DOP036 The therapeutic efficacy of anti-TNF requires Fc-gamma receptors and can be improved by antibody hypo-fucosylation
Bloemendaal F.*1, Levin A.2, Wildenberg M.2, Koelink P.2, Visser R.3, Claassens J.4, Bradford M.5, D'Haens G.2, Verbeek S.4, Vidarsson G.3, van den Brink G.2
1University of Amsterdam, Gastroenterology, Amsterdam, Netherlands 2Academic Medical Center, Gastroenterology, Amsterdam, Netherlands 3Sanquin Research, Department of Experimental Immunohematology, Amsterdam, Netherlands 4Leiden University Medical Center, Department of Human Genetics, Leiden, Netherlands 5Abbvie Bioresearch Center, Worcester, United States
Treatment with the IgG1 anti-TNF antibodies infliximab and adalimumab achieves complete mucosal healing in a considerable proportion of patients with Crohn's disease. In contrast, the Fab' fragment certolizumab showed only 4% endoscopic remission. These observations suggest that the Fc-region of anti-TNF contributes to the induction of mucosal healing. We have previously showed that anti-TNF induces CD206+ regulatory macrophages and that these macrophages were increased in the lamina propria of anti-TNF responders, but not in non-responders. Here, we investigate the importance of Fc-gamma receptor (FcgR) engagement by anti-TNF for achieving therapeutic efficacy in IBD.
Rag1−/− mice lacking all activating FcgR were generated. We constructed hypo-fucosylated anti-murine TNF and hypo-fucosylated adalimumab.
Anti-TNF treatment achieved near complete intestinal healing in the T-cell transfer model. However, mice lacking FcgR were completely unresponsive to anti-TNF therapy. In line with our previous human data, colons of mice treated with anti-TNF contained increased amounts of CD206+ macrophages, but this effect was completely abrogated in animals mice lacking FcgR.
FcgR engagement by anti-TNF is required for the therapeutic efficacy in IBD. Increasing the Fc binding affinity of anti-TNF with hypo-fucosylation significantly improved therapeutic outcome. Anti-TNF therapy currently achieves mucosal healing in less than 50% of patients, antibody glycoengineering could be an effective future strategy and might be of special interest for patients carrying the low affinity FcgRIIIa158F allotype.