Bradford L McRae1, Alon D Levin2, Manon E Wildenberg3, Pim J Koelink2, Peter Bousquet1, Igor Mikaelian1, Annette Schwartz Sterman1, Shaughn Bryant1, Geert D'Haens4, Rajesh Kamath1, Jochen Salfeld1, Gijs R van den Brink5. 1. Abbvie Bioresearch Center, Worcester, MA, USA. 2. Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. 3. Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands. 4. Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands. 5. Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands g.r.vandenbrink@amc.nl.
Abstract
BACKGROUND AND AIMS: Anti-tumour necrosis factor [TNF] monoclonal antibodies [infliximab, adalimumab] induce complete mucosal healing in a proportion of patients with Crohn's disease whereas a TNF receptor fusion protein [etanercept] is not effective and the anti-TNF F[ab']2 fragment [certolizumab] shows a very low rate of complete mucosal healing. In contrast, all four TNF-neutralising drugs have demonstrated efficacy in the treatment of rheumatoid arthritis. These observations suggest that factors other than neutralisation of TNF may contribute to clinical outcomes 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. METHODS: We modified an IgG2c mouse anti-TNF antibody that binds the high-affinity FcRs to generate an IgG1 isotype with strongly diminished binding. We examined the therapeutic effects of both antibodies in the T cell transfer model of inflammatory bowel disease and the collagen-induced arthritis model. RESULTS: The IgG2c anti-TNF antibody prevented colonic inflammation in the T cell transfer model of colitis, whereas the IgG1 anti-TNF did not. Conversely, both the IgG2c and IgG1 anti-TNFs were similarly effective in reducing the severity of articular inflammation in mouse collagen-induced arthritis. CONCLUSION: These data support the concept that the mechanism of action for TNF-neutralising drugs 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.
BACKGROUND AND AIMS: Anti-tumour necrosis factor [TNF] monoclonal antibodies [infliximab, adalimumab] induce complete mucosal healing in a proportion of patients with Crohn's disease whereas a TNF receptor fusion protein [etanercept] is not effective and the anti-TNF F[ab']2 fragment [certolizumab] shows a very low rate of complete mucosal healing. In contrast, all four TNF-neutralising drugs have demonstrated efficacy in the treatment of rheumatoid arthritis. These observations suggest that factors other than neutralisation of TNF may contribute to clinical outcomes 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. METHODS: We modified an IgG2c mouse anti-TNF antibody that binds the high-affinity FcRs to generate an IgG1 isotype with strongly diminished binding. We examined the therapeutic effects of both antibodies in the T cell transfer model of inflammatory bowel disease and the collagen-induced arthritis model. RESULTS: The IgG2c anti-TNF antibody prevented colonic inflammation in the T cell transfer model of colitis, whereas the IgG1 anti-TNF did not. Conversely, both the IgG2c and IgG1 anti-TNFs were similarly effective in reducing the severity of articular inflammation in mouse collagen-induced arthritis. CONCLUSION: These data support the concept that the mechanism of action for TNF-neutralising drugs 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.
Authors: Manon E Wildenberg; Alon D Levin; Alessandro Ceroni; Zhen Guo; Pim J Koelink; Theodorus B M Hakvoort; Liset Westera; Felicia M Bloemendaal; Johannan F Brandse; Alison Simmons; Geert R D'Haens; Daniel Ebner; Gijs R van den Brink Journal: J Crohns Colitis Date: 2017-12-04 Impact factor: 9.071
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