TL1A Reporter HEK 293 Cells

Cell line description

HEK-Blue™ TL1A cells were generated by stable transfection of the human embryonic kidney HEK293 cell line with the gene encoding the human Death Receptor 3 (DR3) and a SEAP (secreted embryonic alkaline phosphatase) reporter gene under the control of the IFN-β minimal promoter fused to five AP-1 and five NF-κB binding sites.

The binding of TL1A to its receptor triggers a signaling cascade leading to AP-1/NF-κB activation and the subsequent production of SEAP.  This can be readily assessed in the supernatant using QUANTI-Blue™ Solution, a SEAP detection reagent. HEK-Blue™ TL1A cells detect human (h) and mouse (m) TL1A. Of note, these cells also respond to two other human AP-1/ NF-κB-signaling cytokines, TNF-α and IL-1 β. However, they do not respond to other cytokines of the TNF superfamily: APRIL, BAFF, RANKL, and CD40L (see figures).

TL1A background

Tumor necrosis factor (TNF)-like 1A (TL1A), also called TNFSF15, is a cytokine that belongs to the TNF superfamily. TL1A is produced by endothelial cells, activated dendritic cells, and macrophages. It is synthesized as a membrane-bound trimeric molecule. Alternative splicing or cleavage by the tumor necrosis factor-alpha converting enzyme results in soluble TL1A [1]. Both forms bind the homotrimeric transmembrane death receptor 3 (DR3), triggering TRADD/TRAF2/RIP signaling, and ultimately leading to NF-κB and MAPKs activation. Subsequent gene expression in target cells drives the production of pro-inflammatory cytokines and differentiation of T helper subsets [1].

Relevance for therapeutics development

TL1A is normally responsible for mediating protective immune responses. However, it can also play a role in chronic inflammatory disorders and have harmful impacts. Abnormal TL1A expression or TL1A overactivity promotes excessive inflammation and immune cell infiltration, contributing to tissue damage and further inflammation amplification [1].

Pharmaceutical companies have developed potent monoclonal antibodies to block TL1A signaling and stop the downstream inflammatory cascade and tissue damage, primarily in the onset of asthma and Crohn’s disease. Anti-TL1A inhibitors such as Tulisokibart (MK-7240 or PRA023, Merck), RVT-3101 (PF-06480605, Roche), and Duvakitug (TEV-48574, Sanofi & Teva Pharmaceuticals) have demonstrated "best-in-class" potential for treating inflammation and scarring in IBD [2-4]. Duvakitug is currently being studied for its safety as an asthma medication [5-6].

References:

1. Xu W.D., et al., 2022. Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review. Front. Immunol. 13: 891328.
2. Sands, B.E., et al., 2024. Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis. N Engl J Med, 391(12): p. 1119-1129.
3. Danese, S., et al., 2021. Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clinical Gastroenterology and Hepatology. 19(11): p. 2324-2332.e6.
4. Solitano, V., et al., 2024. TL1A inhibition for inflammatory bowel disease treatment: From inflammation to fibrosis. Med. 5(5): p. 386-400.
5. Balyan, R., et al.,, 2024. P633 First-in-Human Pharmacokinetic and Safety Study of an Anti-TL1A Antibody, TEV-48574, in Healthy Volunteers and Asthma Patients. Journal of Crohn's and Colitis. 18(Supplement_1): p. i1215-i1216.
6. Raphael, G., et al., 2024. P1061 TEV-48574, an anti-TL1A antibody in development for use in IBD, is safe and well tolerated following 16 weeks of subcutaneous treatment in adults with severe uncontrolled T2-low/non T2 asthma. Journal of Crohn's and Colitis. 18(Supplement_1): p. i1908-i1908.