P0506 AZD7798, a monoclonal antibody depleting CCR9+ T cells, with the potential to target hard-to-treat small bowel Crohn’s disease
Bibliographic record
Abstract
Abstract Background Crohn’s disease (CD) can affect any part of the gastrointestinal tract, but about 30% of patients have inflammation restricted to the ileum. In clinical trials, patients are typically enrolled irrespective of the disease localisation, with clinical outcomes focusing on a broad patient population. Anecdotally, small bowel healing in CD is often reported as challenging. Our aims were to investigate the unmet need in treating ileal CD and explore potential drug targets for this patient subpopulation. Methods A systematic review and meta-analysis was conducted of efficacy by disease location (Montreal classification L1 + L2) in placebo-controlled clinical trials in CD. As this revealed markedly different outcomes in ileal compared to colonic CD, transcriptomic data from 1185 small and large intestine biopsies of 594 CD patients were explored to identify potential small bowel specific drug targets, from which the chemokine receptor CCR9 emerged as high interest. AZD7798, a monoclonal antibody designed to deplete CCR9+ T cells, was evaluated in a randomized, placebo-controlled, double-blind first-in-human healthy volunteer study (NCT05452304), and in small bowel Crohn’s patients in a PET imaging study (NCT06053424). Results In the meta-analysis, marked differences were observed in efficacy of existing CD treatments in small compared to large bowel disease (Fig.1). Outcomes across mechanisms of action were not significantly different from placebo in small bowel CD (OR 1. 07, 95% CI 0.64-1.78, p=0.79) yet were superior in colonic CD (OR 3.86, 95% CI 2.75-5.42, p<0.001). Next, transcriptomic analyses identified CCR9 and its ligand CCL25 as highly and selectively expressed in terminal ileum compared to large bowel. Subsequently AZD7798, a CCR9+ T cell depleting antibody, was evaluated in 106 healthy participants in a first-in-human study, and in 6 CD patients in a Phase 1b study. There were no SAEs or treatment discontinuations, and rapid and sustained depletion of CCR9+ T cells in blood was observed in both studies. Moreover, AZD7798 reduced target cells in small bowel in CD patients as detected using a novel CCR9 tracer (Fig.2). Conclusion Ileal CD represents a high unmet need patient subpopulation, where existing treatments appear less effective than for colonic disease. CCR9 is identified as an attractive target for small bowel-dominant inflammation. AZD7798, a first-in-class CCR9+ T cell depleting antibody, demonstrated acceptable safety and tolerability alongside sustained CCR9+ T cell reductions in blood and small intestine.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.005 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".