Oral Presentation International Celiac Disease Symposium 2026

CD122 Antagonism Demonstrated Greater Reduction of Intestinal Inflammation in the Gut Epithelial Layer and Lamina Propria Compared with IL‑15 Antagonism Alone in a Murine Model of Celiac Disease (146601)

Richard T Frank 1 , Valerie ABADIE 2 , Tierney Kauffman 2 , John Sedy 1 , Matthew Hsu 1 , Cheryl Herrera 1 , Noah Siegel 1 , Yangsu Ren 1 , Eric Hare 1 , Stephen Parmley 1 , Martin Dahl 1
  1. First Tracks Biotherapeutics, San Diego, CALIFORNIA, United States
  2. Department of Medicine, University of Chicago, Chicago, Illinois, United States

Background & Objectives:

In celiac disease (CeD), IL-15- and IL-2-driven inflammation leads to excessive signaling through CD122 (the beta subunit of both receptors) and persistence of pathogenic CD8+ T, CD4+ T, and NK cells. ANB033 is a novel CD122 antagonist monoclonal antibody that binds with high affinity, potently inhibiting IL-15 and IL-2 signaling.

This study evaluated whether inhibition of IL-15 and IL-2 signaling via CD122 reduced CeD-associated inflammation and pathology better than IL-15 antagonism alone.

 Materials & Methods:

DQ8-Dd-villin-IL-15tg mice were sensitized to dietary gluten, placed on a gluten-free diet for a recovery period, and subsequently rechallenged with gluten, mimicking the design of human clinical trials. CeD pathology was evaluated via immunohistochemistry and flow cytometry. The treatment regimen included isotype control, an IL-15 antagonist, and a CD122 antagonist (a murine-specific surrogate of ANB033). In vitro analyses compared the effects of CD122 and IL-15 antagonism for reducing T cell proliferation and cytokine secretion by CeD patient-derived PBMCs.

 Results:

CD122 (ANB033 surrogate) and IL-15 antagonism each reduced gluten-dependent expansion of cytotoxic CD8+ intraepithelial lymphocytes and preserved the villus-height-to-crypt-depth ratio compared to isotype control; however, the impact by CD122 antagonism was greater across both metrics. Unlike IL‑15 antagonism, CD122 antagonism reduced the expansion of CD8+ and activated memory CD4+ T cells in the lamina propria, including IFNγ-expressing cells within both subsets. In CeD patient-derived PBMCs, ANB033 demonstrated greater reductions of IL-15- and IL-2-induced CD8+ and CD4+ T cell proliferation, inflammatory cytokine secretion, and cytotoxic mediators compared to a reference IL-15 antagonist antibody.

 Conclusion:

Together, these data show that CD122 antagonism, which inhibits both IL-15 and IL-2 signalling, more effectively reduced expansion and functional activity of cytotoxic CD8+ T and activated CD4+ T cells than IL-15 antagonism alone, supporting the ongoing evaluation of ANB033 in a Phase 1b study in CeD.