Antitumor Necrosis Factor-like Ligand 1A Therapy Targets Tissue Inflammation and Fibrosis Pathways and Reduces Gut Pathobionts in Ulcerative Colitis. Issue 3 (24th August 2021)

• Record Type: Journal Article
• Authors: Hassan-Zahraee, Mina; Ye, Zhan; Xi, Li; Baniecki, Mary Lynn; Li, Xingpeng; Hyde, Craig L; Zhang, Jenny; Raha, Nancy; Karlsson, Fridrik; Quan, Jie; Ziemek, Daniel; Neelakantan, Srividya; Lepsy, Christopher; Allegretti, Jessica R; Romatowski, Jacek; Scherl, Ellen J; Klopocka, Maria; Danese, Silvio; Chandra, Deepa E; Schoenbeck, Uwe; Vincent, Michael S; Longman, Randy; Hung, Kenneth E
• Is Part Of: Inflammatory bowel diseases. Volume 28:Issue 3(2022)
• Page Start: 434
• Page End: 446
• Publication Date: 2021-08-24
• Subjects: TL1A inhibition -- transcriptional response -- inflammatory bowel disease -- ulcerative colitis; Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izab193
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: Background: The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. Methods: Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. Results: Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. Conclusions: The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD. Graphical Abstract: