AVX-470: a novel oral anti-TNF antibody with therapeutic potential in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that affects over 5 million people in North America and Europe, and its increasing incidence and prevalence in many regions of the world point to its emergence as a global disease1. The two forms of IBD, ulcerative colitis and Crohn’s disease, are caused by dysregulated intestinal immune homeostasis resulting in mucosal inflammation2–4. Increased levels of both soluble and membrane-bound forms of tumor necrosis factor (TNF) are believed to play a central pathogenic role in IBD5. TNF is thought to be at the top of a cascading network of cellular pathways that result in inflammation and tissue destruction in IBD and other autoimmune diseases6. Monoclonal anti-TNF antibodies, most notably infliximab and adalimumab, have transformed the treatment of IBD7. Despite their impressive efficacy, the use of these antibodies is associated with an increased risk of serious side effects, including the reactivation of tuberculosis, opportunistic infections and a long-term risk of malignancy. These side effects result from systemic immunosuppression as a consequence of the inhibition of TNF’s host defense functions8,9. An ideal anti-TNF antibody therapy for IBD would deliver antibodies directly to the site of inflammation in the gut while avoiding systemic exposure and immunosuppression. To this end, we set out to develop an orally-delivered anti-TNF antibody. Breakdown of an antibody therapeutic in the hostile environment of the gut is a central challenge to the use of an oral biologic. We reasoned that bovine antibodies from milk or colostrum might be suitable for oral delivery by virtue of their known stability to digestion in the gastrointestinal tract10. A second challenge to the use of an oral biologic arises from the need to penetrate the gut wall to reach the site of inflammation. We reasoned that the increased mucosal permeability seen in IBD patients11 may allow an orally-dosed antibody to diffuse to the site of TNF production in the gut mucosa. A novel antibody therapeutic, AVX-470, was generated by purifying immunoglobulin (Ig) from the colostrum of cows immunized with recombinant human TNF. The in vitro activity of this bovine polyclonal anti-TNF antibody was defined and compared with the activity of infliximab. A surrogate antibody specific for murine TNF, AVX-470m, was generated in parallel and tested in three well-established mouse models of IBD in which anti-TNF antibodies are known to be active: preventative models of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and acute dextran sodium sulfate (DSS)-induced colitis, as well as a treatment model of established DSS-induced colitis12,13. In all studies, the primary assessment of disease activity was video endoscopy, a method that provides a robust clinical readout of disease severity14. Oral administration of AVX-470m was shown to inhibit gut inflammation and disease in these mouse models of IBD without significant systemic exposure. These data suggest that orally delivered AVX-470 antibody may be effective as a first line therapy for patients with IBD.