Purpose: AVX-470 is a polyclonal bovine anti-TNF antibody in development as an oral therapeutic for inflammatory bowel disease (IBD). We have previously reported that oral administration of AVX-470m, a surrogate bovine polyclonal antibody specific for murine TNF, significantly reduced disease severity in a murine IBD model induced by dextran sulfate sodium (DSS). The aim of this study is to determine whether the induction of anti-drug antibodies (MABA: mouse anti-bovine immunoglobulin antibodies) reduces the efficacy of oral AVX-470m in a mouse DSS-induced colitis model. Methods: AVX-470m or control immunoglobulin (Ig) was administered to C57BL/6 mice by oral gavage b.i.d. for two weeks, and after a three-day washout period, colitis was induced by exposing the mice to 3% DSS in drinking water for the following six days (Days 16-21). Animals with established colitis were then treated with saline, AVX-470m (5 mg/dose) or control Ig (5 mg/dose) twice a day by oral gavage for two weeks (Days 22-35). Efficacy was measured by video endoscopy on day 35. Animals were then sacrificed and blood, intestinal content, and colon tissues were collected. MABA and bovine Ig were measured in the serum and intestinal content by ELISA. Colon tissues were examined for histopathology and localization of bovine Ig in the tissues by immunohistochemistry (IHC). Results: A two-week dosing of normal C57BL/6 mice with AVX-470m or control Ig resulted in induction of serum MABA in the majority of mice (90-100%). MABA was also detected in the colon content of 60-70% of these mice, and to a lesser extent in content of the small intestines. Tissue penetration of the drug was confirmed by IHC labeling of bovine Ig in the colon tissue of animals with established colitis after treatment with AVX-470m or control Ig, consistent with previous studies, and this was maintained in the presence of MABA. Endoscopy scoring results demonstrated that mice treated with AVX-470m had similar reductions in disease severity, with or without the presence of MABA, compared to the salinetreated or control-Ig-treated controls. These findings show that MABA in the intestinal lumen or blood did not interfere with the efficacy of AVX-470m in this model. Conclusion: Efficacy of AVX-470m, an oral anti-TNF antibody, was not reduced in the mouse DSS-induced colitis model by the presence of anti-drug antibodies, as has been reported for injected monoclonal anti-TNF antibodies in humans. AVX-470m was localized in inflamed colon tissues, with minimal systemic exposure. These results support the therapeutic potential of AVX-470 oral anti-TNF antibody for gut-targeted therapy of IBD. Disclosure - Dr. Bhol, Ms. Erlich, Ms. Lemos, Dr. Tracey, Dr. Hartman - Employee, Stockholder/Ownership Interest: Avaxia Biologics. Dr. Fox - Employee, Stockholder/Ownership Interest, Board Member: Avaxia Biologics. All authors supported by NIH Grant 2R44DK083810-03.