Inflammatory bowel disease and targeted oral anti-TNFα therapy

Abstract

Antibodies have provided invaluable treatment options for many diseases, with immunotherapy revolutionising the treatment of several inflammatory disorders including inflammatory bowel disease (IBD). Accumulating evidence suggests that IBD results from an inappropriate response to intestinal microbes and environmental factors in genetically susceptible individuals, with overactivity of the pro-inflammatory pathways. On a pathophysiological level, IBD is a complex disease with intestinal fibrosis, stenosis and an increased incidence of cancer observed in those whose disease is inadequately controlled over time. Regulating the actions of the pro-inflammatory cytokine human tumor necrosis factor-alpha (hTNFα) through the use of anti-TNFα monoclonal antibodies (e.g. infliximab, certolizumab, adalimumab and golimumab) has proven an effective intervention for IBD with their increased use a testament of their effectiveness. These agents are administered systemically thereby causing their distribution throughout the body in a condition that is localised to the gastrointestinal (GI) tract. Immunogenicity, the induction of anti-drug antibodies (ADAs), serum sickness and other undesirable side effects limit their use, whilst up to 50% of patients do not respond to initial therapy. Diseases confined to the GI tract are ideal for targeting by oral therapy which mitigates side effects and allows for lower doses to be administered. Several oral anti-TNFα agents have been investigated with success but are not yet in general clinical use. This partially reflects the fact that the oral administration of antibodies has many barriers including the harsh environment of the GI tract and the presence of enzymes including pepsin, trypsin and chymotrypsin in the intestine which provide significant challenges to targeted oral therapy.

Keywords: Crohn's disease; Gastrointestinal tract; Inflammatory bowel disease; Monoclonal antibodies; Oral immunotherapy; Polyclonal antibodies; Tumor necrosis factor-alpha; Ulcerative colitis.