| First Author | Bloemendaal FM | Year | 2017 |
| Journal | Gastroenterology | Volume | 153 |
| Issue | 5 | Pages | 1351-1362.e4 |
| PubMed ID | 28756234 | Mgi Jnum | J:249119 |
| Mgi Id | MGI:6093812 | Doi | 10.1053/j.gastro.2017.07.021 |
| Citation | Bloemendaal FM, et al. (2017) Anti-Tumor Necrosis Factor With a Glyco-Engineered Fc-Region Has Increased Efficacy in Mice With Colitis. Gastroenterology 153(5):1351-1362.e4 |
| abstractText | BACKGROUND & AIMS: Although tumor necrosis factor (TNF) antagonists reduce many clinical features of inflammatory bowel disease, complete mucosal healing occurs in fewer than 50% of patients. The Fc-region of monoclonal antibodies against TNF has immunosuppressive properties via effects on macrophage polarization. We examined the interaction between the anti-TNF Fc-region and Fcgamma receptors (FcgammaR), and whether the absence of the Fc core fucose (which increases binding to FcgammaRIIIa) increases the efficacy of anti-TNF in mice with colitis. METHODS: We generated Rag1(-/-) mice that lack all activating FcgammaRs (FcgammaRI, FcgammaRIII, and FcgammaRIV; called FcgammaR(-/-)Rag1(-/-) mice). We produced hypo-fucosylated antibodies against mouse and human TNF (adalimumab). Colitis was induced in mice by transfer of CD4+CD45RB(hi) to FcgammaR(-/-)Rag1(-/-) or Rag1(-/-) littermates; mice were given different antibodies against TNF or isotype (control) antibodies and disease activity index scores were determined. Colon tissues were collected and analyzed by histology. Human peripheral blood mononuclear cells (PBMCs) were isolated from blood of healthy donors. T-cell proliferation and proportions of CD206(+) (immune regulatory) macrophages were measured in mixed lymphocyte reactions. Human PBMCs were genotyped for FCGR3A158 (the FcgammaRIIIa-158F allotype displays a lower Fc binding affinity) using the TaqMan single nucleotide polymorphism genotype assay. RESULTS: Rag1(-/-) mice with colitis given anti-TNF had near complete mucosal healing and Rag1(-/-) mice given an isotype control antibody developed severe colitis. In contrast, FcgammaR(-/-)Rag1(-/-) mice were refractory to the effects of anti-TNF: their histological colitis scores were as severe as those from FcgammaR(-/-)Rag1(-/-) mice given a control antibody. Colons from Rag1(-/-) mice that received anti-TNF had an increased number of CD206(+) macrophages compared with Rag1(-/-) mice given control antibody; in FcgammaR(-/-)Rag1(-/-) mice given anti-TNF these numbers were as low as FcgammaR(-/-)Rag1(-/-) given the control antibody. In human PBMCs, anti-TNF increased the number of CD206(+) macrophages: this required expression of FcgammaRIIIa; numbers of these cells were reduced in PBMCs with the low-affinity FcgammaRIIIa-158F genotype. A hypo-fucosylated form of adalimumab bound human FcgammaRIIIa with a higher affinity than control adalimumab. When hypo-fucosylated adalimumab was added to PBMCs, a larger number of CD206(+) macrophages formed and T-cell proliferation was reduced, compared with addition of a control adalimumab. Hypo-fucosylated adalimumab increased the number of CD206(+) macrophages in PMBCs that expressed the low-affinity FcgammaRIIIa. In mice with colitis, hypo-fucosylated anti-TNF significantly increased the number of CD206(+) macrophages in the colon compared with control anti-TNF and was more effective in reducing colitis severity as measured by histology. CONCLUSIONS: In a study of the in vitro and in vivo mechanisms of anti-TNF, we found FcgammaR engagement by anti-TNF to be required for reduction of colitis in mice and development of CD206(+) macrophages. A hypo-fucosylated form of anti-TNF binds FcgammaRIIIa with higher affinity and induces development of CD206(+) macrophages in human PBMCs, especially PBMCs that express low-affinity FcgammaRIIIa. Hypo-fucosylated anti-TNF might be more effective in patients with inflammatory bowel disease. |
