Single-cell and bulk-RNA transcriptomics reveal nemolizumab effects on pruritus, hyperplasia, and fibrosis markers

Summary: Nemolizumab is an anti-IL-31Ra monoclonal antibody tested in two phase III clinical trials (ARCADIA1:NCT03985932/ARACADIA2:NCT03989349) for the treatment of moderate-to-severe atopic dermatitis in patients aged>12 years. This study characterizes transcriptomic changes in a subset of patients from ARCADIA1 pre- and post-nemolizumab treatment using single-cell (scRNA-seq) and bulk RNA-seq. Tape strips were collected from the lesional(LS) and nonlesional(NL) skin of 72 patients with AD at baseline and after 16 weeks of nemolizumab (+topical corticosteroids with or without topical calcineurin inhibitors[TCS/TCI]) and of 39 patients receiving placebo (+TCS/TCI). RNAseq analysis identified differentially expressed genes (|FCH|>1.5, FDR<0.05). scRNA-seq of LS and NL skin of 6 patients with AD and 15 healthy controls were integrated with bulk-RNAseq data from patients treated with nemolizumab. At 16 weeks, 142 genes were upregulated and 797 downregulated in LS skin compared to baseline. Nemolizumab downregulated key markers related to pruritus (TRPV1/3, OSMR), epidermal hyperplasia/fibrosis (KRT6C, SERPINB, COL10A1/12A1, IGFBP3), Th1 markers (CCL2, MX1, OASL), and Th17/Th22 (S100A7/8/9/12, IL36G, PI3). scRNA-seq mapping revealed nemolizumab attenuated genes associated with inflammatory, follicular, and supraspinous keratinocyte subpopulations (IL-18+, IVL+, KRT10+), profibrotic fibroblasts (COL11A1+, APOE+, SFRP2/4+), and endothelial and nerve cell-associated genes (FN1+, PGF+, BDNF+, MAP2+). These findings suggest nemolizumab modulates keratinocyte, fibroblast, and nerve cell-associated pathways, reducing fibrosis, pruritus, and inflammation, supporting its potential for patients with itch dominant and hyperplastic AD phenotypes. Daniel Liu¹, Ester Del Duca¹, Megan Lau¹, J Pulsinelli¹, Jessica Tordjman¹, Jonathan Bar¹, Joel Correa da Rosa¹, Yeriel Estrada¹, Jonathan I. Silverberg³, Diamant Thaci⁴, Johann E. Gudjonsson⁵, Nicolas Delaleu², Valérie Julia², Emma Guttman-Yassky¹ 1. Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States. 2. Galderma SA, Zug, ZG, Switzerland. 3. Dermatology, The George Washington University, Washington, DC, United States. 4. Dermatology, University of Lübeck, Lübeck, Germany. 5. Dermatology, University of Michigan, Ann Arbor, MI, United States. Translational Studies: Cell and Molecular Biology