CCL20 as a biomarker of drug efficacy in IBD

The chemokine CCL20 (Mip-3α) plays an important role in recruiting Th17 cells (which express the corresponding receptor, CCR6) to sites of inflammation, thus playing a role in the pathogenesis of chronic inflammatory conditions such as Crohn's disease. In a recent paper in the Journal of Crohn's and Colitis, Giovanni Monteleone and colleagues presented data from clinical and laboratory studies on Mongersen, a Smad7 antisense oligonucleotide, which demonstrated the following:

Cell culture studies using two colonic epithelial cell lines (one normal and one adenocarcinoma), demonstrated that CCL20 protein levels were increased in response to TNF‑α and that this response was inhibited by pre-treatment with TGF‑β1. The inhibitory effect of TGF‑β1 on TNF‑α‑stimulated CCL20 expression was shown to be inhibited by over-expression of Smad7.

Smad7 and CCL20 were co-expressed in the intestinal epithelium of Crohn's disease patients, and treatment with Mongersen inhibited CCL20 expression in mucosal explants from these patients.

In a phase 2 clinical trial, patients with active Crohn's disease who demonstrated remission in response to a two-week duration Mongersen dosing regimen, showed a significant reduction in CCL20 levels immediately after treatment cessation, which was maintained for a further 10 weeks. For patients that showed a clinical response (a reduction in disease, but no remission) the reduction in CCL20 became significant by 10 weeks after ending Mongersen therapy. A reduction in CCL20 levels was not observed in Mongersen non-responders, or in patients receiving placebo (including those showing a placebo response). There was no difference in baseline CCL20 levels between the different outcome groups.

The conclusion of the study was that enhanced Smad7 signalling in Crohn's disease maintains high levels of CCL20 and that determination of serum CCL20 was a useful measure for determining patient response to Mongersen.

Marafini I et al. Journal of Crohn's and Colitis, 2017, 603–609. doi:10.1093/ecco-jcc/jjw191.

 

The modulation of CCL20 expression in IBD patients and an adoptive T cell transfer model of colitis in mice was also highlighted in a study by Holm and colleagues, published in the journal, Inflammatory Bowel Disease. This study was focused on defining the role of GLP‑1 signalling in intestinal epithelial cell homeostasis. GLP‑1 is an incretin hormone and released in response to the presence of nutrients in the gut lumen by intestinal epithelial L cells. The main findings of the paper were:

A specific set of genes modulated by GLP‑1 was defined, which included the genes coding for CCL20, IL‑33 and muc5b.

Analysis of colonic biopsies from patients with both Crohn's disease and ulcerative colitis demonstrated an upregulation of CCL20 and IL‑33 mRNAs, with the expression of each being greater in areas of mucosa demonstrating inflammation, relative to adjacent non-inflamed regions.

Up-regulation of CCL20 and IL‑33 proteins was also observed in an adoptive T cell transfer mouse model of colitis. Administration of the GLP-1 agonist, liraglutide, ameliorated colitis gross pathology and histopathology in comparison to vehicle control, as did an anti‑IL‑12/IL‑23 p40 IgG. For both agents, the decrease in disease was associated with a significant reduction in CCL20.

Whilst the paper's primary conclusion relates to the application of modulating the GLP‑1 signalling pathway to prevent gut injury, the data do highlight the potential of using CCL20 as a biomarker for subject response to therapeutics in chronic inflammatory disease of the bowel, in agreement with the data presented by Monteleone and colleagues.

Epistem offer a wide portfolio of assays for biomarker analysis, including luminex-based multiplex analysis of cytokines/chemokines in plasma/serum samples, or in tissue lysates. Luminex kits for analysis of Th17-associated cytokines and chemokines (including CCL20 and IL‑33) are available from a range of suppliers. Our Pharmacogenomics division overs a wide range of services including Laser Capture Microdissection, microarray analysis, NGS and qPCR.

Epistem have extensive experience of running in vivo colitis models including off-the-shelf models of adoptive T cell transfer-mediated and DSS-induced acute colitis; in addition, we are happy to develop and run bespoke models in collaboration with Sponsors.

Bang-Berthelsen CH et al. Inflamm Bowel Dis. 2016 Sep; 22(9):2078-97. doi: 10.1097/MIB.0000000000000847.

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