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

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.

Targeted Analysis of the Gut Microbiome for Diagnosis, Prognosis and Treatment Individualization in Pediatric Inflammatory Bowel Disease

“…We found that the IBD-associated pathogen H. parainfluenzae [ 46 ] had a relatively higher abundance in the IBD patients compared to the non-IBD symptomatic patients. Schirmer et al found in their study of pediatric UC patients that H. parainfluenzae constituted one of the most significant changes in abundance linked to disease severity [ 47 ].…”

TL1A promotes the postoperative cognitive dysfunction in mice through NLRP3‐mediated A1 differentiation of astrocytes

“…As a member of the tumor necrosis factor family, TL1A plays a crucial role in apoptosis and T cell activation. It has been found to act importantly in inflammatory bowel disease, neuroimmunity, and neuroinflammation 10 . Besides, TL1A can mediate the activation of downstream signals like NLRP3 through TNFRs 11 .…”

Gut microbiota in mucosa and feces of newly diagnosed, treatment-naïve adult inflammatory bowel disease and irritable bowel syndrome patients

“… 21 , 56 One of the hallmarks of UC in our study was the expansion of H. parainfluenzae , which has been associated with increased level of acylcarnitine in IBD. 57 Expansion of H. parainfluenzae was found in pediatric UC patients, 32 , 38 , 58 and its reduction in colonic biopsies of adult UC patients in response to novel anti-TNF neutralizing antibody has been reported, 59 suggesting a potential role of H. parainfluenzae in IBD pathogenesis. The enrichment of Haemophilus in biopsies of CD patients was reported in the pediatric treatment-naïve cohorts, 27 , 60 but we did not observe a similar trend.…”