Thyroid eye disease (TED), also known as Graves' orbitopathy, is a progressive fibro-inflammatory disorder affecting orbital tissue in approximately 13 per 100,000 individuals annually. Its pathophysiology is characterised by lymphocytic infiltration, expansion of orbital adipose tissue, extraocular muscle enlargement, and progressive tissue remodelling, culminating in proptosis, diplopia, and, in severe cases, compressive optic neuropathy. Since 2020, the anti-IGF-1R monoclonal antibody teprotumumab (Tepezza) has represented the standard of care in the United States, offering meaningful proptosis reduction for many patients. However, significant residual disease activity, high recurrence rates, and an imperfect adverse event profile underscore the continuing unmet need for safer and more mechanistically targeted therapies.

IL-11, a pleiotropic cytokine of the IL-6 family, signals through its receptor IL-11Ra and co-receptor gp130 to form a hexameric complex that activates JAK/STAT3, ERK/MAPK, and PI3K/AKT pathways. Unlike IL-6R, which is predominantly expressed on immune cells, IL-11Ra is preferentially expressed on stromal cells, fibroblasts, smooth muscle cells, and endothelial cells, making it a mechanistically attractive target in diseases driven by pathological stromal activation. While early literature attributed anti-inflammatory properties to IL-11, subsequent work using species-appropriate reagents demonstrated that the cytokine functions as a potent pro-fibrotic and pro-inflammatory mediator in stromal compartments. King et al. (2026) sought to definitively establish whether blockade of IL-11 signalling could represent a viable therapeutic strategy in TED, using both patient-derived orbital fibroblasts and a rigorous clinical development programme.

Orbital adipose/connective tissue was surgically obtained from 22 TED patients undergoing orbital decompression. Freshly isolated orbital fibroblasts (OFs) confirmed prior reports of IL-11 and IL-11Ra upregulation at the mRNA level relative to healthy donor controls. Stimulation with recombinant IL-11 activated all three canonical downstream pathways (pSTAT3, pERK1/2, pAKT) in TED OFs. IGF-1, the driver pathway targeted by teprotumumab, produced relatively weaker ERK activation but stronger AKT induction, and the combination of IL-11 and IGF-1 produced supra-additive AKT phosphorylation.

LASN01, a fully human IgG4 monoclonal antibody to IL-11Ra isolated from a phage display library, demonstrated exceptional potency: a binding KD of 37 pM by biolayer interferometry and functional IC50 values of 0.4 nM (pSTAT3) and 0.1 nM (pERK) in DLD-1 cells stimulated with IL-11.

Hyaluronan (HA) production is a well-established translational readout in TED drug development, underpinning the rationale for teprotumumab's mechanism validation in orbital fibroblast models. LASN01 potently inhibited IL-11-stimulated HA release with an IC50 of approximately 50 ng/mL. Under dual IGF-1/IL-11 stimulation, conditions that produced supra-additive HA output, both LASN01 and teprotumumab achieved comparable maximal inhibition, but through distinct mechanisms: LASN01 acted via HAS2 transcriptional suppression downstream PI3K/AKT, while teprotumumab appeared to act through an alternative, HAS2-independent pathway. Critically, combining both agents drove HA secretion to near-baseline levels, establishing a strong mechanistic rationale for combination therapy.

Luminex-based proteomic profiling across six donors revealed that LASN01 broadly suppressed the IL-11/IGF-1-stimulated secretome, including IL-6, CCL2, and numerous additional cytokines and chemokines implicated in orbital immune recruitment. TGFb-stimulated procollagen I release was significantly reduced by LASN01, with procollagen output significantly correlating with endogenous IL-11 secretion across donors (p = 0.049), further supporting IL-11 as a fibrotic effector in TED.

Bulk RNAseq of OFs from eight TED donors stimulated for 6 or 48 hours with IL-11 alone, or IL-11 + IGF-1, yielded a striking picture of cytokine crosstalk. IL-11 alone upregulated 960 genes and downregulated 764 at 48 hours; combined stimulation altered over 3,350 genes. VENN analysis identified 95 robustly IL-11-specific genes at 48 hours, including HAS2, complement factors C3 and C4B, fibrotic markers APLNR and CHI3L1, and the lipofibroblast-associated gene RASD1.

Gene ontology (GO) analysis delivered perhaps the most strategically significant finding of the study. Of 1,950 total differentially expressed genes in the combined stimulation context, LASN01 regulated 1,361 while teprotumumab regulated only 509, with just 80 shared targets. LASN01 predominantly suppressed pathways linked to inflammation, cytokine signalling, glycosaminoglycan biosynthesis, and extracellular matrix production. Teprotumumab, by contrast, downregulated lipid biosynthetic, cholesterol metabolic, and adipogenic pathways, consistent with its known anti-adipogenic activity. This complementarity at the transcriptomic level provides a compelling molecular framework for why LASN01 achieves superior inflammatory resolution while teprotumumab excels at proptosis reduction.

Teprotumumab biosimilar antibody from Ichorbio served as the primary head-to-head comparator throughout the entire preclinical study, spanning HA production assays, cytokine profiling, procollagen quantification, and the full RNAseq/GO transcriptomic analysis.

LASN01 was evaluated in a multi-part Phase 1 study (NCT05331300) in healthy volunteers, IPF patients, and TED patients, spanning single ascending doses of 25-1200 mg through to Q4W multi-dose regimens of up to 24 weeks. PK was typical of a human IgG4 mAb, with dose-linear kinetics above 100 mg and a half-life extending to approximately 295 hours at 1200 mg. An ex vivo whole-blood hyper-IL-11 stimulation assay demonstrated complete, dose-dependent pSTAT3 suppression persisting for up to two months post-dose at the 600 and 1200 mg doses, confirming durable target engagement in circulation. No serious or severe drug-related adverse events were recorded across any cohort, and no anti-drug antibodies were detected.

The Phase 2 placebo-controlled, double-blinded study (NCT06226545) randomised patients with moderate-to-severe active TED (CAS >= 4, proptosis >= 3 mm above expected for race/sex) to 300 mg LASN01, 600 mg LASN01, or placebo Q4W for up to 48 weeks. The primary efficacy endpoints at Week 37 were proptosis response (>= 2 mm reduction) and CAS response (CAS <= 1).

Proptosis response did not reach statistical significance, 35% in the pooled LASN01 group vs. 33.5% placebo, a result the authors partially attribute to milder baseline disease in the enrolled cohort (mean proptosis 21.5-22.2 mm vs. 22.6 mm in the teprotumumab OPTIC study) and to LASN01's non-adipogenic mechanism. This interpretation is well-supported by the transcriptomic data.

The CAS response, however, was striking. An 88% CAS response rate in the pooled LASN01 group vs. 44% in placebo (p = 0.028) represents the highest CAS response rate reported in any TED clinical trial to date, exceeding responses observed with teprotumumab, tocilizumab, and satralizumab in comparable patient populations. Fifty-nine percent of LASN01-treated patients achieved a CAS of zero — complete resolution of all inflammatory parameters.

The divergent transcriptomic profiles of LASN01 and teprotumumab reframe the mechanistic landscape of TED. Rather than competing therapies, these agents appear to address complementary pathological axes: IL-11R blockade resolves active fibroinflammation, while IGF-1R blockade suppresses adipogenesis and orbital volume expansion. The near-baseline HA suppression achieved by combination treatment in vitro foreshadows a potential clinical combination strategy that could deliver both superior inflammatory control and more robust proptosis reduction than either agent alone.

More broadly, IL-11 upregulation is documented across a range of fibro-inflammatory conditions — idiopathic pulmonary fibrosis (IPF), metabolic dysfunction-associated steatohepatitis (MASH), systemic sclerosis, ulcerative colitis, and others — and the Phase 1 IPF cohort in this study represents an early step toward evaluating LASN01 in those indications. The emerging role of IL-11 in the senescence-associated secretory phenotype (SASP) and evidence that IL-11 blockade extends healthspan in murine models further positions IL-11R as a target of interest in aging-associated inflammatory pathology.

Citation: King D.J. et al. "IL-11 receptor is a novel target for drug development with pharmacological activity in fibro-inflammatory disease." Scientific Reports (2026). DOI: 10.1038/s41598-026-51600-0.