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IL-11 receptor is a novel target for drug development with pharmacological activity in fibro-inflammatory disease

ABSTRACT: IL-11, a novel target for drug development, has been associated with several fibroinflammatory diseases including thyroid eye disease (TED), where it plays an important role in signaling to stromal cells activating multiple intracellular pathways. In TED patient tissue, IL-11 is elevated and stimulates multiple effects important in disease progression, including the production of proinflammatory cytokines, hyaluronic acid (HA) and fibrotic markers. LASN01, a potent antibody to IL-11 receptor, inhibits these effects and is a potential therapeutic agent for TED. Teprotumumab, an antibody to IGF-1 receptor, inhibits HA production and adipogenesis and is effective in reduction of proptosis. Activation of the IGF-1 and IL-11 pathways in TED tissue induces the expression of fibroinflammatory genes regulated by LASN01 and lipid biosynthetic genes regulated by Teprotumumab. Clinical studies show that LASN01 is well tolerated and in a placebo-controlled phase II trial in TED, LASN01 resulted in a statistically significant resolution of clinical activity score (CAS) in 88% of treated patients (p=0.028), but had lesser effects on proptosis. The data supports the importance of IL-11 biology in fibroinflammatory disease and that IL-11 receptor is a pharmacologically active target for drug development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314304 | GEO | 2026/07/08

REPOSITORIES: GEO

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Project description:Thyroid eye disease (TED) is an orbital autoimmune disease which severely affects vision, appearance, and quality of life. TED is the most common extrathyroidal manifestation of Graves' disease, which is mainly featured by hyperthyroidism. Current assessments of TED severity and activity, do not effectively guide regimen, especially the selection of target agents. Peripheral blood samples from 161 TED patients and 20 Graves' hyperthyroidism (GH) patients without eye disease were collected for transcriptome sequencing, and corresponding clinical information was systematically compiled. We then comparatively derived a unique gene expression profile for TED compared to GH, and based on this, unsupervised clustering of TED patients using ConsensusClusterPlus was conducted. Next, immune infiltration analysis, weighted gene co-expression network analysis (WGCNA), hub gene screening, and drug sensitivity analysis were performed for different clusters. TED exhibited elevated of autoantigens, immune responses, cellular proliferation, and metabolic disorders than GH. A novel two-cluster classification scheme was established for TED, independent of classical assessment of severity and activity. Cluster 1 patients received more intravenous glucocorticoids and surgeries but experienced less pain and excessive tearing. They had higher peripheral blood lymphocytes, including CD4+ T cells, CD8+ T cells, T follicular helper cells, natural killer cells, and B cells, than cluster 2 patients. WGCNA identified cluster-related gene modules, and least absolute shrinkage and selection operator (LASSO) regression analysis yielded six hub genes (DDR2, LRP1B, NTRK2, PALB2, PTPRD, and SLC25A6) for cluster 1 and three hub genes (MON2, SNORA74B, and STX16) for cluster 2 as potential biomarkers. Considering current TED therapies, cluster 1 patients may prefer insulin-like growth factor 1 receptor (IGF-1R) antibodies, while cluster 2 patients may favor glucocorticoids. We described the specific gene profile of TED compared to GH and built a new molecular classification of TED patients into two clusters with different immune infiltration, hub genes, and drug sensitivity. It paves the way for improved application of precision medicine in TED.

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IL-11 receptor is a novel target for drug development with pharmacological activity in fibro-inflammatory disease

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