CCR9 antagonism: potential in the treatment of Inflammatory Bowel Disease

Abstract

Inflammatory Bowel Disease (IBD), mainly comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic condition that primarily affects the intestine and is characterized by leukocytic infiltration. Blocking the migration of leukocytes from the circulation is therefore a reasonable therapeutic goal. Recent clinical trials using this approach have shown promise, with the monoclonal antibody to α₄β₇ integrin, vedolizumab, and previously with the monoclonal antibody to the α₄ subunit, natalizumab. Directly targeting the subset of α₄β₇ expressing cells that co-express CC chemokine receptor 9 (CCR9), using the orally administered antagonist, CCX282-B, also known as vercirnon, has also been evaluated in Phase II and III trials that have produced mixed results. Although CCX282-B showed efficacy in inducing response in active CD in early studies, this was not confirmed in a Phase III study. CCX282-B was also more effective than placebo in maintaining remission, and this result has yet to be confirmed in Phase III. The efficacy of blocking CCR9 in UC, where vedolizumab was effective, has not been tested. The prospect of targeting CCR9 in IBD remains attractive. Much of the local accumulation of inflammatory cells in the intestine arises from migration rather than local proliferation and genetic and pharmacological targeting of CCR9 or its ligand in preclinical models that mimic UC and CD ameliorate inflammation in some cases. Furthermore, binding of chemokine ligands to receptor is a critical step in activating integrin binding, so there is a potential for synergistic action between integrin and chemokine antagonists. CCR9 is expressed on a smaller proportion of circulating cells than α₄β₇ integrin, which may offer greater specificity of effect, particularly in long term use. Furthermore, while α₄β₇ is widely expressed on T and B cell subsets, CCR9 is mainly expressed on effector memory Th1 cells. Indications for the use of intestine-specific integrin and chemokine receptor targeting may also extend beyond IBD, to include, for example, postoperative ileus, and primary sclerosing cholangitis.

Keywords:

• Crohn’s disease
• ulcerative colitis
• CCL25
• CCX282-B
• Traficet-EN
• GSK10605786
• CC chemokine receptor 9

Disclosure

Dr Keshav has provided consultancy services for a number of pharmaceutical and healthcare companies including Abbvie, Astra-Zeneca, ChemoCentryx, Dr Falk Pharma, Ferring, GSK, MSD, Mitsubishi Pharma, Pfizer, Vifor, and Warner-Chilcott, and received research support from Chemo-Centryx, MSD, and Warner-Chilcott. Dr Wendt has received grant support and reagents from ChemoCentryx Inc.