DOP003. FcR-mediated effector function contributes to the therapeutic response of anti-TNF monoclonal antibodies in a mouse model of IBD
A. Levin1, M. Wildenberg1, G. D'Haens2, G. van den Brink2, 1Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, Netherlands, 2Academic Medical Center, Gastroenterology & Hepatology, Amsterdam, Netherlands
Anti-TNF monoclonal antibodies (infliximab, adalimumab) are effective in the treatment of Crohn's disease while a TNF receptor fusion protein (etanercept) is not effective and an anti-TNF F(ab′)2 fragment (certolizumab) shows a very low rate of complete mucosal healing. In contrast, all four TNF neutralizing drugs have demonstrated efficacy in the treatment of rheumatoid arthritis. These clinical observations suggest that factors other than neutralization of TNF may contribute to the clinical outcomes for TNF inhibitors in Crohn's disease. Here we tested the hypothesis that Fc receptor (FcR)-mediated effects may contribute to the therapeutic response of anti-TNF antibodies in inflammatory bowel disease.
We modified an IgG2c mouse anti-TNF antibody that effectively binds the high affinity FcRs to generate an IgG1 isotype with strongly diminished binding to the high affinity FcRs. We examined the therapeutic effects with both antibodies in the T cell transfer model of inflammatory bowel disease and the collagen-induced arthritis model.
The IgG2c anti-TNF antibody had a significant effect in preventing colonic inflammation in the T cell transfer model of colitis while the IgG1 anti-TNF did not elicit a significant effect. Differences in the anti-inflammatory response for each antibody could not be explained by differences in TNF potency or antibody pharmacokinetics. Conversely, both the IgG2c and IgG1 anti-TNF were similarly effective in reducing the severity of articular inflammation in mouse collagen-induced arthritis.
These data suggest that the mechanism of action for TNF neutralizing biologics may differ across immune mediated diseases and, potentially, between therapeutics within a particular disease. Our data suggest a specific role of Fc-mediated immune regulation in the resolution of intestinal inflammation by anti-TNF monoclonal antibodies.