TL1A Pathway: Embarking on New Frontiers in IBD Therapy with Biocytogen’s Humanized Mice

TL1A Pathway: Embarking on New Frontiers in IBD Therapy with Biocytogen’s Humanized Mice

Humanized TL1A Mice for IBD Research

On December 17, Sanofi’s TL1A antibody, duvakitug, demonstrated success in a Phase IIb study, improving clinical remission rates in patients with moderate to severe ulcerative colitis and Crohn’s disease. Currently, several TL1A inhibitors—including monoclonal and bispecific antibodies such as tulisokibart, PF-07261271, and FG-M701—are in development to address unmet needs in the treatment of inflammatory bowel diseases (IBD).

 

Current TL1A Pipeline of Leading Multinational Corporations (MNCs)

Current TL1A Pipeline of Leading Multinational Corporations (MNCs)

 

TL1A (TNF-like cytokine 1A), encoded by the TNFSF15 gene, is a member of the TNF superfamily. By binding to death receptor 3 (DR3), TL1A activates pathways involved in cell proliferation, apoptosis, and cytokine production, playing a key role in maintaining the balance between innate and adaptive immune homeostasis.

TL1A in Chronic Colitis. (Source: Takedatsu et al., 2008)
TL1A in Chronic Colitis. (Source: Takedatsu et al., 2008) (A) Chronic colitis compromises the intestinal epithelial barrier, allowing gut bacteria to penetrate the lamina propria (LP) and stimulate antigen-presenting cells (APCs). Stimulation of APCs, LP macrophages, or dendritic cells (DCs) upregulates TL1A, which enhances the ability of IL-12 and IL-23 to promote TH1 and TH17 cell activation, leading to excessive cytokine production and worsening inflammation. (B) Anti-TL1A antibodies reduce IFN-γ, IL-17, and IL-6 secretion, alleviating inflammation while maintaining bacterial clearance.

 

TL1A is abnormally overexpressed in several autoimmune diseases, where it plays a significant role in the pathogenesis of conditions such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBD). Its unique mechanism of action positions it as a critical factor in both inflammatory responses and immune regulation. In the context of IBD, including ulcerative colitis and Crohn’s disease, TL1A has emerged as a highly promising therapeutic target, drawing considerable attention for its potential in treatment strategies.

TL1A-Related Mouse Models at Biocytogen

Biocytogen has developed a series of humanized mouse models targeting TL1A signaling pathways and established stable IBD models using diverse induction methods across various genetic backgrounds. These models support preclinical research and efficacy evaluation in IBD.

TL1A-related mouse models at Biocytogen

Case Study: B-hTL1A Mice

Protein expression analysis

Soluble human TL1A expression in B-hTL1A mice
Soluble human TL1A was detected exclusively in the supernatant of bone marrow-derived dendritic cells (BMDCs) stimulated from homozygous B-hTL1A mice, with no detection in wild-type mice.

TNBS-induced acute colitis in B-hTL1A mice

TNBS-induced acute colitis in B-hTL1A mice
An acute colitis model was established in B-hTL1A mice (female, 8–10 weeks old, n=8) by TNBS instillation, with PBS as a control (Sham). The anti-human TL1A antibody, Tulisokibart (PRA023, 25 mpk, provided by WuXi AppTec), was administered to the treatment group. Body weight and DAI score were recorded daily. On day 5, the mice were sacrificed, and colon length and weight were recorded. Colon tissue was later processed for H&E and Masson staining. (A) Body weight change. (B) DAI score. (C) Colon Index. (D) Pathological score. (E) Masson staining score. Tulisokibart effectively improved TNBS-induced colitis, demonstrating B-hTL1A mice as a robust model for evaluating anti-human TL1A antibodies. (Study conducted by WuXi AppTec)

DSS-induced acute colitis in B-hTL1A mice

DSS-induced acute colitis in B-hTL1A mice
B-hTL1A mice (female, 7–8 weeks old, n=8) were given drinking water containing DSS for 9 consecutive days to induce an acute colitis model. The anti-human TL1A antibody, Tulisokibart (PRA023, 25 mpk, provided by WuXi AppTec), was administered to the treatment group. Body weight changes and clinical scores (weight loss, stool consistency, blood in stool, and total DAI score) were recorded throughout the experiment. On day 8, the mice were sacrificed, and colon length and weight were measured. (A) Body weight change. (B) DAI score. (C) Colon Index. Tulisokibart improved the clinical symptoms of DSS-induced acute colitis, demonstrating that B-hTL1A mice are a robust model for evaluating the in vivo efficacy of anti-human TL1A antibodies. (Study conducted by WuXi AppTec)

Case Study: B-hTL1A/hIL23A/hIL12B Mice

Protein expression analysis

Soluble human TL1A and IL-23 were detected exclusively in the supernatant of bone marrow-derived dendritic cells (BMDCs) stimulated from homozygous B-hTL1A/hIL23A/hIL12B mice, with no detection in wild-type mice.
Soluble human TL1A and IL-23 were detected exclusively in the supernatant of bone marrow-derived dendritic cells (BMDCs) stimulated from homozygous B-hTL1A/hIL23A/hIL12B mice, with no detection in wild-type mice.

DSS-induced IBD mouse model in B-hTL1A/hIL23A/hIL12B mice

DSS-induced IBD mouse model in B-hTL1A/hIL23A/hIL12B mice
A TNBS-induced acute colitis model in B-hTL1A/hIL23A/hIL12B mice demonstrated improved outcomes with anti-human TL1A antibody Tulisokibart and anti-human IL23p19 antibody Risankizumab, with enhanced efficacy when combined. Results highlight B-hTL1A/hIL23A/hIL12B mice as a valuable tool for evaluating the in vivo efficacy of these antibody combinations. (Study conducted by WuXi AppTec).

There’s More

In addition to TL1A-related mouse models, Biocytogen has developed humanized models targeting other IBD-related pathways, as well as chemical-induced and adoptive transfer models of IBD. We also offer pharmacology services to support clinical evaluations and pathological analyses.

List of IBD-related targeted humanized mice at Biocytogen

IBD models and pharmacology services at Biocytogen

Other IBD Models and Pharmacology Services at Biocytogen

Contact us to learn more about Biocytogen’s IBD-related models and services!

 

References

Boyman, Onur, and Jonathan Sprent. “The role of interleukin-2 during homeostasis and activation of the immune system.” Nature Reviews Immunology 12.3 (2012): 180-190.

Zhang, Xiaohong, et al. “Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15.” Immunity 8.5 (1998): 591-599.

Schluns, Kimberly S., Kimberly D. Klonowski, and Leo Lefrançois. “Transregulation of memory CD8 T-cell proliferation by IL-15Rα+ bone marrow–derived cells.” Blood 103.3 (2004): 988-994.

Yang, Ying, and Andreas Lundqvist. “Immunomodulatory effects of IL-2 and IL-15; implications for cancer immunotherapy.” Cancers 12.12 (2020): 3586.

Holcomb, Erin A., and Weiping Zou. “A forced marriage of IL-2 and PD-1 antibody nurtures tumor-infiltrating T cells.” The Journal of Clinical Investigation 132.3 (2022).

Waldmann, Thomas A. “The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy.” Cancer immunology research 3.3 (2015): 219-227.

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