Beyond tumor necrosis factor: next-generation biologic therapy for inflammatory bowel disease

Even as further refinements of anti-TNF continue to emerge, new biologics targeting alternative mechanisms are progressing through clinical development programs and offer the opportunity for categorically new therapeutics in the years ahead. Several of these target regulatory cytokines occupy important nodal positions in the intricate pathways mediating immune and inflammatory injury. A number of agents which antagonize the IL-12/IL-23 axis appear to offer promise. The apparent efficacy of these anti-cytokine agents has served as a stimulus for development of therapeutics that inhibits the signaling pathway common to their action. In addition to the focus of new biologic development on additional components of the cytokine network, other biologics target mechanisms of recruitment of various key cell populations to mucosa involved in inflammatory bowel disease. Natalizumab is already approved for clinical use and targets alpha4 with proven efficacy in Crohn's disease. A more specific antibody designated finds alpha4beta7 (also known as MAdCAM) trials has had efficacy in ulcerative colitis and probable efficacy in Crohn's disease. Efforts continue to exploit increasing understanding of the mechanisms necessary for T cell activation, and most especially co-stimulatory molecules to intervene in immune-related injury. A chimeric protein encompassing CTLA4 and an immunoglobulin tail (abatacept) has yielded promising results. Another mechanistic strategy to intervene with recruitment of key leukocytes to sites of disease activity has focused on members of the chemokine family that appear to be especially critical to the intestinal mucosa. In summary, the expanding knowledge of mechanisms that contribute to the pathogenesis of inflammatory bowel diseases has yielded a wealth of new potential targets and the results of the variety of agents currently being developed offer promise for a rich mix of next-generation biologics.