Antitumor Necrosis Factor-like Ligand 1A Therapy Targets Tissue Inflammation and Fibrosis Pathways and Reduces Gut Pathobionts in Ulcerative Colitis

Mina Hassan-Zahraee, Zhan Ye, Li Xi, Mary Lynn Baniecki, Xingpeng Li, Craig L. Hyde, Jenny Zhang, Nancy Raha, Fridrik Karlsson, Jie Quan, Daniel Ziemek, Srividya Neelakantan, Christopher Lepsy, Jessica R. Allegretti, Jacek Romatowski, Ellen J. Scherl, Maria Klopocka, Silvio Danese, Deepa E. Chandra, Uwe SchoenbeckMichael S. Vincent, Randy Longman, Kenneth E. Hung

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)434-446
Number of pages13
JournalInflammatory Bowel Diseases
Volume28
Issue number3
DOIs
StatePublished - 1 Mar 2022
Externally publishedYes

Keywords

  • TL1A inhibition
  • inflammatory bowel disease
  • transcriptional response
  • ulcerative colitis

Fingerprint

Dive into the research topics of 'Antitumor Necrosis Factor-like Ligand 1A Therapy Targets Tissue Inflammation and Fibrosis Pathways and Reduces Gut Pathobionts in Ulcerative Colitis'. Together they form a unique fingerprint.

Cite this