OSM binds to two receptor complexes:
Type I: gp130 + leukemia inhibitory factor receptor (LIFR)
Type II: gp130 + OSMRβ
These interactions activate signaling pathways such as JAK/STAT, MAPK, and PI3K/AKT, driving pro-inflammatory cytokine production, fibrosis, and tumor growth . OSM is implicated in RA, SSc, and cancers, where it promotes synovial fibroblast invasion, fibrotic tissue deposition, and metastasis .
Note: While anti-OSM antibodies like GSK2330811 neutralize OSM directly, their clinical utility is limited by on-target toxicities (e.g., hematologic effects) .
Key Insight: Anti-OSMR antibodies show broader therapeutic potential by targeting the receptor rather than the cytokine, potentially avoiding systemic OSM suppression .
Ovarian Cancer: OSMR overexpression correlates with metastasis and cisplatin resistance. Anti-OSMR antibodies (e.g., B14/B21) block STAT3 activation, reducing tumor growth and peritoneal dissemination .
Glioblastoma: OSMRβ knockdown suppresses STAT3-driven mesenchymal transition and tumor growth .
In SSc, OSMRβ expression in fibroblasts and endothelial cells drives collagen deposition and vascular remodeling. Anti-OSM/OSMR strategies aim to disrupt this axis but face challenges in clinical translation .
Bispecific Antibodies: Combining anti-OSMR with anti-PD-1/PD-L1 to enhance immunotherapy in cancers.
Biomarker-Driven Trials: Stratifying patients by OSMRβ expression levels to optimize therapeutic response .
| Strategy | Advantages | Limitations |
|---|---|---|
| Anti-OSM (e.g., GSK2330811) | Direct neutralization of cytokine | Systemic OSM suppression; hematologic toxicity |
| Anti-OSMR (e.g., B14/B21) | Tissue-specific targeting; preserves anti-inflammatory OSM roles | Requires OSMRβ expression in target tissues |