P037 Antagonism of chemokine receptor CCR9 synergises with anti-TNFα immunotherapy to reduce inflammation in the MDR1a−/− mouse model of colitis

J. Campbell1, L. Ertl1, K. Ebsworth1, J. McMahon2, P. Zhang2, V. Chhina1, I. Charo1, T. Schall1

1Department of Biology, ChemoCentryx, Inc., Mountain View, CA, USA, 2Department of Chemistry, ChemoCentryx, Inc., Mountain View, CA, USA


The development of anti-TNFα immunotherapies has led to great advances in quality of life for Crohn’s and colitis patients and has allowed a reduction in steroid use for these diseases. However, a significant proportion of IBD patients is resistant to anti-TNFα agents, or becomes resistant to such treatments over time. Preclinical research and clinical trials have suggested that CCR9 antagonism can effectively reduce colon inflammation. CCR9 is expressed on a subset of T cells dedicated to monitoring the immune status of the intestine. When activated by its only known chemokine ligand, CCL25/TECK, CCR9 triggers the adhesion of gut-specific T cells to vascular endothelium and the subsequent ingress of these cells to intestinal tissues. Antagonism of this receptor inhibits the accumulation of T cells within inflamed intestinal epithelium and lamina propria. Since anti-TNFα and CCR9 antagonists act through entirely different mechanisms, we asked whether these two approaches might synergise and expand the effectiveness and scope of each therapy.


We used a piroxicam-accelerated version of the MDR1a−/− spontaneous colitis model in mice. In this model, 7week MDR1a−/− mice (or WT FVB controls) receive piroxicam in powdered chow for 10 days. Mice are monitored both during and after the piroxicam feeding period, for a total of 21 days. Treatment groups (eight mice each) include an antibody (a saturating dose of either anti-TNFα or its isotype-matched control) and a CCR9 antagonist (or its vehicle alone as a control). Body weight and diarrhoea score were recorded throughout the entire 21 days period, after which colons were obtained from sacrificed animals for weighing, length measurement and imaging.


We have found that combined dosing of piroxicam-fed MDR1a−/− mice with a CCR9 antagonist and an anti-TNFα MAb significantly reverses loss of body weight, diarrhoea score and colon inflammation. The combined dosing was more effective than anti-TNFα or CCR9 antagonist alone, as measured by colon length/weight ratio, neutrophil accumulation in the colonic epithelium and reversal of the loss in body weight characteristic of this model.


These data suggest that combining a CCR9 antagonist with existing anti-TNFα treatment regimens may extend the benefits of anti-TNFα immunotherapy to a larger class of patients suffering from IBD and may prolong the effectiveness of anti-TNFα immunotherapy for those patients already undergoing such treatments.