Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which is currently treated with injected monoclonal antibodies specific for tumor necrosis factor (TNF). We developed and characterized AVX-470, a novel polyclonal antibody specific for human TNF. We evaluated the oral activity of AVX-470m, a surrogate antibody specific for murine TNF, in several well-accepted mouse models of IBD.
Methods: AVX-470 and AVX-470m were isolated from the colostrum of dairy cows that had been immunized with TNF. The potency, specificity, and affinity of both AVX-470 and AVX-470m were evaluated in vitro and compared with infliximab. AVX-470m was orally administered to mice either before or after induction of colitis, and activity was measured by endoscopy, histopathology, immunohistochemistry, and quantitative measurement of messenger RNA levels. Colitis was induced using either 2,4,6-trinitrobenzene sulfonate or dextran sodium sulfate.
Results: AVX-470 and AVX-470m were shown to be functionally comparable in vitro. Moreover, the specificity, neutralizing potency, and affinity of AVX-470 were comparable with infliximab. Orally administered AVX-470m effectively reduced disease severity in several mouse models of IBD. Activity was comparable with that of oral prednisolone or parenteral etanercept. The antibody penetrated the colonic mucosa and inhibited TNF-driven mucosal inflammation with minimal systemic exposure.
Conclusions: AVX-470 is a novel polyclonal anti-TNF antibody with an in vitro activity profile comparable to that of infliximab. Oral administration of a surrogate antibody specific for mouse TNF is effective in treating mouse models of IBD, delivering the anti-TNF to the site of inflammation with minimal systemic exposure.
Article first published online 14 August 2013
*Avaxia Biologics, Inc., Lexington, Massachusetts;
†Biomodels, LLC, Watertown, Massachusetts; and
‡Xtal BioStructures, Natick, Massachusetts.
Reprints: Barbara S. Fox, PhD, Avaxia Biologics, Inc., 128 Spring Street, Suite 620, Lexington, MA 02142 (e-mail: firstname.lastname@example.org).
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.ibdjournal.org).
Supported in part by NIH Grant R44 DK083810.
Bhol, Tracey, Lemos, Erlich, Keane, Quesenberry, and Fox are employed by Avaxia Biologics and own either stock or stock options in Avaxia. Schlehuber owns stock in Avaxia. The remaining authors have no conflicts of interest to disclose.
Received May 12, 2013
Accepted June 18, 2013