Biologic targeting in the treatment of inflammatory bowel diseases

Abstract

The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which nonspecifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Under normal situations, the intestinal mucosa is in a state of "controlled" inflammation regulated by a delicate balance of proinflammatory (tumor necrosis factor [TNF-alpha], interferon-gamma [IFN-gamma], interleukin-1 [IL-1], IL-6, IL-12 and anti-inflammatory cytokines IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may therefore be a logical target for inflammatory bowel disease therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-kappaB), and other miscellaneous therapies are being evaluated as potential therapies for the treatment of inflammatory bowel disease. In this context, infliximab and adalimumab are currently the only biologic agents approved in Europe for the treatment of inflammatory Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP571, certolizumab pegol, etanercept, onercept. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanism involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutics agents to inhibit leukocyte trafficking include natalizumab (approved for use in Crohn's disease in USA), MLN-02, and ISIS 2302. Other agents being investigated for the treatment of Crohn's disease include inhibitors of T cell activation, proinflammatory cytokine receptors, Th1 polarization, growth hormone, and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned above. Controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspective on the development of therapies for inflammatory bowel disease. A review is made of the main areas of research exploring the mechanisms associated with the pathogenesis of IBD, providing advances in the agents currently in use, and identifying a host of new therapeutic biologic targets.

Keywords: Crohn’s disease; biological therapy; ulcerative colitis.

Figure 1

Activation pattern leading to TNF production and sites of potential TNF antagonism. Each activation pathway may vary depending on the cell type. The circled numbers show each step in TNF production and secretion pathway, which may be a potential target for therapeutic manipulation using specific inhibitors. Oxypentifylline and other type IV phosphodiesterase inhibitors interfere with gene expression at step I. Mesalazine inhibits TNF-mediated effects on intestinal epithelial cell proliferation at steps 1 and 2. Thalidomide enhances TNF mRNA degradation at step 6. The monoclonal antibodies infliximab CDP 571 and etanercept directly antagonize TNF binding to its membrane receptors at step 8 and 9. Abbreviations: AP-1, activator protein 1; ERK, extracellular signal-regulated kinase; IV, intravenous; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; mTNF, membrane-anchored TNF precursor; TNF, tumor necrosis factor; sTNF, secreted TNF molecule; TACE, TNF-converting enzyme; TNFR-Fc, etanercept.

Figure 2

Overview of therapeutics targets for biologic agents in inflammatory bowel disease. They may be divided into the following areas: 1) antigen and antigen presentation; 2) activation of effector T cells; 3) cytokine mediated response amplification; 4) adhesion an recruitment; and 5) injury and repair. Copyright © 2000. Reproduced with permission from the American Gastroenterological Association. Papadakis CA, Targan SA. Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology. 2000; 119:1148–1157.