Sclerotic GVHD and scleroderma share dysregulated gene expression that is ameliorated by EREG therapeutic antibody

Immune-driven fibrotic skin diseases, including scleroderma/systemic sclerosis (SSc) and chronic graft-versus-host disease (GVHD), cause skin stiffening that has a major impact on patient quality of life and associated patient mortality. Therapies to improve sclerotic skin resulting from these diseases are largely ineffective. We previously showed that epiregulin (EREG), a dendritic cell type 3-derived epidermal growth factor receptor (EGFR) ligand, is elevated in the skin and lungs of patients with SSc and required for the maintenance of skin fibrosis. Here, we developed a fully human anti-EREG neutralizing antibody that has both high affinity and specificity. We found this therapeutic antibody to be functional and safe in vivo using human EREG knockin mice. To understand the antifibrotic mechanism of targeting EREG, we aligned skin single-cell transcriptomic profiles of SSc, morphea (localized scleroderma), and sclerotic GVHD (SclGVHD) with disease biomarkers. EREG expression in the skin was elevated in all 3 fibrotic diseases and is a driver of tenascin C (TNC) production by myofibroblasts. TNC is a proinflammatory extracellular glycoprotein that functions as an endogenous Toll-like receptor 4 (TLR4) ligand, which induces expression of TLR4 target genes CCL2 and interleukin-6. Examination of skin explants from patients with active SclGVHD treated with anti-EREG therapeutic antibody by spatial transcriptomics demonstrated upregulation of matrix degradation by increased MMP and decreased TIMP1 expression. Protein measurements showed reduced secretion of EREG targets TNC, CCL2, and TIMP1 in all patients and type I collagen and FN1 in three-fourths of patients. Thus, sclerotic skin treated with the anti-EREG therapeutic antibody reduced inflammatory and fibrosis biomarkers associated with EGFR and TLR4 signaling.