Avx-470

Abstract

Background Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the GI tract that 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 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 mRNA levels. Colitis was induced using either 2,4,6-trinitrobenzene sulfonate (TNBS) or dextran sodium sulfate (DSS). 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 to infliximab. Orally administered AVX-470m effectively reduced disease severity in several mouse models of IBD. Activity was comparable to 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.

Transient Expression of Secretory IgA In Planta is Optimal Using a Multi-Gene Vector and may be Further Enhanced by Improving Joining Chain Incorporation

“…Because sIgA is stable in the gut, sIgA-based therapy could be localized. Luminal administration of an anti-TNF-α antibody was effective in mouse models of IBD ( Bhol et al, 2013 ) and local drug administration has been suggested to be important for efficacy of IBD therapies ( Neurath, 2014 ).…”

Survival and digestibility of orally-administered immunoglobulin preparations containing IgG through the gastrointestinal tract in humans

“…It is generally well-recognized that secretory IgA (sIgA), the primary class of Ig in human colostrum and breast milk as well as being found in the intestinal tract, are stable against enzymatic degradation. Other Igs, such as IgG and IgM, are also less susceptible than typical dietary proteins to digestion, yet this knowledge remains underappreciated despite numerous clinical studies in humans which illustrate recovery of intact and immunologically active IgG from the ileum and feces [ 4 - 7 ]. The purpose of this review is to summarize human clinical studies which assess digestibility of IgG purified from either colostrum or serum in ileal aspirates and stool.…”

Synthesis of tumor necrosis factor α for use as a mirror-image phage display target

“…Such an approach has already been shown to be effective in a mouse IBD model using very high doses of a bovine anti-TNFα antibody. 57 A d -peptide could provide a smaller and lower cost solution, with the potential for better gut tissue penetration and lower dosing. Also, the low immunogenicity of d -peptides could enable less toxic intermittent systemic dosing to treat acute flare-ups (not recommended with current agents due to increased risk of an anti-drug immune response), 8 allowing the immune system to recover while the disease is in remission.…”