Oral anti-TNF antibody for treatment of Inflammatory Bowel Disease

Abstract

AVX-470m, a novel orally delivered anti-TNF antibody therapeutic, was evaluated in the murine DSS and TNBS colitis models of inflammatory bowel disease. AVX-470m is a polyclonal anti-TNF antibody isolated from the early milk (colostrum) of immunized cows. Bovine colostral antibody is ideally suited for oral delivery, as the antibody is stable to gastric digestion, safe for oral consumption, and inexpensive to manufacture on a large scale. AVX-470m was generated by immunizing pregnant dairy cows with recombinant murine TNF. Colostrum was collected and the immunoglobulin fraction purified and shown to bind murine TNF by ELISA and to neutralize murine TNF in the L929 assay. AVX-470m selectively neutralized murine TNF as compared with rat, rabbit or human TNF. AVX-470m was evaluated in the murine DSS colitis model. C57BL/6 mice were exposed to 3% DSS in the drinking water from day 0-5. From day 6-19, animals were dosed with varying doses of AVX-470m twice a day by oral gavage. Controls included vehicle (saline), control bovine immunoglobulin isolated from normal colostrum and oral prednisolone. AVX-470m significantly reduced the severity of disease (as measured by endoscopy on days 12 and 19), body weight, colon length and weight and tissue pathology. No treatment effect was seen with control bovine immunoglobulin, and the beneficial effect of AVX-470m was greater than that seen with 1 mg/kg oral prednisolone. The statistically-significant activity of orally-administered AVX-470m was confirmed in two additional studies in which AVX-470m dosing was initiated 12 hr prior to the induction of colitis (one in the DSS colitis model and one in the TNBS colitis model). In the majority of animals, no bovine immunoglobulin was detectable in the serum; however, bovine immunoglobulin could be detected in colon sections by immunohistochemistry suggesting that AVX-470m is acting locally within the GI tract. These data support the further development of an orally-delivered anti-TNF antibody for the treatment of inflammatory bowel disease. Bovine colostral antibody specific for human TNF (AVX-470) is currently being produced in anticipation of initial clinical trials. It is hoped that AVX-470 will be an effective oral therapy for inflammatory bowel disease, maintaining the known efficacy of anti-TNF antibodies while minimizing the immunosuppression that arises from systemic exposure.