OP23 Guselkumab induction restores intestinal immune homeostasis and promotes epithelial repair in moderately to severely active Ulcerative Colitis

作者：Saranya Sridhar, Andrew P. Hart, S Venkat, Darren Ruane, Daniel M. Horowitz, Teresa Lee, Dawn M. Waterworth, K H G Huang, Matthew Germinaro, M Vetter, Daniel Cua, Tom C. Freeman, Christopher Sisk, Bradford L. McRae, Bram Verstockt, David T. Rubin, Bruce E. Sands, Patrick J. Branigan · 发表于：Journal of Crohn s and Colitis · 年份：2024 · DOI：10.1093/ecco-jcc/jjad212.0023 · 被引用次数：3 · 研究领域：Inflammatory Bowel Disease、IL-33, ST2, and ILC Pathways、Immunodeficiency and Autoimmune Disorders

Abstract Background Selective inhibition of interleukin-23 (IL-23) through antagonism of the IL-23p19 subunit has demonstrated clinical efficacy in inflammatory bowel disease, but the mechanism of action (MoA) has not been fully defined. Here we provide a detailed evaluation of the cellular and molecular MoA of guselkumab (GUS), an IL-23p19 subunit antagonist, in patients (pts) with moderately to severely active ulcerative colitis (UC) from the QUASAR Phase 2b induction study (NCT04033445). Methods Serum proteins were evaluated from 302 pts treated with intravenous GUS induction therapy or placebo (PBO) who had at least one paired sample at Weeks (WK) 0 and 4 or WK12. Matched colonic biopsies at WK0 and 12 were available for 255 pts. Transcriptional profiling was performed with bulk RNA sequencing (RNAseq). Transcriptional modules derived from public UC single cell RNAseq (scRNAseq) were evaluated with differential expression in the bulk RNAseq dataset. Flow cytometry and scRNAseq were performed on a subset of matched WK0 and WK12 cryopreserved biopsies from 60 pts. Results Both GUS induction doses were effective vs PBO in achieving key endpoints including clinical remission, endoscopic and histologic outcomes. GUS reduced serum IL-22, IFNγ and IL-17A (p<1e-05) as early as WK4, which further declined through WK12. Unsupervised analysis of tissue transcriptomic modules (n=69) revealed 57 that were significantly changed with GUS at WK12. The top 6 downregulated modules represen...