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

Authors :
Hassan-Zahraee M
Ye Z
Xi L
Baniecki ML
Li X
Hyde CL
Zhang J
Raha N
Karlsson F
Quan J
Ziemek D
Neelakantan S
Lepsy C
Allegretti JR
Romatowski J
Scherl EJ
Klopocka M
Danese S
Chandra DE
Schoenbeck U
Vincent MS
Longman R
Hung KE
Source :
Inflammatory bowel diseases [Inflamm Bowel Dis] 2022 Mar 02; Vol. 28 (3), pp. 434-446.
Publication Year :
2022

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.<br />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.<br />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.<br />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.<br /> (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Details

Language :
English
ISSN :
1536-4844
Volume :
28
Issue :
3
Database :
MEDLINE
Journal :
Inflammatory bowel diseases
Publication Type :
Academic Journal
Accession number :
34427649
Full Text :
https://doi.org/10.1093/ibd/izab193