficacy.

Immunopharmacology Disease
Disease	X-Refs	Comment	References
Asthma	Disease Ontology: DOID:2841 OMIM: 600807	An IL-1 family cytokine involved in the initiation of the type 2 immune response during parasitic infection and allergic diseases such as asthma. IL-33 is an investigational therapeutic target for asthma.