ABSTRACT
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.
Subject(s)
Antibodies/administration & dosage , Colitis/drug therapy , Disease Models, Animal , Immunoglobulin G/administration & dosage , Inflammation/drug therapy , Intestinal Mucosa/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antibodies/pharmacology , Antibodies, Monoclonal/pharmacology , Blotting, Western , Cattle , Colitis/chemically induced , Colitis/immunology , Dextran Sulfate/toxicity , Enzyme-Linked Immunosorbent Assay , Humans , Immunoenzyme Techniques , Immunoglobulin G/pharmacology , Inflammation/etiology , Inflammation/pathology , Infliximab , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Male , Mice , Mice, Inbred C57BL , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Trinitrobenzenesulfonic Acid/toxicity , Tumor Necrosis Factor-alpha/immunologyABSTRACT
It is widely recognized that humoral and phagocyte-associated lectins constitute critical components of innate immunity in vertebrates and invertebrates. Their functions include not only self/non-self recognition but also engaging associated effector mechanisms, such as complement-mediated opsonization and killing of potential pathogens. One of the unresolved questions concerns the diversity in recognition capacity of the lectin repertoire, particularly in those organisms lacking adaptive immunity. In this paper, we discuss evidence suggesting that lectin repertoire in invertebrates and protochordates is highly diversified, and includes most of the lectin classes described so far in vertebrate species, as well as associated effector pathways.
